Current Good Manufacturing Practice-Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act; Draft Guidance for Industry; Availability, 63651-63656 [2018-26724]
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Dated: December 4, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018–26725 Filed 12–10–18; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2014–D–0779]
Current Good Manufacturing
Practice—Guidance for Human Drug
Compounding Outsourcing Facilities
Under Section 503B of the FD&C Act;
Draft Guidance for Industry;
Availability
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice of availability.
The Food and Drug
Administration (FDA or the Agency) is
announcing the availability of a revised
draft guidance entitled ‘‘Current Good
Manufacturing Practice—Guidance for
Human Drug Compounding Outsourcing
Facilities Under Section 503B of the
FD&C Act.’’ This revised draft guidance
describes FDA’s policies regarding
compounders registered under section
503B of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) as outsourcing
facilities and the current good
manufacturing practice (CGMP)
requirements in FDA regulations. Based
on feedback from stakeholders and
comments received on the initial draft
guidance, the guidance is being revised,
in part, to reflect further consideration
of how CGMP requirements should be
applied in light of the size and scope of
an outsourcing facility’s operations.
DATES: Submit either electronic or
written comments on the revised draft
guidance by February 11, 2019 to ensure
that the Agency considers your
comment on this draft guidance before
it begins work on the final version of the
guidance. Submit either electronic or
written comments concerning the
collection of information under the
Paperwork Reduction Act of 1995 (PRA)
proposed in the revised draft guidance
by February 11, 2019.
ADDRESSES: You may submit comments
on any guidance at any time as follows:
SUMMARY:
Electronic Submissions
Submit electronic comments in the
following way:
• Federal eRulemaking Portal:
https://www.regulations.gov. Follow the
instructions for submitting comments.
Comments submitted electronically,
including attachments, to https://
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www.regulations.gov will be posted to
the docket unchanged. Because your
comment will be made public, you are
solely responsible for ensuring that your
comment does not include any
confidential information that you or a
third party may not wish to be posted,
such as medical information, your or
anyone else’s Social Security number, or
confidential business information, such
as a manufacturing process. Please note
that if you include your name, contact
information, or other information that
identifies you in the body of your
comments, that information will be
posted on https://www.regulations.gov.
• If you want to submit a comment
with confidential information that you
do not wish to be made available to the
public, submit the comment as a
written/paper submission and in the
manner detailed (see ‘‘Written/Paper
Submissions’’ and ‘‘Instructions’’).
Written/Paper Submissions
Submit written/paper submissions as
follows:
• Mail/Hand Delivery/Courier (for
written/paper submissions): Dockets
Management Staff (HFA–305), Food and
Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments
submitted to the Dockets Management
Staff, FDA will post your comment, as
well as any attachments, except for
information submitted, marked and
identified, as confidential, if submitted
as detailed in ‘‘Instructions.’’
Instructions: All submissions received
must include the Docket No. FDA–
2014–D–0779 for ‘‘Current Good
Manufacturing Practice—Guidance for
Human Drug Compounding Outsourcing
Facilities Under Section 503B of the
FD&C Act.’’ Received comments will be
placed in the docket and, except for
those submitted as ‘‘Confidential
Submissions,’’ publicly viewable at
https://www.regulations.gov or at the
Dockets Management Staff between 9
a.m. and 4 p.m., Monday through
Friday.
• Confidential Submissions—To
submit a comment with confidential
information that you do not wish to be
made publicly available, submit your
comments only as a written/paper
submission. You should submit two
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with a heading or cover note that states
‘‘THIS DOCUMENT CONTAINS
CONFIDENTIAL INFORMATION.’’ The
Agency will review this copy, including
the claimed confidential information, in
its consideration of comments. The
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claimed confidential information
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redacted/blacked out, will be available
for public viewing and posted on
https://www.regulations.gov. Submit
both copies to the Dockets Management
Staff. If you do not wish your name and
contact information to be made publicly
available, you can provide this
information on the cover sheet and not
in the body of your comments and you
must identify this information as
‘‘confidential.’’ Any information marked
as ‘‘confidential’’ will not be disclosed
except in accordance with 21 CFR 10.20
and other applicable disclosure law. For
more information about FDA’s posting
of comments to public dockets, see 80
FR 56469, September 18, 2015, or access
the information at: https://www.gpo.gov/
fdsys/pkg/FR-2015-09-18/pdf/201523389.pdf.
Docket: For access to the docket to
read background documents or the
electronic and written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852.
Submit comments on information
collection issues under the PRA to the
Office of Management and Budget
(OMB) in the following ways:
• Fax to the Office of Information and
Regulatory Affairs, OMB, Attn: FDA
Desk Officer, Fax: 202–395–7285, or
email to oira_submission@omb.eop.gov.
All comments should be identified with
the title ‘‘Current Good Manufacturing
Practice—Guidance for Human Drug
Compounding Outsourcing Facilities
Under Section 503B of the FD&C Act.’’
You may submit comments on any
guidance at any time (see 21 CFR
10.115(g)(5)).
Submit written requests for single
copies of the draft guidance to the
Division of Drug Information, Center for
Drug Evaluation and Research, Food
and Drug Administration, 10001 New
Hampshire Ave., Hillandale Building,
4th Floor, Silver Spring, MD 20993–
0002. Send one self-addressed adhesive
label to assist that office in processing
your requests. See the SUPPLEMENTARY
INFORMATION section for electronic
access to the draft guidance document.
FOR FURTHER INFORMATION CONTACT:
Marci Kiester, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 2258,
Silver Spring, MD 20993–0002, 301–
796–0600.
SUPPLEMENTARY INFORMATION:
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I. Background
FDA is announcing the availability of
a revised draft guidance for industry
entitled ‘‘Current Good Manufacturing
Practice—Guidance for Human Drug
Compounding Outsourcing Facilities
Under Section 503B of the FD&C Act.’’
Under section 503B(b) of the FD&C Act
(21 U.S.C. 353b(b)), a compounder can
register as an outsourcing facility with
FDA. Drug products compounded in an
outsourcing facility can qualify for
exemptions from FDA approval
requirements in section 505 of the FD&C
Act (21 U.S.C. 355), the requirement to
label products with adequate directions
for use under section 502(f)(1) of the
FD&C Act (21 U.S.C. 352(f)(1)), and the
drug supply chain security requirements
in section 582 of the FD&C Act (21
U.S.C. 360eee–1), if the requirements in
section 503B are met. Outsourcing
facilities are inspected by FDA
according to a risk-based schedule and
must comply with other provisions of
the FD&C Act, including CGMP
requirements under section 501(a)(2)(B)
(21 U.S.C. 351(a)(2)(B)). FDA intends to
issue CGMP regulations specific to
outsourcing facilities. Until final
regulations are issued, this draft
guidance describes FDA’s policies
regarding outsourcing facilities and the
CGMP requirements in 21 CFR parts 210
and 211.
This draft guidance revises the draft
guidance for industry entitled ‘‘Current
Good Manufacturing Practice—Interim
Guidance for Human Drug
Compounding Outsourcing Facilities
Under Section 503B of the FD&C Act,’’
which published in July 2014 (79 FR
37743). This revised draft guidance
applies to drugs compounded in
accordance with section 503B. In
addition, this guidance generally
applies to drugs that outsourcing
facilities repackage and biological
products that outsourcing facilities mix,
dilute, or repackage in accordance with
relevant guidance for outsourcing
facilities. This revised draft guidance
reflects FDA’s intent to recognize the
differences between outsourcing
facilities and conventional drug
manufacturers and to tailor CGMP
requirements to the nature of the
specific compounding operations
conducted by outsourcing facilities
while maintaining the minimum
standards necessary to protect patients
from the risks of contaminated or
otherwise substandard drug products.
The comment period on the initial
draft guidance ended on September 2,
2014. FDA received 26 comments on the
draft guidance. In response to received
comments or on its own initiative, FDA
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made changes and updates in the
revised draft guidance as follows.
FDA received a number of comments
regarding the requirements in FDA
regulations applicable to nonsterile drug
products because the draft guidance
focused primarily on sterile
compounding. To address these
comments, the revised draft guidance
differentiates between requirements
applicable to sterile drug products and
nonsterile drug products where
appropriate. The revised draft guidance
also distinguishes the risks presented by
using sterile and nonsterile components
in producing sterile drug products and
offers recommendations and policies on
quality control commensurate with the
risk. Further, the revised draft guidance
addresses concerns raised regarding
FDA’s policies in several other areas.
FDA made significant revisions to
address comments on (1) stability
testing, including the assignment of a
beyond use date (BUD) as an expiration
date; (2) release testing; (3) the potential
use of a drug master file to address
contract laboratory testing arrangements
and testing of component quality before
use in compounding; (4) the use of
accredited third-party laboratories to
perform testing; (5) a clear definition of
‘‘in-use time,’’ distinguishing it from
‘‘BUD’’ and ‘‘expiration date’’; and (6)
reserve samples.
We note that the default BUDs and
storage conditions associated with
nonsterile drug products described in
this revised draft guidance differ from
those described for nonsterile
repackaged drug products in FDA’s
guidance for industry entitled
‘‘Repackaging of Certain Human Drug
Products by Pharmacies and
Outsourcing Facilities’’ (Repackaging
guidance). FDA believes that the BUDs
described in this revised draft CGMP
guidance are also relevant to nonsterile
drug products repackaged by
outsourcing facilities. When this
guidance is finalized, we intend to make
conforming revisions to the BUDs for
repackaged nonsterile drug products in
the Repackaging guidance, as
appropriate.
Finally, this revised draft contains
revisions to the conditions under which
the Agency generally would not intend
to take regulatory action regarding the
requirement to test the finished product
before release (see § 211.165 (21 CFR
211.165)). These revisions make a
broader range of production volumes
eligible for the relevant enforcement
policy, which we believe would
encourage additional compounders to
register as outsourcing facilities.
Compared to compounders that are not
registered under section 503B of the
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FD&C Act, outsourcing facilities are
subject to increased Federal oversight
through FDA inspection on a risk-based
schedule, as well as to additional
standards that help to assure the quality
of their compounded drug products.
Outsourcing facilities produce drug
products for hospitals, clinics, or
healthcare practitioners to keep on hand
as ‘‘office stock’’ for patients who
present with an immediate need for
them. The revised draft guidance
addresses standards critical to reducing
the risk of patient harm while balancing
appropriate flexibility. FDA is seeking
public comment on whether the
conditions outlined in the revised draft
appropriately balance the risks and
needs associated with drugs produced
for office stock, including comments on
the production volumes specified in the
guidance.
This revised draft guidance is being
issued consistent with FDA’s good
guidance practices regulation (21 CFR
10.115). The draft guidance, when
finalized, will represent the current
thinking of FDA on ‘‘Current Good
Manufacturing Practice—Guidance for
Human Drug Compounding Outsourcing
Facilities Under Section 503B of the
FD&C Act.’’ It does not establish any
rights for any person and is not binding
on FDA or the public. You can use an
alternative approach if it satisfies the
requirements of the applicable statutes
and regulations. This guidance is not
subject to Executive Order 12866.
II. Paperwork Reduction Act of 1995
Under the PRA (44 U.S.C. 3501–
3520), Federal Agencies must obtain
approval from OMB for each collection
of information that they conduct or
sponsor. ‘‘Collection of Information’’ is
defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes Agency requests
or requirements that members of the
public submit reports, keep records, or
provide information to a third party.
Section 3506(c)(2)(A) of the PRA (44
U.S.C. 3506(c)(2)(A)) requires Federal
Agencies to provide a 60-day notice in
the Federal Register for each proposed
collection of information before
submitting the collection to OMB for
approval. To comply with this
requirement, FDA is publishing notice
of the proposed collection of
information set forth in this document.
With respect to the collection of
information associated with this
document, FDA invites comments on
these topics: (1) Whether the proposed
information collected is necessary for
the proper performance of FDA’s
functions, including whether the
information will have practical utility;
(2) the accuracy of FDA’s estimate of the
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burden of the proposed collection of
information, including the validity of
the methodology and assumptions used;
(3) ways to enhance the quality, utility,
and clarity of the information collected;
and (4) ways to minimize the burden of
the collection of information on
respondents, including through the use
of automated collection techniques,
when appropriate, and other forms of
information technology.
1. Quality Assurance Activities
A quality control unit must be
established by outsourcing facilities to
oversee various aspects of drug
production and to monitor quality
assurance (see, e.g., § 211.22 (21 CFR
211.22)). The responsibilities of the
quality control unit must be established
in procedures (§ 211.22(d)) and should
include investigations and development
and oversight of appropriate corrective
and preventive actions regarding results
of tests and examinations, unexpected
results or trends, failures that occur
during validation or revalidation of
sterilization or depyrogenation
processes, stability failures,
environmental and personnel
monitoring results that exceed alert or
action limits, process deviations or
equipment malfunctions that involve
critical equipment, and complaints that
indicate possible drug product
contamination or other risks to patients.
The quality control unit must
periodically (at least annually) review
records of compounding operations to
evaluate the quality standards for each
drug product to determine the need for
changes in specifications or control
procedures (21 CFR 211.180(e)).
FDA estimates that annually
approximately 74 outsourcing facilities 1
(‘‘No. of Recordkeepers’’ in table 1, row
1) will individually establish
approximately 13 procedures on the
responsibilities of the quality control
unit (‘‘No. of Records per Recordkeeper’’
in table 1, row 1) as described in section
III.A of the guidance. FDA also
estimates that preparing and
maintaining these procedures will take
approximately 3 hours for each record
(‘‘Average Burden per Recordkeeping’’
in table 1, row 1).
2. Facility Design
The revised draft guidance describes
those elements of facility design of
outsourcing facilities that are
considered critical to assuring the
quality of sterile drug products at those
facilities. For example, the draft
1 This figure is based on the number of
outsourcing facilities that were registered on July
27, 2018.
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guidance states that sterile drugs should
be produced only in ISO 5 (International
Organization for Standardization) or
better air quality and that the ISO 5 zone
or critical area must be qualified (i.e.,
shown to meet the specifications) (see
§§ 211.42 and 211.113(b) (21 CFR
211.42 and 211.113(b))). The revised
draft guidance lists certain studies and
tests that should be successfully
performed for outsourcing facilities and
states that the results of these studies
and tests should be documented.
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
2) will individually document
approximately 20 studies and tests
(‘‘No. of Records per Recordkeeper’’ in
table 1, row 2) that are critical to
assuring the quality of sterile drug
products. FDA also estimates that
preparing and maintaining each record
as described in the guidance will take
on average approximately 1.5 hours for
each record (‘‘Average Burden per
Recordkeeping’’ in table 1, row 2).
3. Control Systems and Procedures for
Maintaining Suitable Facilities
The revised draft guidance describes
procedures that should be established
and followed that assign responsibility
for sanitation and describe the cleaning
schedules, methods, equipment, and
materials to be used in cleaning
buildings and facilities. For multiuse
facilities and nondedicated equipment,
changeover and cleaning procedures for
equipment and utensils must be
established and followed to prevent
contamination (see §§ 211.42 and
211.67). Procedures for cleaning and
disinfecting must also be established
(see §§ 211.42, 211.56, and 211.67). If
powder drugs are handled, procedures
must be established and followed to
appropriately manage crosscontamination risk (§ 211.100 (21 CFR
211.100)). Processes and procedures
should minimize contamination risks
posed by the number and complexity of
manipulations, number of simultaneous
operations and workstations, and
staging of materials used in the process.
Temperature and humidity must be
maintained in cleanrooms; such
controls are critical to reduce microbial
growth (see 21 CFR 211.46). In addition,
the guidance describes that procedures
should ensure recording of instances
when there is a loss of positive pressure
in the cleanroom during production.
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
3) will individually establish and
maintain approximately 6 records
(procedures and documentation) for
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maintaining suitable outsourcing
facilities (‘‘No. of Records per
Recordkeeper’’ in table 1, row 3). FDA
also estimates that preparing and
maintaining each record as described in
the guidance will take on average
approximately 5 hours for each record
(‘‘Average Burden per Recordkeeping’’
in table 1, row 3).
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4. Environmental and Personnel
Monitoring
The revised draft guidance states that
operations and appropriate written
procedures designed to prevent
microbial contamination include a welldefined and documented program for
environmental monitoring that
evaluates the potential routes of
microbial contamination of the human
drug that could arise from the air,
surfaces, process, operation, and
personnel practices (see
§§ 211.42(c)(10)(iv), 211.100, and
211.113(b)). Personnel monitoring
should include a routine program for
daily/shift monitoring of operators’
gloves and an appropriate schedule for
monitoring other critical sites of the
gown (e.g., gown sleeves for hood work)
during or immediately after completion
of aseptic operations; establish and
justify limits that are based on the
criticality of the operation relative to the
contamination risk to the product; and
call for an investigation of results that
exceed the established levels or
demonstrate an adverse trend, a
determination of the impact on the
sterility assurance of finished products
intended to be sterile, and the
development and execution of
appropriate corrective actions. This
monitoring should take place before
planned disinfection so that actual
operating conditions are being assessed.
In addition, an outsourcing facility or its
contract laboratory should establish
procedures for establishing the validity
of media if microbiological media used
in performing tests, including
environmental and personnel
monitoring, are not purchased from a
qualified supplier.
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
4) will individually establish
approximately 1,200 environmental and
personnel monitoring procedures and
records to document test results (‘‘No. of
Records per Recordkeeper’’ in table 1,
row 4) for aseptic processing areas. FDA
also estimates that preparing and
maintaining the environmental and
personnel monitoring procedures as
described in the guidance will take on
average approximately 0.25 hours for
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each record (‘‘Average Burden per
Recordkeeping’’ in table 1, row 4).
5. Containers and Closures
Scientifically sound and appropriate
criteria for containers and closures must
be established to ensure that containers
and closures used for drug products are
suitable for each drug product for which
they will be used (see § 211.160(b) (21
CFR 211.160(b))). Appropriate
procedures must be established for
testing the containers and closures to
determine whether they meet the
criteria for use, and the tests and results
must be documented (see 21 CFR
211.84(d)(3) and 211.184). Procedures
for storage, if appropriate, of sterilized
containers or closures must be
established in a manner to prevent
contamination and to maintain sterility
(see 21 CFR 211.80(a) and (b)).
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
5) will individually establish and
maintain approximately 300 procedures
and pieces of documentation for testing
containers and closures (‘‘No. of
Records per Recordkeeper’’ in table 1,
row 5) in the aseptic processing areas.
FDA also estimates that preparing and
maintaining these procedures and
documentation as described in the
guidance will take on average
approximately 0.25 hours for each
record (‘‘Average Burden per
Recordkeeping’’ in table 1, row 5).
6. Equipment
Procedures should be established and
records maintained for routine
calibration and maintenance of
equipment (mechanical, electronic, or
automated).
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
6) will individually establish and
maintain approximately 150 procedures
and pieces of documentation for the
calibration and maintenance of
equipment (‘‘No. of Records per
Recordkeeper’’ in table 1, row 6). FDA
also estimates that preparing and
maintaining these records will take on
average approximately 0.25 hours for
each record (‘‘Average Burden per
Recordkeeping’’ in table 1, row 6).
7. Components
Procedures should be established and
records maintained concerning the
source and quality of components such
as raw materials or ingredients used in
producing nonsterile and sterile drug
products at outsourcing facilities. The
revised draft guidance also states that
FDA generally does not intend to take
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regulatory action against an outsourcing
facility regarding testing components if
an adequate supplier quality agreement
is in place and maintained
appropriately.
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
7) will individually establish and
maintain approximately 150 records of
testing to ensure the quality of
components used in producing drug
products, as recommended in the
guidance (‘‘No. of Records per
Recordkeeper’’ in table 1, row 7). FDA
also estimates that preparing and
maintaining these records will take on
average approximately 4 hours for each
record (‘‘Average Burden per
Recordkeeping’’ in table 1, row 7).
8. Production and Process Controls
Production and process
documentation and procedures, such as
batch records, must be established to
assure the quality of drug products at
outsourcing facilities (see § 211.100).
Training on aseptic technique,
cleanroom behavior, gowning, and
procedures covering aseptic
manufacturing area operations must be
established (see 21 CFR 211.25(a)). The
validation of sterilization operations
(e.g., holding vessels, filling equipment,
lyophilizers) and periodic verification
activities and results must be
documented (see § 211.113(b)).
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
8) will individually establish and
maintain approximately 1,325 records
pertaining to production and process
controls, such as validation procedures
and training, to ensure the quality of
sterile drug products (‘‘No. of Records
per Recordkeeper’’ in table 1, row 8).
FDA also estimates that preparing and
maintaining these records, as described
in the guidance, will take on average
approximately 0.25 hours for each
record (‘‘Average Burden per
Recordkeeping’’ in table 1, row 8).
9. Release Testing
Drug products produced at
outsourcing facilities must be tested to
determine whether they meet final
product specifications before release for
distribution, and procedures for final
release testing must be established and
followed (§§ 211.165 and 211.167).
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
9) will individually establish and
maintain approximately 1,725 records
pertaining to final release testing of drug
products, including release testing
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procedures and documentation (‘‘No. of
Records per Recordkeeper’’ in table 1,
row 9). FDA also estimates that
preparing and maintaining these
records, as described in the guidance,
will take on average approximately 1.5
hours for each record (‘‘Average Burden
per Recordkeeping’’ in table 1, row 9).
If sterility testing is not completed
before release under certain conditions
described in Appendix A of the
guidance, procedures should be
established that specify that if the
product fails to meet a criterion for
sterility, all healthcare and other
facilities that received the product
should be immediately notified of the
test results and provided with any
appropriate information and
recommendations to aid in the
treatment of patients; the notification
should be documented; and FDA should
be notified in writing.
FDA estimates that annually
approximately 10 outsourcing facilities
(‘‘No. of Respondents’’ in table 2, row 1)
will individually send approximately 1
notification of test results to all
healthcare and other facilities that
received the drug product and provide
them with any appropriate information
and recommendations to aid in the
treatment of patients (No. of Disclosures
per Respondent’’ in table 2, row 1). FDA
also estimates that preparing and
sending each notification will take
approximately 5 hours (‘‘Average
Burden per Disclosure’’ in table 2,
row 1).
FDA also estimates that annually
approximately 10 outsourcing facilities
(‘‘No. of Respondents’’ in table 3) will
individually submit to FDA 1
notification of the test results for any
drug product that fails to meet a sterility
criterion (‘‘No. of Responses per
Respondent’’ in table 3). Preparing and
submitting this information will take
approximately 5 hours per notification
(‘‘Average Burden per Response’’ in
table 3).
10. Laboratory Controls
Each laboratory used to conduct
testing of components, in-process
materials, and finished drug products
for outsourcing facilities must follow
written procedures for the conduct of
each test and must document the
results; establish sampling and testing
procedures to ensure that components,
in-process materials, and drug products
conform to the product specifications;
keep complete records of all tests
performed to ensure compliance with
established specifications and
standards, including examinations and
assays; and, if using a validated or an
established compendial test, verify and
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document that the test procedure works
under the conditions of actual use (see
§§ 211.160 and 211.194).
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
10) will individually establish and
maintain approximately 200 laboratory
records as described in the guidance
(‘‘No. of Records per Recordkeeper’’ in
table 1, row 10). FDA also estimates that
preparing and maintaining these records
will take on average approximately 0.5
hours for each record (‘‘Average Burden
per Recordkeeping’’ in table 1, row 10).
11. Stability/Expiration Dating
Stability testing is used to ensure that
a drug product will retain its quality
(e.g., strength) and remain sterile, if
applicable, through the labeled
expiration date. The draft guidance
states that procedures established by
outsourcing facilities for assessing the
stability of drug products must include
the following: Using stability-indicating
test methods that are reliable,
meaningful, and specific; evaluating
samples of the drug product in the same
container-closure system in which the
drug product will be marketed;
evaluating samples for stability that are
representative of the lot or batch from
which they were obtained and are
stored under suitable conditions; and
testing to evaluate antimicrobial
effectiveness for drug products labeled
or intended to be multiple dose (see
§§ 211.122, 211.160, and 211.166). The
guidance states that regardless of
whether an expiration date or BUD to be
used as an expiration date is used,
container-closure integrity testing and
antimicrobial effectiveness testing (for
products labeled as multiple dose) are
required to be completed before a batch
is released (see §§ 211.166 and 211.167).
Each of these studies only needs to be
conducted once for each formulation
and container-closure system, and a
bracketing or matrixing approach can be
considered to minimize the amount of
testing needed. Outsourcing facilities
are also responsible for including
appropriate labeled directions for use
for drug products, which may include
in-use time if the product requires
additional manipulation before
administration. Appropriate studies,
including stability studies, would need
to support the stated in-use time.
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
11) will individually establish and
maintain approximately 75 procedures
for stability studies to determine an
expiration date (‘‘No. of Records per
Recordkeeper’’ in table 1, row 11) for
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63655
drug products. FDA also estimates that
preparing and maintaining these
procedures as described in the guidance
will take approximately 5 hours for each
record (‘‘Average Burden per
Recordkeeping’’ in table 1, row 11).
FDA also estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Respondents’’ in table 2, row 2)
will add approximately 540 expiration
dates to the labeling of drug products
(‘‘No. of Disclosures per Respondent’’ in
table 2, row 2). FDA also estimates that
preparing the labeling will take
approximately 0.25 hours (‘‘Average
Burden per Disclosure’’ in table 2, row
2).
12. Packaging and Labels
Packaging of drugs must ensure the
sterility, if applicable, and integrity of
the product until it is administered to a
patient, product labels must contain
required information, and labeling
operations must include controls to
prevent mixups (see §§ 211.94, 211.122,
211.125, 211.130, and 211.134). The
following must be implemented by
outsourcing facilities for packaging and
labeling operations to ensure the quality
of drug products: The container,
closure, and packaging systems
adequately protect against foreseeable
external factors in storage, shipment,
and use that can cause contamination or
deterioration; packaging records include
specimens or copies of all labels used;
adequate controls are established for
issuing labels, examining issued labels,
and reconciling used labels to prevent
mixups; different labeling and
packaging operations are adequately
separated to prevent mixups; and
controls are established that ensure
proper identification of any filled
containers of products that are stored
unlabeled for any period of time (see
§§ 211.94, 211.122, 211.125, 211.130,
211.134, and 211.188).
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
12) will individually establish and
maintain approximately 20 procedures
for packaging and labeling operations
(‘‘Records per Recordkeeper’’ in table 1,
row 12) for drug products. FDA also
estimates that preparing and
maintaining these procedures as
described in the guidance will take
approximately 5.5 hours for each record
(‘‘Average Burden per Recordkeeping’’
in table 1, row 12).
13. Reserve Samples
An appropriately identified reserve
sample that is representative of each lot
or batch of drug product must be
retained and stored under conditions
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consistent with product labeling (21
CFR 211.170).
FDA estimates that annually
approximately 74 outsourcing facilities
(‘‘No. of Recordkeepers’’ in table 1, row
13) will individually establish and
records as described in the guidance
will take approximately 0.5 hours for
each record (‘‘Average Burden per
Recordkeeping’’ in table 1, row 13).
FDA estimates the burden of this
collection of information as follows:
maintain approximately 12 procedures
and records for reserve samples
(‘‘Records per Recordkeeper’’ in table 1,
row 13) for drug products. FDA also
estimates that preparing and
maintaining these procedures and
TABLE 1—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1
Number of
recordkeepers
Activity
Number of
records per
recordkeeper
Average
burden per
recordkeeping
Total annual
records
Total hours
Quality assurance activities .....................................
Facility design ..........................................................
Control systems and procedures for maintaining
suitable facilities.
Environmental and personnel monitoring ................
Containers and closures ..........................................
Equipment ................................................................
Components .............................................................
Production and process controls .............................
Release testing ........................................................
Laboratory controls ..................................................
Stability/Expiration dating .........................................
Packaging and labels ...............................................
Reserve samples .....................................................
74
74
74
13
20
6
962
1,480
444
3 ................................
1.5 .............................
5 ................................
2,886
2,220
2,220
74
74
74
74
74
74
74
74
74
74
1,200
300
150
150
1,325
1,725
200
75
20
12
88,800
22,200
11,100
11,100
98,050
127,650
14,800
5,550
1,480
888
0.25 (15 minutes) ......
0.25 (15 minutes) ......
0.25 (15 minutes) ......
4 ................................
0.25 (15 minutes) ......
1.5 .............................
0.5 (30 minutes) ........
5 ................................
5.5 .............................
0.5 (30 minutes) ........
22,200
5,550
2,775
44,400
24,513
191,475
7,400
27,750
8,140
444
Total ..................................................................
........................
........................
........................
....................................
341,973
1 There
are no capital costs or operating and maintenance costs associated with this collection of information.
TABLE 2—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1
Notification that a drug product fails to meet a sterility criterion.
An expiration date is added to the drug product’s
label.
Total ..................................................................
1 There
Number of
disclosures per
respondent
Number of
respondents
Type of disclosure
Average
burden per
disclosure
Total annual
disclosures
Total hours
10
1
10
5 ................................
50
74
540
39,960
0.25 (15 minutes) ......
9,990
........................
........................
........................
....................................
10,040
are no capital costs or operating and maintenance costs associated with this collection of information.
TABLE 3—ESTIMATED ANNUAL REPORTING BURDEN 1
Type of reporting
Number of
respondents
Number of
responses per
respondent
Total annual
responses
Average
burden per
response
Total hours
Notification to FDA that a drug product fails to meet a sterility criterion .....................................................................
10
1
10
5
50
1 There
are no capital costs or operating and maintenance costs associated with this collection of information.
III. Electronic Access
amozie on DSK3GDR082PROD with NOTICES1
Persons with access to the internet
may obtain the draft guidance at either
https://www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/
Guidances/default.htm or https://
www.regulations.gov.
Dated: December 4, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018–26724 Filed 12–10–18; 8:45 am]
BILLING CODE 4164–01–P
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17:51 Dec 10, 2018
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2018–N–1990]
Su-Chiao Kuo: Debarment Order
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA) is issuing an
order under the Federal Food, Drug, and
Cosmetic Act (FD&C Act) debarring Dr.
SUMMARY:
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Su-Chiao Kuo for a period of 3 years
from providing services in any capacity
to a person that has an approved or
pending drug product application. FDA
bases this order on a finding that Dr.
Kuo was convicted of a misdemeanor
under the FD&C Act for causing the
introduction or delivery for introduction
into interstate commerce of prescription
drugs that were misbranded. In
addition, FDA has determined that the
type of conduct that served as the basis
for the conviction undermines the
process for the regulation of drugs. Dr.
Kuo was given notice of the proposed
E:\FR\FM\11DEN1.SGM
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]]>Agencies
[Federal Register Volume 83, Number 237 (Tuesday, December 11, 2018)]
[Notices]
[Pages 63651-63656]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-26724]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2014-D-0779]
Current Good Manufacturing Practice--Guidance for Human Drug
Compounding Outsourcing Facilities Under Section 503B of the FD&C Act;
Draft Guidance for Industry; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of availability.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or the Agency) is
announcing the availability of a revised draft guidance entitled
``Current Good Manufacturing Practice--Guidance for Human Drug
Compounding Outsourcing Facilities Under Section 503B of the FD&C
Act.'' This revised draft guidance describes FDA's policies regarding
compounders registered under section 503B of the Federal Food, Drug,
and Cosmetic Act (FD&C Act) as outsourcing facilities and the current
good manufacturing practice (CGMP) requirements in FDA regulations.
Based on feedback from stakeholders and comments received on the
initial draft guidance, the guidance is being revised, in part, to
reflect further consideration of how CGMP requirements should be
applied in light of the size and scope of an outsourcing facility's
operations.
DATES: Submit either electronic or written comments on the revised
draft guidance by February 11, 2019 to ensure that the Agency considers
your comment on this draft guidance before it begins work on the final
version of the guidance. Submit either electronic or written comments
concerning the collection of information under the Paperwork Reduction
Act of 1995 (PRA) proposed in the revised draft guidance by February
11, 2019.
ADDRESSES: You may submit comments on any guidance at any time as
follows:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2014-D-0779 for ``Current Good Manufacturing Practice--Guidance for
Human Drug Compounding Outsourcing Facilities Under Section 503B of the
FD&C Act.'' Received comments will be placed in the docket and, except
for those submitted as ``Confidential Submissions,'' publicly viewable
at https://www.regulations.gov or at the Dockets Management Staff
between 9 a.m. and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information
[[Page 63652]]
redacted/blacked out, will be available for public viewing and posted
on https://www.regulations.gov. Submit both copies to the Dockets
Management Staff. If you do not wish your name and contact information
to be made publicly available, you can provide this information on the
cover sheet and not in the body of your comments and you must identify
this information as ``confidential.'' Any information marked as
``confidential'' will not be disclosed except in accordance with 21 CFR
10.20 and other applicable disclosure law. For more information about
FDA's posting of comments to public dockets, see 80 FR 56469, September
18, 2015, or access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
Submit comments on information collection issues under the PRA to
the Office of Management and Budget (OMB) in the following ways:
Fax to the Office of Information and Regulatory Affairs,
OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, or email to
[email protected]. All comments should be identified with the
title ``Current Good Manufacturing Practice--Guidance for Human Drug
Compounding Outsourcing Facilities Under Section 503B of the FD&C
Act.''
You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
Submit written requests for single copies of the draft guidance to
the Division of Drug Information, Center for Drug Evaluation and
Research, Food and Drug Administration, 10001 New Hampshire Ave.,
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002. Send one
self-addressed adhesive label to assist that office in processing your
requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the draft guidance document.
FOR FURTHER INFORMATION CONTACT: Marci Kiester, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 2258, Silver Spring, MD 20993-0002, 301-
796-0600.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a revised draft guidance for
industry entitled ``Current Good Manufacturing Practice--Guidance for
Human Drug Compounding Outsourcing Facilities Under Section 503B of the
FD&C Act.'' Under section 503B(b) of the FD&C Act (21 U.S.C. 353b(b)),
a compounder can register as an outsourcing facility with FDA. Drug
products compounded in an outsourcing facility can qualify for
exemptions from FDA approval requirements in section 505 of the FD&C
Act (21 U.S.C. 355), the requirement to label products with adequate
directions for use under section 502(f)(1) of the FD&C Act (21 U.S.C.
352(f)(1)), and the drug supply chain security requirements in section
582 of the FD&C Act (21 U.S.C. 360eee-1), if the requirements in
section 503B are met. Outsourcing facilities are inspected by FDA
according to a risk-based schedule and must comply with other
provisions of the FD&C Act, including CGMP requirements under section
501(a)(2)(B) (21 U.S.C. 351(a)(2)(B)). FDA intends to issue CGMP
regulations specific to outsourcing facilities. Until final regulations
are issued, this draft guidance describes FDA's policies regarding
outsourcing facilities and the CGMP requirements in 21 CFR parts 210
and 211.
This draft guidance revises the draft guidance for industry
entitled ``Current Good Manufacturing Practice--Interim Guidance for
Human Drug Compounding Outsourcing Facilities Under Section 503B of the
FD&C Act,'' which published in July 2014 (79 FR 37743). This revised
draft guidance applies to drugs compounded in accordance with section
503B. In addition, this guidance generally applies to drugs that
outsourcing facilities repackage and biological products that
outsourcing facilities mix, dilute, or repackage in accordance with
relevant guidance for outsourcing facilities. This revised draft
guidance reflects FDA's intent to recognize the differences between
outsourcing facilities and conventional drug manufacturers and to
tailor CGMP requirements to the nature of the specific compounding
operations conducted by outsourcing facilities while maintaining the
minimum standards necessary to protect patients from the risks of
contaminated or otherwise substandard drug products.
The comment period on the initial draft guidance ended on September
2, 2014. FDA received 26 comments on the draft guidance. In response to
received comments or on its own initiative, FDA made changes and
updates in the revised draft guidance as follows.
FDA received a number of comments regarding the requirements in FDA
regulations applicable to nonsterile drug products because the draft
guidance focused primarily on sterile compounding. To address these
comments, the revised draft guidance differentiates between
requirements applicable to sterile drug products and nonsterile drug
products where appropriate. The revised draft guidance also
distinguishes the risks presented by using sterile and nonsterile
components in producing sterile drug products and offers
recommendations and policies on quality control commensurate with the
risk. Further, the revised draft guidance addresses concerns raised
regarding FDA's policies in several other areas. FDA made significant
revisions to address comments on (1) stability testing, including the
assignment of a beyond use date (BUD) as an expiration date; (2)
release testing; (3) the potential use of a drug master file to address
contract laboratory testing arrangements and testing of component
quality before use in compounding; (4) the use of accredited third-
party laboratories to perform testing; (5) a clear definition of ``in-
use time,'' distinguishing it from ``BUD'' and ``expiration date''; and
(6) reserve samples.
We note that the default BUDs and storage conditions associated
with nonsterile drug products described in this revised draft guidance
differ from those described for nonsterile repackaged drug products in
FDA's guidance for industry entitled ``Repackaging of Certain Human
Drug Products by Pharmacies and Outsourcing Facilities'' (Repackaging
guidance). FDA believes that the BUDs described in this revised draft
CGMP guidance are also relevant to nonsterile drug products repackaged
by outsourcing facilities. When this guidance is finalized, we intend
to make conforming revisions to the BUDs for repackaged nonsterile drug
products in the Repackaging guidance, as appropriate.
Finally, this revised draft contains revisions to the conditions
under which the Agency generally would not intend to take regulatory
action regarding the requirement to test the finished product before
release (see Sec. 211.165 (21 CFR 211.165)). These revisions make a
broader range of production volumes eligible for the relevant
enforcement policy, which we believe would encourage additional
compounders to register as outsourcing facilities. Compared to
compounders that are not registered under section 503B of the
[[Page 63653]]
FD&C Act, outsourcing facilities are subject to increased Federal
oversight through FDA inspection on a risk-based schedule, as well as
to additional standards that help to assure the quality of their
compounded drug products. Outsourcing facilities produce drug products
for hospitals, clinics, or healthcare practitioners to keep on hand as
``office stock'' for patients who present with an immediate need for
them. The revised draft guidance addresses standards critical to
reducing the risk of patient harm while balancing appropriate
flexibility. FDA is seeking public comment on whether the conditions
outlined in the revised draft appropriately balance the risks and needs
associated with drugs produced for office stock, including comments on
the production volumes specified in the guidance.
This revised draft guidance is being issued consistent with FDA's
good guidance practices regulation (21 CFR 10.115). The draft guidance,
when finalized, will represent the current thinking of FDA on ``Current
Good Manufacturing Practice--Guidance for Human Drug Compounding
Outsourcing Facilities Under Section 503B of the FD&C Act.'' It does
not establish any rights for any person and is not binding on FDA or
the public. You can use an alternative approach if it satisfies the
requirements of the applicable statutes and regulations. This guidance
is not subject to Executive Order 12866.
II. Paperwork Reduction Act of 1995
Under the PRA (44 U.S.C. 3501-3520), Federal Agencies must obtain
approval from OMB for each collection of information that they conduct
or sponsor. ``Collection of Information'' is defined in 44 U.S.C.
3502(3) and 5 CFR 1320.3(c) and includes Agency requests or
requirements that members of the public submit reports, keep records,
or provide information to a third party. Section 3506(c)(2)(A) of the
PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal Agencies to provide a
60-day notice in the Federal Register for each proposed collection of
information before submitting the collection to OMB for approval. To
comply with this requirement, FDA is publishing notice of the proposed
collection of information set forth in this document.
With respect to the collection of information associated with this
document, FDA invites comments on these topics: (1) Whether the
proposed information collected is necessary for the proper performance
of FDA's functions, including whether the information will have
practical utility; (2) the accuracy of FDA's estimate of the burden of
the proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information collected; and (4) ways to
minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
1. Quality Assurance Activities
A quality control unit must be established by outsourcing
facilities to oversee various aspects of drug production and to monitor
quality assurance (see, e.g., Sec. 211.22 (21 CFR 211.22)). The
responsibilities of the quality control unit must be established in
procedures (Sec. 211.22(d)) and should include investigations and
development and oversight of appropriate corrective and preventive
actions regarding results of tests and examinations, unexpected results
or trends, failures that occur during validation or revalidation of
sterilization or depyrogenation processes, stability failures,
environmental and personnel monitoring results that exceed alert or
action limits, process deviations or equipment malfunctions that
involve critical equipment, and complaints that indicate possible drug
product contamination or other risks to patients. The quality control
unit must periodically (at least annually) review records of
compounding operations to evaluate the quality standards for each drug
product to determine the need for changes in specifications or control
procedures (21 CFR 211.180(e)).
FDA estimates that annually approximately 74 outsourcing facilities
\1\ (``No. of Recordkeepers'' in table 1, row 1) will individually
establish approximately 13 procedures on the responsibilities of the
quality control unit (``No. of Records per Recordkeeper'' in table 1,
row 1) as described in section III.A of the guidance. FDA also
estimates that preparing and maintaining these procedures will take
approximately 3 hours for each record (``Average Burden per
Recordkeeping'' in table 1, row 1).
---------------------------------------------------------------------------
\1\ This figure is based on the number of outsourcing facilities
that were registered on July 27, 2018.
---------------------------------------------------------------------------
2. Facility Design
The revised draft guidance describes those elements of facility
design of outsourcing facilities that are considered critical to
assuring the quality of sterile drug products at those facilities. For
example, the draft guidance states that sterile drugs should be
produced only in ISO 5 (International Organization for Standardization)
or better air quality and that the ISO 5 zone or critical area must be
qualified (i.e., shown to meet the specifications) (see Sec. Sec.
211.42 and 211.113(b) (21 CFR 211.42 and 211.113(b))). The revised
draft guidance lists certain studies and tests that should be
successfully performed for outsourcing facilities and states that the
results of these studies and tests should be documented.
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 2) will individually document
approximately 20 studies and tests (``No. of Records per Recordkeeper''
in table 1, row 2) that are critical to assuring the quality of sterile
drug products. FDA also estimates that preparing and maintaining each
record as described in the guidance will take on average approximately
1.5 hours for each record (``Average Burden per Recordkeeping'' in
table 1, row 2).
3. Control Systems and Procedures for Maintaining Suitable Facilities
The revised draft guidance describes procedures that should be
established and followed that assign responsibility for sanitation and
describe the cleaning schedules, methods, equipment, and materials to
be used in cleaning buildings and facilities. For multiuse facilities
and nondedicated equipment, changeover and cleaning procedures for
equipment and utensils must be established and followed to prevent
contamination (see Sec. Sec. 211.42 and 211.67). Procedures for
cleaning and disinfecting must also be established (see Sec. Sec.
211.42, 211.56, and 211.67). If powder drugs are handled, procedures
must be established and followed to appropriately manage cross-
contamination risk (Sec. 211.100 (21 CFR 211.100)). Processes and
procedures should minimize contamination risks posed by the number and
complexity of manipulations, number of simultaneous operations and
workstations, and staging of materials used in the process. Temperature
and humidity must be maintained in cleanrooms; such controls are
critical to reduce microbial growth (see 21 CFR 211.46). In addition,
the guidance describes that procedures should ensure recording of
instances when there is a loss of positive pressure in the cleanroom
during production.
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 3) will individually
establish and maintain approximately 6 records (procedures and
documentation) for
[[Page 63654]]
maintaining suitable outsourcing facilities (``No. of Records per
Recordkeeper'' in table 1, row 3). FDA also estimates that preparing
and maintaining each record as described in the guidance will take on
average approximately 5 hours for each record (``Average Burden per
Recordkeeping'' in table 1, row 3).
4. Environmental and Personnel Monitoring
The revised draft guidance states that operations and appropriate
written procedures designed to prevent microbial contamination include
a well-defined and documented program for environmental monitoring that
evaluates the potential routes of microbial contamination of the human
drug that could arise from the air, surfaces, process, operation, and
personnel practices (see Sec. Sec. 211.42(c)(10)(iv), 211.100, and
211.113(b)). Personnel monitoring should include a routine program for
daily/shift monitoring of operators' gloves and an appropriate schedule
for monitoring other critical sites of the gown (e.g., gown sleeves for
hood work) during or immediately after completion of aseptic
operations; establish and justify limits that are based on the
criticality of the operation relative to the contamination risk to the
product; and call for an investigation of results that exceed the
established levels or demonstrate an adverse trend, a determination of
the impact on the sterility assurance of finished products intended to
be sterile, and the development and execution of appropriate corrective
actions. This monitoring should take place before planned disinfection
so that actual operating conditions are being assessed. In addition, an
outsourcing facility or its contract laboratory should establish
procedures for establishing the validity of media if microbiological
media used in performing tests, including environmental and personnel
monitoring, are not purchased from a qualified supplier.
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 4) will individually
establish approximately 1,200 environmental and personnel monitoring
procedures and records to document test results (``No. of Records per
Recordkeeper'' in table 1, row 4) for aseptic processing areas. FDA
also estimates that preparing and maintaining the environmental and
personnel monitoring procedures as described in the guidance will take
on average approximately 0.25 hours for each record (``Average Burden
per Recordkeeping'' in table 1, row 4).
5. Containers and Closures
Scientifically sound and appropriate criteria for containers and
closures must be established to ensure that containers and closures
used for drug products are suitable for each drug product for which
they will be used (see Sec. 211.160(b) (21 CFR 211.160(b))).
Appropriate procedures must be established for testing the containers
and closures to determine whether they meet the criteria for use, and
the tests and results must be documented (see 21 CFR 211.84(d)(3) and
211.184). Procedures for storage, if appropriate, of sterilized
containers or closures must be established in a manner to prevent
contamination and to maintain sterility (see 21 CFR 211.80(a) and (b)).
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 5) will individually
establish and maintain approximately 300 procedures and pieces of
documentation for testing containers and closures (``No. of Records per
Recordkeeper'' in table 1, row 5) in the aseptic processing areas. FDA
also estimates that preparing and maintaining these procedures and
documentation as described in the guidance will take on average
approximately 0.25 hours for each record (``Average Burden per
Recordkeeping'' in table 1, row 5).
6. Equipment
Procedures should be established and records maintained for routine
calibration and maintenance of equipment (mechanical, electronic, or
automated).
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 6) will individually
establish and maintain approximately 150 procedures and pieces of
documentation for the calibration and maintenance of equipment (``No.
of Records per Recordkeeper'' in table 1, row 6). FDA also estimates
that preparing and maintaining these records will take on average
approximately 0.25 hours for each record (``Average Burden per
Recordkeeping'' in table 1, row 6).
7. Components
Procedures should be established and records maintained concerning
the source and quality of components such as raw materials or
ingredients used in producing nonsterile and sterile drug products at
outsourcing facilities. The revised draft guidance also states that FDA
generally does not intend to take regulatory action against an
outsourcing facility regarding testing components if an adequate
supplier quality agreement is in place and maintained appropriately.
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 7) will individually
establish and maintain approximately 150 records of testing to ensure
the quality of components used in producing drug products, as
recommended in the guidance (``No. of Records per Recordkeeper'' in
table 1, row 7). FDA also estimates that preparing and maintaining
these records will take on average approximately 4 hours for each
record (``Average Burden per Recordkeeping'' in table 1, row 7).
8. Production and Process Controls
Production and process documentation and procedures, such as batch
records, must be established to assure the quality of drug products at
outsourcing facilities (see Sec. 211.100). Training on aseptic
technique, cleanroom behavior, gowning, and procedures covering aseptic
manufacturing area operations must be established (see 21 CFR
211.25(a)). The validation of sterilization operations (e.g., holding
vessels, filling equipment, lyophilizers) and periodic verification
activities and results must be documented (see Sec. 211.113(b)).
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 8) will individually
establish and maintain approximately 1,325 records pertaining to
production and process controls, such as validation procedures and
training, to ensure the quality of sterile drug products (``No. of
Records per Recordkeeper'' in table 1, row 8). FDA also estimates that
preparing and maintaining these records, as described in the guidance,
will take on average approximately 0.25 hours for each record
(``Average Burden per Recordkeeping'' in table 1, row 8).
9. Release Testing
Drug products produced at outsourcing facilities must be tested to
determine whether they meet final product specifications before release
for distribution, and procedures for final release testing must be
established and followed (Sec. Sec. 211.165 and 211.167).
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 9) will individually
establish and maintain approximately 1,725 records pertaining to final
release testing of drug products, including release testing
[[Page 63655]]
procedures and documentation (``No. of Records per Recordkeeper'' in
table 1, row 9). FDA also estimates that preparing and maintaining
these records, as described in the guidance, will take on average
approximately 1.5 hours for each record (``Average Burden per
Recordkeeping'' in table 1, row 9).
If sterility testing is not completed before release under certain
conditions described in Appendix A of the guidance, procedures should
be established that specify that if the product fails to meet a
criterion for sterility, all healthcare and other facilities that
received the product should be immediately notified of the test results
and provided with any appropriate information and recommendations to
aid in the treatment of patients; the notification should be
documented; and FDA should be notified in writing.
FDA estimates that annually approximately 10 outsourcing facilities
(``No. of Respondents'' in table 2, row 1) will individually send
approximately 1 notification of test results to all healthcare and
other facilities that received the drug product and provide them with
any appropriate information and recommendations to aid in the treatment
of patients (No. of Disclosures per Respondent'' in table 2, row 1).
FDA also estimates that preparing and sending each notification will
take approximately 5 hours (``Average Burden per Disclosure'' in table
2, row 1).
FDA also estimates that annually approximately 10 outsourcing
facilities (``No. of Respondents'' in table 3) will individually submit
to FDA 1 notification of the test results for any drug product that
fails to meet a sterility criterion (``No. of Responses per
Respondent'' in table 3). Preparing and submitting this information
will take approximately 5 hours per notification (``Average Burden per
Response'' in table 3).
10. Laboratory Controls
Each laboratory used to conduct testing of components, in-process
materials, and finished drug products for outsourcing facilities must
follow written procedures for the conduct of each test and must
document the results; establish sampling and testing procedures to
ensure that components, in-process materials, and drug products conform
to the product specifications; keep complete records of all tests
performed to ensure compliance with established specifications and
standards, including examinations and assays; and, if using a validated
or an established compendial test, verify and document that the test
procedure works under the conditions of actual use (see Sec. Sec.
211.160 and 211.194).
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 10) will individually
establish and maintain approximately 200 laboratory records as
described in the guidance (``No. of Records per Recordkeeper'' in table
1, row 10). FDA also estimates that preparing and maintaining these
records will take on average approximately 0.5 hours for each record
(``Average Burden per Recordkeeping'' in table 1, row 10).
11. Stability/Expiration Dating
Stability testing is used to ensure that a drug product will retain
its quality (e.g., strength) and remain sterile, if applicable, through
the labeled expiration date. The draft guidance states that procedures
established by outsourcing facilities for assessing the stability of
drug products must include the following: Using stability-indicating
test methods that are reliable, meaningful, and specific; evaluating
samples of the drug product in the same container-closure system in
which the drug product will be marketed; evaluating samples for
stability that are representative of the lot or batch from which they
were obtained and are stored under suitable conditions; and testing to
evaluate antimicrobial effectiveness for drug products labeled or
intended to be multiple dose (see Sec. Sec. 211.122, 211.160, and
211.166). The guidance states that regardless of whether an expiration
date or BUD to be used as an expiration date is used, container-closure
integrity testing and antimicrobial effectiveness testing (for products
labeled as multiple dose) are required to be completed before a batch
is released (see Sec. Sec. 211.166 and 211.167). Each of these studies
only needs to be conducted once for each formulation and container-
closure system, and a bracketing or matrixing approach can be
considered to minimize the amount of testing needed. Outsourcing
facilities are also responsible for including appropriate labeled
directions for use for drug products, which may include in-use time if
the product requires additional manipulation before administration.
Appropriate studies, including stability studies, would need to support
the stated in-use time.
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 11) will individually
establish and maintain approximately 75 procedures for stability
studies to determine an expiration date (``No. of Records per
Recordkeeper'' in table 1, row 11) for drug products. FDA also
estimates that preparing and maintaining these procedures as described
in the guidance will take approximately 5 hours for each record
(``Average Burden per Recordkeeping'' in table 1, row 11).
FDA also estimates that annually approximately 74 outsourcing
facilities (``No. of Respondents'' in table 2, row 2) will add
approximately 540 expiration dates to the labeling of drug products
(``No. of Disclosures per Respondent'' in table 2, row 2). FDA also
estimates that preparing the labeling will take approximately 0.25
hours (``Average Burden per Disclosure'' in table 2, row 2).
12. Packaging and Labels
Packaging of drugs must ensure the sterility, if applicable, and
integrity of the product until it is administered to a patient, product
labels must contain required information, and labeling operations must
include controls to prevent mixups (see Sec. Sec. 211.94, 211.122,
211.125, 211.130, and 211.134). The following must be implemented by
outsourcing facilities for packaging and labeling operations to ensure
the quality of drug products: The container, closure, and packaging
systems adequately protect against foreseeable external factors in
storage, shipment, and use that can cause contamination or
deterioration; packaging records include specimens or copies of all
labels used; adequate controls are established for issuing labels,
examining issued labels, and reconciling used labels to prevent mixups;
different labeling and packaging operations are adequately separated to
prevent mixups; and controls are established that ensure proper
identification of any filled containers of products that are stored
unlabeled for any period of time (see Sec. Sec. 211.94, 211.122,
211.125, 211.130, 211.134, and 211.188).
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 12) will individually
establish and maintain approximately 20 procedures for packaging and
labeling operations (``Records per Recordkeeper'' in table 1, row 12)
for drug products. FDA also estimates that preparing and maintaining
these procedures as described in the guidance will take approximately
5.5 hours for each record (``Average Burden per Recordkeeping'' in
table 1, row 12).
13. Reserve Samples
An appropriately identified reserve sample that is representative
of each lot or batch of drug product must be retained and stored under
conditions
[[Page 63656]]
consistent with product labeling (21 CFR 211.170).
FDA estimates that annually approximately 74 outsourcing facilities
(``No. of Recordkeepers'' in table 1, row 13) will individually
establish and maintain approximately 12 procedures and records for
reserve samples (``Records per Recordkeeper'' in table 1, row 13) for
drug products. FDA also estimates that preparing and maintaining these
procedures and records as described in the guidance will take
approximately 0.5 hours for each record (``Average Burden per
Recordkeeping'' in table 1, row 13).
FDA estimates the burden of this collection of information as
follows:
Table 1--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Activity Number of records per Total annual Average burden per recordkeeping Total hours
recordkeepers recordkeeper records
--------------------------------------------------------------------------------------------------------------------------------------------------------
Quality assurance activities................ 74 13 962 3......................................... 2,886
Facility design............................. 74 20 1,480 1.5....................................... 2,220
Control systems and procedures for 74 6 444 5......................................... 2,220
maintaining suitable facilities.
Environmental and personnel monitoring...... 74 1,200 88,800 0.25 (15 minutes)......................... 22,200
Containers and closures..................... 74 300 22,200 0.25 (15 minutes)......................... 5,550
Equipment................................... 74 150 11,100 0.25 (15 minutes)......................... 2,775
Components.................................. 74 150 11,100 4......................................... 44,400
Production and process controls............. 74 1,325 98,050 0.25 (15 minutes)......................... 24,513
Release testing............................. 74 1,725 127,650 1.5....................................... 191,475
Laboratory controls......................... 74 200 14,800 0.5 (30 minutes).......................... 7,400
Stability/Expiration dating................. 74 75 5,550 5......................................... 27,750
Packaging and labels........................ 74 20 1,480 5.5....................................... 8,140
Reserve samples............................. 74 12 888 0.5 (30 minutes).......................... 444
-----------------------------------------------------------------------------------------------------------
Total................................... .............. .............. .............. .......................................... 341,973
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 2--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Type of disclosure Number of disclosures Total annual Average burden per disclosure Total hours
respondents per respondent disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notification that a drug product fails to 10 1 10 5......................................... 50
meet a sterility criterion.
An expiration date is added to the drug 74 540 39,960 0.25 (15 minutes)......................... 9,990
product's label.
-----------------------------------------------------------------------------------------------------------
Total................................... .............. .............. .............. .......................................... 10,040
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 3--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Type of reporting Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notification to FDA that a drug product fails to meet a sterility 10 1 10 5 50
criterion.........................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
III. Electronic Access
Persons with access to the internet may obtain the draft guidance
at either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or
https://www.regulations.gov.
Dated: December 4, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-26724 Filed 12-10-18; 8:45 am]
BILLING CODE 4164-01-P
