Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That Are Regulated Under a Biologics License Application, and Animal Drugs, 60169-60224 [2016-20471]
Download as PDF
Vol. 81
Wednesday,
No. 169
August 31, 2016
Part III
Department of Health and Human Services
mstockstill on DSK3G9T082PROD with RULES2
Food and Drug Administration
21 CFR Parts 20, 201, 207, et al.
Requirements for Foreign and Domestic Establishment Registration and
Listing for Human Drugs, Including Drugs That Are Regulated Under a
Biologics License Application, and Animal Drugs; Final Rule
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
PO 00000
Frm 00001
Fmt 4717
Sfmt 4717
E:\FR\FM\31AUR2.SGM
31AUR2
60170
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 201, 207, 314, 514,
515, 601, 607, and 1271
[Docket No. FDA–2005–N–0464 (formerly
Docket No. 2005N–0403)]
RIN 0910–AA49
Requirements for Foreign and
Domestic Establishment Registration
and Listing for Human Drugs,
Including Drugs That Are Regulated
Under a Biologics License Application,
and Animal Drugs
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule.
The Food and Drug
Administration (FDA) is amending its
regulations governing drug
establishment registration and drug
listing. These amendments reorganize,
modify, and clarify current regulations
concerning who must register
establishments and list human drugs,
human drugs that are also biological
products, and animal drugs. The final
rule requires electronic submission,
unless waived in certain circumstances,
of registration and listing information.
This rulemaking pertains to finished
drug products and to active
pharmaceutical ingredients (APIs) alone
or together with one or more other
ingredients. The final rule describes
how and when owners or operators of
establishments at which drugs are
manufactured or processed must register
their establishments with FDA and list
the drugs they manufacture or process.
In addition, the rule makes certain
changes to the National Drug Code
(NDC) system. We are taking this action
to improve management of drug
establishment registration and drug
listing requirements and make these
processes more efficient and effective
for industry and for us. This action also
supports implementation of the
electronic prescribing provisions of the
Medicare Prescription Drug,
Improvement, and Modernization Act of
2003 (MMA) and the availability of
current drug labeling information
through DailyMed, a computerized
repository of drug information
maintained by the National Library of
Medicine.
mstockstill on DSK3G9T082PROD with RULES2
SUMMARY:
This rule is effective on
November 29, 2016. See section IV for
compliance dates.
FOR FURTHER INFORMATION CONTACT:
DATES:
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
For information pertaining to human
drug products: Paul Loebach, Center for
Drug Evaluation and Research, Food
and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 2262,
Silver Spring, MD 20993, 301–796–
2173.
For information pertaining to human
biological drug products or human cells,
tissue, and cellular and tissue-based
products (HCT/Ps) regulated solely
under section 361 of the Public Health
Service Act: Stephen Ripley, Center for
Biologics Evaluation and Research,
Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm.
7301, Silver Spring, MD 20993, 240–
402–7911.
For information pertaining to animal
drug products: Charise Kasser, Center
for Veterinary Medicine (HFV–212),
Food and Drug Administration, 7519
Standish Pl., Rm. 2626, Rockville, MD
20855, 240–402–6816; or Isabel
Pocurull, Center for Veterinary
Medicine (HFV–226), Food and Drug
Administration, 7519 Standish Pl., Rm.
2636, Rockville, MD 20855, 240–402–
5877.
SUPPLEMENTARY INFORMATION:
Table of Contents
Executive Summary
Purpose of the Regulatory Action
Summary of the Major Provisions of the
Regulatory Action
Benefits and Costs
I. Background
II. Overview of the Final Rule Including
Changes to the Proposed Rule
A. Overview
B. Changes to the Proposed Rule
III. Comments on the Proposed Rule
A. Labeling (§§ 201.2 and 201.25)
B. General Information (Part 207, Subpart
A)
C. Registration (Part 207, Subpart B)
D. National Drug Code (Part 207, Subpart
C)
E. Listing (Part 207, Subpart D)
F. Electronic Format for Registration and
Listing (Part 207, Subpart E)
G. Miscellaneous (Part 207, Subpart F)
H. Human Cells, Tissues, and Cellular and
Tissue-Based Products (Part 1271)
IV. Compliance Dates
V. Legal Authority
VI. Analysis of Environmental Impact
VII. Economic Analysis of Impacts
A. Introduction
B. Summary of Benefits and Costs
C. Response to Comments on the
Preliminary Impact Analysis of the
Proposed Rule
VIII. Paperwork Reduction Act of 1995
A. Registration Information Collection
Under Part 207
B. Listing Information Collection Under
Part 207
C. Registration and Listing Information
Collection Under Part 607
D. Registration and Listing Information
Collection Under Part 1271
PO 00000
Frm 00002
Fmt 4701
Sfmt 4700
E. Waiver Request Information
F. Public Disclosure Exemption Requests
G. Standard Operating Procedure for
Electronic Submission
H. Capital Costs
IX. Federalism
X. References
Executive Summary
Purpose of the Regulatory Action
This final rule amends FDA’s
longstanding regulations governing drug
establishment registration and drug
listing. The amendments are aimed at
modernizing these regulations and
improving efficiency and reliability for
FDA and drug manufacturers. These
amendments also bring FDA’s
regulations governing drug
establishment registration and listing
into conformance with section 510 of
the Federal Food, Drug, and Cosmetic
Act (the FD&C Act) (21 U.S.C. 360) as
amended by the Food and Drug
Administration Amendments Act
(FDAAA) (Pub. L. 110–85) and the Food
and Drug Administration Safety and
Innovation Act (FDASIA) (Pub. L. 112–
144).
Since the 1962 Kefauver Harris
amendments to the FD&C Act (Pub. L.
87–781), drug manufacturers have been
required to register their establishments
with FDA annually. Among other
things, drug establishment registration
identifies establishments for inspection
by FDA. In 1973, the FD&C Act was
further amended to require each
registered establishment to submit a list
of drugs it manufactures. FDA’s
regulations implementing these
requirements are found in part 207 (21
CFR part 207) (pertaining to drugs and
biological products generally) and part
607 (21 CFR part 607) (pertaining to
blood and blood products).
Manufacturers of HCT/Ps register and
list either under part 207, part 807 (21
CFR 807), or under part 1271 (21 CFR
part 1271), issued under authority of the
Public Health Service Act (PHS Act),
depending on the type of HCT/P
product they manufacture.
The amendments to parts 207 and 607
adopted by this final rule modernize
those regulations and bring them into
conformance with section 510 of the
FD&C Act following recent
amendments.
Summary of the Major Provisions of the
Regulatory Action
This final rule requires electronic
submission, unless waived in certain
circumstances, of drug establishment
registration and listing information. The
electronic submission requirement is
consistent with FDAAA and with
current practice.
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
The rule makes clear that the
establishment registration and listing
obligation rests with persons who
manufacture, repack, relabel, or salvage
drug products. The rule does not require
persons who act only as private label
distributors of drug products to register
establishments or list drugs, but allows
them to submit drug listing information
as agents acting on behalf of persons
who manufacture, repack, relabel, or
salvage drug products. The amendments
make several adjustments to the timing
and substance of the submission of
information to register a drug
establishment and list drugs
manufactured, repacked, relabeled, or
salvaged at the establishment. The
amendments also update longstanding
regulatory provisions governing FDA
disclosure of drug registration and
listing information, stating that with
certain exceptions, establishment
registration and drug listing information
is generally available for public
disclosure.
This final rule does not include
certain aspects of the proposed rule that
were opposed by many who submitted
comments. Features of the proposed
rule that have not been finalized include
most significantly: (1) A requirement
that FDA, not registrants, develop
national drug codes (NDCs) for
assignment to listed drugs and (2) a
requirement that the NDC appear in
human-readable form on the label of
each listed drug and provisions that
would have defined the appropriate
NDC for that purpose. As discussed in
section III, revisions to the FD&C Act
60171
require human-readable NDCs on
certain drug labels.
Benefits and Costs
All incremental costs from the final
rule are one-time costs, except for
registrants’ annually recurring costs of
certifying no change to listings upon
annual registration for part 207
registrants. We estimate one-time total
costs of $59.7 million and recurring
costs of $0.5 million. These costs
represent total annualized costs of $9
million when calculated at a 7-percent
discount rate over 10 years, and $7.5
million when calculated using a 3percent discount rate. The largest cost
elements will be for registrants reading
and understanding the final rule and
making changes to their standard
operating procedures.
SUMMARY OF TOTAL INCREMENTAL COST OF THE FINAL RULE
[$ millions]
One-time
costs
Affected firms
Recurring
costs
(annual)
Total costs
annualized at
7%
Total costs
annualized at
3%
Drugs and biological products (part 207) ........................................................
Human blood products (part 607) ...................................................................
Human cell and tissue products (part 1271) ...................................................
$48.9
5.1
5.7
$0.5
N/A
N/A
$7.5
0.7
0.8
$6.2
0.6
0.7
Total 1 ........................................................................................................
59.7
0.5
9.0
7.5
1 Total
costs are annualized over a 10-year period. Recurring costs include only annual time costs of certifying that there are no changes to
listings; these costs are unique to part 207. All estimates reflect rounded 2014 dollars.
By codifying the statutory
requirements of FDAAA and FDASIA,
the final rule clarifies and completes the
modernization of our electronic
registration and listing systems. Thus,
the final rule will improve management
of the establishment registration and
drug listing requirements and make
these processes more efficient and
effective for industry and for us. The
final rule also supports implementation
of the electronic prescribing provisions
of the MMA and the availability of
current drug labeling information
through DailyMed, a computerized
repository of drug information
maintained by the National Library of
Medicine.
mstockstill on DSK3G9T082PROD with RULES2
I. Background
In the Federal Register of August 29,
2006 (71 FR 51276), FDA proposed to
amend its regulations governing drug
establishment registration and drug
listing in part 207 (proposed rule). The
proposed rule included ancillary
amendments to parts 20, 201, 314, 514,
515, 601, 607, and 1271 (21 CFR parts
20, 201, 314, 514, 515, 601, 607, and
1271). These amendments reorganize,
modify, and clarify current regulations
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
concerning who must register
establishments and list human drugs,
human drugs that are also biological
products, and animal drugs. The
proposed rule and the final rule both
specify that drug establishment
registration and drug listing information
generally must be submitted to FDA
electronically.
After the proposed rule was
published, FDAAA was adopted into
law. FDAAA amended section 510(p) of
the FD&C Act to require electronic
submission of drug establishment
registration and listing information,
unless FDA waives the electronic
submission requirement in individual
cases. In June 2009, FDA announced
publication of a guidance for industry
on ‘‘Providing Regulatory Submissions
in Electronic Format—Drug
Establishment Registration and Drug
Listing’’ consistent with FDAAA (74 FR
26248, June 1, 2009, available on the
Internet at https://www.fda.gov/Drugs
under Guidances (Drugs)) (the electronic
registration and listing guidance). This
guidance applied to establishment
registration and listing required under
part 207. It did not apply to information
required solely under part 607 (blood
PO 00000
Frm 00003
Fmt 4701
Sfmt 4700
and blood products), part 807 (devices),
or part 1271 (human cells, tissues, and
cellular and tissue-based products).
FDA generally stopped receiving drug
establishment registration and listing
information required under part 207
submitted on paper in June 2009,
allowing paper submissions only if
supported by a waiver from the
electronic submission requirement in
individual cases. This final rule is
consistent with the electronic
submission provisions of FDAAA.
FDASIA made further amendments to
section 510 of the FD&C Act in 2012 to
specify that:
• Annual registration of
establishments takes place during the
period beginning on October 1 and
ending on December 31.
• The information registrants supply
for annual registration includes a
Unique Facility Identifier (UFI) for the
establishment and includes a point-ofcontact email address.
This final rule includes changes to the
proposed rule consistent with these
statutory provisions. The electronic
registration and listing guidance stated
that FDA intended to use the Data
Universal Numbering System (DUNS)
number, assigned and managed by Dun
E:\FR\FM\31AUR2.SGM
31AUR2
60172
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
• Amends § 201.25 to allow an FDA
Center Director to approve an additional
bar code standard or format.
• Revises part 207 significantly.
• Amends § 314.81(b)(3)(iv)
(requiring holders of approved new drug
applications (NDAs) to report the
withdrawal of approved drug products
from sale) to make it consistent with
part 207.
• Makes a minor conforming
amendment to § 314.125(b)(11) (stating
II. Overview of the Final Rule Including FDA may refuse to approve a new drug
Changes to the Proposed Rule
application if the drug will be
manufactured in whole or in part in an
A. Overview
establishment that is not registered and
not exempt from registration under
The final rule adopts significant
section 510 of the FD&C Act and part
amendments to FDA’s regulations
207).
governing drug registration and listing.
• Adds new § 514.111(a)(12) stating
It modernizes these regulations to
FDA will refuse to approve a new
require electronic submission of drug
animal drug application if the drug will
establishment registration and listing
be produced in whole or in part in an
information and to otherwise match
establishment that is not registered and
current statutory requirements and
is not exempt from registration under
FDA’s information needs.
section 510 of the FD&C Act and part
The final rule:
207.
• Makes minor technical amendments
• Makes a minor technical
to §§ 20.100, 20.116, and 201.1
amendment to § 515.10(b)(8), updating a
(updating citations to regulations in part reference to the regulations in part 207.
207).
• Adds new § 601.2(f) requiring
holders of biologics license applications
• Removes from § 201.2 a statement
(BLAs) to report to FDA electronically
about the manner in which NDCs are
in accordance with part 207 the
displayed on drug labels.
& Bradstreet, as a registration number.
In 2014, FDA announced publication of
a guidance for industry on
‘‘Specifications of the Unique Facility
Identifier (UFI) System for Drug
Establishment Registration,’’ (79 FR
65977, November 6, 2014, available on
the Internet at https://www.fda.gov/Drugs
under Guidances (Drugs)), in which
FDA specified the DUNS number as the
preferred UFI.
withdrawal from sale of licensed
biological products.
• Amends part 607
(ESTABLISHMENT REGISTRATION
AND PRODUCT LISTING FOR
MANUFACTURERS OF HUMAN
BLOOD AND BLOOD PRODUCTS)
consistent with the amendments to part
207, to require electronic submission of
establishment registration and listing
information.
• Amends part 1271 (HUMAN
CELLS, TISSUES, AND CELLULAR
AND TISSUE–BASED PRODUCTS) to
require electronic submission of
establishment registration and listing
information, to state that manufacturers
of HCT/Ps that are regulated as drugs,
devices, and/or biological products
under section 351 of the PHS Act (42
U.S.C. 262) or under the FD&C Act are
subject to registration and listing under
part 207 or part 807, and to make other
revisions consistent with the
amendments to part 207.
B. Changes to the Proposed Rule
The final rule has been revised in
response to comments received on the
proposed rule. Our responses are
discussed in section III. The final rule
also includes several minor editorial
revisions. The final rule makes the
changes summarized in table 1.
TABLE 1—SUBSTANTIVE CHANGES FROM THE PROPOSED RULE TO THE FINAL RULE
21 CFR Section
in final rule
Description of change from proposed rule
201.2 .................
Labeling.
• Does not include proposed revisions to § 201.2 requiring human-readable NDCs on labels.
Bar code label requirements.
• Revises § 201.25(c)(1) to accommodate alternatively formatted NDCs in bar codes.
• Does not include other proposed amendments to § 201.25.
Definitions.
• Includes definitions for the terms ‘‘finished drug product,’’ ‘‘unfinished drug product,’’ ‘‘bulk drug substance,’’ ‘‘private
label distribution,’’ ‘‘registrant,’’ and ‘‘outsourcing facility’’ not included in the proposed rule.
• States that the definitions and interpretations of terms in sections 201 (21 U.S.C. 321) and 510 of the FD&C Act apply
to the terms used in part 207, if not otherwise defined in § 207.1.
• Includes revised definitions of the terms ‘‘active pharmaceutical ingredient,’’ ‘‘commercial distribution,’’ ‘‘content of labeling,’’ ‘‘importer,’’ ‘‘manufacture,’’ ‘‘private label distributor,’’ ‘‘relabel,’’ ‘‘repack,’’ and ‘‘representative sampling of any
other labeling’’.
Who does this part cover?
• Clarifies that private label distributors are subject to part 207 (because they must have labeler codes).
• States that all drugs regulated under a BLA, except human blood or blood products regulated under part 607, are subject to part 207 and clarifies that for this purpose certain products are not included in the phrase ‘‘human whole blood
and blood products’’.
• States that HCT/Ps regulated as drugs under section 505 of the FD&C Act (21 U.S.C. 355) or section 351 of the PHS
Act are subject to part 207.
Who is exempt from the registration and listing requirements?
• Generally exempts from registration and listing individuals or establishments engaged solely in recovering cells or tissues to become components of a biological product at a registered establishment.
• Eliminates a reference to salvagers of inactive ingredients because salvaging, as defined, is performed only on finished
drug products.
• Revises § 207.13 to clarify the applicability of part 207 to medicated feeds.
• Revises § 207.13 to remove a reference to HCT/Ps made unnecessary by revisions to § 207.9.
• Adds an exemption for outsourcing facilities registered under section 503B of the FD&C Act (21 U.S.C. 353b) so as to
avoid duplicative registration for those entities.
• Retains the previous establishment registration exemptions for certain drugs entering foreign trade zones and certain
drugs imported for export.
Who must register?
201.25 ...............
207.1 .................
207.9 .................
mstockstill on DSK3G9T082PROD with RULES2
207.13 ...............
207.17 ...............
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
PO 00000
Frm 00004
Fmt 4701
Sfmt 4700
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
60173
TABLE 1—SUBSTANTIVE CHANGES FROM THE PROPOSED RULE TO THE FINAL RULE—Continued
21 CFR Section
in final rule
207.25 ...............
207.29 ...............
207.33 ...............
207.35 ...............
207.37 ...............
207.41 ...............
207.45 ...............
207.49 ...............
mstockstill on DSK3G9T082PROD with RULES2
207.53 ...............
207.54 ...............
207.57 ...............
VerDate Sep<11>2014
Description of change from proposed rule
• Revises § 207.17(b) to state that FDA will accept establishment registration or listing information submitted by a private
label distributor if it is acting as an authorized agent for an establishment that manufactures, repacks, relabels, or
salvages drugs.
What information is required for registration?
• Revises proposed § 207.25 to include the UFI required as part of establishment registration under FDASIA.
What are the requirements for reviewing and updating registration information?
• Revises § 207.29 to specify that registrants must review and update registration information between October 1 and
December 31 each year, consistent with FDASIA.
What is the National Drug Code (NDC), how is it assigned, and what are its requirements?
• Allows for 10- or 11-digit NDCs, consistent with a longstanding statement in § 207.35(b)(2)(i), as it read prior to this
final rule, that FDA will expand the NDC labeler code from 5 to 6 numeric characters when the available 5-character
code combinations are exhausted.
• States that registrants will propose NDCs for assignment by FDA.
• Includes formatting requirements for registrants to follow when formulating their own proposed NDCs.
• Allows for alternatively formatted NDCs for certain HCT/Ps.
• Explains how a labeler code can be obtained.
• Allows registrants to reserve an NDC for a drug product under development.
• Eliminates proposed § 207.33(c). (What information must a manufacturer submit before we will assign an NDC number
to a drug?)
• Adds some information elements described in proposed § 207.33(c) to the drug listing information now described in
§ 207.49 (Added to the listing information required under § 207.49 are the names of inactive ingredients in the listed
drug and in the case of an unfinished drug, the number assigned to the Drug Master File or Veterinary Master File, if
any, that describes the manufacture of the drug).
• The option to submit an approved U.S. application number instead of a list of inactive ingredients for a finished drug
product (as proposed in § 207.33(c)) is not retained in § 207.49 of this final rule.
What changes require a new NDC?
• Introduces new § 207.35 to more clearly explain what changes to drugs require a new NDC and does not include inactive ingredient changes in this section.
What restrictions pertain to the use of the NDC?
• Revises § 207.37 to state that a product may be deemed to be misbranded if an NDC is used improperly.
Who must list drugs and what drugs must they list?
• Revises § 207.41 to clarify the manner in which human drugs that are manufactured, repacked, or relabeled for private
label distribution are listed.
When, after initial registration of an establishment, must drug listing information be submitted?
• Revises § 207.45 to state that drug listing must take place no later than 3 calendar days after initial registration of an
establishment, rather than ‘‘at the time of’’ initial registration.
What listing information must a registrant submit for a drug it manufactures?
• Revises § 207.49 to reflect that registrants will propose their own NDCs under the final rule.
• Eliminates the requirement of proposed §§ 207.49(f), 207.53(c), and 207.54(b)(4) (which would have required foreign
establishments to identify importers when listing drugs they manufacture, repack, relabel, or salvage). (This is now reported only as establishment registration information for foreign establishments.).
• Expands the language of proposed § 207.49(d) (now § 207.49(a)(11)) to make clear that a registrant’s own establishment(s) must be identified in drug listing information as well as other establishments involved in the production of unfinished drugs received by the registrant and to require identification of all such establishments using their UFIs.
• Removes from proposed § 207.49 the option to provide an approved U.S. application number instead of labeling.
• Revises § 207.49 (also §§ 207.1 and 207.53) to categorize certain drug products according to whether they are subject
to sections 505 or 512 of the FD&C Act (21 U.S.C. 355 or 360b) or section 351 of the PHS Act, rather than whether
registrants regard them as subject to those provisions.
• Adds §§ 207.49(a)(15)(iv) and 207.53(d)(4) to require the submission of labels for listed drugs not elsewhere described
in §§ 207.49(a)(14) and 207.53(d).
• Clarifies in new §§ 207.49(a)(15) and 207.53(f) the information a registrant must submit when listing a human drug
manufactured for private label distribution.
• Adds § 207.49(b) to describe drug listing information that is requested of registrants but not required.
• Adds § 207.49(a)(2) so that drug listing information includes package size and type.
What listing information must a registrant submit for a drug that it repacks or relabels?
• Shifts from proposed § 207.33(d)(1)(iii) to new § 207.53(b) the requirement that for a repacked or relabeled drug, registrants identify the NDC assigned to the finished drug received by the registrant for repacking or relabeling and exempts repackaged medical gases from this requirement.
• Requires identification of establishments where repacking, or relabeling is performed based on their UFIs rather than
by their registration numbers.
• Clarifies that all current labeling (new labeling) for a repacked or relabeled drug must be submitted, not only the
changed labeling.
• Specifies that for animal drugs subject to section 512 of the FD&C Act, all current labeling is submitted, whereas a
copy of the current label, and other information, is submitted for other animal drugs.
What listing information must a registrant submit for a drug that it salvages?
• Requires identification of establishments where salvaging is performed by their UFIs rather than by their registration
numbers.
• Deletes references to salvaged drugs distributed by private label distributors.
What information must registrants submit when updating listing information and when?
• Revises proposed § 207.57 to improve clarity and to delete the proposed requirement that registrants routinely update
information provided under § 207.55.
20:25 Aug 30, 2016
Jkt 238001
PO 00000
Frm 00005
Fmt 4701
Sfmt 4700
E:\FR\FM\31AUR2.SGM
31AUR2
60174
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
TABLE 1—SUBSTANTIVE CHANGES FROM THE PROPOSED RULE TO THE FINAL RULE—Continued
21 CFR Section
in final rule
207.61 ...............
207.65 ...............
207.69 ...............
207.77 ...............
207.81 ...............
314.81 ...............
.
601.2(f) .............
607.1 .................
607.3 .................
607.22 ...............
607.25 ...............
mstockstill on DSK3G9T082PROD with RULES2
607.26 ...............
607.30 ...............
607.37 ...............
607.40 ...............
VerDate Sep<11>2014
Description of change from proposed rule
• Allows registrants to submit a blanket ‘‘no changes’’ certification applicable to listing information they have previously
submitted electronically, rather than making product-by-product ‘‘no changes’’ certifications for individual listed drugs.
How is registration and listing information provided to FDA?
• Revises § 207.61 to improve clarity, to state that we may periodically issue guidance on electronic registration and listing, and to clarify that when foreign language labeling is used under § 201.15(c), the content of labeling must be submitted in that foreign language along with an accurate English translation.
• Removes the option to submit advertisements and certain labeling in paper format, consistent with the electronic submission requirement of section 510(p) of the FD&C Act, as amended by FDAAA.
How can a waiver of the electronic submission requirement be obtained?
• Clarifies that requests for waivers of the electronic submission requirement cannot be relied upon until FDA grants
them.
• States more broadly the conditions under which FDA will grant waiver requests.
• Specifies that waiver requests must be submitted in writing and must state reasons why electronic submission is not
reasonable for the registrant.
• States that FDA will specify terms of waivers and may limit their duration.
What are the requirements for an official contact and a United States agent?
• Revises proposed § 207.69 to state that designated official contacts and United States agents are both responsible for
reviewing, disseminating, routing, and responding to all communications from FDA, including emergency communications.
What legal status is conferred by registration and listing?
• Includes minor revisions to improve clarity and mentions the UFI that will be used to identify establishments.
What registration and listing information will FDA make available for public disclosure?
• Reorganizes § 207.81 so that registration and listing information that will be disclosed is described in paragraph (a),
and exceptions are described in paragraphs (b) and (c).
• Categorizes updated drug listing information submitted under § 207.57 as generally disclosable.
• Adds § 207.81(b)(2) to make explicit that FDA will generally not disclose the names of inactive ingredients in listed drug
products if the registrant makes a valid assertion of confidentiality.
• Categorizes the information submitted to reserve an NDC under new § 207.33(d)(3) as generally not disclosable.
• Categorizes the identities of the establishments involved in manufacturing, repacking, relabeling, or salvaging listed
drugs as generally not disclosable.
• Categorizes as generally not disclosable the NDC assigned to an unfinished drug received by a registrant for use in
the manufacture of a listed drug reported under § 207.49(a)(12) (i.e., the association between the unfinished drug and
the listed drug is generally not disclosable).
• No longer categorizes the NDC assigned to a drug immediately before it is received by a registrant for salvaging as
generally not disclosable (because the NDC assigned to a drug does not change when a drug is merely salvaged and
not also repackaged or relabeled).
Other postmarketing reports (reporting the discontinuation of a drug that is the subject of an approved NDA).
• Renumbers proposed § 314.81(b)(3)(iii) as § 314.81(b)(3)(iv) and revises this section to provide for electronic or written
submissions in certain circumstances, under both paragraphs (a) and (b).
Applications for biologics licenses (reporting the discontinuation of a drug that is licensed under a BLA).
• Revises proposed § 601.2(f) to reference the electronic submission requirement of § 207.61 and the waiver provision of
§ 207.65 and to clarify that the date on which the product is expected to be no longer in commercial distribution must
be reported rather than the ‘‘date of withdrawal from sale’’.
Scope (Establishment registration and product listing for manufacturers of human blood and blood products.)
• Adds a new scope provision (§ 607.1) to part 607 for clarity.
Definitions (Establishment registration and listing for blood and blood products).
• Adds a definition of ‘‘foreign’’.
• Revises the proposed definition of ‘‘importer’’.
How to register blood product establishments and list blood products.
• Revises proposed § 607.22 to remove references to Form FDA 2830 and to state that blood product establishment registration and blood product listing must be transmitted to FDA electronically through the Blood Establishment Registration and Product Listing system, unless FDA waives the electronic submission requirement in individual cases.
Information required for establishment registration and blood product listing.
• Removes references to Form FDA 2830.
• Requires submission of a UFI when registering blood and blood product establishments along with a registration number if previously assigned by FDA.
• Adds the UFI of the parent establishment to blood product listing information required under § 607.25(b)(3).
Amendments to establishment registration.
• Revises § 607.26 regarding amendments to establishment registration to reference the Blood Establishment Registration and Listing System in place of Form FDA 2830.
• Clarifies that 5 days refers to 5 calendar days in this section.
Updating blood product listing information.
• Revises § 607.30 regarding updates to blood product listing information to reference the Blood Establishment Registration and Listing System in place of Form FDA 2830.
Public disclosure of establishment registration and blood product listing information.
• Revises § 607.37 to remove references to Form FDA 2830.
• Structures § 607.37 in a way that matches § 207.81 (public disclosure of drug registration and listing information).
Establishment registration and blood product listing requirements for foreign blood product establishments.
• Retains the exemptions applicable to foreign trade zones and products imported under section 801(d)(4) of the FD&C
Act (21 U.S.C. 381(d)(4)).
20:25 Aug 30, 2016
Jkt 238001
PO 00000
Frm 00006
Fmt 4701
Sfmt 4700
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
60175
TABLE 1—SUBSTANTIVE CHANGES FROM THE PROPOSED RULE TO THE FINAL RULE—Continued
21 CFR Section
in final rule
607.80 ...............
1271.1 ...............
1271.3 ...............
1271.20 .............
mstockstill on DSK3G9T082PROD with RULES2
1271.25 .............
Description of change from proposed rule
• Revises proposed § 607.40 to state more broadly the circumstances under which FDA will waive the electronic submission requirement for foreign blood product establishments.
Applicability of part 607 to licensed devices.
• Adds a new § 607.80 clarifying the applicability of part 607 to certain licensed devices.
What are the purpose and scope of this part? (HCT/Ps)
• Adds the word ‘‘electronic’’ in place of ‘‘unified’’ in § 1271.1.
How does FDA define important terms in this part?
• Revises the definition of ‘‘importer’’ in proposed § 1271.3(mm) to include ‘‘at the time of entry’’.
If my HCT/Ps do not meet the criteria in § 1271.10, and I do not qualify for any of the exceptions, what regulations apply?
• Adds a further amendment to § 1271.20 to indicate that subpart B of part 1271 (procedures for registration and listing)
does not apply to HCT/Ps that do not meet the criteria set out in § 1271.10(a). (In other words, HCT/Ps not regulated
solely under section 361 of the PHS Act are subject to registration and listing under part 207 or part 807 rather than
part 1271.)
What information is required for establishment registration and HCT/P listing?
• Removes from proposed § 1271.25(a)(6) the requirement that each foreign HCT/P establishment designate only one
United States agent.
• Removes a reference to Form FDA 3356 in proposed § 1271.25(c)(4).
• Revises proposed § 1271.25(d) to clarify that it pertains to HCT/Ps regulated under BLAs and to state that establishment registration and listing information for such products must be submitted in accordance with the electronic submission requirements of part 207, subpart E.
This final rule does not include the
proposed amendments to §§ 330.1,
610.60, and 610.61, all of which dealt
with NDCs on labels. This final rule also
does not include the proposed minor
amendment to § 1271.37 (regarding
public disclosure of HCT/P
establishment registration and listing
information) in light of the technical
amendments adopted on April 3, 2015
(80 FR 18087).
Some changes from the proposed rule
not addressed in section III (Comments
on the Proposed Rule) are addressed in
the following paragraphs.
Active pharmaceutical ingredient: To
prevent confusion, we proposed to
replace the term ‘‘bulk drug substance’’
with the more descriptive term ‘‘active
pharmaceutical ingredient.’’ This
change is retained in the final rule.
Sections 503A(b)(1)(A) and 503B(a)(2) of
the FD&C Act (21 U.S.C. 353a(b)(1)(A)
and 353b(a)(2)), however, refer
specifically to the definition of ‘‘bulk
drug substance’’ within part 207. To
ensure conformity with the FD&C Act,
both ‘‘bulk drug substance’’ and ‘‘active
pharmaceutical ingredient’’ are defined
in § 207.1 of the final rule. As intended
by the proposed rule, ‘‘active
pharmaceutical ingredient’’ will have
the same meaning as ‘‘bulk drug
substance.’’
Salvage: In this final rule, the term
‘‘salvage’’ is defined to mean the act of
segregating out those finished drug
products that may have been subjected
to improper storage conditions (such as
extremes in temperature, humidity,
smoke, fumes, pressure, age, or
radiation) for the purpose of returning
the products to the marketplace and
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
includes applying manufacturing
controls such as those required by
current good manufacturing practice in
parts 210 and 211 (21 CFR parts 210 and
211). Substantively, this matches the
definition of ‘‘drug product salvaging’’
included in the proposed rule, but the
words have been rearranged for greater
clarity. This final rule also includes a
definition for the term ‘‘salvager.’’
Establishment registration number
and Unique Facility Identifier: We
proposed to define the term
‘‘establishment registration number’’ in
§ 207.1 to mean ‘‘the number assigned
by FDA to the establishment during the
establishment registration process
required in this part.’’ The final rule
changes the definition of ‘‘establishment
registration number’’ slightly to state
that the number is assigned ‘‘after’’ the
registration process, rather than
‘‘during.’’
The establishment registration
number identifies establishments for
inspection by FDA. Historically, an
establishment registration number is
assigned to each establishment of each
manufacturer, repacker, relabeler, or
salvager after the initial registration,
when such activities begin. In the
preamble to the proposed rule, we
explained that ‘‘[c]urrently, the FDA
Establishment Identifier (FEI) will be
the number we assign as the
establishment registration number. In
the future, however, we may use a
different number as the establishment
registration number’’ (71 FR 51276 at
51288).
After the proposed rule was
published, FDASIA amended section
510 of the FD&C Act to require persons
PO 00000
Frm 00007
Fmt 4701
Sfmt 4700
subject to the drug establishment
registration requirement to submit a
UFI. In the electronic registration and
listing guidance, FDA stated that it
intended to use the DUNS number,
assigned and managed by Dun &
Bradstreet, as a registration number. To
implement the UFI provision of
FDASIA, FDA also issued guidance in
2014 that specified the DUNS number as
the preferred UFI.1
Under the final rule, the
establishment registration number and
the UFI are two distinct numbers. For
now, FDA will continue to assign an FEI
as the establishment registration number
after an establishment is registered for
the first time. The final rule requires
registrants to submit the establishment
registration number (currently the FEI),
‘‘if previously assigned by FDA,’’ under
§ 207.25. Someone registering an
establishment for the first time is not
expected to have a registration number
for the establishment. Such a registrant
is required to submit its registration
number at the time of the first annual
review and update of registration
information under § 207.29(b) of this
final rule and is encouraged to submit
the registration number sooner, as soon
as it is received from FDA. The
establishment registration number does
not need to be submitted at the time of
each annual registration update under
§ 207.29 unless the establishment
registration number has changed.
Likewise, the UFI, currently specified as
1 See the guidance for industry ‘‘Specification of
the Unique Facility Identifier (UFI) System for Drug
Establishment Registration,’’ November 2014,
available on the Internet at https://www.fda.gov/
Drugs under Guidances (Drugs).
E:\FR\FM\31AUR2.SGM
31AUR2
60176
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
mstockstill on DSK3G9T082PROD with RULES2
the DUNS number, must be submitted
when registering an establishment for
the first time under § 207.25. The UFI
does not need to be submitted at the
time of each annual registration update
under § 207.29 unless the UFI has
changed.
Bar code label requirements
(§ 201.25): As explained in section III,
this final rule does not include two
proposed amendments to § 201.25. It
does, however, include a minor new
amendment to § 201.25. To
accommodate the possibility of
alternatively formatted NDCs in bar
codes, § 201.25 is amended in this final
rule to allow FDA’s Center Directors to
approve additional standards or formats
for bar codes.
Submission of approved U.S.
application number instead of inactive
ingredients (§ 207.33(c)(2)): Information
registrants would have submitted under
§ 207.33(c) of the proposed rule to
obtain an NDC has been shifted to drug
listing information required under
§ 207.49 of this final rule. Under
§ 207.49(a)(5) of this final rule, a
registrant must provide the name of
each inactive ingredient in a listed drug
it manufactures. The option to submit
an approved application number instead
of a list of inactive ingredients is not
retained in the final rule because FDA
is not currently able to pull inactive
ingredient information from approved
applications to our drug listing systems.
III. Comments on the Proposed Rule
In the Federal Register of October 31,
2006 (71 FR 63726), FDA announced an
extension of the comment period for
this rulemaking and a public meeting to
discuss the proposed changes to the
NDC system presented in the proposed
rule. The public meeting was held on
December 11, 2006. In the Federal
Register of February 8, 2007 (72 FR
5944), FDA announced a reopening of
the comment period because technical
problems prevented some persons from
submitting comments electronically on
the last day of the previous comment
period. The Agency received numerous
comments, including oral presentations
made at the December 2006 public
meeting and approximately 200 written
comments placed in the docket.
Comments were received from
prescription and nonprescription drug
manufacturers and related companies,
trade associations representing drug
manufacturers and other interested
parties, academic institutions, and
professional associations.
The docket for this rulemaking,
Docket No. FDA–2005–N–0464, was
also used to collect comments on FDA’s
draft guidance for industry entitled
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
‘‘Providing Regulatory Submissions in
Electronic Format—Drug Establishment
Registration and Drug Listing’’ (74 FR
26248). In this final rule, we are
responding to comments that pertain to
the rulemaking, i.e., comments that
relate to the changes in regulations
proposed on August 29, 2006.
To make it easier to identify
comments and our responses, the word
‘‘Comment,’’ in parentheses, appears
before the comment’s description, and
the word ‘‘Response,’’ in parentheses,
appears before our response. We have
numbered each comment to help
distinguish between different
comments. Similar comments are
grouped together under the same
number. The number assigned to each
comment is purely for organizational
purposes and does not signify the
comment’s value or importance or the
order in which comments were
received.
A. Labeling (§§ 201.2 and 201.25)
The proposed rule included
amendments to § 201.2 that would have
required drugs subject to the listing
requirement of part 207 to have labels
that bear the appropriate NDC in
human-readable form. As discussed in
this document, this final rule does not
include the proposed amendments that
would have made human-readable
NDCs mandatory on drug labels.
Section 201.2 currently states that
NDCs are ‘‘requested but not required’’
to appear on all drug labels. Section
201.25 currently requires bar codes on
prescription human drug labels with
certain exceptions and on certain
nonprescription human drug labels.
Section 201.25(c) currently specifies
that each bar code must contain, at a
minimum, the appropriate NDC.
Sections 201.2 and 201.25 currently
do not specify which NDC should
appear on labels and in bar codes apart
from referring to it as ‘‘the appropriate’’
NDC (§ 201.25(c)). This implies that the
NDC appearing on a drug’s label match
an NDC under which the drug is
appropriately listed under part 207.
1. NDC Numbers (§ 201.2)
Pharmacists and health care providers
use NDCs currently appearing on drug
labels in a variety of ways, including to
help prevent medication errors and to
process prescription drug
reimbursement claims. We believe there
is currently a high level of cooperation
with FDA’s request in § 201.2 that NDCs
appear in human-readable form on
labels, as drug manufacturers recognize
the importance of this information.
In addition to making human-readable
NDCs on drug labels mandatory, the
PO 00000
Frm 00008
Fmt 4701
Sfmt 4700
proposed rule would have specified
which NDC must appear on labels.
Specifically, proposed § 201.2(b) sought
to define the appropriate NDC for this
purpose as being that of the last
manufacturer, repacker, relabeler, or
private label distributor responsible for
the drug immediately before it is
received by the wholesaler or retailer.
(Comment 1) Several comments
recognized the importance of having
NDCs in human-readable form on labels,
but many objected to FDA’s proposed
provisions defining the appropriate
NDC in proposed § 201.2(b). In
particular, certain repackers objected to
the proposed requirement that a
repacker’s NDC, rather than that of the
original manufacturer, appear on the
labels of repackaged drug products.
(Response) This final rule does not
include the proposed amendments to
§ 201.2 that would have made humanreadable NDCs mandatory on drug
labels. It includes only a conforming
amendment to that section (replacing
the reference to § 207.3(b)(3) with an
updated reference to new § 207.1).
The Drug Quality and Security Act
(DQSA) (Pub. L. 113–54) of 2013
includes as Title II the Drug Supply
Chain Security Act (DSCSA). The
DSCSA requires drug manufacturers and
repackagers (as defined in sections
581(10) and 581(16) of the FD&C Act,
respectively) to affix or imprint a
product identifier on packages for
certain prescription drugs for human
use. Under section 581(14) of the FD&C
Act, a ‘‘product identifier’’ is a
standardized graphic that includes, in
both human-readable form and on a
machine-readable data carrier, the
‘‘standardized numerical identifier,’’ lot
number, and expiration date of the
product. The NDC is one component of
the standardized numerical identifier.
FDA has determined that because the
DSCSA requires the inclusion of NDCs
on certain prescription drug labels (as
part of a product identifier), it is
unnecessary to include the proposed
amendments to § 201.2 in this final rule.
Our determination that the proposed
amendments to § 201.2 should not be
finalized renders moot many comments
concerning identification of the
appropriate NDC for labeling purposes,
along with placement and formatting
issues. Therefore, we do not respond to
those comments.
The DSCSA does not require
manufacturers or repackagers to affix or
imprint product identifiers on
nonprescription human drug products
or on animal drugs. Therefore, we will
maintain the status quo for those drug
products, meaning FDA will continue to
request that NDCs in human-readable
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
mstockstill on DSK3G9T082PROD with RULES2
form appear on all drug labels and in all
drug labeling, as indicated in § 201.2.
We may revisit a regulatory requirement
that human-readable NDCs appear on
the labels of nonprescription human
drug products and animal drugs in the
future.
2. Bar Code Label Requirements
(§ 201.25)
Section 201.25 currently requires that
a human drug product’s NDC be
included in its bar code. We proposed
to amend § 201.25 in two minor ways:
(1) To add a cross-reference to proposed
new § 201.2(b), which would have
described the ‘‘appropriate NDC’’ for
labeling purposes and (2) to add new
§ 201.25(e) stating that a bar code may
be displayed on certain drug product
labels voluntarily but only if it meets
the requirements of § 201.25(c). Neither
proposed amendment to § 201.25 is
retained in the final rule.
(Comment 2) The Animal Health
Institute expressed concern that
proposed § 201.25(e) would
unreasonably burden its members who,
although they are not currently required
by § 201.25 to place bar codes on animal
drug labels (because it applies to human
drugs), may do so for logistical reasons.
They asked that the animal health
industry be exempt from the
requirement to include an NDC in any
bar codes appearing on animal drug
labels. Similar comments were received
from manufacturers of allergenic
extracts. Allergenic extracts are
currently exempt from the bar code
requirement (see § 201.25(b)(1)(i)(B)).
Commenters explained that
manufacturers of allergenic extracts may
place bar codes on their labels for
inventory, warehousing, and other
logistical purposes. They objected to
proposed § 201.25(e) to the extent that it
would require such bar codes to include
NDCs.
(Response) FDA has not retained
proposed § 201.25(e) in this final rule.
(Comment 3) A group of comments
asserted that 11-digit NDCs cannot be
encoded into a bar code that meets
European Article Number/Uniform
Code Council or Health Industry
Business Communications Council
standards, as required by current
§ 201.25(c). Another comment urged
FDA to remove the NDC from bar codes.
(Response) This final rule
acknowledges that 10-digit NDCs will be
exhausted at some point in the future as
a mathematical inevitability. As
discussed in our response to Comment
52, this final rule reduces the number of
occasions when a change to a drug
requires a new NDC under § 207.35.
This final rule also amends § 201.25 to
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
allow FDA’s Center Directors to approve
additional bar code standards and
formats.
As discussed in response to Comment
1, the DSCSA requires the inclusion of
product identifiers on prescription
human drug labels and defines ‘‘product
identifier’’ to mean a standardized
graphic that includes, in both humanreadable form and on a machinereadable data carrier the standardized
numerical identifier, lot number, and
expiration date of the product. The
standardized numerical identifier, a
component of the product identifier, is
comprised of the NDC and a serial
number.
FDA continues to recognize the
importance of NDCs on drug labels in
both machine-readable and humanreadable form. We remind
manufacturers of the current
requirement in § 201.25 that bar codes
on human drug labels include the
appropriate NDC, and we encourage
manufacturers to continue to provide
the NDC in human-readable form on
drug labels where not required by the
DSCSA.
B. General Information (Part 207,
Subpart A)
1. What definitions and interpretations
of terms apply to this part? (§ 207.1)
The proposed rule included a set of
terms and definitions in §§ 207.1, 607.3,
and 1271.3. These definitions are
retained in the final rule with several
modifications. Additionally, the final
rule includes definitions for the terms
‘‘finished drug product,’’ ‘‘unfinished
drug product,’’ ‘‘bulk drug substance,’’
‘‘outsourcing facility,’’ ‘‘private label
distribution,’’ and ‘‘registrant’’ in
§ 207.1 and a definition of ‘‘foreign’’ in
§ 607.3.
a. Commercial distribution. In the
proposed rule, the definition of
‘‘commercial distribution’’ excluded
‘‘the internal or interplant transfer of an
active pharmaceutical ingredient
between registered establishments
within the same parent, subsidiary, and/
or affiliate company.’’
In the final rule, the definition does
not include the phrase ‘‘an active
pharmaceutical ingredient’’ so that
internal or interplant transfers between
such registered establishments are not
treated as commercial distribution
under part 207, whether the transfer
involves active pharmaceutical
ingredients, other unfinished drug
products, or finished drug products.
(Comment 4) A comment suggested
that the definition of ‘‘commercial
distribution’’ be revised to exclude
transfers between a registered
PO 00000
Frm 00009
Fmt 4701
Sfmt 4700
60177
establishment and a marketing
authorization holder when the two are
in a contractual relationship. Otherwise,
this comment argued, products
marketed by private label distributors
who employ contract manufacturers are
held to a higher burden of
documentation than products
manufactured and distributed by the
same entity.
(Response) We disagree with the
suggestion that a transfer of drugs from
a contract manufacturer to another
contracting party should not qualify as
commercial distribution. Such an
exemption would interfere with FDA’s
ability to track drugs and establishments
for inspection. However, by revising the
definition of ‘‘commercial distribution’’
to exclude internal or interplant
transfers of drugs, including active
pharmaceutical ingredients, other
unfinished drugs, and finished drug
products, between registered
establishments under common
ownership and control, we have
reduced the drug listing burden
generally. This exclusion accommodates
the common practices of specialized
manufacturing at different registered
establishments under common
ownership and control. This practice
often results in multiple internal and
interplant transfers of these materials
prior to marketing, which we do not
consider commercial distribution for
registration and listing purposes.
b. Content of labeling. The proposed
rule included a multipart definition for
the term ‘‘content of labeling’’ with
separate provisions applicable to:
• Human prescription drugs that the
manufacturer regards as subject to
section 505 of the FD&C Act or section
351 of the PHS Act, i.e., subject to
premarket approval from FDA;
• Human prescription drugs that the
manufacturer regards as not subject to
section 505 of the FD&C Act or section
351 of the PHS Act;
• Human nonprescription drugs; and
• Animal drugs.
The term ‘‘content of labeling’’ was
used in the proposed rule to describe
some, but not all, labeling that must be
submitted with drug listing information.
For example, proposed § 207.49(g)(2)(i)
stated that listing information for certain
human over-the-counter (OTC) drugs
must include ‘‘all current labeling . . .
including the content of labeling.’’
Content of labeling is defined in a very
similar way in the final rule with
deletion of the phrase ‘‘that the
manufacturer regards as’’ and the
addition of a reference to the labeling
requirements for veterinary drugs in 21
CFR part 201.
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60178
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
We removed the language ‘‘that the
manufacturer regards as subject to
section 505 [or 512] of the FD&C Act or
section 351 of the PHS Act’’ and added
in its place language that refers to drugs
as being either subject or not subject to
those provisions. We made this change
after determining that the manner in
which content of labeling is defined
should not depend on a manufacturer’s
subjective understanding or intent with
respect to sections 505 or 512 of the
FD&C Act or section 351 of the PHS Act.
The revised definition includes,
among others, the category ‘‘human
prescription drugs that are not subject to
section 505 of the FD&C Act or section
351 of the PHS Act.’’ We have retained
this construction even though FDA
considers it unlikely that any currently
marketed human prescription drug
product is grandfathered or is otherwise
not a new drug subject to those
provisions. However, the Agency
recognizes that the existence of such
drugs is at least theoretically possible.
No part of this final rule is a finding as
to the legal status of any particular drug
product.
Regarding animal drugs, in part four
of the definition of ‘‘content of labeling’’
and in other places throughout this final
rule, the phrase ‘‘subject to section 512’’
means, for purposes of this final rule,
drugs meeting the definition of ‘‘new
animal drug’’ as that term is defined in
section 201(v) of the FD&C Act, and
which therefore are subject to some or
all of the provisions relating to new
animal drugs found in section 512 of the
FD&C Act. This term includes not only
new animal drugs that are approved
under section 512 but also new animal
drugs that are conditionally approved
under section 571 of the FD&C Act (21
U.S.C. 360ccc) or indexed under section
572 of the FD&C Act (21 U.S.C. 360ccc–
1). The phrase ‘‘all other animal drugs’’
as used in provisions of this final rule
at §§ 207.49(a)(15)(iii) and 207.53(d)(3)
describing the labeling registrants must
provide as part of the listing for an
animal drug, refers to animal drugs that
do not meet the definition of new
animal drug found in section 201(v) of
the FD&C Act (e.g., grandfathered
animal drugs). Although the Agency
recognizes that the existence of such
animal drugs is theoretically possible,
we believe it is unlikely that any
currently marketed animal drug product
is grandfathered or otherwise not a
‘‘new animal drug’’ subject to section
512 of the FD&C Act.
(Comment 5) Commenters asked FDA
to clarify how content of labeling differs
from package inserts and final printed
labeling.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
(Response) A prescription human
drug product’s FDA-approved labeling
is sometimes referred to as a ‘‘package
insert’’ or as ‘‘professional labeling.’’ In
defining the term ‘‘content of labeling,’’
for human drugs, we use the phrase
‘‘prescription drug labeling’’ (instead of
‘‘package insert’’ or ‘‘professional
labeling’’) to mean FDA-approved
labeling for prescription drug products
described in §§ 201.56, 201.57, and
201.80. For human prescription drugs
that are subject to section 505 of the
FD&C Act or section 351 of the PHS Act,
content of labeling is defined as the
content of the prescription drug
labeling. For human OTC drugs, content
of labeling is not defined in these terms;
it includes ‘‘all text, tables, and figures
including the drug facts labeling
required by § 201.66.’’ For animal drugs,
‘‘content of labeling’’ is defined to mean
labeling that accompanies the drug that
is necessary to enable safe and proper
administration of the drug. This would
generally include package inserts and
final printed labeling. Sections 207.49
and 207.53 require submission of
labeling with drug listing information.
In most cases, all current labeling must
be submitted, including the content of
labeling.
(Comment 6) A comment stated that
FDA should more clearly delineate
between the terms ‘‘label’’ and
‘‘labeling’’ throughout the rulemaking,
rather than using the term ‘‘labeling’’ to
refer to both. This comment pointed out
that the proposed rule’s definition of
content of labeling for human OTC
drugs referred to ‘‘labeling required by
§ 201.66,’’ but § 201.66 pertains to
information appearing on the ‘‘outside
container or wrapper of the retail
package, or the immediate container
label if there is no outside container or
wrapper’’ (§ 201.66(c)).
(Response) We have clarified in
§ 207.1(a) of the final rule that the
definitions and interpretations of terms
in sections 201 and 510 of the FD&C Act
apply to the terms used in part 207
unless otherwise defined. Accordingly,
the term ‘‘label’’ means a display of
written, printed, or graphic matter upon
the immediate container of any article
consistent with section 201(k) of the
FD&C Act. The term ‘‘labeling’’ more
broadly includes both immediate
container labels and other written,
printed, or graphic matter
accompanying such article consistent
with section 201(m) of the FD&C Act.
When we intend to refer only to
immediate container or package labels,
we use the term ‘‘label.’’ More often, we
use the broader term ‘‘labeling’’ in this
final rule to encompass both immediate
container labels and/or other written,
PO 00000
Frm 00010
Fmt 4701
Sfmt 4700
printed, or graphic matter
accompanying the drug, as the labeling
definition in section 201(m) of the FD&C
Act has been interpreted. The term
‘‘content of labeling’’ is defined slightly
differently for human prescription
drugs, human OTC drugs, and animal
drugs, and the term is intended to
encompass both labels and labeling.
The proposed rule (proposed § 207.1)
referred only to definitions in section
510 of the FD&C Act, and the preamble
to the proposed rule suggested that
reference to the definitions in section
201 of the FD&C Act was intentionally
omitted (71 FR 51276 at 51285).
Consistent with 21 CFR 1.1(b), this final
rule clarifies that the definitions in
section 201 of the FD&C Act apply to
the terms used in part 207.
c. Establishment. We proposed to
define ‘‘establishment’’ in § 207.1 as ‘‘a
place of business under one
management at one geographic
location.’’ The definition in proposed
§ 207.1 also stated ‘‘one geographic
location may include separate buildings
within the same city if their activities
are closely related to the same business
enterprise and are under the supervision
of the same local management.’’
Rather than adopt this proposed
definition, the final rule retains the
definition of the term ‘‘establishment’’
that has appeared in the part 207
regulations since 1980. This definition
states that an establishment is ‘‘at one
general physical location.’’
(Comment 7) One comment suggested
that the phrase ‘‘within the same city’’
used in the proposed definition of
‘‘establishment’’ was too specific. This
comment argued that a manufacturing
facility located in a city with a
warehouse located just outside that city
should together be treated as a single
establishment for registration purposes.
(Response) In reviewing this comment
and considering it in light of the
longstanding definition of
‘‘establishment’’ and the objectives
behind the establishment registration
requirement, we determined that the
existing definition in part 207 is clearer
and better serves our objectives than
would the proposed amended
definition. The longstanding language,
‘‘one general physical location,’’
generally restricts a single establishment
to one street address or one or more
contiguous plots of land. We do not
agree with the comment that a second
facility located in a different city should
be covered by the first facility’s
establishment registration.
We note, however, that a facility
operated only as a warehouse may not
require registration. Section 510 of the
FD&C Act and § 207.17 of this final rule
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
require registration of establishments
where drugs are manufactured,
repacked, relabeled, or salvaged. A
facility at which drugs are merely stored
may not require registration under this
final rule, unless the facility includes,
for example, controlled storage for
stability testing as an element of good
manufacturing practices. Other Federal
and State requirements may apply to
such facilities.
Likewise, the corporate headquarters
of a drug establishment should not
register under this rule if drugs are not
manufactured, repacked, relabeled, or
salvaged at that location.
d. Foreign. We proposed to use the
term ‘‘foreign’’ to refer to a
manufacturer, repacker, relabeler, drug
product salvager, or private label
distributor who is located in a foreign
country and who manufactures, repacks,
relabels, salvages, or distributes a drug
that is imported or offered for import
into the United States. When used to
modify ‘‘establishment,’’ we proposed to
use ‘‘foreign’’ to refer to an
establishment that is located in a foreign
country and is the site where a drug that
is imported or offered for import into
the United States was manufactured,
repacked, relabeled, salvaged or
distributed.
We have omitted the words ‘‘or
distributed’’ from this definition
because only establishments at which
drugs are manufactured, repacked,
relabeled, or salvaged are required to be
registered.
(Comment 8) One comment urged us
to revise the definition of ‘‘foreign’’ to
mean ‘‘located in a foreign country’’
while stating in § 207.9 that part 207
applies to foreign entities who import or
offer for import products into the United
States.
(Response) We do not agree that the
proposed rule was confusing or difficult
to understand in this respect and have
decided against making this change.
e. Importer. Section 207.25 of this
final rule and section 510(i) of the FD&C
Act require foreign establishments,
when registering, to provide names and
contact information for each importer in
the United States of drugs
manufactured, repacked, relabeled, or
salvaged at the establishment that is
known to the establishment. We
proposed to define ‘‘importer’’ to mean,
in part, ‘‘a company or individual in the
United States that is an owner,
consignee, or recipient of the foreign
establishment’s drug that is imported
into the United States.’’ In proposing
this language, we recognized that a
foreign establishment may have more
than one importer, and we proposed to
include in this term any owner,
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
consignee, or recipient, even if not the
initial owner, consignee, or recipient, of
the foreign establishment’s drug that is
imported into the United States.
(Comment 9) Some comments stated
that our proposed definition of the term
‘‘importer’’ was too broad and would
increase the burden on manufacturers to
provide unnecessary information
concerning a wide variety of entities
that are not responsible for the drug.
One comment noted that the inclusion
of downstream recipients in our
definition of ‘‘importer’’ would impose
a significant reporting burden on foreign
establishments that is not required of
domestic establishments.
(Response) We agree that we should
clarify and narrow the proposed
definition of ‘‘importer.’’ As proposed,
the definition included every U.S.
recipient of a foreign-produced drug,
excepting only the final consumer or
patient. Of this large group, foreign
establishments would be required to
identify in their establishment
registration submissions only those
importers that are known to the
establishment. To make this information
element more useful to FDA and to
reduce the burden on registered
establishments, we have determined
that in this context the term ‘‘importer’’
should include a U.S. owner, consignee,
or recipient at the time of the drug’s
entry into the United States and should
not include additional subsequent
owners, consignees, or recipients of the
drug. We have revised the definition of
importer in § 207.1 of the final rule
accordingly.
(Comment 10) One comment
recommended that we change
‘‘company or individual’’ to ‘‘person,’’
in the rule’s definition of ‘‘importer,’’
consistent with the definition of the
term ‘‘person’’ in section 201(e) of the
FD&C Act.
(Response) We agree that the term
‘‘person,’’ as defined in the FD&C Act,
is an improvement over ‘‘company or
individual’’ in this definition. We have
made this change in §§ 207.1 and 607.3
of the final rule, and as discussed in our
response to comment 6, we have also
added a statement in §§ 207.1(a) and
607.3(a) that the definitions and
interpretations of terms in sections 201
and 510 of the FD&C Act apply if not
otherwise defined.
f. Person who imports or offers for
import. Section 207.25 of this final rule
and section 510(i) of the FD&C Act also
require foreign establishments, when
registering, to supply names and contact
information for each person who
imports or offers for import drugs
manufactured, repacked, relabeled, or
salvaged at the establishment. The
PO 00000
Frm 00011
Fmt 4701
Sfmt 4700
60179
proposed rule’s definition of ‘‘person
who imports or offers for import’’
included ‘‘an agent, broker, or other
entity, other than a carrier, that the
foreign establishment uses to facilitate
the import of its drug into the United
States.’’ We invited comments on the
use and interpretation of the term
‘‘facilitate.’’
(Comment 11) Some comments
expressed concern regarding the
potential breadth of this definition,
noting in particular that the word
‘‘facilitate’’ could, in theory, encompass
entities such as foreign insurance
adjusters, underwriters, and
international banks. Commenters
pointed out the significant burden
associated with the identification of
such entities in foreign establishment
registrations and updates to
registrations, noting that international
supply chains and business
relationships are not static. One
comment urged FDA to exclude customs
brokers from the rule’s definition of
‘‘person who imports or offers for
import.’’ Another comment encouraged
FDA to exclude middlemen from this
definition, as their identities would
change frequently.
(Response) Although we did not
intend for the word ‘‘facilitate’’ to be
read as broadly as some comments
suggested, FDA agrees that the
definition of ‘‘person who imports or
offers for import’’ should be made more
precise, narrow, and useful.
We note, as a matter of clarification,
that in section 510(i) of the FD&C Act
and in § 207.25 of the final rule, the
requirement that foreign establishments
identify each person who imports or
offers for import is not said to be limited
to persons known to the establishment
(unlike the requirement that they
identify ‘‘importers’’). The preamble to
the proposed rule included statements
that were inconsistent with the FD&C
Act in this regard, suggesting that
foreign establishments would be
required to report the name of each
person known to the establishment who
imports or offers for import its drug(s)
into the United States. See, e.g., 71 FR
51276 at 51289. In fact, the proposed
rule (proposed § 207.25), the final rule,
and the FD&C Act all require foreign
establishments to report, when
registering, the name of each person
who imports or offers for import its
drug(s) into the United States without
regard to whether such persons are
known to the establishment. Therefore,
it is important that we define ‘‘person
who imports or offers for import’’ in a
way that is practical, useful, and
consistent with this understanding.
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60180
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
Our intention in defining this term is
to include foreign persons who are
primarily responsible for sending a drug
to the United States. Foreign
establishments are reasonably expected
to know the identities of such persons.
In many cases, the establishment itself
will be a person who imports or offers
for import its drugs into the United
States. In other cases, it will be a person
the foreign establishment engages to
send one or more drugs to the United
States. It will generally be the foreign
person who owns the drug and sells or
enters into a contractual obligation to
supply the drug to a person in the
United States.
In light of the comments received and
FDA’s objectives, the final rule defines
‘‘person who imports or offers for
import’’ to mean the owner or exporter
of a drug who consigns and ships a drug
from a foreign country to the United
States. This definition includes persons
who send a drug to the United States by
international mail or other private
delivery service, but does not include
carriers who merely transport the drug.
This definition is not intended to
include persons operating merely as
customs brokers.
g. Manufacture, manufacturer. The
definitions of ‘‘manufacture’’ and
‘‘manufacturer’’ in § 207.1 of this final
rule include minor editorial revisions
for clarity and new references to animal
feed bearing or containing a new animal
drug.
(Comment 12) Some comments stated
that the definition of ‘‘manufacturer’’
should specify that it applies only to
entities manufacturing drugs for
commercial distribution.
(Response) We disagree with the
recommendation that the definition of
‘‘manufacturer’’ be limited to drugs
manufactured ‘‘for commercial
distribution.’’ The underlying statutory
provisions require registration of
establishments where drugs are
manufactured, without regard to
commercial distribution (section 510(c)
of the FD&C Act), but require listing of
drugs that are manufactured for
commercial distribution (section 510(j)
of the FD&C Act). Accordingly, under
§ 207.17 of this final rule, each domestic
establishment where a drug is
manufactured (or repacked, relabeled, or
salvaged) must be registered unless
exempt from registration under section
510(g) of the FD&C Act or under
§ 207.13, regardless of whether the drug
is commercially distributed. The drug
listing obligation, as described in
§ 207.41, applies to drugs that are
manufactured, repacked, relabeled, or
salvaged for commercial distribution.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
(See separate definition of ‘‘commercial
distribution.’’)
(Comment 13) One comment asked
that drug sponsors be included in the
definition of manufacturer. Other
comments suggested that FDA add
‘‘product formulator’’ to the definition
of ‘‘manufacturer’’ or provide
definitions for terms such as ‘‘drug
sponsor.’’ These comments pointed out
that the holder of an approved
application, such as an NDA, or the
formulator of a nonprescription
monograph product may use a contract
manufacturer to produce the product for
distribution under the name of the
application holder or the product
formulator. Some comments
recommended that the final rule treat
such application holders or product
formulators as manufacturers so they
would register their establishments and
list such products and that it exempt
contract manufacturers from the drug
listing requirement.
(Response) We decline to add the
application holder or ‘‘product
formulator’’ concepts to the definition of
‘‘manufacturer.’’ Under section 510(c) of
the FD&C Act, the obligation to register
drug establishments rests on owners or
operators of establishments engaged in
the manufacture (including repacking,
relabeling, and salvaging) of drugs, and
the listing obligation applies to ‘‘every
person who registers.’’ FDA recognizes
that this language could be read broadly
to encompass entities that develop or
formulate drug products without
performing manufacturing operations.
However, considering the objectives
behind drug registration and listing, we
are currently interested in the
registration of establishments where
manufacturing operations (including
repacking, relabeling, and salvaging)
take place and the listing of drugs
handled at those establishments.
We recognize, however, that an
application holder or a product
formulator using a contract
manufacturer to manufacture a drug
may wish to submit drug listing
information for that product directly to
FDA. Although the actual manufacturer
of the drug has the legal obligation to
list it, FDA would accept listing
information for the drug submitted by
its formulator or any other person acting
as an authorized agent for the
manufacturer. When we use the term
‘‘authorized agent’’ in this final rule, we
mean a person who is authorized to act
on behalf of another. The term
‘‘authorized agent’’ should not be
confused with the United States agent
referred to in § 207.69(b).
(Comment 14) Several comments
asked for clarification on how the terms
PO 00000
Frm 00012
Fmt 4701
Sfmt 4700
‘‘manufacture,’’ ‘‘repackage,’’ ‘‘relabel’’
and ‘‘private label distributor’’ would
apply to the medical gas industry and
pointed out that certain medical gas
operations, such as the transfilling of
gas from one container to another, have
long been treated as drug manufacturing
by FDA but, under the proposed rule,
would seem to qualify as ‘‘repacking.’’
These comments asked FDA to classify
medical gas refillers as ‘‘manufacturers’’
rather than ‘‘repackers’’ in the final rule.
(Response) FDA agrees that these
important points require clarification.
Nothing in this final rule is intended to
alter the definitions applicable to FDA’s
regulations governing current good
manufacturing practices for drug
products, parts 210 and 211. Therefore,
the definition of ‘‘manufacture,
processing, packing, or holding of a
drug product’’ currently appearing in
§ 210.3(b)(12) will continue to apply to
medical gases as that definition has
always applied.
For purposes of part 207, we will
interpret the definition of
‘‘manufacture’’ in § 207.1 as including
the initial manufacturing process that
produces or purifies a medical gas,
whether by air separation, chemical
reaction, or other process. Additionally,
the mixing of two or more medical gases
to produce a combination would also
qualify as ‘‘manufacture’’ under § 207.1.
The impact of this interpretation is that
a person who thus qualifies as a
manufacturer of a medical gas will be
required to submit the drug listing
information required under § 207.49 of
this final rule (‘‘What listing
information must a registrant submit for
a drug it manufactures?’’) in addition to
registering the establishment(s) at which
manufacturing is conducted.
All subsequent transfillings of a
medical gas from one container to
another (i.e., from tanker trucks into
standing tanks and from standing tanks
into smaller containers, etc.) would fall
within the definition of ‘‘repack or
repackage’’ in § 207.1 of this final rule.
The impact of this interpretation is that
a person who thus qualifies as a
repacker of a medical gas will be
required to submit the drug listing
information required under § 207.53 of
this final rule (‘‘What information must
a registrant submit for a drug that it
repacks or relabels?’’) in addition to
registering the establishment(s) at which
repackaging is conducted. Comments
opposing this classification expressed
concern that under the proposed rule,
repackers would be required to identify
the NDC assigned to a drug immediately
before it is received by the repacker as
information that must be submitted to
obtain an NDC for a repackaged drug
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
under proposed § 207.33(d)(1)(ii). See
our response to Comment 73 regarding
an exemption for medical gases from the
requirement that registrants submit such
source NDCs for drugs they repackage or
relabel.
The definition of ‘‘relabel’’ in § 207.1
of this final rule applies to medical
gases. It refers to changing or altering
the existing label on a drug or drug
package, without repacking the drug or
drug package. A person who places a
label on a repackaged drug (e.g., a
medical gas recently filled into a
canister) for the first time qualifies as a
‘‘repackager’’ as that term is defined in
this final rule.
The term ‘‘private label distributor’’ is
defined in § 207.1 of this final rule to
mean, with respect to a particular drug,
a person who did not manufacture,
repack, relabel, or salvage the drug but
under whose label or trade name the
drug is commercially distributed. This
definition applies equally to private
label distributors of medical gases and
other drugs. A medical gas transfiller is
a repackager, and not a private label
distributor, under this final rule. As
discussed in our response to comment
16, private label distributors do not—by
reason of their status as private label
distributors—have an obligation to
register establishments or list drugs.
They must have labeler codes, obtained
under new § 207.33(c), and they may
submit drug listing information or
establishment registration information if
acting as the authorized agent of a
registrant on whose behalf the
information is submitted.
h. Material change. In the proposed
rule, ‘‘material change’’ was defined as
any change in any drug listing
information, excluding labeling changes
in arrangement or printing or labeling
changes of an editorial nature. This
definition is retained in the final rule
with minor revisions to clarify that
material change also does not include
changes in the format of labeling, or the
inclusion of a bar code or the initial
inclusion of an NDC on a label.
(Comment 15) One comment asked
FDA to clarify the types of labeling
changes that would qualify as a material
change and, hence, require reporting as
an update to drug listing information
under § 207.57. This comment
specifically suggested examples of
labeling changes that would qualify as
significant changes in the labeling of a
prescription drug product or significant
changes in the label or package insert of
an OTC drug product.
(Response) In referring to
‘‘significant’’ labeling changes, this
comment seems to relate to the
longstanding definition of ‘‘material
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
change’’ in § 207.3(a)(3), prior to this
final rule, which encompassed labeling
changes described as ‘‘significant.’’
Today’s final rule revises that definition
so that material change includes any
labeling change other than changes in
the format of labeling, changes of an
editorial nature, inclusion of a bar code,
or initial inclusion of an NDC. In this
context, changes of an editorial nature
would not include any changes that add
or revise meaning.
Thus, the new definition of ‘‘material
change’’ adopted as part of this final
rule is broader than the previous
definition and is not limited to
‘‘significant’’ changes. The definition
includes—with very few exceptions—
any change in previously reported drug
listing information. FDA intends to rely
primarily on new § 207.57 to maintain
an up-to-date database of current drug
labeling. Registrants should submit
current labeling (and a resubmission of
all listing information) each time they
submit a drug listing update to report
changed information under § 207.57.
i. Private label distributor. We
proposed to define ‘‘private label
distributor’’ to mean a person who owns
or operates an establishment that
commercially distributes, under its own
label or trade name, any drug
manufactured, repacked, relabeled, or
salvaged by a registered establishment.
In the preamble to the proposed rule we
explained that the private label
distributor does not engage in any
activities performed by a manufacturer,
repacker, relabeler, or salvager for the
drug it distributes (71 FR 51276 at
51290).
In the final rule, private label
distributor is defined to mean, with
respect to a particular drug, a person
who did not manufacture, repack,
relabel, or salvage the drug but under
whose label or trade name the drug is
commercially distributed. We have also
defined ‘‘private label distribution’’ in
this final rule to mean commercial
distribution of a drug under the label or
trade name of a person who did not
manufacture, repack, relabel, or salvage
that drug.
(Comment 16) Some comments
requested clarification regarding the
distinction between private label
distributors, manufacturers, and
wholesale distributors. Others urged
FDA to allow private label distributors
to list the drugs they distribute. One
comment requested clarification
regarding the responsibilities of private
label distributors under part 207.
(Response) We agree that more clarity
is needed regarding these terms and the
registration and listing obligations
associated with private label
PO 00000
Frm 00013
Fmt 4701
Sfmt 4700
60181
distribution of drug products. We have
eliminated the mention of establishment
ownership in the proposed rule’s
definition of ‘‘private label distributor’’
because private label distributors do not
necessarily own establishments that
require registration under section 510 of
the FD&C Act. We have also clarified
that an entity may act as a private label
distributor with respect to a particular
drug. For example, if a drug
manufacturer distributes, under its own
name or trade name, a drug
manufactured entirely by a contract
manufacturer, it is acting as a private
label distributor with respect to that
drug. The difference between private
label distributors and wholesale
distributors or others involved in drug
distribution is that a private label
distributor’s name, trade name, or label
appears on the product. A common
example of private label distribution is
the sale of aspirin under a retail
pharmacy’s brand name when the retail
pharmacy did not manufacture the
product. As defined in this final rule,
private label distribution encompasses
the use of any brand name or business
name on a drug product where the
named business or the owner of the
brand name did not manufacture the
drug. Thus, as we are defining the term
in part 207, a private label distributor
may, but does not necessarily, operate
retail stores or play a role in the
physical distribution of the drug
product. Even without using a brand
name, if an entity is identified as the
distributor or marketer of a drug under
§ 201.1 of the drug labeling regulations,
without having manufactured the drug,
that person will qualify as a private
label distributor as the term is defined
in this final rule.
Under this final rule, private label
distributors do not have registration or
listing obligations with respect to drugs
for which they merely act as private
label distributors. Only manufacturers,
repackers, relabelers, and salvagers have
an obligation to register and list. Private
label distributors are subject to this final
rule only in that they must apply for an
NDC labeler code as described in
§ 207.33(c) and update the information
submitted under that section when the
information changes. Private label
distributors are in the best position to
obtain their own labeler codes and
update information associated with
those codes, thereby preventing
potential submissions of inconsistent or
inaccurate information by multiple
contract manufacturers.
A person who is a private label
distributor with respect to a particular
drug does not for that reason incur an
establishment registration or listing
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60182
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
obligation. The FD&C Act and the
regulations in part 207 both place the
registration and listing obligation on
persons who manufacture, repack,
relabel, or salvage drugs. The
registration and listing obligation thus
rests with the actual manufacturer,
repacker, relabeler, or salvager whether
or not a product is intended for private
label distribution. For this reason, the
final rule does not include provisions
regarding establishment registrations or
drug listings submitted by private label
distributors.
We recognize, however, that some
private label distributors are in a
position to supply listing information,
including NDCs, for drugs distributed
under their names and may prefer to do
so. FDA will accept registration and
listing information submitted by any
authorized agent acting on behalf of a
manufacturer, repacker, relabeler, or
salvager, and this includes a private
label distributor authorized by a
manufacturer, repacker, relabeler, or
salvager, to submit drug listing
information on its behalf. In these cases,
the manufacturer, repacker, relabeler, or
salvager remains responsible for
compliance with all registration and
listing requirements and the accuracy of
the information submitted by its agent.
A person who acts merely as a
wholesale distributor of a drug product
(i.e, a person who did not manufacture,
repack, relabel, or salvage the drug
product and whose name, trade name,
or label does not appear on the drug
product) does not incur obligations
under this rule.
j. Relabel, relabeler, repack, repacker.
We proposed to define ‘‘relabel’’ to
mean changing the label or labels on a
drug or drug package, or adding to the
labeling for a drug or drug package,
without repacking the drug or drug
package. We also proposed to define
‘‘relabeler’’ to mean a person who owns
or operates an establishment that
relabels a drug.
We proposed to define ‘‘repack’’ to
mean repack or repackage or otherwise
change the container or wrapper of a
drug or drug package. Similarly, we
proposed to define ‘‘repacker’’ to mean
a person who owns or operates an
establishment that repacks a drug or
drug package.
In the final rule, these definitions are
clarified and revised in response to
comments.
(Comment 17) Some comments noted
that the definition of relabel could
include wholesale drug distributors who
add information to outer container
labels for purposes of delivery to a
customer, customer identification,
inventory management, special
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
handling instructions, or to aid in
compliance with Federal and State
pedigree requirements. Commenters
urged us not to require establishments
(e.g., distribution facilities) where such
relabeling occurs to register and list.
(Response) We agree generally with
these comments and have revised the
definition of ‘‘relabel’’ in the final rule
to exclude the addition or modification
of information affixed solely for
purposes of delivery to a customer,
customer identification, or inventory
management. However, we did not
exclude the addition of special handling
instructions from the definition of
‘‘relabel,’’ as recommended in these
comments. Such an exclusion might be
misinterpreted as accommodating
revised storage instructions in drug
labeling. However, FDA would not
object to the addition of storage
information to an outer label if such
information is not inconsistent in any
way with storage instructions appearing
elsewhere in the drug’s labeling. In that
case, FDA would not regard the addition
of such storage information to an outer
container label as relabeling that would
subject a person to registration and
listing.
k. Representative sampling of
advertisements and Representative
sampling of any other labeling. The
definitions of these terms included in
the proposed rule appear in this final
rule with one minor revision.
(Comment 18) The preamble to the
proposed rule included a brief
discussion of these definitions. That
discussion pointed out a confusing
aspect of the previous definitions of
these terms and the previous definition
of the term ‘‘advertising and labeling’’ in
part 207. See 71 FR 51276 at 51291. One
comment argued that there was no
conflict in these definitions and urged
FDA to retain our previous definitions
of ‘‘representative sampling of
advertisements’’ and ‘‘representative
sampling of any other labeling.’’ This
comment pointed out that the examples
given in those previous definitions were
helpful.
(Response) We disagree with this
comment. The revised definitions are
intended to eliminate some confusion
associated with the previous definitions
as explained in the preamble to the
proposed rule. The examples appearing
in the previous definitions read as
follows: ‘‘If more than one medical
journal advertisement is used but the
promotional content is essentially
identical, only one need be submitted’’
and ‘‘if more than one brochure is used
but the promotional content is
essentially identical, only one need be
submitted.’’ The quoted language served
PO 00000
Frm 00014
Fmt 4701
Sfmt 4700
as common sense guidance regarding
the application of the definitions
without being a central part of the
definitions. Although omitting that
language from the definitions included
in the proposed rule and this final rule,
FDA is not disavowing the examples or
suggesting that registrants should take a
different approach.
2. Who does this part cover? (§ 207.9)
The Agency proposed new § 207.9 to
clarify the types of businesses that are
subject to drug establishment
registration and listing under part 207.
Section 207.9 is retained in this final
rule with certain revisions and
clarifications.
Section 207.9(a)(3) of this final rule
clarifies that private label distributors
are subject to part 207. As discussed
previously in this document, private
label distributors do not have an
obligation to register an establishment
or list any drugs arising from their
activities as private label distributors.
They are, however, expected to obtain
NDC labeler codes under § 207.33(c) of
this final rule and update the
information reported to FDA under
§ 207.33(c) as required by § 207.33(c)(2).
Section 207.9(a)(4) of this final rule is
revised to state more clearly its
applicability to establishments engaged
in the manufacture, repacking,
relabeling, or salvaging of drugs
regulated under a BLA. These
establishments are subject to part 207
unless they are required to register and
list under part 607 (ESTABLISHMENT
REGISTRATION AND PRODUCT
LISTING FOR MANUFACTURERS OF
HUMAN BLOOD AND BLOOD
PRODUCTS).
Section 207.9(a)(5) of this final rule is
revised to state that HCT/Ps, as defined
in § 1271.3(d), are subject to registration
and listing under part 207 if they are
drugs regulated under section 505 of the
FD&C Act or under section 351 of the
PHS Act. A conforming amendment is
made to § 1271.1. Manufacturers of
HCT/Ps that are regulated under section
361 of the PHS Act (42 U.S.C. 264) and
not under section 351 will remain
subject to registration and listing under
part 1271.
(Comment 19) Comments requested
clarification on the applicability of this
rule to contract manufacturers and
private label distributors of drug
products, saying it was not clear in the
proposed rule how contract
manufacturers are to handle
establishment registration and labeler
code assignment.
(Response) Manufacturers of drug
products are obligated by the FD&C Act
and by this final rule—whether or not
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
they are contract manufacturers—to
register their establishments and list the
drugs they manufacture for commercial
distribution (as the term ‘‘commercial
distribution’’ is defined in new § 207.1).
Sections 207.49 and 207.53 of this final
rule require manufacturers, repackers,
and relabelers to provide their own NDC
(an NDC that includes the registrant’s
own labeler code) for each drug they
list. (Salvagers are not required to
provide new NDCs when listing drugs
they salvage because a drug’s NDC does
not change when it is merely salvaged,
and not repacked or relabeled. A person
who salvages and then repacks or
relabels a drug is a repacker or relabeler,
as those terms are defined in § 207.1,
and must register and list as a repacker
or relabeler.) This provision requires
manufacturers, repackers, and relabelers
responsible for listing drugs, including
contract manufacturers, to obtain an
NDC labeler code in accordance with
new § 207.33(c).
When listing a human drug
manufactured for private label
distribution (distribution under the
name or trade name of someone other
than the drug’s manufacturer, as defined
in new § 207.1), §§ 207.49 and 207.53
require registrants to provide two NDCs,
one that includes the registrant’s own
NDC labeler code and one that includes
the NDC labeler code of the private label
distributor. As stated in response to
comment 16, FDA will accept drug
listing information submitted by a
private label distributor (or anyone else)
if properly authorized to act as an agent
for the actual manufacturer. The use of
an agent to handle establishment
registration or drug listing submissions
does not, however, transfer legal
responsibility for complying with this
final rule from a manufacturer, repacker,
relabeler, or salvager to its agent.
Animal drugs manufactured for private
label distribution should be listed under
a single NDC that includes the labeler
code of the private label distributor.
Note that the term ‘‘private label
distributor’’ is defined in new § 207.1 to
mean, with respect to a particular drug,
a person who did not manufacture,
repack, relabel, or salvage the drug but
under whose label or trade name the
drug is commercially distributed. FDA’s
statements in this document that private
label distributors are not obligated to
register their establishments or list the
drugs they distribute are premised on
this definition. If someone who would
otherwise qualify as a private label
distributor carries out testing or control
procedures applied to the final product,
e.g., systematic batch release testing
required under current good
manufacturing practices, that person
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
may qualify as a manufacturer (see the
definition of ‘‘manufacture’’ in new
§ 207.1) and need to register its
establishment where the testing or
control procedures are carried out. (But
if a private label distributor uses a
contract laboratory to carry out the
testing or control procedures, the
contract laboratory, not the private label
distributor, may qualify as a
manufacturer and need to register its
establishment.) Likewise, if someone
qualifies as a private label distributor
with respect to one or more drugs, but
also qualifies as a manufacturer,
repacker, or relabeler with respect to
other drugs, that person would need to
register the establishment where
manufacturing, repacking, or relabeling
is conducted and list the drugs that are
manufactured, repacked, or relabeled for
commercial distribution at the
registered establishment.
Entities that qualify as private label
distributors under this final rule and do
not also manufacture, repack, relabel, or
salvage any drugs may already have
effective establishment registrations and
drug listings submitted in the past. We
do not expect these entities to renew
their registrations after the effective date
of this final rule. They may either cancel
their registrations or allow their
registrations to lapse by not making any
further submissions. Any drug listings
submitted in the past by entities that
qualify as private label distributors
under this final rule for drugs they do
not manufacture, repack, relabel, or
salvage should be transferred to the
actual manufacturers, repackers,
relabelers, or salvagers of the listed
drugs.
(Comment 20) One comment asked
FDA to clarify whether radiologic
products are subject to this rule.
(Response) This comment did not
elaborate on the types of products
encompassed by the question so we are
unable to respond specifically. There is
not an exemption from the
establishment registration and drug
listing requirements for manufacturers
of radioactive drugs, also known as
radiopharmaceutical products. Anyone
with questions about the applicability of
part 207, either before or after this final
rule, to radioactive drug products
should contact the electronic Drug
Registration and Listing System staff in
the Office of Compliance at FDA’s
Center for Drug Evaluation and Research
(CDER). For diagnostic device products
that include a radioactive drug
constituent part, see our response to
comment 22 in this document regarding
drug/device combination products. Also
see part 807 regarding establishment
registration and listing for radiologic
PO 00000
Frm 00015
Fmt 4701
Sfmt 4700
60183
device products. Positron emission
tomography (PET) drugs are subject to
part 207, as stated in § 207.13(l)(1) and
as discussed in the proposed rule (71 FR
51276 at 51285).
(Comment 21) One comment
requested guidance regarding the
information needed for ‘‘active drug
substance manufacturers’’ to register
and list.
(Response) In this final rule, the term
‘‘active pharmaceutical ingredient’’
(API) is defined in § 207.1. The
registration obligation applies to each
domestic establishment that
manufacturers, repacks, relabels, or
salvages a drug or an animal feed
bearing or containing a new animal drug
(whether or not that product is
commercially distributed). It also
applies to each foreign establishment
that manufacturers, repacks, relabels, or
salvages a drug or an animal feed
bearing or containing a new animal drug
that is imported or offered for import
into the United States. In each case, the
term ‘‘drug’’ includes: (1) An API by
itself, (2) an API that has been combined
with one or more other APIs or inactive
ingredients (see definition of
‘‘unfinished drug’’ in § 207.1), and (3)
finished drug products (see definition of
‘‘finished drug product’’ in § 207.1).
The information that must be
submitted for establishment registration
is set forth in new § 207.25. These
information elements do not differ
depending on whether the registrant
handles APIs, other unfinished drugs, or
finished drugs.
The information that must be
submitted with a drug listing is set forth
in new § 207.49 for a drug the registrant
manufactures, § 207.53 for a drug the
registrant repacks or relabels, and in
§ 207.54 for a drug the registrant
salvages. As specified in § 207.41, the
drug listing obligation applies only to
drugs that are manufactured, repacked,
relabeled, or salvaged for commercial
distribution. Sections 207.49, 207.53,
and 207.54 indicate some minor
differences in the information that must
be submitted depending on whether the
drug is finished or unfinished. For
example, § 207.49(a)(15)(iv) describes
the labeling that must be submitted for
an unfinished drug.
(Comment 22) One comment asked, in
the context of the proposed rule’s
requirement that NDCs appear on drug
labels, how the rule would apply to
drug/device combination products.
Other comments asked how registration
and listing should be handled for drug/
device combination product kits. (See
the definition of ‘‘combination product’’
in § 3.2(e) (21 CFR 3.2(e)), unaffected by
this rulemaking.)
E:\FR\FM\31AUR2.SGM
31AUR2
60184
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
mstockstill on DSK3G9T082PROD with RULES2
(Response) We acknowledge that the
proposed rule did not include an
explanation of its applicability to drug/
device combination products, including
how manufacturers of such products
should register their establishments, list
their combination products, and provide
related information on the labels of their
combination products. The codified of
this final rule likewise does not contain
specific provisions regarding drug/
device combination products. FDA
expects to further address drug/device
combination product registration and
listing in the future. As stated
previously in this document, we also are
not finalizing the proposed amendment
to § 201.2 that would have required
human-readable NDCs on the labels of
all drugs subject to the listing
requirement.
3. Who is exempt from registration and
listing requirements? (§ 207.13)
The proposed rule included a new
§ 207.13 aimed at clarifying the types of
businesses that are exempt from drug
establishment registration and listing
under part 207. Section 207.13 is
retained in this final rule with certain
revisions and clarifications. Some
exemptions described in § 207.13 are
derived directly from section 510(g) of
the FD&C Act. Other exemptions are
established under section 510(g)(5) of
the FD&C Act supported by our finding
that registration by such classes of
persons is not necessary for the
protection of the public health.
(Comment 23) Several comments
argued against the elimination of two
existing exemptions from registration
and listing that the proposed rule would
have revoked. These two exemptions
encompass: (1) Drugs imported under
section 801(d)(3) of the FD&C Act (often
referred to as ‘‘import for export’’) and
(2) drugs that enter a foreign trade zone
and are re-exported from that foreign
trade zone without having entered U.S.
commerce.
(Response) Previous § 207.40(b) stated
that no drug may be imported or offered
for import into the United States unless
the drug is listed and manufactured,
prepared, propagated, compounded, or
processed at a registered foreign
establishment. The section also stated
that this prohibition did not apply to,
among other things, components of
drugs imported under section 801(d)(3)
of the FD&C Act. Section 801(d)(3)
allows persons to import certain
articles, including components of drugs,
if specified conditions are met, provided
that the imported articles are further
processed or incorporated into products
and exported or, if not used, the
imported articles are destroyed or
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
exported. Thus, previous § 207.40(b)
exempted certain foreign establishments
from the establishment registration and
listing requirement.
Previous § 207.40(a) stated that a
foreign establishment was not required
to comply with the registration and
listing requirements if its drug entered
a foreign trade zone and was re-exported
from that foreign trade zone without
having entered U.S. commerce.
Upon careful consideration of the
comments received, we have decided to
retain both exemptions in this final rule.
Therefore, under § 207.13(j) of this final
rule, if all the conditions of section
801(d)(3) of the FD&C Act are satisfied,
a component of a drug will not be
excluded from importation into the
United States by reason that it is
unlisted or was manufactured at an
unregistered foreign establishment.
Additionally, under § 207.13(j) of this
final rule, a foreign establishment does
not incur a registration and listing
obligation if its drug enters a foreign
trade zone and is re-exported from that
foreign trade zone without having
entered U.S. commerce. These
exemptions pertain only to drugs that
are re-exported or components of drugs
that are processed or incorporated into
products and then exported, and these
exemptions pertain only to foreign
establishments. If an establishment
located within a foreign trade zone
manufactures, repacks, relabels, or
salvages a drug for commercial
distribution in the United States, that
establishment would need to register
and list those drugs it handles for U.S.
commercial distribution. Additionally,
if a foreign establishment exports drugs
to the United States relying on either of
these exemptions, but also exports other
drugs for commercial distribution in the
United States, it must comply with the
registration and listing requirements for
those drugs that are commercially
distributed in the United States.
The corresponding exemptions for
blood product establishments are also
retained in § 607.40 under this final
rule.
(Comment 24) One comment asked
FDA to confirm that animal biological
products are not subject to this rule.
(Response) Some biological drugs
intended for administration to animals
are regulated by the U.S. Department of
Agriculture (USDA) under the Virus,
Serum, and Toxins Act of 1913. Section
510.4 (21 CFR 510.4) states that animal
drugs produced and distributed in full
conformance with the Virus, Serum, and
Toxins Act and any regulations issued
thereunder shall not be deemed to be
subject to section 512 of the FD&C Act
(includes premarket approval and other
PO 00000
Frm 00016
Fmt 4701
Sfmt 4700
requirements for new animal drugs
regulated by FDA). As proposed in
§ 207.13(g), the final rule includes an
exemption applicable to these products
in § 207.13(h).
(Comment 25) Comments from the
medical gas industry expressed concern
about the ability of entities such as
pharmacies, hospitals, clinics, and
emergency responders to refill medical
gas cylinders if the repackaging would
require the repacker’s NDC to appear on
the label of the repackaged product. The
comment stated that if these entities are
exempt from part 207, they cannot
obtain an NDC.
(Response) Our decision not to
include the proposed amendments to
§ 201.2 that would have required
human-readable NDCs on drug labels
renders the concern expressed in this
comment moot. We would like to
confirm that pharmacies, hospitals,
clinics, other health care entities, and
public health agencies that qualify as
exempt from the registration and listing
requirements under § 207.13 of this final
rule do not lose their exemptions by
dispensing medical gases or filling
medical gas containers in the normal
course of their activities.
C. Registration (Part 207, Subpart B)
1. Who must register? (§ 207.17)
Section 207.17 describes who is
required to register an establishment
under part 207. This section is reworded
in the final rule: (1) To distinguish
between domestic and foreign
manufacturers, repackers, relabelers,
and salvagers and (2) to clarify that FDA
will accept registration information
submitted by a private label distributor
only if it is acting as an authorized agent
for and submitting information
pertaining to an entity that has an
establishment registration obligation.
(Comment 26) One comment asked
FDA to clarify whether a storage facility
that does not repack or relabel drugs is
required to register under part 207.
(Response) A facility at which drugs
are stored, such as a warehouse, does
not need to be registered provided drugs
are not manufactured, repacked,
relabeled, or salvaged (as those terms
are defined in § 207.1) at the facility.
Note that the definition of
‘‘manufacture’’ includes sampling,
testing, or control procedures applied to
the final product or to any part of the
process. Thus, for example, if a
warehouse includes a temperaturecontrolled storage area where drug
samples are stored for stability testing to
satisfy current good manufacturing
practice requirements, that activity
would qualify as a manufacturing
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
operation and require registration of the
warehouse as a drug establishment.
Other State or Federal requirements may
apply to such facilities.
As explained in response to Comment
17, we have revised the definitions of
‘‘relabel’’ and ‘‘relabeler’’ so they do not
include the addition or modification of
information affixed to drug packaging
solely for purposes of delivery to a
customer, customer identification, or
inventory management. Therefore, the
addition or modification of such
information at a warehouse does not
trigger the need to register it as an
establishment.
mstockstill on DSK3G9T082PROD with RULES2
2. When must initial registration
information be provided? (§ 207.21)
Proposed § 207.21 described when
initial registration information must be
submitted for an establishment newly
required to register under part 207. The
provision is retained in this final rule
and reorganized into paragraphs (a) and
(b) for improved clarity.
(Comment 27) One comment
suggested that the words ‘‘for
commercial distribution’’ be added to
§ 207.21, suggesting that establishment
registration is required only for
establishments at which drugs intended
for commercial distribution are
manufactured, repacked, relabeled, or
salvaged.
(Response) The absence of these
words—‘‘for commercial distribution’’—
from § 207.21 is intentional and
comports with section 510 of the FD&C
Act. Any establishment at which drugs
are manufactured, repacked, relabeled,
or salvaged must be registered under
part 207, unless exempt from
registration under section 510(g) of the
FD&C Act or under the relevant
regulations (§§ 207.13, 607.65, or
1271.15, as applicable) whether or not
the drugs are commercially distributed.
Accordingly, an establishment at which
an investigational drug is manufactured
is subject to the establishment
registration requirement. The listing
obligation, on the other hand, applies to
drugs that are for commercial
distribution.
3. What information is required for
registration? (§ 207.25)
Proposed § 207.25 described the
information that must be submitted to
register an establishment. The provision
is retained in the final rule with minor
substantive and editorial revisions.
Substantively, new § 207.25 no longer
requires the submission of fax numbers
to register establishments and now
includes the new statutory requirement
that registrants provide a UFI for each
establishment. (See our discussion of
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
establishment registration numbers and
UFIs in section II.B, Changes to the
Proposed Rule.) New § 207.25 also
clarifies that the physical address of
each establishment is required (rather
than a post office box, for example), and
a mailing address is required for the
establishment’s official contact.
(Comment 28) One comment asked
FDA to clarify what format should be
used when a foreign establishment
submits contact information for each
importer. This comment also asked FDA
to explain who should submit
establishment registration information
when a business has both foreign and
U.S. establishments.
(Response) According to new
§ 207.61, all information transmitted to
FDA under part 207, including
establishment registration information,
must be transmitted to FDA in
electronic format unless a waiver is
granted. FDA’s systems for electronic
registration include fields for
information elements such as the
required contact information for U.S.
importers of drugs manufactured,
repacked, relabeled, or salvaged at a
foreign establishment.
Section 207.17 addresses this
comment’s second question, who
should submit establishment
registration information when a
business has both foreign and U.S.
establishments? This section states that
when operations are conducted at more
than one establishment, and common
ownership and control among all the
establishments exists, the parent,
subsidiary, or affiliate company may
submit registration information for all
establishments. This applies whether
the establishments are domestic,
foreign, or both.
(Comment 29) One comment asked
FDA to exempt contract manufacturers
from the requirement that
establishments identify each importer in
the United States of drugs they
manufacture, repack, relabel, or salvage
that is known to the establishment as
well as each person who imports or
offers for import such drugs to the
United States. This comment stated that
contract manufactures may not have this
information.
(Response) This requirement is
retained in the final rule, in § 207.25(h).
The provision implements a statutory
requirement (section 510(i)(1) of the
FD&C Act). This requirement pertains
only to foreign establishments, and it
requires them to identify ‘‘importers’’
known to the establishment and
‘‘persons who import or offer for
import,’’ as these terms are defined in
§ 207.1. Both of these definitions have
been refined and narrowed in this final
PO 00000
Frm 00017
Fmt 4701
Sfmt 4700
60185
rule. A foreign contract manufacturer
exporting drugs to the United States
should be able to identify such persons.
4. What are the requirements for
reviewing and updating registration
information? (§ 207.29)
Section 207.29 describes the
requirements for: (1) Expedited
updating of certain changes to
establishment registration information
and (2) annual reviewing and updating
of establishment registration. This
section is retained in the final rule with
very minor revisions. Fax numbers are
no longer mentioned in § 207.29(a)
because they are no longer required for
establishment registration. Additionally,
the dates during which the annual
review and update of registration
information must take place have been
adjusted to match section 510(b)(2) of
the FD&C Act, added by FDAAA.
(Comment 30) Some comments
opposed the requirement that if no
changes have occurred since the last
registration, registrants certify that no
changes have occurred.
(Response) The annual review and
updating of establishment registration
information is critical to the integrity of
FDA’s database. The requirement that
registrants certify that no changes have
occurred when that is true provides
important assurance that registrants
have reviewed the establishment
registration information they previously
submitted. Otherwise, FDA would need
to interpret silence from a registrant as
indicating either that the information
remains up to date or that the registrant
may have neglected to review and
update the information. We further note
that section 510(b)(1) of the FD&C Act
now requires annual registration of
establishments between October 1 and
December 31, and the option to certify
that no changes have occurred since the
last registration is a minimally
burdensome implementation of this
statutory requirement.
Please see our response to Comment
74, which addresses this issue in the
context of drug listing updates.
D. National Drug Code (Part 207,
Subpart C)
1. What is the national drug code (NDC),
how is it assigned, and what are its
requirements? (§ 207.33)
The NDC provisions in this final rule
have been revised in response to
comments received on the proposed
rule. Most significantly, new § 207.33:
• Allows for 11 digits in the NDC
(when 10-digit combinations are
exhausted).
• Reflects that registrants will
propose their own NDCs for drugs they
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60186
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
list. Under the proposed rule, FDA
would have assigned NDCs in response
to submissions from registrants. Under
this final rule, each registrant must
propose its own NDC for each drug the
registrant lists. FDA will assign the
proposed NDCs to the listed drugs
unless they are improperly formatted,
previously assigned to a listed drug, or
reserved.
• Includes new NDC formatting
requirements for registrants to observe
when proposing NDCs.
• Transfers some information that
would have been required under
proposed § 207.33(c) (What information
must a manufacturer submit before we
will assign an NDC number to a drug?)
to information that must be included in
a drug listing submission.
• Allows certain drug products to be
assigned alternatively formatted NDCs if
approved by the Center Director. This
applies to the HCT/Ps specified in new
§ 207.33(b)(4) if they are minimally
manipulated.
• Includes a new § 207.33(c) that
explains who must obtain an NDC
labeler code and how labeler codes are
assigned and updated.
• Includes new provisions in
§ 207.33(d) that explain how a proposed
NDC can be voluntarily reserved.
Comments on the NDC provisions of
the proposed rule and FDA’s responses
are summarized in this document. This
does not include some comments that
have been made moot by the revisions
summarized previously.
(Comment 31) FDA received many
comments opposing the proposed rule’s
requirement that FDA, rather than
registrants, generate and assign the
complete NDC for drugs that are subject
to listing. Some comments were
concerned about possible delays
associated with NDC request
submissions. Others were concerned
about losing control over numbering
conventions that individual registrants
may apply to their own product codes
and package codes. One comment
expressed concern that subjecting OTC
monograph products to an NDC
assignment process could begin to
resemble an FDA approval process for
such products.
(Response) The objective behind
FDA’s proposal to generate and assign
NDCs was to assure they are assigned
appropriately. Although we did not
intend FDA’s issuance of NDCs to be
time consuming or to operate as an
approval process, we recognize that
FDA’s objectives can be met in a way
that is more flexible and less
burdensome for registrants.
Accordingly, the proposed requirement
that FDA generate the complete NDC for
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
each listed drug is not included in this
final rule.
Under new § 207.33(d), registrants,
not FDA, will generate NDCs for
assignment to their listed drugs. An
NDC is considered to be ‘‘proposed for
assignment’’ when a registrant submits
it for the first time with drug listing
information in accordance with § 207.49
or § 207.53. If the proposed NDC
conforms to the formatting requirements
of § 207.33, is not reserved for a
different drug, and was not previously
assigned to a different listed drug, FDA
will assign the proposed NDC when it
receives all required listing information
for the drug.
(Comment 32) Some comments asked
how far in advance of marketing a drug
for the first time an NDC may be
requested. Comments also pointed out
that manufacturers need to know the
NDC for a drug in development prior to
the time of drug listing.
(Response) As explained in response
to Comment 31, this final rule requires
registrants to propose their own NDCs
for drugs they list. FDA will assign a
proposed NDC to the drug identified by
the registrant if the proposed NDC
conforms to the formatting requirements
of § 207.33, is not reserved for a
different drug, and was not previously
assigned to a different listed drug.
We recognize that a mechanism for
reserving a specific NDC may be
helpful, as this would provide greater
certainty that a proposed NDC will be
accepted by FDA when it is included
with a listing submission at the time of
marketing. Accordingly, this final rule
includes a new § 207.33(d)(3) that
allows a person to voluntarily reserve a
proposed NDC for a period of 2 years
prior to its inclusion in a drug listing
submission for the first time. Note that
an NDC reserved under § 207.33(d)(3)
would need to include most importantly
a labeler code and a product code. At
the discretion of the person submitting
the reservation request, a single package
code could be included, or not, with one
or more package codes included later in
NDC(s) submitted with complete drug
listing information.
Certain minimal information must be
submitted to reserve a proposed NDC, as
specified in new § 207.33(d)(3). This
information does not include
identification of the drug’s inactive
ingredients. Many comments opposed
the inclusion of such detailed
information in the proposed rule’s
provision governing NDC requests.
NDCs reserved under § 207.33(d)(3)
would be reserved for 2 years unless the
person whose labeler code is included
in the NDC asks FDA to cancel the
reservation earlier. If a reserved NDC is
PO 00000
Frm 00018
Fmt 4701
Sfmt 4700
not used during the 2-year reservation
period (i.e., is not submitted to FDA
with complete listing information for
the drug matching the reservation), the
NDC will be available for assignment to
another drug. Anyone wishing to extend
an NDC reservation beyond 2 years may
submit another reservation request.
In addition to the procedure
established under § 207.33(d)(3), a
registrant wishing to reserve an NDC
also has the option of submitting
complete listing information for a drug
that is under development and
specifying a future ‘‘start marketing
date’’ in the listing submission. That
listing submission could then be
updated, as needed, when the actual
marketing date arrives.
(Comment 33) One comment
questioned how, when listing a drug for
the first time, a registrant can supply a
drug’s labeling if the labeling must
include the drug’s NDC, and if the NDC
is not assigned until the drug is listed.
(Response) As explained in response
to Comment 1, unlike the proposed rule,
this final rule does not require NDCs to
appear in human-readable form on drug
labels (but an intervening statutory
amendment, the DSCSA, does require
NDCs to appear as part of the product
identifier on certain drug labels). After
the effective date of this final rule, our
regulations will continue to encourage,
but not require, the appearance of
human-readable NDCs on drug labels
(§ 201.2) and continue to require that
NDCs appear in bar codes on drug labels
(§ 201.25(c)).
Under this final rule, unlike the
proposed rule, registrants are able to
develop and propose their own NDCs to
FDA. Upon receipt of a first-time listing
submission, FDA will assign the NDC
proposed by the registrant to the drug
being listed unless the NDC is
improperly formatted, reserved for a
different drug, or was previously
assigned to a different listed drug.
Registrants are also able to reserve an
NDC for a drug under development
under § 207.33(d)(3) of this final rule.
Accordingly, registrants should not have
difficulty determining, with adequate
certainty, the NDC for a drug under
development.
(Comment 34) Some comments
supported the proposed rule’s
revocation of then-current
§ 207.35(b)(4)(ii), which stated that the
product code of a discontinued product
could be reassigned to another product
5 years after the expiration date of the
discontinued product or, if there is no
expiration date, 5 years after the last
shipment of the discontinued product.
Commenters generally agreed that the
reuse of old NDCs for a different
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
product in the future can be confusing.
One comment, however, urged FDA to
allow for the reuse of NDCs.
(Response) FDA is retaining this
general prohibition against the reuse of
NDCs in the final rule. As indicated in
new § 207.33(d)(2), an NDC will not be
assigned to a drug if it was previously
assigned to a different drug. The
prohibition against reuse of NDCs
applies to listings submitted on or after
the effective date of this final rule.
Drugs that are currently listed under
NDCs that have been reused in
accordance with previous
§ 207.35(b)(4)(ii) may continue to be
listed under such NDCs.
Conversely, if a registrant
reintroduces a drug it listed and
discontinued in the past, that registrant
must list the drug using the same NDC
under which it was listed in the past.
See § 207.37(b) of this final rule.
However, if the reintroduced drug
includes changes, compared to the
discontinued drug, that would warrant
a new NDC under new § 207.35, then it
should be listed under a new NDC.
As discussed in response to Comment
19, under new § 207.49, if a private label
distributor uses a contract manufacturer
to produce a human drug, the contract
manufacturer has an obligation to list
the drug under two NDCs, one that
includes the labeler code of the contract
manufacturer and one that includes the
labeler code of the private label
distributor. If the private label
distributor switches to a new contract
manufacturer in the future, that new
contract manufacturer would also have
an obligation to list the drug under two
NDCs, one that includes its own labeler
code and one that includes the labeler
code of the private label distributor. The
NDC that includes the new contract
manufacturer’s labeler code will
obviously differ from the NDC under
which the previous contract
manufacturer listed the drug (because
the labeler codes will differ). The NDC
that includes the private label
distributor’s labeler code may be the
same as that under which the previous
contract manufacturer listed the drug
provided: (1) There have been no
changes to the drug that warrant a new
NDC under § 207.35 and (2) the
previous contract manufacturer updates
its listing information to indicate it no
longer manufactures the drug (as it is
required to do under § 207.57 at the
time of its next June or December listing
update, or sooner at its discretion). If
those two conditions do not exist, FDA
would accept a listing from the new
contract manufacturer under a new NDC
that includes the private label
distributor’s labeler code.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
(Comment 35) We received several
comments concerning the format of the
NDC. Many comments expressed
concern about the impact of any
changes in the NDC format on various
systems that track and use NDCs. Some
comments urged FDA to retain the 10digit NDC format. Others encouraged
the adoption of a standard 11-digit NDC.
Some comments opposed the possible
introduction of alphanumeric NDCs,
preferring all numeric NDCs. Others
were concerned about the possible
coexistence of 10- and 11-digit NDCs.
(Response) FDA is sensitive to these
concerns. Section 207.33(b) of this final
rule specifies the format of an NDC
recognized by FDA. The final rule
necessarily includes more specifications
than did the proposed rule concerning
NDC formatting because under the final
rule, registrants, not FDA, develop their
own proposed NDCs, and they must all
meet certain formatting parameters. The
final rule states, for example, that the
NDC is 10 or 11 digits to preclude the
submission of longer NDCs.
Our regulations have long stated that
FDA will expand the labeler code from
five to six numeric characters when the
available five-character code
combinations are exhausted (previous
§ 207.35(b)(2)(i)). This occurrence is
mathematically inevitable and is
reflected in new § 207.33(b)(1), which
states that the NDC must consist of 10
or 11 digits. FDA will begin issuing 6digit labeler codes, leading to 11-digit
NDCs, only when the available 5-digit
labeler codes are exhausted. FDA will
not assign 11-digit NDCs until we begin
to issue 6-digit labeler codes.
FDA recognizes the desirability of a
single, standard format for NDCs, having
three segments of consistent lengths, as
we eventually transition to six-digit
labeler codes. We intend to initiate a
public discussion of future formatting
options in the near future. In the
meantime, the provisions included in
this final rule are intended to
accommodate the range of existing NDC
formats, leaving room for necessary
expansion to 11 digits.
This final rule refers to the NDC as a
numeric code, not an alphanumeric
code. This takes into account comments
that objected to the inclusion of alpha
characters in NDCs as disruptive of
current systems and practices.
(Comment 36) Some comments urged
FDA not to require NDCs for HCT/Ps,
citing the International Society of Blood
Transfusion (ISBT) number as a better
means of identifying these products.
(Response) In response to these
comments, § 207.33(b)(4) of this final
rule states that an alternatively
formatted NDC may be used for certain
PO 00000
Frm 00019
Fmt 4701
Sfmt 4700
60187
identified HCT/Ps if they are minimally
manipulated and if the alternatively
formatted NDC is approved by the
Center Director (CDER or CBER, as
appropriate). Such approval may be
indicated in Guidance for Industry
issued by one or both Centers or in this
preamble, for example. Accordingly,
FDA identifies ISBT–128 as a currently
approved alternatively formatted NDC
to identify HCT/Ps within the scope of
§ 207.33(b)(4). ISBT–128 is an
international standard for the
identification of medical products of
human origin. Please note that an
alternatively formatted NDC approved
under § 207.33(b)(4) qualifies as an
NDC. HCT/Ps that are not within the
scope of § 207.33(b)(4) require
traditionally formatted NDCs.
(Comment 37) One comment
encouraged FDA to allow a single NDC,
with a single package code, to be
assigned to an API, which may be
commercially distributed in various
quantities.
(Response) This comment refers to
APIs, but the question applies to any
bulk product supplied in variable
quantities. We would like to accept nonnumeric characters, such as one or more
asterisks, in the package code segment
of an NDC to indicate a bulk product
supplied in various quantities (as was
previously done in paper submissions).
However, the SPL format, currently
specified in the electronic registration
and listing guidance, does not
accommodate non-numeric characters.
Manufacturers in this situation may
adopt a variety of practices. They may
submit multiple NDCs with package
codes corresponding to a variety of
commonly ordered package sizes. They
may submit an NDC package code
corresponding to 1 kilogram (kg), for
example, and then treat a shipment of
10 kg as being comprised of 10 units. In
some cases, they may submit an NDC
with a package code corresponding to a
55-gallon drum, for example, and use
that packaging to ship 55-gallon orders
as well as orders that are slightly less
than 55 gallons in volume.
(Comment 38) One comment
recommended that the NDC for a drug
that was repacked or relabeled include
the product code of the source drug.
(Response) Section 207.53 of this final
rule requires repackers and relabelers to
list drugs they repack or relabel and
requires them to submit an appropriate
NDC for each such drug that includes
the repacker’s/relabeler’s labeler code. It
would not be feasible to require the
NDC for a repacked or relabled drug to
include the labeler code of the repacker
or relabeler combined with the product
code of the source drug. Such a
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60188
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
requirement might produce an NDC that
was previously assigned to a different
drug. Because registrants will continue
to propose their own NDCs under this
final rule, a repacker or relabeler may
generally adopt the convention
proposed in the comment, but may not
list a drug under an NDC that was
previously assigned to a different listed
drug.
Listing submissions for repacked or
relabeled drugs must also include the
complete NDC assigned to each finished
drug received by the registrant for
repacking or relabeling (i.e., the source
drug), so this link will exist in the
drug’s listing information.
(Comment 39) Two comments asked
whether FDA will assign NDCs to
products that do not have application
numbers, i.e., products that are not the
subject of an approved application.
(Response) This question was posed
in the context of the proposed
requirement that registrants request an
NDC from FDA by submitting
information specified in proposed
§ 207.33(c) prior to a listing submission.
In the case of finished drugs, proposed
§ 207.33(c) would have allowed
registrants to submit an approved U.S.
application number in place of certain
information. As discussed in response
to Comment 31, this final rule allows
registrants to propose their own NDCs
with listing submissions, and FDA will
accept those proposed NDCs unless they
are formatted incorrectly, reserved for a
different drug, or previously assigned to
a different drug. Under this final rule,
NDCs are still ‘‘assigned’’ only by FDA,
after all required listing information is
received. We affirm that NDCs will be
assigned in this manner to all drugs
subject to the listing requirement,
including drugs that do not have
application numbers. As we have stated
in the past (e.g., previous § 207.39 and
in the preamble to the proposed rule (71
FR 51276 at 51305)), FDA’s assignment
of an NDC does not in any way denote
FDA approval of a product. Section
207.37 of this final rule states that a
product may be deemed misbranded if
an NDC is used to denote or imply FDA
approval.
(Comment 40) Some comments asked
how NDCs will be assigned to multidrug
kits. Here we are addressing kits that do
not contain medical devices. (See
related discussion of drug/device
combination products in response to
Comment 22.)
(Response) If a product contains more
than one finished drug product, copackaged as a kit, and that kit is
commercially distributed, the kit itself
must be listed in accordance with
§ 207.41, under § 207.49 or § 207.53, as
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
appropriate. A registrant submitting the
listing should propose an NDC for the
kit itself, distinct from any NDCs
assigned to individual drug constituents
contained in the kit. The NDC proposed
for the kit should include the labeler
code of the registrant obligated to
submit the listing. If the kit is packaged
for private label distribution, it should
be listed under an additional NDC that
includes the labeler code of the private
label distributor.
(Comment 41) A comment asked
whether a finished drug product,
manufactured under one approved
application at two different
manufacturing sites under the same
ownership and control could be listed
under a single NDC. In this example, the
finished product from each
manufacturing site would have the same
composition and physical appearance.
The comment also asked whether the
answer would change if the
manufacturing sites are located in two
different countries.
(Response) Each manufacturing site
would need its own establishment
registration under § 207.17 unless
exempt under section 510(g) of the
FD&C Act or under § 207.13. (Foreign
establishments must register only if they
manufacture, repack, relabel, or salvage
drugs that are imported or offered for
import into the United States.) With
respect to the drug listing requirement,
the proposed rule and the final rule
specify in § 207.41(a) that when
operations are conducted at more than
one establishment, and common
ownership and control exists among all
the establishments, the parent,
subsidiary, or affiliate company may
submit listing information for any drug
manufactured, repacked, relabeled, or
salvaged at any such establishment.
This language allows a registrant that
manufactures a drug at more than one
of its own establishments to submit a
single listing for that product, while
identifying all establishments where the
registrant manufactures the drug under
§ 207.49(a)(12). The listed drug would
have a single NDC in this scenario. The
answer does not change if one or more
manufacturing sites are located outside
the United States.
Note, however, that FDA would also
accept multiple listings if a
manufacturer in this situation wished
for any reason to submit separate
listings and NDCs for the same drug
manufactured at multiple
establishments.
This analysis does not apply to an
entity that uses one or more contract
manufacturers to manufacture, repack,
relabel, or salvage a drug. In that case,
each contract manufacturing site must
PO 00000
Frm 00020
Fmt 4701
Sfmt 4700
be registered under § 207.17, unless
exempt under section 510(g) of the
FD&C Act or under § 207.13. If more
than one contract manufacturing site is
used, and those sites are under common
ownership and control, the contract
manufacturer could submit a single
listing for this drug covering its
activities at multiple sites (also listing
other drugs it is required to list under
§ 207.49 or § 207.53). Furthermore, as
discussed in our response to comment
19, contract manufacturers must
generally list a drug under two NDCs,
one that includes the contract
manufacturer’s labeler code and one
that includes the private label
distributor’s labeler code. In this
scenario, a single NDC that includes the
private label distributor’s labeler code
could be used with a drug manufactured
at multiple contractor sites along with a
single NDC that includes the contract
manufacturer’s labeler code, provided
there are no differences in the product
produced at the various sites that would
warrant a new NDC under § 207.35.
(Comment 42) One comment asked
how registrants should assess whether
their existing NDCs comply with this
rule. Some comments noted a statement
in the preamble to the proposed rule
that FDA intends to validate that current
NDCs comply with the new regulations
when the rule is finalized (71 FR 51276
at 51280) and requested more
information about this process.
(Response) This final rule is not
intended to require extensive changes to
NDCs themselves. The NDC formatting
provisions of new § 207.33(b) are
intended to accommodate NDC formats
currently in use. The 10-digit NDC
formats provided for under § 207.33(b)
of this final rule include (in terms of
numbers of digits in the labeler code,
product code, and package code
respectively) 4–4–2, 5–3–2, and 5–4–1.
Any NDC in one of those formats that
is not assigned to multiple drug
products and is not assigned to a nondrug product should comply with this
final rule. When five-digit labeler codes
are exhausted, FDA will begin issuing
six-digit labeler codes, allowing for
additional formats of 6–3–2 and 6–4–1.
(Comment 43) Some comments
encouraged FDA to permit one
registrant or business to maintain more
than one labeler code. These comments
pointed out that mergers and
acquisitions in the pharmaceutical
industry result in corporate entities
responsible for drugs listed under
multiple NDC labeler codes.
Consolidation of such NDCs to a single
labeler code would be burdensome and
may not be possible in some cases if, for
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
example, one product code has been
used with two different labeler codes.
(Response) FDA agrees with this
comment. We encourage registrants and
private label distributors to maintain a
single labeler code wherever possible.
But FDA will not require each registrant
and private label distributor to maintain
only one labeler code. This flexible
approach accommodates mergers and
acquisitions. It departs from a statement
in the preamble to the proposed rule
that only one labeler code would be
used for new NDC numbers that FDA
would have assigned prospectively for
any given manufacturer, repacker, or
relabeler (71 FR 51276 at 51299). It also
accommodates situations in which any
registrant wishes to maintain different
labeler codes for different product lines
or situations in which a registrant risks
exhausting all available labeler code and
product code combinations if the
registrant operates with a single labeler
code. Importantly, new § 207.33(c)(2)
requires each person who is assigned a
labeler code to update the information
required under § 207.33(c)(1). This will
allow FDA to reliably associate every
labeler code with the person to whom
it is assigned and the person’s contact
information.
Registrants and private label
distributors who currently have NDC
labeler codes but for whom FDA does
not have up-to-date information
described in § 207.33(c)(2) on the
effective date of this rule are required to
update their information. FDA may
refuse to accept new drug listings that
include an NDC labeler code for which
the information required by
§ 207.33(c)(2) is not current in our
system.
(Comment 44) One comment asked
FDA to confirm that a business owning
many registered establishments may
maintain only one labeler code, so that
all of its NDCs include a single labeler
code.
(Response) FDA prefers that such a
business maintain only one labeler
code, and that it use this single labeler
code when proposing NDCs for drugs it
manufactures, repacks, relabels, or
salvages at establishments under
common ownership and control.
However, as explained in our response
to Comment 43, FDA will not require
any business to maintain only one
labeler code.
(Comment 45) One comment
interpreted the proposed rule as
preventing an entity that does not
distribute its own products from
maintaining its own labeler code. The
comment recommended that such an
entity not be required to assume
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
distribution responsibilities to retain its
labeler code.
(Response) FDA is not certain
whether this comment is concerned
with which NDC would have been
required to appear on product labels
had we finalized the proposed
amendments to § 201.2, or more
generally concerned with the NDCs
under which private label distributor
products are listed. Under § 207.33(c) of
this final rule, a labeler code must be
requested and maintained by any person
who engages in manufacturing,
repacking, relabeling, or private label
distribution of drug products. The term
‘‘private label distribution’’ is defined in
§ 207.1 of this final rule to mean
commercial distribution of a drug under
the label or trade name of a person who
did not manufacture, repack, relabel, or
salvage that drug. A private label
distributor does not need to physically
engage in drug distribution to qualify as
a private label distributor under this
definition and maintain a labeler code
under § 207.33(c).
(Comment 46) One comment gave an
example of two establishments ‘‘located
in the same geographical location
within two cities located five miles
apart’’ and asked whether those
establishments would need separate
NDC labeler codes and registration
numbers.
(Response) Under the final rule’s
definition of ‘‘establishment,’’ two
establishments located 5 miles apart
would not qualify as being at ‘‘one
general physical location’’ and would
therefore require two separate
registrations. Each establishment would
be associated with its own UFI and
establishment registration number. As
stated in § 207.17 of this final rule,
when operations are conducted at more
than one establishment and common
ownership and control among all the
establishments exists, the parent,
subsidiary, or affiliate company may
submit registration information for all
establishments. Likewise, with respect
to drug listing information, § 207.41
states that when operations are
conducted at more than one
establishment, and common ownership
and control exists among all the
establishments, the parent, subsidiary,
or affiliate company may submit listing
information for any drug manufactured,
repacked, relabeled, or salvaged at any
such establishment. A single labeler
code may be used in the NDCs for all
drugs proposed by such a parent,
subsidiary, or affiliate company.
(Comment 47) A comment asked FDA
to confirm that the NDC assignment
requirement for APIs applies to all APIs,
PO 00000
Frm 00021
Fmt 4701
Sfmt 4700
60189
whether they are supplied by domestic
or foreign establishments.
(Response) Any drug, including an
API, manufactured at a domestic
establishment for commercial
distribution in the United States must
be listed under § 207.49 unless exempt
under § 207.13. As proposed and under
this final rule, the registration and
listing requirements apply to foreign
establishments whose drugs, including
APIs, are imported or offered for import
into the United States. See §§ 207.13(j),
207.49, and 207.53.
(Comment 48) Some comments urged
FDA to exempt allergenic extract
products from the NDC requirement or
from drug establishment registration
and listing generally. These comments
argued that the proposed rule would
require manufacturers of allergenic
extracts to manage a large number of
NDCs without obvious benefits.
(Response) Allergenic extracts are
used in the diagnosis and treatment of
allergies. As such, they are
appropriately regulated as drugs under
the FD&C Act and FDA’s regulations.
Section 510 of the FD&C Act authorizes
FDA to exempt certain persons from
establishment registration (and hence
listing) if registration ‘‘is not necessary
for the protection of the public health.’’
We decline to make this finding for
allergenic extracts. Such an exemption
would diminish FDA’s ability to inspect
establishments at which allergenic
extracts are manufactured and track
marketed products.
Both before and after this final rule,
our regulations in part 207 have
required that each listed drug product
have an NDC. We understand that this
requires manufacturers of allergenic
extracts to associate a unique NDC with
each product they manufacture for
commercial distribution, and this may
result in a large number of NDCs. We
believe the public health benefits
associated with drug registration and
listing outweigh the burden this places
on manufacturers to manage a large
number of NDCs.
(Comment 49) One comment asked
whether drug samples are subject to the
NDC requirement.
(Response) Under this final rule,
registrants must list drugs they
manufacture, repack, relabel, or salvage
for commercial distribution. The term
‘‘commercial distribution’’ is defined in
a way that encompasses free samples.
Because any listed drug requires an
NDC, drugs packaged for distribution as
promotional samples are expected to
have NDCs.
(Comment 50) Some comments
recommended that pharmacy
compounded drugs be eligible for NDC
E:\FR\FM\31AUR2.SGM
31AUR2
60190
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
mstockstill on DSK3G9T082PROD with RULES2
assignment. These comments noted that
hospital pharmacies use the NDC to
reduce medication errors.
(Response) Drug products
compounded by a licensed pharmacist
or a licensed physician in conformance
with section 503A of the FD&C Act are
generally exempt from drug
establishment registration and listing
under part 207 before and after this final
rule, consistent with the exemptions for
pharmacies and practitioners in section
510(g) of the FD&C Act. The DQSA
added section 503B to the FD&C Act.
Under section 503B, a compounder can
register with FDA as an ‘‘outsourcing
facility.’’ Because the FD&C Act now
establishes a separate registration and
drug product reporting process for such
outsourcing facilities, this final rule
exempts outsourcing facilities from the
registration and listing requirements of
part 207. (See new § 207.13(k).)
Compounders that meet the
conditions for exemption from
registration and listing requirements
under part 207 may elect to voluntarily
register and list their products under
part 207 and obtain NDCs.
2. What changes require a new NDC?
(§ 207.35)
Section 207.33(f) of the proposed rule
identified the types of changes to a drug
that require a new NDC. This final rule
includes new § 207.35 that states with
greater clarity the types of changes to a
drug that require a new NDC.
Substantively, new § 207.35 is similar to
the corresponding requirements in the
proposed rule, but the provision does
not require a new NDC when changes
are made to inactive ingredients or
when the Drug Master File number or
Veterinary Master File number, if any,
assigned to an API changes.
(Comment 51) Some comments were
concerned about the types of changes to
a drug that would require a new NDC
in the proposed rule. In particular,
many comments opposed the proposed
requirement that changes in a drug’s
inactive ingredients would necessitate a
new NDC.
(Response) This proposed
requirement—that a change in a drug’s
inactive ingredients would necessitate a
new NDC—has not been retained in the
final rule. Under both the proposed rule
and the final rule, any change in
information submitted with a drug
listing must be reflected in an updated
listing under § 207.57. Certain more
significant changes also require a new
NDC, as specified in new § 207.35.
Upon careful consideration, we agree
with those comments that stated it
would be unreasonably burdensome to
require registrants to submit a new NDC
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
each time they change the inactive
ingredient composition of a product.
Some comments questioned the scope
of the proposed requirement: Would it
apply to changes from one inactive
ingredient supplier to another? Would it
apply to changes in the quantity at
which an inactive ingredient is used?
Would it apply to changes in the
compositional specifications of an
inactive ingredient?
The justification for this requirement
suggested in the proposed rule was that
some patients may be sensitive to
certain inactive ingredients, and a
change in NDC would flag for those
patients and their pharmacists and
health care providers that a drug’s
composition may have changed (or that
some other characteristic identified in
§ 207.35 changed).
Upon careful consideration, we agree
with those comments that challenged
this justification. Paying attention to
changes in NDCs would be an inexact
way for patients, pharmacists, and
health care providers to discover
changes in inactive ingredients. As
proposed and under this final rule,
updates to drug listing information
(including a new NDC) will be
submitted each June and December, or
sooner at the registrant’s discretion.
Thus, manufacturers will not be
obligated to change an NDC
immediately upon changing an inactive
ingredient and update the NDC on their
labels on a batch specific basis.
Comments pointed out that,
particularly in the case of OTC
monograph products, manufacturers
currently have the flexibility to use
certain inactive ingredients
interchangeably. FDA’s current
guidance regarding the labeling of OTC
drug products acknowledges this
practice and includes formatting
recommendations to accommodate the
practice.2 The proposed rule did not
explain, for example, how the new NDC
requirement would apply in a situation
where the manufacturer of an OTC
monograph product may have switched
inactive ingredients in several different
batches in the 6 months leading up to
a semiannual listing update submission.
Rather than impose this burden on
some manufacturers, and recognizing
that ingredient labeling and reference to
batch numbers are more useful and
exact ways to ascertain a drug’s
composition, this final rule does not
require a new NDC when a drug’s
inactive ingredients change.
2 See the guidance for industry ‘‘Labeling OTC
Human Drug Products—Questions and Answers,’’
December 2008, pp. 10–11, available on the Internet
at https://www.fda.gov/Drugs under Guidances
(Drugs).
PO 00000
Frm 00022
Fmt 4701
Sfmt 4700
(Comment 52) One group of
comments expressed concern about the
many situations in which a new NDC
would be needed under the proposed
rule. In addition to mentioning changes
in inactive ingredients, the comments
cited any addition to a drug’s label or
labeling, including the addition of
stickers with delivery and handling
instructions and ‘‘any material change
to a drug’s labeling or packaging insert’’
as things that should not warrant a new
NDC. The comments emphasized the
burden associated with changes to a
drug’s NDC.
(Response) Several changes in this
final rule will reduce the number of
occasions when a drug requires a new
or additional NDC, compared to the
proposed rule. See the response to
comment 51 regarding changes to
inactive ingredients. See our response to
Comment 17 regarding the revised
definition of ‘‘relabel’’ in the final rule
to exclude the addition or modification
of information affixed solely for
purposes of delivery to a customer,
customer identification, or inventory
management. Under this final rule,
changes or additions to a label that do
not qualify as relabeling do not
necessitate a drug listing submission
and NDC under § 207.53. Section 207.35
of this final rule does not include ‘‘any
material change’’ to a drug’s labeling or
package insert among the changes that
necessitate a new NDC. Labeling
changes are generally not included in
new § 207.35. Some labeling changes
will be incidental to the changes
included in new § 207.35 (e.g., a change
to a drug’s established or proprietary
name), but labeling changes themselves
do not trigger the need for a new NDC
under this final rule. FDA has also
determined that changes in Drug Master
File numbers or Veterinary Master File
numbers describing APIs, alone, should
not necessitate new NDCs. Changes in
APIs themselves, i.e., a change in the
identity of an API, will continue to
necessitate new NDCs under new
§ 207.35.
(Comment 53) The Animal Health
Institute noted that Animal Drug User
Fee Act (ADUFA) fees are assessed for
each animal drug NDC. This comment
pointed out that manufacturers of
animal drug products will be potentially
charged twice for a single drug product
due to a change in the NDC during a
fiscal year or due to multiple listings for
a single product required under this
final rule. The comment urged FDA to
exempt animal drug manufacturers from
paying such extra product fees imposed
by this final rule.
(Response) As noted in our response
to Comment 52, several changes in this
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
final rule will reduce the number of
occasions when a drug requires a new
or additional NDC, compared to the
proposed rule. Under ADUFA, the term
‘‘animal drug product’’ means each
specific strength or potency of a
particular active ingredient or
ingredients in final dosage form
marketed by a particular manufacturer
or distributor, which is uniquely
identified by the labeler code and
product code portions of the NDC, and
for which an animal drug application or
a supplemental animal drug application
has been approved. See section 739(3) of
the FD&C Act. Because product fees are
assessed under ADUFA for animal drug
products meeting this definition, fees
are not assessed for unfinished animal
drugs or animal drugs that are not
marketed. However, there may be
instances where a change is made to a
marketed animal drug product that
necessitates a new NDC for that product
during a single fiscal year, resulting in
a new ADUFA product fee. This is an
issue that has existed prior to this final
rule.
(Comment 54) One comment asked
whether a new NDC will be required
when a manufacturer changes to a new
supplier of an API or, relatedly, whether
multiple NDCs would be needed if
multiple suppliers of an API are
indicated in an approval application for
a finished drug product.
(Response) Section 207.35 of this final
rule requires a new NDC when there is
a change to any API. This provision
includes changes from one API to
another (e.g., a change from
acetaminophen to ibuprofen) and
changes in the strength of an API. The
provision does not encompass changes
in suppliers and does not require
multiple NDC product codes
corresponding to multiple API
suppliers.
(Comment 55) One comment
requested clarification regarding when a
change in drug product strength will
require a new NDC (or when multiple
strengths will require multiple NDCs).
This comment distinguished between
concentration and strength.
(Response) Section 207.35 of this final
rule requires a new NDC if the strength
of any API changes. The term ‘‘strength’’
is generally used to refer to the absolute
quantity of API in a single unit dose
(e.g., 250 milligrams (mg) per tablet).
Concentration, on the other hand, refers
to the amount of an ingredient per
defined weight or volume of product
(e.g., 1 mg/1 milliliter (mL)). Examples
of multiple strengths requiring separate
NDCs include 100 mg/tablet, 250 mg/
tablet, 1 mg/1 mL, and 2 mg/2 mL. Each
of these would require its own NDC if
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
each is supplied as a unit dose. This is
true even though the last two
concentrations are equivalent.
(Comment 56) Some comments
questioned whether two digits are
sufficient for the package code segment
of the NDC. Relatedly, some comments
requested clarification regarding the
need for a new NDC when changes are
made to a drug’s package size or type.
For example, would a change from one
type of plastic bottle to another
necessitate a new NDC? Another
comment argued that changes in
medical gas packaging should not
necessitate many new NDCs.
(Response) A 2-digit package code
segment accommodates 100 different
packaging configurations, counting ‘‘00’’
as one possibility.
There should be a separate package
code for each package size. Therefore, if
a package is enlarged to hold more of a
drug product, it would need a new NDC.
A change in package configuration,
such as a change from a bottle to a
blister pack, would also require a new
NDC.
Under new § 207.35(c), a new NDC
(specifically a new package code
segment) is needed for changes in the
composition of packaging material that
are significant enough so that the
packaging type description previously
submitted is no longer accurate. When
submitting drug listing information
electronically, registrants are currently
prompted to identify the package type
by selecting a choice from a drop down
list. For example, ‘‘Bottle, Plastic’’ is
currently one available selection in the
drop down list. If a registrant originally
described its packaging material using
this term and later switched from one
type of plastic bottle to another, there
would be no need for a new NDC. But
if a change in packaging material is
more significant, from plastic bottle to
glass bottle, for example, so that a new
package type should be selected from
the drop down list, FDA would require
a new NDC with a new package code
segment to accompany the revised
listing under § 207.35(c). (This
discussion pertains only to drug listing
obligations. Please see the FDA
guidance for industry on ‘‘Container
Closure Systems for Packaging Human
Drugs and Biologics’’ (May 1999,
available on the Internet at https://
www.fda.gov/Drugs under Guidances
(Drugs)) regarding filing requirements
for changes to container closure systems
in the case of drug products that are the
subject of an approved application
(NDA, abbreviated new drug application
(ANDA), or BLA)).
Medical gases are generally packaged
in tanks, canisters, or cylinders. A
PO 00000
Frm 00023
Fmt 4701
Sfmt 4700
60191
registrant listing a medical gas would
choose the appropriate packaging type
from the drop down list, populated with
such terms, in our electronic drug
establishment registration and listing
system. We do not currently require
more detail about the composition of a
tank, canister, or cylinder in which a
medical gas is packaged and would not
require a listing update or a new NDC
if the composition of a tank, canister, or
cylinder changes. Therefore, we do not
anticipate an unreasonable proliferation
of NDCs associated with medical gas
packaging under this final rule.
If a registrant exhausts all 100 package
codes for a single product, that
registrant may add a second product
code, effectively making 100 more
package codes available. This provision
is reflected in § 207.35(c) of this final
rule.
(Comment 57) One comment stated
that many minor changes are made to a
drug’s packaging, such as resin
composition and size optimization. This
comment stated that these minor
changes are already the subject of
submissions to FDA, for example, as an
annual report (submitted under
§ 314.81(b)(2)), a prior approval
supplement to an NDA, or a changesbeing-effected supplement. This
comment implicitly questioned the need
for new NDC package codes triggered by
these changes.
(Response) Section 207.35(c) of this
final rule requires new NDCs,
specifically new package codes, when
changes are made to a drug’s package
size or type. See our response to
comment 56 regarding our
interpretation of this requirement. We
acknowledge that certain postapproval
packaging changes are reported to an
NDA, BLA, or ANDA consistent with
current § 314.70 and FDA https://
www.fda.gov/Drugss guidance for
industry ‘‘Container Closure Systems for
Packaging Human Drugs and Biologics;
Chemistry Manufacturing, and Controls
Documentation’’ (May 1999, available
on the Internet at https://www.fda.gov/
Drugs under Guidances (Drugs)) and to
a new animal drug application (NADA)
or an abbreviated new animal drug
application (ANADA) consistent with
current § 514.8 and FDA’s guidance for
industry ‘‘Chemistry, Manufacturing,
and Controls Changes to an Approved
NADA or ANDA’’ (May 2007, available
on the Internet at https://www.fda.gov/
Drugs under Guidances (Drugs)). These
submissions, however, do not duplicate
or satisfy the Agency’s objectives behind
drug listing and the use of the NDC to
identify individual marketed drug
products. These submissions also are
E:\FR\FM\31AUR2.SGM
31AUR2
60192
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
mstockstill on DSK3G9T082PROD with RULES2
not made for drugs that are not subject
to the new drug approval requirements.
3. What restrictions pertain to the use of
the NDC? (§ 207.37)
Proposed § 207.37 set forth
restrictions pertaining to the use of
NDCs. These provisions are retained in
the final rule with minor revisions. New
§ 207.37 clarifies that a product
improperly bearing an NDC may be
deemed to be misbranded. Additionally,
new § 207.37 is not addressed only to
‘‘manufacturers, repackers, and
relabelers.’’ Persons who are not subject
to part 207 are cautioned against
concluding that the restrictions stated in
§ 207.37 do not apply to them. Improper
use of an NDC, as described in § 207.37,
may result in a misbranding charge
under the FD&C Act, whether or not the
responsible party is generally subject to
part 207.
(Comment 58) One comment agreed
that NDCs should not appear in the
labeling of dietary supplements, foods,
and medical devices, but encouraged
FDA to exercise enforcement discretion
in this area. Other comments urged FDA
to permit the use of NDCs on medical
devices and medical foods. Others asked
FDA to implement an alternative
identification system for medical
devices before finalizing this rule.
(Response) Section 207.37 of this final
rule states that a product may be
deemed to be misbranded if an NDC is
used on the product but it is not subject
to part 207. Since publication of the
proposed rule, FDA has issued a final
rule requiring UDIs on medical devices
(78 FR 58786, September 24, 2013).
Section 801.57 of that rule (21 CFR
801.57) generally prohibits the use of an
NDC on the label of a medical device
after the date on which it must bear a
UDI.
The use of an NDC on the label of a
product that is not regulated as a drug
may confuse and mislead consumers
and health care providers into believing
FDA regulates the product as a drug.
Any enforcement actions in this area
will be subject to a determination that
a product violates § 801.57 or is
misbranded, or otherwise violates the
FD&C Act.
(Comment 59) One comment argued
against the proposed rule’s prohibition
against the use of NDCs on non-drug
products and asked, if this prohibition
is retained in the final rule, how long
manufacturers of such products would
have to remove NDCs from their labels.
(Response) Please see our response to
comment 58 regarding the nature of
§ 207.37, specifically our clarification
that the use of NDCs in the labeling of
non-drug products may be handled as
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
misbranding violations or as violations
of § 801.57 as appropriate. See FDA’s
Unique Device Identifier rule (78 FR
58786) and any guidance FDA may
issue regarding the compliance deadline
for § 801.57. When an NDC in the
labeling of a non-drug product creates
the misleading impression that FDA
regulates the product as a drug, that
product may be subject to enforcement
action.
E. Listing (Part 207, Subpart D)
1. Who must list drugs and what drugs
must they list? (§ 207.41)
Proposed § 207.41 specified who must
list drugs, and the provision is retained
in this final rule. Section 207.41(c) now
includes more detail about the manner
in which drugs manufactured for private
label distribution are listed.
(Comment 60) Some comments urged
FDA to allow private label distributors
to list drugs that are distributed under
their names.
(Response) Please see our response to
comment 16 regarding the definitions of
‘‘private label distributor’’ and ‘‘private
label distribution’’ in § 207.1 for a
discussion of the responsibilities of
private label distributors in this final
rule. Private label distributors are not
obligated—by their status as private
label distributors—to register an
establishment or list drugs. They may,
however, submit drug listing
information or establishment
registration information if acting as the
authorized agent of a registrant on
whose behalf the information is
submitted.
2. When, after initial registration of an
establishment, must drug listing
information be submitted? (§ 207.45)
Proposed § 207.45 described an
establishment’s drug listing obligation at
the time of initial registration. It stated
that an establishment must, at the time
of initial registration, list any drug then
being manufactured, repacked,
relabeled, or salvaged for commercial
distribution at the establishment.
Section 207.45 is revised in this final
rule to state that such drugs must be
listed no later than 3 calendar days after
initial registration of the establishment.
(Comment 61) One comment
encouraged FDA to provide flexibility in
the timing of new drug listing
submissions. The comment stated that it
supported the current requirement of 5
calendar days from the start of
manufacturing.
(Response) Several provisions of this
final rule relate to the time periods
within which establishment
registrations, drug listings, and drug
PO 00000
Frm 00024
Fmt 4701
Sfmt 4700
listing updates must be submitted.
Section 207.21 states that domestic
establishments must register for the first
time no later than 5 calendar days after
beginning to manufacture, repack,
relabel, or salvage a drug or an animal
feed bearing or containing a new animal
drug (whether or not commercially
distributed). This 5-day window for
initial establishment registration starts
at the beginning of manufacture, not the
beginning of commercial distribution.
Section 207.45 states that each drug
being manufactured, repacked,
relabeled, or salvaged for commercial
distribution at the time of initial
registration must be listed no later than
3 calendar days after initial registration.
Thus, the 3-day window established in
§ 207.45 relates to those drugs being
manufactured at the establishment for
commercial distribution at the time of
initial registration. We will interpret the
phrase ‘‘for commercial distribution’’ in
§ 207.45 flexibly as meaning immediate
or near-term commercial distribution,
not for storage prior to an initial product
launch.
FDA recognizes that because it has
made findings that nondisclosure of
most drug listing information would be
inconsistent with the protection of the
public health (see § 207.81), registrants
may be reluctant to list drugs that have
not yet been commercially launched.
FDA intends to interpret the timing
requirements in a way that
accommodates this concern. FDA also
encourages and expects registrants to
list drugs promptly upon commercial
launch (following § 207.45 or § 207.57
as appropriate), recognizing that
manufacturers have an incentive to list
drugs promptly and have their proposed
NDCs assigned by FDA. After a drug is
listed, it should appear in our public
NDC database within approximately 1
business day and in our internal
database almost immediately.
3. What listing information must a
registrant submit for a drug it
manufactures? (§ 207.49)
Proposed § 207.49 identified the
information that a registrant must
provide with a drug listing submission
for a drug it manufactures. Section
207.49 is retained and reorganized in
this final rule. Some information
included in proposed § 207.33(c) (what
information must a manufacturer submit
before we will assign an NDC number to
a drug?) has been incorporated into new
§ 207.49 as drug listing information
because it is not necessary under this
final rule for manufacturers to request
an NDC from FDA.
(Comment 62) One comment noted
that an approved U.S. application
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
number is included with drug listing
information identified in § 207.49 and
asked FDA to clarify whether an
application must be approved before
drug listing information is submitted.
(Response) Section 207.49(a)(7) of this
final rule requires registrants to provide
the approved U.S. application number
with listing information for a drug if one
exists. Thus, § 207.49 requires that an
approved U.S. application number be
provided with drug listing information
only if it exists. Unapproved drugs can
and must be listed without an
application number.
Drugs that are the subject of an
application need not be listed until they
are manufactured for commercial
distribution. Registrants who are
awaiting approval of an application may
voluntarily reserve an NDC for the drug
that is the subject of the application
prior to its approval under new
§ 207.33(d)(3). These registrants are also
permitted, but not required, to list a
drug before it is marketed, while
providing a future start marketing date.
(Comment 63) Many comments
opposed the submission of production
volume information with drug listing
information.
(Response) In the preamble to the
proposed rule, FDA stated that it was
considering whether to require
establishments to provide the number of
batches and batch size for each drug
subject to the listing requirement that
they manufactured, repacked, or
relabeled since the establishment last
provided listing information (71 FR
51276 at 51312). We have decided not
to include such a requirement in this
final rule.
(Comment 64) One comment urged
FDA to eliminate the requirement that
registrants submit representative
samples of any other labeling for OTC
drug products.
(Response) Section 207.49(a)(14)(ii)(b)
of this final rule requires that for each
human nonprescription drug not subject
to section 505 of the FD&C Act or
section 351 of the PHS Act (i.e., not
subject to premarket approval), drug
listing information include the current
label, the package insert (if any), and a
representative sampling of any other
labeling. The submission of ‘‘any other
labeling’’ for such drugs is a
requirement of section 510(j)(1)(B)(ii) of
the FD&C Act.
(Comment 65) One comment
questioned the proposed requirement
that the ‘‘drug facts’’ labeling for OTC
drug products be included in drug
listing information, arguing that
required labeling for OTC products is
set forth in OTC monographs and in
FDA’s regulations in § 201.66.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
(Response) We disagree with this
comment. Section 207.49(a)(14)(ii)(B) of
this final rule requires that labeling
submitted with drug listing information
for human nonprescription drugs not
subject to section 505 of the FD&C Act
or section 351 of the PHS Act include
the ‘‘content of labeling.’’ This term is
defined in § 207.1(b) to include, for
these drugs, the drug facts labeling
required by § 201.66. The submission of
drug listing information is the only
mechanism by which FDA has quick
access to the labeling that is currently in
use for marketed OTC drug products.
Furthermore, section 510(j)(1)(B)(ii) of
the FD&C Act requires that the label,
package insert, and a representative
sampling of any other labeling be
provided with listing information for all
such drugs, thus encompassing the drug
facts labeling.
(Comment 66) One comment urged
FDA to require that drug listing
information for human OTC drugs
include the current product label, but
not other labeling. This comment also
urged FDA to accept such labels in
portable document format (PDF) files
rather than structured product labeling
(SPL).
(Response) As explained in response
to Comments 64 and 65, the FD&C Act
requires that drug listing information for
OTC human drugs not subject to section
505 of the FD&C Act or section 351 of
the PHS Act include the label, package
insert, and a representative sampling of
‘‘any other labeling.’’ Therefore, this
comment’s recommendation that only
the current product label (i.e., the
container label) be submitted for such
products is contrary to the FD&C Act,
and we decline to adopt it. Drug listing
information is the only mechanism by
which FDA collects labeling for such
products, and it is important that we
have it readily available.
This final rule does not specify a file
format for the submission of drug listing
information, but it does require
electronic submission in a format FDA
can ‘‘process, review, and archive.’’ (See
§ 207.61(a) of this final rule.) As
explained in our electronic registration
and listing guidance, to facilitate the
submission of drug establishment
registration and drug listing information
(including the content of labeling), FDA
has adopted the use of extensible
markup language (XML) files in a
standard SPL format. The automated
submission process functions most
efficiently and effectively when this
information is provided in a
standardized format with defined code
sets and codes. Information in a
properly created and complete SPL file
can facilitate processing and allows for
PO 00000
Frm 00025
Fmt 4701
Sfmt 4700
60193
greater precision and accuracy through
the use of coded data fields rather than
merely electronic text. For these
reasons, we will continue to expect drug
listing information in SPL format.
In the case of unfinished drugs,
§ 207.49(a)(15)(iv) requires submission
of the label (if any) but does not require
registrants to submit the content of
labeling. Because FDA does not
currently electronically process the
labels submitted for unfinished drugs,
we have accepted and will continue to
accept electronic submission unfinished
drug labels in JPEG (Joint Photographic
Experts Group) file format.
(Comment 67) One comment
questioned the proposed requirement
that drug listing information include the
name of each inactive ingredient in a
listed drug. Another comment argued
that drug listing submissions for animal
drug products in particular should not
be required to identify inactive
ingredients.
(Response) This requirement is
retained in the final rule, specifically in
new § 207.49(a)(5), applicable to both
human and animal drugs. FDA finds it
important to maintain up-to-date
inactive ingredient information for all
marketed drug products. This allows
FDA, for example, to determine the
extent to which a particular inactive
ingredient is currently in use and
identify drug products that contain it.
FDA does not have access to this
information in the form of a searchable
database outside of our drug registration
and listing information.
(Comment 68) We received several
comments pertaining to the drug listing
obligations of contract manufacturers,
contract packagers, and contract
laboratories. One requested clarification
regarding the manner in which a
contract manufacturer or packager
would submit listing information for an
investigational drug manufactured or
packaged for use in a clinical trial.
(Response) Contract manufacturers,
packagers, and laboratories—unless they
are exempt under section 510(g) of the
FD&C Act or § 207.13—will generally
qualify as manufacturers under this
final rule and will be required to register
their establishments. Under § 207.41 of
this final rule, registrants must list drugs
they manufacture, repack, relabel or
salvage for commercial distribution. The
definition of ‘‘commercial distribution
in new § 207.1 excludes drugs
distributed for investigational use under
part 312 (21 CFR part 312) or part 511
(21 CFR part 511). The drugs referred to
in this comment may be exempt from
listing under this analysis.
(Comment 69) Another comment
asked how a contract manufacturer or
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60194
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
packager should be expected to submit
twice annual drug listing updates,
attesting for example that there have
been no changes to a drug’s labeling,
when the contract manufacturer or
packager is not responsible for or aware
of labeling changes in the ordinary
course of its business.
(Response) This comment relates to a
wide variety of situations. We recognize
that contractors play an important role
in drug manufacture. Some perform
specialized operations for another
manufacturer (e.g., blister packaging),
and others perform all manufacturing
operations for a virtual drug company.
Some contract manufacturers handle
drugs that are the subject of an approved
application and are sold under the name
of the application holder. Others
manufacture OTC drugs for multiple
private label distributors. Each situation
will require its own analysis under this
final rule, and there may be more than
one way to satisfy the rule’s
requirements.
If a contract manufacturer is
performing one or more steps in a larger
manufacturing operation, it may be
shipping an unfinished drug to another
contracting party. In that case, the
contract manufacturer would submit
listing information under § 207.49 for
the unfinished drug it distributes
commercially, i.e., the unfinished drug
that leaves its registered
establishment(s). This would include
labeling information required under
§ 207.49(a)(15)(iv), meaning the label
applied to the unfinished drug. In this
scenario, the contract manufacturer
would not be responsible for listing
updates that describe labeling changes
for the finished drug product, if the
contract manufacturer does not
commercially distribute the finished
drug product.
If a contractor is performing all steps
or just the final steps in a drug
manufacturing process, the contractor
should describe the finished drug
product in its listing submission. In
some cases, a contract manufacturer
may be responsible for formulating the
product and developing its labeling.
This might be true in the case of an OTC
store brand, private label distribution
product, for example. In that situation,
the contracting parties would likely
agree that the contract manufacturer is
in the best position to submit drug
listing information and updates (as it is
required to do under this final rule), and
this would include the submission of
any labeling changes with twice annual
listing updates. In other cases, a
contractor might play a much smaller
role. It might only place a product
manufactured and developed by
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
someone else into its final packaging. In
that case, the contractor would be
required by this final rule to submit
listing information pertaining to the
finished drug product, including the
twice annual updates. The contractor
might satisfy this obligation by
consulting with the drug’s developer
about any changes in drug listing
information or by letting the drug’s
developer act as its authorized agent for
the submission of drug listing
information and updates. At all times,
however, the actual manufacturer of a
drug (or repacker, relabeler, or salvager)
is legally responsible for ensuring that
the requirements of this final rule are
satisfied.
(Comment 70) One comment stated
that ‘‘the proposed requirement for
finished product contract testing
laboratories to list all of the products
they test should be eliminated.’’ The
comment pointed out that testing
laboratories only handle representative
samples of products that do not enter
the supply chain.
(Response) This comment addresses
an issue that arises under the FD&C Act
and the drug registration and listing
regulations as they have long existed.
(See the definition of ‘‘manufacturing or
processing’’ that has existed in § 207.3
prior to this final rule.) Testing
laboratories, whether they test finished
drug products or in-process materials,
may have important roles in drug
manufacturing and are appropriately
treated as manufacturers under part 207
if they engage in testing or control
procedures necessary for manufacture
under current good manufacturing
practices. Any testing laboratory that
qualifies as a ‘‘manufacturer’’ under this
final rule must register its
establishment(s) where drugs are tested.
The listing obligation, however, applies
only to drugs that a registrant places
into commercial distribution. Therefore,
if a laboratory tests in-process materials
or finished product and then
commercially distributes the tested
product, e.g., for further processing or
for distribution as finished product, that
laboratory would have an obligation to
list the drugs it commercially
distributes. More likely, however, if the
laboratory merely tests product samples
and reports the test results to another
party without further distributing the
tested samples, it has no listing
obligation.
(Comment 71) One comment
expressed concern that importers would
have to identify manufacturers for their
drug components and provide a chain of
custody description for each handler
from manufacturer to importer.
PO 00000
Frm 00026
Fmt 4701
Sfmt 4700
(Response) This comment reflects a
misunderstanding of a statement in the
proposed rule describing section
801(d)(3) of the FD&C Act. To clarify,
§ 207.49(a)(12) of this final rule requires
a registrant listing a drug it
manufacturers to provide: (1) The name
and UFI of the establishment where the
registrant manufactures the drug and (2)
the name and UFI of every other
establishment where manufacturing is
performed for the drug. With respect to
this second category of information, if
the registrant provides a properly
assigned and listed NDC for unfinished
drug(s) it uses to produce the listed drug
(sometimes referred to as ‘‘immediate
source NDCs’’), the registrant does not
need to provide names and UFIs of the
upstream establishments.
(Comment 72) One comment asked
FDA to clarify a statement in the
preamble of the proposed rule regarding
certificates of analysis for imported
articles.
(Response) This comment reflects a
misunderstanding of the proposed rule.
The passage it refers to quotes section
801(d)(3) of the FD&C Act (71 FR 51276
at 51284). Section 801(d)(3) of the FD&C
Act applies only to certain imported
products, and this final rule does not
implement it.
4. What listing information must a
registrant submit for a drug it repacks or
relabels? (§ 207.53)
Proposed § 207.53 identified the
information that a registrant must
provide with a listing submission for a
drug it repacks or relabels. Section
207.53 is retained and reorganized in
this final rule. Some information
included in proposed § 207.33(d) (What
information must a repacker or relabeler
submit before we will assign an NDC
number to a drug?) has been
incorporated into new § 207.53 as drug
listing information because it is not
necessary under this final rule for
manufacturers to request an NDC from
FDA.
(Comment 73) A comment from the
medical gas industry expressed concern
about the proposed rule’s requirement
that repackers identify, in drug listing
information, the NDC associated with a
drug immediately before it is received
by the repacker for repackaging. This
comment argued that the complexity of
medical gas distribution makes this
requirement difficult to satisfy.
(Response) We agree that medical gas
repackers would need to significantly
change the way they currently do
business to identify immediate source
NDCs as specified in the proposed rule.
In response to this comment, we have
included an exception in § 207.53 of
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
mstockstill on DSK3G9T082PROD with RULES2
this final rule so that repackers and
relabelers of medical gases are not
required to include with drug listing
submissions the NDC assigned to each
medical gas they receive for repacking
or relabeling.
5. What are the requirements for
reviewing and updating listing
information? (§ 207.57)
Proposed § 207.57 described the
requirements for reviewing and
updating drug listing information. The
provision is retained in this final rule
with editorial revisions intended to
improve clarity. Additionally, the
section now says registrants are
encouraged to submit listing updates at
the time of any change affecting
previously submitted information. We
have also deleted a reference to
§ 207.55. Under § 207.55, FDA may ask
a registrant to explain the basis for its
belief that a drug is not subject to
approval. We do not expect registrants
to routinely update information
provided to us under § 207.55.
(Comment 74) Some comments
opposed the requirement that to satisfy
the June and December listing update
obligation, registrants must certify that
no changes have occurred if no changes
have occurred since the last review and
update of listing information.
(Response) The preamble to the
proposed rule specifically requested
comments regarding the burden that
may result from the no changes
certification requirement in the context
of drug listing updates (71 FR 51276 at
51314). We have retained in this final
rule the requirement in § 207.57(b) that
registrants update their submitted drug
listing information each June and
December. The review and updating of
drug listing information is critical to the
integrity of FDA’s database. We
recognize, however, that requiring
registrants to submit a twice-annual ‘‘no
changes’’ certification, on a product-byproduct basis, for each of their listings
would impose a substantial burden on
registrants, particularly those that
maintain hundreds or thousands of drug
listings. Therefore, § 207.57 of this final
rule requires registrants to report
changes to drug listing information
either at the time of any change affecting
information previously reported or
during the next June or December listing
update following the change. At the
time of the annual registration update
under § 207.29(b), a registrant may
submit a blanket ‘‘no changes’’
certification covering all of its listed
drug products for which no changes
affecting previously reported listing
information were made since the last
annual registration update or listing
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
submission. This blanket, ‘‘no changes’’
certification applies only to drug listing
information that has been submitted
electronically, as it would be too
burdensome for FDA to maintain
certifications for information that has
not been submitted electronically.
Therefore, it cannot be used to report
that drug listing information submitted
on paper in the past remains current.
This limitation is intended to ease
FDA’s administrative burden and allow
FDA to consider drug listing
information to be fully migrated from
paper submissions to our electronic
drug registration and listing system.
Please see our response to Comment
30, which addresses this issue in the
context of establishment registration
updates.
(Comment 75) One comment stated
that the obligation to provide updates
on individual drug listings within 30
days will demand a great deal of
resources from manufacturers.
(Response) This comment did not cite
the specific provision of the proposed
rule at issue. The preamble to the
proposed rule acknowledged that
proposed § 207.57(b) would require that
drug listing information be reviewed
and updated only every June and
December, but also stated that FDA
would request updates to listing
information within 30 calendar days of
a change, to maintain the accuracy of
our drug listing database (71 FR 51276
at 51314). Under § 207.57 of this final
rule, registrants are encouraged to
submit updated drug listing information
at the time of any change affecting
information previously submitted, but
they are required to submit such
information only every June and
December.
(Comment 76) Two comments asked
FDA to clarify whether a registrant may
report all changes to drug listing
information when they occur, i.e., on a
rolling basis, instead of conducting a
review and update each June and
December.
(Response) Under § 207.57 of this
final rule, registrants must review and
update their drug listing information
each June and December. This is a
requirement of section 510(j)(2) of the
FD&C Act. Registrants are additionally
encouraged, but not required, to update
drug listing information at the time
when changes are made to previously
reported information. These updates do
not, however, take the place of the June
and December updates, which may be
satisfied by a no changes certification if
no changes have occurred since the last
review and update. We will read ‘‘since
the last review and update’’ in
§ 207.57(b)(2) as referring to the
PO 00000
Frm 00027
Fmt 4701
Sfmt 4700
60195
registrant’s most recent listing update
for a given drug, whether submitted in
June, December, or at any other time.
(Comment 77) One comment
encouraged FDA to codify a registrant’s
ability to submit updated listing
information at the time a change is
made, rather than waiting for the next
June or December review and update.
This comment referred to a statement in
the preamble to the proposed rule
stating that registrants are requested to
submit listing information within 30
days of a change.
(Response) We agree with this
comment and have revised § 207.57
accordingly. New § 207.57 states that
registrants are encouraged to submit
listing updates at the time of any change
affecting information previously
submitted. This provision of the final
rule does not refer to a 30-day window
for such listing updates. We intend to
read ‘‘at the time of any change’’
flexibly, encouraging registrants to
submit listing updates as soon as
possible, but allowing such updates at
any time before they are due at the next
June or December review and update.
(Comment 78) One comment
expressed concern regarding the manner
in which a drug’s discontinuation is to
be reported under § 207.57. This
comment noted that historically, many
registrants have waited to report that a
drug has been discontinued until they
no longer have to report the drug under
applicable agreements with the Centers
for Medicare and Medicaid Services.
According to this comment, if an NDC
is identified as discontinued while the
drug is still in distribution up until
expiration, there may be problems
related to reimbursement and other
matters.
(Response) The FD&C Act and
§ 207.57 of this final rule require listing
updates, including information that a
drug has been discontinued, at the
latest, at the time of the next June or
December review and update following
the discontinuation. In the case of drugs
that are subject to part 314,
§ 314.81(b)(3)(iv) also requires that their
withdrawal from sale be reported to
FDA. The reporting deadline under
§ 314.81(b)(3)(iv) is within 15 working
days of the withdrawal from sale before
the effective date of this final rule and
within 30 calendar days of the
withdrawal from sale after the effective
date of this final rule. It is important
that FDA receive this information soon
after discontinuation for the integrity of
our database.
In this final rule, as in the proposed
rule, § 207.57 requires registrants, when
reporting that a listed drug has been
discontinued, to provide the expiration
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60196
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
date of the last lot manufactured,
repacked, relabeled, or salvaged. FDA
regards this date as the ‘‘end marketing
date’’ and includes it in the public NDC
database when a drug is reported to be
discontinued.
Please note that, in addition to the
requirements just discussed, section
506C of the FD&C Act, as amended by
FDASIA, requires manufacturers of
certain drugs that are life-supporting,
life-sustaining, or intended for use in
the prevention or treatment of a
debilitating disease or condition, to
notify FDA of a permanent
discontinuance or certain interruptions
in manufacture at least 6 months prior
to the date of discontinuance or
interruption or as soon as practicable if
6-month’s prior notice is not possible.
(Comment 79) Two comments
opposed the requirement in § 207.57
that registrants provide, for a
discontinued drug, the expiration date
of the last lot manufactured, repacked,
relabeled, or salvaged, arguing that the
expiration date of the last lot provides
no assurance that the drug product will
be available to consumers until that date
is reached.
(Response) As explained in response
to Comment 78, our use of the
expiration date of the last lot as an ‘‘end
marketing date’’ facilitates
reimbursement while remaining stock of
a discontinued drug works its way
through distribution.
(Comment 80) Two comments
requested clarification regarding how
the inclusion of an approved
application number in a drug listing
submission can take the place of the
content of labeling in SPL format,
specifically how updated labeling
would be provided at the time of a
listing update if only the application
number is referenced.
(Response) The proposed rule
indicated that if ‘‘a manufacturer
provides a drug’s approved U.S.
application number as part of a drug’s
listing information, the labeling
required under proposed § 207.49(g)(1)
and . . . 207.49(g)(2) would be deemed
to accompany the listing information’’
(71 FR 51276 at 51309). This was
written prior to FDA’s adoption of SPL
as the submission standard and is not an
accurate reflection of how the process
operates today. However, FDA has
considered how our electronic system
can avoid unnecessary duplication of
effort between the submission of
labeling updates to applications and the
submission of drug listing information.
Under this final rule, a drug listing
submission, whether it includes an
approved application number or not,
must include content of labeling as
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
specified in § 207.49. An advantage of
the SPL format is that it allows the
holder of a newly approved application
to submit the content of labeling once,
satisfying its obligations under parts 314
and 207 in a single submission. Upon
initial approval, an applicant is required
to submit a copy of final approved
labeling. An electronic drug listing
submission that includes the content of
labeling in SPL format can satisfy this
obligation. Even if the drug product is
not yet ready for commercial
distribution upon approval, SPL allows
for a future start marketing date in the
listing information so that a second
submission is not necessary when the
product is commercially launched.
As discussed in response to Comment
15, most drug labeling changes
necessitate a listing update under
§ 207.57 of this final rule. Registrants
who submit drug listing information
through FDA’s CDER Direct electronic
submission portal (as well as those
using some commercial software) will
be able to recall a previous submission,
including the content of labeling, and
make appropriate changes when a
listing update is due. But reference to an
application number alone will not
satisfy the requirement that updated
content of labeling be submitted under
§ 207.57 in this final rule.
F. Electronic Format for Registration
and Listing (Part 207, Subpart E)
Proposed § 207.61 stated that
establishment registration and listing
information must be submitted to FDA
electronically. As proposed, § 207.61
would have allowed advertisements and
some labeling to be submitted to FDA
either in paper or electronic format. In
this final rule, § 207.61 is revised for
clarity. Additionally, the final version of
§ 207.61 requires electronic submission
of all establishment registration and
listing information, consistent with
FDAAA (no longer allowing for the
submission of advertising on paper),
unless a waiver is granted, and states
that FDA may issue guidance from time
to time on how to provide information
in electronic format. Because the SPL
format currently used for electronic
submission of registration and listing
information does not accommodate the
submission of drug advertising, taking
into account various types of advertising
media currently in use, FDA is not
currently collecting advertisements as
part of drug listing information. If this
technical limitation is resolved, we will
explain in future guidance how and
what registrants should transmit
electronically as a representative
sampling of advertisements. In the
meantime, we may ask individual
PO 00000
Frm 00028
Fmt 4701
Sfmt 4700
registrants to submit a representative
sampling of advertisements for specific
prescription human drug products not
subject to section 505 of the FD&C Act,
relying on our authority under section
510(j)(1)(B)(i) of the FD&C Act and
§ 207.49(a)(14) of this final rule.
The final version of § 207.61 also
clarifies that, while drug registration
and listing information must generally
be submitted in the English language, in
some cases the content of labeling may
be submitted in a foreign language along
with an accurate English translation.
(Comment 81) One comment stated
that information should be included in
the final rule to address whether FDA
intends to develop a separate database
for animal health products or
incorporate animal drugs into the
proposed electronic drug registration
and listing database. The comment
recommended that if a separate database
is planned, information on whether the
same data elements will be required to
obtain an NDC number and list products
would be helpful.
(Response) At issue in this
rulemaking are changes to FDA’s
regulations governing drug
establishment registration and listing,
i.e., changes to the codified language
presented in the proposed rule and in
this final rule. These regulations do not
describe the electronic drug registration
and listing systems developed by FDA,
which may change from time to time.
Currently, FDA maintains separate
electronic systems for establishment
registration and listing for human drugs
and for animal drugs. The information
that must be submitted with a drug
listing submission, for both human
drugs and animal drugs, is described in
the regulations codified in part 207 as
amended by this final rule.
(Comment 82) One comment noted
that at the time of the proposed rule and
the comment period, FDA’s electronic
drug registration and listing system had
yet to be developed. Accordingly,
stakeholders were unable to comment
on an electronic system that had yet to
be developed.
(Response) We understand
stakeholder interest in the development
of our electronic system for drug
registration and listing. As noted in
response to Comment 81, however, the
amended regulations adopted in this
rulemaking do not describe the
electronic drug registration and listing
systems developed by FDA. They
generally describe information that must
be submitted to FDA, and they require
that it be submitted electronically.
Therefore, the proposed rule did not
solicit comments on the electronic drug
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
registration and listing system then
under development.
After the proposed rule was
published, Congress amended the FD&C
Act to require electronic submission of
drug establishment registration and
listing information. To implement this
statutory change, FDA published draft
guidance in 2008 and final guidance in
2009 concerning electronic submission
of drug establishment registration and
listing information. Stakeholders had an
opportunity to comment on the
electronic system described in our draft
guidance and, as with all FDA guidance,
have an ongoing opportunity to
comment at any time.
FDA currently accepts drug
establishment registration and drug
listing information submitted
electronically. We expect registrants to
find electronic submission less
burdensome than the use of paper
forms, and we accept comments and
suggestions from stakeholders regarding
improvements to our electronic
submission systems.
(Comment 83) One comment
recommended that to facilitate the
annual review and updating of both
establishment registration and drug
listing information, FDA provide
registrants with a report of their current
registration and listing information.
(Response) This comment does not
relate to language that would be
included in the codified portion of this
final rule, but it does raise an important
issue we would like to address. At all
times, registrants are responsible for
keeping track of registration and listing
information they have submitted to FDA
and should ensure the information is
securely stored and can be retrieved.
Registrants who use an agent to
submit establishment registration and
drug listing information to FDA are
encouraged to maintain their own
records of the submitted information or
obtain assurances that the agent will do
so and will make the information
available to the registrant on request,
including if their business relationship
is terminated.
FDA currently maintains publicly
searchable databases that can be used to
confirm an establishment is registered.
Information about registered blood
establishments is available through
FDA’s electronic Blood Establishment
Registration (eBER) public query
application. Information about
registered HCT/P establishments is
available through the Human Cell and
Tissue Establishment Registration
(HCTERS) public query application.
Information about registered drug
establishments can be obtained through
FDA’s Drug Establishments Current
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
Registration Site (DECRS). Additionally,
FDA’s NDC Directory currently includes
listed finished drug products, but not
unfinished drug products. It may be
expanded in the future to include all
listed drugs. Registrants can check these
sources and may also request a report of
their own registration and listing
information from CDER’s Drug
Registration and Listing staff.
(Comment 84) Comments noted that
changes to part 11 (21 CFR part 11) are
being considered by the Agency and
recommended that electronic
submission of drug registration and
listing information be delayed or
exempt from compliance with part 11
until these changes have been decided.
(Response) Because of changes to
section 510(p) of the FD&C Act adopted
in FDAAA, registration and listing
information is currently submitted
electronically. Exceptions from the
electronic submission requirement will
be handled in accordance with the
waiver provisions in this final rule
(§§ 207.65, 607.22, and 1271.23).
Part 11 sets forth criteria under which
FDA considers electronic records and
signatures to be trustworthy and
reliable. Part 11 applies to electronic
records that are created, modified,
maintained, archived, retrieved, or
transmitted under statutory and
regulatory requirements. In 2003, FDA
published guidance for industry titled
‘‘Part 11, Electronic Records; Electronic
Signatures—Scope and Application’’
(2003 Part 11 Guidance, available on the
Internet at https://www.fda.gov/Drugs
under Guidances (Drugs)) and
announced its availability in the
Federal Register (68 FR 52779,
September 5, 2003). This guidance
announced a reexamination of part 11,
a narrow interpretation of its scope, and
a policy of enforcement discretion with
respect to certain of its requirements.
Part 11 currently remains in effect, and
FDA’s policy of enforcement discretion
applies as described in the guidance.
Against this backdrop, the proposed
rule included a discussion of how FDA
intended to apply part 11 to electronic
drug registration and listing. (See 71 FR
51276 at 51317.) Proposed §§ 207.61,
607.22, and 1271.22 specified that
certain requirements of part 11 would
not apply to information submitted to
FDA under parts 207, 607, and 1271. In
§ 207.61 of this final rule, the
applicability of part 11 is stated as
follows: The submission of
advertisements and labeling is exempt
from the requirements of § 11.10(a), (c)
through (h), and (k) and the
corresponding requirements of § 11.30.
Other information submitted under part
207, as well as information submitted
PO 00000
Frm 00029
Fmt 4701
Sfmt 4700
60197
under parts 607 and 1271, is exempt
from the requirements of § 11.10(b), (c),
and (e) and the corresponding
requirements of § 11.30. These
statements in the codified portion of
this final rule are intended to be read
together with any current FDA guidance
concerning our enforcement of part 11.
For example, FDA’s 2003 Part 11
Guidance states that we do not intend
to take action to enforce compliance
with the validation and audit trail
requirements of part 11. This includes
requirements described in § 11.10(a) and
(e). Until our 2003 Part 11 Guidance is
withdrawn or modified, these
statements regarding enforcement
discretion remain current. Therefore,
any person submitting information
electronically to FDA under this final
rule may rely on the exemptions from
part 11 written into parts 207, 607, and
1271, in addition to statements
regarding part 11 enforcement
discretion in current FDA guidance.
(Comment 85) One comment noted
that a citizen petition is currently
pending before FDA requesting that part
11 be revoked in its entirety (Docket No.
FDA–2004–P–0036, formerly Docket No.
2004P–0429/CP1). This comment asked
FDA to respond to the citizen petition
before it completes this rulemaking.
(Response) The referenced citizen
petition remains under review, and the
part 11 regulations are currently being
implemented as explained in FDA’s
2003 Part 11 Guidance. FDA’s
publication of this final rule should not
be interpreted as providing any
indication of the manner in which the
citizen petition will be resolved.
G. Miscellaneous (Part 207, Subpart F)
Section 207.81 of the proposed rule
identified establishment registration and
listing information that will be available
or not available for public disclosure
after it is submitted to FDA. Section
510(f) of the FD&C Act states that
establishment registration information is
available for inspection and drug listing
information is generally not available
for inspection unless the Secretary (by
delegation FDA) finds that an
exemption from disclosure would be
inconsistent with protection of the
public health. Consistent with this
statutory provision, proposed § 207.81
stated that establishment registration
information would be generally
available for disclosure and that most,
but not all, drug listing information
would be available for disclosure, as its
nondisclosure would be inconsistent
with protection of the public health.
Generally categorized as not available
for disclosure in the proposed rule was
information obtained under:
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60198
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
• Proposed § 207.33(d)(1)(ii)—Source
NDCs for repacked or relabeled drugs
submitted in the context of an NDC
request for such drugs,
• Proposed § 207.54(b)(1)—Source
NDCs for salvaged drugs, and
• Information submitted as the basis
upon which it has been determined that
a particular drug product is not subject
to section 505 or 512 of the FD&C Act,
the premarket approval requirement for
new drugs and new animal drugs.
In this final rule, § 207.81 has been
revised in several ways. The section has
been reorganized so that registration and
listing information that will be available
for public disclosure is identified in
paragraph (a), and exceptions are
identified in paragraphs (b) and (c).
Cited section numbers have been
revised, consistent with the
renumbering of sections in this final
rule (and the shifting of some
information required in the proposed
rule as supporting an NDC request to
information required in the final rule as
drug listing information). Substantively,
§ 207.81 of this final rule identifies an
expanded set of information obtained
under the following sections as
information that will not be available for
public disclosure:
• § 207.53(b)—Immediate source
NDCs for repacked or relabeled drugs;
• § 207.54(a)—Immediate source
NDCs for salvaged drugs;
• § 207.54(c)—The name or UFI of an
establishment where a specific drug is
salvaged;
• § 207.55—Information submitted as
the basis upon which it has been
determined that a particular drug is not
subject to section 505 or 512 of the
Federal Food, Drug, and Cosmetic Act
or section 351 of the Public Health
Service Act;
• § 207.33(d)(3)—Information
submitted to reserve an NDC;
• § 207.49(a)(9)—For unfinished
drugs, the number assigned to the Drug
Master File or Veterinary Master File, if
any;
• § 207.49(a)(12)—The names and
UFIs of establishments where
manufacturing is performed for listed
drugs and/or immediate source NDCs;
• § 207.53(c)—The names and UFIs of
establishments where repacking or
relabeling is performed for listed drugs;
and
• § 207.49(a)(5)—The names of any
inactive ingredients submitted with
drug listing information for which the
registrant makes a valid assertion of
confidentiality.
In this final rule, establishment
registration information will be
available for disclosure, consistent with
section 510(f) of the FD&C Act, except
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
in limited circumstances as described in
§ 207.81(c). FDA has found that
nondisclosure of most drug listing
information for marketed drugs would
be inconsistent with the protection of
the public health. In most cases, drug
listing information is obvious or is
disclosed elsewhere (e.g., a drug’s
established and proprietary names, its
dosage form and route of
administration, its active ingredient(s)).
Specifically, FDA has made a finding
that nondisclosure of the listing
information identified in the following
bulleted list would be inconsistent with
protection of the public health, except
in limited circumstances as described in
§ 207.81(c):
• Information obtained under
§ 207.33 will be available for public
disclosure, but only after a drug is
marketed. This information that will be
available for public disclosure includes
information a registrant or private label
distributor submits or updates under
§ 207.33(c) to obtain an NDC labeler
code but does not include information
submitted under § 207.33(d)(3) to
reserve an NDC. Information submitted
under § 207.33(c) to obtain a labeler
code (and updates to the information)
includes basic contact information for
the registrant or private label distributor
to whom the labeler code is assigned,
the types of activities (e.g., manufacture,
repackaging, or private label
distribution) in which the person
requesting the labeler code engages with
respect to drugs, and the types of drugs
to which the labeler code will be
applied. This is not necessarily, but is
arguably, classified as drug listing
information because it relates to NDCs
and labeler code segments of NDCs.
FDA makes the finding referred to in
section 510(f) of the FD&C Act that
nondisclosure of this information, in the
case of marketed drugs, would be
inconsistent with protection of the
public health. The contact information
described in § 207.33(c)(1)(i) allows
consumers to verify in some cases that
they do not have a counterfeit product.
It also provides additional contact
information for the consumer’s
reference. Disclosure of the types of
activities reported under
§ 207.33(c)(1)(ii) may provide additional
clarity as to a labeler’s role in producing
or marketing a drug. Information on the
types of drugs to which a labeler code
will be applied, described in
§ 207.33(c)(1)(iii), is largely available to
the public, but centralizing it promotes
the free flow of information to interested
consumers.
• Most information obtained under
§ 207.49 (listing information a registrant
must submit for a drug it manufactures)
PO 00000
Frm 00030
Fmt 4701
Sfmt 4700
will be available for public disclosure
after a drug is marketed. This
information includes the drug’s NDC; its
established and proprietary name; the
name and quantity of each active
pharmaceutical ingredient in the drug;
the name of each inactive ingredient
(unless a valid assertion of
confidentiality is made); the dosage
form; the drug’s approved U.S.
application number if any; the drug type
(finished vs. unfinished, human vs.
animal, prescription vs.
nonprescription); for drugs subject to
the imprinting requirements of 21 CFR
part 206, the drug’s size, shape, color,
scoring, and code imprint (if any); the
route or routes of administration of the
drug; the schedule of the drug under the
Controlled Substances Act;
advertisements; labeling; contact
information for private label
distributors; OTC monograph references
if any; and the date on which a drug was
introduced into commercial
distribution. FDA makes the finding
referred to in section 510(f) of the FD&C
Act that nondisclosure of the foregoing
information, in the case of marketed
drugs, would be inconsistent with
protection of the public health. The
drug information described in
§§ 207.49(a)(1), (3), (10), (15), and
207.49(b)(1) and (2) will enable
individuals with concerns about
counterfeiting to compare information
about a product in their possession with
information provided to FDA. The
ingredient information described in
§§ 207.49(a)(4) and (5) will in some
cases allow individuals to verify
ingredient information provided in
labeling against FDA’s records. The
information described in §§ 207.49(a)(6),
(8), and (11) relates to proper physical
form and use of a drug. The application
number described in § 207.49(a)(7)
allows individuals to access disclosable
FDA records about a drug’s approval.
Whether and how a drug is scheduled
under the Controlled Substances Act
(§ 207.49(a)(13)) relates to safe use of the
drug. The advertisements and labeling
described in §§ 207.49(a)(14) and (15)
may include information individuals
have not seen elsewhere describing the
risks and benefits of a drug.
Furthermore, FDA’s disclosure of
labeling information obtained under
§ 207.49(a)(15) will allow for the
availability of current drug labeling
information through DailyMed, a
computerized repository of drug
information maintained by the National
Library of Medicine. The contact
information described in
§ 207.49(a)(16)(ii) may provide
additional contact information for an
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
individual’s reference. All of this
information is largely available to the
public, but centralizing it promotes the
free flow of information to interested
consumers, health care providers, and
others. Note that two types of
information obtained under § 207.49
will not be available for public
disclosure: (1) The names of inactive
ingredients in a listed drug if the
registrant listing the drug makes a valid
assertion of confidentiality for them at
the time of drug listing and (2) the
number assigned to the Drug Master File
or Veterinary Master File, if any, that
describes the manufacture of an
unfinished drug.
• Most information obtained under
§ 207.53 (listing information a registrant
must submit for a drug that it repacks
or relabels) will be available for public
disclosure after a drug is marketed. This
information includes the repacked or
relabeled drug’s NDC, labeling,
advertisements, and contact information
for private label distributors. FDA
makes the finding referred to in section
510(f) of the FD&C Act that
nondisclosure of the foregoing
information, in the case of marketed
drugs, would be inconsistent with
protection of the public health. The
NDC described in § 207.53(a) helps
identify who repacked or relabeled a
drug. Labeling and advertising
information described in §§ 207.53(d)
and 207.53(e) may include information
individuals have not seen elsewhere
describing the risks and benefits of a
drug. Furthermore, FDA’s disclosure of
labeling information obtained under
§ 207.53(d) will allow for the
availability of current drug labeling
information through DailyMed, a
computerized repository of drug
information maintained by the National
Library of Medicine. The contact
information for private label distributors
described in § 207.53(f)(2) may provide
additional contact information for an
individual’s reference. All of this
information is largely available to the
public, but centralizing it will promote
the free flow of information. Note that
two types of information obtained under
§ 207.53 are not available for disclosure:
(1) The NDC assigned to a finished drug
received by a registrant for repacking or
relabeling and (2) the name and UFI of
establishments where repacking or
relabeling is performed.
• Some information obtained under
§ 207.54 (listing information a registrant
must submit for a drug it salvages) will
be available for public disclosure after a
drug is marketed. This information
includes the salvaged drug’s lot number
and expiration date. FDA makes the
finding referred to in section 510(f) of
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
the FD&C Act that nondisclosure of the
foregoing information, in the case of
marketed drugs, would be inconsistent
with protection of the public health.
Disclosure of the lot number and
expiration date information described in
§ 207.54(b) may help address any
concerns about a salvaged product’s
quality, potency, and shelf life.
• Most information obtained under
§ 207.57 (information registrants must
submit when updating listing
information) will be available for public
disclosure. In most cases, information
submitted under § 207.57 updates
information previously submitted under
§§ 207.49, 207.53, or 207.54. The same
disclosure rules will apply whether
information is submitted in an original
drug listing submission or in an updated
listing. Our findings under section
510(f) of the FD&C Act, described
previously, that nondisclosure of certain
listing information obtained under
§§ 207.49, 207.53, and 207.54 would be
inconsistent with protection of the
public health apply whether the
information is obtained in an original
listing submission or an updated listing
submission. Accordingly, the reasons
supporting this finding discussed
previously apply to updates submitted
under § 207.57. Some information
obtained under § 207.57 will not have
been received previously under
§§ 207.49, 207.53, or 207.54. This
information includes: (1) The date a
registrant discontinues the manufacture,
repacking, relabeling, or salvaging for
commercial distribution of a listed drug
and the expiration date of the last lot
manufactured, repacked, relabeled, or
salvaged, (2) the date a registrant
resumes the manufacture, repacking, or
relabeling, for commercial distribution
or a drug previously discontinued, and
(3) certifications that no changes have
occurred since the last listing review
and update. FDA makes the finding
referred to in section 510(f) of the FD&C
Act that nondisclosure of the foregoing
information, in the case of marketed or
discontinued drugs, would be
inconsistent with protection of the
public health. The date a business
discontinues or resumes manufacturing
a drug, submitted under
§ 207.57(b)(1)(ii) or (iii), may help
address concerns some individuals may
have about whether a drug in their
possession is counterfeit. The
certification that no changes have
occurred described in § 207.57(b)(2) will
inform individuals that drug listing
information previously submitted to
FDA is up to date as of the no changes
certification date.
(Comment 86) One comment
requested that FDA not disclose the
PO 00000
Frm 00031
Fmt 4701
Sfmt 4700
60199
names of inactive ingredients in animal
drugs submitted with drug listing
information. This comment stated that
inactive ingredients in animal drugs are
generally not listed on labels. Another
comment urged FDA not to place the
burden on registrants to proactively
request that the names of inactive
ingredients in human drugs be treated
as trade secrets.
(Response) The proposed rule
included a discussion about disclosure
of inactive ingredients reported in drug
listing submissions and stated that FDA
will disclose this information unless it
is subject to trade secret protection. See
71 FR 51276 at 51321. In this final rule,
we are codifying that approach by
making it clear in § 207.81 that we will
not disclose the names of any inactive
ingredients submitted with drug listing
information for which the registrant
makes a valid assertion of
confidentiality under § 20.61 or other
applicable provision of law.
This approach will apply to both
human and animal drugs in an
ingredient-specific way. In other words,
in the absence of a well-supported
assertion of confidentiality for any given
inactive ingredient reported under
§ 207.49, the name of that inactive
ingredient will be available for public
disclosure. The inactive ingredient
composition of a drug product is of
interest to consumers and in most cases
is already disclosed on drug labels. We
find that categorical nondisclosure of
inactive ingredient information would
be inconsistent with protection of the
public health. It is therefore appropriate
that FDA consider this information
disclosable in the absence of a valid
assertion of confidentiality that supports
nondisclosure.
(Comment 87) One comment urged
FDA not to disclose the relationship
between customs brokers and their
clients. This comment noted that the
proposed rule would have required
foreign establishments to identify in
their establishment registrations each
person who imports or offers for import
their drugs into the United States. The
proposed rule would have defined the
term ‘‘person who imports or offers for
import’’ broadly to include agents and
brokers. As with establishment
registration information generally, this
information would have been available
for disclosure under § 207.81 of the
proposed rule.
(Response) As explained in our
response to comment 11, in this final
rule, we define the term ‘‘person who
imports or offers for import’’ more
narrowly than it was defined in the
proposed rule. The new definition is not
intended to include persons operating
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60200
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
merely as customs brokers. Therefore, a
person operating merely as a customs
broker will not be identified in a foreign
establishment’s registration information
and hence will not have its relationship
with the foreign establishment disclosed
under § 207.81.
(Comment 88) One comment asked
FDA to clarify the confidentiality of
information submitted to obtain an
NDC. Several comments stated that
disclosure of listing information is
inappropriate for a yet-to-be approved
product.
(Response) As discussed in response
to comment 31, under this final rule,
registrants will propose their own NDCs
with drug listing submissions. It is not
necessary under this final rule to
request an NDC from FDA and support
that request with the information
specified in § 207.33(c) of the proposed
rule. Some of the information specified
in proposed § 207.33(c) (e.g., the drug’s
proprietary name and established name)
has been added to drug listing
information required under §§ 207.49,
207.53, and 207.54 of this final rule. The
foregoing discussion explains which
drug listing information will be
available for disclosure and that it will
not be available for disclosure until after
the drug is marketed.
Section 207.33(d)(3) of this final rule
allows anyone with a labeler code to
voluntarily reserve an NDC for a drug
product under development before it is
listed. Information submitted under
§ 207.33(d)(3) to reserve an NDC is
identified in § 207.81(b)(3) as generally
exempt from disclosure. Because
information submitted to FDA under
§ 207.33(d)(3) will relate to drug
products under development, this
exemption from disclosure prior to
marketing is not inconsistent with
protection of the public health.
(Comment 89) Two comments stated
that under the proposed rule, drug
listing information would be exempt
from public disclosure unless the
Secretary deemed its release to be
necessary. These comments asked FDA
to clarify the circumstances under
which disclosure of drug listing
information would be considered
necessary.
(Response) These comments reflect a
misunderstanding of the proposed rule.
In the proposed rule, § 207.81 stated
unambiguously that ‘‘[a]fter a drug is
listed, all information obtained for that
drug under §§ 207.33, 207.49, 207.53,
and 207.54,’’ except for stated
exceptions, would be made available for
public disclosure upon request or at
FDA’s discretion (71 FR 51276 at
51353). We have determined, under
section 510(f) of the FD&C Act and as
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
explained in the foregoing discussion,
that most drug listing information
relating to marketed products will be
categorically presumed to be available
for public disclosure because an
exemption from disclosure would be
inconsistent with protection of the
public health. In the foregoing
discussion, we have explained that
§ 207.81 of this final rule identifies a set
of drug listing information that will
generally not be available for public
disclosure.
(Comment 90) One comment urged
FDA not to disclose registration and
listing information that reveals business
relationships among trading partners,
such as those between a drug’s
manufacturer and a private label
distributor or between a manufacturer
and a retail service repackager.
(Response) We have carefully
considered this comment, along with
section 510(f) of the FD&C Act and our
longstanding rules and policies
regarding disclosure of registration and
listing information. As a statutory
matter, establishment registration
information is generally disclosable.
(See section 510(f) of the FD&C Act.)
Thus, information required for
establishment registration under
§ 207.25 of this final rule is disclosable.
This final rule requires that foreign
establishments report the name of each
importer known to the establishment
and the name of each person who
imports or offers to import its drugs into
the United States. This information is
treated as establishment registration
information under section 510(i) of the
FD&C Act and under § 207.25 of this
final rule, rather than as drug listing
information. Because the information is
establishment registration information,
both the FD&C Act and this final rule
require that it be available for public
disclosure. FDA’s intention to make this
information available for disclosure was
highlighted in the proposed rule (71 FR
51276 at 51321).
Drug listing information will not be
available for public disclosure under
this final rule unless its nondisclosure
would be inconsistent with protection
of the public health, as set forth in
section 510(f) of the FD&C Act. Most
drug listing information is obvious or is
disclosed elsewhere such as in labeling
(e.g., size, shape, color, scoring, route of
administration, approved application
number, active ingredient(s)) and its
nondisclosure would be inconsistent
with protection of the public health.
However, we recognize that, as
emphasized in this comment, some drug
listing information may reveal
confidential business relationships. This
final rule exempts from public
PO 00000
Frm 00032
Fmt 4701
Sfmt 4700
disclosure drug listing information
obtained under § 207.49(a)(12) (name
and UFI of the establishments where a
drug is manufactured and/or immediate
source NDCs), § 207.53(c) (name and
UFI of establishments where repacking
or relabeling is performed), or
§ 207.54(c) (name and UFI of
establishments where salvaging is
performed).
(Comment 91) One comment urged
FDA to treat all registration and listing
information as categorically exempt
from disclosure.
(Response) We decline to take this
approach. As explained in the foregoing
discussion, the disclosure provisions in
this final rule are consistent with
section 510(f) of the FD&C Act, notably
its requirement that establishment
registration information be made
publicly available and that drug listing
information be disclosed only to the
extent that its nondisclosure would be
inconsistent with protection of the
public health.
H. Human Cells, Tissues, and Cellular
and Tissue-Based Products (Part 1271)
The proposed rule included relatively
minor amendments to part 1271 to
require electronic submission of
establishment registration and listing
information for HCT/Ps. These
amendments are retained in this final
rule with some revisions. Under this
final rule, manufacturers of HCT/Ps that
are regulated solely under section 361 of
the PHS Act are subject to establishment
registration and listing under part 1271.
Manufacturers of HCT/Ps that are
regulated under section 351 of the PHS
Act or as drugs under section 505 of the
FD&C Act are subject to establishment
registration and listing under part 207.
(HCT/Ps that are regulated as medical
devices under the FD&C Act are subject
to establishment registration and listing
under part 807.)
(Comment 92) One comment was
concerned about the breadth of the
definition of ‘‘importer’’ in proposed
§ 1271.3(mm). This comment noted that
the proposed rule’s definition of
‘‘importer’’ appeared to include
domestic transplant centers (hospitals)
housing patients awaiting hematopoietic
stem cell (HSC) transplant and argued
that requiring foreign establishments to
identify such hospitals as ‘‘importers’’
would be unreasonably burdensome.
(Response) Please see our response to
Comment 9 regarding the definition of
‘‘importer’’ in § 207.1. We agree with
those comments that challenged the
proposed definition as too broad,
particularly as it would have captured
downstream recipients of imported
products. In parts 207, 607, and 1271,
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
we have narrowed the new definitions
of ‘‘importer’’ by adding the words ‘‘at
the time of entry.’’ Therefore, these
definitions no longer capture
downstream recipients such as
hospitals.
IV. Compliance Dates
This final rule is effective November
29, 2016.
The proposed rule included proposed
compliance dates by which registrants
and other affected persons would be
required to comply with different
aspects of a final rule. For example, we
proposed that manufacturers, repackers,
and relabelers be given 3 years from the
effective date of a final rule to ensure
that the appropriate NDC appear on
their labels. Proposed compliance
deadlines were set forth in the preamble
to the proposed rule but were not
reflected in proposed codified
regulatory language. (See 71 FR 51276 at
51345.)
The compliance dates are adjusted in
this final rule to account for changes we
have made in the final rule and to
account for our 2009 implementation of
electronic registration and listing under
part 207 in accordance with revisions to
the FD&C Act. Compliance dates
associated with this final rule are
presented in table 2.
Registrants are encouraged to comply
with this final rule as soon as possible
after its effective date. In many cases,
the final rule will not necessitate
changes in a registrant’s current
registration and listing practices because
electronic submission of registration
60201
and listing information already takes
place, and the information currently
collected generally comports with this
final rule. We recognize, however, that
this final rule introduces new
requirements, and some registrants will
need to adjust their registration and
listing activities. Table 2 should be read
as a statement that FDA intends to
exercise enforcement discretion
between the effective date of this final
rule and the compliance deadlines set
forth in the table with respect to
changes introduced in this final rule. At
all times, however, persons subject to
registration and listing must fulfill their
statutory obligations and the relevant
regulatory provisions set forth in parts
207, 607, and 1271, either before or after
the effective date of this final rule.
TABLE 2—COMPLIANCE DEADLINES
Requirement
Effective date or compliance deadline
mstockstill on DSK3G9T082PROD with RULES2
Effective date of the final rule ..................................................................
Electronic submission of establishment registration and listing information under amended part 207.
90 days after publication.
For products currently subject to part 207, the electronic submission requirement in section 510(p) of the FD&C Act was largely implemented through FDA’s 2009 electronic registration and listing guidance (74 FR 26248). Upon the effective date of this final rule, FDA
expects continued electronic submission of registration and listing information in accordance with our electronic registration and listing
guidance and with new § 207.61. This applies to newly submitted
registration and listing information as well as updates to information
previously submitted. FDA will accept waiver requests in accordance
with § 207.65 of this final rule upon its effective date.
Two years after the effective date of this final rule, FDA intends to remove from our current electronic database establishment registration
and listing information submitted in the past on paper and not updated with a more recent electronic submission. The purpose of this
removal is to purge outdated information from our database, such as
information registrants failed to update after discontinuing a drug
product or closing an establishment. Therefore, registrants must migrate their establishment registration and listing information to our
electronic system (or obtain a waiver from the electronic submission
requirement) before that time if they have not already done so. Registrants may not rely on a ‘‘no changes’’ certification to migrate information submitted in the past on paper to our electronic system. They
must enter and transmit current registration and listing information to
FDA electronically.
Electronic submission of blood establishment registration and listing in- Owners or operators of human blood product establishments currently
formation under amended part 607.
register and list either electronically or by submitting Form FDA 2830
by mail. FDA will stop accepting paper submissions and require electronic submission of establishment registration and product listing information under amended part 607, unless individual waivers are
granted, 1 year after the effective date of this final rule.
Electronic submission of HCT/P establishment registration and listing Owners or operators of HCT/P establishments currently register and
information under part 1271.
list either electronically or by submitting Form FDA 3356 by mail.
FDA will stop accepting paper submissions and require electronic
submission of establishment registration and product listing information under amended part 1271, unless individual waivers are granted, 1 year after the effective date of this final rule.
Part 207, Subpart B—Registration (timing of establishment registration Registrants are required to submit and update establishment registraand update submissions and substance of the information submitted).
tion information in accordance with amended subpart B of part 207
no later than the time when registration information is due after the
first anniversary of the effective date of this final rule. If the effective
date falls between October 1 and December 31, registrants must
submit information required by amended subpart B no later than the
next October through December annual review and update period.
However, registrants must comply with new § 207.29(a) (expedited updates when certain establishment registration information changes)
upon the effective date of this final rule.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
PO 00000
Frm 00033
Fmt 4701
Sfmt 4700
E:\FR\FM\31AUR2.SGM
31AUR2
60202
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
TABLE 2—COMPLIANCE DEADLINES—Continued
Requirement
Effective date or compliance deadline
Part 207, Subpart D—Listing (timing of drug listing and update submissions and substance of the information submitted).
Registrants are required to submit and update drug listing information
in accordance with amended subpart D of part 207 (including the
submission of NDCs that are formatted in accordance with subpart C
of part 207) no later than the time when listing information is due
after the first anniversary of the effective date of this final rule. If the
effective date falls during either June or December, registrants must
submit information required by subpart D no later than the June or
December listing update 12 months after the effective date.
Registrants are required to submit and update establishment registration information in accordance with amended part 607 no later than
the time when establishment registration information is due after the
first anniversary of the effective date of this final rule. If the effective
date falls between October 1 and December 31, registrants must
submit establishment registration information required by amended
part 607 no later than the next October through December annual
review and update period.
However, registrants must comply with new § 607.26 (amendments to
establishment registration for certain changes such as ownership or
location) upon the effective date of this final rule.
Registrants are required to submit and update product listing information in accordance with amended part 607 no later than the time
when listing information is due after the first anniversary of the effective date of this final rule. If the effective date falls during either June
or December, registrants must submit information required by subpart D no later than the June or December listing update 12 months
after the effective date.
Registrants are required to submit and update establishment registration information in accordance with amended part 1271 no later than
the time when registration information is due after the first anniversary of the effective date of this final rule. If the effective date falls in
December, registrants must submit establishment registration information required by amended part 1271 no later than the next December annual review and update period under § 1271.21(b).
Registrants are required to submit and update listing information in accordance with amended part 1271 no later than the time when listing
information is due after the first anniversary of the effective date of
this final rule. If the effective date falls during either June or December, registrants must submit information required by amended part
1271 no later than the June or December listing update 12 months
after the effective date.
Part 607—Establishment registration for blood and blood products .......
Part 607—Listing for blood and blood products ......................................
Part 1271—Establishment registration for HCT/Ps ..................................
mstockstill on DSK3G9T082PROD with RULES2
Part 1271—Product listing for HCT/Ps ....................................................
V. Legal Authority
We have the legal authority to amend
our regulations on foreign and domestic
establishment registration and listing for
human drugs, including drugs that are
regulated under a BLA, and animal
drugs. The statutory basis for our
authority includes sections 201, 301,
501, 502, 503, 505, 506, 506A, 506B,
506C, 510, 512, 513–516, 518–520, 701,
704, 721, 801, and 903 of the FD&C Act
(21 U.S.C. 321, 331, 351, 352, 353, 355,
356, 356a, 356b, 356c, 360, 360b, 360c–
360f, 360h–360j, 371, 374, 379e, 381,
and 393); 15 U.S.C. 1451–1561; sections
351 and 361 of the PHS Act (42 U.S.C.
262 and 264); and section 122, Pub. L.
105–115, 111 Stat. 2322 (21 U.S.C. 355
note).
Section 510(c) of the FD&C Act
requires every person upon first
engaging in the manufacture,
preparation, propagation, compounding,
or processing of a drug to immediately
register with the Secretary his name,
place of business, any such
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
manufacturing establishments and their
unique facility identifiers, and a pointof-contact email address. The provisions
in section 510(b) and (d) of the FD&C
Act require annual registration
beginning on October 1 and ending on
December 31 of each year and
registration of additional
establishments, respectively. Section
510(i) of the FD&C Act requires any
establishment within any foreign
country engaged in the manufacture,
preparation, propagation, compounding,
or processing of a drug that is imported
or offered for import into the United
States to register with the Secretary by
providing certain information. These
provisions, together with section 701(a)
of the FD&C Act (among others),
authorize us to require the submission
of the registration information specified
in the final rule. The information
specified in this final rule will help us
identify who is manufacturing,
repacking, relabeling, or salvaging drugs
and where those operations are being
PO 00000
Frm 00034
Fmt 4701
Sfmt 4700
performed. In addition, some
information (e.g., official contact
information) will help us communicate
with establishments more effectively
and schedule inspections more
efficiently.
Section 510(j)(1) of the FD&C Act
requires every person who registers to
file with the Secretary, at the time of
registration, a list of all drugs that are
being manufactured, prepared,
propagated, compounded, or processed
by the registrant for commercial
distribution. That list must be prepared
in the form and manner prescribed by
the Secretary and must be accompanied
by a copy of labeling (or the label and
package insert) and, in some cases,
advertising. Section 510(j)(2) of the
FD&C Act requires listing information
updates every June and December. This
listing information gives us a current
inventory of marketed drugs. These
provisions of the FD&C Act and others,
together with section 701(a) of the FD&C
Act, provide authority for requiring the
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
submission of listing information set
forth in this proposal. The drug listing
information specified in this final rule
will help us: (1) Develop a more current,
robust inventory of drugs as a counterterrorism measure; (2) more effectively
administer our postmarketing
surveillance programs; (3) facilitate
recalls of products; (4) identify drugs or
ingredients in short supply in the event
of a national emergency; and (5) identify
drugs marketed in violation of the law.
Section 510(b) of the FD&C Act
requires that information registrants
supply for annual registration includes
a UFI for the establishment and includes
a point-of-contact email address. FDA
published final guidance in November
2014 specifying that FDA’s preferred
UFI for drug establishment registration
is the DUNS number, assigned and
managed by Dun & Bradstreet.
Section 510(p) of the FD&C Act
requires electronic submission of
establishment registration and listing
information, unless FDA waives the
electronic submission requirement in
individual cases. Establishments that
manufacture HCT/Ps currently register
and list HCT/Ps under FDA’s
regulations in part 1271. Pursuant to
authority under section 361 of the PHS
Act, FDA is requiring electronic
submission of registration and listing
information for HCT/Ps.
Section 510(j) requires biannual
updates of certain listing information.
Requiring certification under section
701(a) authority will help us with the
efficient enforcement of the FD&C Act
because we will be able to distinguish
between situations where there has been
noncompliance with registration and
listing requirements from situations
where there have been no changes in
information. The failure to register or
list under section 510 is a prohibited act
under section 301(p) of the FD&C Act,
and the failure to do either renders a
drug misbranded under section 502(o)
of the FD&C Act.
mstockstill on DSK3G9T082PROD with RULES2
VI. Analysis of Environmental Impact
We have determined under 21 CFR
25.30(h) that this action is of a type that
does not individually or cumulatively
have a significant effect on the human
environment. Therefore, neither an
environmental assessment nor an
environmental impact statement is
required.
VII. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the
final rule under Executive Order 12866,
Executive Order 13563, the Regulatory
Flexibility Act (5 U.S.C. 601–612), and
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
the Unfunded Mandates Reform Act of
1995 (Pub. L. 104–4). Executive Orders
12866 and 13563 direct us to assess all
costs and benefits of available regulatory
alternatives and, when regulation is
necessary, to select regulatory
approaches that maximize net benefits
(including potential economic,
environmental, public health and safety,
and other advantages; distributive
impacts; and equity). We have
developed a comprehensive Economic
Analysis of Impacts that assesses the
impacts of the final rule. We believe that
this final rule is not a significant
regulatory action as defined by
Executive Order 12866.
The Regulatory Flexibility Act
requires us to analyze regulatory options
that would minimize any significant
impact of a rule on small entities.
Because the final requirements will not
impose a significant burden on a
substantial number of small entities
(annualized costs represent at most, 0.01
percent of sales for small firms, and
0.002 percent for large firms, on
average), we certify that the final rule
will not have a significant economic
impact on a substantial number of small
entities.
The Unfunded Mandates Reform Act
of 1995 (section 202(a)) requires us to
prepare a written statement, which
includes an assessment of anticipated
costs and benefits, before issuing ‘‘any
rule that includes any Federal mandate
that may result in the expenditure by
State, local, and tribal governments, in
the aggregate, or by the private sector, of
$100,000,000 or more (adjusted
annually for inflation) in any one year.’’
The current threshold after adjustment
for inflation is $146 million, using the
most current (2015) Implicit Price
Deflator for the Gross Domestic Product.
This final rule will not result in an
expenditure in any year that meets or
exceeds this amount.
B. Summary of Benefits and Costs
The full assessment of the economic
analysis is available in Docket No. FDA–
2005–N–0464 (Ref. 1) and at https://
www.fda.gov/AboutFDA/
ReportsManualsForms/Reports/
EconomicAnalyses/default.htm.
The final rule clarifies and codifies
the Congressionally mandated
requirements in FDAAA and FDASIA,
and adds a few additional requirements
to the information needed to list
products. The final rule will improve
management of the establishment
registration and drug listing
requirements and make these processes
more efficient and effective for industry
and for FDA. Maintaining a
comprehensive electronic registration
PO 00000
Frm 00035
Fmt 4701
Sfmt 4700
60203
and listing system supports
implementation of the electronic
prescribing provisions of the MMA.
Because registrants submit electronic
copies of the drug labeling with their
drug listing, this rule also ensures the
availability of current drug information
through DailyMed, a computerized
repository of drug labeling maintained
by the National Library of Medicine.
Establishment registration information
helps FDA identify who is
manufacturing, repacking, relabeling,
and salvaging drugs and where those
operations are performed. Quickly
accessible electronic information about
each establishment in the supply chain
will help inform our enforcement efforts
and improve our oversight of the entire
drug supply chain. Product listing
information also gives FDA a current
inventory of drugs manufactured,
repacked, relabeled, or salvaged for
commercial distribution. Under current
practices, registrants would only update
listings when the listing information has
changed. Consequently, some registrants
have never submitted listings in an
electronic format. By requiring
electronic listings for all marketed
drugs, the final rule will modernize our
electronic systems and close an existing
gap in data for drugs that are listed in
our legacy system but not currently
listed in our electronic system. Because
the final rule primarily codifies current
business practices, we anticipate that
most of the benefits of a modern
electronic drug registration and listing
system were achieved as firms
implemented electronic submissions in
response to the FDAAA and FDASIA
legislation. The incremental changes
required by the final rule will yield
benefits in addition to those already
achieved. However, we lack sufficient
information to quantify these marginal
benefits.
Table 3 provides an itemized
description of each incremental cost
associated with registration and listing
for part 207, part 607, and part 1271
registrants. For part 207 registrants, the
final rule will require immediate source
NDCs for unfinished drugs, listing
missing inactive ingredients, and
certification of no changes to their drug
listings. Without the final rule, FDA
faces an information gap because
companies do not always notify the
Agency when they stop marketing a
product. For part 607 and part 1271
registrants, the requirements are quite
slight for those that already submit
registration and listing information
electronically and minimal for the much
smaller number of establishments that
need to migrate their paper registration
E:\FR\FM\31AUR2.SGM
31AUR2
60204
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
and listing records to electronic format.
All registrants will incur costs
associated with reading and
understanding the rule and revising
their standard operating procedures
(SOPs), and these items represent the
largest incremental cost. Most
incremental costs are one-time only; the
only recurring costs are for part 207
registrants for certifying no changes to
their listings the previous year when
they renew their registrations.
TABLE 3—ITEMIZED INCREMENTAL COSTS
[$ millions] 1
Incremental costs
Number of
hours
per unit
Frequency
Drugs and biological products (part 207):
Identify source of unfinished drugs (from source
NDCs).
Listing inactive ingredients ...................................
Listing legacy products ........................................
Read and understand the final rule .....................
Revise SOPs for registration and listing ..............
Revise SOPs for reusing NDCs ...........................
Certification of no-change ....................................
Number of units
Total cost
Once ................................
93,700 listings ..................
$3.1
Once ................................
Once ................................
Once ................................
Once ................................
Once ................................
Recurring annually ...........
0.25
2.5
21
19
11
0.5
40,800 listings ..................
26,300 listings ..................
5,900 registrants ..............
5,900 registrants ..............
2,950 registrants ..............
7,300 establishments .......
1.4
8.7
16.5
14.9
4.3
0.5
..........................................
........................
..........................................
49.4
Once ................................
Once ................................
Once ................................
Total costs (part 207) ....................................
Human-blood products (part 607):
Read and understand the final rule .....................
Revise SOPs for registration and listing ..............
Migrating records to FDA’s electronic systems ...
0.25
14
11
1
2,700 registrants ..............
27 registrants ...................
27 registrants ...................
5.0
0.04
0.0
Total costs (part 607) ....................................
Human-cell and tissue products (part 1271):
Read and understand the final rule .....................
Revise SOPs for registration and listing ..............
Migrating records to FDA’s electronic system .....
..........................................
........................
..........................................
5.1
Once ................................
Once ................................
Once ................................
14
11
1
2,800 registrants ..............
280 registrants .................
280 registrants .................
5.2
0.4
0.0
Total costs (part 1271) ..................................
..........................................
........................
..........................................
5.7
1 We
considered the length of the final rule, the number of small and large firms affected, and the extent each firm is affected in order to estimate the burden to read and understand the rule. For part 607 registration and listing, the cost estimate shown as $0.0 million represents
$3,591. For part 1271 registration and listing, the cost estimate shown as $0.0 million represents $37,240.
Table 4 summarizes the total
incremental costs; total annualized costs
are $9.0 million when calculated at a 7percent discount rate over 10 years, or
$7.5 million when calculated using a 3percent discount rate.
TABLE 4—ECONOMIC DATA: COSTS AND BENEFITS STATEMENT
Units
Category
Benefits:
Annualized Monetized
$ millions/year.
Annualized Quantified
Qualitative ..................
Primary
estimate
($millions)
Low
estimate
($millions)
High
estimate
($millions)
Year
dollars
Discount
rate
(percent)
....................
....................
....................
....................
....................
....................
....................
....................
Period
covered
(years)
7
3
7
3
The final rule will complete and codify modernization of the registration and listing system, thus allowing FDA to
identify establishments, specific drugs or ingredients, to facilitate recalls or information alerts, and to exercise
competent oversight of this important industry.
mstockstill on DSK3G9T082PROD with RULES2
Costs:
Annualized Monetized
$ millions/year.
$ 9.0
$ 7.5
....................
....................
2014
2014
7
3
10
10
Annualized Quantified
....................
....................
....................
....................
....................
....................
....................
....................
7
3
....................
....................
Qualitative
Transfers:
VerDate Sep<11>2014
Notes
20:25 Aug 30, 2016
Jkt 238001
PO 00000
Frm 00036
Fmt 4701
Sfmt 4700
E:\FR\FM\31AUR2.SGM
31AUR2
Recurring costs include
only annual time costs
of certifying there are no
changes to listings;
these costs are unique
to part 207 registrants.
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
60205
TABLE 4—ECONOMIC DATA: COSTS AND BENEFITS STATEMENT—Continued
Units
Category
Federal Annualized
Monetized $ millions/year.
From/To
Low
estimate
($millions)
High
estimate
($millions)
Year
dollars
....................
....................
....................
....................
From:
Other Annualized
Monetized $ millions/year.
From/To
Primary
estimate
($millions)
....................
Discount
rate
(percent)
Period
covered
(years)
Notes
7
3
To:
....................
....................
From:
....................
7
3
To:
Effects:
State, Local or Tribal Government: No estimated effect.
Small Business: The final rule will have little impact on small businesses; annualized costs represent, at most, 0.01 percent of annual sales
for small firms and 0.002 percent for large firms, on average.
mstockstill on DSK3G9T082PROD with RULES2
C. Response to Comments on the
Preliminary Impact Analysis of the
Proposed Rule
Most of the comments on the
regulatory impact analysis of the
proposed rule (PRIA) concerned the
assignment of NDC numbers and the
requirement that they be printed on
container labels. Because these
proposed changes are not included in
the final rule, the comments are moot
and are not discussed here. We also do
not discuss the comments on the
analysis of the proposed
implementation of mandatory electronic
registration and listing as this was
mandated by FDAAA and largely
implemented by guidance in 2009.
Interested parties were able to comment
on the burden estimates presented in
the draft guidance entitled ‘‘Providing
Regulatory Submissions in Electronic
Format—Drug Establishment
Registration and Drug Listing’’ when it
was announced in the Federal Register
of July 11, 2008 (73 FR 39964) (available
on the Internet at https://www.fda.gov/
Drugs under Guidances (Drugs). The
remaining comments have been grouped
by topic; the order in which they are
discussed is not a reflection of
importance.
(Comment 93) Some manufacturers
believed the PRIA did not address the
financial impact on their sector of the
industry and disagreed with the
Agency’s assertion of no significant
economic impact on a substantial
number of small businesses. In
particular, manufacturers of medical
foods and medical devices did not
believe we properly addressed the loss
of revenue they could experience if they
could not use NDC numbers on their
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
products. Contract manufacturers felt
there should be a separate analysis of
their sector of the industry as did
medical gas firms who asserted their
numbers were underrepresented.
(Response) We disagree with the
comments. NDC numbers were never
intended for use on medical foods. The
medical food industry began using
NDCs to simplify reimbursement
payments by insurance companies.
There are other mechanisms that can be
used for medical food product
reimbursement, and the secondary
impact from FDA enforcement of
existing rules is not part of a regulatory
impact analysis of new requirements.
The Unique Device Identification
System final rule (78 FR 58786,
September 24, 2013) replaces the use of
NDC numbers on medical devices with
a UDI number. The impact of this
change was accounted for in that rule.
The PRIA measured the incremental
cost to comply with the new or changed
requirements on a per-establishment
and per-listing basis. Most of the data in
the analysis of the proposed rule are not
relevant for the final rule because
mandatory electronic submission began
in June 2009 with the statutory
implementation authorized by FDAAA;
however, the methodology is relevant.
We estimated the incremental cost for
registration on a per establishment
basis. We included all registered
establishments in our estimate, so
establishments in all industry sectors
required to register are included in the
analysis if they comply with the
requirement. The information required
for each establishment is essentially the
same. Any economies of scale for a large
firm to register multiple establishments
at one time are economically
PO 00000
Frm 00037
Fmt 4701
Sfmt 4700
insignificant. The same is true for the
incremental cost to list products. A
contract manufacturer, or a repackager,
may have more than one product to list,
but the information required for each
product is essentially the same for a
contract manufacture and other
manufacturers. The final rule provides
that a private label distributer can list
the products it distributes on behalf of
contract manufacturers, but the legal
obligation remains the contract
manufacturers’.
The Regulatory Flexibility Act
requires Agencies to assess the
regulatory impact on domestic small
entities and to analyze options that
would lessen the burden on small
entities. The Small Business
Administration defines a drug
manufacturer as small if it employs
fewer than 750 people and a biological
products entity as small if it employs
fewer than 500.
The size of the entity is determined by
the total employment of the ultimate
parent firm, which can include
companies outside the drug and
biological products industries. For
example, if a drug manufacturer’s
ultimate parent is a financial holding
company that employs more than 750
people across a variety of industrial and
service sectors, the firm would be
considered large even if employment in
drug manufacturing is only 100
employees.
For the proposed rule, we used a
crude method, using U.S. Census
information and a database of FDA’s
‘‘Approved Drug Products with
Therapeutic Equivalence Evaluations’’
(commonly referred to as the Orange
Book) to characterize the number and
size of the affected firms and used U.S.
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60206
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
Census data from the 2002 Economic
Census and County Business Patterns
for the financial information in the
regulatory flexibility analysis. The
Census data are reported by North
American Industry Classification
System codes (NAICS). Depending on
the survey, the economic data are
collected on an establishment or firm
level. Companies whose primary NAICS
code is not a drug or biologic
manufacturer would not be included in
the financial survey data. For example,
the primary NAICS code for many small
medical gas companies is not
pharmaceutical preparations
manufacturing (NAICS 325412), so these
establishments are not included in the
Census data for NAICS 325412.
Including the financial data for medical
gas establishments in the analysis
would be optimal, but we are not aware
of publicly available data that would
capture this information. Although the
financial information characterizing the
industry did not include the medical gas
sector, medical gas establishments were
included in the burden estimates.
The regulatory impact analysis for
this final rule uses Dun & Bradstreet
information on total employment of the
ultimate parent company to determine
the size of entities affected by the rule,
but we still use the Census data for
NAICS 325412 and 325414 for the
financial information because of
limitations of available data.
There were a number of comments
regarding the burden of submitting
certain information in listing, in
particular batch information, inactive
ingredients, and certifying that there has
been no change to a listing.
(Comment 94) Some comments noted
that batch information is already
included in annual reports for products
that require applications, so the
information is a duplication of effort.
These comments also noted that this
information can change often and adds
an additional element that needs to be
tracked and updated.
(Response) After considering the
comments, FDA has decided not to
include the batch information
requirement in the final rule.
(Comment 95) Some comments
suggested FDA reconsider the
requirement or frequency of the
requirement to certify that no change is
necessary for listings every June and
December. Using the 0.25-hour estimate
from the proposed rule for the time
required to verify and certify a listing,
one company with 800 products
calculated that it would take 114 hours
(around 14, 8-hour days) twice a year to
comply with the requirement, assuming
about 60 percent of their total products
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
did not require updates in June and
December. Another company with over
7,000 products said it would take 6
months to validate and certify their
listings with no changes. They
suggested making the no changes
certification requirement every 2 years
rather than biannually. Another
comment suggested that changing the
requirement to certifying by
establishment, rather than by listing,
would result in a savings of $1 million
per year.
(Response) After considering the
comments, we have revised the
requirement for no changes certification
from a per-listing basis to an
establishment basis. Rather than
certifying each June and December that
there is no change to each individual
listing, registrants can certify by
establishment that the electronically
listed products are up to date when they
annually renew their registrations.
(Comment 96) Some comments
regarding submitting inactive
ingredients as part of listing stated it
was unnecessary, burdensome, and in
some cases would result in the release
of information a company considered
proprietary. These comments noted that
inactive ingredients are included in
human and animal drug applications
and must be listed on the labels of OTC
products. Some manufacturers of animal
drugs claimed that inactive ingredients
are not customarily supplied on the
label and were concerned with the
release of proprietary information.
(Response) Although inactive
ingredients are identified in product
applications and, in many cases, on
product labels, the information is not
easily accessible and the names are not
fully standardized. Listing is the only
mechanism by which FDA can readily
access ingredient information across all
products. Entering the inactive
ingredients using defined terminology
increases the accuracy and the
efficiency of data searches. We use the
information in listing to inform many
processes FDA uses for protecting
public health, including surveillance for
serious drug adverse reactions,
inspection of facilities used for drug
manufacturing and processing, and
monitoring drug products imported into
the United States. To prevent public
disclosure of information a registrant
views as confidential, an inactive
ingredient can be designated as
confidential during the listing process.
VIII. Paperwork Reduction Act of 1995
This final rule contains information
collection requirements that are subject
to review by the Office of Management
and Budget (OMB) under the Paperwork
PO 00000
Frm 00038
Fmt 4701
Sfmt 4700
Reduction Act of 1995 (the PRA) (44
U.S.C. 3501–3520). The title,
description, and respondent description
of the information collection provisions
are shown with an estimate of the
annual reporting burden. Included in
the estimate is the time for reviewing
instructions, searching existing data
sources, gathering and maintaining the
data needed, and completing and
reviewing each collection of
information.
Title: Requirements for Foreign and
Domestic Establishment Registration
and Listing for Human Drugs, Including
Drugs That Are Regulated Under a
Biologics License Application, and
Animal Drugs.
Description: The final rule
reorganizes, consolidates, clarifies, and
modifies current regulations on
registering establishments and listing
drugs codified in part 207 for human
and animal drugs, in part 607 for blood
and blood products, and in part 1271 for
HCT/Ps. The final rule describes when
and how to register and list and what
information must be submitted for
registration and listing. The final rule
clarifies the NDC system for drugs and
requires that each drug product subject
to the listing requirements of this final
rule have a unique NDC.
The final rule codifies the current
statutory requirement that registration
and listing information be submitted to
FDA electronically instead of using
paper forms unless a waiver is obtained.
Historically, drug establishment
registration and drug listing information
was submitted using Form FDA 2656
(Registration of Drug Establishment/
Labeler Code Assignment), Form FDA
2657 (Drug Product Listing), and Form
FDA 2658 (Registered Establishments’
Report of Private Label Distributors).
Before the enactment of FDAAA, section
510(p) of the FD&C Act expressly
provided for electronic submission of
drug establishment registration
information upon a finding that
electronic receipt was feasible, and
section 510(j) of the FD&C Act specified
that drug listing information was to be
prepared in the form and manner
prescribed by FDA. Section 224 of
FDAAA, which amended section 510(p)
of the FD&C Act, now requires
electronic drug listing in addition to
electronic drug establishment
registration. In certain cases, and as
discussed in section VIII.E, if it is
unreasonable to expect a person to
submit registration and listing
information electronically, FDA may
grant a waiver from the electronic
submission requirement.
In June 2009, FDA made available the
electronic registration and listing
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
guidance (74 FR 26248, available on the
Internet at https://www.fda.gov/Drugs
under Guidances (Drugs)) to provide
recommendations on fulfilling the
statutory requirement to submit
electronically drug establishment
registration and drug listing
information. The guidance describes the
types of information to include for
purposes of drug establishment
registration and drug listing and how to
prepare and submit the information in
an electronic format (Structured Product
Labeling (SPL) files) that FDA can
process, review, and archive. In June
2009, FDA began accepting submissions
required under the part 207 regulations
into our electronic drug registration and
listing system. The format for these
electronic submissions employs
Extensible Markup Language (XML) and
uses the SPL standard to organize the
data within the file. This electronic
registration and listing enables FDA to
employ a number of automated
validations to ensure the quality of the
data received.
In addition to the information that
previously was collected on the FDA
forms, the electronic registration and
listing guidance addresses, with respect
to part 207, the electronic submission of
other statutorily required information as
follows:
• The name of each importer that is
known to the establishment (the U.S.
company or individual in the United
States that is an owner, consignee, or
recipient of the foreign establishment’s
drug that is imported into the United
States) (section 510(i)(1)(A) of the FD&C
Act);
• The name of each person who
imports or offers the foreign
establishment’s drug for import (the
name of each agent, broker, or other
entity, other than a carrier, that the
foreign drug establishment uses to
facilitate the import of its drug into the
United States) (section 510(i)(1)(A) of
the FD&C Act); and
• For a registered foreign drug
establishment, the name, address, and
telephone number of its U.S. agent
(§ 207.40(c)).
The electronic registration and listing
guidance also recommends the
voluntary submission of the following
additional information, when
applicable:
• The email address for the United
States agent, and the telephone
number(s) and email address for the
importer and person who imports or
offers for import their drug;
• A site-specific Data Universal
Numbering System (DUNS) number for
each entity (in November 2014, we
issued the guidance for industry entitled
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
‘‘Specification of the Unique Facility
Identifier System for Drug
Establishment Registration’’ (79 FR
65977, available on the Internet at
https://www.fda.gov/Drugs under
Guidances (Drugs)) and obtained OMB
approval to broaden the entity
identification number covered in OMB
control number 0910–0045);
• The NDC product code for the
source drug that is repacked or
relabeled;
• Distinctive characteristics of certain
listed drugs (i.e., the flavor, the color,
and image of the actual solid dosage
form); and
• Registrants may indicate that they
view as confidential an inactive
ingredient or the registrant’s business
relationship with an establishment.
We currently have OMB approval
under the PRA (OMB control number
0910–0045) for the information
collection in current part 207, the
information that was submitted using
Form FDA 2656, Form FDA 2657, and
Form FDA 2658, and the information
collection set forth in the electronic
registration and listing guidance,
including the electronic submission of
registration and listing information as
required by FDAAA. The information
collection for current part 607 is
approved by OMB under OMB control
number 0910–0052. The information
collection for current part 1271 is
approved by OMB under OMB control
number 0910–0543.
In tables 5, 6, 7, and 8, we estimate
the total burden to comply with the
applicable information collection
requirements for parts 207, 607, and
1271 as set forth in this final rule. These
burden estimates for the applicable
regulations will replace some of the
currently approved estimates in OMB
control numbers 0910–0045, 0910–0052,
and 0910–0543. These estimates are
based on FDA’s experience with
reviewing registration and listing
submissions under part 207 since June
2009 and on the number of submissions
currently received, the number of
respondents submitting this
information, and the number of
registered establishments and listed
drugs, blood products, and HCT/Ps
currently in FDA’s drug registration and
listing database.
A. Registration Information Collection
Under Part 207
1. Requirements
Under § 207.17, manufacturers,
repackers, relabelers, and drug product
salvagers must register their
establishments. This is consistent with
current registration information
PO 00000
Frm 00039
Fmt 4701
Sfmt 4700
60207
collection, except that PET drug
producers are not exempt from
registration under the final rule, and the
final rule states that FDA will accept
registration information from a private
label distributor if it is acting as an
authorized agent for and submitting
information that pertains to an
establishment that manufactures,
repacks, relabels, or salvages drugs.
Under § 207.21, domestic
manufacturers, domestic repackers,
domestic relabelers, and domestic drug
product salvagers must complete initial
registration of each establishment no
later than 5 calendar days after
beginning to manufacture, repack,
relabel, or salvage a drug. In addition,
foreign manufacturers, foreign
repackers, foreign relabelers, and foreign
drug product salvagers must register
each establishment before the drug is
imported or offered for import into the
United States. This is consistent with
current registration information
collection.
The information that must be
provided to FDA for registration is
described in § 207.25. The final rule
does not require the following currently
required information collection:
• Kind of ownership or operation.
• Title of each corporate officer and
director.
The final rule requires the following
new registration information collection:
• Type of operations performed at
each establishment.
• Contact information for the
establishment’s official contact.
Under § 207.29, registrants must
review their registration information
annually between October 1 and
December 31and report all changes to
their registration information or certify
that no changes have occurred. In
addition to the annual review and
update, registrants must submit
expedited reports of certain changes
within 30 calendar days of the change.
Currently, registrants must renew their
registration information annually and
submit certain amendments to
registration within 5 days of a change.
Section 207.29 differs from the current
requirement to submit amendments to
registration in the following ways:
• The final rule lengthens the current
time period for reporting changes to
registration information from 5 days (10
business days for a change in United
States agent information) to 30 calendar
days.
• The final rule revokes the current
requirement to report a change in
individual ownership and corporate or
partnership structure and the current
requirement to submit a signed
E:\FR\FM\31AUR2.SGM
31AUR2
60208
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
mstockstill on DSK3G9T082PROD with RULES2
statement for a change in a registered
establishment’s firm name.
New registration information
collected under the final rule includes
the certification that no changes have
occurred and reporting certain changes
as expedited updates within 30 calendar
days.
2. Burden Estimates
Based on the number of new
establishments that currently register
each year, we estimate that
approximately 1,400 registrants will
submit electronically approximately
2,800 new establishment registrations
annually. Based on the number of
registered establishments in our
database, we estimate that
approximately 10,000 registrants will
provide approximately 10,000 annual
reviews and updates of registration
information (including expedited
updates) or reviews and certifications
that no changes have occurred.
The estimates include the registration
of establishments for both domestic and
foreign manufacturers, repackers,
relabelers, and drug product salvagers,
and registration information submitted
by anyone acting as an authorized agent
for an establishment that manufactures,
repacks, relabels, or salvages drugs. The
estimates include an additional 80 PET
drug producers who are not exempt
from registration under the final rule
and approximately 30 manufacturers of
plasma derivatives.
We estimate that it will take
approximately 1 hour for registrants to
submit initial registration information
electronically for each new
establishment.
We also estimate that it will take
approximately 30 minutes for each
annual review and update of registration
information (including any expedited
updates) or each review and
certification that no changes have
occurred.
The burden hour estimates are based
on our familiarity with the amount of
time it takes registrants to input
registration information electronically
since June 2009. The estimates are an
average of the time it would take to
register a domestic or foreign
establishment and an average of the
time it would take to review registration
information and update several
registration items in the database or
review registration information and only
certify that no changes have occurred.
B. Listing Information Collection Under
Part 207
1. Requirements
Under § 207.41, registrants must list
drugs they manufacture, repack, relabel,
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
or salvage for commercial distribution.
This requirement is consistent with
current listing information collection,
except that drug product salvagers are
not currently required to list under part
207.
The final rule revises current NDCrelated listing submissions as follows:
• A registrant must list each drug it
manufactures, repacks, or relabels using
an NDC that includes the registrant’s
own labeler code, regardless of whether
the drug is commercially distributed
under the registrant’s own label or trade
name or under the label or trade name
of a private label distributor.
• Each registrant must list each drug
it manufactures, repacks, or relabels for
commercial distribution under the trade
name or label of a private label
distributor using an NDC that includes
such private label distributor’s labeler
code.
• During listing, each manufacturer,
repacker, or relabeler must propose for
assignment by FDA an NDC that
includes its own labeler code for each
package size and type of drug that it
manufactures, repacks, or relabels for
commercial distribution.
• If a drug is distributed under the
trade name or label of a private label
distributor, the manufacturer, repacker,
or relabeler must also propose for
assignment by FDA an NDC that
includes the labeler code of the private
label distributor under whose trade
name or label the drug is distributed, for
each package size and type so
distributed.
• A manufacturer, repacker, relabeler,
or private label distributor may also
reserve a proposed NDC for a drug,
before the drug is listed, by submitting
certain information.
Under § 207.45, registrants must list,
no later than 3 calendar days after the
initial registration of each
establishment, any drug being
manufactured, repacked, relabeled, or
salvaged for commercial distribution at
that establishment. This requirement is
consistent with current listing
information collection, except that the
final rule specifies within 3 calendar
days after initial registration.
Under the final rule, the information
registrants must submit to list a drug,
including the information that must be
submitted (by a registrant or a private
label distributor) to receive a labeler
code, is described in §§ 207.33, 207.49,
207.53, 207.54, 207.55, and 207.61.
Under current part 207, we assign a
labeler code to each registrant and the
registrant assigns the product code and
the package code for each drug
product’s NDC.
PO 00000
Frm 00040
Fmt 4701
Sfmt 4700
The listing and NDC information
collections required by the final rule are
already approved by OMB under OMB
control number 0910–0045, except for
the following: (1) The name of each
inactive ingredient in a listed drug
(assertions of confidentiality associated
with individual inactive ingredients are
covered in the electronic registration
and listing guidance); (2) additional
information, such as email address, to
identify a domestic registrant
(identifying information for foreign
registrants is part of the electronic
registration and listing guidance
information collection and in current
§ 207.40(c)); (3) the drug master file or
veterinary master file number, if one
exists, must be submitted by the
manufacturer for an unfinished drug; (4)
drug product salvagers (who do not
repack or relabel) must submit the lot
number and expiration date and NDC
assigned to the drug immediately before
the drug is received by the drug product
salvager; (5) all new labeling for a
repacked or relabeled drug must be
submitted, and not only the changed
labeling; (6) package type and volume
information corresponding to the
package code segment of the NDC must
be submitted; (7) a drug’s OTC
monograph reference (if any) and the
date on which the drug was or will be
introduced into commercial distribution
are both requested for voluntary
submission; and (8) the name and
Unique Facility Identifier (UFI) of the
establishment where the registrant who
lists the drug manufactures it and the
type of operation performed on the drug
at that establishment, and, if an
immediate source NDC is not provided,
the name and UFI of every other
establishment where manufacturing is
performed for the drug and the type of
operation performed at each such
establishment must be provided.
Under § 207.57, registrants must
update drug listing information
submitted previously (either when the
change is made or, at a minimum, each
June and December). Registrants must
also notify FDA if any listed drug has
been discontinued from marketing or if
any discontinued drug has been
reintroduced and provide listing
information for any drug not yet listed
(at the time of annual establishment
registration if not sooner). Under
§ 207.35, registrants must notify us of a
change in any of the drug characteristics
(except certain identifying information)
for an NDC in § 207.33, and assign a
new product code and package code for
that drug. Current listing information
collection does not specifically require
any type of certification if there are no
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
mstockstill on DSK3G9T082PROD with RULES2
changes, and only material changes to
listing information must be reported.
2. Burden Estimates
Based on the number of drugs listed
annually since June 2009, we estimate
that approximately 1,713 registrants will
submit electronically approximately
12,469 new listings annually (including
the information submitted to obtain a
labeler code and to reserve an NDC for
future use).
Based on the number of drugs in our
listing database and the current number
of changes to listing information
submitted, we estimate that
approximately 5,300 registrants will
provide approximately 10,000 June and
10,000 December reviews and updates
of listing information—a total of
approximately 20,000 submissions
annually (including the information
submitted to revise an NDC).
The estimates for the number of drug
listings include both domestic and
foreign listings, listings submitted by
registrants for products sold under their
own names as well as products intended
for private label distribution, and
information submitted related to an
NDC and to obtain a labeler code. The
estimate for the number of drugs subject
to the listing requirements includes PET
drugs and approximately 30 plasma
derivatives. The estimates for the
number of June and December reviews
and updates of listing information
include the number of changes to drug
characteristics pertaining to the drug
product code to obtain a new NDC and
the reports of the withdrawal of an
approved drug from sale under
§ 314.81(b)(3)(iii).
Based on our familiarity with the time
required to input listing information
electronically since June 2009, we
estimate that it will take registrants
approximately 1 hour and 30 minutes to
submit information electronically for
each drug they list for the first time (for
both foreign and domestic registrant
listings). These estimates are an average
of the time it will take manufacturers,
repackers, relabelers, and drug product
salvagers, with drug product salvagers
taking considerably less time than
manufacturers. The estimates include
the time for submitting the content of
labeling and other labeling in electronic
format. (For drugs subject to an
approved marketing application, the
electronic submission of the content of
labeling under current § 314.50(l)(1)(i) is
also approved under OMB control
number 0910–0001.) We also estimate
that it will take approximately 45
minutes for each June and December
review and update of listing
information. These estimates are an
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
average of the time it would take to
review and update listing information or
to review and certify that no changes
have occurred. The estimates include
the time for submitting any labeling for
each drug, changes to the drug’s
characteristics submitted for a new
NDC, and reports of the withdrawal of
an approved drug from sale under
§ 314.81(b)(3)(iii).
C. Registration and Listing Information
Collection Under Part 607
1. Requirements
Under § 607.22(a) of the final rule,
blood establishments must submit
initial and subsequent registration and
product listing electronically through
the Blood Establishment Registration
and Product Listing system, or any
future superseding electronic system.
All information submitted under this
part must be transmitted to FDA
electronically. Currently, under
§ 607.22, manufacturers must register
establishments and list blood products
on Form FDA 2830. The requested
information is consistent with the
current requirement to register
establishments and list products
approved under OMB control number
0910–0052. A separate discussion
regarding waivers under § 607.22(b) is
discussed in section E.
Under §§ 607.25(a) and 607.25 (b)(3)
of the final rule, establishments must
include the Unique Facility Identifier as
part of the registration and product
listing. The other requested information
under this regulation is consistent with
the current requirements to register
establishments and list products
approved under OMB control number
0910–0052.
Under § 607.25(b)(1) of the final rule,
blood establishments are required to list
blood products by the established and
proprietary name. This is consistent
with the current listing requirement
approved under OMB control number
0910–0052. Currently, manufacturers of
plasma derivatives and bulk product
substances register and list under both
parts 607 and 207. The final rule revises
this requirement by requiring persons
who engage solely in the production of
plasma derivatives, bulk product
substances, and recombinant version of
plasma derivatives or animal derived
plasma derivatives to register and list
only under part 207. Any reduction in
burden is expected to be minimal
(approximately 20 establishments) and
will be reflected under OMB control
number 0910–0052. To be consistent
with part 207, we are also deleting the
reference in part 607 to Form FDA 2250
(National Drug Code Directory Input)
PO 00000
Frm 00041
Fmt 4701
Sfmt 4700
60209
because this form is no longer being
used by CDER or CBER.
Under current § 607.40, foreign
establishments must include
information for the United States agent
as part of its initial and updated
registration. The final rule requires
submission of minimal additional
information (i.e., email address) for the
United States agent. This information is
consistent with the current registration
information approved under OMB
control number 0910–0052. The final
rule requires the foreign establishment
to report to FDA changes in the United
States agent’s name, address, telephone
number, and email address within 30
calendar days of the change. The final
rule lengthens from 10 business days to
30 calendar days the time period for
reporting changes in the United States
agent’s information to FDA.
2. Burden Estimates
Based on the number of new
establishments that currently register
with FDA each year, we estimate 68
establishments will provide new
establishment registration and product
listings annually under §§ 607.22(a),
607.25(a), and (b)(3).
We estimate that it takes
approximately 60 minutes to provide
the initial registration and listing
information for each new establishment.
Based on the number of
establishments that currently submit
registration and product listing updates,
we estimate 2,615 establishments will
provide establishment registration and
product listing updates annually under
§§ 607.22(a), 607.25(a), and (b)(3).
We estimate that it takes
approximately 30 minutes to provide
the establishment registration and
listing update information for
establishment.
These burden hour estimates are
based on institutional experience with
the current registration and listing
requirements.
D. Registration and Listing Information
Collection Under Part 1271
1. Requirements
Under § 1271.22, establishments must
register, list products, and provide
updates electronically. The current
regulation includes the option to submit
registration, listing, and updates
electronically.
Under § 1271.25, establishments must
also submit the telephone number and
email address of the reporting official.
Each foreign establishment must submit
the name, the address, telephone
number, and email address of each
importer that is known to the
E:\FR\FM\31AUR2.SGM
31AUR2
60210
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
establishment and the name of each
person who imports or offers for import
such HCT/P to the United States.
Foreign establishments must also
submit the name, the address, telephone
number, and email address of their
United States agent.
Under § 1271.26, establishments must
report a change to the United States
agent’s name, address, telephone
number, or email address. The final rule
will also lengthen to 30 calendar days
the current requirement of reporting the
changes within 5 days.
mstockstill on DSK3G9T082PROD with RULES2
2. Burden Estimates
Based on the number of new
establishments that currently register
with FDA each year, we estimate that
approximately 225 establishments will
provide new establishment registration
annually. Based on information from
FDA’s database, we estimate that
approximately 2,700 establishments are
registered and listed with FDA and will
provide establishment and listing
updates. The number of establishments
that currently register and list with FDA
includes both foreign and domestic
establishments. If no change has
occurred, an update is not required.
Based on the number of establishments
from FDA’s database, we estimate that
approximately 1,200 establishments will
provide changes to establishment
ownership or location, or changes to the
United States agent’s information.
We estimate that it would take
approximately 45 minutes to provide
the initial registration and listing
information for each new establishment.
We estimate that it would take
approximately 30 minutes for each
annual review and update of registration
and listing information for each
establishment.
We estimate that it would take
approximately 15 minutes for each
establishment to provide a change in
ownership and location, or a change to
the U.S. agent’s information.
These burden hour estimates are
based on institutional experience with
the current registration and listing
requirements. The estimates are an
average of the time it would take to
register an establishment, and an
average of the time it would take to
review registration and listing
information, and update several
registration and listing items in the
database.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
E. Waiver Request Information
1. Part 207
Under § 207.65, registrants may
request a waiver from the requirement
in § 207.61 that information must be
provided to us in electronic format. We
expect very few waiver requests because
only a computer, Internet access, and an
email address are needed to register and
list electronically and because
electronic submission has been required
since June 2009.
We estimate that approximately one
registrant will request a waiver annually
and that each request will take
approximately 30 minutes to prepare
and submit to us.
2. Part 607
Under § 607.22(b), both domestic and
foreign establishments may request a
waiver from the requirement that
information must be provided to FDA in
electronic format. We expect few waiver
requests because only a computer,
Internet access, and an email address
are needed to register and list
electronically.
We estimate that approximately 25
manufacturers will request a waiver
annually and that each request will take
approximately 1 hour to prepare and
submit to us.
When we grant a request for a waiver,
we intend to make available to the
manufacturer the paper form—Form
FDA 2830 for registration and listing.
3. Part 1271
Under § 1271.23, manufacturers may
request a waiver from the requirement
in § 1271.22 that information must be
provided to FDA in electronic format.
We expect a limited number of waiver
requests because only a computer,
Internet access, and an email address
are needed to register and list
electronically.
We estimate that approximately 100
manufacturers will request a waiver
annually and that each request will take
approximately 1 hour to prepare and
submit to FDA.
When we grant a request for a waiver,
we intend to make available to the
manufacturer the paper form—revised
Form FDA 3356 for registration and
listing.
F. Public Disclosure Exemption
Requests
Under § 207.81(c), registrants may
request that certain information in
§ 207.81(a) not be made available from
their registration and listing
information. Based on our experience
PO 00000
Frm 00042
Fmt 4701
Sfmt 4700
with registration and listing information
inspection requests under current
§ 207.37, we estimate that
approximately 100 registrants will
submit this request annually and that
each request will take approximately 1
hour to prepare and submit to us.
(Assertions of confidentiality associated
with individual inactive ingredients or
the registrant’s business relationship
with an establishment is part of the June
2009 electronic registration and listing
guidance information collection and is
covered under OMB control number
0910–0045).
G. Standard Operating Procedure for
Electronic Submission
The requirement under section 510(p)
of the FD&C Act for electronic drug
establishment registration and
electronic drug listing resulted in our
amending OMB control number 0910–
0045 in June 2009 to include the burden
for preparing a standard operating
procedure (SOP) for the electronic
submission requirement, creating the
SPL file, including accessing and
reviewing the technical specifications
and instructional documents provided
by FDA, reviewing and selecting
appropriate terms and codes used to
create the SPL file, obtaining the digital
certificate used with FDA’s electronic
submission gateway, and uploading the
SPL file for submission. Although most
registrants have already prepared an
SOP for the electronic submission
requirements, each year additional firms
will need to create an SOP. As provided
in table 6, FDA estimates that
approximately 1,000 firms will have to
expend a one-time burden to prepare,
review, and approve an SOP, and we
estimate that it will take approximately
40 hours per recordkeeper to create
1,000 new SOPs, for a total of 40,000
hours. We also estimate approximately
3,295 hours for annual recordkeeping
maintenance of these records.
H. Capital Costs
There are one-time capital costs
associated with this rulemaking. These
costs are discussed in section VII,
‘‘Economic Analysis of Impacts.’’
Description of Respondents:
Manufacturers, repackers, relabelers,
drug product salvagers, and private
label distributors as described in the
final rule.
Burden Estimate: Tables 5, 6, 7, and
8 provide the annual reporting and
recordkeeping burdens for this final
rule.
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
60211
TABLE 5—ESTIMATED ANNUAL REPORTING BURDEN UNDER PART 207
Number of
respondents
21 CFR Sections and reporting requirements
Initial Establishment Registration (§§ 207.17, 207.21,
207.25) .............................................................................
Annual Review and Update of Registration Information (including expedited updates) (§ 207.29) .............................
Initial Listing (including NDC) Information (§§ 207.33,
207.41, 207.45, 207.49, 207.53, 207.54, 207.55) ...........
June and December Review and Update (or Certification)
of Listing (including NDC) Information (§§ 207.35,
207.57) .............................................................................
Waiver requests (§ 207.65) ..................................................
Public disclosure exemption requests (§ 207.81(c)) ............
Total Reporting Burden ................................................
Number of
responses per
respondent
Total annual
responses
Hours per
registration or
listing
Total hours
1,400
2
2,800
1
2,800
10,000
1
10,000
0.50
5,000
1,713
7.28
12,470
1.5
18,705
5,300
1
100
20
1
1
106,000
1
100
0.75
0.50
1
79,500
0.5
100
........................
........................
........................
........................
106,105
TABLE 6—ESTIMATED ANNUAL RECORDKEEPING BURDEN UNDER PART 207
Number of
recordkeepers
Number of
records per
Recordkeeper
One-time preparation of SOP ..............................................
SOP maintenance ................................................................
1,000
3,295
1
1
1,000
3,295
40
1
40,000
3,295
Total ..............................................................................
........................
........................
........................
........................
43,295
SOP for creating and uploading the SPL File
Total annual
records
Average
burden per
recordkeeping
Total hours
TABLE 7—ESTIMATED ANNUAL REPORTING BURDEN UNDER PART 607
Number of
respondents
21 CFR Sections
Number of
responses per
respondent
Total annual
responses
Average
burden per
response
Total hours
Initial Establishment Registration and Product Listing
(607.22(a) and 607.25(a) and (b)(3)) ...............................
Annual Review and Update of Establishment Registration
and Blood Product Listing (607.22(a) and 607.25(a) and
(b)(3)) ................................................................................
Waiver requests (607.22(b)) ................................................
68
1
68
1
68
2,615
25
1
1
2,615
25
0.5
1
1,308
25
Total Reporting Burden ................................................
........................
........................
........................
........................
1,401
TABLE 8—ESTIMATED ANNUAL REPORTING BURDEN UNDER PART 1271
Number of
respondents
21 CFR Sections
Number of
responses per
respondent
Total annual
responses
Average
burden per
response
Total hours
225
1
225
0.75
168.75
2,700
100
1,200
1
1
1
2,700
100
1,200
0.5
1
0.25
1,350
100
300
Total Reporting Burden ................................................
mstockstill on DSK3G9T082PROD with RULES2
Initial Establishment Registration and Listing (1271.25) .....
Annual Review and Update of Establishment Registration
and Listing (1271.25) .......................................................
Waiver requests (1271.23) ..................................................
Amend Establishment Registration (1271.26) .....................
........................
........................
........................
........................
1,918.75
The information collection provisions
of this final rule have been submitted to
OMB for review, as required by section
3507(d) of the PRA. Prior to the effective
date of this final rule, FDA will publish
a notice in the Federal Register
announcing OMB’s decision to approve,
modify, or disapprove the information
collection provisions in this final rule.
An Agency may not conduct or sponsor,
and a person is not required to respond
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
to, a collection of information unless it
displays a currently valid OMB control
number.
IX. Federalism
FDA has analyzed this final rule in
accordance with the principles set forth
in Executive Order 13132. FDA has
determined that the rule does not
contain policies that have substantial
direct effects on the States, on the
PO 00000
Frm 00043
Fmt 4701
Sfmt 4700
relationship between the National
Government and the States, or on the
distribution of power and
responsibilities among the various
levels of government. Accordingly, the
Agency has concluded that the rule does
not contain policies that have
federalism implications as defined in
the Executive order and, consequently,
a federalism summary impact statement
is not required.
E:\FR\FM\31AUR2.SGM
31AUR2
60212
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
X. References
The following reference is on display
in the Division of Dockets Management,
(HFA–305), Food and Drug
Administration, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852, and is
available for viewing by interested
persons between 9 a.m. and 4 p.m.,
Monday through Friday. It is also
available electronically at https://
www.regulations.gov and at https://
www.fda.gov/AboutFDA/
ReportsManualsForms/Reports/
EconomicAnalyses/default.htm.
1. FDA/Economics Staff, ‘‘Requirements for
Foreign and Domestic Establishment
Registration and Listing for Human
Drugs, Including Drugs That Are
Regulated Under a Biologics License
Application, and Animal Drugs, Final
Regulatory Impact Analysis, Final
Regulatory Flexibility Analysis,
Unfunded Mandates Reform Act
Analysis,’’ 2016.
List of Subjects
21 CFR Part 20
Confidential business information,
Courts, Freedom of information,
Government employees.
§ 20.100
[Amended]
2. Amend § 20.100(c)(9) by removing
‘‘§ 207.37’’ and by adding in its place
‘‘§ 207.81’’.
■
■
3. Revise § 20.116 to read as follows:
§ 20.116 Drug and device registration and
listing information.
Information submitted to the Food
and Drug Administration pursuant to
section 510(a) through (j) of the Federal
Food, Drug, and Cosmetic Act shall be
subject only to the special disclosure
provisions established in §§ 207.81 and
807.37 of this chapter.
Authority: 21 U.S.C. 321, 331, 351, 352,
353, 355, 358, 360, 360b, 360gg–360ss, 371,
374, 379e; 42 U.S.C. 216, 241, 262, 264.
§ 201.1
[Amended]
5. Amend § 201.1(f) by removing
‘‘§ 207.3(b)’’ and adding in its place
‘‘§ 207.1’’.
■
§ 201.2
[Amended]
6. Amend § 201.2 by removing the last
sentence.
■
21 CFR Parts 514 and 515
Administrative practice and
procedure, Animal drugs, Confidential
business information, Reporting and
recordkeeping requirements.
21 CFR Part 601
Administrative practice and
procedure, Biologics, Confidential
business information.
7. In § 201.25 revise the first sentence
of paragraph (c)(1) introductory text to
read as follows:
■
§ 201.25
Bar code label requirements.
*
21 CFR Part 607
Blood.
mstockstill on DSK3G9T082PROD with RULES2
Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19
U.S.C. 2531–2582; 21 U.S.C. 321–393, 1401–
1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,
243, 262, 263, 263b–263n, 264, 265, 300u–
300u–5, 300aa–l.
4. The authority citation for part 201
continues to read as follows:
21 CFR Part 314
Administrative practice and
procedure, Confidential business
information, Drugs, Reporting and
recordkeeping requirements.
21 CFR Part 1271
Biologics, Drugs, Human cells and
tissue-based products, Medical devices,
Reporting and recordkeeping
requirements.
Therefore, under the Federal Food,
Drug, and Cosmetic Act, the Public
Health Service Act, and under authority
delegated to the Commissioner of Food
and Drugs, 21 CFR parts 20, 201, 207,
Jkt 238001
1. The authority citation for part 20
continues to read as follows:
■
■
21 CFR Part 207
Drugs, Reporting and recordkeeping
requirements.
20:25 Aug 30, 2016
PART 20—PUBLIC INFORMATION
PART 201—LABELING
21 CFR Part 201
Drugs, Labeling, Reporting and
recordkeeping requirements.
VerDate Sep<11>2014
314, 514, 515, 601, 607, and 1271 are
amended as follows:
*
*
*
*
(c) * * *
(1) Each drug product described in
paragraph (b) of this section must have
a bar code that contains, at a minimum,
the appropriate National Drug Code
(NDC) number in a linear bar code that
meets European Article Number/
Uniform Code Council (EAN/UCC) or
Health Industry Business
Communications Council (HIBCC)
standards or another standard or format
that has been approved by the relevant
Food and Drug Administration Center
Director. * * *
*
*
*
*
*
■
8. Revise part 207 to read as follows:
PO 00000
Frm 00044
Fmt 4701
Sfmt 4700
PART 207—REQUIREMENTS FOR
FOREIGN AND DOMESTIC
ESTABLISHMENT REGISTRATION
AND LISTING FOR HUMAN DRUGS,
INCLUDING DRUGS THAT ARE
REGULATED UNDER A BIOLOGICS
LICENSE APPLICATION, AND ANIMAL
DRUGS, AND THE NATIONAL DRUG
CODE
Subpart A—General
Sec.
207.1 What definitions and interpretations
of terms apply to this part?
207.3 Bulk drug substance.
207.5 What is the purpose of this part?
207.9 Who does this part cover?
207.13 Who is exempt from the registration
and listing requirements?
Subpart B—Registration
207.17 Who must register?
207.21 When must initial registration
information be provided?
207.25 What information is required for
registration?
207.29 What are the requirements for
reviewing and updating registration
information?
Subpart C—National Drug Code
207.33 What is the National Drug Code
(NDC), how is it assigned, and what are
its requirements?
207.35 What changes require a new NDC?
207.37 What restrictions pertain to the use
of the NDC?
Subpart D—Listing
207.41 Who must list drugs and what drugs
must they list?
207.45 When, after initial registration of an
establishment, must drug listing
information be submitted?
207.49 What listing information must a
registrant submit for a drug that it
manufactures?
207.53 What listing information must a
registrant submit for a drug that it
repacks or relabels?
207.54 What listing information must a
registrant submit for a drug that it
salvages?
207.55 What additional drug listing
information may FDA require?
207.57 What information must registrants
submit when updating listing
information and when?
Subpart E—Electronic Format for
Registration and Listing
207.61 How is registration and listing
information provided to FDA?
207.65 How can a waiver of the electronic
submission requirement be obtained?
Subpart F—Miscellaneous
207.69 What are the requirements for an
official contact and a United States
agent?
207.77 What legal status is conferred by
registration and listing?
207.81 What registration and listing
information will FDA make available for
public disclosure?
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
Authority: 21 U.S.C. 321, 331, 351, 352,
355, 360, 360b, 371, 374, 381, 393; 42 U.S.C.
262, 264, 271.
Subpart A—General
mstockstill on DSK3G9T082PROD with RULES2
§ 207.1 What definitions and
interpretations of terms apply to this part?
The definitions and interpretations of
terms in sections 201 and 510 of the
Federal Food, Drug, and Cosmetic Act
apply to the terms used in this part, if
not otherwise defined in this section.
The following definitions apply to this
part:
Active pharmaceutical ingredient
means any substance that is intended
for incorporation into a finished drug
product and is intended to furnish
pharmacological activity or other direct
effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease, or to
affect the structure or any function of
the body. Active pharmaceutical
ingredient does not include
intermediates used in the synthesis of
the substance.
Bulk drug substance, as referenced in
sections 503A(b)(1)(A) and 503B(a)(2) of
the Federal Food, Drug, and Cosmetic
Act, means the same as ‘‘active
pharmaceutical ingredient’’ as defined
in § 207.1(b).
Commercial distribution means any
distribution of a human drug, except for
investigational use under part 312 of
this chapter, and any distribution of an
animal drug or an animal feed bearing
or containing an animal drug, except for
investigational use under part 511 of
this chapter. The term does not include
internal or interplant transfer between
registered establishments under
common ownership and control,
including a parent, subsidiary, or
affiliate company. For foreign
establishments that manufacture,
repack, relabel, or salvage, or for foreign
private label distributors, the term
‘‘commercial distribution’’ has the same
meaning except the term does not
include distribution of any drug that is
neither imported nor offered for import
into the United States.
Content of labeling means:
(1) For human prescription drugs that
are subject to section 505 of the Federal
Food, Drug, and Cosmetic Act or section
351 of the Public Health Service Act:
The content of the prescription drug
labeling (as specified in §§ 201.56,
201.57, and 201.80 of this chapter),
including all text, tables, and figures.
(2) For human prescription drugs that
are not subject to section 505 of the
Federal Food, Drug, and Cosmetic Act
or section 351 of the Public Health
Service Act: The labeling equivalent to
the content of the prescription drug
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
labeling (as specified in §§ 201.56,
201.57, and 201.80 of this chapter),
including all text, tables, and figures.
(3) For human over-the-counter (OTC)
drugs: All text, tables, and figures
including the drug facts labeling
required by § 201.66 of this chapter.
(4) For animal drugs (including, but
not limited to, drugs that are subject to
section 512 of the Federal Food, Drug,
and Cosmetic Act): The content of the
labeling that accompanies the drug that
is necessary to enable safe and proper
administration of the drug (e.g., the
labeling applicable to veterinary drugs
specified in part 201 of this chapter),
including all text, tables, and figures.
Domestic for purposes of registration
and listing under this part, when used
to modify the term ‘‘registrant,’’
‘‘manufacturer,’’ ‘‘repacker,’’
‘‘relabeler,’’ ‘‘salvager,’’ ‘‘private label
distributor,’’ or ‘‘establishment,’’ refers
to a registrant, manufacturer, repacker,
relabeler, salvager, private label
distributor, or establishment within any
State or Territory of the United States,
the District of Columbia, or the
Commonwealth of Puerto Rico.
Drug, for the purposes of registration
and listing under this part, has the
meaning given in section 201(g)(1) of
the Federal Food, Drug, and Cosmetic
Act.
Establishment means a place of
business under one management at one
general physical location. The term
includes, among others, independent
laboratories that engage in control
activities for a registered drug
establishment (e.g., consulting
laboratories), manufacturers of
medicated feeds and of vitamin
products that are drugs in accordance
with section 201(g) of the Federal Food,
Drug, and Cosmetic Act, human blood
donor centers, and animal facilities used
for the production or control testing of
licensed biologicals, and establishments
engaged in salvaging.
Establishment registration number
means the number assigned to the
establishment, as identified by FDA,
after the establishment registration
required in this part.
Finished drug product means a
finished dosage form (e.g., tablet,
capsule, or solution) that contains at
least one active pharmaceutical
ingredient, generally, but not
necessarily, in association with other
ingredients in finished package form
suitable for distribution to pharmacies,
hospitals, or other sellers or dispensers
of the drug product to patients or
consumers.
Foreign for the purposes of
registration and listing under this part:
PO 00000
Frm 00045
Fmt 4701
Sfmt 4700
60213
(1) When used to modify the term
‘‘manufacturer,’’ ‘‘repacker,’’
‘‘relabeler,’’ or ‘‘salvager,’’ refers to a
manufacturer, repacker, relabeler, or
salvager, who is located in a foreign
country and who manufactures, repacks,
relabels, or salvages a drug, or an animal
feed bearing or containing a new animal
drug, that is imported or offered for
import into the United States.
(2) When used to modify the term
‘‘establishment’’ refers to an
establishment that is located in a foreign
country and is engaged in the
manufacture, repackaging, relabeling, or
salvaging of any drug, or any animal
feed bearing or containing a new animal
drug, that is imported or offered for
import into the United States.
Importer means, for purposes of this
part, a person in the United States that
is an owner, consignee, or recipient, at
the time of entry, of a foreign
establishment’s drug, or an animal feed
bearing or containing a new animal
drug, that is imported into the United
States.
Manufacture means each step in the
manufacture, preparation, propagation,
compounding, or processing of a drug or
an animal feed bearing or containing a
new animal drug. Manufacture includes
the making by chemical, physical,
biological, or other procedures or
manipulations of a drug, or an animal
feed bearing or containing a new animal
drug, including control procedures
applied to the final product or to any
part of the process. Manufacture
includes manipulation, sampling,
testing, or control procedures applied to
the final product or to any part of the
process, including, for example,
analytical testing of drugs for another
registered establishment’s drug. For
purposes of this part, and in order to
clarify the responsibilities of the entities
engaged in different operations, the term
manufacture is defined and used
separately from the terms relabel,
repackage, and salvage, although the
term ‘‘manufacture, preparation,
propagation, compounding, or
processing,’’ as used in section 510 of
the Federal Food, Drug, and Cosmetic
Act, includes relabeling, repackaging,
and salvaging activities.
Manufacturer means a person who
owns or operates an establishment that
manufactures a drug or an animal feed
bearing or containing a new animal
drug. This term includes, but is not
limited to, control laboratories, contract
laboratories, contract manufacturers,
contract packers, contract labelers, and
other entities that manufacture a drug,
or an animal feed bearing or containing
a new animal drug, as defined in this
paragraph. For purposes of this part,
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
60214
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
and in order to clarify the
responsibilities of the entities engaged
in different operations, the term
manufacturer is defined and used
separately from the terms relabeler,
repacker, and salvager, although the
term ‘‘manufacture, preparation,
propagation, compounding, or
processing,’’ as used in section 510 of
the Federal Food, Drug, and Cosmetic
Act, includes the activities of relabelers,
repackers, and salvagers. Repackers,
relabelers, and salvagers are subject to
the provisions of this part that are
applicable to repackers, relabelers, and
salvagers, but are not subject to the
provisions of this part that are
applicable to manufacturers. When not
modified by ‘‘domestic’’ or ‘‘foreign,’’
the term includes both domestic
manufacturers and foreign
manufacturers.
Material change means any change in
any drug listing information, as required
under §§ 207.49, 207.53, 207.54, 207.55,
or 207.57 except changes in format of
labeling, labeling changes of an editorial
nature, or inclusion of a bar code or
initial inclusion of an NDC on the label.
Outsourcing facility means a
compounder that has elected to register
with FDA under section 503B of the
Federal Food, Drug, and Cosmetic Act
and that meets all of the conditions of
section 503B.
Person who imports or offers for
import means, for purposes of this part,
the owner or exporter of a drug who
consigns and ships a drug from a foreign
country to the United States. This
includes persons who send a drug to the
United States by international mail or
other private delivery service, but it
does not include carriers who merely
transport the drug.
Private label distribution means
commercial distribution of a drug under
the label or trade name of a person who
did not manufacture, repack, relabel, or
salvage that drug.
Private label distributor means, with
respect to a particular drug, a person
who did not manufacture, repack,
relabel, or salvage the drug but under
whose label or trade name the drug is
commercially distributed.
Registrant means any person that
owns or operates an establishment that
manufactures, repacks, relabels, or
salvages a drug, and is not otherwise
exempt from establishment registration
requirements under section 510 of the
Federal Food, Drug, and Cosmetic Act
or this part.
Relabel means to change the existing
label or labels on a drug or drug
package, or change or alter the existing
labeling for a drug or drug package,
without repacking the drug or drug
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
package. This term does not include the
addition or modification of information
affixed solely for purposes of delivery to
a customer, customer identification,
and/or inventory management.
Relabeler means a person who owns
or operates an establishment that
relabels a drug. When not modified by
‘‘domestic’’ or ‘‘foreign,’’ the term
includes both domestic relabelers and
foreign relabelers.
Repack or repackage means the act of
taking a finished drug product or
unfinished drug from the container in
which it was placed in commercial
distribution and placing it into a
different container without
manipulating, changing, or affecting the
composition or formulation of the drug.
Repacker means a person who owns
or operates an establishment that
repacks a drug or drug package. When
not modified by ‘‘domestic’’ or
‘‘foreign,’’ the term includes both
domestic repackers and foreign
repackers.
Representative sampling of
advertisements means typical
advertising material (including the
promotional material described in
§ 202.1(l)(1) of this chapter, but
excluding labeling as determined in
§ 202.1(l)(2) of this chapter), that gives
a balanced picture of the promotional
claims used for the drug.
Representative sampling of any other
labeling means typical labeling material
(including the labeling material
described in § 202.1(l)(2) of this chapter,
but excluding labels and package
inserts) that gives a balanced picture of
the promotional claims used for the
drug.
Salvage means the act of segregating
out those finished drug products that
may have been subjected to improper
storage conditions (such as extremes in
temperature, humidity, smoke, fumes,
pressure, age, or radiation) for the
purpose of returning the products to the
marketplace and includes applying
manufacturing controls such as those
required by current good manufacturing
practice in parts 210 and 211 of this
chapter.
Salvager means a person who owns or
operates an establishment that engages
in salvaging. When not modified by
‘‘domestic’’ or ‘‘foreign,’’ the term
includes both domestic and foreign
salvagers.
Unfinished drug means an active
pharmaceutical ingredient either alone
or together with one or more other
ingredients but does not include
finished drug products.
PO 00000
Frm 00046
Fmt 4701
Sfmt 4700
§ 207.3
Bulk drug substance.
Bulk drug substance, as referenced in
sections 503A(b)(1)(A) and 503B(a)(2) of
the Federal Food, Drug, and Cosmetic
Act, previously defined in § 207.3(a)(4),
means the same as ‘‘active
pharmaceutical ingredient’’ as defined
in § 207.1(b).
§ 207.5
What is the purpose of this part?
Establishment registration
information helps FDA identify who is
manufacturing, repacking, relabeling,
and salvaging drugs and where those
operations are performed. Drug listing
information gives FDA a current
inventory of drugs manufactured,
repacked, relabeled, or salvaged for
commercial distribution. Both types of
information facilitate implementation
and enforcement of the Federal Food,
Drug, and Cosmetic Act and are used for
many important public health purposes.
§ 207.9
Who does this part cover?
(a) Except as provided in paragraph
(b) of this section, this part applies to:
(1) Domestic manufacturers, domestic
repackers, domestic relabelers and
domestic salvagers, not exempt under
section 510(g) of the Federal Food, Drug,
and Cosmetic Act or § 207.13, regardless
of whether their drugs enter interstate
commerce;
(2) Foreign manufacturers, foreign
repackers, foreign relabelers and foreign
salvagers, not exempt under section
510(g) of the Federal Food, Drug, and
Cosmetic Act or § 207.13;
(3) Private label distributors, because
they must have labeler codes;
(4) Establishments engaged in the
manufacture, repacking, relabeling, or
salvaging of human drugs regulated
under a biologics license application
(BLA). These establishments are subject
to the requirements of this part unless
they are required to register and list
such drugs as human blood or blood
products under part 607 of this chapter
and do not engage in activities that
would otherwise require them to
register and list under this part.
(5) Establishments engaged in the
manufacture (as defined in § 1271.3(e)
of this chapter) of human cells, tissues,
and cellular and tissue-based products
(HCT/Ps) (as defined in § 1271.3(d) of
this chapter) that, under § 1271.20 of
this chapter, are also drugs regulated
under section 351 of the Public Health
Service Act or section 505 of the Federal
Food, Drug, and Cosmetic Act. These
establishments must register and list
those HCT/Ps following the procedures
described in this part.
(b) This part does not apply to owners
and operators of establishments that
collect or process human whole blood
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
and blood products unless the
establishment also manufactures,
repacks, or relabels other drugs. For
purposes of this paragraph (b), human
whole blood and blood products do not
include plasma derivatives such as
albumin, Immune Globulin, Factor VIII
and Factor IX, and recombinant versions
of plasma derivatives or animal derived
plasma derivatives, or bulk product
substances such as fractionation
intermediates or pastes. Establishments
that collect or process human whole
blood and blood products as well as
establishments involved in testing of
human whole blood and blood products
must register and list under part 607 of
this chapter. Manufacturers of licensed
devices and manufacturers of licensed
biological products used in a licensed
device must register and list under part
607 of this chapter.
(c) This part does not apply to
establishments that solely manufacture,
prepare, propagate, compound,
assemble, or process medical devices.
Registration and listing regulations for
such establishments are codified in part
807 of this chapter.
mstockstill on DSK3G9T082PROD with RULES2
§ 207.13 Who is exempt from the
registration and listing requirements?
Except as provided in § 207.13(l), the
following classes of persons are exempt
from registration and drug listing in
accordance with section 510(g) of the
Federal Food, Drug, and Cosmetic Act
or because FDA has determined, under
section 510(g)(5) of the Federal Food,
Drug, and Cosmetic Act, that their
registration is not necessary for the
protection of the public health. This
exemption is limited to establishment
registration and drug listing
requirements and does not relieve a
person from other statutory or
regulatory obligations.
(a)(1) Pharmacies that:
(i) Operate in conformance with all
applicable local laws regulating the
practice of pharmacy and medicine,
including all applicable local laws
regulating the dispensing of prescription
drugs;
(ii) Regularly engage in dispensing
prescription drugs upon a valid
prescription by practitioners licensed by
law to administer these drugs to patients
under their professional care; and
(iii) Do not manufacture, repack,
relabel, or salvage drugs other than in
the regular course of their business of
dispensing or selling drugs at retail.
(2) The exemption in this paragraph
(a) is limited to pharmacies located in
any State as defined in section 201(a)(1)
of the Federal Food, Drug, and Cosmetic
Act.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
(b)(1) Hospitals, clinics, other health
care entities, and public health agencies
that:
(i) Operate establishments in
conformance with all applicable local
laws regulating the practice of pharmacy
and medicine, including all applicable
local laws regulating the dispensing of
prescription drugs;
(ii) Regularly engage in dispensing
prescription drugs, other than human
whole blood or blood products, upon a
valid order or prescription by
practitioners licensed by law to
administer these drugs to patients under
their professional care; and
(iii) Do not manufacture, repack,
relabel, or salvage drugs other than in
the regular course of their practice of
pharmacy, including dispensing.
(2) The exemption in this paragraph
(b) is limited to hospitals, clinics, other
health care entities, and public health
agencies located in any State as defined
in section 201(a)(1) of the Federal Food,
Drug, and Cosmetic Act.
(c) Individuals or establishments
under contract, agreement, or other
arrangement with a registered
establishment and engaged solely in
recovering cells or tissues and sending
the recovered cells or tissues to the
registered establishment to become
components of a biological product are
exempt from registration and listing
under this part unless FDA determines
that drug establishment registration and
listing is necessary for the protection of
the public health.
(d) Practitioners who are licensed by
law to prescribe or administer drugs and
who manufacture, repack, relabel, or
salvage drugs solely for use in their
professional practice.
(e) Manufacturers, repackers,
relabelers, or salvagers who
manufacture, repack, relabel, or salvage
drugs solely for use in research,
teaching, or chemical analysis and not
for sale.
(f) Manufacturers, repackers, and
relabelers of harmless inactive
ingredients such as excipients,
colorings, flavorings, emulsifiers,
lubricants, preservatives, or solvents
that become components of drugs.
(g) Manufacturers, repackers,
relabelers, or salvagers of Type B or
Type C medicated feeds, except for
persons who manufacture, repack,
relabel, or salvage Type B or Type C
medicated feeds starting from Category
II, Type A medicated articles for which
a medicated feed mill license approved
under part 515 of this chapter is
required. This exemption also does not
apply to persons that would otherwise
be required to register (such as
manufacturers, repackers, relabelers, or
PO 00000
Frm 00047
Fmt 4701
Sfmt 4700
60215
salvagers of certain free-choice feeds, as
defined in § 510.455 of this chapter, or
certain liquid feeds, as defined in
§ 558.5 of this chapter, where the
specifications and/or formulas are not
published and a medicated feed mill
license is required). All manufacturers,
repackers, relabelers, or salvagers of
Type B or Type C medicated feeds are
exempt from listing.
(h) Any manufacturer, repacker,
relabeler, or salvager of a virus, serum,
toxin, or analogous product intended for
the treatment of domestic animals who
holds an unsuspended and unrevoked
license issued by the Secretary of
Agriculture under the animal virusserum-toxin law of March 4, 1913 (37
Stat. 832 (21 U.S.C. 151 et seq.)),
provided that this exemption from
registration applies only to the
manufacturer, repacker, relabeler, or
salvager of that animal virus, serum,
toxin, or analogous product.
(i) Carriers, in their receipt, carriage,
holding, or delivery of drugs in the
usual course of business as carriers.
(j) Foreign establishments whose
drugs are imported or offered for import
into the United States must comply with
the establishment registration and
listing requirements of this part unless
exempt under this section or unless:
(1) Their drugs enter a foreign trade
zone and are re-exported without having
entered U.S. commerce, or
(2) Their drugs are imported in
conformance with section 801(d)(3) of
the Federal Food, Drug, and Cosmetic
Act.
(k) Entities that are registered with
FDA as outsourcing facilities and that
compound drugs in conformance with
section 503B of the Federal Food, Drug,
and Cosmetic Act.
(l) The exemptions provided in
paragraphs (a) through (k) of this section
do not apply to such persons if they:
(1) Manufacture (as defined in
§ 207.1(b)), repack, relabel, or salvage
compounded positron emission
tomography drugs as defined in section
201(ii) of the Federal Food, Drug, and
Cosmetic Act;
(2) Manufacture (as defined in
§ 600.3(u) of this chapter) a human
biological product subject to licensing
under section 351 of the Public Health
Service Act; or
(3) Engage in activities that would
otherwise require them to register under
this part.
Subpart B—Registration
§ 207.17
Who must register?
(a) Unless exempt under section
510(g) of the Federal Food, Drug, and
Cosmetic Act or this part, all
E:\FR\FM\31AUR2.SGM
31AUR2
60216
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
manufacturers, repackers, relabelers,
and salvagers must register each
domestic establishment that
manufactures, repacks, relabels, or
salvages a drug, or an animal feed
bearing or containing a new animal
drug, and each foreign establishment
that manufactures, repacks, relabels, or
salvages a drug, or an animal feed
bearing or containing a new animal
drug, that is imported or offered for
import into the United States. When
operations are conducted at more than
one establishment and common
ownership and control among all the
establishments exists, the parent,
subsidiary, or affiliate company may
submit registration information for all
establishments.
(b) Private label distributors who do
not also manufacture, repack, relabel, or
salvage drugs are not required to register
under this part. FDA will accept
registration or listing information
submitted by a private label distributor
only if it is acting as an authorized agent
for and submitting information that
pertains to an establishment that
manufactures, repacks, relabels, or
salvages drugs.
§ 207.21 When must initial registration
information be provided?
(a) Registrants must register each
domestic establishment no later than 5
calendar days after beginning to
manufacture, repack, relabel, or salvage
a drug or an animal feed bearing or
containing a new animal drug at such
establishment.
(b) Registrants must register each
foreign establishment before a drug or
an animal feed bearing or containing a
new animal drug manufactured,
repacked, relabeled, or salvaged at the
establishment is imported or offered for
import into the United States.
mstockstill on DSK3G9T082PROD with RULES2
§ 207.25 What information is required for
registration?
Registrants must provide the
following information:
(a) Name of the owner or operator of
each establishment; if a partnership, the
name of each partner; if a corporation,
the name of each corporate officer and
director, and the place of incorporation;
(b) Each establishment’s name,
physical address, and telephone
number(s);
(c) All name(s) of the establishment,
including names under which the
establishment conducts business or
names by which the establishment is
known;
(d) Registration number of each
establishment, if previously assigned by
FDA;
(e) A Unique Facility Identifier in
accordance with the system specified
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
under section 510 of the Federal Food,
Drug, and Cosmetic Act.
(f) All types of operations performed
at each establishment;
(g) Name, mailing address, telephone
number, and email address of the
official contact for the establishment, as
provided in § 207.69(a); and
(h) Additionally, with respect to
foreign establishments subject to
registration, the name, mailing address,
telephone number, and email address
must be provided for:
(1) The United States agent, as
provided in § 207.69(b);
(2) Each importer in the United States
of drugs manufactured, repacked,
relabeled, or salvaged at the
establishment that is known to the
establishment; and
(3) Each person who imports or offers
for import such drug to the United
States.
§ 207.29 What are the requirements for
reviewing and updating registration
information?
(a) Expedited updates. Registrants
must update their registration
information no later than 30 calendar
days after:
(1) Closing or selling an
establishment;
(2) Changing an establishment’s name
or physical address; or
(3) Changing the name, mailing
address, telephone number, or email
address of the official contact or the
United States agent. A registrant, official
contact, or United States agent may
notify FDA about a change of
information for the designated official
contact or United States agent, but only
a registrant is permitted to designate a
new official contact or United States
agent.
(b) Annual review and update of
registration information. Registrants
must review and update all registration
information required under § 207.25 for
each establishment.
(1) The first review and update must
occur during the period beginning on
October 1 and ending December 31 of
the year of initial registration, if the
initial registration occurs prior to
October 1. Subsequent reviews and
updates must occur annually, during the
period beginning on October 1 and
ending December 31 of each calendar
year.
(2) The updates must reflect all
changes that have occurred since the
last annual review and update.
(3) If no changes have occurred since
the last registration, registrants must
certify that no changes have occurred.
PO 00000
Frm 00048
Fmt 4701
Sfmt 4700
Subpart C—National Drug Code
§ 207.33 What is the National Drug Code
(NDC), how is it assigned, and what are its
requirements?
(a) What is the NDC for a drug and
what products must have unique NDCs?
The NDC for a drug is a numeric code.
Each finished drug product or
unfinished drug subject to the listing
requirements of this part must have a
unique NDC to identify its labeler,
product, and package size and type.
(b) What is the format of an NDC? (1)
Except as described in paragraph (b)(4)
of this section, the NDC must consist of
10 or 11 digits, divided into three
segments as follows:
(i) The first segment of the NDC is the
labeler code and consists of 4, 5, or 6
digits. The labeler code is assigned by
FDA.
(ii) The second segment of the NDC is
the product code and consists of 3 or 4
digits, as specified in paragraphs (b)(2)
and (3) of this section.
(iii) The third segment of the NDC is
the package code and consists of 1 or 2
digits as specified in paragraphs (b)(2)
and (3) of this section. The package code
identifies the package size and type of
the drug and differentiates between
different quantitative and qualitative
attributes of the product packaging.
(2) The following combinations of
labeler code, product code and package
code character lengths are permissible:
(i) If a labeler code is either 5 or 6
digits in length, it may be combined
with:
(A) A product code consisting of 4
digits and a package code consisting of
1 digit for a total NDC length of 10 or
11 digits (5–4–1 or 6–4–1), or
(B) A product code consisting of 3
digits and a package code consisting of
2 digits for a total NDC length of 10 or
11 digits (5–3–2 or 6–3–2).
(ii) If a labeler code is 4 digits in
length, it may be combined only with a
product code consisting of 4 digits and
a package code consisting of 2 digits for
a total NDC length of 10 digits (4–4–2).
(3) A registrant or private label
distributor with a given labeler code
must use only one Product-Package
Code configuration (e.g., a 3-digit
product code combined with a 2-digit
package code or a 4-digit product code
combined with a 1-digit package code).
This single configuration must be used
in all NDCs that include the given
labeler code that are reserved in
accordance with § 207.33(d)(3) or listed
in accordance with § 207.49 or § 207.53.
(4) An alternatively formatted NDC
that is approved for use by the relevant
Center Director may be used for the
following HCT/Ps if they are minimally
E:\FR\FM\31AUR2.SGM
31AUR2
mstockstill on DSK3G9T082PROD with RULES2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
manipulated: Hematopoietic stem/
progenitor cells derived from peripheral
and cord blood, and lymphocytes
collected from peripheral blood.
(c) Who must obtain an NDC labeler
code and how is the code assigned and
updated? (1) Each person who engages
in manufacturing, repacking, relabeling,
or private label distribution of a drug
subject to listing under this part must
apply for an NDC labeler code, by
providing the following information:
(i) The name, physical address, email
address, and other contact information
FDA may request, of the person for
whom the NDC labeler code is
requested;
(ii) The type(s) of activities (e.g.,
manufacture or repacking) in which the
person requesting the NDC labeler code
engages with respect to human drugs;
and
(iii) The type(s) of drug(s) (human,
animal, or both, and prescription,
nonprescription, or both) to which the
NDC labeler code will be applied.
(2) Each person who is assigned an
NDC labeler code must update the
information submitted under paragraph
(c)(1)of this section within 30 calendar
days after any change to that
information.
(d) How is an NDC proposed for
assignment by FDA, when is an NDC
assigned by FDA, and how can a
proposed NDC be reserved? (1) An NDC
is proposed for assignment by FDA
when it is submitted for the first time
with listing information in accordance
with § 207.49 or § 207.53, as applicable.
(i) Each manufacturer, repacker, or
relabeler must propose for assignment
by FDA an NDC that includes its own
labeler code for each package size and
type of drug that it manufactures,
repacks, or relabels for commercial
distribution.
(ii) In addition, if a drug is distributed
under the trade name or label of a
private label distributor, the
manufacturer, repacker, or relabeler
must also propose for assignment by
FDA an NDC that includes the labeler
code of the private label distributor
under whose trade name or label the
drug is distributed, for each package
size and type so distributed.
(2) If a proposed NDC conforms to the
requirements of this section and is not
reserved for a different drug or was not
previously assigned to a different drug,
FDA will assign the NDC to a drug when
it receives listing information required
for that drug under § 207.49 or § 207.53.
(3) A manufacturer, repacker,
relabeler, or private label distributor
may voluntarily reserve a proposed NDC
for a drug, before the drug is listed, by
submitting the following information:
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
(i) A proposed NDC that conforms to
the requirements of this section;
(ii) The established name of the active
ingredient(s) and the strength of each
active ingredient in the drug; and
(iii) In the case of a finished drug
product, the dosage form, and route of
administration.
(4) If the required information is
submitted and the proposed NDC is
properly formatted and not already
assigned or reserved, FDA will reserve
the proposed NDC for a period of 2
years from the date of submission. If the
drug for which the proposed NDC is
reserved is not listed in accordance with
§ 207.49 or § 207.53 during such 2-year
period, the reservation of the proposed
NDC will lapse. FDA may also cancel
the reservation of a proposed NDC at
any time on the request of the person
whose labeler code is included in the
proposed NDC.
(e) How must the information be
submitted to us? The information
described in paragraphs (c) and (d) of
this section must be submitted
electronically unless FDA grants a
waiver under § 207.65.
§ 207.35
NDC?
What changes require a new
(a) Once an NDC has been assigned by
FDA, the registrant must propose a new
and unique NDC for a drug when there
is a change, after the drug is initially
marketed, to any of the information
identified in paragraphs (b) and (c) of
this section. A new NDC must be
proposed to FDA for assignment
through an updated listing in
accordance with § 207.57.
(b) The proposed new NDC must
include a new product code when there
is a change to any of the following
information:
(1) The drug’s established name or
proprietary name, if any;
(2) Any active pharmaceutical
ingredient or the strength of any active
pharmaceutical ingredient;
(3) The dosage form;
(4) A change in the drug’s status,
between prescription and
nonprescription, or for animal drugs,
between prescription, nonprescription,
or veterinary feed directive (VFD) status;
(5) A change in the drug’s intended
use between human and animal; or
(6) The drug’s distinguishing
characteristics such as size, shape,
color, code imprint, flavor, and scoring
(if any).
(c) When there is a change only to the
package size or type, including the
immediate unit-of-use container, if any,
the proposed new NDC must include
only a new package code and retain the
existing product code unless all
PO 00000
Frm 00049
Fmt 4701
Sfmt 4700
60217
available package codes have already
been combined with the existing
product code in NDCs assigned by FDA.
§ 207.37 What restrictions pertain to the
use of the NDC?
(a) A product may be deemed to be
misbranded if an NDC is used:
(1) To represent a different drug than
the drug for which the NDC has been
assigned, as described in § 207.33;
(2) To denote or imply FDA approval
of a drug; or
(3) On products that are not subject to
parts 207, 607 of this chapter, or 1271
of this chapter, such as dietary
supplements and medical devices.
(b) If marketing is resumed for a
discontinued drug, and no changes have
been made to the drug that would
require a new NDC under § 207.35, the
drug must have the same NDC that was
assigned to it as described in § 207.33,
before marketing was discontinued.
Subpart D—Listing
§ 207.41 Who must list drugs and what
drugs must they list?
(a) Each registrant must list each drug
that it manufactures, repacks, relabels,
or salvages for commercial distribution.
Each domestic registrant must list each
such drug regardless of whether the
drug enters interstate commerce. When
operations are conducted at more than
one establishment, and common
ownership and control exists among all
the establishments, the parent,
subsidiary, or affiliate company may
submit listing information for any drug
manufactured, repacked, relabeled, or
salvaged at any such establishment. A
drug manufactured, repacked, or
relabeled for private label distribution
must be listed in accordance with
paragraph (c) of this section.
(b) Registrants must provide listing
information for each drug in accordance
with the listing requirements described
in §§ 207.49, 207.53, and 207.54 that
correspond to the activity or activities
they engage in for that drug.
(c)(1) For both animal and human
drugs, each registrant must list each
drug it manufactures, repacks, or
relabels for commercial distribution
under the trade name or label of a
private label distributor using an NDC
that includes such private label
distributor’s labeler code.
(2) Additionally, in the case of human
drugs, each registrant must list each
human drug it manufactures, repacks, or
relabels using an NDC that includes the
registrant’s own labeler code, regardless
of whether the drug is commercially
distributed under the registrant’s own
label or trade name or under the label
E:\FR\FM\31AUR2.SGM
31AUR2
60218
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
or trade name of a private label
distributor.
§ 207.45 When, after initial registration of
an establishment, must drug listing
information be submitted?
For each drug being manufactured,
repacked, relabeled, or salvaged for
commercial distribution at an
establishment at the time of initial
registration, drug listing information
must be submitted no later than 3
calendar days after the initial
registration of the establishment.
mstockstill on DSK3G9T082PROD with RULES2
§ 207.49 What listing information must a
registrant submit for a drug it
manufactures?
(a) Each registrant must provide the
following listing information for each
drug it manufactures for commercial
distribution.
(1) The appropriate NDC(s), as
described in § 207.33, that include all
package code variations. In the case of
human drugs, the appropriate NDC(s)
submitted under this paragraph include
the registrant’s labeler code. In the case
of animal drugs, the appropriate NDC(s)
submitted under this paragraph include
the registrant’s labeler code, except that
when the drug is manufactured for
commercial distribution under the trade
name or label of a private label
distributor, the appropriate NDC(s) for
animal drugs include the private label
distributor’s labeler code;
(2) Package type and volume
information corresponding to the
package code segment of the NDC;
(3) The listed drug’s established name
and proprietary name, if any;
(4) The name and quantity of each
active pharmaceutical ingredient in the
listed drug;
(5) The name of each inactive
ingredient in the listed drug, along with
any assertions of confidentiality
associated with individual inactive
ingredients;
(6) The dosage form;
(7) The drug’s approved U.S.
application number, if any;
(8) The drug type (e.g., as applicable,
finished vs. unfinished, human vs.
animal, prescription vs.
nonprescription);
(9) In the case of an unfinished drug,
the number assigned to the Drug Master
File or Veterinary Master File, if any,
that describes the manufacture of the
drug;
(10) For each drug that is subject to
the imprinting requirements of part 206
of this chapter including products that
are exempted under § 206.7(b), the
drug’s size, shape, color, scoring, and
code imprint (if any);
(11) The route or routes of
administration of the drug;
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
(12) For each drug bearing an NDC:
(i) The name and Unique Facility
Identifier of the establishment where the
registrant who lists the drug
manufactures it and the type of
operation performed on the drug at that
establishment, and
(ii) The name and Unique Facility
Identifier of every other establishment
where manufacturing is performed for
the drug and the type of operation
performed at each such establishment.
This includes all establishments
involved in the production of each
unfinished drug received by the
registrant for use in the production of
the drug being listed. The names,
Unique Facility Identifiers, and type of
operations for establishments involved
in production of each unfinished drug
received by the registrant for use in the
production of the drug being listed may
be provided by including the properly
assigned and listed NDC for such
unfinished drug.
(13) The schedule of the drug under
section 202 of the Controlled Substances
Act, if applicable;
(14) Advertisements:
(i) A representative sampling of
advertisements for a human prescription
drug that is not subject to section 505 of
the Federal Food, Drug, and Cosmetic
Act or section 351 of the Public Health
Service Act;
(ii) If FDA requests it, for good cause,
a copy of all advertisements for a human
prescription drug that is not subject to
section 505 of the Federal Food, Drug,
and Cosmetic Act or section 351 of the
Public Health Service Act, including
those advertisements described in
§ 202.1(l)(1) of this chapter. Such
advertisements must be submitted
within 30 calendar days after FDA’s
request.
(15) For drugs bearing the NDC(s)
reported under paragraph (a)(1) of this
section, except those drugs
manufactured exclusively for private
label distribution and not distributed
under the registrant’s own name and
label, provide the following labeling, as
applicable:
(i) Human prescription drugs. All
current labeling except that only one
representative container or carton label
need be submitted where differences
exist only in the quantity of contents
statement or the bar code. This labeling
submission must include the content of
labeling, as defined in § 207.1(b).
(ii) Human nonprescription drugs. (A)
For each human nonprescription drug
subject to section 505 of the Federal
Food, Drug, and Cosmetic Act or section
351 of the Public Health Service Act, all
current labeling, except that only one
representative container or carton label
PO 00000
Frm 00050
Fmt 4701
Sfmt 4700
need be submitted where differences
exist only in the quantity of contents
statement or the bar code. This labeling
submission must include the content of
labeling, as defined in § 207.1(b).
(B) For each human nonprescription
drug not subject to section 505 of the
Federal Food, Drug, and Cosmetic Act
or section 351 of the Public Health
Service Act, the current label (except
that only one representative container or
carton label need be submitted where
differences exist only in the quantity of
contents statement or the bar code), the
package insert (if any), and a
representative sampling of any other
labeling. This labeling submission must
include the content of labeling as
defined in section § 207.1(b).
(iii) Animal drugs. (A) For each
animal drug that is subject to section
512 of the Federal Food, Drug, and
Cosmetic Act, which includes, but is not
limited to, new animal drugs that have
been approved, conditionally approved,
or indexed under sections 512, 571, or
572 of the Federal Food, Drug, and
Cosmetic Act, a copy of all current
labeling (except that only one
representative container or carton label
need be submitted where differences
exist only in the quantity of contents
statement), including the content of
labeling as defined in § 207.1(b);
(B) For all other animal drugs, a copy
of the current label (except that only one
representative container or carton label
need be submitted where differences
exist only in the quantity of contents
statement), the package insert, the
content of labeling as defined in
§ 207.1(b), and a representative
sampling of any other labeling;
(iv) All other listed drugs. For all
other listed drugs, including unfinished
drugs, the label (if any), except that only
one representative label need be
submitted where differences exist only
in the quantity of contents statement.
(16) Listing submissions described in
§ 207.41(c)(2) for human drugs
manufactured for private label
distribution must include all
information specified in § 207.49(a)(2)
through (14) and:
(i) The appropriate NDC(s) (as
described in § 207.33) that include the
private label distributor’s labeler code
and all package code variations;
(ii) The name, mailing address,
telephone number, and email address of
the private label distributor; and
(iii) For drugs bearing the NDC(s)
reported under paragraph (a)(16)(i) of
this section, labeling as described in
paragraph (a)(15) of this section that
accompanies the private label
distributor’s product.
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
(b) Additionally, each registrant is
requested, but not required, to provide
the following information for each
human drug it manufactures for
commercial distribution:
(1) The drug’s over-the-counter
monograph reference, if any; and
(2) The date on which the drug was
or will be introduced into commercial
distribution.
mstockstill on DSK3G9T082PROD with RULES2
§ 207.53 What listing information must a
registrant submit for a drug that it repacks
or relabels?
Each registrant must provide the
following listing information for each
drug it repacks or relabels:
(a) NDC. The appropriate NDC(s), as
described in § 207.33, that include the
registrant’s labeler code and all package
code variations;
(b) Source NDC. The NDC assigned to
each finished drug received by the
registrant for repacking or relabeling,
with the exception of medical gases.
Each such NDC must be associated with
the corresponding NDC(s) for repacked
or relabeled drugs, reported under
paragraph (a) of this section.
(c) Name and Unique Facility
Identifier. For each drug identified by an
NDC reported under paragraph (a) of
this section, the name and Unique
Facility Identifier of every establishment
where repacking or relabeling is
performed for the drug and the type of
operation (repacking vs. relabeling)
performed at each such establishment.
(d) Labeling. For each drug identified
by an NDC reported under paragraph (a)
of this section, except those human
drugs repacked or relabeled exclusively
for private label distribution and not
distributed under the registrant’s own
name and label, provide the following:
(1) Human prescription drugs. All
current labeling for the repacked or
relabeled drug except that only one
representative container or carton label
need be submitted where differences
exist only in the quantity of contents
statement or the bar code. This labeling
submission must include the content of
labeling, as defined in section
§ 207.1(b).
(2) Human nonprescription drugs. (i)
For each human nonprescription drug
subject to section 505 of the Federal
Food, Drug, and Cosmetic Act or section
351 of the Public Health Service Act, all
current labeling, except that only one
representative container or carton label
need be submitted where differences
exist only in the quantity of contents
statement or the bar code. This labeling
submission must include the content of
labeling, as defined in § 207.1(b).
(ii) For each human nonprescription
drug not subject to section 505 of the
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
Federal Food, Drug, and Cosmetic Act
or section 351 of the Public Health
Service Act, the current label (except
that only one representative container or
carton label need be submitted where
differences exist only in the quantity of
contents statement or the bar code), the
package insert (if any), and a
representative sampling of any other
labeling. This labeling submission must
include the content of labeling as
defined in § 207.1(b).
(3) Animal drugs. (i) For each animal
drug that is subject to section 512 of the
Federal Food, Drug, and Cosmetic Act,
which includes but is not limited to,
new animal drugs that have been
approved, conditionally approved, or
indexed under sections 512, 571, or 572
of the Federal Food, Drug, and Cosmetic
Act, a copy of all current labeling
(except that only one representative
container or carton label need be
submitted where differences exist only
in the quantity of contents statement),
including the content of labeling as
defined in § 207.1(b);
(ii) For all other animal drugs, a copy
of the current label (except that only one
representative container or carton label
need be submitted where differences
exist only in the quantity of contents
statement), the package insert, the
content of labeling as defined in
§ 207.1(b), and a representative
sampling of any other labeling;
(4) All other. For all other listed
drugs, including unfinished drugs, the
label (if any), except that only one
representative label need be submitted
where differences exist only in the
quantity of contents statement.
(e) Advertisements. (1) A
representative sampling of
advertisements for a human prescription
drug that is not subject to section 505 of
the Federal Food, Drug, and Cosmetic
Act or section 351 of the Public Health
Service Act;
(2) If we request it for good cause, a
copy of all advertisements for a
particular drug described in paragraph
(e)(1) of this section, including
advertisements described in § 202.1(l)(1)
of this chapter. Such advertisements
must be submitted within 30 calendar
days after our request.
(f) Private label distributor products.
A listing submission for a human drug
distributed by a private label distributor
described in § 207.41(c)(2) must include
information specified in § 207.53(b)
through (e) as applicable and:
(1) The appropriate NDC(s) (as
described in § 207.33) that include the
private label distributor’s labeler code
and all package code variations;
PO 00000
Frm 00051
Fmt 4701
Sfmt 4700
60219
(2) The name, mailing address,
telephone number, and email address of
the private label distributor; and
(3) For drugs bearing the NDC(s)
reported under paragraph (f)(1) of this
section, labeling as described in
paragraphs (d)(1) through (4) of this
section, as applicable, that accompanies
the private label distributor’s product.
§ 207.54 What listing information must a
registrant submit for a drug that it
salvages?
A registrant who also relabels or
repacks a drug that it salvages must list
the drug it relabels or repacks in
accordance with § 207.53 rather than in
accordance with this section. A
registrant who performs only salvaging
with respect to a drug must provide the
following listing information for that
drug.
(a) The NDC assigned to the drug
immediately before the drug is received
by the registrant for salvaging;
(b) The lot number and expiration
date of the salvaged drug product; and
(c) The name and Unique Facility
Identifier for each establishment where
the registrant salvages the drug.
§ 207.55 What additional drug listing
information may FDA require?
For a particular listed drug, upon our
request, the registrant must briefly state
the basis for its belief that the drug is
not subject to section 505 or 512 of the
Federal Food, Drug, and Cosmetic Act
or section 351 of the Public Health
Service Act.
§ 207.57 What information must
registrants submit when updating listing
information and when?
Registrants must review and update
listing information at a minimum, as
follows:
(a) Registrants must provide listing
information at the time of annual
establishment registration for any drug
manufactured, repacked, relabeled, or
salvaged by them for commercial
distribution that has not been listed
previously.
(b) Registrants must review and
update their drug listing information
each June and December. When doing
so, registrants must:
(1)(i) Provide listing information, in
accordance with §§ 207.49, 207.53, and
207.54, for any drug manufactured,
repacked, relabeled, or salvaged by them
for commercial distribution that has not
been previously listed;
(ii) Submit the date that they
discontinued the manufacture,
repacking, relabeling or salvaging for
commercial distribution of a listed drug
and provide the expiration date of the
E:\FR\FM\31AUR2.SGM
31AUR2
60220
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
last lot manufactured, repacked,
relabeled, or salvaged;
(iii) Submit the date that they
resumed the manufacture, repacking, or
relabeling for commercial distribution of
a drug previously discontinued, and
provide any required listing information
not previously submitted; and
(iv) Submit any material changes in
any information previously submitted
pursuant to §§ 207.49, 207.53, 207.54, or
other relevant sections of this part; or
(2) For each listed drug, certify that no
changes subject to reporting under
paragraph (b)(1)(iv) of this section have
occurred if no such changes have
occurred since the last review and
update. If a drug is discontinued and
FDA has received the information
required under paragraph (b)(1)(ii) of
this section, no further certifications are
necessary for the discontinued drug.
After initial electronic listing,
registrants may satisfy the listing update
requirement with respect to unchanged
listing information by making a single
‘‘no changes’’ certification during the
annual registration update under
§ 207.29(b) applicable to all of the
registrant’s listed drugs for which no
changes have been made since the
previous annual registration update.
(c) Registrants are encouraged to
submit listing information for every
drug subject to listing under this part
prior to commercial distribution and are
encouraged to update listing
information at the time of any change
affecting information previously
submitted.
Subpart E—Electronic Format for
Registration and Listing
mstockstill on DSK3G9T082PROD with RULES2
§ 207.61 How is registration and listing
information provided to FDA?
(a) Electronic format. (1) Except as
provided in § 207.65, all information
submitted under this part must be
transmitted to FDA in electronic format
by using our electronic drug registration
and listing system, in a form that we can
process, review, and archive. We may
periodically issue guidance on how to
provide registration and listing
information in electronic format
(specifying for example method of
transmission, media, file formats,
preparation, and organization of files).
(2) Information provided in electronic
format must comply with part 11 of this
chapter, except as follows:
(i) Advertisements and labeling,
including the content of labeling,
required under this part are exempt
from the requirements in § 11.10(a), (c)
through (h), and (k) of this chapter and
the corresponding requirements in
§ 11.30 of this chapter.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
(ii) All other information submitted
under this part is exempt from the
requirements in § 11.10(b), (c), and (e) of
this chapter and the corresponding
requirements in § 11.30 of this chapter.
(b) English language. Drug
establishment registration and drug
listing information must be provided in
the English language. The content of
labeling must be provided at a
minimum in the English language.
Where § 201.15(c) of this chapter
permits product labeling solely in a
foreign language, the content of labeling
must be submitted in that language
along with an accurate English
translation.
§ 207.65 How can a waiver of the
electronic submission requirement be
obtained?
(a) All information submitted under
this part must be transmitted to FDA
electronically in accordance with
§ 207.61(a) unless FDA has granted a
request for waiver of this requirement
prior to the date on which submission
of such information is due. Submission
of a request for waiver does not excuse
timely compliance with the registration
and listing requirements. FDA will grant
a waiver request if FDA determines that
the use of electronic means for
submission of registration and listing
information is not reasonable for the
registrant making the waiver request.
(b) Waiver requests under this section
must be submitted in writing and must
include the specific reasons why
electronic submission is not reasonable
for the registrant and a U.S. telephone
number and mailing address where FDA
can contact the registrant. All waiver
requests must be sent to: SPL
Coordinator, U.S. Food and Drug
Administration, 10903 New Hampshire
Ave., Bldg. 32, Silver Spring, MD 20993.
(c) If FDA grants the waiver request,
FDA may limit its duration and will
specify terms of the waiver and provide
information on how to submit
establishment registration, drug listings,
other information, and updates, as
applicable.
Subpart F—Miscellaneous
§ 207.69 What are the requirements for an
official contact and a United States agent?
(a) Official contact. Registrants subject
to the registration requirements of this
part must designate an official contact
for each establishment. The official
contact is responsible for:
(1) Ensuring the accuracy of
registration and listing information; and
(2) Reviewing, disseminating, routing,
and responding to all communications
from FDA including emergency
communications.
PO 00000
Frm 00052
Fmt 4701
Sfmt 4700
(b) United States agent. Registrants of
foreign establishments subject to this
part must designate a single United
States agent. The United States agent
must reside or maintain a place of
business in the United States and may
not be a mailbox, answering machine or
service, or other place where a person
acting as the United States agent is not
physically present. The United States
agent is responsible for:
(1) Reviewing, disseminating, routing,
and responding to all communications
from FDA including emergency
communications;
(2) Responding to questions
concerning those drugs that are
imported or offered for import to the
United States;
(3) Assisting FDA in scheduling
inspections; and
(4) If FDA is unable to contact a
foreign registrant directly or
expeditiously, FDA may provide the
information and/or documents to the
United States agent. FDA’s providing
information and/or documents to the
United States agent is equivalent to
providing the same information and/or
documents to the foreign registrant.
§ 207.77 What legal status is conferred by
registration and listing?
(a) Registration of an establishment or
listing of a drug does not denote
approval of the establishment, the drug,
or other drugs of the establishment, nor
does it mean that a product may be
legally marketed. Any representation
that creates an impression of official
approval or that a drug is approved or
is legally marketable because of
registration or listing is misleading and
constitutes misbranding.
(b) FDA’s acceptance of registration
and listing information, inclusion of a
drug in our database of drugs, or
assignment of an NDC does not denote
approval of the establishment or the
drug or any other drugs of the
establishment, nor does it mean that the
drug may be legally marketed. Any
representation that creates the
impression that a drug is approved or is
legally marketable because it appears in
our database of drugs, has been assigned
or displays an NDC, or the
establishment has been assigned an
establishment registration number or
Unique Facility Identifier is misleading
and constitutes misbranding. Failure to
comply with § 207.37 may also
constitute misbranding.
(c) Neither registration nor listing
constitutes a determination by FDA that
a product is a drug as defined by section
201(g)(1) of the Federal Food, Drug, and
Cosmetic Act. Registration or listing
may, however, be evidence that a
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
facility intends to or does manufacture,
repack, relabel, distribute, or salvage
drugs or that a product is intended to be
a drug.
§ 207.81 What registration and listing
information will FDA make available for
public disclosure?
(a) Except as provided in paragraphs
(b) and (c) of this section, the following
information will be available for public
disclosure, upon request or at FDA’s
discretion:
(1) All establishment registration
information, and
(2) After a drug is marketed,
information obtained under § 207.33,
§ 207.49, § 207.53, § 207.54, or § 207.57.
(b) Unless such information is
publicly available or FDA finds that
confidentiality would be inconsistent
with protection of the public health,
FDA will not make publicly available:
(1) Any information submitted under
§ 207.55 as the basis upon which it has
been determined that a particular drug
is not subject to section 505 or 512 of
the Federal Food, Drug, and Cosmetic
Act or section 351 of the Public Health
Service Act,
(2) The names of any inactive
ingredients submitted under
§ 207.49(a)(4) for which the registrant
makes a valid assertion of
confidentiality under § 20.61 of this
chapter or other provision of law, or
(3) Drug listing information obtained
under § 207.33(d)(3), § 207.49(a)(9) and
(12), § 207.53(b) and (c), or § 207.54(a)
or (c).
(c) FDA may determine, in limited
circumstances and on a case-by-case
basis, that it would be consistent with
the protection of the public health and
the Freedom of Information Act to
exempt from public disclosure specific
information identified in paragraph (a)
of this section.
relabelers subject to part 207 of this
chapter must submit the following
information about the drug, in
accordance with the applicable
requirements described in §§ 207.61 and
207.65:
(1) The National Drug Code (NDC);
(2) The identity of the drug by
established name and by proprietary
name, if any;
(3) The new drug application number
or abbreviated application number;
(4) The date on which the drug is
expected to be no longer in commercial
distribution. FDA requests that the
reason for withdrawal of the drug from
sale be included with the information.
(b) Within 30 calendar days of the
withdrawal of an approved drug from
sale, applicants who are not subject to
part 207 of this chapter must submit the
information listed in paragraphs
(b)(3)(iv)(a)(1) through (4) of this
section. The information must be
submitted either electronically or in
writing to the Drug Registration and
Listing Office, Food and Drug
Administration, Center for Drug
Evaluation and Research.
(c) Reporting under paragraph
(b)(3)(iv)(a) of this section constitutes
compliance with the requirements of
§ 207.57 of this chapter to update drug
listing information with respect to the
withdrawal from sale.
*
*
*
*
*
§ 314.125
[Amended]
11. Amend § 314.125 in paragraph
(b)(11) by removing the words ‘‘or
processed’’.
■
PART 514—NEW ANIMAL DRUG
APPLICATIONS
12. The authority citation for part 514
continues to read as follows:
■
Authority: 21 U.S.C. 321, 331, 351, 352,
354, 356a, 360b, 360ccc, 371, 379e, 381.
§ 515.10
60221
[Amended]
15. In § 515.10(b)(8), remove the
phrase ‘‘§§ 207.20 and 207.21’’ and add
in its place the phrase ‘‘part 207’’.
■
PART 601—LICENSING
16. The authority citation for part 601
continues to read as follows:
■
Authority: 15 U.S.C. 1451–1561; 21 U.S.C.
321, 351, 352, 353, 355, 356b, 360, 360c–
360f, 360h–360j, 371, 374, 379e, 381; 42
U.S.C. 216, 241, 262, 263, 264; sec. 122, Pub.
L. 105–115, 111 Stat. 2322 (21 U.S.C. 355
note).
17. In § 601.2, add paragraph (f) to
read as follows:
■
§ 601.2 Applications for biologics
licenses; procedures for filing.
*
*
*
*
*
(f) Withdrawal from sale of approved
biological products. A holder of a
biologics license application (BLA) must
report to FDA, in accordance with the
requirements of §§ 207.61 and 207.65,
the withdrawal from sale of an approved
biological product. The information
must be submitted to FDA within 30
working days of the biological product’s
withdrawal from sale. The following
information must be submitted: The
holder’s name; product name; BLA
number; the National Drug Code; and
the date on which the product is
expected to be no longer in commercial
distribution. The reason for the
withdrawal of the biological product is
requested but not required to be
submitted.
PART 607—ESTABLISHMENT
REGISTRATION AND PRODUCT
LISTING FOR MANUFACTURERS OF
HUMAN BLOOD AND BLOOD
PRODUCTS AND LICENSED DEVICES
18. The authority citation for part 607
continues to read as follows:
■
PART 314—APPLICATIONS FOR FDA
APPROVAL TO MARKET A NEW DRUG
■
13. In § 514.111 add paragraph (a)(12)
to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352,
355, 360, 371, 374, 381, 393; 42 U.S.C. 262,
264, 271.
■
9. The authority citation for part 314
continues to read as follows:
§ 514.111 Refusal to approve an
application.
■
Authority: 21 U.S.C. 321, 331, 351, 352,
353, 355, 356, 356a, 356b, 356c, 356e, 371,
374, 379e, 379k–1.
(a) * * *
(12) The drug will be produced in
whole or in part in an establishment
that is not registered and not exempt
from registration under section 510 of
the Federal Food, Drug, and Cosmetic
Act and part 207 of this chapter.
*
*
*
*
*
10. In § 314.81, revise paragraph
(b)(3)(iv) to read as follows:
■
mstockstill on DSK3G9T082PROD with RULES2
§ 314.81
Other postmarketing reports.
*
*
*
*
*
(b) * * *
(3) * * *
(iv) Withdrawal of approved drug
product from sale. (a) Within 30
calendar days of the withdrawal of an
approved drug from sale, applicants
who are manufacturers, repackers, or
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
PART 515—MEDICATED FEED MILL
LICENSE
14. The authority citation for part 515
continues to read as follows:
■
Authority: 21 U.S.C. 360b, 371.
PO 00000
Frm 00053
Fmt 4701
Sfmt 4700
19. Revise the heading for part 607 to
read as set forth above.
■ 20. Add § 607.1 to subpart A to read
as follows:
§ 607.1
Scope.
(a) This part establishes establishment
registration and product listing
requirements for manufacturers of
human blood and blood products.
(b) This part establishes establishment
registration and product listing
requirements for manufacturers of
products that meet the definition of a
device under the Federal Food, Drug,
and Cosmetic Act and that are licensed
under section 351 of the Public Health
E:\FR\FM\31AUR2.SGM
31AUR2
60222
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
Service Act, as well as licensed
biological products used in the
manufacture of a licensed device.
■ 21. In § 607.3 revise the second
sentence in paragraph (b) and add
paragraphs (k) and (l) to read as follows:
§ 607.3
Definitions.
*
*
*
*
*
(b) * * * For the purposes of this part
only, blood and blood product also
means those products that meet the
definition of a device under the Federal
Food, Drug, and Cosmetic Act and that
are licensed under section 351 of the
Public Health Service Act, as well as
licensed biological products used in the
manufacture of a licensed device.
*
*
*
*
*
(k) Importer means a person in the
United States that is an owner,
consignee, or recipient, at the time of
entry, of a foreign establishment’s blood
product that is imported into the United
States.
(l) Foreign for the purpose of
registration and listing under this part
when used to modify the term
‘‘establishment’’ refers to an
establishment that is located in a foreign
country and is the site where a blood
product that is imported or offered for
import into the United States was
manufactured.
■ 22. Revise § 607.7 to read as follows:
§ 607.7 Establishment registration and
product listing of blood banks and other
firms manufacturing human blood and
blood products.
All owners or operators of
establishments that engage in the
manufacturing of blood products are
required to register, pursuant to section
510 of the Federal Food, Drug, and
Cosmetic Act. Registration and listing of
blood products must comply with this
part. Registration does not permit any
blood bank or similar establishment to
ship blood products in interstate
commerce.
■ 23. In § 607.20 revise the first sentence
in paragraph (c) to read as follows:
§ 607.20 Who must register and submit a
blood product list.
mstockstill on DSK3G9T082PROD with RULES2
*
*
*
*
*
(c) Except in the case of licensed
device manufacturers, no registration
fee is required. * * *
■ 24. In § 607.21 revise the last sentence
to read as follows:
§ 607.21 Times for establishment
registration and blood product listing.
* * * Owners or operators of all
establishments so engaged must register
annually between October 1 and
December 31 and must update their
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
blood product listing every June and
December.
■ 25. Revise § 607.22 to read as follows:
§ 607.22 How to register establishments
and list blood products.
(a) Initial and subsequent registrations
and product listings must be submitted
electronically through the Blood
Establishment Registration and Product
Listing system, or any future
superseding electronic system. This
information must be submitted in
accordance with part 11 of this chapter,
except for the requirements in
§ 11.10(b), (c), and (e), and the
corresponding requirements in § 11.30.
All information submitted under this
part must be transmitted to FDA
electronically unless FDA has granted a
request for waiver of this requirement
prior to the date on which the
information is due. Submission of a
request for waiver does not excuse
timely compliance with the registration
and listing requirements. FDA will grant
a waiver request if FDA determines that
the use of electronic means for
submission of registration and listing
information is not reasonable for the
registrant making the waiver request.
(b) Waiver requests under this section
must be submitted in writing and must
include the specific reasons why
electronic submission is not reasonable
for the registrant and a U.S. telephone
number and mailing address where FDA
can contact the registrant. All waiver
requests must be sent to the Director of
FDA’s Center for Biologics Evaluation
and Research through the Document
Control Center (see addresses in
§ 600.2).
(c) If FDA grants the waiver request,
FDA may limit its duration and will
specify terms of the waiver and provide
information on how to submit
establishment registration, drug listings,
other information, and updates, as
applicable.
■ 26. Revise § 607.25 to read as follows:
§ 607.25 Information required for
establishment registration and blood
product listing.
(a) The Blood Establishment
Registration and Product Listing system
requires furnishing or confirming
registration information required by the
Federal Food, Drug, and Cosmetic Act.
This information includes the name and
street address of the establishment,
including post office code; a registration
number if previously assigned by FDA
and a Unique Facility Identifier in
accordance with the system specified
under section 510 of the Federal Food,
Drug, and Cosmetic Act; all trade names
used by the establishment; the kind of
PO 00000
Frm 00054
Fmt 4701
Sfmt 4700
ownership or operation (that is,
individually owned partnership, or
corporation); and the name of the owner
or operator of such establishment. The
term ‘‘name of the owner or operator’’
must include, in the case of a
partnership, the name of each partner
and, in the case of a corporation, the
name and title of each corporate officer
and director and the name of the State
of incorporation. The information
required must be given separately for
each establishment, as defined in
§ 607.3(c).
(b) The following information must
also be provided:
(1) A list of blood products by
established name as defined in section
502(e) of the Federal Food, Drug, and
Cosmetic Act and by proprietary name,
if any, which are being manufactured
for commercial distribution at the
identified establishment and which
have not been included in any list
previously submitted to FDA through
the Blood Establishment Registration
and Product Listing system or any
future superseding electronic system.
(2) For each blood product so listed
that is subject to section 351 of the
Public Health Service Act, the license
number of the manufacturer issued by
the Center for Biologics Evaluation and
Research, Food and Drug
Administration.
(3) For each blood product listed, the
registration number if previously
assigned by FDA and the Unique
Facility Identifier of the parent
establishment. An establishment not
owned, operated, or controlled by
another firm or establishment is its own
parent establishment.
■ 27. In § 607.26 revise the first sentence
to read as follows:
§ 607.26 Amendments to establishment
registration.
Changes in individual ownership,
corporate or partnership structure,
location, or blood product handling
activity must be submitted
electronically through the Blood
Establishment Registration and Product
Listing system, or any future
superseding electronic system, as an
amendment to registration within 5
calendar days of such changes. * * *
■ 28. In § 607.30 revise the introductory
text of paragraph (a) to read as follows:
§ 607.30 Updating blood product listing
information.
(a) After submission of the initial
blood product listing information, every
person who is required to list blood
products under § 607.20 must submit
electronically through the Blood
Establishment Registration and Product
E:\FR\FM\31AUR2.SGM
31AUR2
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
Listing system, or any future
superseding electronic system, at a
minimum once in June and December of
every year, the following information:
*
*
*
*
*
■ 29. Revise § 607.35 to read as follows:
§ 607.35 Blood product establishment
registration number.
An establishment registration number
will be assigned to each blood product
establishment registered in accordance
with this part.
■ 30. Revise § 607.37 to read as follows:
§ 607.37 Public disclosure of
establishment registration and blood
product listing information.
(a) Except as provided in paragraph
(b) of this section, all registration and
listing information obtained under
§§ 607.25, 607.26, and 607.30 will be
made available for public disclosure
through the Center for Biologics
Evaluation and Research (CBER) Blood
Establishment Registration Database
Web site by using the CBER electronic
Web-based application or by going in
person to the Food and Drug
Administration, Division of Freedom of
Information Public Reading Room (see
addresses in § 20.120(a) of this chapter).
(b) FDA may find, in limited
circumstances and on a case-by-case
basis, that it would be consistent with
the protection of the public health to
exempt from public disclosure specific
listing information obtained under
§ 607.25 or § 607.30.
(c) Other requests for information
regarding blood establishment
registrations and blood product listings
should be directed to the Food and Drug
Administration, Center for Biologics
Evaluation and Research Office of
Communication, Outreach, and
Development, 10903 New Hampshire
Ave., Bldg. 71, Rm. 3103, Silver Spring,
MD 20993–0002.
■ 31. Revise § 607.39 to read as follows:
mstockstill on DSK3G9T082PROD with RULES2
§ 607.39 Misbranding by reference to
establishment registration, validation of
registration, or to registration number.
Registration of an establishment,
validation of registration, or assignment
of a registration number does not in any
way denote approval of the firm or its
products nor does it mean that the
products may be legally marketed. Any
representation that creates an
impression of official approval because
of establishment registration, validation
of registration, or possession of a
registration number is misleading and
constitutes misbranding.
■ 32. In § 607.40 revise paragraphs (d)
introductory text and (d)(3) and add
paragraph (e) to read as follows:
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
§ 607.40 Establishment registration and
blood product listing requirements for
foreign blood product establishments.
*
*
*
*
*
(d) Each foreign establishment
required to register under paragraph (a)
of this section must submit the name,
address, telephone number, and email
address of its United States agent as part
of its initial and updated registration
information in accordance with subpart
B of this part. Each foreign
establishment must designate only one
United States agent.
*
*
*
*
*
(3) The foreign establishment or the
United States agent must report changes
in the United States agent’s name,
address, telephone number, or email
address to FDA within 30 calendar days
of the change.
(e) Each foreign establishment
required to register under paragraph (a)
of this section must register and list
blood products using the Blood
Establishment Registration and Product
Listing system, or any superseding
electronic system, unless FDA waives
the electronic submission requirement
in accordance with § 607.22.
33. In § 607.65 add paragraph (g) to
read as follows:
■
§ 607.65 Exemptions for blood product
establishments.
*
*
*
*
*
(g) Persons who engage solely in the
production of any plasma derivative,
including, but not limited to, albumin,
Immune Globulin, Factor VIII and
Factor IX, bulk product substances such
as fractionation intermediates or pastes,
or recombinant versions of plasma
derivatives or animal derived plasma
derivatives. These persons must register
and list under part 207 of this chapter.
60223
PART 1271—HUMAN CELLS, TISSUES,
AND CELLULAR AND TISSUE–BASED
PRODUCTS
35. The authority citation for part
1271 continues to read as follows:
■
Authority: 42 U.S.C. 216, 243, 263a, 264,
271.
§ 1271.1
[Amended]
36. Amend § 1271.1 in paragraphs (a)
and (b)(2) by removing ‘‘207.20(f)’’ and
adding in its place ‘‘207.9(a)(5)’’; in
paragraph (a) by removing the term ‘‘a
unified’’ and adding in its place the
term ‘‘an electronic’’; and in paragraph
(b)(2) by removing the phrase ‘‘in
subpart B of this part’’ and adding in its
place the phrase ‘‘in part 207 (if a drug
and/or biological product) of this
chapter or part 807 (if a device) of this
chapter’’.
■ 37. In § 1271.3 add paragraphs (mm)
and (nn) to read as follows:
■
§ 1271.3 How does FDA define important
terms in this part?
*
*
*
*
*
(mm) Importer means a company or
individual in the United States that is
the owner, consignee, or recipient, at
the time of entry, of the foreign
establishment’s HCT/P that is imported
into the United States.
(nn) United States agent means a
person residing or maintaining a place
of business in the United States whom
a foreign establishment designates as its
agent. This definition excludes
mailboxes, answering machines or
services, or other places where an
individual acting as the foreign
establishment’s agent is not physically
present.
§ 1271.20
[Amended]
Subpart E—Establishment Registration
and Product Listing Of Licensed
Devices
38. Amend § 1271.20 by removing
‘‘207.20(f)’’ and adding in its place
‘‘207.9(a)(5)’’ and by removing the
phrase ‘‘subparts B, C, and D of this
part’’ and adding in its place ‘‘subparts
C and D of this part’’.
■ 39. Revise § 1271.22 to read as
follows:
§ 607.80 Applicability of part 607 to
licensed devices.
§ 1271.22 How do I register and submit an
HCT/P list?
34. Add subpart E, consisting of
§ 607.80, to part 607 to read as follows:
■
Manufacturers of products that meet
the definition of a device under the
Federal Food, Drug, and Cosmetic Act
and that are licensed under section 351
of the Public Health Service Act, as well
as licensed biological products used in
the manufacture of a licensed device,
must register and list following the
procedures under this part, with respect
to their manufacture of those products,
unless otherwise noted in this section.
PO 00000
Frm 00055
Fmt 4701
Sfmt 4700
■
(a) You must use the electronic
registration and listing system at https://
www.fda.gov/cber/tissue/tisreg.htm in
accordance with § 1271.25 for:
(1) Establishment registration,
(2) HCT/P listings, and
(3) Updates of registration and HCT/
P listing.
(b) FDA will periodically issue
guidance on recommended procedures
for providing registration and listing
information in electronic format (for
E:\FR\FM\31AUR2.SGM
31AUR2
60224
Federal Register / Vol. 81, No. 169 / Wednesday, August 31, 2016 / Rules and Regulations
example, method of transmission,
media, file formats, preparation, and
organization of files).
(c) You must provide the information
under paragraph (a) of this section in
accordance with part 11 of this chapter,
except for the requirements in
§ 11.10(b), (c), and (e) and the
corresponding requirements in § 11.30.
■ 40. Add § 1271.23 to subpart B to read
as follows:
§ 1271.23 How is a waiver from the
electronic format requirements requested?
mstockstill on DSK3G9T082PROD with RULES2
(a) You may request a waiver from the
requirement in § 1271.22 that
information must be provided to FDA in
electronic format. Submission of a
request for waiver does not excuse
timely compliance with the registration
and listing requirements. FDA will grant
a waiver request if FDA determines that
the use of electronic means for
submission of registration and listing
information is not reasonable for the
registrant making the waiver request.
(b) Waiver requests under this section
must be submitted in writing and must
include the specific reasons why
electronic submission is not reasonable
for the registrant and a U.S. telephone
number and mailing address where FDA
can contact the registrant. Waiver
requests may be sent to the Center for
Biologics Evaluation and Research
(CBER), Document Control Center (see
addresses in § 600.2 of this chapter).
(c) If FDA grants the waiver request,
FDA may limit its duration and will
specify terms of the waiver and provide
information on how to submit
establishment registration, listings,
other information, and updates, as
applicable.
VerDate Sep<11>2014
20:25 Aug 30, 2016
Jkt 238001
41. In § 1271.25 revise paragraphs (a)
introductory text and (a)(2) and (3), add
paragraphs (a)(5) and (6), revise
paragraph (c)(4), and add paragraph (d)
to read as follows:
■
§ 1271.25 What information is required for
establishment registration and HCT/P
listing?
(a) Your establishment registration
must include:
*
*
*
*
*
(2) Each physical location, including
the street address, telephone number,
email address, and the postal service
ZIP code of the establishment;
(3) The name, address, telephone
number, email address, and title of the
reporting official;
*
*
*
*
*
(5) Each foreign establishment must
also submit the name, address,
telephone number, and email address of
each importer that is known to the
establishment, and the name of each
person who imports or offers for import
such HCT/P to the United States for
purposes of importation; and
(6) Each foreign establishment must
also submit the name, address,
telephone number, and email address of
its United States agent.
(i) The United States agent must
reside or maintain a place of business in
the United States.
(ii) Upon request from FDA, the
United States agent must assist FDA in
communications with the foreign
establishment, respond to questions
concerning the foreign establishment’s
products that are imported or offered for
import into the United States, and assist
FDA in scheduling inspections of the
foreign establishment. If the Agency is
unable to contact the foreign
PO 00000
Frm 00056
Fmt 4701
Sfmt 9990
establishment directly or expeditiously,
FDA may provide information or
documents to the United States agent,
and such an action is equivalent to
providing the same information or
documents to the foreign establishment.
(iii) The foreign establishment or the
United States agent must report changes
in the United States agent’s name,
address, telephone number, or email
address to FDA within 30 calendar days
of the change.
*
*
*
*
*
(c) * * *
(4) Any material change in any
information previously submitted.
Material changes include any change in
registration and listing information,
submitted, such as whether the HCT/P
meets the criteria set out in § 1271.10.
(d) If your HCT/P is described under
§ 1271.20 and is regulated under a BLA,
you must submit the information
required under part 207 of this chapter
using the procedures under subpart E of
part 207.
■ 42. Revise § 1271.26 to read as
follows:
§ 1271.26 When must I amend my
establishment registration?
If the ownership or location of your
establishment changes, or if there is a
change in the United States agent’s
name, address, telephone number, or
email address, you must submit an
amendment to registration within 30
calendar days of the change.
Dated: August 22, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016–20471 Filed 8–30–16; 8:45 am]
BILLING CODE 4164–01–P
E:\FR\FM\31AUR2.SGM
31AUR2
Agencies
[Federal Register Volume 81, Number 169 (Wednesday, August 31, 2016)]
[Rules and Regulations]
[Pages 60169-60224]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-20471]
[[Page 60169]]
Vol. 81
Wednesday,
No. 169
August 31, 2016
Part III
Department of Health and Human Services
-----------------------------------------------------------------------
Food and Drug Administration
-----------------------------------------------------------------------
21 CFR Parts 20, 201, 207, et al.
Requirements for Foreign and Domestic Establishment Registration and
Listing for Human Drugs, Including Drugs That Are Regulated Under a
Biologics License Application, and Animal Drugs; Final Rule
Federal Register / Vol. 81 , No. 169 / Wednesday, August 31, 2016 /
Rules and Regulations
[[Page 60170]]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 201, 207, 314, 514, 515, 601, 607, and 1271
[Docket No. FDA-2005-N-0464 (formerly Docket No. 2005N-0403)]
RIN 0910-AA49
Requirements for Foreign and Domestic Establishment Registration
and Listing for Human Drugs, Including Drugs That Are Regulated Under a
Biologics License Application, and Animal Drugs
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations governing drug establishment registration and drug listing.
These amendments reorganize, modify, and clarify current regulations
concerning who must register establishments and list human drugs, human
drugs that are also biological products, and animal drugs. The final
rule requires electronic submission, unless waived in certain
circumstances, of registration and listing information. This rulemaking
pertains to finished drug products and to active pharmaceutical
ingredients (APIs) alone or together with one or more other
ingredients. The final rule describes how and when owners or operators
of establishments at which drugs are manufactured or processed must
register their establishments with FDA and list the drugs they
manufacture or process. In addition, the rule makes certain changes to
the National Drug Code (NDC) system. We are taking this action to
improve management of drug establishment registration and drug listing
requirements and make these processes more efficient and effective for
industry and for us. This action also supports implementation of the
electronic prescribing provisions of the Medicare Prescription Drug,
Improvement, and Modernization Act of 2003 (MMA) and the availability
of current drug labeling information through DailyMed, a computerized
repository of drug information maintained by the National Library of
Medicine.
DATES: This rule is effective on November 29, 2016. See section IV for
compliance dates.
FOR FURTHER INFORMATION CONTACT:
For information pertaining to human drug products: Paul Loebach,
Center for Drug Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 51, Rm. 2262, Silver Spring, MD 20993,
301-796-2173.
For information pertaining to human biological drug products or
human cells, tissue, and cellular and tissue-based products (HCT/Ps)
regulated solely under section 361 of the Public Health Service Act:
Stephen Ripley, Center for Biologics Evaluation and Research, Food and
Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301,
Silver Spring, MD 20993, 240-402-7911.
For information pertaining to animal drug products: Charise Kasser,
Center for Veterinary Medicine (HFV-212), Food and Drug Administration,
7519 Standish Pl., Rm. 2626, Rockville, MD 20855, 240-402-6816; or
Isabel Pocurull, Center for Veterinary Medicine (HFV-226), Food and
Drug Administration, 7519 Standish Pl., Rm. 2636, Rockville, MD 20855,
240-402-5877.
SUPPLEMENTARY INFORMATION:
Table of Contents
Executive Summary
Purpose of the Regulatory Action
Summary of the Major Provisions of the Regulatory Action
Benefits and Costs
I. Background
II. Overview of the Final Rule Including Changes to the Proposed
Rule
A. Overview
B. Changes to the Proposed Rule
III. Comments on the Proposed Rule
A. Labeling (Sec. Sec. 201.2 and 201.25)
B. General Information (Part 207, Subpart A)
C. Registration (Part 207, Subpart B)
D. National Drug Code (Part 207, Subpart C)
E. Listing (Part 207, Subpart D)
F. Electronic Format for Registration and Listing (Part 207,
Subpart E)
G. Miscellaneous (Part 207, Subpart F)
H. Human Cells, Tissues, and Cellular and Tissue-Based Products
(Part 1271)
IV. Compliance Dates
V. Legal Authority
VI. Analysis of Environmental Impact
VII. Economic Analysis of Impacts
A. Introduction
B. Summary of Benefits and Costs
C. Response to Comments on the Preliminary Impact Analysis of
the Proposed Rule
VIII. Paperwork Reduction Act of 1995
A. Registration Information Collection Under Part 207
B. Listing Information Collection Under Part 207
C. Registration and Listing Information Collection Under Part
607
D. Registration and Listing Information Collection Under Part
1271
E. Waiver Request Information
F. Public Disclosure Exemption Requests
G. Standard Operating Procedure for Electronic Submission
H. Capital Costs
IX. Federalism
X. References
Executive Summary
Purpose of the Regulatory Action
This final rule amends FDA's longstanding regulations governing
drug establishment registration and drug listing. The amendments are
aimed at modernizing these regulations and improving efficiency and
reliability for FDA and drug manufacturers. These amendments also bring
FDA's regulations governing drug establishment registration and listing
into conformance with section 510 of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. 360) as amended by the Food and
Drug Administration Amendments Act (FDAAA) (Pub. L. 110-85) and the
Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub.
L. 112-144).
Since the 1962 Kefauver Harris amendments to the FD&C Act (Pub. L.
87-781), drug manufacturers have been required to register their
establishments with FDA annually. Among other things, drug
establishment registration identifies establishments for inspection by
FDA. In 1973, the FD&C Act was further amended to require each
registered establishment to submit a list of drugs it manufactures.
FDA's regulations implementing these requirements are found in part 207
(21 CFR part 207) (pertaining to drugs and biological products
generally) and part 607 (21 CFR part 607) (pertaining to blood and
blood products). Manufacturers of HCT/Ps register and list either under
part 207, part 807 (21 CFR 807), or under part 1271 (21 CFR part 1271),
issued under authority of the Public Health Service Act (PHS Act),
depending on the type of HCT/P product they manufacture.
The amendments to parts 207 and 607 adopted by this final rule
modernize those regulations and bring them into conformance with
section 510 of the FD&C Act following recent amendments.
Summary of the Major Provisions of the Regulatory Action
This final rule requires electronic submission, unless waived in
certain circumstances, of drug establishment registration and listing
information. The electronic submission requirement is consistent with
FDAAA and with current practice.
[[Page 60171]]
The rule makes clear that the establishment registration and
listing obligation rests with persons who manufacture, repack, relabel,
or salvage drug products. The rule does not require persons who act
only as private label distributors of drug products to register
establishments or list drugs, but allows them to submit drug listing
information as agents acting on behalf of persons who manufacture,
repack, relabel, or salvage drug products. The amendments make several
adjustments to the timing and substance of the submission of
information to register a drug establishment and list drugs
manufactured, repacked, relabeled, or salvaged at the establishment.
The amendments also update longstanding regulatory provisions governing
FDA disclosure of drug registration and listing information, stating
that with certain exceptions, establishment registration and drug
listing information is generally available for public disclosure.
This final rule does not include certain aspects of the proposed
rule that were opposed by many who submitted comments. Features of the
proposed rule that have not been finalized include most significantly:
(1) A requirement that FDA, not registrants, develop national drug
codes (NDCs) for assignment to listed drugs and (2) a requirement that
the NDC appear in human-readable form on the label of each listed drug
and provisions that would have defined the appropriate NDC for that
purpose. As discussed in section III, revisions to the FD&C Act require
human-readable NDCs on certain drug labels.
Benefits and Costs
All incremental costs from the final rule are one-time costs,
except for registrants' annually recurring costs of certifying no
change to listings upon annual registration for part 207 registrants.
We estimate one-time total costs of $59.7 million and recurring costs
of $0.5 million. These costs represent total annualized costs of $9
million when calculated at a 7-percent discount rate over 10 years, and
$7.5 million when calculated using a 3-percent discount rate. The
largest cost elements will be for registrants reading and understanding
the final rule and making changes to their standard operating
procedures.
Summary of Total Incremental Cost of the Final Rule
[$ millions]
----------------------------------------------------------------------------------------------------------------
Recurring Total costs Total costs
Affected firms One-time costs costs annualized at annualized at
(annual) 7% 3%
----------------------------------------------------------------------------------------------------------------
Drugs and biological products (part 207)........ $48.9 $0.5 $7.5 $6.2
Human blood products (part 607)................. 5.1 N/A 0.7 0.6
Human cell and tissue products (part 1271)...... 5.7 N/A 0.8 0.7
---------------------------------------------------------------
Total \1\................................... 59.7 0.5 9.0 7.5
----------------------------------------------------------------------------------------------------------------
\1\ Total costs are annualized over a 10-year period. Recurring costs include only annual time costs of
certifying that there are no changes to listings; these costs are unique to part 207. All estimates reflect
rounded 2014 dollars.
By codifying the statutory requirements of FDAAA and FDASIA, the
final rule clarifies and completes the modernization of our electronic
registration and listing systems. Thus, the final rule will improve
management of the establishment registration and drug listing
requirements and make these processes more efficient and effective for
industry and for us. The final rule also supports implementation of the
electronic prescribing provisions of the MMA and the availability of
current drug labeling information through DailyMed, a computerized
repository of drug information maintained by the National Library of
Medicine.
I. Background
In the Federal Register of August 29, 2006 (71 FR 51276), FDA
proposed to amend its regulations governing drug establishment
registration and drug listing in part 207 (proposed rule). The proposed
rule included ancillary amendments to parts 20, 201, 314, 514, 515,
601, 607, and 1271 (21 CFR parts 20, 201, 314, 514, 515, 601, 607, and
1271). These amendments reorganize, modify, and clarify current
regulations concerning who must register establishments and list human
drugs, human drugs that are also biological products, and animal drugs.
The proposed rule and the final rule both specify that drug
establishment registration and drug listing information generally must
be submitted to FDA electronically.
After the proposed rule was published, FDAAA was adopted into law.
FDAAA amended section 510(p) of the FD&C Act to require electronic
submission of drug establishment registration and listing information,
unless FDA waives the electronic submission requirement in individual
cases. In June 2009, FDA announced publication of a guidance for
industry on ``Providing Regulatory Submissions in Electronic Format--
Drug Establishment Registration and Drug Listing'' consistent with
FDAAA (74 FR 26248, June 1, 2009, available on the Internet at https://www.fda.gov/Drugs under Guidances (Drugs)) (the electronic registration
and listing guidance). This guidance applied to establishment
registration and listing required under part 207. It did not apply to
information required solely under part 607 (blood and blood products),
part 807 (devices), or part 1271 (human cells, tissues, and cellular
and tissue-based products). FDA generally stopped receiving drug
establishment registration and listing information required under part
207 submitted on paper in June 2009, allowing paper submissions only if
supported by a waiver from the electronic submission requirement in
individual cases. This final rule is consistent with the electronic
submission provisions of FDAAA.
FDASIA made further amendments to section 510 of the FD&C Act in
2012 to specify that:
Annual registration of establishments takes place during
the period beginning on October 1 and ending on December 31.
The information registrants supply for annual registration
includes a Unique Facility Identifier (UFI) for the establishment and
includes a point-of-contact email address.
This final rule includes changes to the proposed rule consistent
with these statutory provisions. The electronic registration and
listing guidance stated that FDA intended to use the Data Universal
Numbering System (DUNS) number, assigned and managed by Dun
[[Page 60172]]
& Bradstreet, as a registration number. In 2014, FDA announced
publication of a guidance for industry on ``Specifications of the
Unique Facility Identifier (UFI) System for Drug Establishment
Registration,'' (79 FR 65977, November 6, 2014, available on the
Internet at https://www.fda.gov/Drugs under Guidances (Drugs)), in which
FDA specified the DUNS number as the preferred UFI.
II. Overview of the Final Rule Including Changes to the Proposed Rule
A. Overview
The final rule adopts significant amendments to FDA's regulations
governing drug registration and listing. It modernizes these
regulations to require electronic submission of drug establishment
registration and listing information and to otherwise match current
statutory requirements and FDA's information needs.
The final rule:
Makes minor technical amendments to Sec. Sec. 20.100,
20.116, and 201.1 (updating citations to regulations in part 207).
Removes from Sec. 201.2 a statement about the manner in
which NDCs are displayed on drug labels.
Amends Sec. 201.25 to allow an FDA Center Director to
approve an additional bar code standard or format.
Revises part 207 significantly.
Amends Sec. 314.81(b)(3)(iv) (requiring holders of
approved new drug applications (NDAs) to report the withdrawal of
approved drug products from sale) to make it consistent with part 207.
Makes a minor conforming amendment to Sec. 314.125(b)(11)
(stating FDA may refuse to approve a new drug application if the drug
will be manufactured in whole or in part in an establishment that is
not registered and not exempt from registration under section 510 of
the FD&C Act and part 207).
Adds new Sec. 514.111(a)(12) stating FDA will refuse to
approve a new animal drug application if the drug will be produced in
whole or in part in an establishment that is not registered and is not
exempt from registration under section 510 of the FD&C Act and part
207.
Makes a minor technical amendment to Sec. 515.10(b)(8),
updating a reference to the regulations in part 207.
Adds new Sec. 601.2(f) requiring holders of biologics
license applications (BLAs) to report to FDA electronically in
accordance with part 207 the withdrawal from sale of licensed
biological products.
Amends part 607 (ESTABLISHMENT REGISTRATION AND PRODUCT
LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS) consistent
with the amendments to part 207, to require electronic submission of
establishment registration and listing information.
Amends part 1271 (HUMAN CELLS, TISSUES, AND CELLULAR AND
TISSUE-BASED PRODUCTS) to require electronic submission of
establishment registration and listing information, to state that
manufacturers of HCT/Ps that are regulated as drugs, devices, and/or
biological products under section 351 of the PHS Act (42 U.S.C. 262) or
under the FD&C Act are subject to registration and listing under part
207 or part 807, and to make other revisions consistent with the
amendments to part 207.
B. Changes to the Proposed Rule
The final rule has been revised in response to comments received on
the proposed rule. Our responses are discussed in section III. The
final rule also includes several minor editorial revisions. The final
rule makes the changes summarized in table 1.
Table 1--Substantive Changes From the Proposed Rule to the Final Rule
------------------------------------------------------------------------
21 CFR Section in final
rule Description of change from proposed rule
------------------------------------------------------------------------
201.2.................... Labeling.
Does not include proposed
revisions to Sec. 201.2 requiring human-
readable NDCs on labels.
201.25................... Bar code label requirements.
Revises Sec. 201.25(c)(1) to
accommodate alternatively formatted NDCs
in bar codes.
Does not include other proposed
amendments to Sec. 201.25.
207.1.................... Definitions.
Includes definitions for the
terms ``finished drug product,''
``unfinished drug product,'' ``bulk drug
substance,'' ``private label
distribution,'' ``registrant,'' and
``outsourcing facility'' not included in
the proposed rule.
States that the definitions and
interpretations of terms in sections 201
(21 U.S.C. 321) and 510 of the FD&C Act
apply to the terms used in part 207, if
not otherwise defined in Sec. 207.1.
Includes revised definitions of
the terms ``active pharmaceutical
ingredient,'' ``commercial
distribution,'' ``content of labeling,''
``importer,'' ``manufacture,'' ``private
label distributor,'' ``relabel,''
``repack,'' and ``representative sampling
of any other labeling''.
207.9.................... Who does this part cover?
Clarifies that private label
distributors are subject to part 207
(because they must have labeler codes).
States that all drugs regulated
under a BLA, except human blood or blood
products regulated under part 607, are
subject to part 207 and clarifies that
for this purpose certain products are not
included in the phrase ``human whole
blood and blood products''.
States that HCT/Ps regulated as
drugs under section 505 of the FD&C Act
(21 U.S.C. 355) or section 351 of the PHS
Act are subject to part 207.
207.13................... Who is exempt from the registration and
listing requirements?
Generally exempts from
registration and listing individuals or
establishments engaged solely in
recovering cells or tissues to become
components of a biological product at a
registered establishment.
Eliminates a reference to
salvagers of inactive ingredients because
salvaging, as defined, is performed only
on finished drug products.
Revises Sec. 207.13 to clarify
the applicability of part 207 to
medicated feeds.
Revises Sec. 207.13 to remove a
reference to HCT/Ps made unnecessary by
revisions to Sec. 207.9.
Adds an exemption for outsourcing
facilities registered under section 503B
of the FD&C Act (21 U.S.C. 353b) so as to
avoid duplicative registration for those
entities.
Retains the previous
establishment registration exemptions for
certain drugs entering foreign trade
zones and certain drugs imported for
export.
207.17................... Who must register?
[[Page 60173]]
Revises Sec. 207.17(b) to state
that FDA will accept establishment
registration or listing information
submitted by a private label distributor
if it is acting as an authorized agent
for an establishment that manufactures,
repacks, relabels, or salvages drugs.
207.25................... What information is required for
registration?
Revises proposed Sec. 207.25 to
include the UFI required as part of
establishment registration under FDASIA.
207.29................... What are the requirements for reviewing and
updating registration information?
Revises Sec. 207.29 to specify
that registrants must review and update
registration information between October
1 and December 31 each year, consistent
with FDASIA.
207.33................... What is the National Drug Code (NDC), how is
it assigned, and what are its requirements?
Allows for 10- or 11-digit NDCs,
consistent with a longstanding statement
in Sec. 207.35(b)(2)(i), as it read
prior to this final rule, that FDA will
expand the NDC labeler code from 5 to 6
numeric characters when the available 5-
character code combinations are
exhausted.
States that registrants will
propose NDCs for assignment by FDA.
Includes formatting requirements
for registrants to follow when
formulating their own proposed NDCs.
Allows for alternatively
formatted NDCs for certain HCT/Ps.
Explains how a labeler code can
be obtained.
Allows registrants to reserve an
NDC for a drug product under development.
Eliminates proposed Sec.
207.33(c). (What information must a
manufacturer submit before we will assign
an NDC number to a drug?)
Adds some information elements
described in proposed Sec. 207.33(c) to
the drug listing information now
described in Sec. 207.49 (Added to the
listing information required under Sec.
207.49 are the names of inactive
ingredients in the listed drug and in the
case of an unfinished drug, the number
assigned to the Drug Master File or
Veterinary Master File, if any, that
describes the manufacture of the drug).
The option to submit an approved
U.S. application number instead of a list
of inactive ingredients for a finished
drug product (as proposed in Sec.
207.33(c)) is not retained in Sec.
207.49 of this final rule.
207.35................... What changes require a new NDC?
Introduces new Sec. 207.35 to
more clearly explain what changes to
drugs require a new NDC and does not
include inactive ingredient changes in
this section.
207.37................... What restrictions pertain to the use of the
NDC?
Revises Sec. 207.37 to state
that a product may be deemed to be
misbranded if an NDC is used improperly.
207.41................... Who must list drugs and what drugs must they
list?
Revises Sec. 207.41 to clarify
the manner in which human drugs that are
manufactured, repacked, or relabeled for
private label distribution are listed.
207.45................... When, after initial registration of an
establishment, must drug listing information
be submitted?
Revises Sec. 207.45 to state
that drug listing must take place no
later than 3 calendar days after initial
registration of an establishment, rather
than ``at the time of'' initial
registration.
207.49................... What listing information must a registrant
submit for a drug it manufactures?
Revises Sec. 207.49 to reflect
that registrants will propose their own
NDCs under the final rule.
Eliminates the requirement of
proposed Sec. Sec. 207.49(f),
207.53(c), and 207.54(b)(4) (which would
have required foreign establishments to
identify importers when listing drugs
they manufacture, repack, relabel, or
salvage). (This is now reported only as
establishment registration information
for foreign establishments.).
Expands the language of proposed
Sec. 207.49(d) (now Sec.
207.49(a)(11)) to make clear that a
registrant's own establishment(s) must be
identified in drug listing information as
well as other establishments involved in
the production of unfinished drugs
received by the registrant and to require
identification of all such establishments
using their UFIs.
Removes from proposed Sec.
207.49 the option to provide an approved
U.S. application number instead of
labeling.
Revises Sec. 207.49 (also Sec.
Sec. 207.1 and 207.53) to categorize
certain drug products according to
whether they are subject to sections 505
or 512 of the FD&C Act (21 U.S.C. 355 or
360b) or section 351 of the PHS Act,
rather than whether registrants regard
them as subject to those provisions.
Adds Sec. Sec.
207.49(a)(15)(iv) and 207.53(d)(4) to
require the submission of labels for
listed drugs not elsewhere described in
Sec. Sec. 207.49(a)(14) and 207.53(d).
Clarifies in new Sec. Sec.
207.49(a)(15) and 207.53(f) the
information a registrant must submit when
listing a human drug manufactured for
private label distribution.
Adds Sec. 207.49(b) to describe
drug listing information that is
requested of registrants but not
required.
Adds Sec. 207.49(a)(2) so that
drug listing information includes package
size and type.
207.53................... What listing information must a registrant
submit for a drug that it repacks or
relabels?
Shifts from proposed Sec.
207.33(d)(1)(iii) to new Sec. 207.53(b)
the requirement that for a repacked or
relabeled drug, registrants identify the
NDC assigned to the finished drug
received by the registrant for repacking
or relabeling and exempts repackaged
medical gases from this requirement.
Requires identification of
establishments where repacking, or
relabeling is performed based on their
UFIs rather than by their registration
numbers.
Clarifies that all current
labeling (new labeling) for a repacked or
relabeled drug must be submitted, not
only the changed labeling.
Specifies that for animal drugs
subject to section 512 of the FD&C Act,
all current labeling is submitted,
whereas a copy of the current label, and
other information, is submitted for other
animal drugs.
207.54................... What listing information must a registrant
submit for a drug that it salvages?
Requires identification of
establishments where salvaging is
performed by their UFIs rather than by
their registration numbers.
Deletes references to salvaged
drugs distributed by private label
distributors.
207.57................... What information must registrants submit when
updating listing information and when?
Revises proposed Sec. 207.57 to
improve clarity and to delete the
proposed requirement that registrants
routinely update information provided
under Sec. 207.55.
[[Page 60174]]
Allows registrants to submit a
blanket ``no changes'' certification
applicable to listing information they
have previously submitted electronically,
rather than making product-by-product
``no changes'' certifications for
individual listed drugs.
207.61................... How is registration and listing information
provided to FDA?
Revises Sec. 207.61 to improve
clarity, to state that we may
periodically issue guidance on electronic
registration and listing, and to clarify
that when foreign language labeling is
used under Sec. 201.15(c), the content
of labeling must be submitted in that
foreign language along with an accurate
English translation.
Removes the option to submit
advertisements and certain labeling in
paper format, consistent with the
electronic submission requirement of
section 510(p) of the FD&C Act, as
amended by FDAAA.
207.65................... How can a waiver of the electronic submission
requirement be obtained?
Clarifies that requests for
waivers of the electronic submission
requirement cannot be relied upon until
FDA grants them.
States more broadly the
conditions under which FDA will grant
waiver requests.
Specifies that waiver requests
must be submitted in writing and must
state reasons why electronic submission
is not reasonable for the registrant.
States that FDA will specify
terms of waivers and may limit their
duration.
207.69................... What are the requirements for an official
contact and a United States agent?
Revises proposed Sec. 207.69 to
state that designated official contacts
and United States agents are both
responsible for reviewing, disseminating,
routing, and responding to all
communications from FDA, including
emergency communications.
207.77................... What legal status is conferred by
registration and listing?
Includes minor revisions to
improve clarity and mentions the UFI that
will be used to identify establishments.
207.81................... What registration and listing information
will FDA make available for public
disclosure?
Reorganizes Sec. 207.81 so that
registration and listing information that
will be disclosed is described in
paragraph (a), and exceptions are
described in paragraphs (b) and (c).
Categorizes updated drug listing
information submitted under Sec. 207.57
as generally disclosable.
Adds Sec. 207.81(b)(2) to make
explicit that FDA will generally not
disclose the names of inactive
ingredients in listed drug products if
the registrant makes a valid assertion of
confidentiality.
Categorizes the information
submitted to reserve an NDC under new
Sec. 207.33(d)(3) as generally not
disclosable.
Categorizes the identities of the
establishments involved in manufacturing,
repacking, relabeling, or salvaging
listed drugs as generally not
disclosable.
Categorizes as generally not
disclosable the NDC assigned to an
unfinished drug received by a registrant
for use in the manufacture of a listed
drug reported under Sec. 207.49(a)(12)
(i.e., the association between the
unfinished drug and the listed drug is
generally not disclosable).
No longer categorizes the NDC
assigned to a drug immediately before it
is received by a registrant for salvaging
as generally not disclosable (because the
NDC assigned to a drug does not change
when a drug is merely salvaged and not
also repackaged or relabeled).
314.81................... Other postmarketing reports (reporting the
discontinuation of a drug that is the
subject of an approved NDA).
. Renumbers proposed Sec.
314.81(b)(3)(iii) as Sec.
314.81(b)(3)(iv) and revises this section
to provide for electronic or written
submissions in certain circumstances,
under both paragraphs (a) and (b).
601.2(f)................. Applications for biologics licenses
(reporting the discontinuation of a drug
that is licensed under a BLA).
Revises proposed Sec. 601.2(f)
to reference the electronic submission
requirement of Sec. 207.61 and the
waiver provision of Sec. 207.65 and to
clarify that the date on which the
product is expected to be no longer in
commercial distribution must be reported
rather than the ``date of withdrawal from
sale''.
607.1.................... Scope (Establishment registration and product
listing for manufacturers of human blood and
blood products.)
Adds a new scope provision (Sec.
607.1) to part 607 for clarity.
607.3.................... Definitions (Establishment registration and
listing for blood and blood products).
Adds a definition of ``foreign''.
Revises the proposed definition
of ``importer''.
607.22................... How to register blood product establishments
and list blood products.
Revises proposed Sec. 607.22 to
remove references to Form FDA 2830 and to
state that blood product establishment
registration and blood product listing
must be transmitted to FDA electronically
through the Blood Establishment
Registration and Product Listing system,
unless FDA waives the electronic
submission requirement in individual
cases.
607.25................... Information required for establishment
registration and blood product listing.
Removes references to Form FDA
2830.
Requires submission of a UFI when
registering blood and blood product
establishments along with a registration
number if previously assigned by FDA.
Adds the UFI of the parent
establishment to blood product listing
information required under Sec.
607.25(b)(3).
607.26................... Amendments to establishment registration.
Revises Sec. 607.26 regarding
amendments to establishment registration
to reference the Blood Establishment
Registration and Listing System in place
of Form FDA 2830.
Clarifies that 5 days refers to 5
calendar days in this section.
607.30................... Updating blood product listing information.
Revises Sec. 607.30 regarding
updates to blood product listing
information to reference the Blood
Establishment Registration and Listing
System in place of Form FDA 2830.
607.37................... Public disclosure of establishment
registration and blood product listing
information.
Revises Sec. 607.37 to remove
references to Form FDA 2830.
Structures Sec. 607.37 in a way
that matches Sec. 207.81 (public
disclosure of drug registration and
listing information).
607.40................... Establishment registration and blood product
listing requirements for foreign blood
product establishments.
Retains the exemptions applicable
to foreign trade zones and products
imported under section 801(d)(4) of the
FD&C Act (21 U.S.C. 381(d)(4)).
[[Page 60175]]
Revises proposed Sec. 607.40 to
state more broadly the circumstances
under which FDA will waive the electronic
submission requirement for foreign blood
product establishments.
607.80................... Applicability of part 607 to licensed
devices.
Adds a new Sec. 607.80
clarifying the applicability of part 607
to certain licensed devices.
1271.1................... What are the purpose and scope of this part?
(HCT/Ps)
Adds the word ``electronic'' in
place of ``unified'' in Sec. 1271.1.
1271.3................... How does FDA define important terms in this
part?
Revises the definition of
``importer'' in proposed Sec.
1271.3(mm) to include ``at the time of
entry''.
1271.20.................. If my HCT/Ps do not meet the criteria in Sec.
1271.10, and I do not qualify for any of
the exceptions, what regulations apply?
Adds a further amendment to Sec.
1271.20 to indicate that subpart B of
part 1271 (procedures for registration
and listing) does not apply to HCT/Ps
that do not meet the criteria set out in
Sec. 1271.10(a). (In other words, HCT/
Ps not regulated solely under section 361
of the PHS Act are subject to
registration and listing under part 207
or part 807 rather than part 1271.)
1271.25.................. What information is required for
establishment registration and HCT/P
listing?
Removes from proposed Sec.
1271.25(a)(6) the requirement that each
foreign HCT/P establishment designate
only one United States agent.
Removes a reference to Form FDA
3356 in proposed Sec. 1271.25(c)(4).
Revises proposed Sec.
1271.25(d) to clarify that it pertains to
HCT/Ps regulated under BLAs and to state
that establishment registration and
listing information for such products
must be submitted in accordance with the
electronic submission requirements of
part 207, subpart E.
------------------------------------------------------------------------
This final rule does not include the proposed amendments to
Sec. Sec. 330.1, 610.60, and 610.61, all of which dealt with NDCs on
labels. This final rule also does not include the proposed minor
amendment to Sec. 1271.37 (regarding public disclosure of HCT/P
establishment registration and listing information) in light of the
technical amendments adopted on April 3, 2015 (80 FR 18087).
Some changes from the proposed rule not addressed in section III
(Comments on the Proposed Rule) are addressed in the following
paragraphs.
Active pharmaceutical ingredient: To prevent confusion, we proposed
to replace the term ``bulk drug substance'' with the more descriptive
term ``active pharmaceutical ingredient.'' This change is retained in
the final rule. Sections 503A(b)(1)(A) and 503B(a)(2) of the FD&C Act
(21 U.S.C. 353a(b)(1)(A) and 353b(a)(2)), however, refer specifically
to the definition of ``bulk drug substance'' within part 207. To ensure
conformity with the FD&C Act, both ``bulk drug substance'' and ``active
pharmaceutical ingredient'' are defined in Sec. 207.1 of the final
rule. As intended by the proposed rule, ``active pharmaceutical
ingredient'' will have the same meaning as ``bulk drug substance.''
Salvage: In this final rule, the term ``salvage'' is defined to
mean the act of segregating out those finished drug products that may
have been subjected to improper storage conditions (such as extremes in
temperature, humidity, smoke, fumes, pressure, age, or radiation) for
the purpose of returning the products to the marketplace and includes
applying manufacturing controls such as those required by current good
manufacturing practice in parts 210 and 211 (21 CFR parts 210 and 211).
Substantively, this matches the definition of ``drug product
salvaging'' included in the proposed rule, but the words have been
rearranged for greater clarity. This final rule also includes a
definition for the term ``salvager.''
Establishment registration number and Unique Facility Identifier:
We proposed to define the term ``establishment registration number'' in
Sec. 207.1 to mean ``the number assigned by FDA to the establishment
during the establishment registration process required in this part.''
The final rule changes the definition of ``establishment registration
number'' slightly to state that the number is assigned ``after'' the
registration process, rather than ``during.''
The establishment registration number identifies establishments for
inspection by FDA. Historically, an establishment registration number
is assigned to each establishment of each manufacturer, repacker,
relabeler, or salvager after the initial registration, when such
activities begin. In the preamble to the proposed rule, we explained
that ``[c]urrently, the FDA Establishment Identifier (FEI) will be the
number we assign as the establishment registration number. In the
future, however, we may use a different number as the establishment
registration number'' (71 FR 51276 at 51288).
After the proposed rule was published, FDASIA amended section 510
of the FD&C Act to require persons subject to the drug establishment
registration requirement to submit a UFI. In the electronic
registration and listing guidance, FDA stated that it intended to use
the DUNS number, assigned and managed by Dun & Bradstreet, as a
registration number. To implement the UFI provision of FDASIA, FDA also
issued guidance in 2014 that specified the DUNS number as the preferred
UFI.\1\
---------------------------------------------------------------------------
\1\ See the guidance for industry ``Specification of the Unique
Facility Identifier (UFI) System for Drug Establishment
Registration,'' November 2014, available on the Internet at https://www.fda.gov/Drugs under Guidances (Drugs).
---------------------------------------------------------------------------
Under the final rule, the establishment registration number and the
UFI are two distinct numbers. For now, FDA will continue to assign an
FEI as the establishment registration number after an establishment is
registered for the first time. The final rule requires registrants to
submit the establishment registration number (currently the FEI), ``if
previously assigned by FDA,'' under Sec. 207.25. Someone registering
an establishment for the first time is not expected to have a
registration number for the establishment. Such a registrant is
required to submit its registration number at the time of the first
annual review and update of registration information under Sec.
207.29(b) of this final rule and is encouraged to submit the
registration number sooner, as soon as it is received from FDA. The
establishment registration number does not need to be submitted at the
time of each annual registration update under Sec. 207.29 unless the
establishment registration number has changed. Likewise, the UFI,
currently specified as
[[Page 60176]]
the DUNS number, must be submitted when registering an establishment
for the first time under Sec. 207.25. The UFI does not need to be
submitted at the time of each annual registration update under Sec.
207.29 unless the UFI has changed.
Bar code label requirements (Sec. 201.25): As explained in section
III, this final rule does not include two proposed amendments to Sec.
201.25. It does, however, include a minor new amendment to Sec.
201.25. To accommodate the possibility of alternatively formatted NDCs
in bar codes, Sec. 201.25 is amended in this final rule to allow FDA's
Center Directors to approve additional standards or formats for bar
codes.
Submission of approved U.S. application number instead of inactive
ingredients (Sec. 207.33(c)(2)): Information registrants would have
submitted under Sec. 207.33(c) of the proposed rule to obtain an NDC
has been shifted to drug listing information required under Sec.
207.49 of this final rule. Under Sec. 207.49(a)(5) of this final rule,
a registrant must provide the name of each inactive ingredient in a
listed drug it manufactures. The option to submit an approved
application number instead of a list of inactive ingredients is not
retained in the final rule because FDA is not currently able to pull
inactive ingredient information from approved applications to our drug
listing systems.
III. Comments on the Proposed Rule
In the Federal Register of October 31, 2006 (71 FR 63726), FDA
announced an extension of the comment period for this rulemaking and a
public meeting to discuss the proposed changes to the NDC system
presented in the proposed rule. The public meeting was held on December
11, 2006. In the Federal Register of February 8, 2007 (72 FR 5944), FDA
announced a reopening of the comment period because technical problems
prevented some persons from submitting comments electronically on the
last day of the previous comment period. The Agency received numerous
comments, including oral presentations made at the December 2006 public
meeting and approximately 200 written comments placed in the docket.
Comments were received from prescription and nonprescription drug
manufacturers and related companies, trade associations representing
drug manufacturers and other interested parties, academic institutions,
and professional associations.
The docket for this rulemaking, Docket No. FDA-2005-N-0464, was
also used to collect comments on FDA's draft guidance for industry
entitled ``Providing Regulatory Submissions in Electronic Format--Drug
Establishment Registration and Drug Listing'' (74 FR 26248). In this
final rule, we are responding to comments that pertain to the
rulemaking, i.e., comments that relate to the changes in regulations
proposed on August 29, 2006.
To make it easier to identify comments and our responses, the word
``Comment,'' in parentheses, appears before the comment's description,
and the word ``Response,'' in parentheses, appears before our response.
We have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same number.
The number assigned to each comment is purely for organizational
purposes and does not signify the comment's value or importance or the
order in which comments were received.
A. Labeling (Sec. Sec. 201.2 and 201.25)
The proposed rule included amendments to Sec. 201.2 that would
have required drugs subject to the listing requirement of part 207 to
have labels that bear the appropriate NDC in human-readable form. As
discussed in this document, this final rule does not include the
proposed amendments that would have made human-readable NDCs mandatory
on drug labels.
Section 201.2 currently states that NDCs are ``requested but not
required'' to appear on all drug labels. Section 201.25 currently
requires bar codes on prescription human drug labels with certain
exceptions and on certain nonprescription human drug labels. Section
201.25(c) currently specifies that each bar code must contain, at a
minimum, the appropriate NDC.
Sections 201.2 and 201.25 currently do not specify which NDC should
appear on labels and in bar codes apart from referring to it as ``the
appropriate'' NDC (Sec. 201.25(c)). This implies that the NDC
appearing on a drug's label match an NDC under which the drug is
appropriately listed under part 207.
1. NDC Numbers (Sec. 201.2)
Pharmacists and health care providers use NDCs currently appearing
on drug labels in a variety of ways, including to help prevent
medication errors and to process prescription drug reimbursement
claims. We believe there is currently a high level of cooperation with
FDA's request in Sec. 201.2 that NDCs appear in human-readable form on
labels, as drug manufacturers recognize the importance of this
information.
In addition to making human-readable NDCs on drug labels mandatory,
the proposed rule would have specified which NDC must appear on labels.
Specifically, proposed Sec. 201.2(b) sought to define the appropriate
NDC for this purpose as being that of the last manufacturer, repacker,
relabeler, or private label distributor responsible for the drug
immediately before it is received by the wholesaler or retailer.
(Comment 1) Several comments recognized the importance of having
NDCs in human-readable form on labels, but many objected to FDA's
proposed provisions defining the appropriate NDC in proposed Sec.
201.2(b). In particular, certain repackers objected to the proposed
requirement that a repacker's NDC, rather than that of the original
manufacturer, appear on the labels of repackaged drug products.
(Response) This final rule does not include the proposed amendments
to Sec. 201.2 that would have made human-readable NDCs mandatory on
drug labels. It includes only a conforming amendment to that section
(replacing the reference to Sec. 207.3(b)(3) with an updated reference
to new Sec. 207.1).
The Drug Quality and Security Act (DQSA) (Pub. L. 113-54) of 2013
includes as Title II the Drug Supply Chain Security Act (DSCSA). The
DSCSA requires drug manufacturers and repackagers (as defined in
sections 581(10) and 581(16) of the FD&C Act, respectively) to affix or
imprint a product identifier on packages for certain prescription drugs
for human use. Under section 581(14) of the FD&C Act, a ``product
identifier'' is a standardized graphic that includes, in both human-
readable form and on a machine-readable data carrier, the
``standardized numerical identifier,'' lot number, and expiration date
of the product. The NDC is one component of the standardized numerical
identifier. FDA has determined that because the DSCSA requires the
inclusion of NDCs on certain prescription drug labels (as part of a
product identifier), it is unnecessary to include the proposed
amendments to Sec. 201.2 in this final rule.
Our determination that the proposed amendments to Sec. 201.2
should not be finalized renders moot many comments concerning
identification of the appropriate NDC for labeling purposes, along with
placement and formatting issues. Therefore, we do not respond to those
comments.
The DSCSA does not require manufacturers or repackagers to affix or
imprint product identifiers on nonprescription human drug products or
on animal drugs. Therefore, we will maintain the status quo for those
drug products, meaning FDA will continue to request that NDCs in human-
readable
[[Page 60177]]
form appear on all drug labels and in all drug labeling, as indicated
in Sec. 201.2. We may revisit a regulatory requirement that human-
readable NDCs appear on the labels of nonprescription human drug
products and animal drugs in the future.
2. Bar Code Label Requirements (Sec. 201.25)
Section 201.25 currently requires that a human drug product's NDC
be included in its bar code. We proposed to amend Sec. 201.25 in two
minor ways: (1) To add a cross-reference to proposed new Sec.
201.2(b), which would have described the ``appropriate NDC'' for
labeling purposes and (2) to add new Sec. 201.25(e) stating that a bar
code may be displayed on certain drug product labels voluntarily but
only if it meets the requirements of Sec. 201.25(c). Neither proposed
amendment to Sec. 201.25 is retained in the final rule.
(Comment 2) The Animal Health Institute expressed concern that
proposed Sec. 201.25(e) would unreasonably burden its members who,
although they are not currently required by Sec. 201.25 to place bar
codes on animal drug labels (because it applies to human drugs), may do
so for logistical reasons. They asked that the animal health industry
be exempt from the requirement to include an NDC in any bar codes
appearing on animal drug labels. Similar comments were received from
manufacturers of allergenic extracts. Allergenic extracts are currently
exempt from the bar code requirement (see Sec. 201.25(b)(1)(i)(B)).
Commenters explained that manufacturers of allergenic extracts may
place bar codes on their labels for inventory, warehousing, and other
logistical purposes. They objected to proposed Sec. 201.25(e) to the
extent that it would require such bar codes to include NDCs.
(Response) FDA has not retained proposed Sec. 201.25(e) in this
final rule.
(Comment 3) A group of comments asserted that 11-digit NDCs cannot
be encoded into a bar code that meets European Article Number/Uniform
Code Council or Health Industry Business Communications Council
standards, as required by current Sec. 201.25(c). Another comment
urged FDA to remove the NDC from bar codes.
(Response) This final rule acknowledges that 10-digit NDCs will be
exhausted at some point in the future as a mathematical inevitability.
As discussed in our response to Comment 52, this final rule reduces the
number of occasions when a change to a drug requires a new NDC under
Sec. 207.35. This final rule also amends Sec. 201.25 to allow FDA's
Center Directors to approve additional bar code standards and formats.
As discussed in response to Comment 1, the DSCSA requires the
inclusion of product identifiers on prescription human drug labels and
defines ``product identifier'' to mean a standardized graphic that
includes, in both human-readable form and on a machine-readable data
carrier the standardized numerical identifier, lot number, and
expiration date of the product. The standardized numerical identifier,
a component of the product identifier, is comprised of the NDC and a
serial number.
FDA continues to recognize the importance of NDCs on drug labels in
both machine-readable and human-readable form. We remind manufacturers
of the current requirement in Sec. 201.25 that bar codes on human drug
labels include the appropriate NDC, and we encourage manufacturers to
continue to provide the NDC in human-readable form on drug labels where
not required by the DSCSA.
B. General Information (Part 207, Subpart A)
1. What definitions and interpretations of terms apply to this part?
(Sec. 207.1)
The proposed rule included a set of terms and definitions in
Sec. Sec. 207.1, 607.3, and 1271.3. These definitions are retained in
the final rule with several modifications. Additionally, the final rule
includes definitions for the terms ``finished drug product,''
``unfinished drug product,'' ``bulk drug substance,'' ``outsourcing
facility,'' ``private label distribution,'' and ``registrant'' in Sec.
207.1 and a definition of ``foreign'' in Sec. 607.3.
a. Commercial distribution. In the proposed rule, the definition of
``commercial distribution'' excluded ``the internal or interplant
transfer of an active pharmaceutical ingredient between registered
establishments within the same parent, subsidiary, and/or affiliate
company.''
In the final rule, the definition does not include the phrase ``an
active pharmaceutical ingredient'' so that internal or interplant
transfers between such registered establishments are not treated as
commercial distribution under part 207, whether the transfer involves
active pharmaceutical ingredients, other unfinished drug products, or
finished drug products.
(Comment 4) A comment suggested that the definition of ``commercial
distribution'' be revised to exclude transfers between a registered
establishment and a marketing authorization holder when the two are in
a contractual relationship. Otherwise, this comment argued, products
marketed by private label distributors who employ contract
manufacturers are held to a higher burden of documentation than
products manufactured and distributed by the same entity.
(Response) We disagree with the suggestion that a transfer of drugs
from a contract manufacturer to another contracting party should not
qualify as commercial distribution. Such an exemption would interfere
with FDA's ability to track drugs and establishments for inspection.
However, by revising the definition of ``commercial distribution'' to
exclude internal or interplant transfers of drugs, including active
pharmaceutical ingredients, other unfinished drugs, and finished drug
products, between registered establishments under common ownership and
control, we have reduced the drug listing burden generally. This
exclusion accommodates the common practices of specialized
manufacturing at different registered establishments under common
ownership and control. This practice often results in multiple internal
and interplant transfers of these materials prior to marketing, which
we do not consider commercial distribution for registration and listing
purposes.
b. Content of labeling. The proposed rule included a multipart
definition for the term ``content of labeling'' with separate
provisions applicable to:
Human prescription drugs that the manufacturer regards as
subject to section 505 of the FD&C Act or section 351 of the PHS Act,
i.e., subject to premarket approval from FDA;
Human prescription drugs that the manufacturer regards as
not subject to section 505 of the FD&C Act or section 351 of the PHS
Act;
Human nonprescription drugs; and
Animal drugs.
The term ``content of labeling'' was used in the proposed rule to
describe some, but not all, labeling that must be submitted with drug
listing information. For example, proposed Sec. 207.49(g)(2)(i) stated
that listing information for certain human over-the-counter (OTC) drugs
must include ``all current labeling . . . including the content of
labeling.'' Content of labeling is defined in a very similar way in the
final rule with deletion of the phrase ``that the manufacturer regards
as'' and the addition of a reference to the labeling requirements for
veterinary drugs in 21 CFR part 201.
[[Page 60178]]
We removed the language ``that the manufacturer regards as subject
to section 505 [or 512] of the FD&C Act or section 351 of the PHS Act''
and added in its place language that refers to drugs as being either
subject or not subject to those provisions. We made this change after
determining that the manner in which content of labeling is defined
should not depend on a manufacturer's subjective understanding or
intent with respect to sections 505 or 512 of the FD&C Act or section
351 of the PHS Act.
The revised definition includes, among others, the category ``human
prescription drugs that are not subject to section 505 of the FD&C Act
or section 351 of the PHS Act.'' We have retained this construction
even though FDA considers it unlikely that any currently marketed human
prescription drug product is grandfathered or is otherwise not a new
drug subject to those provisions. However, the Agency recognizes that
the existence of such drugs is at least theoretically possible. No part
of this final rule is a finding as to the legal status of any
particular drug product.
Regarding animal drugs, in part four of the definition of ``content
of labeling'' and in other places throughout this final rule, the
phrase ``subject to section 512'' means, for purposes of this final
rule, drugs meeting the definition of ``new animal drug'' as that term
is defined in section 201(v) of the FD&C Act, and which therefore are
subject to some or all of the provisions relating to new animal drugs
found in section 512 of the FD&C Act. This term includes not only new
animal drugs that are approved under section 512 but also new animal
drugs that are conditionally approved under section 571 of the FD&C Act
(21 U.S.C. 360ccc) or indexed under section 572 of the FD&C Act (21
U.S.C. 360ccc-1). The phrase ``all other animal drugs'' as used in
provisions of this final rule at Sec. Sec. 207.49(a)(15)(iii) and
207.53(d)(3) describing the labeling registrants must provide as part
of the listing for an animal drug, refers to animal drugs that do not
meet the definition of new animal drug found in section 201(v) of the
FD&C Act (e.g., grandfathered animal drugs). Although the Agency
recognizes that the existence of such animal drugs is theoretically
possible, we believe it is unlikely that any currently marketed animal
drug product is grandfathered or otherwise not a ``new animal drug''
subject to section 512 of the FD&C Act.
(Comment 5) Commenters asked FDA to clarify how content of labeling
differs from package inserts and final printed labeling.
(Response) A prescription human drug product's FDA-approved
labeling is sometimes referred to as a ``package insert'' or as
``professional labeling.'' In defining the term ``content of
labeling,'' for human drugs, we use the phrase ``prescription drug
labeling'' (instead of ``package insert'' or ``professional labeling'')
to mean FDA-approved labeling for prescription drug products described
in Sec. Sec. 201.56, 201.57, and 201.80. For human prescription drugs
that are subject to section 505 of the FD&C Act or section 351 of the
PHS Act, content of labeling is defined as the content of the
prescription drug labeling. For human OTC drugs, content of labeling is
not defined in these terms; it includes ``all text, tables, and figures
including the drug facts labeling required by Sec. 201.66.'' For
animal drugs, ``content of labeling'' is defined to mean labeling that
accompanies the drug that is necessary to enable safe and proper
administration of the drug. This would generally include package
inserts and final printed labeling. Sections 207.49 and 207.53 require
submission of labeling with drug listing information. In most cases,
all current labeling must be submitted, including the content of
labeling.
(Comment 6) A comment stated that FDA should more clearly delineate
between the terms ``label'' and ``labeling'' throughout the rulemaking,
rather than using the term ``labeling'' to refer to both. This comment
pointed out that the proposed rule's definition of content of labeling
for human OTC drugs referred to ``labeling required by Sec. 201.66,''
but Sec. 201.66 pertains to information appearing on the ``outside
container or wrapper of the retail package, or the immediate container
label if there is no outside container or wrapper'' (Sec. 201.66(c)).
(Response) We have clarified in Sec. 207.1(a) of the final rule
that the definitions and interpretations of terms in sections 201 and
510 of the FD&C Act apply to the terms used in part 207 unless
otherwise defined. Accordingly, the term ``label'' means a display of
written, printed, or graphic matter upon the immediate container of any
article consistent with section 201(k) of the FD&C Act. The term
``labeling'' more broadly includes both immediate container labels and
other written, printed, or graphic matter accompanying such article
consistent with section 201(m) of the FD&C Act. When we intend to refer
only to immediate container or package labels, we use the term
``label.'' More often, we use the broader term ``labeling'' in this
final rule to encompass both immediate container labels and/or other
written, printed, or graphic matter accompanying the drug, as the
labeling definition in section 201(m) of the FD&C Act has been
interpreted. The term ``content of labeling'' is defined slightly
differently for human prescription drugs, human OTC drugs, and animal
drugs, and the term is intended to encompass both labels and labeling.
The proposed rule (proposed Sec. 207.1) referred only to
definitions in section 510 of the FD&C Act, and the preamble to the
proposed rule suggested that reference to the definitions in section
201 of the FD&C Act was intentionally omitted (71 FR 51276 at 51285).
Consistent with 21 CFR 1.1(b), this final rule clarifies that the
definitions in section 201 of the FD&C Act apply to the terms used in
part 207.
c. Establishment. We proposed to define ``establishment'' in Sec.
207.1 as ``a place of business under one management at one geographic
location.'' The definition in proposed Sec. 207.1 also stated ``one
geographic location may include separate buildings within the same city
if their activities are closely related to the same business enterprise
and are under the supervision of the same local management.''
Rather than adopt this proposed definition, the final rule retains
the definition of the term ``establishment'' that has appeared in the
part 207 regulations since 1980. This definition states that an
establishment is ``at one general physical location.''
(Comment 7) One comment suggested that the phrase ``within the same
city'' used in the proposed definition of ``establishment'' was too
specific. This comment argued that a manufacturing facility located in
a city with a warehouse located just outside that city should together
be treated as a single establishment for registration purposes.
(Response) In reviewing this comment and considering it in light of
the longstanding definition of ``establishment'' and the objectives
behind the establishment registration requirement, we determined that
the existing definition in part 207 is clearer and better serves our
objectives than would the proposed amended definition. The longstanding
language, ``one general physical location,'' generally restricts a
single establishment to one street address or one or more contiguous
plots of land. We do not agree with the comment that a second facility
located in a different city should be covered by the first facility's
establishment registration.
We note, however, that a facility operated only as a warehouse may
not require registration. Section 510 of the FD&C Act and Sec. 207.17
of this final rule
[[Page 60179]]
require registration of establishments where drugs are manufactured,
repacked, relabeled, or salvaged. A facility at which drugs are merely
stored may not require registration under this final rule, unless the
facility includes, for example, controlled storage for stability
testing as an element of good manufacturing practices. Other Federal
and State requirements may apply to such facilities.
Likewise, the corporate headquarters of a drug establishment should
not register under this rule if drugs are not manufactured, repacked,
relabeled, or salvaged at that location.
d. Foreign. We proposed to use the term ``foreign'' to refer to a
manufacturer, repacker, relabeler, drug product salvager, or private
label distributor who is located in a foreign country and who
manufactures, repacks, relabels, salvages, or distributes a drug that
is imported or offered for import into the United States. When used to
modify ``establishment,'' we proposed to use ``foreign'' to refer to an
establishment that is located in a foreign country and is the site
where a drug that is imported or offered for import into the United
States was manufactured, repacked, relabeled, salvaged or distributed.
We have omitted the words ``or distributed'' from this definition
because only establishments at which drugs are manufactured, repacked,
relabeled, or salvaged are required to be registered.
(Comment 8) One comment urged us to revise the definition of
``foreign'' to mean ``located in a foreign country'' while stating in
Sec. 207.9 that part 207 applies to foreign entities who import or
offer for import products into the United States.
(Response) We do not agree that the proposed rule was confusing or
difficult to understand in this respect and have decided against making
this change.
e. Importer. Section 207.25 of this final rule and section 510(i)
of the FD&C Act require foreign establishments, when registering, to
provide names and contact information for each importer in the United
States of drugs manufactured, repacked, relabeled, or salvaged at the
establishment that is known to the establishment. We proposed to define
``importer'' to mean, in part, ``a company or individual in the United
States that is an owner, consignee, or recipient of the foreign
establishment's drug that is imported into the United States.'' In
proposing this language, we recognized that a foreign establishment may
have more than one importer, and we proposed to include in this term
any owner, consignee, or recipient, even if not the initial owner,
consignee, or recipient, of the foreign establishment's drug that is
imported into the United States.
(Comment 9) Some comments stated that our proposed definition of
the term ``importer'' was too broad and would increase the burden on
manufacturers to provide unnecessary information concerning a wide
variety of entities that are not responsible for the drug. One comment
noted that the inclusion of downstream recipients in our definition of
``importer'' would impose a significant reporting burden on foreign
establishments that is not required of domestic establishments.
(Response) We agree that we should clarify and narrow the proposed
definition of ``importer.'' As proposed, the definition included every
U.S. recipient of a foreign-produced drug, excepting only the final
consumer or patient. Of this large group, foreign establishments would
be required to identify in their establishment registration submissions
only those importers that are known to the establishment. To make this
information element more useful to FDA and to reduce the burden on
registered establishments, we have determined that in this context the
term ``importer'' should include a U.S. owner, consignee, or recipient
at the time of the drug's entry into the United States and should not
include additional subsequent owners, consignees, or recipients of the
drug. We have revised the definition of importer in Sec. 207.1 of the
final rule accordingly.
(Comment 10) One comment recommended that we change ``company or
individual'' to ``person,'' in the rule's definition of ``importer,''
consistent with the definition of the term ``person'' in section 201(e)
of the FD&C Act.
(Response) We agree that the term ``person,'' as defined in the
FD&C Act, is an improvement over ``company or individual'' in this
definition. We have made this change in Sec. Sec. 207.1 and 607.3 of
the final rule, and as discussed in our response to comment 6, we have
also added a statement in Sec. Sec. 207.1(a) and 607.3(a) that the
definitions and interpretations of terms in sections 201 and 510 of the
FD&C Act apply if not otherwise defined.
f. Person who imports or offers for import. Section 207.25 of this
final rule and section 510(i) of the FD&C Act also require foreign
establishments, when registering, to supply names and contact
information for each person who imports or offers for import drugs
manufactured, repacked, relabeled, or salvaged at the establishment.
The proposed rule's definition of ``person who imports or offers for
import'' included ``an agent, broker, or other entity, other than a
carrier, that the foreign establishment uses to facilitate the import
of its drug into the United States.'' We invited comments on the use
and interpretation of the term ``facilitate.''
(Comment 11) Some comments expressed concern regarding the
potential breadth of this definition, noting in particular that the
word ``facilitate'' could, in theory, encompass entities such as
foreign insurance adjusters, underwriters, and international banks.
Commenters pointed out the significant burden associated with the
identification of such entities in foreign establishment registrations
and updates to registrations, noting that international supply chains
and business relationships are not static. One comment urged FDA to
exclude customs brokers from the rule's definition of ``person who
imports or offers for import.'' Another comment encouraged FDA to
exclude middlemen from this definition, as their identities would
change frequently.
(Response) Although we did not intend for the word ``facilitate''
to be read as broadly as some comments suggested, FDA agrees that the
definition of ``person who imports or offers for import'' should be
made more precise, narrow, and useful.
We note, as a matter of clarification, that in section 510(i) of
the FD&C Act and in Sec. 207.25 of the final rule, the requirement
that foreign establishments identify each person who imports or offers
for import is not said to be limited to persons known to the
establishment (unlike the requirement that they identify
``importers''). The preamble to the proposed rule included statements
that were inconsistent with the FD&C Act in this regard, suggesting
that foreign establishments would be required to report the name of
each person known to the establishment who imports or offers for import
its drug(s) into the United States. See, e.g., 71 FR 51276 at 51289. In
fact, the proposed rule (proposed Sec. 207.25), the final rule, and
the FD&C Act all require foreign establishments to report, when
registering, the name of each person who imports or offers for import
its drug(s) into the United States without regard to whether such
persons are known to the establishment. Therefore, it is important that
we define ``person who imports or offers for import'' in a way that is
practical, useful, and consistent with this understanding.
[[Page 60180]]
Our intention in defining this term is to include foreign persons
who are primarily responsible for sending a drug to the United States.
Foreign establishments are reasonably expected to know the identities
of such persons. In many cases, the establishment itself will be a
person who imports or offers for import its drugs into the United
States. In other cases, it will be a person the foreign establishment
engages to send one or more drugs to the United States. It will
generally be the foreign person who owns the drug and sells or enters
into a contractual obligation to supply the drug to a person in the
United States.
In light of the comments received and FDA's objectives, the final
rule defines ``person who imports or offers for import'' to mean the
owner or exporter of a drug who consigns and ships a drug from a
foreign country to the United States. This definition includes persons
who send a drug to the United States by international mail or other
private delivery service, but does not include carriers who merely
transport the drug. This definition is not intended to include persons
operating merely as customs brokers.
g. Manufacture, manufacturer. The definitions of ``manufacture''
and ``manufacturer'' in Sec. 207.1 of this final rule include minor
editorial revisions for clarity and new references to animal feed
bearing or containing a new animal drug.
(Comment 12) Some comments stated that the definition of
``manufacturer'' should specify that it applies only to entities
manufacturing drugs for commercial distribution.
(Response) We disagree with the recommendation that the definition
of ``manufacturer'' be limited to drugs manufactured ``for commercial
distribution.'' The underlying statutory provisions require
registration of establishments where drugs are manufactured, without
regard to commercial distribution (section 510(c) of the FD&C Act), but
require listing of drugs that are manufactured for commercial
distribution (section 510(j) of the FD&C Act). Accordingly, under Sec.
207.17 of this final rule, each domestic establishment where a drug is
manufactured (or repacked, relabeled, or salvaged) must be registered
unless exempt from registration under section 510(g) of the FD&C Act or
under Sec. 207.13, regardless of whether the drug is commercially
distributed. The drug listing obligation, as described in Sec. 207.41,
applies to drugs that are manufactured, repacked, relabeled, or
salvaged for commercial distribution. (See separate definition of
``commercial distribution.'')
(Comment 13) One comment asked that drug sponsors be included in
the definition of manufacturer. Other comments suggested that FDA add
``product formulator'' to the definition of ``manufacturer'' or provide
definitions for terms such as ``drug sponsor.'' These comments pointed
out that the holder of an approved application, such as an NDA, or the
formulator of a nonprescription monograph product may use a contract
manufacturer to produce the product for distribution under the name of
the application holder or the product formulator. Some comments
recommended that the final rule treat such application holders or
product formulators as manufacturers so they would register their
establishments and list such products and that it exempt contract
manufacturers from the drug listing requirement.
(Response) We decline to add the application holder or ``product
formulator'' concepts to the definition of ``manufacturer.'' Under
section 510(c) of the FD&C Act, the obligation to register drug
establishments rests on owners or operators of establishments engaged
in the manufacture (including repacking, relabeling, and salvaging) of
drugs, and the listing obligation applies to ``every person who
registers.'' FDA recognizes that this language could be read broadly to
encompass entities that develop or formulate drug products without
performing manufacturing operations. However, considering the
objectives behind drug registration and listing, we are currently
interested in the registration of establishments where manufacturing
operations (including repacking, relabeling, and salvaging) take place
and the listing of drugs handled at those establishments.
We recognize, however, that an application holder or a product
formulator using a contract manufacturer to manufacture a drug may wish
to submit drug listing information for that product directly to FDA.
Although the actual manufacturer of the drug has the legal obligation
to list it, FDA would accept listing information for the drug submitted
by its formulator or any other person acting as an authorized agent for
the manufacturer. When we use the term ``authorized agent'' in this
final rule, we mean a person who is authorized to act on behalf of
another. The term ``authorized agent'' should not be confused with the
United States agent referred to in Sec. 207.69(b).
(Comment 14) Several comments asked for clarification on how the
terms ``manufacture,'' ``repackage,'' ``relabel'' and ``private label
distributor'' would apply to the medical gas industry and pointed out
that certain medical gas operations, such as the transfilling of gas
from one container to another, have long been treated as drug
manufacturing by FDA but, under the proposed rule, would seem to
qualify as ``repacking.'' These comments asked FDA to classify medical
gas refillers as ``manufacturers'' rather than ``repackers'' in the
final rule.
(Response) FDA agrees that these important points require
clarification. Nothing in this final rule is intended to alter the
definitions applicable to FDA's regulations governing current good
manufacturing practices for drug products, parts 210 and 211.
Therefore, the definition of ``manufacture, processing, packing, or
holding of a drug product'' currently appearing in Sec. 210.3(b)(12)
will continue to apply to medical gases as that definition has always
applied.
For purposes of part 207, we will interpret the definition of
``manufacture'' in Sec. 207.1 as including the initial manufacturing
process that produces or purifies a medical gas, whether by air
separation, chemical reaction, or other process. Additionally, the
mixing of two or more medical gases to produce a combination would also
qualify as ``manufacture'' under Sec. 207.1. The impact of this
interpretation is that a person who thus qualifies as a manufacturer of
a medical gas will be required to submit the drug listing information
required under Sec. 207.49 of this final rule (``What listing
information must a registrant submit for a drug it manufactures?'') in
addition to registering the establishment(s) at which manufacturing is
conducted.
All subsequent transfillings of a medical gas from one container to
another (i.e., from tanker trucks into standing tanks and from standing
tanks into smaller containers, etc.) would fall within the definition
of ``repack or repackage'' in Sec. 207.1 of this final rule. The
impact of this interpretation is that a person who thus qualifies as a
repacker of a medical gas will be required to submit the drug listing
information required under Sec. 207.53 of this final rule (``What
information must a registrant submit for a drug that it repacks or
relabels?'') in addition to registering the establishment(s) at which
repackaging is conducted. Comments opposing this classification
expressed concern that under the proposed rule, repackers would be
required to identify the NDC assigned to a drug immediately before it
is received by the repacker as information that must be submitted to
obtain an NDC for a repackaged drug
[[Page 60181]]
under proposed Sec. 207.33(d)(1)(ii). See our response to Comment 73
regarding an exemption for medical gases from the requirement that
registrants submit such source NDCs for drugs they repackage or
relabel.
The definition of ``relabel'' in Sec. 207.1 of this final rule
applies to medical gases. It refers to changing or altering the
existing label on a drug or drug package, without repacking the drug or
drug package. A person who places a label on a repackaged drug (e.g., a
medical gas recently filled into a canister) for the first time
qualifies as a ``repackager'' as that term is defined in this final
rule.
The term ``private label distributor'' is defined in Sec. 207.1 of
this final rule to mean, with respect to a particular drug, a person
who did not manufacture, repack, relabel, or salvage the drug but under
whose label or trade name the drug is commercially distributed. This
definition applies equally to private label distributors of medical
gases and other drugs. A medical gas transfiller is a repackager, and
not a private label distributor, under this final rule. As discussed in
our response to comment 16, private label distributors do not--by
reason of their status as private label distributors--have an
obligation to register establishments or list drugs. They must have
labeler codes, obtained under new Sec. 207.33(c), and they may submit
drug listing information or establishment registration information if
acting as the authorized agent of a registrant on whose behalf the
information is submitted.
h. Material change. In the proposed rule, ``material change'' was
defined as any change in any drug listing information, excluding
labeling changes in arrangement or printing or labeling changes of an
editorial nature. This definition is retained in the final rule with
minor revisions to clarify that material change also does not include
changes in the format of labeling, or the inclusion of a bar code or
the initial inclusion of an NDC on a label.
(Comment 15) One comment asked FDA to clarify the types of labeling
changes that would qualify as a material change and, hence, require
reporting as an update to drug listing information under Sec. 207.57.
This comment specifically suggested examples of labeling changes that
would qualify as significant changes in the labeling of a prescription
drug product or significant changes in the label or package insert of
an OTC drug product.
(Response) In referring to ``significant'' labeling changes, this
comment seems to relate to the longstanding definition of ``material
change'' in Sec. 207.3(a)(3), prior to this final rule, which
encompassed labeling changes described as ``significant.'' Today's
final rule revises that definition so that material change includes any
labeling change other than changes in the format of labeling, changes
of an editorial nature, inclusion of a bar code, or initial inclusion
of an NDC. In this context, changes of an editorial nature would not
include any changes that add or revise meaning.
Thus, the new definition of ``material change'' adopted as part of
this final rule is broader than the previous definition and is not
limited to ``significant'' changes. The definition includes--with very
few exceptions--any change in previously reported drug listing
information. FDA intends to rely primarily on new Sec. 207.57 to
maintain an up-to-date database of current drug labeling. Registrants
should submit current labeling (and a resubmission of all listing
information) each time they submit a drug listing update to report
changed information under Sec. 207.57.
i. Private label distributor. We proposed to define ``private label
distributor'' to mean a person who owns or operates an establishment
that commercially distributes, under its own label or trade name, any
drug manufactured, repacked, relabeled, or salvaged by a registered
establishment. In the preamble to the proposed rule we explained that
the private label distributor does not engage in any activities
performed by a manufacturer, repacker, relabeler, or salvager for the
drug it distributes (71 FR 51276 at 51290).
In the final rule, private label distributor is defined to mean,
with respect to a particular drug, a person who did not manufacture,
repack, relabel, or salvage the drug but under whose label or trade
name the drug is commercially distributed. We have also defined
``private label distribution'' in this final rule to mean commercial
distribution of a drug under the label or trade name of a person who
did not manufacture, repack, relabel, or salvage that drug.
(Comment 16) Some comments requested clarification regarding the
distinction between private label distributors, manufacturers, and
wholesale distributors. Others urged FDA to allow private label
distributors to list the drugs they distribute. One comment requested
clarification regarding the responsibilities of private label
distributors under part 207.
(Response) We agree that more clarity is needed regarding these
terms and the registration and listing obligations associated with
private label distribution of drug products. We have eliminated the
mention of establishment ownership in the proposed rule's definition of
``private label distributor'' because private label distributors do not
necessarily own establishments that require registration under section
510 of the FD&C Act. We have also clarified that an entity may act as a
private label distributor with respect to a particular drug. For
example, if a drug manufacturer distributes, under its own name or
trade name, a drug manufactured entirely by a contract manufacturer, it
is acting as a private label distributor with respect to that drug. The
difference between private label distributors and wholesale
distributors or others involved in drug distribution is that a private
label distributor's name, trade name, or label appears on the product.
A common example of private label distribution is the sale of aspirin
under a retail pharmacy's brand name when the retail pharmacy did not
manufacture the product. As defined in this final rule, private label
distribution encompasses the use of any brand name or business name on
a drug product where the named business or the owner of the brand name
did not manufacture the drug. Thus, as we are defining the term in part
207, a private label distributor may, but does not necessarily, operate
retail stores or play a role in the physical distribution of the drug
product. Even without using a brand name, if an entity is identified as
the distributor or marketer of a drug under Sec. 201.1 of the drug
labeling regulations, without having manufactured the drug, that person
will qualify as a private label distributor as the term is defined in
this final rule.
Under this final rule, private label distributors do not have
registration or listing obligations with respect to drugs for which
they merely act as private label distributors. Only manufacturers,
repackers, relabelers, and salvagers have an obligation to register and
list. Private label distributors are subject to this final rule only in
that they must apply for an NDC labeler code as described in Sec.
207.33(c) and update the information submitted under that section when
the information changes. Private label distributors are in the best
position to obtain their own labeler codes and update information
associated with those codes, thereby preventing potential submissions
of inconsistent or inaccurate information by multiple contract
manufacturers.
A person who is a private label distributor with respect to a
particular drug does not for that reason incur an establishment
registration or listing
[[Page 60182]]
obligation. The FD&C Act and the regulations in part 207 both place the
registration and listing obligation on persons who manufacture, repack,
relabel, or salvage drugs. The registration and listing obligation thus
rests with the actual manufacturer, repacker, relabeler, or salvager
whether or not a product is intended for private label distribution.
For this reason, the final rule does not include provisions regarding
establishment registrations or drug listings submitted by private label
distributors.
We recognize, however, that some private label distributors are in
a position to supply listing information, including NDCs, for drugs
distributed under their names and may prefer to do so. FDA will accept
registration and listing information submitted by any authorized agent
acting on behalf of a manufacturer, repacker, relabeler, or salvager,
and this includes a private label distributor authorized by a
manufacturer, repacker, relabeler, or salvager, to submit drug listing
information on its behalf. In these cases, the manufacturer, repacker,
relabeler, or salvager remains responsible for compliance with all
registration and listing requirements and the accuracy of the
information submitted by its agent.
A person who acts merely as a wholesale distributor of a drug
product (i.e, a person who did not manufacture, repack, relabel, or
salvage the drug product and whose name, trade name, or label does not
appear on the drug product) does not incur obligations under this rule.
j. Relabel, relabeler, repack, repacker. We proposed to define
``relabel'' to mean changing the label or labels on a drug or drug
package, or adding to the labeling for a drug or drug package, without
repacking the drug or drug package. We also proposed to define
``relabeler'' to mean a person who owns or operates an establishment
that relabels a drug.
We proposed to define ``repack'' to mean repack or repackage or
otherwise change the container or wrapper of a drug or drug package.
Similarly, we proposed to define ``repacker'' to mean a person who owns
or operates an establishment that repacks a drug or drug package.
In the final rule, these definitions are clarified and revised in
response to comments.
(Comment 17) Some comments noted that the definition of relabel
could include wholesale drug distributors who add information to outer
container labels for purposes of delivery to a customer, customer
identification, inventory management, special handling instructions, or
to aid in compliance with Federal and State pedigree requirements.
Commenters urged us not to require establishments (e.g., distribution
facilities) where such relabeling occurs to register and list.
(Response) We agree generally with these comments and have revised
the definition of ``relabel'' in the final rule to exclude the addition
or modification of information affixed solely for purposes of delivery
to a customer, customer identification, or inventory management.
However, we did not exclude the addition of special handling
instructions from the definition of ``relabel,'' as recommended in
these comments. Such an exclusion might be misinterpreted as
accommodating revised storage instructions in drug labeling. However,
FDA would not object to the addition of storage information to an outer
label if such information is not inconsistent in any way with storage
instructions appearing elsewhere in the drug's labeling. In that case,
FDA would not regard the addition of such storage information to an
outer container label as relabeling that would subject a person to
registration and listing.
k. Representative sampling of advertisements and Representative
sampling of any other labeling. The definitions of these terms included
in the proposed rule appear in this final rule with one minor revision.
(Comment 18) The preamble to the proposed rule included a brief
discussion of these definitions. That discussion pointed out a
confusing aspect of the previous definitions of these terms and the
previous definition of the term ``advertising and labeling'' in part
207. See 71 FR 51276 at 51291. One comment argued that there was no
conflict in these definitions and urged FDA to retain our previous
definitions of ``representative sampling of advertisements'' and
``representative sampling of any other labeling.'' This comment pointed
out that the examples given in those previous definitions were helpful.
(Response) We disagree with this comment. The revised definitions
are intended to eliminate some confusion associated with the previous
definitions as explained in the preamble to the proposed rule. The
examples appearing in the previous definitions read as follows: ``If
more than one medical journal advertisement is used but the promotional
content is essentially identical, only one need be submitted'' and ``if
more than one brochure is used but the promotional content is
essentially identical, only one need be submitted.'' The quoted
language served as common sense guidance regarding the application of
the definitions without being a central part of the definitions.
Although omitting that language from the definitions included in the
proposed rule and this final rule, FDA is not disavowing the examples
or suggesting that registrants should take a different approach.
2. Who does this part cover? (Sec. 207.9)
The Agency proposed new Sec. 207.9 to clarify the types of
businesses that are subject to drug establishment registration and
listing under part 207. Section 207.9 is retained in this final rule
with certain revisions and clarifications.
Section 207.9(a)(3) of this final rule clarifies that private label
distributors are subject to part 207. As discussed previously in this
document, private label distributors do not have an obligation to
register an establishment or list any drugs arising from their
activities as private label distributors. They are, however, expected
to obtain NDC labeler codes under Sec. 207.33(c) of this final rule
and update the information reported to FDA under Sec. 207.33(c) as
required by Sec. 207.33(c)(2).
Section 207.9(a)(4) of this final rule is revised to state more
clearly its applicability to establishments engaged in the manufacture,
repacking, relabeling, or salvaging of drugs regulated under a BLA.
These establishments are subject to part 207 unless they are required
to register and list under part 607 (ESTABLISHMENT REGISTRATION AND
PRODUCT LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS).
Section 207.9(a)(5) of this final rule is revised to state that
HCT/Ps, as defined in Sec. 1271.3(d), are subject to registration and
listing under part 207 if they are drugs regulated under section 505 of
the FD&C Act or under section 351 of the PHS Act. A conforming
amendment is made to Sec. 1271.1. Manufacturers of HCT/Ps that are
regulated under section 361 of the PHS Act (42 U.S.C. 264) and not
under section 351 will remain subject to registration and listing under
part 1271.
(Comment 19) Comments requested clarification on the applicability
of this rule to contract manufacturers and private label distributors
of drug products, saying it was not clear in the proposed rule how
contract manufacturers are to handle establishment registration and
labeler code assignment.
(Response) Manufacturers of drug products are obligated by the FD&C
Act and by this final rule--whether or not
[[Page 60183]]
they are contract manufacturers--to register their establishments and
list the drugs they manufacture for commercial distribution (as the
term ``commercial distribution'' is defined in new Sec. 207.1).
Sections 207.49 and 207.53 of this final rule require manufacturers,
repackers, and relabelers to provide their own NDC (an NDC that
includes the registrant's own labeler code) for each drug they list.
(Salvagers are not required to provide new NDCs when listing drugs they
salvage because a drug's NDC does not change when it is merely
salvaged, and not repacked or relabeled. A person who salvages and then
repacks or relabels a drug is a repacker or relabeler, as those terms
are defined in Sec. 207.1, and must register and list as a repacker or
relabeler.) This provision requires manufacturers, repackers, and
relabelers responsible for listing drugs, including contract
manufacturers, to obtain an NDC labeler code in accordance with new
Sec. 207.33(c).
When listing a human drug manufactured for private label
distribution (distribution under the name or trade name of someone
other than the drug's manufacturer, as defined in new Sec. 207.1),
Sec. Sec. 207.49 and 207.53 require registrants to provide two NDCs,
one that includes the registrant's own NDC labeler code and one that
includes the NDC labeler code of the private label distributor. As
stated in response to comment 16, FDA will accept drug listing
information submitted by a private label distributor (or anyone else)
if properly authorized to act as an agent for the actual manufacturer.
The use of an agent to handle establishment registration or drug
listing submissions does not, however, transfer legal responsibility
for complying with this final rule from a manufacturer, repacker,
relabeler, or salvager to its agent. Animal drugs manufactured for
private label distribution should be listed under a single NDC that
includes the labeler code of the private label distributor.
Note that the term ``private label distributor'' is defined in new
Sec. 207.1 to mean, with respect to a particular drug, a person who
did not manufacture, repack, relabel, or salvage the drug but under
whose label or trade name the drug is commercially distributed. FDA's
statements in this document that private label distributors are not
obligated to register their establishments or list the drugs they
distribute are premised on this definition. If someone who would
otherwise qualify as a private label distributor carries out testing or
control procedures applied to the final product, e.g., systematic batch
release testing required under current good manufacturing practices,
that person may qualify as a manufacturer (see the definition of
``manufacture'' in new Sec. 207.1) and need to register its
establishment where the testing or control procedures are carried out.
(But if a private label distributor uses a contract laboratory to carry
out the testing or control procedures, the contract laboratory, not the
private label distributor, may qualify as a manufacturer and need to
register its establishment.) Likewise, if someone qualifies as a
private label distributor with respect to one or more drugs, but also
qualifies as a manufacturer, repacker, or relabeler with respect to
other drugs, that person would need to register the establishment where
manufacturing, repacking, or relabeling is conducted and list the drugs
that are manufactured, repacked, or relabeled for commercial
distribution at the registered establishment.
Entities that qualify as private label distributors under this
final rule and do not also manufacture, repack, relabel, or salvage any
drugs may already have effective establishment registrations and drug
listings submitted in the past. We do not expect these entities to
renew their registrations after the effective date of this final rule.
They may either cancel their registrations or allow their registrations
to lapse by not making any further submissions. Any drug listings
submitted in the past by entities that qualify as private label
distributors under this final rule for drugs they do not manufacture,
repack, relabel, or salvage should be transferred to the actual
manufacturers, repackers, relabelers, or salvagers of the listed drugs.
(Comment 20) One comment asked FDA to clarify whether radiologic
products are subject to this rule.
(Response) This comment did not elaborate on the types of products
encompassed by the question so we are unable to respond specifically.
There is not an exemption from the establishment registration and drug
listing requirements for manufacturers of radioactive drugs, also known
as radiopharmaceutical products. Anyone with questions about the
applicability of part 207, either before or after this final rule, to
radioactive drug products should contact the electronic Drug
Registration and Listing System staff in the Office of Compliance at
FDA's Center for Drug Evaluation and Research (CDER). For diagnostic
device products that include a radioactive drug constituent part, see
our response to comment 22 in this document regarding drug/device
combination products. Also see part 807 regarding establishment
registration and listing for radiologic device products. Positron
emission tomography (PET) drugs are subject to part 207, as stated in
Sec. 207.13(l)(1) and as discussed in the proposed rule (71 FR 51276
at 51285).
(Comment 21) One comment requested guidance regarding the
information needed for ``active drug substance manufacturers'' to
register and list.
(Response) In this final rule, the term ``active pharmaceutical
ingredient'' (API) is defined in Sec. 207.1. The registration
obligation applies to each domestic establishment that manufacturers,
repacks, relabels, or salvages a drug or an animal feed bearing or
containing a new animal drug (whether or not that product is
commercially distributed). It also applies to each foreign
establishment that manufacturers, repacks, relabels, or salvages a drug
or an animal feed bearing or containing a new animal drug that is
imported or offered for import into the United States. In each case,
the term ``drug'' includes: (1) An API by itself, (2) an API that has
been combined with one or more other APIs or inactive ingredients (see
definition of ``unfinished drug'' in Sec. 207.1), and (3) finished
drug products (see definition of ``finished drug product'' in Sec.
207.1).
The information that must be submitted for establishment
registration is set forth in new Sec. 207.25. These information
elements do not differ depending on whether the registrant handles
APIs, other unfinished drugs, or finished drugs.
The information that must be submitted with a drug listing is set
forth in new Sec. 207.49 for a drug the registrant manufactures, Sec.
207.53 for a drug the registrant repacks or relabels, and in Sec.
207.54 for a drug the registrant salvages. As specified in Sec.
207.41, the drug listing obligation applies only to drugs that are
manufactured, repacked, relabeled, or salvaged for commercial
distribution. Sections 207.49, 207.53, and 207.54 indicate some minor
differences in the information that must be submitted depending on
whether the drug is finished or unfinished. For example, Sec.
207.49(a)(15)(iv) describes the labeling that must be submitted for an
unfinished drug.
(Comment 22) One comment asked, in the context of the proposed
rule's requirement that NDCs appear on drug labels, how the rule would
apply to drug/device combination products. Other comments asked how
registration and listing should be handled for drug/device combination
product kits. (See the definition of ``combination product'' in Sec.
3.2(e) (21 CFR 3.2(e)), unaffected by this rulemaking.)
[[Page 60184]]
(Response) We acknowledge that the proposed rule did not include an
explanation of its applicability to drug/device combination products,
including how manufacturers of such products should register their
establishments, list their combination products, and provide related
information on the labels of their combination products. The codified
of this final rule likewise does not contain specific provisions
regarding drug/device combination products. FDA expects to further
address drug/device combination product registration and listing in the
future. As stated previously in this document, we also are not
finalizing the proposed amendment to Sec. 201.2 that would have
required human-readable NDCs on the labels of all drugs subject to the
listing requirement.
3. Who is exempt from registration and listing requirements? (Sec.
207.13)
The proposed rule included a new Sec. 207.13 aimed at clarifying
the types of businesses that are exempt from drug establishment
registration and listing under part 207. Section 207.13 is retained in
this final rule with certain revisions and clarifications. Some
exemptions described in Sec. 207.13 are derived directly from section
510(g) of the FD&C Act. Other exemptions are established under section
510(g)(5) of the FD&C Act supported by our finding that registration by
such classes of persons is not necessary for the protection of the
public health.
(Comment 23) Several comments argued against the elimination of two
existing exemptions from registration and listing that the proposed
rule would have revoked. These two exemptions encompass: (1) Drugs
imported under section 801(d)(3) of the FD&C Act (often referred to as
``import for export'') and (2) drugs that enter a foreign trade zone
and are re-exported from that foreign trade zone without having entered
U.S. commerce.
(Response) Previous Sec. 207.40(b) stated that no drug may be
imported or offered for import into the United States unless the drug
is listed and manufactured, prepared, propagated, compounded, or
processed at a registered foreign establishment. The section also
stated that this prohibition did not apply to, among other things,
components of drugs imported under section 801(d)(3) of the FD&C Act.
Section 801(d)(3) allows persons to import certain articles, including
components of drugs, if specified conditions are met, provided that the
imported articles are further processed or incorporated into products
and exported or, if not used, the imported articles are destroyed or
exported. Thus, previous Sec. 207.40(b) exempted certain foreign
establishments from the establishment registration and listing
requirement.
Previous Sec. 207.40(a) stated that a foreign establishment was
not required to comply with the registration and listing requirements
if its drug entered a foreign trade zone and was re-exported from that
foreign trade zone without having entered U.S. commerce.
Upon careful consideration of the comments received, we have
decided to retain both exemptions in this final rule. Therefore, under
Sec. 207.13(j) of this final rule, if all the conditions of section
801(d)(3) of the FD&C Act are satisfied, a component of a drug will not
be excluded from importation into the United States by reason that it
is unlisted or was manufactured at an unregistered foreign
establishment. Additionally, under Sec. 207.13(j) of this final rule,
a foreign establishment does not incur a registration and listing
obligation if its drug enters a foreign trade zone and is re-exported
from that foreign trade zone without having entered U.S. commerce.
These exemptions pertain only to drugs that are re-exported or
components of drugs that are processed or incorporated into products
and then exported, and these exemptions pertain only to foreign
establishments. If an establishment located within a foreign trade zone
manufactures, repacks, relabels, or salvages a drug for commercial
distribution in the United States, that establishment would need to
register and list those drugs it handles for U.S. commercial
distribution. Additionally, if a foreign establishment exports drugs to
the United States relying on either of these exemptions, but also
exports other drugs for commercial distribution in the United States,
it must comply with the registration and listing requirements for those
drugs that are commercially distributed in the United States.
The corresponding exemptions for blood product establishments are
also retained in Sec. 607.40 under this final rule.
(Comment 24) One comment asked FDA to confirm that animal
biological products are not subject to this rule.
(Response) Some biological drugs intended for administration to
animals are regulated by the U.S. Department of Agriculture (USDA)
under the Virus, Serum, and Toxins Act of 1913. Section 510.4 (21 CFR
510.4) states that animal drugs produced and distributed in full
conformance with the Virus, Serum, and Toxins Act and any regulations
issued thereunder shall not be deemed to be subject to section 512 of
the FD&C Act (includes premarket approval and other requirements for
new animal drugs regulated by FDA). As proposed in Sec. 207.13(g), the
final rule includes an exemption applicable to these products in Sec.
207.13(h).
(Comment 25) Comments from the medical gas industry expressed
concern about the ability of entities such as pharmacies, hospitals,
clinics, and emergency responders to refill medical gas cylinders if
the repackaging would require the repacker's NDC to appear on the label
of the repackaged product. The comment stated that if these entities
are exempt from part 207, they cannot obtain an NDC.
(Response) Our decision not to include the proposed amendments to
Sec. 201.2 that would have required human-readable NDCs on drug labels
renders the concern expressed in this comment moot. We would like to
confirm that pharmacies, hospitals, clinics, other health care
entities, and public health agencies that qualify as exempt from the
registration and listing requirements under Sec. 207.13 of this final
rule do not lose their exemptions by dispensing medical gases or
filling medical gas containers in the normal course of their
activities.
C. Registration (Part 207, Subpart B)
1. Who must register? (Sec. 207.17)
Section 207.17 describes who is required to register an
establishment under part 207. This section is reworded in the final
rule: (1) To distinguish between domestic and foreign manufacturers,
repackers, relabelers, and salvagers and (2) to clarify that FDA will
accept registration information submitted by a private label
distributor only if it is acting as an authorized agent for and
submitting information pertaining to an entity that has an
establishment registration obligation.
(Comment 26) One comment asked FDA to clarify whether a storage
facility that does not repack or relabel drugs is required to register
under part 207.
(Response) A facility at which drugs are stored, such as a
warehouse, does not need to be registered provided drugs are not
manufactured, repacked, relabeled, or salvaged (as those terms are
defined in Sec. 207.1) at the facility. Note that the definition of
``manufacture'' includes sampling, testing, or control procedures
applied to the final product or to any part of the process. Thus, for
example, if a warehouse includes a temperature-controlled storage area
where drug samples are stored for stability testing to satisfy current
good manufacturing practice requirements, that activity would qualify
as a manufacturing
[[Page 60185]]
operation and require registration of the warehouse as a drug
establishment. Other State or Federal requirements may apply to such
facilities.
As explained in response to Comment 17, we have revised the
definitions of ``relabel'' and ``relabeler'' so they do not include the
addition or modification of information affixed to drug packaging
solely for purposes of delivery to a customer, customer identification,
or inventory management. Therefore, the addition or modification of
such information at a warehouse does not trigger the need to register
it as an establishment.
2. When must initial registration information be provided? (Sec.
207.21)
Proposed Sec. 207.21 described when initial registration
information must be submitted for an establishment newly required to
register under part 207. The provision is retained in this final rule
and reorganized into paragraphs (a) and (b) for improved clarity.
(Comment 27) One comment suggested that the words ``for commercial
distribution'' be added to Sec. 207.21, suggesting that establishment
registration is required only for establishments at which drugs
intended for commercial distribution are manufactured, repacked,
relabeled, or salvaged.
(Response) The absence of these words--``for commercial
distribution''--from Sec. 207.21 is intentional and comports with
section 510 of the FD&C Act. Any establishment at which drugs are
manufactured, repacked, relabeled, or salvaged must be registered under
part 207, unless exempt from registration under section 510(g) of the
FD&C Act or under the relevant regulations (Sec. Sec. 207.13, 607.65,
or 1271.15, as applicable) whether or not the drugs are commercially
distributed. Accordingly, an establishment at which an investigational
drug is manufactured is subject to the establishment registration
requirement. The listing obligation, on the other hand, applies to
drugs that are for commercial distribution.
3. What information is required for registration? (Sec. 207.25)
Proposed Sec. 207.25 described the information that must be
submitted to register an establishment. The provision is retained in
the final rule with minor substantive and editorial revisions.
Substantively, new Sec. 207.25 no longer requires the submission of
fax numbers to register establishments and now includes the new
statutory requirement that registrants provide a UFI for each
establishment. (See our discussion of establishment registration
numbers and UFIs in section II.B, Changes to the Proposed Rule.) New
Sec. 207.25 also clarifies that the physical address of each
establishment is required (rather than a post office box, for example),
and a mailing address is required for the establishment's official
contact.
(Comment 28) One comment asked FDA to clarify what format should be
used when a foreign establishment submits contact information for each
importer. This comment also asked FDA to explain who should submit
establishment registration information when a business has both foreign
and U.S. establishments.
(Response) According to new Sec. 207.61, all information
transmitted to FDA under part 207, including establishment registration
information, must be transmitted to FDA in electronic format unless a
waiver is granted. FDA's systems for electronic registration include
fields for information elements such as the required contact
information for U.S. importers of drugs manufactured, repacked,
relabeled, or salvaged at a foreign establishment.
Section 207.17 addresses this comment's second question, who should
submit establishment registration information when a business has both
foreign and U.S. establishments? This section states that when
operations are conducted at more than one establishment, and common
ownership and control among all the establishments exists, the parent,
subsidiary, or affiliate company may submit registration information
for all establishments. This applies whether the establishments are
domestic, foreign, or both.
(Comment 29) One comment asked FDA to exempt contract manufacturers
from the requirement that establishments identify each importer in the
United States of drugs they manufacture, repack, relabel, or salvage
that is known to the establishment as well as each person who imports
or offers for import such drugs to the United States. This comment
stated that contract manufactures may not have this information.
(Response) This requirement is retained in the final rule, in Sec.
207.25(h). The provision implements a statutory requirement (section
510(i)(1) of the FD&C Act). This requirement pertains only to foreign
establishments, and it requires them to identify ``importers'' known to
the establishment and ``persons who import or offer for import,'' as
these terms are defined in Sec. 207.1. Both of these definitions have
been refined and narrowed in this final rule. A foreign contract
manufacturer exporting drugs to the United States should be able to
identify such persons.
4. What are the requirements for reviewing and updating registration
information? (Sec. 207.29)
Section 207.29 describes the requirements for: (1) Expedited
updating of certain changes to establishment registration information
and (2) annual reviewing and updating of establishment registration.
This section is retained in the final rule with very minor revisions.
Fax numbers are no longer mentioned in Sec. 207.29(a) because they are
no longer required for establishment registration. Additionally, the
dates during which the annual review and update of registration
information must take place have been adjusted to match section
510(b)(2) of the FD&C Act, added by FDAAA.
(Comment 30) Some comments opposed the requirement that if no
changes have occurred since the last registration, registrants certify
that no changes have occurred.
(Response) The annual review and updating of establishment
registration information is critical to the integrity of FDA's
database. The requirement that registrants certify that no changes have
occurred when that is true provides important assurance that
registrants have reviewed the establishment registration information
they previously submitted. Otherwise, FDA would need to interpret
silence from a registrant as indicating either that the information
remains up to date or that the registrant may have neglected to review
and update the information. We further note that section 510(b)(1) of
the FD&C Act now requires annual registration of establishments between
October 1 and December 31, and the option to certify that no changes
have occurred since the last registration is a minimally burdensome
implementation of this statutory requirement.
Please see our response to Comment 74, which addresses this issue
in the context of drug listing updates.
D. National Drug Code (Part 207, Subpart C)
1. What is the national drug code (NDC), how is it assigned, and what
are its requirements? (Sec. 207.33)
The NDC provisions in this final rule have been revised in response
to comments received on the proposed rule. Most significantly, new
Sec. 207.33:
Allows for 11 digits in the NDC (when 10-digit
combinations are exhausted).
Reflects that registrants will propose their own NDCs for
drugs they
[[Page 60186]]
list. Under the proposed rule, FDA would have assigned NDCs in response
to submissions from registrants. Under this final rule, each registrant
must propose its own NDC for each drug the registrant lists. FDA will
assign the proposed NDCs to the listed drugs unless they are improperly
formatted, previously assigned to a listed drug, or reserved.
Includes new NDC formatting requirements for registrants
to observe when proposing NDCs.
Transfers some information that would have been required
under proposed Sec. 207.33(c) (What information must a manufacturer
submit before we will assign an NDC number to a drug?) to information
that must be included in a drug listing submission.
Allows certain drug products to be assigned alternatively
formatted NDCs if approved by the Center Director. This applies to the
HCT/Ps specified in new Sec. 207.33(b)(4) if they are minimally
manipulated.
Includes a new Sec. 207.33(c) that explains who must
obtain an NDC labeler code and how labeler codes are assigned and
updated.
Includes new provisions in Sec. 207.33(d) that explain
how a proposed NDC can be voluntarily reserved.
Comments on the NDC provisions of the proposed rule and FDA's
responses are summarized in this document. This does not include some
comments that have been made moot by the revisions summarized
previously.
(Comment 31) FDA received many comments opposing the proposed
rule's requirement that FDA, rather than registrants, generate and
assign the complete NDC for drugs that are subject to listing. Some
comments were concerned about possible delays associated with NDC
request submissions. Others were concerned about losing control over
numbering conventions that individual registrants may apply to their
own product codes and package codes. One comment expressed concern that
subjecting OTC monograph products to an NDC assignment process could
begin to resemble an FDA approval process for such products.
(Response) The objective behind FDA's proposal to generate and
assign NDCs was to assure they are assigned appropriately. Although we
did not intend FDA's issuance of NDCs to be time consuming or to
operate as an approval process, we recognize that FDA's objectives can
be met in a way that is more flexible and less burdensome for
registrants. Accordingly, the proposed requirement that FDA generate
the complete NDC for each listed drug is not included in this final
rule.
Under new Sec. 207.33(d), registrants, not FDA, will generate NDCs
for assignment to their listed drugs. An NDC is considered to be
``proposed for assignment'' when a registrant submits it for the first
time with drug listing information in accordance with Sec. 207.49 or
Sec. 207.53. If the proposed NDC conforms to the formatting
requirements of Sec. 207.33, is not reserved for a different drug, and
was not previously assigned to a different listed drug, FDA will assign
the proposed NDC when it receives all required listing information for
the drug.
(Comment 32) Some comments asked how far in advance of marketing a
drug for the first time an NDC may be requested. Comments also pointed
out that manufacturers need to know the NDC for a drug in development
prior to the time of drug listing.
(Response) As explained in response to Comment 31, this final rule
requires registrants to propose their own NDCs for drugs they list. FDA
will assign a proposed NDC to the drug identified by the registrant if
the proposed NDC conforms to the formatting requirements of Sec.
207.33, is not reserved for a different drug, and was not previously
assigned to a different listed drug.
We recognize that a mechanism for reserving a specific NDC may be
helpful, as this would provide greater certainty that a proposed NDC
will be accepted by FDA when it is included with a listing submission
at the time of marketing. Accordingly, this final rule includes a new
Sec. 207.33(d)(3) that allows a person to voluntarily reserve a
proposed NDC for a period of 2 years prior to its inclusion in a drug
listing submission for the first time. Note that an NDC reserved under
Sec. 207.33(d)(3) would need to include most importantly a labeler
code and a product code. At the discretion of the person submitting the
reservation request, a single package code could be included, or not,
with one or more package codes included later in NDC(s) submitted with
complete drug listing information.
Certain minimal information must be submitted to reserve a proposed
NDC, as specified in new Sec. 207.33(d)(3). This information does not
include identification of the drug's inactive ingredients. Many
comments opposed the inclusion of such detailed information in the
proposed rule's provision governing NDC requests.
NDCs reserved under Sec. 207.33(d)(3) would be reserved for 2
years unless the person whose labeler code is included in the NDC asks
FDA to cancel the reservation earlier. If a reserved NDC is not used
during the 2-year reservation period (i.e., is not submitted to FDA
with complete listing information for the drug matching the
reservation), the NDC will be available for assignment to another drug.
Anyone wishing to extend an NDC reservation beyond 2 years may submit
another reservation request.
In addition to the procedure established under Sec. 207.33(d)(3),
a registrant wishing to reserve an NDC also has the option of
submitting complete listing information for a drug that is under
development and specifying a future ``start marketing date'' in the
listing submission. That listing submission could then be updated, as
needed, when the actual marketing date arrives.
(Comment 33) One comment questioned how, when listing a drug for
the first time, a registrant can supply a drug's labeling if the
labeling must include the drug's NDC, and if the NDC is not assigned
until the drug is listed.
(Response) As explained in response to Comment 1, unlike the
proposed rule, this final rule does not require NDCs to appear in
human-readable form on drug labels (but an intervening statutory
amendment, the DSCSA, does require NDCs to appear as part of the
product identifier on certain drug labels). After the effective date of
this final rule, our regulations will continue to encourage, but not
require, the appearance of human-readable NDCs on drug labels (Sec.
201.2) and continue to require that NDCs appear in bar codes on drug
labels (Sec. 201.25(c)).
Under this final rule, unlike the proposed rule, registrants are
able to develop and propose their own NDCs to FDA. Upon receipt of a
first-time listing submission, FDA will assign the NDC proposed by the
registrant to the drug being listed unless the NDC is improperly
formatted, reserved for a different drug, or was previously assigned to
a different listed drug. Registrants are also able to reserve an NDC
for a drug under development under Sec. 207.33(d)(3) of this final
rule. Accordingly, registrants should not have difficulty determining,
with adequate certainty, the NDC for a drug under development.
(Comment 34) Some comments supported the proposed rule's revocation
of then-current Sec. 207.35(b)(4)(ii), which stated that the product
code of a discontinued product could be reassigned to another product 5
years after the expiration date of the discontinued product or, if
there is no expiration date, 5 years after the last shipment of the
discontinued product. Commenters generally agreed that the reuse of old
NDCs for a different
[[Page 60187]]
product in the future can be confusing. One comment, however, urged FDA
to allow for the reuse of NDCs.
(Response) FDA is retaining this general prohibition against the
reuse of NDCs in the final rule. As indicated in new Sec.
207.33(d)(2), an NDC will not be assigned to a drug if it was
previously assigned to a different drug. The prohibition against reuse
of NDCs applies to listings submitted on or after the effective date of
this final rule. Drugs that are currently listed under NDCs that have
been reused in accordance with previous Sec. 207.35(b)(4)(ii) may
continue to be listed under such NDCs.
Conversely, if a registrant reintroduces a drug it listed and
discontinued in the past, that registrant must list the drug using the
same NDC under which it was listed in the past. See Sec. 207.37(b) of
this final rule. However, if the reintroduced drug includes changes,
compared to the discontinued drug, that would warrant a new NDC under
new Sec. 207.35, then it should be listed under a new NDC.
As discussed in response to Comment 19, under new Sec. 207.49, if
a private label distributor uses a contract manufacturer to produce a
human drug, the contract manufacturer has an obligation to list the
drug under two NDCs, one that includes the labeler code of the contract
manufacturer and one that includes the labeler code of the private
label distributor. If the private label distributor switches to a new
contract manufacturer in the future, that new contract manufacturer
would also have an obligation to list the drug under two NDCs, one that
includes its own labeler code and one that includes the labeler code of
the private label distributor. The NDC that includes the new contract
manufacturer's labeler code will obviously differ from the NDC under
which the previous contract manufacturer listed the drug (because the
labeler codes will differ). The NDC that includes the private label
distributor's labeler code may be the same as that under which the
previous contract manufacturer listed the drug provided: (1) There have
been no changes to the drug that warrant a new NDC under Sec. 207.35
and (2) the previous contract manufacturer updates its listing
information to indicate it no longer manufactures the drug (as it is
required to do under Sec. 207.57 at the time of its next June or
December listing update, or sooner at its discretion). If those two
conditions do not exist, FDA would accept a listing from the new
contract manufacturer under a new NDC that includes the private label
distributor's labeler code.
(Comment 35) We received several comments concerning the format of
the NDC. Many comments expressed concern about the impact of any
changes in the NDC format on various systems that track and use NDCs.
Some comments urged FDA to retain the 10-digit NDC format. Others
encouraged the adoption of a standard 11-digit NDC. Some comments
opposed the possible introduction of alphanumeric NDCs, preferring all
numeric NDCs. Others were concerned about the possible coexistence of
10- and 11-digit NDCs.
(Response) FDA is sensitive to these concerns. Section 207.33(b) of
this final rule specifies the format of an NDC recognized by FDA. The
final rule necessarily includes more specifications than did the
proposed rule concerning NDC formatting because under the final rule,
registrants, not FDA, develop their own proposed NDCs, and they must
all meet certain formatting parameters. The final rule states, for
example, that the NDC is 10 or 11 digits to preclude the submission of
longer NDCs.
Our regulations have long stated that FDA will expand the labeler
code from five to six numeric characters when the available five-
character code combinations are exhausted (previous Sec.
207.35(b)(2)(i)). This occurrence is mathematically inevitable and is
reflected in new Sec. 207.33(b)(1), which states that the NDC must
consist of 10 or 11 digits. FDA will begin issuing 6-digit labeler
codes, leading to 11-digit NDCs, only when the available 5-digit
labeler codes are exhausted. FDA will not assign 11-digit NDCs until we
begin to issue 6-digit labeler codes.
FDA recognizes the desirability of a single, standard format for
NDCs, having three segments of consistent lengths, as we eventually
transition to six-digit labeler codes. We intend to initiate a public
discussion of future formatting options in the near future. In the
meantime, the provisions included in this final rule are intended to
accommodate the range of existing NDC formats, leaving room for
necessary expansion to 11 digits.
This final rule refers to the NDC as a numeric code, not an
alphanumeric code. This takes into account comments that objected to
the inclusion of alpha characters in NDCs as disruptive of current
systems and practices.
(Comment 36) Some comments urged FDA not to require NDCs for HCT/
Ps, citing the International Society of Blood Transfusion (ISBT) number
as a better means of identifying these products.
(Response) In response to these comments, Sec. 207.33(b)(4) of
this final rule states that an alternatively formatted NDC may be used
for certain identified HCT/Ps if they are minimally manipulated and if
the alternatively formatted NDC is approved by the Center Director
(CDER or CBER, as appropriate). Such approval may be indicated in
Guidance for Industry issued by one or both Centers or in this
preamble, for example. Accordingly, FDA identifies ISBT-128 as a
currently approved alternatively formatted NDC to identify HCT/Ps
within the scope of Sec. 207.33(b)(4). ISBT-128 is an international
standard for the identification of medical products of human origin.
Please note that an alternatively formatted NDC approved under Sec.
207.33(b)(4) qualifies as an NDC. HCT/Ps that are not within the scope
of Sec. 207.33(b)(4) require traditionally formatted NDCs.
(Comment 37) One comment encouraged FDA to allow a single NDC, with
a single package code, to be assigned to an API, which may be
commercially distributed in various quantities.
(Response) This comment refers to APIs, but the question applies to
any bulk product supplied in variable quantities. We would like to
accept non-numeric characters, such as one or more asterisks, in the
package code segment of an NDC to indicate a bulk product supplied in
various quantities (as was previously done in paper submissions).
However, the SPL format, currently specified in the electronic
registration and listing guidance, does not accommodate non-numeric
characters. Manufacturers in this situation may adopt a variety of
practices. They may submit multiple NDCs with package codes
corresponding to a variety of commonly ordered package sizes. They may
submit an NDC package code corresponding to 1 kilogram (kg), for
example, and then treat a shipment of 10 kg as being comprised of 10
units. In some cases, they may submit an NDC with a package code
corresponding to a 55-gallon drum, for example, and use that packaging
to ship 55-gallon orders as well as orders that are slightly less than
55 gallons in volume.
(Comment 38) One comment recommended that the NDC for a drug that
was repacked or relabeled include the product code of the source drug.
(Response) Section 207.53 of this final rule requires repackers and
relabelers to list drugs they repack or relabel and requires them to
submit an appropriate NDC for each such drug that includes the
repacker's/relabeler's labeler code. It would not be feasible to
require the NDC for a repacked or relabled drug to include the labeler
code of the repacker or relabeler combined with the product code of the
source drug. Such a
[[Page 60188]]
requirement might produce an NDC that was previously assigned to a
different drug. Because registrants will continue to propose their own
NDCs under this final rule, a repacker or relabeler may generally adopt
the convention proposed in the comment, but may not list a drug under
an NDC that was previously assigned to a different listed drug.
Listing submissions for repacked or relabeled drugs must also
include the complete NDC assigned to each finished drug received by the
registrant for repacking or relabeling (i.e., the source drug), so this
link will exist in the drug's listing information.
(Comment 39) Two comments asked whether FDA will assign NDCs to
products that do not have application numbers, i.e., products that are
not the subject of an approved application.
(Response) This question was posed in the context of the proposed
requirement that registrants request an NDC from FDA by submitting
information specified in proposed Sec. 207.33(c) prior to a listing
submission. In the case of finished drugs, proposed Sec. 207.33(c)
would have allowed registrants to submit an approved U.S. application
number in place of certain information. As discussed in response to
Comment 31, this final rule allows registrants to propose their own
NDCs with listing submissions, and FDA will accept those proposed NDCs
unless they are formatted incorrectly, reserved for a different drug,
or previously assigned to a different drug. Under this final rule, NDCs
are still ``assigned'' only by FDA, after all required listing
information is received. We affirm that NDCs will be assigned in this
manner to all drugs subject to the listing requirement, including drugs
that do not have application numbers. As we have stated in the past
(e.g., previous Sec. 207.39 and in the preamble to the proposed rule
(71 FR 51276 at 51305)), FDA's assignment of an NDC does not in any way
denote FDA approval of a product. Section 207.37 of this final rule
states that a product may be deemed misbranded if an NDC is used to
denote or imply FDA approval.
(Comment 40) Some comments asked how NDCs will be assigned to
multidrug kits. Here we are addressing kits that do not contain medical
devices. (See related discussion of drug/device combination products in
response to Comment 22.)
(Response) If a product contains more than one finished drug
product, co-packaged as a kit, and that kit is commercially
distributed, the kit itself must be listed in accordance with Sec.
207.41, under Sec. 207.49 or Sec. 207.53, as appropriate. A
registrant submitting the listing should propose an NDC for the kit
itself, distinct from any NDCs assigned to individual drug constituents
contained in the kit. The NDC proposed for the kit should include the
labeler code of the registrant obligated to submit the listing. If the
kit is packaged for private label distribution, it should be listed
under an additional NDC that includes the labeler code of the private
label distributor.
(Comment 41) A comment asked whether a finished drug product,
manufactured under one approved application at two different
manufacturing sites under the same ownership and control could be
listed under a single NDC. In this example, the finished product from
each manufacturing site would have the same composition and physical
appearance. The comment also asked whether the answer would change if
the manufacturing sites are located in two different countries.
(Response) Each manufacturing site would need its own establishment
registration under Sec. 207.17 unless exempt under section 510(g) of
the FD&C Act or under Sec. 207.13. (Foreign establishments must
register only if they manufacture, repack, relabel, or salvage drugs
that are imported or offered for import into the United States.) With
respect to the drug listing requirement, the proposed rule and the
final rule specify in Sec. 207.41(a) that when operations are
conducted at more than one establishment, and common ownership and
control exists among all the establishments, the parent, subsidiary, or
affiliate company may submit listing information for any drug
manufactured, repacked, relabeled, or salvaged at any such
establishment. This language allows a registrant that manufactures a
drug at more than one of its own establishments to submit a single
listing for that product, while identifying all establishments where
the registrant manufactures the drug under Sec. 207.49(a)(12). The
listed drug would have a single NDC in this scenario. The answer does
not change if one or more manufacturing sites are located outside the
United States.
Note, however, that FDA would also accept multiple listings if a
manufacturer in this situation wished for any reason to submit separate
listings and NDCs for the same drug manufactured at multiple
establishments.
This analysis does not apply to an entity that uses one or more
contract manufacturers to manufacture, repack, relabel, or salvage a
drug. In that case, each contract manufacturing site must be registered
under Sec. 207.17, unless exempt under section 510(g) of the FD&C Act
or under Sec. 207.13. If more than one contract manufacturing site is
used, and those sites are under common ownership and control, the
contract manufacturer could submit a single listing for this drug
covering its activities at multiple sites (also listing other drugs it
is required to list under Sec. 207.49 or Sec. 207.53). Furthermore,
as discussed in our response to comment 19, contract manufacturers must
generally list a drug under two NDCs, one that includes the contract
manufacturer's labeler code and one that includes the private label
distributor's labeler code. In this scenario, a single NDC that
includes the private label distributor's labeler code could be used
with a drug manufactured at multiple contractor sites along with a
single NDC that includes the contract manufacturer's labeler code,
provided there are no differences in the product produced at the
various sites that would warrant a new NDC under Sec. 207.35.
(Comment 42) One comment asked how registrants should assess
whether their existing NDCs comply with this rule. Some comments noted
a statement in the preamble to the proposed rule that FDA intends to
validate that current NDCs comply with the new regulations when the
rule is finalized (71 FR 51276 at 51280) and requested more information
about this process.
(Response) This final rule is not intended to require extensive
changes to NDCs themselves. The NDC formatting provisions of new Sec.
207.33(b) are intended to accommodate NDC formats currently in use. The
10-digit NDC formats provided for under Sec. 207.33(b) of this final
rule include (in terms of numbers of digits in the labeler code,
product code, and package code respectively) 4-4-2, 5-3-2, and 5-4-1.
Any NDC in one of those formats that is not assigned to multiple drug
products and is not assigned to a non-drug product should comply with
this final rule. When five-digit labeler codes are exhausted, FDA will
begin issuing six-digit labeler codes, allowing for additional formats
of 6-3-2 and 6-4-1.
(Comment 43) Some comments encouraged FDA to permit one registrant
or business to maintain more than one labeler code. These comments
pointed out that mergers and acquisitions in the pharmaceutical
industry result in corporate entities responsible for drugs listed
under multiple NDC labeler codes. Consolidation of such NDCs to a
single labeler code would be burdensome and may not be possible in some
cases if, for
[[Page 60189]]
example, one product code has been used with two different labeler
codes.
(Response) FDA agrees with this comment. We encourage registrants
and private label distributors to maintain a single labeler code
wherever possible. But FDA will not require each registrant and private
label distributor to maintain only one labeler code. This flexible
approach accommodates mergers and acquisitions. It departs from a
statement in the preamble to the proposed rule that only one labeler
code would be used for new NDC numbers that FDA would have assigned
prospectively for any given manufacturer, repacker, or relabeler (71 FR
51276 at 51299). It also accommodates situations in which any
registrant wishes to maintain different labeler codes for different
product lines or situations in which a registrant risks exhausting all
available labeler code and product code combinations if the registrant
operates with a single labeler code. Importantly, new Sec.
207.33(c)(2) requires each person who is assigned a labeler code to
update the information required under Sec. 207.33(c)(1). This will
allow FDA to reliably associate every labeler code with the person to
whom it is assigned and the person's contact information.
Registrants and private label distributors who currently have NDC
labeler codes but for whom FDA does not have up-to-date information
described in Sec. 207.33(c)(2) on the effective date of this rule are
required to update their information. FDA may refuse to accept new drug
listings that include an NDC labeler code for which the information
required by Sec. 207.33(c)(2) is not current in our system.
(Comment 44) One comment asked FDA to confirm that a business
owning many registered establishments may maintain only one labeler
code, so that all of its NDCs include a single labeler code.
(Response) FDA prefers that such a business maintain only one
labeler code, and that it use this single labeler code when proposing
NDCs for drugs it manufactures, repacks, relabels, or salvages at
establishments under common ownership and control. However, as
explained in our response to Comment 43, FDA will not require any
business to maintain only one labeler code.
(Comment 45) One comment interpreted the proposed rule as
preventing an entity that does not distribute its own products from
maintaining its own labeler code. The comment recommended that such an
entity not be required to assume distribution responsibilities to
retain its labeler code.
(Response) FDA is not certain whether this comment is concerned
with which NDC would have been required to appear on product labels had
we finalized the proposed amendments to Sec. 201.2, or more generally
concerned with the NDCs under which private label distributor products
are listed. Under Sec. 207.33(c) of this final rule, a labeler code
must be requested and maintained by any person who engages in
manufacturing, repacking, relabeling, or private label distribution of
drug products. The term ``private label distribution'' is defined in
Sec. 207.1 of this final rule to mean commercial distribution of a
drug under the label or trade name of a person who did not manufacture,
repack, relabel, or salvage that drug. A private label distributor does
not need to physically engage in drug distribution to qualify as a
private label distributor under this definition and maintain a labeler
code under Sec. 207.33(c).
(Comment 46) One comment gave an example of two establishments
``located in the same geographical location within two cities located
five miles apart'' and asked whether those establishments would need
separate NDC labeler codes and registration numbers.
(Response) Under the final rule's definition of ``establishment,''
two establishments located 5 miles apart would not qualify as being at
``one general physical location'' and would therefore require two
separate registrations. Each establishment would be associated with its
own UFI and establishment registration number. As stated in Sec.
207.17 of this final rule, when operations are conducted at more than
one establishment and common ownership and control among all the
establishments exists, the parent, subsidiary, or affiliate company may
submit registration information for all establishments. Likewise, with
respect to drug listing information, Sec. 207.41 states that when
operations are conducted at more than one establishment, and common
ownership and control exists among all the establishments, the parent,
subsidiary, or affiliate company may submit listing information for any
drug manufactured, repacked, relabeled, or salvaged at any such
establishment. A single labeler code may be used in the NDCs for all
drugs proposed by such a parent, subsidiary, or affiliate company.
(Comment 47) A comment asked FDA to confirm that the NDC assignment
requirement for APIs applies to all APIs, whether they are supplied by
domestic or foreign establishments.
(Response) Any drug, including an API, manufactured at a domestic
establishment for commercial distribution in the United States must be
listed under Sec. 207.49 unless exempt under Sec. 207.13. As proposed
and under this final rule, the registration and listing requirements
apply to foreign establishments whose drugs, including APIs, are
imported or offered for import into the United States. See Sec. Sec.
207.13(j), 207.49, and 207.53.
(Comment 48) Some comments urged FDA to exempt allergenic extract
products from the NDC requirement or from drug establishment
registration and listing generally. These comments argued that the
proposed rule would require manufacturers of allergenic extracts to
manage a large number of NDCs without obvious benefits.
(Response) Allergenic extracts are used in the diagnosis and
treatment of allergies. As such, they are appropriately regulated as
drugs under the FD&C Act and FDA's regulations. Section 510 of the FD&C
Act authorizes FDA to exempt certain persons from establishment
registration (and hence listing) if registration ``is not necessary for
the protection of the public health.'' We decline to make this finding
for allergenic extracts. Such an exemption would diminish FDA's ability
to inspect establishments at which allergenic extracts are manufactured
and track marketed products.
Both before and after this final rule, our regulations in part 207
have required that each listed drug product have an NDC. We understand
that this requires manufacturers of allergenic extracts to associate a
unique NDC with each product they manufacture for commercial
distribution, and this may result in a large number of NDCs. We believe
the public health benefits associated with drug registration and
listing outweigh the burden this places on manufacturers to manage a
large number of NDCs.
(Comment 49) One comment asked whether drug samples are subject to
the NDC requirement.
(Response) Under this final rule, registrants must list drugs they
manufacture, repack, relabel, or salvage for commercial distribution.
The term ``commercial distribution'' is defined in a way that
encompasses free samples. Because any listed drug requires an NDC,
drugs packaged for distribution as promotional samples are expected to
have NDCs.
(Comment 50) Some comments recommended that pharmacy compounded
drugs be eligible for NDC
[[Page 60190]]
assignment. These comments noted that hospital pharmacies use the NDC
to reduce medication errors.
(Response) Drug products compounded by a licensed pharmacist or a
licensed physician in conformance with section 503A of the FD&C Act are
generally exempt from drug establishment registration and listing under
part 207 before and after this final rule, consistent with the
exemptions for pharmacies and practitioners in section 510(g) of the
FD&C Act. The DQSA added section 503B to the FD&C Act. Under section
503B, a compounder can register with FDA as an ``outsourcing
facility.'' Because the FD&C Act now establishes a separate
registration and drug product reporting process for such outsourcing
facilities, this final rule exempts outsourcing facilities from the
registration and listing requirements of part 207. (See new Sec.
207.13(k).)
Compounders that meet the conditions for exemption from
registration and listing requirements under part 207 may elect to
voluntarily register and list their products under part 207 and obtain
NDCs.
2. What changes require a new NDC? (Sec. 207.35)
Section 207.33(f) of the proposed rule identified the types of
changes to a drug that require a new NDC. This final rule includes new
Sec. 207.35 that states with greater clarity the types of changes to a
drug that require a new NDC. Substantively, new Sec. 207.35 is similar
to the corresponding requirements in the proposed rule, but the
provision does not require a new NDC when changes are made to inactive
ingredients or when the Drug Master File number or Veterinary Master
File number, if any, assigned to an API changes.
(Comment 51) Some comments were concerned about the types of
changes to a drug that would require a new NDC in the proposed rule. In
particular, many comments opposed the proposed requirement that changes
in a drug's inactive ingredients would necessitate a new NDC.
(Response) This proposed requirement--that a change in a drug's
inactive ingredients would necessitate a new NDC--has not been retained
in the final rule. Under both the proposed rule and the final rule, any
change in information submitted with a drug listing must be reflected
in an updated listing under Sec. 207.57. Certain more significant
changes also require a new NDC, as specified in new Sec. 207.35. Upon
careful consideration, we agree with those comments that stated it
would be unreasonably burdensome to require registrants to submit a new
NDC each time they change the inactive ingredient composition of a
product.
Some comments questioned the scope of the proposed requirement:
Would it apply to changes from one inactive ingredient supplier to
another? Would it apply to changes in the quantity at which an inactive
ingredient is used? Would it apply to changes in the compositional
specifications of an inactive ingredient?
The justification for this requirement suggested in the proposed
rule was that some patients may be sensitive to certain inactive
ingredients, and a change in NDC would flag for those patients and
their pharmacists and health care providers that a drug's composition
may have changed (or that some other characteristic identified in Sec.
207.35 changed).
Upon careful consideration, we agree with those comments that
challenged this justification. Paying attention to changes in NDCs
would be an inexact way for patients, pharmacists, and health care
providers to discover changes in inactive ingredients. As proposed and
under this final rule, updates to drug listing information (including a
new NDC) will be submitted each June and December, or sooner at the
registrant's discretion. Thus, manufacturers will not be obligated to
change an NDC immediately upon changing an inactive ingredient and
update the NDC on their labels on a batch specific basis.
Comments pointed out that, particularly in the case of OTC
monograph products, manufacturers currently have the flexibility to use
certain inactive ingredients interchangeably. FDA's current guidance
regarding the labeling of OTC drug products acknowledges this practice
and includes formatting recommendations to accommodate the practice.\2\
The proposed rule did not explain, for example, how the new NDC
requirement would apply in a situation where the manufacturer of an OTC
monograph product may have switched inactive ingredients in several
different batches in the 6 months leading up to a semiannual listing
update submission.
---------------------------------------------------------------------------
\2\ See the guidance for industry ``Labeling OTC Human Drug
Products--Questions and Answers,'' December 2008, pp. 10-11,
available on the Internet at https://www.fda.gov/Drugs under
Guidances (Drugs).
---------------------------------------------------------------------------
Rather than impose this burden on some manufacturers, and
recognizing that ingredient labeling and reference to batch numbers are
more useful and exact ways to ascertain a drug's composition, this
final rule does not require a new NDC when a drug's inactive
ingredients change.
(Comment 52) One group of comments expressed concern about the many
situations in which a new NDC would be needed under the proposed rule.
In addition to mentioning changes in inactive ingredients, the comments
cited any addition to a drug's label or labeling, including the
addition of stickers with delivery and handling instructions and ``any
material change to a drug's labeling or packaging insert'' as things
that should not warrant a new NDC. The comments emphasized the burden
associated with changes to a drug's NDC.
(Response) Several changes in this final rule will reduce the
number of occasions when a drug requires a new or additional NDC,
compared to the proposed rule. See the response to comment 51 regarding
changes to inactive ingredients. See our response to Comment 17
regarding the revised definition of ``relabel'' in the final rule to
exclude the addition or modification of information affixed solely for
purposes of delivery to a customer, customer identification, or
inventory management. Under this final rule, changes or additions to a
label that do not qualify as relabeling do not necessitate a drug
listing submission and NDC under Sec. 207.53. Section 207.35 of this
final rule does not include ``any material change'' to a drug's
labeling or package insert among the changes that necessitate a new
NDC. Labeling changes are generally not included in new Sec. 207.35.
Some labeling changes will be incidental to the changes included in new
Sec. 207.35 (e.g., a change to a drug's established or proprietary
name), but labeling changes themselves do not trigger the need for a
new NDC under this final rule. FDA has also determined that changes in
Drug Master File numbers or Veterinary Master File numbers describing
APIs, alone, should not necessitate new NDCs. Changes in APIs
themselves, i.e., a change in the identity of an API, will continue to
necessitate new NDCs under new Sec. 207.35.
(Comment 53) The Animal Health Institute noted that Animal Drug
User Fee Act (ADUFA) fees are assessed for each animal drug NDC. This
comment pointed out that manufacturers of animal drug products will be
potentially charged twice for a single drug product due to a change in
the NDC during a fiscal year or due to multiple listings for a single
product required under this final rule. The comment urged FDA to exempt
animal drug manufacturers from paying such extra product fees imposed
by this final rule.
(Response) As noted in our response to Comment 52, several changes
in this
[[Page 60191]]
final rule will reduce the number of occasions when a drug requires a
new or additional NDC, compared to the proposed rule. Under ADUFA, the
term ``animal drug product'' means each specific strength or potency of
a particular active ingredient or ingredients in final dosage form
marketed by a particular manufacturer or distributor, which is uniquely
identified by the labeler code and product code portions of the NDC,
and for which an animal drug application or a supplemental animal drug
application has been approved. See section 739(3) of the FD&C Act.
Because product fees are assessed under ADUFA for animal drug products
meeting this definition, fees are not assessed for unfinished animal
drugs or animal drugs that are not marketed. However, there may be
instances where a change is made to a marketed animal drug product that
necessitates a new NDC for that product during a single fiscal year,
resulting in a new ADUFA product fee. This is an issue that has existed
prior to this final rule.
(Comment 54) One comment asked whether a new NDC will be required
when a manufacturer changes to a new supplier of an API or, relatedly,
whether multiple NDCs would be needed if multiple suppliers of an API
are indicated in an approval application for a finished drug product.
(Response) Section 207.35 of this final rule requires a new NDC
when there is a change to any API. This provision includes changes from
one API to another (e.g., a change from acetaminophen to ibuprofen) and
changes in the strength of an API. The provision does not encompass
changes in suppliers and does not require multiple NDC product codes
corresponding to multiple API suppliers.
(Comment 55) One comment requested clarification regarding when a
change in drug product strength will require a new NDC (or when
multiple strengths will require multiple NDCs). This comment
distinguished between concentration and strength.
(Response) Section 207.35 of this final rule requires a new NDC if
the strength of any API changes. The term ``strength'' is generally
used to refer to the absolute quantity of API in a single unit dose
(e.g., 250 milligrams (mg) per tablet). Concentration, on the other
hand, refers to the amount of an ingredient per defined weight or
volume of product (e.g., 1 mg/1 milliliter (mL)). Examples of multiple
strengths requiring separate NDCs include 100 mg/tablet, 250 mg/tablet,
1 mg/1 mL, and 2 mg/2 mL. Each of these would require its own NDC if
each is supplied as a unit dose. This is true even though the last two
concentrations are equivalent.
(Comment 56) Some comments questioned whether two digits are
sufficient for the package code segment of the NDC. Relatedly, some
comments requested clarification regarding the need for a new NDC when
changes are made to a drug's package size or type. For example, would a
change from one type of plastic bottle to another necessitate a new
NDC? Another comment argued that changes in medical gas packaging
should not necessitate many new NDCs.
(Response) A 2-digit package code segment accommodates 100
different packaging configurations, counting ``00'' as one possibility.
There should be a separate package code for each package size.
Therefore, if a package is enlarged to hold more of a drug product, it
would need a new NDC.
A change in package configuration, such as a change from a bottle
to a blister pack, would also require a new NDC.
Under new Sec. 207.35(c), a new NDC (specifically a new package
code segment) is needed for changes in the composition of packaging
material that are significant enough so that the packaging type
description previously submitted is no longer accurate. When submitting
drug listing information electronically, registrants are currently
prompted to identify the package type by selecting a choice from a drop
down list. For example, ``Bottle, Plastic'' is currently one available
selection in the drop down list. If a registrant originally described
its packaging material using this term and later switched from one type
of plastic bottle to another, there would be no need for a new NDC. But
if a change in packaging material is more significant, from plastic
bottle to glass bottle, for example, so that a new package type should
be selected from the drop down list, FDA would require a new NDC with a
new package code segment to accompany the revised listing under Sec.
207.35(c). (This discussion pertains only to drug listing obligations.
Please see the FDA guidance for industry on ``Container Closure Systems
for Packaging Human Drugs and Biologics'' (May 1999, available on the
Internet at https://www.fda.gov/Drugs under Guidances (Drugs)) regarding
filing requirements for changes to container closure systems in the
case of drug products that are the subject of an approved application
(NDA, abbreviated new drug application (ANDA), or BLA)).
Medical gases are generally packaged in tanks, canisters, or
cylinders. A registrant listing a medical gas would choose the
appropriate packaging type from the drop down list, populated with such
terms, in our electronic drug establishment registration and listing
system. We do not currently require more detail about the composition
of a tank, canister, or cylinder in which a medical gas is packaged and
would not require a listing update or a new NDC if the composition of a
tank, canister, or cylinder changes. Therefore, we do not anticipate an
unreasonable proliferation of NDCs associated with medical gas
packaging under this final rule.
If a registrant exhausts all 100 package codes for a single
product, that registrant may add a second product code, effectively
making 100 more package codes available. This provision is reflected in
Sec. 207.35(c) of this final rule.
(Comment 57) One comment stated that many minor changes are made to
a drug's packaging, such as resin composition and size optimization.
This comment stated that these minor changes are already the subject of
submissions to FDA, for example, as an annual report (submitted under
Sec. 314.81(b)(2)), a prior approval supplement to an NDA, or a
changes-being-effected supplement. This comment implicitly questioned
the need for new NDC package codes triggered by these changes.
(Response) Section 207.35(c) of this final rule requires new NDCs,
specifically new package codes, when changes are made to a drug's
package size or type. See our response to comment 56 regarding our
interpretation of this requirement. We acknowledge that certain
postapproval packaging changes are reported to an NDA, BLA, or ANDA
consistent with current Sec. 314.70 and FDA https://www.fda.gov/Drugss
guidance for industry ``Container Closure Systems for Packaging Human
Drugs and Biologics; Chemistry Manufacturing, and Controls
Documentation'' (May 1999, available on the Internet at https://www.fda.gov/Drugs under Guidances (Drugs)) and to a new animal drug
application (NADA) or an abbreviated new animal drug application
(ANADA) consistent with current Sec. 514.8 and FDA's guidance for
industry ``Chemistry, Manufacturing, and Controls Changes to an
Approved NADA or ANDA'' (May 2007, available on the Internet at https://www.fda.gov/Drugs under Guidances (Drugs)). These submissions, however,
do not duplicate or satisfy the Agency's objectives behind drug listing
and the use of the NDC to identify individual marketed drug products.
These submissions also are
[[Page 60192]]
not made for drugs that are not subject to the new drug approval
requirements.
3. What restrictions pertain to the use of the NDC? (Sec. 207.37)
Proposed Sec. 207.37 set forth restrictions pertaining to the use
of NDCs. These provisions are retained in the final rule with minor
revisions. New Sec. 207.37 clarifies that a product improperly bearing
an NDC may be deemed to be misbranded. Additionally, new Sec. 207.37
is not addressed only to ``manufacturers, repackers, and relabelers.''
Persons who are not subject to part 207 are cautioned against
concluding that the restrictions stated in Sec. 207.37 do not apply to
them. Improper use of an NDC, as described in Sec. 207.37, may result
in a misbranding charge under the FD&C Act, whether or not the
responsible party is generally subject to part 207.
(Comment 58) One comment agreed that NDCs should not appear in the
labeling of dietary supplements, foods, and medical devices, but
encouraged FDA to exercise enforcement discretion in this area. Other
comments urged FDA to permit the use of NDCs on medical devices and
medical foods. Others asked FDA to implement an alternative
identification system for medical devices before finalizing this rule.
(Response) Section 207.37 of this final rule states that a product
may be deemed to be misbranded if an NDC is used on the product but it
is not subject to part 207. Since publication of the proposed rule, FDA
has issued a final rule requiring UDIs on medical devices (78 FR 58786,
September 24, 2013). Section 801.57 of that rule (21 CFR 801.57)
generally prohibits the use of an NDC on the label of a medical device
after the date on which it must bear a UDI.
The use of an NDC on the label of a product that is not regulated
as a drug may confuse and mislead consumers and health care providers
into believing FDA regulates the product as a drug. Any enforcement
actions in this area will be subject to a determination that a product
violates Sec. 801.57 or is misbranded, or otherwise violates the FD&C
Act.
(Comment 59) One comment argued against the proposed rule's
prohibition against the use of NDCs on non-drug products and asked, if
this prohibition is retained in the final rule, how long manufacturers
of such products would have to remove NDCs from their labels.
(Response) Please see our response to comment 58 regarding the
nature of Sec. 207.37, specifically our clarification that the use of
NDCs in the labeling of non-drug products may be handled as misbranding
violations or as violations of Sec. 801.57 as appropriate. See FDA's
Unique Device Identifier rule (78 FR 58786) and any guidance FDA may
issue regarding the compliance deadline for Sec. 801.57. When an NDC
in the labeling of a non-drug product creates the misleading impression
that FDA regulates the product as a drug, that product may be subject
to enforcement action.
E. Listing (Part 207, Subpart D)
1. Who must list drugs and what drugs must they list? (Sec. 207.41)
Proposed Sec. 207.41 specified who must list drugs, and the
provision is retained in this final rule. Section 207.41(c) now
includes more detail about the manner in which drugs manufactured for
private label distribution are listed.
(Comment 60) Some comments urged FDA to allow private label
distributors to list drugs that are distributed under their names.
(Response) Please see our response to comment 16 regarding the
definitions of ``private label distributor'' and ``private label
distribution'' in Sec. 207.1 for a discussion of the responsibilities
of private label distributors in this final rule. Private label
distributors are not obligated--by their status as private label
distributors--to register an establishment or list drugs. They may,
however, submit drug listing information or establishment registration
information if acting as the authorized agent of a registrant on whose
behalf the information is submitted.
2. When, after initial registration of an establishment, must drug
listing information be submitted? (Sec. 207.45)
Proposed Sec. 207.45 described an establishment's drug listing
obligation at the time of initial registration. It stated that an
establishment must, at the time of initial registration, list any drug
then being manufactured, repacked, relabeled, or salvaged for
commercial distribution at the establishment. Section 207.45 is revised
in this final rule to state that such drugs must be listed no later
than 3 calendar days after initial registration of the establishment.
(Comment 61) One comment encouraged FDA to provide flexibility in
the timing of new drug listing submissions. The comment stated that it
supported the current requirement of 5 calendar days from the start of
manufacturing.
(Response) Several provisions of this final rule relate to the time
periods within which establishment registrations, drug listings, and
drug listing updates must be submitted. Section 207.21 states that
domestic establishments must register for the first time no later than
5 calendar days after beginning to manufacture, repack, relabel, or
salvage a drug or an animal feed bearing or containing a new animal
drug (whether or not commercially distributed). This 5-day window for
initial establishment registration starts at the beginning of
manufacture, not the beginning of commercial distribution. Section
207.45 states that each drug being manufactured, repacked, relabeled,
or salvaged for commercial distribution at the time of initial
registration must be listed no later than 3 calendar days after initial
registration. Thus, the 3-day window established in Sec. 207.45
relates to those drugs being manufactured at the establishment for
commercial distribution at the time of initial registration. We will
interpret the phrase ``for commercial distribution'' in Sec. 207.45
flexibly as meaning immediate or near-term commercial distribution, not
for storage prior to an initial product launch.
FDA recognizes that because it has made findings that nondisclosure
of most drug listing information would be inconsistent with the
protection of the public health (see Sec. 207.81), registrants may be
reluctant to list drugs that have not yet been commercially launched.
FDA intends to interpret the timing requirements in a way that
accommodates this concern. FDA also encourages and expects registrants
to list drugs promptly upon commercial launch (following Sec. 207.45
or Sec. 207.57 as appropriate), recognizing that manufacturers have an
incentive to list drugs promptly and have their proposed NDCs assigned
by FDA. After a drug is listed, it should appear in our public NDC
database within approximately 1 business day and in our internal
database almost immediately.
3. What listing information must a registrant submit for a drug it
manufactures? (Sec. 207.49)
Proposed Sec. 207.49 identified the information that a registrant
must provide with a drug listing submission for a drug it manufactures.
Section 207.49 is retained and reorganized in this final rule. Some
information included in proposed Sec. 207.33(c) (what information must
a manufacturer submit before we will assign an NDC number to a drug?)
has been incorporated into new Sec. 207.49 as drug listing information
because it is not necessary under this final rule for manufacturers to
request an NDC from FDA.
(Comment 62) One comment noted that an approved U.S. application
[[Page 60193]]
number is included with drug listing information identified in Sec.
207.49 and asked FDA to clarify whether an application must be approved
before drug listing information is submitted.
(Response) Section 207.49(a)(7) of this final rule requires
registrants to provide the approved U.S. application number with
listing information for a drug if one exists. Thus, Sec. 207.49
requires that an approved U.S. application number be provided with drug
listing information only if it exists. Unapproved drugs can and must be
listed without an application number.
Drugs that are the subject of an application need not be listed
until they are manufactured for commercial distribution. Registrants
who are awaiting approval of an application may voluntarily reserve an
NDC for the drug that is the subject of the application prior to its
approval under new Sec. 207.33(d)(3). These registrants are also
permitted, but not required, to list a drug before it is marketed,
while providing a future start marketing date.
(Comment 63) Many comments opposed the submission of production
volume information with drug listing information.
(Response) In the preamble to the proposed rule, FDA stated that it
was considering whether to require establishments to provide the number
of batches and batch size for each drug subject to the listing
requirement that they manufactured, repacked, or relabeled since the
establishment last provided listing information (71 FR 51276 at 51312).
We have decided not to include such a requirement in this final rule.
(Comment 64) One comment urged FDA to eliminate the requirement
that registrants submit representative samples of any other labeling
for OTC drug products.
(Response) Section 207.49(a)(14)(ii)(b) of this final rule requires
that for each human nonprescription drug not subject to section 505 of
the FD&C Act or section 351 of the PHS Act (i.e., not subject to
premarket approval), drug listing information include the current
label, the package insert (if any), and a representative sampling of
any other labeling. The submission of ``any other labeling'' for such
drugs is a requirement of section 510(j)(1)(B)(ii) of the FD&C Act.
(Comment 65) One comment questioned the proposed requirement that
the ``drug facts'' labeling for OTC drug products be included in drug
listing information, arguing that required labeling for OTC products is
set forth in OTC monographs and in FDA's regulations in Sec. 201.66.
(Response) We disagree with this comment. Section
207.49(a)(14)(ii)(B) of this final rule requires that labeling
submitted with drug listing information for human nonprescription drugs
not subject to section 505 of the FD&C Act or section 351 of the PHS
Act include the ``content of labeling.'' This term is defined in Sec.
207.1(b) to include, for these drugs, the drug facts labeling required
by Sec. 201.66. The submission of drug listing information is the only
mechanism by which FDA has quick access to the labeling that is
currently in use for marketed OTC drug products. Furthermore, section
510(j)(1)(B)(ii) of the FD&C Act requires that the label, package
insert, and a representative sampling of any other labeling be provided
with listing information for all such drugs, thus encompassing the drug
facts labeling.
(Comment 66) One comment urged FDA to require that drug listing
information for human OTC drugs include the current product label, but
not other labeling. This comment also urged FDA to accept such labels
in portable document format (PDF) files rather than structured product
labeling (SPL).
(Response) As explained in response to Comments 64 and 65, the FD&C
Act requires that drug listing information for OTC human drugs not
subject to section 505 of the FD&C Act or section 351 of the PHS Act
include the label, package insert, and a representative sampling of
``any other labeling.'' Therefore, this comment's recommendation that
only the current product label (i.e., the container label) be submitted
for such products is contrary to the FD&C Act, and we decline to adopt
it. Drug listing information is the only mechanism by which FDA
collects labeling for such products, and it is important that we have
it readily available.
This final rule does not specify a file format for the submission
of drug listing information, but it does require electronic submission
in a format FDA can ``process, review, and archive.'' (See Sec.
207.61(a) of this final rule.) As explained in our electronic
registration and listing guidance, to facilitate the submission of drug
establishment registration and drug listing information (including the
content of labeling), FDA has adopted the use of extensible markup
language (XML) files in a standard SPL format. The automated submission
process functions most efficiently and effectively when this
information is provided in a standardized format with defined code sets
and codes. Information in a properly created and complete SPL file can
facilitate processing and allows for greater precision and accuracy
through the use of coded data fields rather than merely electronic
text. For these reasons, we will continue to expect drug listing
information in SPL format.
In the case of unfinished drugs, Sec. 207.49(a)(15)(iv) requires
submission of the label (if any) but does not require registrants to
submit the content of labeling. Because FDA does not currently
electronically process the labels submitted for unfinished drugs, we
have accepted and will continue to accept electronic submission
unfinished drug labels in JPEG (Joint Photographic Experts Group) file
format.
(Comment 67) One comment questioned the proposed requirement that
drug listing information include the name of each inactive ingredient
in a listed drug. Another comment argued that drug listing submissions
for animal drug products in particular should not be required to
identify inactive ingredients.
(Response) This requirement is retained in the final rule,
specifically in new Sec. 207.49(a)(5), applicable to both human and
animal drugs. FDA finds it important to maintain up-to-date inactive
ingredient information for all marketed drug products. This allows FDA,
for example, to determine the extent to which a particular inactive
ingredient is currently in use and identify drug products that contain
it. FDA does not have access to this information in the form of a
searchable database outside of our drug registration and listing
information.
(Comment 68) We received several comments pertaining to the drug
listing obligations of contract manufacturers, contract packagers, and
contract laboratories. One requested clarification regarding the manner
in which a contract manufacturer or packager would submit listing
information for an investigational drug manufactured or packaged for
use in a clinical trial.
(Response) Contract manufacturers, packagers, and laboratories--
unless they are exempt under section 510(g) of the FD&C Act or Sec.
207.13--will generally qualify as manufacturers under this final rule
and will be required to register their establishments. Under Sec.
207.41 of this final rule, registrants must list drugs they
manufacture, repack, relabel or salvage for commercial distribution.
The definition of ``commercial distribution in new Sec. 207.1 excludes
drugs distributed for investigational use under part 312 (21 CFR part
312) or part 511 (21 CFR part 511). The drugs referred to in this
comment may be exempt from listing under this analysis.
(Comment 69) Another comment asked how a contract manufacturer or
[[Page 60194]]
packager should be expected to submit twice annual drug listing
updates, attesting for example that there have been no changes to a
drug's labeling, when the contract manufacturer or packager is not
responsible for or aware of labeling changes in the ordinary course of
its business.
(Response) This comment relates to a wide variety of situations. We
recognize that contractors play an important role in drug manufacture.
Some perform specialized operations for another manufacturer (e.g.,
blister packaging), and others perform all manufacturing operations for
a virtual drug company. Some contract manufacturers handle drugs that
are the subject of an approved application and are sold under the name
of the application holder. Others manufacture OTC drugs for multiple
private label distributors. Each situation will require its own
analysis under this final rule, and there may be more than one way to
satisfy the rule's requirements.
If a contract manufacturer is performing one or more steps in a
larger manufacturing operation, it may be shipping an unfinished drug
to another contracting party. In that case, the contract manufacturer
would submit listing information under Sec. 207.49 for the unfinished
drug it distributes commercially, i.e., the unfinished drug that leaves
its registered establishment(s). This would include labeling
information required under Sec. 207.49(a)(15)(iv), meaning the label
applied to the unfinished drug. In this scenario, the contract
manufacturer would not be responsible for listing updates that describe
labeling changes for the finished drug product, if the contract
manufacturer does not commercially distribute the finished drug
product.
If a contractor is performing all steps or just the final steps in
a drug manufacturing process, the contractor should describe the
finished drug product in its listing submission. In some cases, a
contract manufacturer may be responsible for formulating the product
and developing its labeling. This might be true in the case of an OTC
store brand, private label distribution product, for example. In that
situation, the contracting parties would likely agree that the contract
manufacturer is in the best position to submit drug listing information
and updates (as it is required to do under this final rule), and this
would include the submission of any labeling changes with twice annual
listing updates. In other cases, a contractor might play a much smaller
role. It might only place a product manufactured and developed by
someone else into its final packaging. In that case, the contractor
would be required by this final rule to submit listing information
pertaining to the finished drug product, including the twice annual
updates. The contractor might satisfy this obligation by consulting
with the drug's developer about any changes in drug listing information
or by letting the drug's developer act as its authorized agent for the
submission of drug listing information and updates. At all times,
however, the actual manufacturer of a drug (or repacker, relabeler, or
salvager) is legally responsible for ensuring that the requirements of
this final rule are satisfied.
(Comment 70) One comment stated that ``the proposed requirement for
finished product contract testing laboratories to list all of the
products they test should be eliminated.'' The comment pointed out that
testing laboratories only handle representative samples of products
that do not enter the supply chain.
(Response) This comment addresses an issue that arises under the
FD&C Act and the drug registration and listing regulations as they have
long existed. (See the definition of ``manufacturing or processing''
that has existed in Sec. 207.3 prior to this final rule.) Testing
laboratories, whether they test finished drug products or in-process
materials, may have important roles in drug manufacturing and are
appropriately treated as manufacturers under part 207 if they engage in
testing or control procedures necessary for manufacture under current
good manufacturing practices. Any testing laboratory that qualifies as
a ``manufacturer'' under this final rule must register its
establishment(s) where drugs are tested. The listing obligation,
however, applies only to drugs that a registrant places into commercial
distribution. Therefore, if a laboratory tests in-process materials or
finished product and then commercially distributes the tested product,
e.g., for further processing or for distribution as finished product,
that laboratory would have an obligation to list the drugs it
commercially distributes. More likely, however, if the laboratory
merely tests product samples and reports the test results to another
party without further distributing the tested samples, it has no
listing obligation.
(Comment 71) One comment expressed concern that importers would
have to identify manufacturers for their drug components and provide a
chain of custody description for each handler from manufacturer to
importer.
(Response) This comment reflects a misunderstanding of a statement
in the proposed rule describing section 801(d)(3) of the FD&C Act. To
clarify, Sec. 207.49(a)(12) of this final rule requires a registrant
listing a drug it manufacturers to provide: (1) The name and UFI of the
establishment where the registrant manufactures the drug and (2) the
name and UFI of every other establishment where manufacturing is
performed for the drug. With respect to this second category of
information, if the registrant provides a properly assigned and listed
NDC for unfinished drug(s) it uses to produce the listed drug
(sometimes referred to as ``immediate source NDCs''), the registrant
does not need to provide names and UFIs of the upstream establishments.
(Comment 72) One comment asked FDA to clarify a statement in the
preamble of the proposed rule regarding certificates of analysis for
imported articles.
(Response) This comment reflects a misunderstanding of the proposed
rule. The passage it refers to quotes section 801(d)(3) of the FD&C Act
(71 FR 51276 at 51284). Section 801(d)(3) of the FD&C Act applies only
to certain imported products, and this final rule does not implement
it.
4. What listing information must a registrant submit for a drug it
repacks or relabels? (Sec. 207.53)
Proposed Sec. 207.53 identified the information that a registrant
must provide with a listing submission for a drug it repacks or
relabels. Section 207.53 is retained and reorganized in this final
rule. Some information included in proposed Sec. 207.33(d) (What
information must a repacker or relabeler submit before we will assign
an NDC number to a drug?) has been incorporated into new Sec. 207.53
as drug listing information because it is not necessary under this
final rule for manufacturers to request an NDC from FDA.
(Comment 73) A comment from the medical gas industry expressed
concern about the proposed rule's requirement that repackers identify,
in drug listing information, the NDC associated with a drug immediately
before it is received by the repacker for repackaging. This comment
argued that the complexity of medical gas distribution makes this
requirement difficult to satisfy.
(Response) We agree that medical gas repackers would need to
significantly change the way they currently do business to identify
immediate source NDCs as specified in the proposed rule. In response to
this comment, we have included an exception in Sec. 207.53 of
[[Page 60195]]
this final rule so that repackers and relabelers of medical gases are
not required to include with drug listing submissions the NDC assigned
to each medical gas they receive for repacking or relabeling.
5. What are the requirements for reviewing and updating listing
information? (Sec. 207.57)
Proposed Sec. 207.57 described the requirements for reviewing and
updating drug listing information. The provision is retained in this
final rule with editorial revisions intended to improve clarity.
Additionally, the section now says registrants are encouraged to submit
listing updates at the time of any change affecting previously
submitted information. We have also deleted a reference to Sec.
207.55. Under Sec. 207.55, FDA may ask a registrant to explain the
basis for its belief that a drug is not subject to approval. We do not
expect registrants to routinely update information provided to us under
Sec. 207.55.
(Comment 74) Some comments opposed the requirement that to satisfy
the June and December listing update obligation, registrants must
certify that no changes have occurred if no changes have occurred since
the last review and update of listing information.
(Response) The preamble to the proposed rule specifically requested
comments regarding the burden that may result from the no changes
certification requirement in the context of drug listing updates (71 FR
51276 at 51314). We have retained in this final rule the requirement in
Sec. 207.57(b) that registrants update their submitted drug listing
information each June and December. The review and updating of drug
listing information is critical to the integrity of FDA's database. We
recognize, however, that requiring registrants to submit a twice-annual
``no changes'' certification, on a product-by-product basis, for each
of their listings would impose a substantial burden on registrants,
particularly those that maintain hundreds or thousands of drug
listings. Therefore, Sec. 207.57 of this final rule requires
registrants to report changes to drug listing information either at the
time of any change affecting information previously reported or during
the next June or December listing update following the change. At the
time of the annual registration update under Sec. 207.29(b), a
registrant may submit a blanket ``no changes'' certification covering
all of its listed drug products for which no changes affecting
previously reported listing information were made since the last annual
registration update or listing submission. This blanket, ``no changes''
certification applies only to drug listing information that has been
submitted electronically, as it would be too burdensome for FDA to
maintain certifications for information that has not been submitted
electronically. Therefore, it cannot be used to report that drug
listing information submitted on paper in the past remains current.
This limitation is intended to ease FDA's administrative burden and
allow FDA to consider drug listing information to be fully migrated
from paper submissions to our electronic drug registration and listing
system.
Please see our response to Comment 30, which addresses this issue
in the context of establishment registration updates.
(Comment 75) One comment stated that the obligation to provide
updates on individual drug listings within 30 days will demand a great
deal of resources from manufacturers.
(Response) This comment did not cite the specific provision of the
proposed rule at issue. The preamble to the proposed rule acknowledged
that proposed Sec. 207.57(b) would require that drug listing
information be reviewed and updated only every June and December, but
also stated that FDA would request updates to listing information
within 30 calendar days of a change, to maintain the accuracy of our
drug listing database (71 FR 51276 at 51314). Under Sec. 207.57 of
this final rule, registrants are encouraged to submit updated drug
listing information at the time of any change affecting information
previously submitted, but they are required to submit such information
only every June and December.
(Comment 76) Two comments asked FDA to clarify whether a registrant
may report all changes to drug listing information when they occur,
i.e., on a rolling basis, instead of conducting a review and update
each June and December.
(Response) Under Sec. 207.57 of this final rule, registrants must
review and update their drug listing information each June and
December. This is a requirement of section 510(j)(2) of the FD&C Act.
Registrants are additionally encouraged, but not required, to update
drug listing information at the time when changes are made to
previously reported information. These updates do not, however, take
the place of the June and December updates, which may be satisfied by a
no changes certification if no changes have occurred since the last
review and update. We will read ``since the last review and update'' in
Sec. 207.57(b)(2) as referring to the registrant's most recent listing
update for a given drug, whether submitted in June, December, or at any
other time.
(Comment 77) One comment encouraged FDA to codify a registrant's
ability to submit updated listing information at the time a change is
made, rather than waiting for the next June or December review and
update. This comment referred to a statement in the preamble to the
proposed rule stating that registrants are requested to submit listing
information within 30 days of a change.
(Response) We agree with this comment and have revised Sec. 207.57
accordingly. New Sec. 207.57 states that registrants are encouraged to
submit listing updates at the time of any change affecting information
previously submitted. This provision of the final rule does not refer
to a 30-day window for such listing updates. We intend to read ``at the
time of any change'' flexibly, encouraging registrants to submit
listing updates as soon as possible, but allowing such updates at any
time before they are due at the next June or December review and
update.
(Comment 78) One comment expressed concern regarding the manner in
which a drug's discontinuation is to be reported under Sec. 207.57.
This comment noted that historically, many registrants have waited to
report that a drug has been discontinued until they no longer have to
report the drug under applicable agreements with the Centers for
Medicare and Medicaid Services. According to this comment, if an NDC is
identified as discontinued while the drug is still in distribution up
until expiration, there may be problems related to reimbursement and
other matters.
(Response) The FD&C Act and Sec. 207.57 of this final rule require
listing updates, including information that a drug has been
discontinued, at the latest, at the time of the next June or December
review and update following the discontinuation. In the case of drugs
that are subject to part 314, Sec. 314.81(b)(3)(iv) also requires that
their withdrawal from sale be reported to FDA. The reporting deadline
under Sec. 314.81(b)(3)(iv) is within 15 working days of the
withdrawal from sale before the effective date of this final rule and
within 30 calendar days of the withdrawal from sale after the effective
date of this final rule. It is important that FDA receive this
information soon after discontinuation for the integrity of our
database.
In this final rule, as in the proposed rule, Sec. 207.57 requires
registrants, when reporting that a listed drug has been discontinued,
to provide the expiration
[[Page 60196]]
date of the last lot manufactured, repacked, relabeled, or salvaged.
FDA regards this date as the ``end marketing date'' and includes it in
the public NDC database when a drug is reported to be discontinued.
Please note that, in addition to the requirements just discussed,
section 506C of the FD&C Act, as amended by FDASIA, requires
manufacturers of certain drugs that are life-supporting, life-
sustaining, or intended for use in the prevention or treatment of a
debilitating disease or condition, to notify FDA of a permanent
discontinuance or certain interruptions in manufacture at least 6
months prior to the date of discontinuance or interruption or as soon
as practicable if 6-month's prior notice is not possible.
(Comment 79) Two comments opposed the requirement in Sec. 207.57
that registrants provide, for a discontinued drug, the expiration date
of the last lot manufactured, repacked, relabeled, or salvaged, arguing
that the expiration date of the last lot provides no assurance that the
drug product will be available to consumers until that date is reached.
(Response) As explained in response to Comment 78, our use of the
expiration date of the last lot as an ``end marketing date''
facilitates reimbursement while remaining stock of a discontinued drug
works its way through distribution.
(Comment 80) Two comments requested clarification regarding how the
inclusion of an approved application number in a drug listing
submission can take the place of the content of labeling in SPL format,
specifically how updated labeling would be provided at the time of a
listing update if only the application number is referenced.
(Response) The proposed rule indicated that if ``a manufacturer
provides a drug's approved U.S. application number as part of a drug's
listing information, the labeling required under proposed Sec.
207.49(g)(1) and . . . 207.49(g)(2) would be deemed to accompany the
listing information'' (71 FR 51276 at 51309). This was written prior to
FDA's adoption of SPL as the submission standard and is not an accurate
reflection of how the process operates today. However, FDA has
considered how our electronic system can avoid unnecessary duplication
of effort between the submission of labeling updates to applications
and the submission of drug listing information.
Under this final rule, a drug listing submission, whether it
includes an approved application number or not, must include content of
labeling as specified in Sec. 207.49. An advantage of the SPL format
is that it allows the holder of a newly approved application to submit
the content of labeling once, satisfying its obligations under parts
314 and 207 in a single submission. Upon initial approval, an applicant
is required to submit a copy of final approved labeling. An electronic
drug listing submission that includes the content of labeling in SPL
format can satisfy this obligation. Even if the drug product is not yet
ready for commercial distribution upon approval, SPL allows for a
future start marketing date in the listing information so that a second
submission is not necessary when the product is commercially launched.
As discussed in response to Comment 15, most drug labeling changes
necessitate a listing update under Sec. 207.57 of this final rule.
Registrants who submit drug listing information through FDA's CDER
Direct electronic submission portal (as well as those using some
commercial software) will be able to recall a previous submission,
including the content of labeling, and make appropriate changes when a
listing update is due. But reference to an application number alone
will not satisfy the requirement that updated content of labeling be
submitted under Sec. 207.57 in this final rule.
F. Electronic Format for Registration and Listing (Part 207, Subpart E)
Proposed Sec. 207.61 stated that establishment registration and
listing information must be submitted to FDA electronically. As
proposed, Sec. 207.61 would have allowed advertisements and some
labeling to be submitted to FDA either in paper or electronic format.
In this final rule, Sec. 207.61 is revised for clarity. Additionally,
the final version of Sec. 207.61 requires electronic submission of all
establishment registration and listing information, consistent with
FDAAA (no longer allowing for the submission of advertising on paper),
unless a waiver is granted, and states that FDA may issue guidance from
time to time on how to provide information in electronic format.
Because the SPL format currently used for electronic submission of
registration and listing information does not accommodate the
submission of drug advertising, taking into account various types of
advertising media currently in use, FDA is not currently collecting
advertisements as part of drug listing information. If this technical
limitation is resolved, we will explain in future guidance how and what
registrants should transmit electronically as a representative sampling
of advertisements. In the meantime, we may ask individual registrants
to submit a representative sampling of advertisements for specific
prescription human drug products not subject to section 505 of the FD&C
Act, relying on our authority under section 510(j)(1)(B)(i) of the FD&C
Act and Sec. 207.49(a)(14) of this final rule.
The final version of Sec. 207.61 also clarifies that, while drug
registration and listing information must generally be submitted in the
English language, in some cases the content of labeling may be
submitted in a foreign language along with an accurate English
translation.
(Comment 81) One comment stated that information should be included
in the final rule to address whether FDA intends to develop a separate
database for animal health products or incorporate animal drugs into
the proposed electronic drug registration and listing database. The
comment recommended that if a separate database is planned, information
on whether the same data elements will be required to obtain an NDC
number and list products would be helpful.
(Response) At issue in this rulemaking are changes to FDA's
regulations governing drug establishment registration and listing,
i.e., changes to the codified language presented in the proposed rule
and in this final rule. These regulations do not describe the
electronic drug registration and listing systems developed by FDA,
which may change from time to time. Currently, FDA maintains separate
electronic systems for establishment registration and listing for human
drugs and for animal drugs. The information that must be submitted with
a drug listing submission, for both human drugs and animal drugs, is
described in the regulations codified in part 207 as amended by this
final rule.
(Comment 82) One comment noted that at the time of the proposed
rule and the comment period, FDA's electronic drug registration and
listing system had yet to be developed. Accordingly, stakeholders were
unable to comment on an electronic system that had yet to be developed.
(Response) We understand stakeholder interest in the development of
our electronic system for drug registration and listing. As noted in
response to Comment 81, however, the amended regulations adopted in
this rulemaking do not describe the electronic drug registration and
listing systems developed by FDA. They generally describe information
that must be submitted to FDA, and they require that it be submitted
electronically. Therefore, the proposed rule did not solicit comments
on the electronic drug
[[Page 60197]]
registration and listing system then under development.
After the proposed rule was published, Congress amended the FD&C
Act to require electronic submission of drug establishment registration
and listing information. To implement this statutory change, FDA
published draft guidance in 2008 and final guidance in 2009 concerning
electronic submission of drug establishment registration and listing
information. Stakeholders had an opportunity to comment on the
electronic system described in our draft guidance and, as with all FDA
guidance, have an ongoing opportunity to comment at any time.
FDA currently accepts drug establishment registration and drug
listing information submitted electronically. We expect registrants to
find electronic submission less burdensome than the use of paper forms,
and we accept comments and suggestions from stakeholders regarding
improvements to our electronic submission systems.
(Comment 83) One comment recommended that to facilitate the annual
review and updating of both establishment registration and drug listing
information, FDA provide registrants with a report of their current
registration and listing information.
(Response) This comment does not relate to language that would be
included in the codified portion of this final rule, but it does raise
an important issue we would like to address. At all times, registrants
are responsible for keeping track of registration and listing
information they have submitted to FDA and should ensure the
information is securely stored and can be retrieved.
Registrants who use an agent to submit establishment registration
and drug listing information to FDA are encouraged to maintain their
own records of the submitted information or obtain assurances that the
agent will do so and will make the information available to the
registrant on request, including if their business relationship is
terminated.
FDA currently maintains publicly searchable databases that can be
used to confirm an establishment is registered. Information about
registered blood establishments is available through FDA's electronic
Blood Establishment Registration (eBER) public query application.
Information about registered HCT/P establishments is available through
the Human Cell and Tissue Establishment Registration (HCTERS) public
query application. Information about registered drug establishments can
be obtained through FDA's Drug Establishments Current Registration Site
(DECRS). Additionally, FDA's NDC Directory currently includes listed
finished drug products, but not unfinished drug products. It may be
expanded in the future to include all listed drugs. Registrants can
check these sources and may also request a report of their own
registration and listing information from CDER's Drug Registration and
Listing staff.
(Comment 84) Comments noted that changes to part 11 (21 CFR part
11) are being considered by the Agency and recommended that electronic
submission of drug registration and listing information be delayed or
exempt from compliance with part 11 until these changes have been
decided.
(Response) Because of changes to section 510(p) of the FD&C Act
adopted in FDAAA, registration and listing information is currently
submitted electronically. Exceptions from the electronic submission
requirement will be handled in accordance with the waiver provisions in
this final rule (Sec. Sec. 207.65, 607.22, and 1271.23).
Part 11 sets forth criteria under which FDA considers electronic
records and signatures to be trustworthy and reliable. Part 11 applies
to electronic records that are created, modified, maintained, archived,
retrieved, or transmitted under statutory and regulatory requirements.
In 2003, FDA published guidance for industry titled ``Part 11,
Electronic Records; Electronic Signatures--Scope and Application''
(2003 Part 11 Guidance, available on the Internet at https://www.fda.gov/Drugs under Guidances (Drugs)) and announced its
availability in the Federal Register (68 FR 52779, September 5, 2003).
This guidance announced a reexamination of part 11, a narrow
interpretation of its scope, and a policy of enforcement discretion
with respect to certain of its requirements. Part 11 currently remains
in effect, and FDA's policy of enforcement discretion applies as
described in the guidance.
Against this backdrop, the proposed rule included a discussion of
how FDA intended to apply part 11 to electronic drug registration and
listing. (See 71 FR 51276 at 51317.) Proposed Sec. Sec. 207.61,
607.22, and 1271.22 specified that certain requirements of part 11
would not apply to information submitted to FDA under parts 207, 607,
and 1271. In Sec. 207.61 of this final rule, the applicability of part
11 is stated as follows: The submission of advertisements and labeling
is exempt from the requirements of Sec. 11.10(a), (c) through (h), and
(k) and the corresponding requirements of Sec. 11.30. Other
information submitted under part 207, as well as information submitted
under parts 607 and 1271, is exempt from the requirements of Sec.
11.10(b), (c), and (e) and the corresponding requirements of Sec.
11.30. These statements in the codified portion of this final rule are
intended to be read together with any current FDA guidance concerning
our enforcement of part 11. For example, FDA's 2003 Part 11 Guidance
states that we do not intend to take action to enforce compliance with
the validation and audit trail requirements of part 11. This includes
requirements described in Sec. 11.10(a) and (e). Until our 2003 Part
11 Guidance is withdrawn or modified, these statements regarding
enforcement discretion remain current. Therefore, any person submitting
information electronically to FDA under this final rule may rely on the
exemptions from part 11 written into parts 207, 607, and 1271, in
addition to statements regarding part 11 enforcement discretion in
current FDA guidance.
(Comment 85) One comment noted that a citizen petition is currently
pending before FDA requesting that part 11 be revoked in its entirety
(Docket No. FDA-2004-P-0036, formerly Docket No. 2004P-0429/CP1). This
comment asked FDA to respond to the citizen petition before it
completes this rulemaking.
(Response) The referenced citizen petition remains under review,
and the part 11 regulations are currently being implemented as
explained in FDA's 2003 Part 11 Guidance. FDA's publication of this
final rule should not be interpreted as providing any indication of the
manner in which the citizen petition will be resolved.
G. Miscellaneous (Part 207, Subpart F)
Section 207.81 of the proposed rule identified establishment
registration and listing information that will be available or not
available for public disclosure after it is submitted to FDA. Section
510(f) of the FD&C Act states that establishment registration
information is available for inspection and drug listing information is
generally not available for inspection unless the Secretary (by
delegation FDA) finds that an exemption from disclosure would be
inconsistent with protection of the public health. Consistent with this
statutory provision, proposed Sec. 207.81 stated that establishment
registration information would be generally available for disclosure
and that most, but not all, drug listing information would be available
for disclosure, as its nondisclosure would be inconsistent with
protection of the public health. Generally categorized as not available
for disclosure in the proposed rule was information obtained under:
[[Page 60198]]
Proposed Sec. 207.33(d)(1)(ii)--Source NDCs for repacked
or relabeled drugs submitted in the context of an NDC request for such
drugs,
Proposed Sec. 207.54(b)(1)--Source NDCs for salvaged
drugs, and
Information submitted as the basis upon which it has been
determined that a particular drug product is not subject to section 505
or 512 of the FD&C Act, the premarket approval requirement for new
drugs and new animal drugs.
In this final rule, Sec. 207.81 has been revised in several ways.
The section has been reorganized so that registration and listing
information that will be available for public disclosure is identified
in paragraph (a), and exceptions are identified in paragraphs (b) and
(c). Cited section numbers have been revised, consistent with the
renumbering of sections in this final rule (and the shifting of some
information required in the proposed rule as supporting an NDC request
to information required in the final rule as drug listing information).
Substantively, Sec. 207.81 of this final rule identifies an expanded
set of information obtained under the following sections as information
that will not be available for public disclosure:
Sec. 207.53(b)--Immediate source NDCs for repacked or
relabeled drugs;
Sec. 207.54(a)--Immediate source NDCs for salvaged drugs;
Sec. 207.54(c)--The name or UFI of an establishment where
a specific drug is salvaged;
Sec. 207.55--Information submitted as the basis upon
which it has been determined that a particular drug is not subject to
section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or
section 351 of the Public Health Service Act;
Sec. 207.33(d)(3)--Information submitted to reserve an
NDC;
Sec. 207.49(a)(9)--For unfinished drugs, the number
assigned to the Drug Master File or Veterinary Master File, if any;
Sec. 207.49(a)(12)--The names and UFIs of establishments
where manufacturing is performed for listed drugs and/or immediate
source NDCs;
Sec. 207.53(c)--The names and UFIs of establishments
where repacking or relabeling is performed for listed drugs; and
Sec. 207.49(a)(5)--The names of any inactive ingredients
submitted with drug listing information for which the registrant makes
a valid assertion of confidentiality.
In this final rule, establishment registration information will be
available for disclosure, consistent with section 510(f) of the FD&C
Act, except in limited circumstances as described in Sec. 207.81(c).
FDA has found that nondisclosure of most drug listing information for
marketed drugs would be inconsistent with the protection of the public
health. In most cases, drug listing information is obvious or is
disclosed elsewhere (e.g., a drug's established and proprietary names,
its dosage form and route of administration, its active ingredient(s)).
Specifically, FDA has made a finding that nondisclosure of the listing
information identified in the following bulleted list would be
inconsistent with protection of the public health, except in limited
circumstances as described in Sec. 207.81(c):
Information obtained under Sec. 207.33 will be available
for public disclosure, but only after a drug is marketed. This
information that will be available for public disclosure includes
information a registrant or private label distributor submits or
updates under Sec. 207.33(c) to obtain an NDC labeler code but does
not include information submitted under Sec. 207.33(d)(3) to reserve
an NDC. Information submitted under Sec. 207.33(c) to obtain a labeler
code (and updates to the information) includes basic contact
information for the registrant or private label distributor to whom the
labeler code is assigned, the types of activities (e.g., manufacture,
repackaging, or private label distribution) in which the person
requesting the labeler code engages with respect to drugs, and the
types of drugs to which the labeler code will be applied. This is not
necessarily, but is arguably, classified as drug listing information
because it relates to NDCs and labeler code segments of NDCs. FDA makes
the finding referred to in section 510(f) of the FD&C Act that
nondisclosure of this information, in the case of marketed drugs, would
be inconsistent with protection of the public health. The contact
information described in Sec. 207.33(c)(1)(i) allows consumers to
verify in some cases that they do not have a counterfeit product. It
also provides additional contact information for the consumer's
reference. Disclosure of the types of activities reported under Sec.
207.33(c)(1)(ii) may provide additional clarity as to a labeler's role
in producing or marketing a drug. Information on the types of drugs to
which a labeler code will be applied, described in Sec.
207.33(c)(1)(iii), is largely available to the public, but centralizing
it promotes the free flow of information to interested consumers.
Most information obtained under Sec. 207.49 (listing
information a registrant must submit for a drug it manufactures) will
be available for public disclosure after a drug is marketed. This
information includes the drug's NDC; its established and proprietary
name; the name and quantity of each active pharmaceutical ingredient in
the drug; the name of each inactive ingredient (unless a valid
assertion of confidentiality is made); the dosage form; the drug's
approved U.S. application number if any; the drug type (finished vs.
unfinished, human vs. animal, prescription vs. nonprescription); for
drugs subject to the imprinting requirements of 21 CFR part 206, the
drug's size, shape, color, scoring, and code imprint (if any); the
route or routes of administration of the drug; the schedule of the drug
under the Controlled Substances Act; advertisements; labeling; contact
information for private label distributors; OTC monograph references if
any; and the date on which a drug was introduced into commercial
distribution. FDA makes the finding referred to in section 510(f) of
the FD&C Act that nondisclosure of the foregoing information, in the
case of marketed drugs, would be inconsistent with protection of the
public health. The drug information described in Sec. Sec.
207.49(a)(1), (3), (10), (15), and 207.49(b)(1) and (2) will enable
individuals with concerns about counterfeiting to compare information
about a product in their possession with information provided to FDA.
The ingredient information described in Sec. Sec. 207.49(a)(4) and (5)
will in some cases allow individuals to verify ingredient information
provided in labeling against FDA's records. The information described
in Sec. Sec. 207.49(a)(6), (8), and (11) relates to proper physical
form and use of a drug. The application number described in Sec.
207.49(a)(7) allows individuals to access disclosable FDA records about
a drug's approval. Whether and how a drug is scheduled under the
Controlled Substances Act (Sec. 207.49(a)(13)) relates to safe use of
the drug. The advertisements and labeling described in Sec. Sec.
207.49(a)(14) and (15) may include information individuals have not
seen elsewhere describing the risks and benefits of a drug.
Furthermore, FDA's disclosure of labeling information obtained under
Sec. 207.49(a)(15) will allow for the availability of current drug
labeling information through DailyMed, a computerized repository of
drug information maintained by the National Library of Medicine. The
contact information described in Sec. 207.49(a)(16)(ii) may provide
additional contact information for an
[[Page 60199]]
individual's reference. All of this information is largely available to
the public, but centralizing it promotes the free flow of information
to interested consumers, health care providers, and others. Note that
two types of information obtained under Sec. 207.49 will not be
available for public disclosure: (1) The names of inactive ingredients
in a listed drug if the registrant listing the drug makes a valid
assertion of confidentiality for them at the time of drug listing and
(2) the number assigned to the Drug Master File or Veterinary Master
File, if any, that describes the manufacture of an unfinished drug.
Most information obtained under Sec. 207.53 (listing
information a registrant must submit for a drug that it repacks or
relabels) will be available for public disclosure after a drug is
marketed. This information includes the repacked or relabeled drug's
NDC, labeling, advertisements, and contact information for private
label distributors. FDA makes the finding referred to in section 510(f)
of the FD&C Act that nondisclosure of the foregoing information, in the
case of marketed drugs, would be inconsistent with protection of the
public health. The NDC described in Sec. 207.53(a) helps identify who
repacked or relabeled a drug. Labeling and advertising information
described in Sec. Sec. 207.53(d) and 207.53(e) may include information
individuals have not seen elsewhere describing the risks and benefits
of a drug. Furthermore, FDA's disclosure of labeling information
obtained under Sec. 207.53(d) will allow for the availability of
current drug labeling information through DailyMed, a computerized
repository of drug information maintained by the National Library of
Medicine. The contact information for private label distributors
described in Sec. 207.53(f)(2) may provide additional contact
information for an individual's reference. All of this information is
largely available to the public, but centralizing it will promote the
free flow of information. Note that two types of information obtained
under Sec. 207.53 are not available for disclosure: (1) The NDC
assigned to a finished drug received by a registrant for repacking or
relabeling and (2) the name and UFI of establishments where repacking
or relabeling is performed.
Some information obtained under Sec. 207.54 (listing
information a registrant must submit for a drug it salvages) will be
available for public disclosure after a drug is marketed. This
information includes the salvaged drug's lot number and expiration
date. FDA makes the finding referred to in section 510(f) of the FD&C
Act that nondisclosure of the foregoing information, in the case of
marketed drugs, would be inconsistent with protection of the public
health. Disclosure of the lot number and expiration date information
described in Sec. 207.54(b) may help address any concerns about a
salvaged product's quality, potency, and shelf life.
Most information obtained under Sec. 207.57 (information
registrants must submit when updating listing information) will be
available for public disclosure. In most cases, information submitted
under Sec. 207.57 updates information previously submitted under
Sec. Sec. 207.49, 207.53, or 207.54. The same disclosure rules will
apply whether information is submitted in an original drug listing
submission or in an updated listing. Our findings under section 510(f)
of the FD&C Act, described previously, that nondisclosure of certain
listing information obtained under Sec. Sec. 207.49, 207.53, and
207.54 would be inconsistent with protection of the public health apply
whether the information is obtained in an original listing submission
or an updated listing submission. Accordingly, the reasons supporting
this finding discussed previously apply to updates submitted under
Sec. 207.57. Some information obtained under Sec. 207.57 will not
have been received previously under Sec. Sec. 207.49, 207.53, or
207.54. This information includes: (1) The date a registrant
discontinues the manufacture, repacking, relabeling, or salvaging for
commercial distribution of a listed drug and the expiration date of the
last lot manufactured, repacked, relabeled, or salvaged, (2) the date a
registrant resumes the manufacture, repacking, or relabeling, for
commercial distribution or a drug previously discontinued, and (3)
certifications that no changes have occurred since the last listing
review and update. FDA makes the finding referred to in section 510(f)
of the FD&C Act that nondisclosure of the foregoing information, in the
case of marketed or discontinued drugs, would be inconsistent with
protection of the public health. The date a business discontinues or
resumes manufacturing a drug, submitted under Sec. 207.57(b)(1)(ii) or
(iii), may help address concerns some individuals may have about
whether a drug in their possession is counterfeit. The certification
that no changes have occurred described in Sec. 207.57(b)(2) will
inform individuals that drug listing information previously submitted
to FDA is up to date as of the no changes certification date.
(Comment 86) One comment requested that FDA not disclose the names
of inactive ingredients in animal drugs submitted with drug listing
information. This comment stated that inactive ingredients in animal
drugs are generally not listed on labels. Another comment urged FDA not
to place the burden on registrants to proactively request that the
names of inactive ingredients in human drugs be treated as trade
secrets.
(Response) The proposed rule included a discussion about disclosure
of inactive ingredients reported in drug listing submissions and stated
that FDA will disclose this information unless it is subject to trade
secret protection. See 71 FR 51276 at 51321. In this final rule, we are
codifying that approach by making it clear in Sec. 207.81 that we will
not disclose the names of any inactive ingredients submitted with drug
listing information for which the registrant makes a valid assertion of
confidentiality under Sec. 20.61 or other applicable provision of law.
This approach will apply to both human and animal drugs in an
ingredient-specific way. In other words, in the absence of a well-
supported assertion of confidentiality for any given inactive
ingredient reported under Sec. 207.49, the name of that inactive
ingredient will be available for public disclosure. The inactive
ingredient composition of a drug product is of interest to consumers
and in most cases is already disclosed on drug labels. We find that
categorical nondisclosure of inactive ingredient information would be
inconsistent with protection of the public health. It is therefore
appropriate that FDA consider this information disclosable in the
absence of a valid assertion of confidentiality that supports
nondisclosure.
(Comment 87) One comment urged FDA not to disclose the relationship
between customs brokers and their clients. This comment noted that the
proposed rule would have required foreign establishments to identify in
their establishment registrations each person who imports or offers for
import their drugs into the United States. The proposed rule would have
defined the term ``person who imports or offers for import'' broadly to
include agents and brokers. As with establishment registration
information generally, this information would have been available for
disclosure under Sec. 207.81 of the proposed rule.
(Response) As explained in our response to comment 11, in this
final rule, we define the term ``person who imports or offers for
import'' more narrowly than it was defined in the proposed rule. The
new definition is not intended to include persons operating
[[Page 60200]]
merely as customs brokers. Therefore, a person operating merely as a
customs broker will not be identified in a foreign establishment's
registration information and hence will not have its relationship with
the foreign establishment disclosed under Sec. 207.81.
(Comment 88) One comment asked FDA to clarify the confidentiality
of information submitted to obtain an NDC. Several comments stated that
disclosure of listing information is inappropriate for a yet-to-be
approved product.
(Response) As discussed in response to comment 31, under this final
rule, registrants will propose their own NDCs with drug listing
submissions. It is not necessary under this final rule to request an
NDC from FDA and support that request with the information specified in
Sec. 207.33(c) of the proposed rule. Some of the information specified
in proposed Sec. 207.33(c) (e.g., the drug's proprietary name and
established name) has been added to drug listing information required
under Sec. Sec. 207.49, 207.53, and 207.54 of this final rule. The
foregoing discussion explains which drug listing information will be
available for disclosure and that it will not be available for
disclosure until after the drug is marketed.
Section 207.33(d)(3) of this final rule allows anyone with a
labeler code to voluntarily reserve an NDC for a drug product under
development before it is listed. Information submitted under Sec.
207.33(d)(3) to reserve an NDC is identified in Sec. 207.81(b)(3) as
generally exempt from disclosure. Because information submitted to FDA
under Sec. 207.33(d)(3) will relate to drug products under
development, this exemption from disclosure prior to marketing is not
inconsistent with protection of the public health.
(Comment 89) Two comments stated that under the proposed rule, drug
listing information would be exempt from public disclosure unless the
Secretary deemed its release to be necessary. These comments asked FDA
to clarify the circumstances under which disclosure of drug listing
information would be considered necessary.
(Response) These comments reflect a misunderstanding of the
proposed rule. In the proposed rule, Sec. 207.81 stated unambiguously
that ``[a]fter a drug is listed, all information obtained for that drug
under Sec. Sec. 207.33, 207.49, 207.53, and 207.54,'' except for
stated exceptions, would be made available for public disclosure upon
request or at FDA's discretion (71 FR 51276 at 51353). We have
determined, under section 510(f) of the FD&C Act and as explained in
the foregoing discussion, that most drug listing information relating
to marketed products will be categorically presumed to be available for
public disclosure because an exemption from disclosure would be
inconsistent with protection of the public health. In the foregoing
discussion, we have explained that Sec. 207.81 of this final rule
identifies a set of drug listing information that will generally not be
available for public disclosure.
(Comment 90) One comment urged FDA not to disclose registration and
listing information that reveals business relationships among trading
partners, such as those between a drug's manufacturer and a private
label distributor or between a manufacturer and a retail service
repackager.
(Response) We have carefully considered this comment, along with
section 510(f) of the FD&C Act and our longstanding rules and policies
regarding disclosure of registration and listing information. As a
statutory matter, establishment registration information is generally
disclosable. (See section 510(f) of the FD&C Act.) Thus, information
required for establishment registration under Sec. 207.25 of this
final rule is disclosable.
This final rule requires that foreign establishments report the
name of each importer known to the establishment and the name of each
person who imports or offers to import its drugs into the United
States. This information is treated as establishment registration
information under section 510(i) of the FD&C Act and under Sec. 207.25
of this final rule, rather than as drug listing information. Because
the information is establishment registration information, both the
FD&C Act and this final rule require that it be available for public
disclosure. FDA's intention to make this information available for
disclosure was highlighted in the proposed rule (71 FR 51276 at 51321).
Drug listing information will not be available for public
disclosure under this final rule unless its nondisclosure would be
inconsistent with protection of the public health, as set forth in
section 510(f) of the FD&C Act. Most drug listing information is
obvious or is disclosed elsewhere such as in labeling (e.g., size,
shape, color, scoring, route of administration, approved application
number, active ingredient(s)) and its nondisclosure would be
inconsistent with protection of the public health. However, we
recognize that, as emphasized in this comment, some drug listing
information may reveal confidential business relationships. This final
rule exempts from public disclosure drug listing information obtained
under Sec. 207.49(a)(12) (name and UFI of the establishments where a
drug is manufactured and/or immediate source NDCs), Sec. 207.53(c)
(name and UFI of establishments where repacking or relabeling is
performed), or Sec. 207.54(c) (name and UFI of establishments where
salvaging is performed).
(Comment 91) One comment urged FDA to treat all registration and
listing information as categorically exempt from disclosure.
(Response) We decline to take this approach. As explained in the
foregoing discussion, the disclosure provisions in this final rule are
consistent with section 510(f) of the FD&C Act, notably its requirement
that establishment registration information be made publicly available
and that drug listing information be disclosed only to the extent that
its nondisclosure would be inconsistent with protection of the public
health.
H. Human Cells, Tissues, and Cellular and Tissue-Based Products (Part
1271)
The proposed rule included relatively minor amendments to part 1271
to require electronic submission of establishment registration and
listing information for HCT/Ps. These amendments are retained in this
final rule with some revisions. Under this final rule, manufacturers of
HCT/Ps that are regulated solely under section 361 of the PHS Act are
subject to establishment registration and listing under part 1271.
Manufacturers of HCT/Ps that are regulated under section 351 of the PHS
Act or as drugs under section 505 of the FD&C Act are subject to
establishment registration and listing under part 207. (HCT/Ps that are
regulated as medical devices under the FD&C Act are subject to
establishment registration and listing under part 807.)
(Comment 92) One comment was concerned about the breadth of the
definition of ``importer'' in proposed Sec. 1271.3(mm). This comment
noted that the proposed rule's definition of ``importer'' appeared to
include domestic transplant centers (hospitals) housing patients
awaiting hematopoietic stem cell (HSC) transplant and argued that
requiring foreign establishments to identify such hospitals as
``importers'' would be unreasonably burdensome.
(Response) Please see our response to Comment 9 regarding the
definition of ``importer'' in Sec. 207.1. We agree with those comments
that challenged the proposed definition as too broad, particularly as
it would have captured downstream recipients of imported products. In
parts 207, 607, and 1271,
[[Page 60201]]
we have narrowed the new definitions of ``importer'' by adding the
words ``at the time of entry.'' Therefore, these definitions no longer
capture downstream recipients such as hospitals.
IV. Compliance Dates
This final rule is effective November 29, 2016.
The proposed rule included proposed compliance dates by which
registrants and other affected persons would be required to comply with
different aspects of a final rule. For example, we proposed that
manufacturers, repackers, and relabelers be given 3 years from the
effective date of a final rule to ensure that the appropriate NDC
appear on their labels. Proposed compliance deadlines were set forth in
the preamble to the proposed rule but were not reflected in proposed
codified regulatory language. (See 71 FR 51276 at 51345.)
The compliance dates are adjusted in this final rule to account for
changes we have made in the final rule and to account for our 2009
implementation of electronic registration and listing under part 207 in
accordance with revisions to the FD&C Act. Compliance dates associated
with this final rule are presented in table 2.
Registrants are encouraged to comply with this final rule as soon
as possible after its effective date. In many cases, the final rule
will not necessitate changes in a registrant's current registration and
listing practices because electronic submission of registration and
listing information already takes place, and the information currently
collected generally comports with this final rule. We recognize,
however, that this final rule introduces new requirements, and some
registrants will need to adjust their registration and listing
activities. Table 2 should be read as a statement that FDA intends to
exercise enforcement discretion between the effective date of this
final rule and the compliance deadlines set forth in the table with
respect to changes introduced in this final rule. At all times,
however, persons subject to registration and listing must fulfill their
statutory obligations and the relevant regulatory provisions set forth
in parts 207, 607, and 1271, either before or after the effective date
of this final rule.
Table 2--Compliance Deadlines
------------------------------------------------------------------------
Effective date or compliance
Requirement deadline
------------------------------------------------------------------------
Effective date of the final rule....... 90 days after publication.
Electronic submission of establishment For products currently subject
registration and listing information to part 207, the electronic
under amended part 207. submission requirement in
section 510(p) of the FD&C Act
was largely implemented
through FDA's 2009 electronic
registration and listing
guidance (74 FR 26248). Upon
the effective date of this
final rule, FDA expects
continued electronic
submission of registration and
listing information in
accordance with our electronic
registration and listing
guidance and with new Sec.
207.61. This applies to newly
submitted registration and
listing information as well as
updates to information
previously submitted. FDA will
accept waiver requests in
accordance with Sec. 207.65
of this final rule upon its
effective date.
Two years after the effective
date of this final rule, FDA
intends to remove from our
current electronic database
establishment registration and
listing information submitted
in the past on paper and not
updated with a more recent
electronic submission. The
purpose of this removal is to
purge outdated information
from our database, such as
information registrants failed
to update after discontinuing
a drug product or closing an
establishment. Therefore,
registrants must migrate their
establishment registration and
listing information to our
electronic system (or obtain a
waiver from the electronic
submission requirement) before
that time if they have not
already done so. Registrants
may not rely on a ``no
changes'' certification to
migrate information submitted
in the past on paper to our
electronic system. They must
enter and transmit current
registration and listing
information to FDA
electronically.
Electronic submission of blood Owners or operators of human
establishment registration and listing blood product establishments
information under amended part 607. currently register and list
either electronically or by
submitting Form FDA 2830 by
mail. FDA will stop accepting
paper submissions and require
electronic submission of
establishment registration and
product listing information
under amended part 607, unless
individual waivers are
granted, 1 year after the
effective date of this final
rule.
Electronic submission of HCT/P Owners or operators of HCT/P
establishment registration and listing establishments currently
information under part 1271. register and list either
electronically or by
submitting Form FDA 3356 by
mail. FDA will stop accepting
paper submissions and require
electronic submission of
establishment registration and
product listing information
under amended part 1271,
unless individual waivers are
granted, 1 year after the
effective date of this final
rule.
Part 207, Subpart B--Registration Registrants are required to
(timing of establishment registration submit and update
and update submissions and substance establishment registration
of the information submitted). information in accordance with
amended subpart B of part 207
no later than the time when
registration information is
due after the first
anniversary of the effective
date of this final rule. If
the effective date falls
between October 1 and December
31, registrants must submit
information required by
amended subpart B no later
than the next October through
December annual review and
update period.
However, registrants must
comply with new Sec.
207.29(a) (expedited updates
when certain establishment
registration information
changes) upon the effective
date of this final rule.
[[Page 60202]]
Part 207, Subpart D--Listing (timing of Registrants are required to
drug listing and update submissions submit and update drug listing
and substance of the information information in accordance with
submitted). amended subpart D of part 207
(including the submission of
NDCs that are formatted in
accordance with subpart C of
part 207) no later than the
time when listing information
is due after the first
anniversary of the effective
date of this final rule. If
the effective date falls
during either June or
December, registrants must
submit information required by
subpart D no later than the
June or December listing
update 12 months after the
effective date.
Part 607--Establishment registration Registrants are required to
for blood and blood products. submit and update
establishment registration
information in accordance with
amended part 607 no later than
the time when establishment
registration information is
due after the first
anniversary of the effective
date of this final rule. If
the effective date falls
between October 1 and December
31, registrants must submit
establishment registration
information required by
amended part 607 no later than
the next October through
December annual review and
update period.
However, registrants must
comply with new Sec. 607.26
(amendments to establishment
registration for certain
changes such as ownership or
location) upon the effective
date of this final rule.
Part 607--Listing for blood and blood Registrants are required to
products. submit and update product
listing information in
accordance with amended part
607 no later than the time
when listing information is
due after the first
anniversary of the effective
date of this final rule. If
the effective date falls
during either June or
December, registrants must
submit information required by
subpart D no later than the
June or December listing
update 12 months after the
effective date.
Part 1271--Establishment registration Registrants are required to
for HCT/Ps. submit and update
establishment registration
information in accordance with
amended part 1271 no later
than the time when
registration information is
due after the first
anniversary of the effective
date of this final rule. If
the effective date falls in
December, registrants must
submit establishment
registration information
required by amended part 1271
no later than the next
December annual review and
update period under Sec.
1271.21(b).
Part 1271--Product listing for HCT/Ps.. Registrants are required to
submit and update listing
information in accordance with
amended part 1271 no later
than the time when listing
information is due after the
first anniversary of the
effective date of this final
rule. If the effective date
falls during either June or
December, registrants must
submit information required by
amended part 1271 no later
than the June or December
listing update 12 months after
the effective date.
------------------------------------------------------------------------
V. Legal Authority
We have the legal authority to amend our regulations on foreign and
domestic establishment registration and listing for human drugs,
including drugs that are regulated under a BLA, and animal drugs. The
statutory basis for our authority includes sections 201, 301, 501, 502,
503, 505, 506, 506A, 506B, 506C, 510, 512, 513-516, 518-520, 701, 704,
721, 801, and 903 of the FD&C Act (21 U.S.C. 321, 331, 351, 352, 353,
355, 356, 356a, 356b, 356c, 360, 360b, 360c-360f, 360h-360j, 371, 374,
379e, 381, and 393); 15 U.S.C. 1451-1561; sections 351 and 361 of the
PHS Act (42 U.S.C. 262 and 264); and section 122, Pub. L. 105-115, 111
Stat. 2322 (21 U.S.C. 355 note).
Section 510(c) of the FD&C Act requires every person upon first
engaging in the manufacture, preparation, propagation, compounding, or
processing of a drug to immediately register with the Secretary his
name, place of business, any such manufacturing establishments and
their unique facility identifiers, and a point-of-contact email
address. The provisions in section 510(b) and (d) of the FD&C Act
require annual registration beginning on October 1 and ending on
December 31 of each year and registration of additional establishments,
respectively. Section 510(i) of the FD&C Act requires any establishment
within any foreign country engaged in the manufacture, preparation,
propagation, compounding, or processing of a drug that is imported or
offered for import into the United States to register with the
Secretary by providing certain information. These provisions, together
with section 701(a) of the FD&C Act (among others), authorize us to
require the submission of the registration information specified in the
final rule. The information specified in this final rule will help us
identify who is manufacturing, repacking, relabeling, or salvaging
drugs and where those operations are being performed. In addition, some
information (e.g., official contact information) will help us
communicate with establishments more effectively and schedule
inspections more efficiently.
Section 510(j)(1) of the FD&C Act requires every person who
registers to file with the Secretary, at the time of registration, a
list of all drugs that are being manufactured, prepared, propagated,
compounded, or processed by the registrant for commercial distribution.
That list must be prepared in the form and manner prescribed by the
Secretary and must be accompanied by a copy of labeling (or the label
and package insert) and, in some cases, advertising. Section 510(j)(2)
of the FD&C Act requires listing information updates every June and
December. This listing information gives us a current inventory of
marketed drugs. These provisions of the FD&C Act and others, together
with section 701(a) of the FD&C Act, provide authority for requiring
the
[[Page 60203]]
submission of listing information set forth in this proposal. The drug
listing information specified in this final rule will help us: (1)
Develop a more current, robust inventory of drugs as a counter-
terrorism measure; (2) more effectively administer our postmarketing
surveillance programs; (3) facilitate recalls of products; (4) identify
drugs or ingredients in short supply in the event of a national
emergency; and (5) identify drugs marketed in violation of the law.
Section 510(b) of the FD&C Act requires that information
registrants supply for annual registration includes a UFI for the
establishment and includes a point-of-contact email address. FDA
published final guidance in November 2014 specifying that FDA's
preferred UFI for drug establishment registration is the DUNS number,
assigned and managed by Dun & Bradstreet.
Section 510(p) of the FD&C Act requires electronic submission of
establishment registration and listing information, unless FDA waives
the electronic submission requirement in individual cases.
Establishments that manufacture HCT/Ps currently register and list HCT/
Ps under FDA's regulations in part 1271. Pursuant to authority under
section 361 of the PHS Act, FDA is requiring electronic submission of
registration and listing information for HCT/Ps.
Section 510(j) requires biannual updates of certain listing
information. Requiring certification under section 701(a) authority
will help us with the efficient enforcement of the FD&C Act because we
will be able to distinguish between situations where there has been
noncompliance with registration and listing requirements from
situations where there have been no changes in information. The failure
to register or list under section 510 is a prohibited act under section
301(p) of the FD&C Act, and the failure to do either renders a drug
misbranded under section 502(o) of the FD&C Act.
VI. Analysis of Environmental Impact
We have determined under 21 CFR 25.30(h) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VII. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct us to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity). We
have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the final rule. We believe that this final rule
is not a significant regulatory action as defined by Executive Order
12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because the final requirements will not impose a significant
burden on a substantial number of small entities (annualized costs
represent at most, 0.01 percent of sales for small firms, and 0.002
percent for large firms, on average), we certify that the final rule
will not have a significant economic impact on a substantial number of
small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before issuing ``any rule that includes
any Federal mandate that may result in the expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more (adjusted annually for inflation) in any one
year.'' The current threshold after adjustment for inflation is $146
million, using the most current (2015) Implicit Price Deflator for the
Gross Domestic Product. This final rule will not result in an
expenditure in any year that meets or exceeds this amount.
B. Summary of Benefits and Costs
The full assessment of the economic analysis is available in Docket
No. FDA-2005-N-0464 (Ref. 1) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
The final rule clarifies and codifies the Congressionally mandated
requirements in FDAAA and FDASIA, and adds a few additional
requirements to the information needed to list products. The final rule
will improve management of the establishment registration and drug
listing requirements and make these processes more efficient and
effective for industry and for FDA. Maintaining a comprehensive
electronic registration and listing system supports implementation of
the electronic prescribing provisions of the MMA. Because registrants
submit electronic copies of the drug labeling with their drug listing,
this rule also ensures the availability of current drug information
through DailyMed, a computerized repository of drug labeling maintained
by the National Library of Medicine. Establishment registration
information helps FDA identify who is manufacturing, repacking,
relabeling, and salvaging drugs and where those operations are
performed. Quickly accessible electronic information about each
establishment in the supply chain will help inform our enforcement
efforts and improve our oversight of the entire drug supply chain.
Product listing information also gives FDA a current inventory of drugs
manufactured, repacked, relabeled, or salvaged for commercial
distribution. Under current practices, registrants would only update
listings when the listing information has changed. Consequently, some
registrants have never submitted listings in an electronic format. By
requiring electronic listings for all marketed drugs, the final rule
will modernize our electronic systems and close an existing gap in data
for drugs that are listed in our legacy system but not currently listed
in our electronic system. Because the final rule primarily codifies
current business practices, we anticipate that most of the benefits of
a modern electronic drug registration and listing system were achieved
as firms implemented electronic submissions in response to the FDAAA
and FDASIA legislation. The incremental changes required by the final
rule will yield benefits in addition to those already achieved.
However, we lack sufficient information to quantify these marginal
benefits.
Table 3 provides an itemized description of each incremental cost
associated with registration and listing for part 207, part 607, and
part 1271 registrants. For part 207 registrants, the final rule will
require immediate source NDCs for unfinished drugs, listing missing
inactive ingredients, and certification of no changes to their drug
listings. Without the final rule, FDA faces an information gap because
companies do not always notify the Agency when they stop marketing a
product. For part 607 and part 1271 registrants, the requirements are
quite slight for those that already submit registration and listing
information electronically and minimal for the much smaller number of
establishments that need to migrate their paper registration
[[Page 60204]]
and listing records to electronic format. All registrants will incur
costs associated with reading and understanding the rule and revising
their standard operating procedures (SOPs), and these items represent
the largest incremental cost. Most incremental costs are one-time only;
the only recurring costs are for part 207 registrants for certifying no
changes to their listings the previous year when they renew their
registrations.
Table 3--Itemized Incremental Costs
[$ millions] \1\
----------------------------------------------------------------------------------------------------------------
Number of
Incremental costs Frequency hours per unit Number of units Total cost
----------------------------------------------------------------------------------------------------------------
Drugs and biological products
(part 207):
Identify source of unfinished Once................. 0.25 93,700 listings...... $3.1
drugs (from source NDCs).
Listing inactive ingredients.. Once................. 0.25 40,800 listings...... 1.4
Listing legacy products....... Once................. 2.5 26,300 listings...... 8.7
Read and understand the final Once................. 21 5,900 registrants.... 16.5
rule.
Revise SOPs for registration Once................. 19 5,900 registrants.... 14.9
and listing.
Revise SOPs for reusing NDCs.. Once................. 11 2,950 registrants.... 4.3
Certification of no-change.... Recurring annually... 0.5 7,300 establishments. 0.5
-----------------------------------------------------------------------------
Total costs (part 207).... ..................... .............. ..................... 49.4
Human-blood products (part 607):
Read and understand the final Once................. 14 2,700 registrants.... 5.0
rule.
Revise SOPs for registration Once................. 11 27 registrants....... 0.04
and listing.
Migrating records to FDA's Once................. 1 27 registrants....... 0.0
electronic systems.
-----------------------------------------------------------------------------
Total costs (part 607).... ..................... .............. ..................... 5.1
Human-cell and tissue products
(part 1271):
Read and understand the final Once................. 14 2,800 registrants.... 5.2
rule.
Revise SOPs for registration Once................. 11 280 registrants...... 0.4
and listing.
Migrating records to FDA's Once................. 1 280 registrants...... 0.0
electronic system.
-----------------------------------------------------------------------------
Total costs (part 1271)... ..................... .............. ..................... 5.7
----------------------------------------------------------------------------------------------------------------
\1\ We considered the length of the final rule, the number of small and large firms affected, and the extent
each firm is affected in order to estimate the burden to read and understand the rule. For part 607
registration and listing, the cost estimate shown as $0.0 million represents $3,591. For part 1271
registration and listing, the cost estimate shown as $0.0 million represents $37,240.
Table 4 summarizes the total incremental costs; total annualized
costs are $9.0 million when calculated at a 7-percent discount rate
over 10 years, or $7.5 million when calculated using a 3-percent
discount rate.
Table 4--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
--------------------------------------------------------------------------------------------------------------------------------------------------------
Primary Low High Discount Period
Category estimate estimate estimate Year rate covered Notes
($millions) ($millions) ($millions) dollars (percent) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $ millions/year... ........... ........... ........... ........... 7
3
Annualized Quantified.................. ........... ........... ........... ........... 7
3
------------------------------------------------------------------------------------------------------------
Qualitative............................ The final rule will complete and codify modernization of the registration and listing system, thus allowing
FDA to identify establishments, specific drugs or ingredients, to facilitate recalls or information alerts,
and to exercise competent oversight of this important industry.
------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized $ millions/year... $ 9.0 ........... ........... 2014 7 10 Recurring costs include only
$ 7.5 2014 3 10 annual time costs of
certifying there are no
changes to listings; these
costs are unique to part 207
registrants.
Annualized Quantified.................. ........... ........... ........... ........... 7
3
Qualitative ........... ........... ........... ........... ........... ........... .............................
Transfers:
[[Page 60205]]
Federal Annualized Monetized $ millions/ ........... ........... ........... ........... 7
year. 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Other Annualized Monetized $ millions/ ........... ........... ........... ........... 7
year. 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
State, Local or Tribal Government: No estimated effect..............................................................................................
Small Business: The final rule will have little impact on small businesses; annualized costs represent, at most, 0.01 percent of annual sales for
small firms and 0.002 percent for large firms, on average..
--------------------------------------------------------------------------------------------------------------------------------------------------------
C. Response to Comments on the Preliminary Impact Analysis of the
Proposed Rule
Most of the comments on the regulatory impact analysis of the
proposed rule (PRIA) concerned the assignment of NDC numbers and the
requirement that they be printed on container labels. Because these
proposed changes are not included in the final rule, the comments are
moot and are not discussed here. We also do not discuss the comments on
the analysis of the proposed implementation of mandatory electronic
registration and listing as this was mandated by FDAAA and largely
implemented by guidance in 2009. Interested parties were able to
comment on the burden estimates presented in the draft guidance
entitled ``Providing Regulatory Submissions in Electronic Format--Drug
Establishment Registration and Drug Listing'' when it was announced in
the Federal Register of July 11, 2008 (73 FR 39964) (available on the
Internet at https://www.fda.gov/Drugs under Guidances (Drugs). The
remaining comments have been grouped by topic; the order in which they
are discussed is not a reflection of importance.
(Comment 93) Some manufacturers believed the PRIA did not address
the financial impact on their sector of the industry and disagreed with
the Agency's assertion of no significant economic impact on a
substantial number of small businesses. In particular, manufacturers of
medical foods and medical devices did not believe we properly addressed
the loss of revenue they could experience if they could not use NDC
numbers on their products. Contract manufacturers felt there should be
a separate analysis of their sector of the industry as did medical gas
firms who asserted their numbers were underrepresented.
(Response) We disagree with the comments. NDC numbers were never
intended for use on medical foods. The medical food industry began
using NDCs to simplify reimbursement payments by insurance companies.
There are other mechanisms that can be used for medical food product
reimbursement, and the secondary impact from FDA enforcement of
existing rules is not part of a regulatory impact analysis of new
requirements. The Unique Device Identification System final rule (78 FR
58786, September 24, 2013) replaces the use of NDC numbers on medical
devices with a UDI number. The impact of this change was accounted for
in that rule.
The PRIA measured the incremental cost to comply with the new or
changed requirements on a per-establishment and per-listing basis. Most
of the data in the analysis of the proposed rule are not relevant for
the final rule because mandatory electronic submission began in June
2009 with the statutory implementation authorized by FDAAA; however,
the methodology is relevant. We estimated the incremental cost for
registration on a per establishment basis. We included all registered
establishments in our estimate, so establishments in all industry
sectors required to register are included in the analysis if they
comply with the requirement. The information required for each
establishment is essentially the same. Any economies of scale for a
large firm to register multiple establishments at one time are
economically insignificant. The same is true for the incremental cost
to list products. A contract manufacturer, or a repackager, may have
more than one product to list, but the information required for each
product is essentially the same for a contract manufacture and other
manufacturers. The final rule provides that a private label distributer
can list the products it distributes on behalf of contract
manufacturers, but the legal obligation remains the contract
manufacturers'.
The Regulatory Flexibility Act requires Agencies to assess the
regulatory impact on domestic small entities and to analyze options
that would lessen the burden on small entities. The Small Business
Administration defines a drug manufacturer as small if it employs fewer
than 750 people and a biological products entity as small if it employs
fewer than 500.
The size of the entity is determined by the total employment of the
ultimate parent firm, which can include companies outside the drug and
biological products industries. For example, if a drug manufacturer's
ultimate parent is a financial holding company that employs more than
750 people across a variety of industrial and service sectors, the firm
would be considered large even if employment in drug manufacturing is
only 100 employees.
For the proposed rule, we used a crude method, using U.S. Census
information and a database of FDA's ``Approved Drug Products with
Therapeutic Equivalence Evaluations'' (commonly referred to as the
Orange Book) to characterize the number and size of the affected firms
and used U.S.
[[Page 60206]]
Census data from the 2002 Economic Census and County Business Patterns
for the financial information in the regulatory flexibility analysis.
The Census data are reported by North American Industry Classification
System codes (NAICS). Depending on the survey, the economic data are
collected on an establishment or firm level. Companies whose primary
NAICS code is not a drug or biologic manufacturer would not be included
in the financial survey data. For example, the primary NAICS code for
many small medical gas companies is not pharmaceutical preparations
manufacturing (NAICS 325412), so these establishments are not included
in the Census data for NAICS 325412. Including the financial data for
medical gas establishments in the analysis would be optimal, but we are
not aware of publicly available data that would capture this
information. Although the financial information characterizing the
industry did not include the medical gas sector, medical gas
establishments were included in the burden estimates.
The regulatory impact analysis for this final rule uses Dun &
Bradstreet information on total employment of the ultimate parent
company to determine the size of entities affected by the rule, but we
still use the Census data for NAICS 325412 and 325414 for the financial
information because of limitations of available data.
There were a number of comments regarding the burden of submitting
certain information in listing, in particular batch information,
inactive ingredients, and certifying that there has been no change to a
listing.
(Comment 94) Some comments noted that batch information is already
included in annual reports for products that require applications, so
the information is a duplication of effort. These comments also noted
that this information can change often and adds an additional element
that needs to be tracked and updated.
(Response) After considering the comments, FDA has decided not to
include the batch information requirement in the final rule.
(Comment 95) Some comments suggested FDA reconsider the requirement
or frequency of the requirement to certify that no change is necessary
for listings every June and December. Using the 0.25-hour estimate from
the proposed rule for the time required to verify and certify a
listing, one company with 800 products calculated that it would take
114 hours (around 14, 8-hour days) twice a year to comply with the
requirement, assuming about 60 percent of their total products did not
require updates in June and December. Another company with over 7,000
products said it would take 6 months to validate and certify their
listings with no changes. They suggested making the no changes
certification requirement every 2 years rather than biannually. Another
comment suggested that changing the requirement to certifying by
establishment, rather than by listing, would result in a savings of $1
million per year.
(Response) After considering the comments, we have revised the
requirement for no changes certification from a per-listing basis to an
establishment basis. Rather than certifying each June and December that
there is no change to each individual listing, registrants can certify
by establishment that the electronically listed products are up to date
when they annually renew their registrations.
(Comment 96) Some comments regarding submitting inactive
ingredients as part of listing stated it was unnecessary, burdensome,
and in some cases would result in the release of information a company
considered proprietary. These comments noted that inactive ingredients
are included in human and animal drug applications and must be listed
on the labels of OTC products. Some manufacturers of animal drugs
claimed that inactive ingredients are not customarily supplied on the
label and were concerned with the release of proprietary information.
(Response) Although inactive ingredients are identified in product
applications and, in many cases, on product labels, the information is
not easily accessible and the names are not fully standardized. Listing
is the only mechanism by which FDA can readily access ingredient
information across all products. Entering the inactive ingredients
using defined terminology increases the accuracy and the efficiency of
data searches. We use the information in listing to inform many
processes FDA uses for protecting public health, including surveillance
for serious drug adverse reactions, inspection of facilities used for
drug manufacturing and processing, and monitoring drug products
imported into the United States. To prevent public disclosure of
information a registrant views as confidential, an inactive ingredient
can be designated as confidential during the listing process.
VIII. Paperwork Reduction Act of 1995
This final rule contains information collection requirements that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the
information collection provisions are shown with an estimate of the
annual reporting burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
Title: Requirements for Foreign and Domestic Establishment
Registration and Listing for Human Drugs, Including Drugs That Are
Regulated Under a Biologics License Application, and Animal Drugs.
Description: The final rule reorganizes, consolidates, clarifies,
and modifies current regulations on registering establishments and
listing drugs codified in part 207 for human and animal drugs, in part
607 for blood and blood products, and in part 1271 for HCT/Ps. The
final rule describes when and how to register and list and what
information must be submitted for registration and listing. The final
rule clarifies the NDC system for drugs and requires that each drug
product subject to the listing requirements of this final rule have a
unique NDC.
The final rule codifies the current statutory requirement that
registration and listing information be submitted to FDA electronically
instead of using paper forms unless a waiver is obtained. Historically,
drug establishment registration and drug listing information was
submitted using Form FDA 2656 (Registration of Drug Establishment/
Labeler Code Assignment), Form FDA 2657 (Drug Product Listing), and
Form FDA 2658 (Registered Establishments' Report of Private Label
Distributors). Before the enactment of FDAAA, section 510(p) of the
FD&C Act expressly provided for electronic submission of drug
establishment registration information upon a finding that electronic
receipt was feasible, and section 510(j) of the FD&C Act specified that
drug listing information was to be prepared in the form and manner
prescribed by FDA. Section 224 of FDAAA, which amended section 510(p)
of the FD&C Act, now requires electronic drug listing in addition to
electronic drug establishment registration. In certain cases, and as
discussed in section VIII.E, if it is unreasonable to expect a person
to submit registration and listing information electronically, FDA may
grant a waiver from the electronic submission requirement.
In June 2009, FDA made available the electronic registration and
listing
[[Page 60207]]
guidance (74 FR 26248, available on the Internet at https://www.fda.gov/Drugs under Guidances (Drugs)) to provide recommendations on fulfilling
the statutory requirement to submit electronically drug establishment
registration and drug listing information. The guidance describes the
types of information to include for purposes of drug establishment
registration and drug listing and how to prepare and submit the
information in an electronic format (Structured Product Labeling (SPL)
files) that FDA can process, review, and archive. In June 2009, FDA
began accepting submissions required under the part 207 regulations
into our electronic drug registration and listing system. The format
for these electronic submissions employs Extensible Markup Language
(XML) and uses the SPL standard to organize the data within the file.
This electronic registration and listing enables FDA to employ a number
of automated validations to ensure the quality of the data received.
In addition to the information that previously was collected on the
FDA forms, the electronic registration and listing guidance addresses,
with respect to part 207, the electronic submission of other
statutorily required information as follows:
The name of each importer that is known to the
establishment (the U.S. company or individual in the United States that
is an owner, consignee, or recipient of the foreign establishment's
drug that is imported into the United States) (section 510(i)(1)(A) of
the FD&C Act);
The name of each person who imports or offers the foreign
establishment's drug for import (the name of each agent, broker, or
other entity, other than a carrier, that the foreign drug establishment
uses to facilitate the import of its drug into the United States)
(section 510(i)(1)(A) of the FD&C Act); and
For a registered foreign drug establishment, the name,
address, and telephone number of its U.S. agent (Sec. 207.40(c)).
The electronic registration and listing guidance also recommends
the voluntary submission of the following additional information, when
applicable:
The email address for the United States agent, and the
telephone number(s) and email address for the importer and person who
imports or offers for import their drug;
A site-specific Data Universal Numbering System (DUNS)
number for each entity (in November 2014, we issued the guidance for
industry entitled ``Specification of the Unique Facility Identifier
System for Drug Establishment Registration'' (79 FR 65977, available on
the Internet at https://www.fda.gov/Drugs under Guidances (Drugs)) and
obtained OMB approval to broaden the entity identification number
covered in OMB control number 0910-0045);
The NDC product code for the source drug that is repacked
or relabeled;
Distinctive characteristics of certain listed drugs (i.e.,
the flavor, the color, and image of the actual solid dosage form); and
Registrants may indicate that they view as confidential an
inactive ingredient or the registrant's business relationship with an
establishment.
We currently have OMB approval under the PRA (OMB control number
0910-0045) for the information collection in current part 207, the
information that was submitted using Form FDA 2656, Form FDA 2657, and
Form FDA 2658, and the information collection set forth in the
electronic registration and listing guidance, including the electronic
submission of registration and listing information as required by
FDAAA. The information collection for current part 607 is approved by
OMB under OMB control number 0910-0052. The information collection for
current part 1271 is approved by OMB under OMB control number 0910-
0543.
In tables 5, 6, 7, and 8, we estimate the total burden to comply
with the applicable information collection requirements for parts 207,
607, and 1271 as set forth in this final rule. These burden estimates
for the applicable regulations will replace some of the currently
approved estimates in OMB control numbers 0910-0045, 0910-0052, and
0910-0543. These estimates are based on FDA's experience with reviewing
registration and listing submissions under part 207 since June 2009 and
on the number of submissions currently received, the number of
respondents submitting this information, and the number of registered
establishments and listed drugs, blood products, and HCT/Ps currently
in FDA's drug registration and listing database.
A. Registration Information Collection Under Part 207
1. Requirements
Under Sec. 207.17, manufacturers, repackers, relabelers, and drug
product salvagers must register their establishments. This is
consistent with current registration information collection, except
that PET drug producers are not exempt from registration under the
final rule, and the final rule states that FDA will accept registration
information from a private label distributor if it is acting as an
authorized agent for and submitting information that pertains to an
establishment that manufactures, repacks, relabels, or salvages drugs.
Under Sec. 207.21, domestic manufacturers, domestic repackers,
domestic relabelers, and domestic drug product salvagers must complete
initial registration of each establishment no later than 5 calendar
days after beginning to manufacture, repack, relabel, or salvage a
drug. In addition, foreign manufacturers, foreign repackers, foreign
relabelers, and foreign drug product salvagers must register each
establishment before the drug is imported or offered for import into
the United States. This is consistent with current registration
information collection.
The information that must be provided to FDA for registration is
described in Sec. 207.25. The final rule does not require the
following currently required information collection:
Kind of ownership or operation.
Title of each corporate officer and director.
The final rule requires the following new registration information
collection:
Type of operations performed at each establishment.
Contact information for the establishment's official
contact.
Under Sec. 207.29, registrants must review their registration
information annually between October 1 and December 31and report all
changes to their registration information or certify that no changes
have occurred. In addition to the annual review and update, registrants
must submit expedited reports of certain changes within 30 calendar
days of the change. Currently, registrants must renew their
registration information annually and submit certain amendments to
registration within 5 days of a change. Section 207.29 differs from the
current requirement to submit amendments to registration in the
following ways:
The final rule lengthens the current time period for
reporting changes to registration information from 5 days (10 business
days for a change in United States agent information) to 30 calendar
days.
The final rule revokes the current requirement to report a
change in individual ownership and corporate or partnership structure
and the current requirement to submit a signed
[[Page 60208]]
statement for a change in a registered establishment's firm name.
New registration information collected under the final rule
includes the certification that no changes have occurred and reporting
certain changes as expedited updates within 30 calendar days.
2. Burden Estimates
Based on the number of new establishments that currently register
each year, we estimate that approximately 1,400 registrants will submit
electronically approximately 2,800 new establishment registrations
annually. Based on the number of registered establishments in our
database, we estimate that approximately 10,000 registrants will
provide approximately 10,000 annual reviews and updates of registration
information (including expedited updates) or reviews and certifications
that no changes have occurred.
The estimates include the registration of establishments for both
domestic and foreign manufacturers, repackers, relabelers, and drug
product salvagers, and registration information submitted by anyone
acting as an authorized agent for an establishment that manufactures,
repacks, relabels, or salvages drugs. The estimates include an
additional 80 PET drug producers who are not exempt from registration
under the final rule and approximately 30 manufacturers of plasma
derivatives.
We estimate that it will take approximately 1 hour for registrants
to submit initial registration information electronically for each new
establishment.
We also estimate that it will take approximately 30 minutes for
each annual review and update of registration information (including
any expedited updates) or each review and certification that no changes
have occurred.
The burden hour estimates are based on our familiarity with the
amount of time it takes registrants to input registration information
electronically since June 2009. The estimates are an average of the
time it would take to register a domestic or foreign establishment and
an average of the time it would take to review registration information
and update several registration items in the database or review
registration information and only certify that no changes have
occurred.
B. Listing Information Collection Under Part 207
1. Requirements
Under Sec. 207.41, registrants must list drugs they manufacture,
repack, relabel, or salvage for commercial distribution. This
requirement is consistent with current listing information collection,
except that drug product salvagers are not currently required to list
under part 207.
The final rule revises current NDC-related listing submissions as
follows:
A registrant must list each drug it manufactures, repacks,
or relabels using an NDC that includes the registrant's own labeler
code, regardless of whether the drug is commercially distributed under
the registrant's own label or trade name or under the label or trade
name of a private label distributor.
Each registrant must list each drug it manufactures,
repacks, or relabels for commercial distribution under the trade name
or label of a private label distributor using an NDC that includes such
private label distributor's labeler code.
During listing, each manufacturer, repacker, or relabeler
must propose for assignment by FDA an NDC that includes its own labeler
code for each package size and type of drug that it manufactures,
repacks, or relabels for commercial distribution.
If a drug is distributed under the trade name or label of
a private label distributor, the manufacturer, repacker, or relabeler
must also propose for assignment by FDA an NDC that includes the
labeler code of the private label distributor under whose trade name or
label the drug is distributed, for each package size and type so
distributed.
A manufacturer, repacker, relabeler, or private label
distributor may also reserve a proposed NDC for a drug, before the drug
is listed, by submitting certain information.
Under Sec. 207.45, registrants must list, no later than 3 calendar
days after the initial registration of each establishment, any drug
being manufactured, repacked, relabeled, or salvaged for commercial
distribution at that establishment. This requirement is consistent with
current listing information collection, except that the final rule
specifies within 3 calendar days after initial registration.
Under the final rule, the information registrants must submit to
list a drug, including the information that must be submitted (by a
registrant or a private label distributor) to receive a labeler code,
is described in Sec. Sec. 207.33, 207.49, 207.53, 207.54, 207.55, and
207.61. Under current part 207, we assign a labeler code to each
registrant and the registrant assigns the product code and the package
code for each drug product's NDC.
The listing and NDC information collections required by the final
rule are already approved by OMB under OMB control number 0910-0045,
except for the following: (1) The name of each inactive ingredient in a
listed drug (assertions of confidentiality associated with individual
inactive ingredients are covered in the electronic registration and
listing guidance); (2) additional information, such as email address,
to identify a domestic registrant (identifying information for foreign
registrants is part of the electronic registration and listing guidance
information collection and in current Sec. 207.40(c)); (3) the drug
master file or veterinary master file number, if one exists, must be
submitted by the manufacturer for an unfinished drug; (4) drug product
salvagers (who do not repack or relabel) must submit the lot number and
expiration date and NDC assigned to the drug immediately before the
drug is received by the drug product salvager; (5) all new labeling for
a repacked or relabeled drug must be submitted, and not only the
changed labeling; (6) package type and volume information corresponding
to the package code segment of the NDC must be submitted; (7) a drug's
OTC monograph reference (if any) and the date on which the drug was or
will be introduced into commercial distribution are both requested for
voluntary submission; and (8) the name and Unique Facility Identifier
(UFI) of the establishment where the registrant who lists the drug
manufactures it and the type of operation performed on the drug at that
establishment, and, if an immediate source NDC is not provided, the
name and UFI of every other establishment where manufacturing is
performed for the drug and the type of operation performed at each such
establishment must be provided.
Under Sec. 207.57, registrants must update drug listing
information submitted previously (either when the change is made or, at
a minimum, each June and December). Registrants must also notify FDA if
any listed drug has been discontinued from marketing or if any
discontinued drug has been reintroduced and provide listing information
for any drug not yet listed (at the time of annual establishment
registration if not sooner). Under Sec. 207.35, registrants must
notify us of a change in any of the drug characteristics (except
certain identifying information) for an NDC in Sec. 207.33, and assign
a new product code and package code for that drug. Current listing
information collection does not specifically require any type of
certification if there are no
[[Page 60209]]
changes, and only material changes to listing information must be
reported.
2. Burden Estimates
Based on the number of drugs listed annually since June 2009, we
estimate that approximately 1,713 registrants will submit
electronically approximately 12,469 new listings annually (including
the information submitted to obtain a labeler code and to reserve an
NDC for future use).
Based on the number of drugs in our listing database and the
current number of changes to listing information submitted, we estimate
that approximately 5,300 registrants will provide approximately 10,000
June and 10,000 December reviews and updates of listing information--a
total of approximately 20,000 submissions annually (including the
information submitted to revise an NDC).
The estimates for the number of drug listings include both domestic
and foreign listings, listings submitted by registrants for products
sold under their own names as well as products intended for private
label distribution, and information submitted related to an NDC and to
obtain a labeler code. The estimate for the number of drugs subject to
the listing requirements includes PET drugs and approximately 30 plasma
derivatives. The estimates for the number of June and December reviews
and updates of listing information include the number of changes to
drug characteristics pertaining to the drug product code to obtain a
new NDC and the reports of the withdrawal of an approved drug from sale
under Sec. 314.81(b)(3)(iii).
Based on our familiarity with the time required to input listing
information electronically since June 2009, we estimate that it will
take registrants approximately 1 hour and 30 minutes to submit
information electronically for each drug they list for the first time
(for both foreign and domestic registrant listings). These estimates
are an average of the time it will take manufacturers, repackers,
relabelers, and drug product salvagers, with drug product salvagers
taking considerably less time than manufacturers. The estimates include
the time for submitting the content of labeling and other labeling in
electronic format. (For drugs subject to an approved marketing
application, the electronic submission of the content of labeling under
current Sec. 314.50(l)(1)(i) is also approved under OMB control number
0910-0001.) We also estimate that it will take approximately 45 minutes
for each June and December review and update of listing information.
These estimates are an average of the time it would take to review and
update listing information or to review and certify that no changes
have occurred. The estimates include the time for submitting any
labeling for each drug, changes to the drug's characteristics submitted
for a new NDC, and reports of the withdrawal of an approved drug from
sale under Sec. 314.81(b)(3)(iii).
C. Registration and Listing Information Collection Under Part 607
1. Requirements
Under Sec. 607.22(a) of the final rule, blood establishments must
submit initial and subsequent registration and product listing
electronically through the Blood Establishment Registration and Product
Listing system, or any future superseding electronic system. All
information submitted under this part must be transmitted to FDA
electronically. Currently, under Sec. 607.22, manufacturers must
register establishments and list blood products on Form FDA 2830. The
requested information is consistent with the current requirement to
register establishments and list products approved under OMB control
number 0910-0052. A separate discussion regarding waivers under Sec.
607.22(b) is discussed in section E.
Under Sec. Sec. 607.25(a) and 607.25 (b)(3) of the final rule,
establishments must include the Unique Facility Identifier as part of
the registration and product listing. The other requested information
under this regulation is consistent with the current requirements to
register establishments and list products approved under OMB control
number 0910-0052.
Under Sec. 607.25(b)(1) of the final rule, blood establishments
are required to list blood products by the established and proprietary
name. This is consistent with the current listing requirement approved
under OMB control number 0910-0052. Currently, manufacturers of plasma
derivatives and bulk product substances register and list under both
parts 607 and 207. The final rule revises this requirement by requiring
persons who engage solely in the production of plasma derivatives, bulk
product substances, and recombinant version of plasma derivatives or
animal derived plasma derivatives to register and list only under part
207. Any reduction in burden is expected to be minimal (approximately
20 establishments) and will be reflected under OMB control number 0910-
0052. To be consistent with part 207, we are also deleting the
reference in part 607 to Form FDA 2250 (National Drug Code Directory
Input) because this form is no longer being used by CDER or CBER.
Under current Sec. 607.40, foreign establishments must include
information for the United States agent as part of its initial and
updated registration. The final rule requires submission of minimal
additional information (i.e., email address) for the United States
agent. This information is consistent with the current registration
information approved under OMB control number 0910-0052. The final rule
requires the foreign establishment to report to FDA changes in the
United States agent's name, address, telephone number, and email
address within 30 calendar days of the change. The final rule lengthens
from 10 business days to 30 calendar days the time period for reporting
changes in the United States agent's information to FDA.
2. Burden Estimates
Based on the number of new establishments that currently register
with FDA each year, we estimate 68 establishments will provide new
establishment registration and product listings annually under
Sec. Sec. 607.22(a), 607.25(a), and (b)(3).
We estimate that it takes approximately 60 minutes to provide the
initial registration and listing information for each new
establishment.
Based on the number of establishments that currently submit
registration and product listing updates, we estimate 2,615
establishments will provide establishment registration and product
listing updates annually under Sec. Sec. 607.22(a), 607.25(a), and
(b)(3).
We estimate that it takes approximately 30 minutes to provide the
establishment registration and listing update information for
establishment.
These burden hour estimates are based on institutional experience
with the current registration and listing requirements.
D. Registration and Listing Information Collection Under Part 1271
1. Requirements
Under Sec. 1271.22, establishments must register, list products,
and provide updates electronically. The current regulation includes the
option to submit registration, listing, and updates electronically.
Under Sec. 1271.25, establishments must also submit the telephone
number and email address of the reporting official. Each foreign
establishment must submit the name, the address, telephone number, and
email address of each importer that is known to the
[[Page 60210]]
establishment and the name of each person who imports or offers for
import such HCT/P to the United States. Foreign establishments must
also submit the name, the address, telephone number, and email address
of their United States agent.
Under Sec. 1271.26, establishments must report a change to the
United States agent's name, address, telephone number, or email
address. The final rule will also lengthen to 30 calendar days the
current requirement of reporting the changes within 5 days.
2. Burden Estimates
Based on the number of new establishments that currently register
with FDA each year, we estimate that approximately 225 establishments
will provide new establishment registration annually. Based on
information from FDA's database, we estimate that approximately 2,700
establishments are registered and listed with FDA and will provide
establishment and listing updates. The number of establishments that
currently register and list with FDA includes both foreign and domestic
establishments. If no change has occurred, an update is not required.
Based on the number of establishments from FDA's database, we estimate
that approximately 1,200 establishments will provide changes to
establishment ownership or location, or changes to the United States
agent's information.
We estimate that it would take approximately 45 minutes to provide
the initial registration and listing information for each new
establishment.
We estimate that it would take approximately 30 minutes for each
annual review and update of registration and listing information for
each establishment.
We estimate that it would take approximately 15 minutes for each
establishment to provide a change in ownership and location, or a
change to the U.S. agent's information.
These burden hour estimates are based on institutional experience
with the current registration and listing requirements. The estimates
are an average of the time it would take to register an establishment,
and an average of the time it would take to review registration and
listing information, and update several registration and listing items
in the database.
E. Waiver Request Information
1. Part 207
Under Sec. 207.65, registrants may request a waiver from the
requirement in Sec. 207.61 that information must be provided to us in
electronic format. We expect very few waiver requests because only a
computer, Internet access, and an email address are needed to register
and list electronically and because electronic submission has been
required since June 2009.
We estimate that approximately one registrant will request a waiver
annually and that each request will take approximately 30 minutes to
prepare and submit to us.
2. Part 607
Under Sec. 607.22(b), both domestic and foreign establishments may
request a waiver from the requirement that information must be provided
to FDA in electronic format. We expect few waiver requests because only
a computer, Internet access, and an email address are needed to
register and list electronically.
We estimate that approximately 25 manufacturers will request a
waiver annually and that each request will take approximately 1 hour to
prepare and submit to us.
When we grant a request for a waiver, we intend to make available
to the manufacturer the paper form--Form FDA 2830 for registration and
listing.
3. Part 1271
Under Sec. 1271.23, manufacturers may request a waiver from the
requirement in Sec. 1271.22 that information must be provided to FDA
in electronic format. We expect a limited number of waiver requests
because only a computer, Internet access, and an email address are
needed to register and list electronically.
We estimate that approximately 100 manufacturers will request a
waiver annually and that each request will take approximately 1 hour to
prepare and submit to FDA.
When we grant a request for a waiver, we intend to make available
to the manufacturer the paper form--revised Form FDA 3356 for
registration and listing.
F. Public Disclosure Exemption Requests
Under Sec. 207.81(c), registrants may request that certain
information in Sec. 207.81(a) not be made available from their
registration and listing information. Based on our experience with
registration and listing information inspection requests under current
Sec. 207.37, we estimate that approximately 100 registrants will
submit this request annually and that each request will take
approximately 1 hour to prepare and submit to us. (Assertions of
confidentiality associated with individual inactive ingredients or the
registrant's business relationship with an establishment is part of the
June 2009 electronic registration and listing guidance information
collection and is covered under OMB control number 0910-0045).
G. Standard Operating Procedure for Electronic Submission
The requirement under section 510(p) of the FD&C Act for electronic
drug establishment registration and electronic drug listing resulted in
our amending OMB control number 0910-0045 in June 2009 to include the
burden for preparing a standard operating procedure (SOP) for the
electronic submission requirement, creating the SPL file, including
accessing and reviewing the technical specifications and instructional
documents provided by FDA, reviewing and selecting appropriate terms
and codes used to create the SPL file, obtaining the digital
certificate used with FDA's electronic submission gateway, and
uploading the SPL file for submission. Although most registrants have
already prepared an SOP for the electronic submission requirements,
each year additional firms will need to create an SOP. As provided in
table 6, FDA estimates that approximately 1,000 firms will have to
expend a one-time burden to prepare, review, and approve an SOP, and we
estimate that it will take approximately 40 hours per recordkeeper to
create 1,000 new SOPs, for a total of 40,000 hours. We also estimate
approximately 3,295 hours for annual recordkeeping maintenance of these
records.
H. Capital Costs
There are one-time capital costs associated with this rulemaking.
These costs are discussed in section VII, ``Economic Analysis of
Impacts.''
Description of Respondents: Manufacturers, repackers, relabelers,
drug product salvagers, and private label distributors as described in
the final rule.
Burden Estimate: Tables 5, 6, 7, and 8 provide the annual reporting
and recordkeeping burdens for this final rule.
[[Page 60211]]
Table 5--Estimated Annual Reporting Burden Under Part 207
----------------------------------------------------------------------------------------------------------------
Number of Hours per
21 CFR Sections and reporting Number of responses per Total annual registration Total hours
requirements respondents respondent responses or listing
----------------------------------------------------------------------------------------------------------------
Initial Establishment 1,400 2 2,800 1 2,800
Registration (Sec. Sec.
207.17, 207.21, 207.25)........
Annual Review and Update of 10,000 1 10,000 0.50 5,000
Registration Information
(including expedited updates)
(Sec. 207.29)................
Initial Listing (including NDC) 1,713 7.28 12,470 1.5 18,705
Information (Sec. Sec.
207.33, 207.41, 207.45, 207.49,
207.53, 207.54, 207.55)........
June and December Review and 5,300 20 106,000 0.75 79,500
Update (or Certification) of
Listing (including NDC)
Information (Sec. Sec.
207.35, 207.57)................
Waiver requests (Sec. 207.65). 1 1 1 0.50 0.5
Public disclosure exemption 100 1 100 1 100
requests (Sec. 207.81(c))....
-------------------------------------------------------------------------------
Total Reporting Burden...... .............. .............. .............. .............. 106,105
----------------------------------------------------------------------------------------------------------------
Table 6--Estimated Annual Recordkeeping Burden Under Part 207
----------------------------------------------------------------------------------------------------------------
Number of Average burden
SOP for creating and uploading Number of records per Total annual per Total hours
the SPL File recordkeepers Recordkeeper records recordkeeping
----------------------------------------------------------------------------------------------------------------
One-time preparation of SOP..... 1,000 1 1,000 40 40,000
SOP maintenance................. 3,295 1 3,295 1 3,295
-------------------------------------------------------------------------------
Total....................... .............. .............. .............. .............. 43,295
----------------------------------------------------------------------------------------------------------------
Table 7--Estimated Annual Reporting Burden Under Part 607
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR Sections Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
----------------------------------------------------------------------------------------------------------------
Initial Establishment 68 1 68 1 68
Registration and Product
Listing (607.22(a) and
607.25(a) and (b)(3))..........
Annual Review and Update of 2,615 1 2,615 0.5 1,308
Establishment Registration and
Blood Product Listing
(607.22(a) and 607.25(a) and
(b)(3))........................
Waiver requests (607.22(b))..... 25 1 25 1 25
-------------------------------------------------------------------------------
Total Reporting Burden...... .............. .............. .............. .............. 1,401
----------------------------------------------------------------------------------------------------------------
Table 8--Estimated Annual Reporting Burden Under Part 1271
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR Sections Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
----------------------------------------------------------------------------------------------------------------
Initial Establishment 225 1 225 0.75 168.75
Registration and Listing
(1271.25)......................
Annual Review and Update of 2,700 1 2,700 0.5 1,350
Establishment Registration and
Listing (1271.25)..............
Waiver requests (1271.23)....... 100 1 100 1 100
Amend Establishment Registration 1,200 1 1,200 0.25 300
(1271.26)......................
-------------------------------------------------------------------------------
Total Reporting Burden...... .............. .............. .............. .............. 1,918.75
----------------------------------------------------------------------------------------------------------------
The information collection provisions of this final rule have been
submitted to OMB for review, as required by section 3507(d) of the PRA.
Prior to the effective date of this final rule, FDA will publish a
notice in the Federal Register announcing OMB's decision to approve,
modify, or disapprove the information collection provisions in this
final rule. An Agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays
a currently valid OMB control number.
IX. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the Agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
[[Page 60212]]
X. References
The following reference is on display in the Division of Dockets
Management, (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852, and is available for viewing by
interested persons between 9 a.m. and 4 p.m., Monday through Friday. It
is also available electronically at https://www.regulations.gov and at
https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
1. FDA/Economics Staff, ``Requirements for Foreign and Domestic
Establishment Registration and Listing for Human Drugs, Including
Drugs That Are Regulated Under a Biologics License Application, and
Animal Drugs, Final Regulatory Impact Analysis, Final Regulatory
Flexibility Analysis, Unfunded Mandates Reform Act Analysis,'' 2016.
List of Subjects
21 CFR Part 20
Confidential business information, Courts, Freedom of information,
Government employees.
21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 207
Drugs, Reporting and recordkeeping requirements.
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Parts 514 and 515
Administrative practice and procedure, Animal drugs, Confidential
business information, Reporting and recordkeeping requirements.
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
21 CFR Part 607
Blood.
21 CFR Part 1271
Biologics, Drugs, Human cells and tissue-based products, Medical
devices, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR parts 20, 201, 207, 314, 514,
515, 601, 607, and 1271 are amended as follows:
PART 20--PUBLIC INFORMATION
0
1. The authority citation for part 20 continues to read as follows:
Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 21
U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-l.
Sec. 20.100 [Amended]
0
2. Amend Sec. 20.100(c)(9) by removing ``Sec. 207.37'' and by adding
in its place ``Sec. 207.81''.
0
3. Revise Sec. 20.116 to read as follows:
Sec. 20.116 Drug and device registration and listing information.
Information submitted to the Food and Drug Administration pursuant
to section 510(a) through (j) of the Federal Food, Drug, and Cosmetic
Act shall be subject only to the special disclosure provisions
established in Sec. Sec. 207.81 and 807.37 of this chapter.
PART 201--LABELING
0
4. The authority citation for part 201 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360,
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
Sec. 201.1 [Amended]
0
5. Amend Sec. 201.1(f) by removing ``Sec. 207.3(b)'' and adding in
its place ``Sec. 207.1''.
Sec. 201.2 [Amended]
0
6. Amend Sec. 201.2 by removing the last sentence.
0
7. In Sec. 201.25 revise the first sentence of paragraph (c)(1)
introductory text to read as follows:
Sec. 201.25 Bar code label requirements.
* * * * *
(c) * * *
(1) Each drug product described in paragraph (b) of this section
must have a bar code that contains, at a minimum, the appropriate
National Drug Code (NDC) number in a linear bar code that meets
European Article Number/Uniform Code Council (EAN/UCC) or Health
Industry Business Communications Council (HIBCC) standards or another
standard or format that has been approved by the relevant Food and Drug
Administration Center Director. * * *
* * * * *
0
8. Revise part 207 to read as follows:
PART 207--REQUIREMENTS FOR FOREIGN AND DOMESTIC ESTABLISHMENT
REGISTRATION AND LISTING FOR HUMAN DRUGS, INCLUDING DRUGS THAT ARE
REGULATED UNDER A BIOLOGICS LICENSE APPLICATION, AND ANIMAL DRUGS,
AND THE NATIONAL DRUG CODE
Subpart A--General
Sec.
207.1 What definitions and interpretations of terms apply to this
part?
207.3 Bulk drug substance.
207.5 What is the purpose of this part?
207.9 Who does this part cover?
207.13 Who is exempt from the registration and listing requirements?
Subpart B--Registration
207.17 Who must register?
207.21 When must initial registration information be provided?
207.25 What information is required for registration?
207.29 What are the requirements for reviewing and updating
registration information?
Subpart C--National Drug Code
207.33 What is the National Drug Code (NDC), how is it assigned, and
what are its requirements?
207.35 What changes require a new NDC?
207.37 What restrictions pertain to the use of the NDC?
Subpart D--Listing
207.41 Who must list drugs and what drugs must they list?
207.45 When, after initial registration of an establishment, must
drug listing information be submitted?
207.49 What listing information must a registrant submit for a drug
that it manufactures?
207.53 What listing information must a registrant submit for a drug
that it repacks or relabels?
207.54 What listing information must a registrant submit for a drug
that it salvages?
207.55 What additional drug listing information may FDA require?
207.57 What information must registrants submit when updating
listing information and when?
Subpart E--Electronic Format for Registration and Listing
207.61 How is registration and listing information provided to FDA?
207.65 How can a waiver of the electronic submission requirement be
obtained?
Subpart F--Miscellaneous
207.69 What are the requirements for an official contact and a
United States agent?
207.77 What legal status is conferred by registration and listing?
207.81 What registration and listing information will FDA make
available for public disclosure?
[[Page 60213]]
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360b, 371,
374, 381, 393; 42 U.S.C. 262, 264, 271.
Subpart A--General
Sec. 207.1 What definitions and interpretations of terms apply to
this part?
The definitions and interpretations of terms in sections 201 and
510 of the Federal Food, Drug, and Cosmetic Act apply to the terms used
in this part, if not otherwise defined in this section. The following
definitions apply to this part:
Active pharmaceutical ingredient means any substance that is
intended for incorporation into a finished drug product and is intended
to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body. Active pharmaceutical
ingredient does not include intermediates used in the synthesis of the
substance.
Bulk drug substance, as referenced in sections 503A(b)(1)(A) and
503B(a)(2) of the Federal Food, Drug, and Cosmetic Act, means the same
as ``active pharmaceutical ingredient'' as defined in Sec. 207.1(b).
Commercial distribution means any distribution of a human drug,
except for investigational use under part 312 of this chapter, and any
distribution of an animal drug or an animal feed bearing or containing
an animal drug, except for investigational use under part 511 of this
chapter. The term does not include internal or interplant transfer
between registered establishments under common ownership and control,
including a parent, subsidiary, or affiliate company. For foreign
establishments that manufacture, repack, relabel, or salvage, or for
foreign private label distributors, the term ``commercial
distribution'' has the same meaning except the term does not include
distribution of any drug that is neither imported nor offered for
import into the United States.
Content of labeling means:
(1) For human prescription drugs that are subject to section 505 of
the Federal Food, Drug, and Cosmetic Act or section 351 of the Public
Health Service Act: The content of the prescription drug labeling (as
specified in Sec. Sec. 201.56, 201.57, and 201.80 of this chapter),
including all text, tables, and figures.
(2) For human prescription drugs that are not subject to section
505 of the Federal Food, Drug, and Cosmetic Act or section 351 of the
Public Health Service Act: The labeling equivalent to the content of
the prescription drug labeling (as specified in Sec. Sec. 201.56,
201.57, and 201.80 of this chapter), including all text, tables, and
figures.
(3) For human over-the-counter (OTC) drugs: All text, tables, and
figures including the drug facts labeling required by Sec. 201.66 of
this chapter.
(4) For animal drugs (including, but not limited to, drugs that are
subject to section 512 of the Federal Food, Drug, and Cosmetic Act):
The content of the labeling that accompanies the drug that is necessary
to enable safe and proper administration of the drug (e.g., the
labeling applicable to veterinary drugs specified in part 201 of this
chapter), including all text, tables, and figures.
Domestic for purposes of registration and listing under this part,
when used to modify the term ``registrant,'' ``manufacturer,''
``repacker,'' ``relabeler,'' ``salvager,'' ``private label
distributor,'' or ``establishment,'' refers to a registrant,
manufacturer, repacker, relabeler, salvager, private label distributor,
or establishment within any State or Territory of the United States,
the District of Columbia, or the Commonwealth of Puerto Rico.
Drug, for the purposes of registration and listing under this part,
has the meaning given in section 201(g)(1) of the Federal Food, Drug,
and Cosmetic Act.
Establishment means a place of business under one management at one
general physical location. The term includes, among others, independent
laboratories that engage in control activities for a registered drug
establishment (e.g., consulting laboratories), manufacturers of
medicated feeds and of vitamin products that are drugs in accordance
with section 201(g) of the Federal Food, Drug, and Cosmetic Act, human
blood donor centers, and animal facilities used for the production or
control testing of licensed biologicals, and establishments engaged in
salvaging.
Establishment registration number means the number assigned to the
establishment, as identified by FDA, after the establishment
registration required in this part.
Finished drug product means a finished dosage form (e.g., tablet,
capsule, or solution) that contains at least one active pharmaceutical
ingredient, generally, but not necessarily, in association with other
ingredients in finished package form suitable for distribution to
pharmacies, hospitals, or other sellers or dispensers of the drug
product to patients or consumers.
Foreign for the purposes of registration and listing under this
part:
(1) When used to modify the term ``manufacturer,'' ``repacker,''
``relabeler,'' or ``salvager,'' refers to a manufacturer, repacker,
relabeler, or salvager, who is located in a foreign country and who
manufactures, repacks, relabels, or salvages a drug, or an animal feed
bearing or containing a new animal drug, that is imported or offered
for import into the United States.
(2) When used to modify the term ``establishment'' refers to an
establishment that is located in a foreign country and is engaged in
the manufacture, repackaging, relabeling, or salvaging of any drug, or
any animal feed bearing or containing a new animal drug, that is
imported or offered for import into the United States.
Importer means, for purposes of this part, a person in the United
States that is an owner, consignee, or recipient, at the time of entry,
of a foreign establishment's drug, or an animal feed bearing or
containing a new animal drug, that is imported into the United States.
Manufacture means each step in the manufacture, preparation,
propagation, compounding, or processing of a drug or an animal feed
bearing or containing a new animal drug. Manufacture includes the
making by chemical, physical, biological, or other procedures or
manipulations of a drug, or an animal feed bearing or containing a new
animal drug, including control procedures applied to the final product
or to any part of the process. Manufacture includes manipulation,
sampling, testing, or control procedures applied to the final product
or to any part of the process, including, for example, analytical
testing of drugs for another registered establishment's drug. For
purposes of this part, and in order to clarify the responsibilities of
the entities engaged in different operations, the term manufacture is
defined and used separately from the terms relabel, repackage, and
salvage, although the term ``manufacture, preparation, propagation,
compounding, or processing,'' as used in section 510 of the Federal
Food, Drug, and Cosmetic Act, includes relabeling, repackaging, and
salvaging activities.
Manufacturer means a person who owns or operates an establishment
that manufactures a drug or an animal feed bearing or containing a new
animal drug. This term includes, but is not limited to, control
laboratories, contract laboratories, contract manufacturers, contract
packers, contract labelers, and other entities that manufacture a drug,
or an animal feed bearing or containing a new animal drug, as defined
in this paragraph. For purposes of this part,
[[Page 60214]]
and in order to clarify the responsibilities of the entities engaged in
different operations, the term manufacturer is defined and used
separately from the terms relabeler, repacker, and salvager, although
the term ``manufacture, preparation, propagation, compounding, or
processing,'' as used in section 510 of the Federal Food, Drug, and
Cosmetic Act, includes the activities of relabelers, repackers, and
salvagers. Repackers, relabelers, and salvagers are subject to the
provisions of this part that are applicable to repackers, relabelers,
and salvagers, but are not subject to the provisions of this part that
are applicable to manufacturers. When not modified by ``domestic'' or
``foreign,'' the term includes both domestic manufacturers and foreign
manufacturers.
Material change means any change in any drug listing information,
as required under Sec. Sec. 207.49, 207.53, 207.54, 207.55, or 207.57
except changes in format of labeling, labeling changes of an editorial
nature, or inclusion of a bar code or initial inclusion of an NDC on
the label.
Outsourcing facility means a compounder that has elected to
register with FDA under section 503B of the Federal Food, Drug, and
Cosmetic Act and that meets all of the conditions of section 503B.
Person who imports or offers for import means, for purposes of this
part, the owner or exporter of a drug who consigns and ships a drug
from a foreign country to the United States. This includes persons who
send a drug to the United States by international mail or other private
delivery service, but it does not include carriers who merely transport
the drug.
Private label distribution means commercial distribution of a drug
under the label or trade name of a person who did not manufacture,
repack, relabel, or salvage that drug.
Private label distributor means, with respect to a particular drug,
a person who did not manufacture, repack, relabel, or salvage the drug
but under whose label or trade name the drug is commercially
distributed.
Registrant means any person that owns or operates an establishment
that manufactures, repacks, relabels, or salvages a drug, and is not
otherwise exempt from establishment registration requirements under
section 510 of the Federal Food, Drug, and Cosmetic Act or this part.
Relabel means to change the existing label or labels on a drug or
drug package, or change or alter the existing labeling for a drug or
drug package, without repacking the drug or drug package. This term
does not include the addition or modification of information affixed
solely for purposes of delivery to a customer, customer identification,
and/or inventory management.
Relabeler means a person who owns or operates an establishment that
relabels a drug. When not modified by ``domestic'' or ``foreign,'' the
term includes both domestic relabelers and foreign relabelers.
Repack or repackage means the act of taking a finished drug product
or unfinished drug from the container in which it was placed in
commercial distribution and placing it into a different container
without manipulating, changing, or affecting the composition or
formulation of the drug.
Repacker means a person who owns or operates an establishment that
repacks a drug or drug package. When not modified by ``domestic'' or
``foreign,'' the term includes both domestic repackers and foreign
repackers.
Representative sampling of advertisements means typical advertising
material (including the promotional material described in Sec.
202.1(l)(1) of this chapter, but excluding labeling as determined in
Sec. 202.1(l)(2) of this chapter), that gives a balanced picture of
the promotional claims used for the drug.
Representative sampling of any other labeling means typical
labeling material (including the labeling material described in Sec.
202.1(l)(2) of this chapter, but excluding labels and package inserts)
that gives a balanced picture of the promotional claims used for the
drug.
Salvage means the act of segregating out those finished drug
products that may have been subjected to improper storage conditions
(such as extremes in temperature, humidity, smoke, fumes, pressure,
age, or radiation) for the purpose of returning the products to the
marketplace and includes applying manufacturing controls such as those
required by current good manufacturing practice in parts 210 and 211 of
this chapter.
Salvager means a person who owns or operates an establishment that
engages in salvaging. When not modified by ``domestic'' or ``foreign,''
the term includes both domestic and foreign salvagers.
Unfinished drug means an active pharmaceutical ingredient either
alone or together with one or more other ingredients but does not
include finished drug products.
Sec. 207.3 Bulk drug substance.
Bulk drug substance, as referenced in sections 503A(b)(1)(A) and
503B(a)(2) of the Federal Food, Drug, and Cosmetic Act, previously
defined in Sec. 207.3(a)(4), means the same as ``active pharmaceutical
ingredient'' as defined in Sec. 207.1(b).
Sec. 207.5 What is the purpose of this part?
Establishment registration information helps FDA identify who is
manufacturing, repacking, relabeling, and salvaging drugs and where
those operations are performed. Drug listing information gives FDA a
current inventory of drugs manufactured, repacked, relabeled, or
salvaged for commercial distribution. Both types of information
facilitate implementation and enforcement of the Federal Food, Drug,
and Cosmetic Act and are used for many important public health
purposes.
Sec. 207.9 Who does this part cover?
(a) Except as provided in paragraph (b) of this section, this part
applies to:
(1) Domestic manufacturers, domestic repackers, domestic relabelers
and domestic salvagers, not exempt under section 510(g) of the Federal
Food, Drug, and Cosmetic Act or Sec. 207.13, regardless of whether
their drugs enter interstate commerce;
(2) Foreign manufacturers, foreign repackers, foreign relabelers
and foreign salvagers, not exempt under section 510(g) of the Federal
Food, Drug, and Cosmetic Act or Sec. 207.13;
(3) Private label distributors, because they must have labeler
codes;
(4) Establishments engaged in the manufacture, repacking,
relabeling, or salvaging of human drugs regulated under a biologics
license application (BLA). These establishments are subject to the
requirements of this part unless they are required to register and list
such drugs as human blood or blood products under part 607 of this
chapter and do not engage in activities that would otherwise require
them to register and list under this part.
(5) Establishments engaged in the manufacture (as defined in Sec.
1271.3(e) of this chapter) of human cells, tissues, and cellular and
tissue-based products (HCT/Ps) (as defined in Sec. 1271.3(d) of this
chapter) that, under Sec. 1271.20 of this chapter, are also drugs
regulated under section 351 of the Public Health Service Act or section
505 of the Federal Food, Drug, and Cosmetic Act. These establishments
must register and list those HCT/Ps following the procedures described
in this part.
(b) This part does not apply to owners and operators of
establishments that collect or process human whole blood
[[Page 60215]]
and blood products unless the establishment also manufactures, repacks,
or relabels other drugs. For purposes of this paragraph (b), human
whole blood and blood products do not include plasma derivatives such
as albumin, Immune Globulin, Factor VIII and Factor IX, and recombinant
versions of plasma derivatives or animal derived plasma derivatives, or
bulk product substances such as fractionation intermediates or pastes.
Establishments that collect or process human whole blood and blood
products as well as establishments involved in testing of human whole
blood and blood products must register and list under part 607 of this
chapter. Manufacturers of licensed devices and manufacturers of
licensed biological products used in a licensed device must register
and list under part 607 of this chapter.
(c) This part does not apply to establishments that solely
manufacture, prepare, propagate, compound, assemble, or process medical
devices. Registration and listing regulations for such establishments
are codified in part 807 of this chapter.
Sec. 207.13 Who is exempt from the registration and listing
requirements?
Except as provided in Sec. 207.13(l), the following classes of
persons are exempt from registration and drug listing in accordance
with section 510(g) of the Federal Food, Drug, and Cosmetic Act or
because FDA has determined, under section 510(g)(5) of the Federal
Food, Drug, and Cosmetic Act, that their registration is not necessary
for the protection of the public health. This exemption is limited to
establishment registration and drug listing requirements and does not
relieve a person from other statutory or regulatory obligations.
(a)(1) Pharmacies that:
(i) Operate in conformance with all applicable local laws
regulating the practice of pharmacy and medicine, including all
applicable local laws regulating the dispensing of prescription drugs;
(ii) Regularly engage in dispensing prescription drugs upon a valid
prescription by practitioners licensed by law to administer these drugs
to patients under their professional care; and
(iii) Do not manufacture, repack, relabel, or salvage drugs other
than in the regular course of their business of dispensing or selling
drugs at retail.
(2) The exemption in this paragraph (a) is limited to pharmacies
located in any State as defined in section 201(a)(1) of the Federal
Food, Drug, and Cosmetic Act.
(b)(1) Hospitals, clinics, other health care entities, and public
health agencies that:
(i) Operate establishments in conformance with all applicable local
laws regulating the practice of pharmacy and medicine, including all
applicable local laws regulating the dispensing of prescription drugs;
(ii) Regularly engage in dispensing prescription drugs, other than
human whole blood or blood products, upon a valid order or prescription
by practitioners licensed by law to administer these drugs to patients
under their professional care; and
(iii) Do not manufacture, repack, relabel, or salvage drugs other
than in the regular course of their practice of pharmacy, including
dispensing.
(2) The exemption in this paragraph (b) is limited to hospitals,
clinics, other health care entities, and public health agencies located
in any State as defined in section 201(a)(1) of the Federal Food, Drug,
and Cosmetic Act.
(c) Individuals or establishments under contract, agreement, or
other arrangement with a registered establishment and engaged solely in
recovering cells or tissues and sending the recovered cells or tissues
to the registered establishment to become components of a biological
product are exempt from registration and listing under this part unless
FDA determines that drug establishment registration and listing is
necessary for the protection of the public health.
(d) Practitioners who are licensed by law to prescribe or
administer drugs and who manufacture, repack, relabel, or salvage drugs
solely for use in their professional practice.
(e) Manufacturers, repackers, relabelers, or salvagers who
manufacture, repack, relabel, or salvage drugs solely for use in
research, teaching, or chemical analysis and not for sale.
(f) Manufacturers, repackers, and relabelers of harmless inactive
ingredients such as excipients, colorings, flavorings, emulsifiers,
lubricants, preservatives, or solvents that become components of drugs.
(g) Manufacturers, repackers, relabelers, or salvagers of Type B or
Type C medicated feeds, except for persons who manufacture, repack,
relabel, or salvage Type B or Type C medicated feeds starting from
Category II, Type A medicated articles for which a medicated feed mill
license approved under part 515 of this chapter is required. This
exemption also does not apply to persons that would otherwise be
required to register (such as manufacturers, repackers, relabelers, or
salvagers of certain free-choice feeds, as defined in Sec. 510.455 of
this chapter, or certain liquid feeds, as defined in Sec. 558.5 of
this chapter, where the specifications and/or formulas are not
published and a medicated feed mill license is required). All
manufacturers, repackers, relabelers, or salvagers of Type B or Type C
medicated feeds are exempt from listing.
(h) Any manufacturer, repacker, relabeler, or salvager of a virus,
serum, toxin, or analogous product intended for the treatment of
domestic animals who holds an unsuspended and unrevoked license issued
by the Secretary of Agriculture under the animal virus-serum-toxin law
of March 4, 1913 (37 Stat. 832 (21 U.S.C. 151 et seq.)), provided that
this exemption from registration applies only to the manufacturer,
repacker, relabeler, or salvager of that animal virus, serum, toxin, or
analogous product.
(i) Carriers, in their receipt, carriage, holding, or delivery of
drugs in the usual course of business as carriers.
(j) Foreign establishments whose drugs are imported or offered for
import into the United States must comply with the establishment
registration and listing requirements of this part unless exempt under
this section or unless:
(1) Their drugs enter a foreign trade zone and are re-exported
without having entered U.S. commerce, or
(2) Their drugs are imported in conformance with section 801(d)(3)
of the Federal Food, Drug, and Cosmetic Act.
(k) Entities that are registered with FDA as outsourcing facilities
and that compound drugs in conformance with section 503B of the Federal
Food, Drug, and Cosmetic Act.
(l) The exemptions provided in paragraphs (a) through (k) of this
section do not apply to such persons if they:
(1) Manufacture (as defined in Sec. 207.1(b)), repack, relabel, or
salvage compounded positron emission tomography drugs as defined in
section 201(ii) of the Federal Food, Drug, and Cosmetic Act;
(2) Manufacture (as defined in Sec. 600.3(u) of this chapter) a
human biological product subject to licensing under section 351 of the
Public Health Service Act; or
(3) Engage in activities that would otherwise require them to
register under this part.
Subpart B--Registration
Sec. 207.17 Who must register?
(a) Unless exempt under section 510(g) of the Federal Food, Drug,
and Cosmetic Act or this part, all
[[Page 60216]]
manufacturers, repackers, relabelers, and salvagers must register each
domestic establishment that manufactures, repacks, relabels, or
salvages a drug, or an animal feed bearing or containing a new animal
drug, and each foreign establishment that manufactures, repacks,
relabels, or salvages a drug, or an animal feed bearing or containing a
new animal drug, that is imported or offered for import into the United
States. When operations are conducted at more than one establishment
and common ownership and control among all the establishments exists,
the parent, subsidiary, or affiliate company may submit registration
information for all establishments.
(b) Private label distributors who do not also manufacture, repack,
relabel, or salvage drugs are not required to register under this part.
FDA will accept registration or listing information submitted by a
private label distributor only if it is acting as an authorized agent
for and submitting information that pertains to an establishment that
manufactures, repacks, relabels, or salvages drugs.
Sec. 207.21 When must initial registration information be provided?
(a) Registrants must register each domestic establishment no later
than 5 calendar days after beginning to manufacture, repack, relabel,
or salvage a drug or an animal feed bearing or containing a new animal
drug at such establishment.
(b) Registrants must register each foreign establishment before a
drug or an animal feed bearing or containing a new animal drug
manufactured, repacked, relabeled, or salvaged at the establishment is
imported or offered for import into the United States.
Sec. 207.25 What information is required for registration?
Registrants must provide the following information:
(a) Name of the owner or operator of each establishment; if a
partnership, the name of each partner; if a corporation, the name of
each corporate officer and director, and the place of incorporation;
(b) Each establishment's name, physical address, and telephone
number(s);
(c) All name(s) of the establishment, including names under which
the establishment conducts business or names by which the establishment
is known;
(d) Registration number of each establishment, if previously
assigned by FDA;
(e) A Unique Facility Identifier in accordance with the system
specified under section 510 of the Federal Food, Drug, and Cosmetic
Act.
(f) All types of operations performed at each establishment;
(g) Name, mailing address, telephone number, and email address of
the official contact for the establishment, as provided in Sec.
207.69(a); and
(h) Additionally, with respect to foreign establishments subject to
registration, the name, mailing address, telephone number, and email
address must be provided for:
(1) The United States agent, as provided in Sec. 207.69(b);
(2) Each importer in the United States of drugs manufactured,
repacked, relabeled, or salvaged at the establishment that is known to
the establishment; and
(3) Each person who imports or offers for import such drug to the
United States.
Sec. 207.29 What are the requirements for reviewing and updating
registration information?
(a) Expedited updates. Registrants must update their registration
information no later than 30 calendar days after:
(1) Closing or selling an establishment;
(2) Changing an establishment's name or physical address; or
(3) Changing the name, mailing address, telephone number, or email
address of the official contact or the United States agent. A
registrant, official contact, or United States agent may notify FDA
about a change of information for the designated official contact or
United States agent, but only a registrant is permitted to designate a
new official contact or United States agent.
(b) Annual review and update of registration information.
Registrants must review and update all registration information
required under Sec. 207.25 for each establishment.
(1) The first review and update must occur during the period
beginning on October 1 and ending December 31 of the year of initial
registration, if the initial registration occurs prior to October 1.
Subsequent reviews and updates must occur annually, during the period
beginning on October 1 and ending December 31 of each calendar year.
(2) The updates must reflect all changes that have occurred since
the last annual review and update.
(3) If no changes have occurred since the last registration,
registrants must certify that no changes have occurred.
Subpart C--National Drug Code
Sec. 207.33 What is the National Drug Code (NDC), how is it assigned,
and what are its requirements?
(a) What is the NDC for a drug and what products must have unique
NDCs? The NDC for a drug is a numeric code. Each finished drug product
or unfinished drug subject to the listing requirements of this part
must have a unique NDC to identify its labeler, product, and package
size and type.
(b) What is the format of an NDC? (1) Except as described in
paragraph (b)(4) of this section, the NDC must consist of 10 or 11
digits, divided into three segments as follows:
(i) The first segment of the NDC is the labeler code and consists
of 4, 5, or 6 digits. The labeler code is assigned by FDA.
(ii) The second segment of the NDC is the product code and consists
of 3 or 4 digits, as specified in paragraphs (b)(2) and (3) of this
section.
(iii) The third segment of the NDC is the package code and consists
of 1 or 2 digits as specified in paragraphs (b)(2) and (3) of this
section. The package code identifies the package size and type of the
drug and differentiates between different quantitative and qualitative
attributes of the product packaging.
(2) The following combinations of labeler code, product code and
package code character lengths are permissible:
(i) If a labeler code is either 5 or 6 digits in length, it may be
combined with:
(A) A product code consisting of 4 digits and a package code
consisting of 1 digit for a total NDC length of 10 or 11 digits (5-4-1
or 6-4-1), or
(B) A product code consisting of 3 digits and a package code
consisting of 2 digits for a total NDC length of 10 or 11 digits (5-3-2
or 6-3-2).
(ii) If a labeler code is 4 digits in length, it may be combined
only with a product code consisting of 4 digits and a package code
consisting of 2 digits for a total NDC length of 10 digits (4-4-2).
(3) A registrant or private label distributor with a given labeler
code must use only one Product-Package Code configuration (e.g., a 3-
digit product code combined with a 2-digit package code or a 4-digit
product code combined with a 1-digit package code). This single
configuration must be used in all NDCs that include the given labeler
code that are reserved in accordance with Sec. 207.33(d)(3) or listed
in accordance with Sec. 207.49 or Sec. 207.53.
(4) An alternatively formatted NDC that is approved for use by the
relevant Center Director may be used for the following HCT/Ps if they
are minimally
[[Page 60217]]
manipulated: Hematopoietic stem/progenitor cells derived from
peripheral and cord blood, and lymphocytes collected from peripheral
blood.
(c) Who must obtain an NDC labeler code and how is the code
assigned and updated? (1) Each person who engages in manufacturing,
repacking, relabeling, or private label distribution of a drug subject
to listing under this part must apply for an NDC labeler code, by
providing the following information:
(i) The name, physical address, email address, and other contact
information FDA may request, of the person for whom the NDC labeler
code is requested;
(ii) The type(s) of activities (e.g., manufacture or repacking) in
which the person requesting the NDC labeler code engages with respect
to human drugs; and
(iii) The type(s) of drug(s) (human, animal, or both, and
prescription, nonprescription, or both) to which the NDC labeler code
will be applied.
(2) Each person who is assigned an NDC labeler code must update the
information submitted under paragraph (c)(1)of this section within 30
calendar days after any change to that information.
(d) How is an NDC proposed for assignment by FDA, when is an NDC
assigned by FDA, and how can a proposed NDC be reserved? (1) An NDC is
proposed for assignment by FDA when it is submitted for the first time
with listing information in accordance with Sec. 207.49 or Sec.
207.53, as applicable.
(i) Each manufacturer, repacker, or relabeler must propose for
assignment by FDA an NDC that includes its own labeler code for each
package size and type of drug that it manufactures, repacks, or
relabels for commercial distribution.
(ii) In addition, if a drug is distributed under the trade name or
label of a private label distributor, the manufacturer, repacker, or
relabeler must also propose for assignment by FDA an NDC that includes
the labeler code of the private label distributor under whose trade
name or label the drug is distributed, for each package size and type
so distributed.
(2) If a proposed NDC conforms to the requirements of this section
and is not reserved for a different drug or was not previously assigned
to a different drug, FDA will assign the NDC to a drug when it receives
listing information required for that drug under Sec. 207.49 or Sec.
207.53.
(3) A manufacturer, repacker, relabeler, or private label
distributor may voluntarily reserve a proposed NDC for a drug, before
the drug is listed, by submitting the following information:
(i) A proposed NDC that conforms to the requirements of this
section;
(ii) The established name of the active ingredient(s) and the
strength of each active ingredient in the drug; and
(iii) In the case of a finished drug product, the dosage form, and
route of administration.
(4) If the required information is submitted and the proposed NDC
is properly formatted and not already assigned or reserved, FDA will
reserve the proposed NDC for a period of 2 years from the date of
submission. If the drug for which the proposed NDC is reserved is not
listed in accordance with Sec. 207.49 or Sec. 207.53 during such 2-
year period, the reservation of the proposed NDC will lapse. FDA may
also cancel the reservation of a proposed NDC at any time on the
request of the person whose labeler code is included in the proposed
NDC.
(e) How must the information be submitted to us? The information
described in paragraphs (c) and (d) of this section must be submitted
electronically unless FDA grants a waiver under Sec. 207.65.
Sec. 207.35 What changes require a new NDC?
(a) Once an NDC has been assigned by FDA, the registrant must
propose a new and unique NDC for a drug when there is a change, after
the drug is initially marketed, to any of the information identified in
paragraphs (b) and (c) of this section. A new NDC must be proposed to
FDA for assignment through an updated listing in accordance with Sec.
207.57.
(b) The proposed new NDC must include a new product code when there
is a change to any of the following information:
(1) The drug's established name or proprietary name, if any;
(2) Any active pharmaceutical ingredient or the strength of any
active pharmaceutical ingredient;
(3) The dosage form;
(4) A change in the drug's status, between prescription and
nonprescription, or for animal drugs, between prescription,
nonprescription, or veterinary feed directive (VFD) status;
(5) A change in the drug's intended use between human and animal;
or
(6) The drug's distinguishing characteristics such as size, shape,
color, code imprint, flavor, and scoring (if any).
(c) When there is a change only to the package size or type,
including the immediate unit-of-use container, if any, the proposed new
NDC must include only a new package code and retain the existing
product code unless all available package codes have already been
combined with the existing product code in NDCs assigned by FDA.
Sec. 207.37 What restrictions pertain to the use of the NDC?
(a) A product may be deemed to be misbranded if an NDC is used:
(1) To represent a different drug than the drug for which the NDC
has been assigned, as described in Sec. 207.33;
(2) To denote or imply FDA approval of a drug; or
(3) On products that are not subject to parts 207, 607 of this
chapter, or 1271 of this chapter, such as dietary supplements and
medical devices.
(b) If marketing is resumed for a discontinued drug, and no changes
have been made to the drug that would require a new NDC under Sec.
207.35, the drug must have the same NDC that was assigned to it as
described in Sec. 207.33, before marketing was discontinued.
Subpart D--Listing
Sec. 207.41 Who must list drugs and what drugs must they list?
(a) Each registrant must list each drug that it manufactures,
repacks, relabels, or salvages for commercial distribution. Each
domestic registrant must list each such drug regardless of whether the
drug enters interstate commerce. When operations are conducted at more
than one establishment, and common ownership and control exists among
all the establishments, the parent, subsidiary, or affiliate company
may submit listing information for any drug manufactured, repacked,
relabeled, or salvaged at any such establishment. A drug manufactured,
repacked, or relabeled for private label distribution must be listed in
accordance with paragraph (c) of this section.
(b) Registrants must provide listing information for each drug in
accordance with the listing requirements described in Sec. Sec.
207.49, 207.53, and 207.54 that correspond to the activity or
activities they engage in for that drug.
(c)(1) For both animal and human drugs, each registrant must list
each drug it manufactures, repacks, or relabels for commercial
distribution under the trade name or label of a private label
distributor using an NDC that includes such private label distributor's
labeler code.
(2) Additionally, in the case of human drugs, each registrant must
list each human drug it manufactures, repacks, or relabels using an NDC
that includes the registrant's own labeler code, regardless of whether
the drug is commercially distributed under the registrant's own label
or trade name or under the label
[[Page 60218]]
or trade name of a private label distributor.
Sec. 207.45 When, after initial registration of an establishment,
must drug listing information be submitted?
For each drug being manufactured, repacked, relabeled, or salvaged
for commercial distribution at an establishment at the time of initial
registration, drug listing information must be submitted no later than
3 calendar days after the initial registration of the establishment.
Sec. 207.49 What listing information must a registrant submit for a
drug it manufactures?
(a) Each registrant must provide the following listing information
for each drug it manufactures for commercial distribution.
(1) The appropriate NDC(s), as described in Sec. 207.33, that
include all package code variations. In the case of human drugs, the
appropriate NDC(s) submitted under this paragraph include the
registrant's labeler code. In the case of animal drugs, the appropriate
NDC(s) submitted under this paragraph include the registrant's labeler
code, except that when the drug is manufactured for commercial
distribution under the trade name or label of a private label
distributor, the appropriate NDC(s) for animal drugs include the
private label distributor's labeler code;
(2) Package type and volume information corresponding to the
package code segment of the NDC;
(3) The listed drug's established name and proprietary name, if
any;
(4) The name and quantity of each active pharmaceutical ingredient
in the listed drug;
(5) The name of each inactive ingredient in the listed drug, along
with any assertions of confidentiality associated with individual
inactive ingredients;
(6) The dosage form;
(7) The drug's approved U.S. application number, if any;
(8) The drug type (e.g., as applicable, finished vs. unfinished,
human vs. animal, prescription vs. nonprescription);
(9) In the case of an unfinished drug, the number assigned to the
Drug Master File or Veterinary Master File, if any, that describes the
manufacture of the drug;
(10) For each drug that is subject to the imprinting requirements
of part 206 of this chapter including products that are exempted under
Sec. 206.7(b), the drug's size, shape, color, scoring, and code
imprint (if any);
(11) The route or routes of administration of the drug;
(12) For each drug bearing an NDC:
(i) The name and Unique Facility Identifier of the establishment
where the registrant who lists the drug manufactures it and the type of
operation performed on the drug at that establishment, and
(ii) The name and Unique Facility Identifier of every other
establishment where manufacturing is performed for the drug and the
type of operation performed at each such establishment. This includes
all establishments involved in the production of each unfinished drug
received by the registrant for use in the production of the drug being
listed. The names, Unique Facility Identifiers, and type of operations
for establishments involved in production of each unfinished drug
received by the registrant for use in the production of the drug being
listed may be provided by including the properly assigned and listed
NDC for such unfinished drug.
(13) The schedule of the drug under section 202 of the Controlled
Substances Act, if applicable;
(14) Advertisements:
(i) A representative sampling of advertisements for a human
prescription drug that is not subject to section 505 of the Federal
Food, Drug, and Cosmetic Act or section 351 of the Public Health
Service Act;
(ii) If FDA requests it, for good cause, a copy of all
advertisements for a human prescription drug that is not subject to
section 505 of the Federal Food, Drug, and Cosmetic Act or section 351
of the Public Health Service Act, including those advertisements
described in Sec. 202.1(l)(1) of this chapter. Such advertisements
must be submitted within 30 calendar days after FDA's request.
(15) For drugs bearing the NDC(s) reported under paragraph (a)(1)
of this section, except those drugs manufactured exclusively for
private label distribution and not distributed under the registrant's
own name and label, provide the following labeling, as applicable:
(i) Human prescription drugs. All current labeling except that only
one representative container or carton label need be submitted where
differences exist only in the quantity of contents statement or the bar
code. This labeling submission must include the content of labeling, as
defined in Sec. 207.1(b).
(ii) Human nonprescription drugs. (A) For each human
nonprescription drug subject to section 505 of the Federal Food, Drug,
and Cosmetic Act or section 351 of the Public Health Service Act, all
current labeling, except that only one representative container or
carton label need be submitted where differences exist only in the
quantity of contents statement or the bar code. This labeling
submission must include the content of labeling, as defined in Sec.
207.1(b).
(B) For each human nonprescription drug not subject to section 505
of the Federal Food, Drug, and Cosmetic Act or section 351 of the
Public Health Service Act, the current label (except that only one
representative container or carton label need be submitted where
differences exist only in the quantity of contents statement or the bar
code), the package insert (if any), and a representative sampling of
any other labeling. This labeling submission must include the content
of labeling as defined in section Sec. 207.1(b).
(iii) Animal drugs. (A) For each animal drug that is subject to
section 512 of the Federal Food, Drug, and Cosmetic Act, which
includes, but is not limited to, new animal drugs that have been
approved, conditionally approved, or indexed under sections 512, 571,
or 572 of the Federal Food, Drug, and Cosmetic Act, a copy of all
current labeling (except that only one representative container or
carton label need be submitted where differences exist only in the
quantity of contents statement), including the content of labeling as
defined in Sec. 207.1(b);
(B) For all other animal drugs, a copy of the current label (except
that only one representative container or carton label need be
submitted where differences exist only in the quantity of contents
statement), the package insert, the content of labeling as defined in
Sec. 207.1(b), and a representative sampling of any other labeling;
(iv) All other listed drugs. For all other listed drugs, including
unfinished drugs, the label (if any), except that only one
representative label need be submitted where differences exist only in
the quantity of contents statement.
(16) Listing submissions described in Sec. 207.41(c)(2) for human
drugs manufactured for private label distribution must include all
information specified in Sec. 207.49(a)(2) through (14) and:
(i) The appropriate NDC(s) (as described in Sec. 207.33) that
include the private label distributor's labeler code and all package
code variations;
(ii) The name, mailing address, telephone number, and email address
of the private label distributor; and
(iii) For drugs bearing the NDC(s) reported under paragraph
(a)(16)(i) of this section, labeling as described in paragraph (a)(15)
of this section that accompanies the private label distributor's
product.
[[Page 60219]]
(b) Additionally, each registrant is requested, but not required,
to provide the following information for each human drug it
manufactures for commercial distribution:
(1) The drug's over-the-counter monograph reference, if any; and
(2) The date on which the drug was or will be introduced into
commercial distribution.
Sec. 207.53 What listing information must a registrant submit for a
drug that it repacks or relabels?
Each registrant must provide the following listing information for
each drug it repacks or relabels:
(a) NDC. The appropriate NDC(s), as described in Sec. 207.33, that
include the registrant's labeler code and all package code variations;
(b) Source NDC. The NDC assigned to each finished drug received by
the registrant for repacking or relabeling, with the exception of
medical gases. Each such NDC must be associated with the corresponding
NDC(s) for repacked or relabeled drugs, reported under paragraph (a) of
this section.
(c) Name and Unique Facility Identifier. For each drug identified
by an NDC reported under paragraph (a) of this section, the name and
Unique Facility Identifier of every establishment where repacking or
relabeling is performed for the drug and the type of operation
(repacking vs. relabeling) performed at each such establishment.
(d) Labeling. For each drug identified by an NDC reported under
paragraph (a) of this section, except those human drugs repacked or
relabeled exclusively for private label distribution and not
distributed under the registrant's own name and label, provide the
following:
(1) Human prescription drugs. All current labeling for the repacked
or relabeled drug except that only one representative container or
carton label need be submitted where differences exist only in the
quantity of contents statement or the bar code. This labeling
submission must include the content of labeling, as defined in section
Sec. 207.1(b).
(2) Human nonprescription drugs. (i) For each human nonprescription
drug subject to section 505 of the Federal Food, Drug, and Cosmetic Act
or section 351 of the Public Health Service Act, all current labeling,
except that only one representative container or carton label need be
submitted where differences exist only in the quantity of contents
statement or the bar code. This labeling submission must include the
content of labeling, as defined in Sec. 207.1(b).
(ii) For each human nonprescription drug not subject to section 505
of the Federal Food, Drug, and Cosmetic Act or section 351 of the
Public Health Service Act, the current label (except that only one
representative container or carton label need be submitted where
differences exist only in the quantity of contents statement or the bar
code), the package insert (if any), and a representative sampling of
any other labeling. This labeling submission must include the content
of labeling as defined in Sec. 207.1(b).
(3) Animal drugs. (i) For each animal drug that is subject to
section 512 of the Federal Food, Drug, and Cosmetic Act, which includes
but is not limited to, new animal drugs that have been approved,
conditionally approved, or indexed under sections 512, 571, or 572 of
the Federal Food, Drug, and Cosmetic Act, a copy of all current
labeling (except that only one representative container or carton label
need be submitted where differences exist only in the quantity of
contents statement), including the content of labeling as defined in
Sec. 207.1(b);
(ii) For all other animal drugs, a copy of the current label
(except that only one representative container or carton label need be
submitted where differences exist only in the quantity of contents
statement), the package insert, the content of labeling as defined in
Sec. 207.1(b), and a representative sampling of any other labeling;
(4) All other. For all other listed drugs, including unfinished
drugs, the label (if any), except that only one representative label
need be submitted where differences exist only in the quantity of
contents statement.
(e) Advertisements. (1) A representative sampling of advertisements
for a human prescription drug that is not subject to section 505 of the
Federal Food, Drug, and Cosmetic Act or section 351 of the Public
Health Service Act;
(2) If we request it for good cause, a copy of all advertisements
for a particular drug described in paragraph (e)(1) of this section,
including advertisements described in Sec. 202.1(l)(1) of this
chapter. Such advertisements must be submitted within 30 calendar days
after our request.
(f) Private label distributor products. A listing submission for a
human drug distributed by a private label distributor described in
Sec. 207.41(c)(2) must include information specified in Sec.
207.53(b) through (e) as applicable and:
(1) The appropriate NDC(s) (as described in Sec. 207.33) that
include the private label distributor's labeler code and all package
code variations;
(2) The name, mailing address, telephone number, and email address
of the private label distributor; and
(3) For drugs bearing the NDC(s) reported under paragraph (f)(1) of
this section, labeling as described in paragraphs (d)(1) through (4) of
this section, as applicable, that accompanies the private label
distributor's product.
Sec. 207.54 What listing information must a registrant submit for a
drug that it salvages?
A registrant who also relabels or repacks a drug that it salvages
must list the drug it relabels or repacks in accordance with Sec.
207.53 rather than in accordance with this section. A registrant who
performs only salvaging with respect to a drug must provide the
following listing information for that drug.
(a) The NDC assigned to the drug immediately before the drug is
received by the registrant for salvaging;
(b) The lot number and expiration date of the salvaged drug
product; and
(c) The name and Unique Facility Identifier for each establishment
where the registrant salvages the drug.
Sec. 207.55 What additional drug listing information may FDA require?
For a particular listed drug, upon our request, the registrant must
briefly state the basis for its belief that the drug is not subject to
section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or
section 351 of the Public Health Service Act.
Sec. 207.57 What information must registrants submit when updating
listing information and when?
Registrants must review and update listing information at a
minimum, as follows:
(a) Registrants must provide listing information at the time of
annual establishment registration for any drug manufactured, repacked,
relabeled, or salvaged by them for commercial distribution that has not
been listed previously.
(b) Registrants must review and update their drug listing
information each June and December. When doing so, registrants must:
(1)(i) Provide listing information, in accordance with Sec. Sec.
207.49, 207.53, and 207.54, for any drug manufactured, repacked,
relabeled, or salvaged by them for commercial distribution that has not
been previously listed;
(ii) Submit the date that they discontinued the manufacture,
repacking, relabeling or salvaging for commercial distribution of a
listed drug and provide the expiration date of the
[[Page 60220]]
last lot manufactured, repacked, relabeled, or salvaged;
(iii) Submit the date that they resumed the manufacture, repacking,
or relabeling for commercial distribution of a drug previously
discontinued, and provide any required listing information not
previously submitted; and
(iv) Submit any material changes in any information previously
submitted pursuant to Sec. Sec. 207.49, 207.53, 207.54, or other
relevant sections of this part; or
(2) For each listed drug, certify that no changes subject to
reporting under paragraph (b)(1)(iv) of this section have occurred if
no such changes have occurred since the last review and update. If a
drug is discontinued and FDA has received the information required
under paragraph (b)(1)(ii) of this section, no further certifications
are necessary for the discontinued drug. After initial electronic
listing, registrants may satisfy the listing update requirement with
respect to unchanged listing information by making a single ``no
changes'' certification during the annual registration update under
Sec. 207.29(b) applicable to all of the registrant's listed drugs for
which no changes have been made since the previous annual registration
update.
(c) Registrants are encouraged to submit listing information for
every drug subject to listing under this part prior to commercial
distribution and are encouraged to update listing information at the
time of any change affecting information previously submitted.
Subpart E--Electronic Format for Registration and Listing
Sec. 207.61 How is registration and listing information provided to
FDA?
(a) Electronic format. (1) Except as provided in Sec. 207.65, all
information submitted under this part must be transmitted to FDA in
electronic format by using our electronic drug registration and listing
system, in a form that we can process, review, and archive. We may
periodically issue guidance on how to provide registration and listing
information in electronic format (specifying for example method of
transmission, media, file formats, preparation, and organization of
files).
(2) Information provided in electronic format must comply with part
11 of this chapter, except as follows:
(i) Advertisements and labeling, including the content of labeling,
required under this part are exempt from the requirements in Sec.
11.10(a), (c) through (h), and (k) of this chapter and the
corresponding requirements in Sec. 11.30 of this chapter.
(ii) All other information submitted under this part is exempt from
the requirements in Sec. 11.10(b), (c), and (e) of this chapter and
the corresponding requirements in Sec. 11.30 of this chapter.
(b) English language. Drug establishment registration and drug
listing information must be provided in the English language. The
content of labeling must be provided at a minimum in the English
language. Where Sec. 201.15(c) of this chapter permits product
labeling solely in a foreign language, the content of labeling must be
submitted in that language along with an accurate English translation.
Sec. 207.65 How can a waiver of the electronic submission requirement
be obtained?
(a) All information submitted under this part must be transmitted
to FDA electronically in accordance with Sec. 207.61(a) unless FDA has
granted a request for waiver of this requirement prior to the date on
which submission of such information is due. Submission of a request
for waiver does not excuse timely compliance with the registration and
listing requirements. FDA will grant a waiver request if FDA determines
that the use of electronic means for submission of registration and
listing information is not reasonable for the registrant making the
waiver request.
(b) Waiver requests under this section must be submitted in writing
and must include the specific reasons why electronic submission is not
reasonable for the registrant and a U.S. telephone number and mailing
address where FDA can contact the registrant. All waiver requests must
be sent to: SPL Coordinator, U.S. Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 32, Silver Spring, MD 20993.
(c) If FDA grants the waiver request, FDA may limit its duration
and will specify terms of the waiver and provide information on how to
submit establishment registration, drug listings, other information,
and updates, as applicable.
Subpart F--Miscellaneous
Sec. 207.69 What are the requirements for an official contact and a
United States agent?
(a) Official contact. Registrants subject to the registration
requirements of this part must designate an official contact for each
establishment. The official contact is responsible for:
(1) Ensuring the accuracy of registration and listing information;
and
(2) Reviewing, disseminating, routing, and responding to all
communications from FDA including emergency communications.
(b) United States agent. Registrants of foreign establishments
subject to this part must designate a single United States agent. The
United States agent must reside or maintain a place of business in the
United States and may not be a mailbox, answering machine or service,
or other place where a person acting as the United States agent is not
physically present. The United States agent is responsible for:
(1) Reviewing, disseminating, routing, and responding to all
communications from FDA including emergency communications;
(2) Responding to questions concerning those drugs that are
imported or offered for import to the United States;
(3) Assisting FDA in scheduling inspections; and
(4) If FDA is unable to contact a foreign registrant directly or
expeditiously, FDA may provide the information and/or documents to the
United States agent. FDA's providing information and/or documents to
the United States agent is equivalent to providing the same information
and/or documents to the foreign registrant.
Sec. 207.77 What legal status is conferred by registration and
listing?
(a) Registration of an establishment or listing of a drug does not
denote approval of the establishment, the drug, or other drugs of the
establishment, nor does it mean that a product may be legally marketed.
Any representation that creates an impression of official approval or
that a drug is approved or is legally marketable because of
registration or listing is misleading and constitutes misbranding.
(b) FDA's acceptance of registration and listing information,
inclusion of a drug in our database of drugs, or assignment of an NDC
does not denote approval of the establishment or the drug or any other
drugs of the establishment, nor does it mean that the drug may be
legally marketed. Any representation that creates the impression that a
drug is approved or is legally marketable because it appears in our
database of drugs, has been assigned or displays an NDC, or the
establishment has been assigned an establishment registration number or
Unique Facility Identifier is misleading and constitutes misbranding.
Failure to comply with Sec. 207.37 may also constitute misbranding.
(c) Neither registration nor listing constitutes a determination by
FDA that a product is a drug as defined by section 201(g)(1) of the
Federal Food, Drug, and Cosmetic Act. Registration or listing may,
however, be evidence that a
[[Page 60221]]
facility intends to or does manufacture, repack, relabel, distribute,
or salvage drugs or that a product is intended to be a drug.
Sec. 207.81 What registration and listing information will FDA make
available for public disclosure?
(a) Except as provided in paragraphs (b) and (c) of this section,
the following information will be available for public disclosure, upon
request or at FDA's discretion:
(1) All establishment registration information, and
(2) After a drug is marketed, information obtained under Sec.
207.33, Sec. 207.49, Sec. 207.53, Sec. 207.54, or Sec. 207.57.
(b) Unless such information is publicly available or FDA finds that
confidentiality would be inconsistent with protection of the public
health, FDA will not make publicly available:
(1) Any information submitted under Sec. 207.55 as the basis upon
which it has been determined that a particular drug is not subject to
section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or
section 351 of the Public Health Service Act,
(2) The names of any inactive ingredients submitted under Sec.
207.49(a)(4) for which the registrant makes a valid assertion of
confidentiality under Sec. 20.61 of this chapter or other provision of
law, or
(3) Drug listing information obtained under Sec. 207.33(d)(3),
Sec. 207.49(a)(9) and (12), Sec. 207.53(b) and (c), or Sec.
207.54(a) or (c).
(c) FDA may determine, in limited circumstances and on a case-by-
case basis, that it would be consistent with the protection of the
public health and the Freedom of Information Act to exempt from public
disclosure specific information identified in paragraph (a) of this
section.
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
0
9. The authority citation for part 314 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a,
356b, 356c, 356e, 371, 374, 379e, 379k-1.
0
10. In Sec. 314.81, revise paragraph (b)(3)(iv) to read as follows:
Sec. 314.81 Other postmarketing reports.
* * * * *
(b) * * *
(3) * * *
(iv) Withdrawal of approved drug product from sale. (a) Within 30
calendar days of the withdrawal of an approved drug from sale,
applicants who are manufacturers, repackers, or relabelers subject to
part 207 of this chapter must submit the following information about
the drug, in accordance with the applicable requirements described in
Sec. Sec. 207.61 and 207.65:
(1) The National Drug Code (NDC);
(2) The identity of the drug by established name and by proprietary
name, if any;
(3) The new drug application number or abbreviated application
number;
(4) The date on which the drug is expected to be no longer in
commercial distribution. FDA requests that the reason for withdrawal of
the drug from sale be included with the information.
(b) Within 30 calendar days of the withdrawal of an approved drug
from sale, applicants who are not subject to part 207 of this chapter
must submit the information listed in paragraphs (b)(3)(iv)(a)(1)
through (4) of this section. The information must be submitted either
electronically or in writing to the Drug Registration and Listing
Office, Food and Drug Administration, Center for Drug Evaluation and
Research.
(c) Reporting under paragraph (b)(3)(iv)(a) of this section
constitutes compliance with the requirements of Sec. 207.57 of this
chapter to update drug listing information with respect to the
withdrawal from sale.
* * * * *
Sec. 314.125 [Amended]
0
11. Amend Sec. 314.125 in paragraph (b)(11) by removing the words ``or
processed''.
PART 514--NEW ANIMAL DRUG APPLICATIONS
0
12. The authority citation for part 514 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b,
360ccc, 371, 379e, 381.
0
13. In Sec. 514.111 add paragraph (a)(12) to read as follows:
Sec. 514.111 Refusal to approve an application.
(a) * * *
(12) The drug will be produced in whole or in part in an
establishment that is not registered and not exempt from registration
under section 510 of the Federal Food, Drug, and Cosmetic Act and part
207 of this chapter.
* * * * *
PART 515--MEDICATED FEED MILL LICENSE
0
14. The authority citation for part 515 continues to read as follows:
Authority: 21 U.S.C. 360b, 371.
Sec. 515.10 [Amended]
0
15. In Sec. 515.10(b)(8), remove the phrase ``Sec. Sec. 207.20 and
207.21'' and add in its place the phrase ``part 207''.
PART 601--LICENSING
0
16. The authority citation for part 601 continues to read as follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C.
216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322
(21 U.S.C. 355 note).
0
17. In Sec. 601.2, add paragraph (f) to read as follows:
Sec. 601.2 Applications for biologics licenses; procedures for
filing.
* * * * *
(f) Withdrawal from sale of approved biological products. A holder
of a biologics license application (BLA) must report to FDA, in
accordance with the requirements of Sec. Sec. 207.61 and 207.65, the
withdrawal from sale of an approved biological product. The information
must be submitted to FDA within 30 working days of the biological
product's withdrawal from sale. The following information must be
submitted: The holder's name; product name; BLA number; the National
Drug Code; and the date on which the product is expected to be no
longer in commercial distribution. The reason for the withdrawal of the
biological product is requested but not required to be submitted.
PART 607--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR
MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS AND LICENSED
DEVICES
0
18. The authority citation for part 607 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374,
381, 393; 42 U.S.C. 262, 264, 271.
0
19. Revise the heading for part 607 to read as set forth above.
0
20. Add Sec. 607.1 to subpart A to read as follows:
Sec. 607.1 Scope.
(a) This part establishes establishment registration and product
listing requirements for manufacturers of human blood and blood
products.
(b) This part establishes establishment registration and product
listing requirements for manufacturers of products that meet the
definition of a device under the Federal Food, Drug, and Cosmetic Act
and that are licensed under section 351 of the Public Health
[[Page 60222]]
Service Act, as well as licensed biological products used in the
manufacture of a licensed device.
0
21. In Sec. 607.3 revise the second sentence in paragraph (b) and add
paragraphs (k) and (l) to read as follows:
Sec. 607.3 Definitions.
* * * * *
(b) * * * For the purposes of this part only, blood and blood
product also means those products that meet the definition of a device
under the Federal Food, Drug, and Cosmetic Act and that are licensed
under section 351 of the Public Health Service Act, as well as licensed
biological products used in the manufacture of a licensed device.
* * * * *
(k) Importer means a person in the United States that is an owner,
consignee, or recipient, at the time of entry, of a foreign
establishment's blood product that is imported into the United States.
(l) Foreign for the purpose of registration and listing under this
part when used to modify the term ``establishment'' refers to an
establishment that is located in a foreign country and is the site
where a blood product that is imported or offered for import into the
United States was manufactured.
0
22. Revise Sec. 607.7 to read as follows:
Sec. 607.7 Establishment registration and product listing of blood
banks and other firms manufacturing human blood and blood products.
All owners or operators of establishments that engage in the
manufacturing of blood products are required to register, pursuant to
section 510 of the Federal Food, Drug, and Cosmetic Act. Registration
and listing of blood products must comply with this part. Registration
does not permit any blood bank or similar establishment to ship blood
products in interstate commerce.
0
23. In Sec. 607.20 revise the first sentence in paragraph (c) to read
as follows:
Sec. 607.20 Who must register and submit a blood product list.
* * * * *
(c) Except in the case of licensed device manufacturers, no
registration fee is required. * * *
0
24. In Sec. 607.21 revise the last sentence to read as follows:
Sec. 607.21 Times for establishment registration and blood product
listing.
* * * Owners or operators of all establishments so engaged must
register annually between October 1 and December 31 and must update
their blood product listing every June and December.
0
25. Revise Sec. 607.22 to read as follows:
Sec. 607.22 How to register establishments and list blood products.
(a) Initial and subsequent registrations and product listings must
be submitted electronically through the Blood Establishment
Registration and Product Listing system, or any future superseding
electronic system. This information must be submitted in accordance
with part 11 of this chapter, except for the requirements in Sec.
11.10(b), (c), and (e), and the corresponding requirements in Sec.
11.30. All information submitted under this part must be transmitted to
FDA electronically unless FDA has granted a request for waiver of this
requirement prior to the date on which the information is due.
Submission of a request for waiver does not excuse timely compliance
with the registration and listing requirements. FDA will grant a waiver
request if FDA determines that the use of electronic means for
submission of registration and listing information is not reasonable
for the registrant making the waiver request.
(b) Waiver requests under this section must be submitted in writing
and must include the specific reasons why electronic submission is not
reasonable for the registrant and a U.S. telephone number and mailing
address where FDA can contact the registrant. All waiver requests must
be sent to the Director of FDA's Center for Biologics Evaluation and
Research through the Document Control Center (see addresses in Sec.
600.2).
(c) If FDA grants the waiver request, FDA may limit its duration
and will specify terms of the waiver and provide information on how to
submit establishment registration, drug listings, other information,
and updates, as applicable.
0
26. Revise Sec. 607.25 to read as follows:
Sec. 607.25 Information required for establishment registration and
blood product listing.
(a) The Blood Establishment Registration and Product Listing system
requires furnishing or confirming registration information required by
the Federal Food, Drug, and Cosmetic Act. This information includes the
name and street address of the establishment, including post office
code; a registration number if previously assigned by FDA and a Unique
Facility Identifier in accordance with the system specified under
section 510 of the Federal Food, Drug, and Cosmetic Act; all trade
names used by the establishment; the kind of ownership or operation
(that is, individually owned partnership, or corporation); and the name
of the owner or operator of such establishment. The term ``name of the
owner or operator'' must include, in the case of a partnership, the
name of each partner and, in the case of a corporation, the name and
title of each corporate officer and director and the name of the State
of incorporation. The information required must be given separately for
each establishment, as defined in Sec. 607.3(c).
(b) The following information must also be provided:
(1) A list of blood products by established name as defined in
section 502(e) of the Federal Food, Drug, and Cosmetic Act and by
proprietary name, if any, which are being manufactured for commercial
distribution at the identified establishment and which have not been
included in any list previously submitted to FDA through the Blood
Establishment Registration and Product Listing system or any future
superseding electronic system.
(2) For each blood product so listed that is subject to section 351
of the Public Health Service Act, the license number of the
manufacturer issued by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
(3) For each blood product listed, the registration number if
previously assigned by FDA and the Unique Facility Identifier of the
parent establishment. An establishment not owned, operated, or
controlled by another firm or establishment is its own parent
establishment.
0
27. In Sec. 607.26 revise the first sentence to read as follows:
Sec. 607.26 Amendments to establishment registration.
Changes in individual ownership, corporate or partnership
structure, location, or blood product handling activity must be
submitted electronically through the Blood Establishment Registration
and Product Listing system, or any future superseding electronic
system, as an amendment to registration within 5 calendar days of such
changes. * * *
0
28. In Sec. 607.30 revise the introductory text of paragraph (a) to
read as follows:
Sec. 607.30 Updating blood product listing information.
(a) After submission of the initial blood product listing
information, every person who is required to list blood products under
Sec. 607.20 must submit electronically through the Blood Establishment
Registration and Product
[[Page 60223]]
Listing system, or any future superseding electronic system, at a
minimum once in June and December of every year, the following
information:
* * * * *
0
29. Revise Sec. 607.35 to read as follows:
Sec. 607.35 Blood product establishment registration number.
An establishment registration number will be assigned to each blood
product establishment registered in accordance with this part.
0
30. Revise Sec. 607.37 to read as follows:
Sec. 607.37 Public disclosure of establishment registration and blood
product listing information.
(a) Except as provided in paragraph (b) of this section, all
registration and listing information obtained under Sec. Sec. 607.25,
607.26, and 607.30 will be made available for public disclosure through
the Center for Biologics Evaluation and Research (CBER) Blood
Establishment Registration Database Web site by using the CBER
electronic Web-based application or by going in person to the Food and
Drug Administration, Division of Freedom of Information Public Reading
Room (see addresses in Sec. 20.120(a) of this chapter).
(b) FDA may find, in limited circumstances and on a case-by-case
basis, that it would be consistent with the protection of the public
health to exempt from public disclosure specific listing information
obtained under Sec. 607.25 or Sec. 607.30.
(c) Other requests for information regarding blood establishment
registrations and blood product listings should be directed to the Food
and Drug Administration, Center for Biologics Evaluation and Research
Office of Communication, Outreach, and Development, 10903 New Hampshire
Ave., Bldg. 71, Rm. 3103, Silver Spring, MD 20993-0002.
0
31. Revise Sec. 607.39 to read as follows:
Sec. 607.39 Misbranding by reference to establishment registration,
validation of registration, or to registration number.
Registration of an establishment, validation of registration, or
assignment of a registration number does not in any way denote approval
of the firm or its products nor does it mean that the products may be
legally marketed. Any representation that creates an impression of
official approval because of establishment registration, validation of
registration, or possession of a registration number is misleading and
constitutes misbranding.
0
32. In Sec. 607.40 revise paragraphs (d) introductory text and (d)(3)
and add paragraph (e) to read as follows:
Sec. 607.40 Establishment registration and blood product listing
requirements for foreign blood product establishments.
* * * * *
(d) Each foreign establishment required to register under paragraph
(a) of this section must submit the name, address, telephone number,
and email address of its United States agent as part of its initial and
updated registration information in accordance with subpart B of this
part. Each foreign establishment must designate only one United States
agent.
* * * * *
(3) The foreign establishment or the United States agent must
report changes in the United States agent's name, address, telephone
number, or email address to FDA within 30 calendar days of the change.
(e) Each foreign establishment required to register under paragraph
(a) of this section must register and list blood products using the
Blood Establishment Registration and Product Listing system, or any
superseding electronic system, unless FDA waives the electronic
submission requirement in accordance with Sec. 607.22.
0
33. In Sec. 607.65 add paragraph (g) to read as follows:
Sec. 607.65 Exemptions for blood product establishments.
* * * * *
(g) Persons who engage solely in the production of any plasma
derivative, including, but not limited to, albumin, Immune Globulin,
Factor VIII and Factor IX, bulk product substances such as
fractionation intermediates or pastes, or recombinant versions of
plasma derivatives or animal derived plasma derivatives. These persons
must register and list under part 207 of this chapter.
0
34. Add subpart E, consisting of Sec. 607.80, to part 607 to read as
follows:
Subpart E--Establishment Registration and Product Listing Of
Licensed Devices
Sec. 607.80 Applicability of part 607 to licensed devices.
Manufacturers of products that meet the definition of a device
under the Federal Food, Drug, and Cosmetic Act and that are licensed
under section 351 of the Public Health Service Act, as well as licensed
biological products used in the manufacture of a licensed device, must
register and list following the procedures under this part, with
respect to their manufacture of those products, unless otherwise noted
in this section.
PART 1271--HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED
PRODUCTS
0
35. The authority citation for part 1271 continues to read as follows:
Authority: 42 U.S.C. 216, 243, 263a, 264, 271.
Sec. 1271.1 [Amended]
0
36. Amend Sec. 1271.1 in paragraphs (a) and (b)(2) by removing
``207.20(f)'' and adding in its place ``207.9(a)(5)''; in paragraph (a)
by removing the term ``a unified'' and adding in its place the term
``an electronic''; and in paragraph (b)(2) by removing the phrase ``in
subpart B of this part'' and adding in its place the phrase ``in part
207 (if a drug and/or biological product) of this chapter or part 807
(if a device) of this chapter''.
0
37. In Sec. 1271.3 add paragraphs (mm) and (nn) to read as follows:
Sec. 1271.3 How does FDA define important terms in this part?
* * * * *
(mm) Importer means a company or individual in the United States
that is the owner, consignee, or recipient, at the time of entry, of
the foreign establishment's HCT/P that is imported into the United
States.
(nn) United States agent means a person residing or maintaining a
place of business in the United States whom a foreign establishment
designates as its agent. This definition excludes mailboxes, answering
machines or services, or other places where an individual acting as the
foreign establishment's agent is not physically present.
Sec. 1271.20 [Amended]
0
38. Amend Sec. 1271.20 by removing ``207.20(f)'' and adding in its
place ``207.9(a)(5)'' and by removing the phrase ``subparts B, C, and D
of this part'' and adding in its place ``subparts C and D of this
part''.
0
39. Revise Sec. 1271.22 to read as follows:
Sec. 1271.22 How do I register and submit an HCT/P list?
(a) You must use the electronic registration and listing system at
https://www.fda.gov/cber/tissue/tisreg.htm in accordance with Sec.
1271.25 for:
(1) Establishment registration,
(2) HCT/P listings, and
(3) Updates of registration and HCT/P listing.
(b) FDA will periodically issue guidance on recommended procedures
for providing registration and listing information in electronic format
(for
[[Page 60224]]
example, method of transmission, media, file formats, preparation, and
organization of files).
(c) You must provide the information under paragraph (a) of this
section in accordance with part 11 of this chapter, except for the
requirements in Sec. 11.10(b), (c), and (e) and the corresponding
requirements in Sec. 11.30.
0
40. Add Sec. 1271.23 to subpart B to read as follows:
Sec. 1271.23 How is a waiver from the electronic format requirements
requested?
(a) You may request a waiver from the requirement in Sec. 1271.22
that information must be provided to FDA in electronic format.
Submission of a request for waiver does not excuse timely compliance
with the registration and listing requirements. FDA will grant a waiver
request if FDA determines that the use of electronic means for
submission of registration and listing information is not reasonable
for the registrant making the waiver request.
(b) Waiver requests under this section must be submitted in writing
and must include the specific reasons why electronic submission is not
reasonable for the registrant and a U.S. telephone number and mailing
address where FDA can contact the registrant. Waiver requests may be
sent to the Center for Biologics Evaluation and Research (CBER),
Document Control Center (see addresses in Sec. 600.2 of this chapter).
(c) If FDA grants the waiver request, FDA may limit its duration
and will specify terms of the waiver and provide information on how to
submit establishment registration, listings, other information, and
updates, as applicable.
0
41. In Sec. 1271.25 revise paragraphs (a) introductory text and (a)(2)
and (3), add paragraphs (a)(5) and (6), revise paragraph (c)(4), and
add paragraph (d) to read as follows:
Sec. 1271.25 What information is required for establishment
registration and HCT/P listing?
(a) Your establishment registration must include:
* * * * *
(2) Each physical location, including the street address, telephone
number, email address, and the postal service ZIP code of the
establishment;
(3) The name, address, telephone number, email address, and title
of the reporting official;
* * * * *
(5) Each foreign establishment must also submit the name, address,
telephone number, and email address of each importer that is known to
the establishment, and the name of each person who imports or offers
for import such HCT/P to the United States for purposes of importation;
and
(6) Each foreign establishment must also submit the name, address,
telephone number, and email address of its United States agent.
(i) The United States agent must reside or maintain a place of
business in the United States.
(ii) Upon request from FDA, the United States agent must assist FDA
in communications with the foreign establishment, respond to questions
concerning the foreign establishment's products that are imported or
offered for import into the United States, and assist FDA in scheduling
inspections of the foreign establishment. If the Agency is unable to
contact the foreign establishment directly or expeditiously, FDA may
provide information or documents to the United States agent, and such
an action is equivalent to providing the same information or documents
to the foreign establishment.
(iii) The foreign establishment or the United States agent must
report changes in the United States agent's name, address, telephone
number, or email address to FDA within 30 calendar days of the change.
* * * * *
(c) * * *
(4) Any material change in any information previously submitted.
Material changes include any change in registration and listing
information, submitted, such as whether the HCT/P meets the criteria
set out in Sec. 1271.10.
(d) If your HCT/P is described under Sec. 1271.20 and is regulated
under a BLA, you must submit the information required under part 207 of
this chapter using the procedures under subpart E of part 207.
0
42. Revise Sec. 1271.26 to read as follows:
Sec. 1271.26 When must I amend my establishment registration?
If the ownership or location of your establishment changes, or if
there is a change in the United States agent's name, address, telephone
number, or email address, you must submit an amendment to registration
within 30 calendar days of the change.
Dated: August 22, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-20471 Filed 8-30-16; 8:45 am]
BILLING CODE 4164-01-P