Bulk Drug Substances That Can Be Used To Compound Drug Products in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic Act; Establishment of a Public Docket, 65765-65768 [2015-27271]
Download as PDF
<![CDATA[
Federal Register / Vol. 80, No. 207 / Tuesday, October 27, 2015 / Notices
Attn: OPRE Reports Clearance Officer.
Email address: OPREinfocollection@
acf.hhs.gov. All requests should be
identified by the title of the information
collection.
The Department specifically requests
comments on (a) whether the proposed
collection of information is necessary
for the proper performance of the
functions of the agency, including
whether the information shall have
practical utility; (b) the accuracy of the
agency’s estimate of the burden of the
proposed collection of information; (c)
the quality, utility, and clarity of the
information to be collected; and (d)
ways to minimize the burden of the
collection of information on
respondents, including through the use
of automated collection techniques or
other forms of information technology.
Consideration will be given to
comments and suggestions submitted
within 60 days of this publication.
Robert Sargis,
Reports Clearance Officer.
[FR Doc. 2015–27239 Filed 10–26–15; 8:45 am]
BILLING CODE 4184–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2015–N–3534]
Bulk Drug Substances That Can Be
Used To Compound Drug Products in
Accordance With Section 503A of the
Federal Food, Drug, and Cosmetic Act;
Establishment of a Public Docket
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice; establishment of public
docket.
The Food and Drug
Administration (FDA or Agency) is
developing a list of bulk drug
substances (active ingredients) that can
be used to compound drug products in
accordance with the Federal Food, Drug,
and Cosmetic Act (the FD&C Act),
although they are neither the subject of
an applicable United States
Pharmacopeia (USP) or National
Formulary (NF) monograph nor
components of FDA-approved drugs
(503A bulks list). The Agency
previously solicited nominations for the
list, but some of the nominated
substances were not supported by
sufficient information for FDA to
evaluate them. FDA is establishing a
public docket where these substances
can be renominated with sufficient
supporting information or to receive
tkelley on DSK3SPTVN1PROD with NOTICES
SUMMARY:
VerDate Sep<11>2014
18:24 Oct 26, 2015
Jkt 238001
nominations of bulk drug substances
that were not previously nominated for
consideration for inclusion on the 503A
bulks list. Interested parties can also
submit comments on nominated
substances via this docket.
DATES: Nominations and comments may
be submitted to this docket at any time.
ADDRESSES: You may submit comments
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): Division of
Dockets Management (HFA–305), Food
and Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments
submitted to the Division of Dockets
Management, 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–
2015–N–3534 for ‘‘Bulk Drug
Substances That Can Be Used To
Compound Drug Products in
Accordance With Section 503A of the
Federal Food, Drug, and Cosmetic Act;
Establishment of a Public Docket.’’
Received comments will be placed in
PO 00000
Frm 00079
Fmt 4703
Sfmt 4703
65765
the docket and, except for those
submitted as ‘‘Confidential
Submissions,’’ publicly viewable at
https://www.regulations.gov or at the
Division of Dockets Management
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
redacted/blacked out, will be available
for public viewing and posted on
https://www.regulations.gov. Submit
both copies to the Division of Dockets
Management. 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.fda.gov/
regulatoryinformation/dockets/
default.htm.
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 Division of Dockets
Management, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Philantha Bowen, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5175,
Silver Spring, MD 20993–0002, 301–
796–2466.
SUPPLEMENTARY INFORMATION:
I. Background
Section 503A of the FD&C Act (21
U.S.C. 353a) describes the conditions
under which a compounded drug
E:\FR\FM\27OCN1.SGM
27OCN1
tkelley on DSK3SPTVN1PROD with NOTICES
65766
Federal Register / Vol. 80, No. 207 / Tuesday, October 27, 2015 / Notices
product may be entitled to an
exemption from certain sections of the
FD&C Act. Those conditions include
that a licensed pharmacist in a State
licensed pharmacy or Federal facility or
a licensed physician compounds the
drug product using bulk drug
substances that: (1) Comply with the
standards of an applicable USP or NF
monograph, if a monograph exists, and
the USP chapter on pharmacy
compounding; (2) if such a monograph
does not exist, are drug substances that
are components of drugs approved by
the Secretary; or (3) if such a monograph
does not exist and the drug substance is
not a component of a drug approved by
the Secretary, that appear on a list
developed by the Secretary through
regulations issued by the Secretary
under subsection (c) of section 503A.
See section 503A(b)(1)(A)(i) of the FD&C
Act. Under section 503A(c)(2) of the
FD&C Act, the criteria for determining
which substances should appear on the
503A bulks list ‘‘shall include historical
use, reports in peer reviewed medical
literature, or other criteria the Secretary
may identify.’’
Section 503A refers to the definition
of ‘‘bulk drug substance’’ in FDA
regulations at § 207.3(a)(4) (21 CFR
207.3(a)(4)). See section 503A(b)(1)(A)
of the FD&C Act. As defined in
§ 207.3(a)(4), a ‘‘bulk drug substance’’ is
any substance that is represented for use
in a drug and that, when used in the
manufacturing, processing, or packaging
of a drug, becomes an active ingredient
or a finished dosage form of the drug,
but the term does not include
intermediates used in the synthesis of
such substances.
An ‘‘active ingredient’’ is any
component that 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 of man or other animals. The
term includes those components that
may undergo chemical change in the
manufacture of the drug product and be
present in the drug product in a
modified form intended to furnish the
specified activity or effect. See 21 CFR
210.3(b)(7).
Any component other than an active
ingredient is an ‘‘inactive ingredient.’’
See 21 CFR 210.3(b)(8). Inactive
ingredients used in compounded drug
products, which commonly include
flavorings, dyes, diluents, or other
excipients, need not appear on the
Secretary’s list of bulk drug substances
to be eligible for use in compounding
drug products and will not be included
on the list.
VerDate Sep<11>2014
18:24 Oct 26, 2015
Jkt 238001
In a notice dated November 27, 2013
(the November 27, 2013, notice),
published in the Federal Register of
December 4, 2013 (78 FR 72841), FDA
invited all interested persons to
nominate bulk drug substances for
inclusion on a list of bulk drug
substances that can be used for
compounding under section 503A of the
FD&C Act. Over 2,000 substances were
nominated. However, many of the
nominations were for substances that
can be used for compounding without
being on the list because they are the
subject of an applicable USP or NF
monograph or are a component of an
FDA-approved drug. In addition, many
of the nominations were not for bulk
drug substances used in compounding
as active ingredients, or did not include
sufficient information to allow FDA to
evaluate the substance for inclusion on
the list. To improve the efficiency of the
process for developing the 503A bulks
list, FDA reopened the nomination
process in July 2014 (79 FR 37742, July
2, 2014) and provided more detailed
information on what it needs to evaluate
nominations for the list. FDA stated that
bulk drug substances that were
previously nominated would not be
considered further unless they were renominated with adequate support to
permit a meaningful evaluation.
Substances that were already eligible for
use in compounding or that were not
adequately supported would not be
evaluated for placement on the list.
In response to the July 2, 2014,
request for nominations, approximately
740 unique substances were nominated.
Of the nominated substances,
approximately 275 are already eligible
for use in compounding because they
are either components of an approved
drug or the subject of an applicable USP
or NF monograph. At least nine of the
nominated substances are not eligible
for inclusion on the list because they are
either a finished drug product, a
biological product subject to licensure
in a biologics license application (BLA),
a radiopharmaceutical drug product, a
substance with no currently accepted
medical use that is included on
Schedule I of the Controlled Substances
Act (21 U.S.C. 812(c)), or they appear on
the list published by FDA of substances
that have been withdrawn or removed
from the market because such drug
products or components of such drug
products have been found to be unsafe
or not effective. Of the substances that
are not components of an FDA-approved
drug or the subject of an applicable USP
or NF monograph, not biological
products subject to licensure in a BLA,
not radiopharmaceuticals, do not appear
PO 00000
Frm 00080
Fmt 4703
Sfmt 4703
on Schedule I, and do not appear on the
withdrawn or removed list,
approximately 390 substances were
nominated with insufficient supporting
evidence for FDA to evaluate them.
II. Establishment of a Docket
As described in section III.B of the
draft guidance entitled, ‘‘Interim Policy
on Compounding Using Bulk Drug
Substances Under Section 503A of the
Federal Food, Drug, and Cosmetic Act,’’
FDA is establishing a public docket so
that interested parties can comment on
nominated bulk drug substances,
nominate bulk drug substances that
were not previously nominated for the
503A bulks list, or renominate with
adequate supporting information bulk
drug substances that were previously
nominated but that were not supported
by sufficient information for FDA to
evaluate them. Docket No. FDA–2013–
N–1525 is closed for comment.
Therefore, this new docket can be used
for commenting on nominations
submitted to that docket as well as for
submitting new nominations.
As stated previously, under section
503A(c)(2) of the FD&C Act, the criteria
for determining which substances
should appear on the 503A bulk drugs
list shall include historical use, reports
in peer reviewed medical literature, or
other criteria the Secretary may identify.
Based on this statutory language and
consultations with the USP and the
Pharmacy Compounding Advisory
Committee (PCAC),1 FDA is considering
the use of the following four criteria to
determine whether a bulk drug
substance is appropriate for use in
compounding: (1) The physical and
chemical characterization of the
substance; (2) any safety issues raised by
the use of the substance in compounded
drug products; (3) historical use of the
substance in compounded drug
products, including information about
the medical condition(s) the substance
has been used to treat and any
references in peer-reviewed medical
literature; and (4) the available evidence
of effectiveness or lack of effectiveness
of a drug product compounded with the
substance, if any such evidence exists.
Therefore, to be considered for
placement on the 503A bulks list, this
information should be submitted for
each nominated substance. FDA will
1 See 64 FR 996, January 7, 1999 (proposed rule
listing bulk drug substances that may be used in
pharmacy compounding). This proposed rule was
withdrawn in the November 27, 2013, notice but
sets forth additional background about the criteria
used in the evaluation of nominated bulk drug
substances. The criteria were discussed with the
PCAC, the membership of which includes a USP
representative, at its meeting on February 22, 2015.
E:\FR\FM\27OCN1.SGM
27OCN1
Federal Register / Vol. 80, No. 207 / Tuesday, October 27, 2015 / Notices
evaluate the nominated substances in
consultation with the USP and the
PCAC.
Interested groups and individuals
may nominate specific bulk drug
substances for inclusion on the 503A
bulks list, renominate previously
nominated substances with additional
information, or comment on nominated
substances. Nominations will only be
evaluated if they are for specific active
ingredients that: (1) Meet the definition
of a bulk drug substance in § 207.3(a)(4);
(2) are not components of FDAapproved drug products; and (3) are not
substances that are the subject of an
applicable USP or NF monograph. To
fully evaluate a bulk drug substance
using the criteria identified above, FDA
needs the following information about
both the nominated bulk drug substance
and the drug product(s) that will be
compounded using such substance:
A. Confirmation That the Nominated
Substance Is a Bulk Drug Substance and
Is Not Already Eligible for 503A
Compounding
• A statement that the nominated
substance is an active ingredient that
meets the definition of ‘‘bulk drug
substance’’ in § 207.3(a)(4), and an
explanation of why the substance is
considered an active ingredient when it
is used in the identified compounded
drug product(s), citing to specific
sources that describe the active
properties of the substance.
• A statement that the nominator has
searched for the active ingredient in all
three sections of the Orange Book (for
prescription drug products, over-thecounter drug products, and
discontinued drug products), available
at https://www.accessdata.fda.gov/
scripts/cder/ob/docs/queryai.cfm, and
the drug substance did not appear in
any of those searches, confirming that
the substance is not a component of any
FDA-approved product.
• A statement that the nominator has
searched applicable USP and NF drug
monographs, available at https://
www.uspnf.com, and the drug substance
is not the subject of such a monograph.
B. General Background on the Bulk Drug
Substance
• Ingredient name;
• Chemical name;
• Common name(s);
• Identifying codes, as available, from
FDA’s Unique Ingredient Identifiers
(UNII) used in the FDA/USP Substance
Registration System, available at https://
fdasis.nlm.nih.gov/srs/. Because
substance names can vary, this code,
where available, will be used by the
Agency to confirm the exact substance
nominated and to identify multiple
nominations of the same substance so
the information can be reviewed
together.
• Chemical grade of the ingredient;
• Description of the strength, quality,
stability, and purity of the ingredient,
and a copy of a certificate of analysis
that is representative of the
characteristics of the nominated
ingredient;
• Information about how the
ingredient is supplied (e.g., powder,
liquid); and
• Information about recognition of the
substance in foreign pharmacopeias and
the status of its registration(s) in other
countries, including whether
information has been submitted to the
USP for consideration of monograph
development.
C. Information on the Drug Product
That Will Be Compounded With the
Bulk Drug Substance
• Information about the dosage
form(s) into which the bulk drug
substance will be compounded;
• Information about the strength(s) of
the compounded drug product(s);
• Information about the anticipated
route(s) of administration of the
compounded product(s);
65767
• A bibliography of safety and
efficacy data for the drug compounded
using the nominated substance, if
available,2 including any relevant peerreviewed medical literature; and
• Information about the past and
proposed use(s) of the compounded
drug product(s), including the rationale
for its use and why the compounded
product(s), as opposed to an FDAapproved product, is necessary.
Information on the rationale for use of
the bulk drug substance and why a
compounded drug product is necessary
must be specific to the compounded
drug product at issue. General or
boilerplate statements regarding the
need for compounded drug products or
the benefits of compounding generally
will not be considered sufficient to
address this issue.
D. Process for Submitting Nominations
and Comments
Because the prior deadline for
submitting nominations has passed,
FDA is opening this docket so that
interested persons can submit
nominations of bulk drug substances
and provide adequate support for FDA
to evaluate whether those substances
should be placed on the 503A bulks list.
Bulk drug substances that were
previously nominated and for which
inadequate information was provided 3
need to be renominated with the
information identified above to be
considered for inclusion on the 503A
bulks list. Nominators are encouraged to
submit as much of the information
identified in this document as possible.
Unless adequate supporting data is
received for a bulk drug substance, FDA
will be unable to consider it further for
inclusion on the list.
For efficient consolidation and review
of nominations, nominators are
encouraged to submit their nominations
in an editable Excel file. Specifically,
nominators are encouraged to format
their nominations as follows:
Column B—Put data specific to the nominated substance
What is the name of the nominated ingredient?
Is the ingredient an active ingredient that meets the definition of ‘‘bulk
drug substance’’ in § 207.3(a)(4)?
tkelley on DSK3SPTVN1PROD with NOTICES
Column A—What information is requested?
Provide the ingredient name.
Provide an explanation for why it is considered an active ingredient
when it is used in specific compounded drug products, and provide
citations to specific sources that describe its active properties.
Confirm whether the ingredient is a component of an FDA-approved
product.
Confirm whether the ingredient is the subject of an applicable USP or
NF monograph.
Chemical name.
Common name.
UNII code.
Is the ingredient listed in any of the three sections of the Orange
Book?
Were any drug monographs for the ingredient found in the USP or NF
monographs?
What is the chemical name of the substance?
What is the common name of the substance?
Does the substance have a UNII code?
2 FDA recognizes that the available safety and
efficacy data supporting consideration of a bulk
drug substance for inclusion on the list may not be
VerDate Sep<11>2014
18:24 Oct 26, 2015
Jkt 238001
of the same type, amount, or quality as is required
to support a new drug application.
3 As referenced above, a list of the substances in
this category is available at https://www.fda.gov/
PO 00000
Frm 00081
Fmt 4703
Sfmt 4703
downloads/Drugs/
GuidanceComplianceRegulatoryInformation/
PharmacyCompounding/UCM467373.pdf.
E:\FR\FM\27OCN1.SGM
27OCN1
65768
Federal Register / Vol. 80, No. 207 / Tuesday, October 27, 2015 / Notices
Column A—What information is requested?
Column B—Put data specific to the nominated substance
What is the chemical grade of the substance?
What is the strength, quality, stability, and purity of the ingredient?
How is the ingredient supplied?
Is the substance recognized in foreign pharmacopeias or registered in
other countries?
Has information been submitted about the substance to the USP for
consideration of drug monograph development?
What dosage form(s) will be compounded using the bulk drug substance?
What strength(s) will be compounded from the nominated substance?
What are the anticipated route(s) of administration of the compounded
drug product(s)?
Are there safety and efficacy data on compounded drugs using the
nominated substance?
tkelley on DSK3SPTVN1PROD with NOTICES
Has the bulk drug substance been used previously to compound drug
product(s)?
What is the proposed use for the drug product(s) to be compounded
with the nominated substance?
What is the reason for use of a compounded drug product rather than
an FDA-approved product?
Is there any other relevant information?
In addition to nominating new
substances or renominating substances
previously nominated without sufficient
supporting information, individuals and
organizations will be able to comment
via the docket established by this notice
on substances nominated for the 503A
bulks list that have not yet been
addressed in a Notice of Proposed
Rulemaking (NPRM). Comments may be
submitted regarding nominations
submitted to both this docket and
Docket No. FDA–2013–N–1525.
Comments may provide any relevant
information about particular bulk drug
substances, including that in support of,
or in opposition to, the placement of a
nominated bulk drug substance on the
503A bulks list. However, comments
submitted should not address the 503A
bulks list generally or other matters
related to the Agency’s regulation of
compounding. Comments about
nominated substances that have been
addressed by the Agency in an NPRM
should be submitted to the docket for
the proposed rulemaking in which the
substance is addressed.
Please do not submit comments that
have already been submitted to other
dockets. Such submissions are
duplicative and not helpful to the
Agency. If comments on particular
documents or issues are submitted to
this docket rather than the docket
specifically opened for the particular
document or issue, the comment might
not be considered as the specific
documents are being finalized and
issues considered. FDA will not respond
to questions submitted to this docket.
VerDate Sep<11>2014
18:24 Oct 26, 2015
Jkt 238001
Provide the chemical grade.
Provide the strength, quality, stability, and purity information and attach
a certificate of analysis.
Describe how the ingredient is supplied (e.g., powder, liquid).
List the foreign pharmacopeias or other countries in which it is registered.
Put yes, no, or unknown. If yes, state the status of the monograph, if
known.
State the dosage form(s).
List the strength(s) of the drug product(s) that will be compounded from
the nominated substance, or a range of strengths, if known.
List the route(s) of administration of the compounded drug product(s).
Provide a bibliography of safety and efficacy data for the drug compounded using the nominated substance, if available, including any
relevant peer-reviewed medical literature.
Describe past uses of the bulk drug substance in compounding.
Provide information on the proposed use of the compounded drug
product.
Provide a rationale for the use of a compounded drug product.
Provide any other information you would like FDA to consider in evaluating the nomination.
Information in the docket will be
publicly available. Therefore, we
remind nominators and commenters not
to submit personal or confidential
information.
Dated: October 21, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015–27271 Filed 10–26–15; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
in compounding under the Federal
Food, Drug, and Cosmetic Act (the
FD&C Act). When final, the guidance
will reflect the Agency’s current
thinking on the issues addressed by the
guidance.
Although you can comment on
any guidance at any time (see 21 CFR
10.115(g)(5)), 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
on the draft guidance by December 28,
2015.
DATES:
ADDRESSES:
You may submit comments
[Docket No. FDA–2015–D–3539]
as follows:
Interim Policy on Compounding Using
Bulk Drug Substances Under Section
503B of the Federal Food, Drug, and
Cosmetic Act; Draft Guidance for
Industry; Availability
Electronic Submissions
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 draft
guidance entitled ‘‘Interim Policy on
Compounding Using Bulk Drug
Substances Under Section 503B of the
Federal Food, Drug, and Cosmetic Act.’’
The draft guidance describes FDA’s
interim regulatory policy regarding
outsourcing facilities that compound
human drug products using bulk drug
substances while FDA develops the list
of bulk drug substances that can be used
SUMMARY:
PO 00000
Frm 00082
Fmt 4703
Sfmt 4703
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
E:\FR\FM\27OCN1.SGM
27OCN1
]]>Agencies
[Federal Register Volume 80, Number 207 (Tuesday, October 27, 2015)]
[Notices]
[Pages 65765-65768]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-27271]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2015-N-3534]
Bulk Drug Substances That Can Be Used To Compound Drug Products
in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic
Act; Establishment of a Public Docket
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; establishment of public docket.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or Agency) is developing
a list of bulk drug substances (active ingredients) that can be used to
compound drug products in accordance with the Federal Food, Drug, and
Cosmetic Act (the FD&C Act), although they are neither the subject of
an applicable United States Pharmacopeia (USP) or National Formulary
(NF) monograph nor components of FDA-approved drugs (503A bulks list).
The Agency previously solicited nominations for the list, but some of
the nominated substances were not supported by sufficient information
for FDA to evaluate them. FDA is establishing a public docket where
these substances can be renominated with sufficient supporting
information or to receive nominations of bulk drug substances that were
not previously nominated for consideration for inclusion on the 503A
bulks list. Interested parties can also submit comments on nominated
substances via this docket.
DATES: Nominations and comments may be submitted to this docket at any
time.
ADDRESSES: You may submit comments 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): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Division of
Dockets Management, 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-2015-N-3534 for ``Bulk Drug Substances That Can Be Used To Compound
Drug Products in Accordance With Section 503A of the Federal Food,
Drug, and Cosmetic Act; Establishment of a Public Docket.'' 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 Division of Dockets Management 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 redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Division of Dockets Management. 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.fda.gov/regulatoryinformation/dockets/default.htm.
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 Division of Dockets Management, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Philantha Bowen, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5175, Silver Spring, MD 20993-0002, 301-
796-2466.
SUPPLEMENTARY INFORMATION:
I. Background
Section 503A of the FD&C Act (21 U.S.C. 353a) describes the
conditions under which a compounded drug
[[Page 65766]]
product may be entitled to an exemption from certain sections of the
FD&C Act. Those conditions include that a licensed pharmacist in a
State licensed pharmacy or Federal facility or a licensed physician
compounds the drug product using bulk drug substances that: (1) Comply
with the standards of an applicable USP or NF monograph, if a monograph
exists, and the USP chapter on pharmacy compounding; (2) if such a
monograph does not exist, are drug substances that are components of
drugs approved by the Secretary; or (3) if such a monograph does not
exist and the drug substance is not a component of a drug approved by
the Secretary, that appear on a list developed by the Secretary through
regulations issued by the Secretary under subsection (c) of section
503A. See section 503A(b)(1)(A)(i) of the FD&C Act. Under section
503A(c)(2) of the FD&C Act, the criteria for determining which
substances should appear on the 503A bulks list ``shall include
historical use, reports in peer reviewed medical literature, or other
criteria the Secretary may identify.''
Section 503A refers to the definition of ``bulk drug substance'' in
FDA regulations at Sec. 207.3(a)(4) (21 CFR 207.3(a)(4)). See section
503A(b)(1)(A) of the FD&C Act. As defined in Sec. 207.3(a)(4), a
``bulk drug substance'' is any substance that is represented for use in
a drug and that, when used in the manufacturing, processing, or
packaging of a drug, becomes an active ingredient or a finished dosage
form of the drug, but the term does not include intermediates used in
the synthesis of such substances.
An ``active ingredient'' is any component that 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 of man or other
animals. The term includes those components that may undergo chemical
change in the manufacture of the drug product and be present in the
drug product in a modified form intended to furnish the specified
activity or effect. See 21 CFR 210.3(b)(7).
Any component other than an active ingredient is an ``inactive
ingredient.'' See 21 CFR 210.3(b)(8). Inactive ingredients used in
compounded drug products, which commonly include flavorings, dyes,
diluents, or other excipients, need not appear on the Secretary's list
of bulk drug substances to be eligible for use in compounding drug
products and will not be included on the list.
In a notice dated November 27, 2013 (the November 27, 2013,
notice), published in the Federal Register of December 4, 2013 (78 FR
72841), FDA invited all interested persons to nominate bulk drug
substances for inclusion on a list of bulk drug substances that can be
used for compounding under section 503A of the FD&C Act. Over 2,000
substances were nominated. However, many of the nominations were for
substances that can be used for compounding without being on the list
because they are the subject of an applicable USP or NF monograph or
are a component of an FDA-approved drug. In addition, many of the
nominations were not for bulk drug substances used in compounding as
active ingredients, or did not include sufficient information to allow
FDA to evaluate the substance for inclusion on the list. To improve the
efficiency of the process for developing the 503A bulks list, FDA
reopened the nomination process in July 2014 (79 FR 37742, July 2,
2014) and provided more detailed information on what it needs to
evaluate nominations for the list. FDA stated that bulk drug substances
that were previously nominated would not be considered further unless
they were re-nominated with adequate support to permit a meaningful
evaluation. Substances that were already eligible for use in
compounding or that were not adequately supported would not be
evaluated for placement on the list.
In response to the July 2, 2014, request for nominations,
approximately 740 unique substances were nominated. Of the nominated
substances, approximately 275 are already eligible for use in
compounding because they are either components of an approved drug or
the subject of an applicable USP or NF monograph. At least nine of the
nominated substances are not eligible for inclusion on the list because
they are either a finished drug product, a biological product subject
to licensure in a biologics license application (BLA), a
radiopharmaceutical drug product, a substance with no currently
accepted medical use that is included on Schedule I of the Controlled
Substances Act (21 U.S.C. 812(c)), or they appear on the list published
by FDA of substances that have been withdrawn or removed from the
market because such drug products or components of such drug products
have been found to be unsafe or not effective. Of the substances that
are not components of an FDA-approved drug or the subject of an
applicable USP or NF monograph, not biological products subject to
licensure in a BLA, not radiopharmaceuticals, do not appear on Schedule
I, and do not appear on the withdrawn or removed list, approximately
390 substances were nominated with insufficient supporting evidence for
FDA to evaluate them.
II. Establishment of a Docket
As described in section III.B of the draft guidance entitled,
``Interim Policy on Compounding Using Bulk Drug Substances Under
Section 503A of the Federal Food, Drug, and Cosmetic Act,'' FDA is
establishing a public docket so that interested parties can comment on
nominated bulk drug substances, nominate bulk drug substances that were
not previously nominated for the 503A bulks list, or renominate with
adequate supporting information bulk drug substances that were
previously nominated but that were not supported by sufficient
information for FDA to evaluate them. Docket No. FDA-2013-N-1525 is
closed for comment. Therefore, this new docket can be used for
commenting on nominations submitted to that docket as well as for
submitting new nominations.
As stated previously, under section 503A(c)(2) of the FD&C Act, the
criteria for determining which substances should appear on the 503A
bulk drugs list shall include historical use, reports in peer reviewed
medical literature, or other criteria the Secretary may identify. Based
on this statutory language and consultations with the USP and the
Pharmacy Compounding Advisory Committee (PCAC),\1\ FDA is considering
the use of the following four criteria to determine whether a bulk drug
substance is appropriate for use in compounding: (1) The physical and
chemical characterization of the substance; (2) any safety issues
raised by the use of the substance in compounded drug products; (3)
historical use of the substance in compounded drug products, including
information about the medical condition(s) the substance has been used
to treat and any references in peer-reviewed medical literature; and
(4) the available evidence of effectiveness or lack of effectiveness of
a drug product compounded with the substance, if any such evidence
exists. Therefore, to be considered for placement on the 503A bulks
list, this information should be submitted for each nominated
substance. FDA will
[[Page 65767]]
evaluate the nominated substances in consultation with the USP and the
PCAC.
---------------------------------------------------------------------------
\1\ See 64 FR 996, January 7, 1999 (proposed rule listing bulk
drug substances that may be used in pharmacy compounding). This
proposed rule was withdrawn in the November 27, 2013, notice but
sets forth additional background about the criteria used in the
evaluation of nominated bulk drug substances. The criteria were
discussed with the PCAC, the membership of which includes a USP
representative, at its meeting on February 22, 2015.
---------------------------------------------------------------------------
Interested groups and individuals may nominate specific bulk drug
substances for inclusion on the 503A bulks list, renominate previously
nominated substances with additional information, or comment on
nominated substances. Nominations will only be evaluated if they are
for specific active ingredients that: (1) Meet the definition of a bulk
drug substance in Sec. 207.3(a)(4); (2) are not components of FDA-
approved drug products; and (3) are not substances that are the subject
of an applicable USP or NF monograph. To fully evaluate a bulk drug
substance using the criteria identified above, FDA needs the following
information about both the nominated bulk drug substance and the drug
product(s) that will be compounded using such substance:
A. Confirmation That the Nominated Substance Is a Bulk Drug Substance
and Is Not Already Eligible for 503A Compounding
A statement that the nominated substance is an active
ingredient that meets the definition of ``bulk drug substance'' in
Sec. 207.3(a)(4), and an explanation of why the substance is
considered an active ingredient when it is used in the identified
compounded drug product(s), citing to specific sources that describe
the active properties of the substance.
A statement that the nominator has searched for the active
ingredient in all three sections of the Orange Book (for prescription
drug products, over-the-counter drug products, and discontinued drug
products), available at https://www.accessdata.fda.gov/scripts/cder/ob/docs/queryai.cfm, and the drug substance did not appear in any of those
searches, confirming that the substance is not a component of any FDA-
approved product.
A statement that the nominator has searched applicable USP
and NF drug monographs, available at https://www.uspnf.com, and the drug
substance is not the subject of such a monograph.
B. General Background on the Bulk Drug Substance
Ingredient name;
Chemical name;
Common name(s);
Identifying codes, as available, from FDA's Unique
Ingredient Identifiers (UNII) used in the FDA/USP Substance
Registration System, available at https://fdasis.nlm.nih.gov/srs/.
Because substance names can vary, this code, where available, will be
used by the Agency to confirm the exact substance nominated and to
identify multiple nominations of the same substance so the information
can be reviewed together.
Chemical grade of the ingredient;
Description of the strength, quality, stability, and
purity of the ingredient, and a copy of a certificate of analysis that
is representative of the characteristics of the nominated ingredient;
Information about how the ingredient is supplied (e.g.,
powder, liquid); and
Information about recognition of the substance in foreign
pharmacopeias and the status of its registration(s) in other countries,
including whether information has been submitted to the USP for
consideration of monograph development.
C. Information on the Drug Product That Will Be Compounded With the
Bulk Drug Substance
Information about the dosage form(s) into which the bulk
drug substance will be compounded;
Information about the strength(s) of the compounded drug
product(s);
Information about the anticipated route(s) of
administration of the compounded product(s);
A bibliography of safety and efficacy data for the drug
compounded using the nominated substance, if available,\2\ including
any relevant peer-reviewed medical literature; and
---------------------------------------------------------------------------
\2\ FDA recognizes that the available safety and efficacy data
supporting consideration of a bulk drug substance for inclusion on
the list may not be of the same type, amount, or quality as is
required to support a new drug application.
---------------------------------------------------------------------------
Information about the past and proposed use(s) of the
compounded drug product(s), including the rationale for its use and why
the compounded product(s), as opposed to an FDA-approved product, is
necessary. Information on the rationale for use of the bulk drug
substance and why a compounded drug product is necessary must be
specific to the compounded drug product at issue. General or
boilerplate statements regarding the need for compounded drug products
or the benefits of compounding generally will not be considered
sufficient to address this issue.
D. Process for Submitting Nominations and Comments
Because the prior deadline for submitting nominations has passed,
FDA is opening this docket so that interested persons can submit
nominations of bulk drug substances and provide adequate support for
FDA to evaluate whether those substances should be placed on the 503A
bulks list. Bulk drug substances that were previously nominated and for
which inadequate information was provided \3\ need to be renominated
with the information identified above to be considered for inclusion on
the 503A bulks list. Nominators are encouraged to submit as much of the
information identified in this document as possible. Unless adequate
supporting data is received for a bulk drug substance, FDA will be
unable to consider it further for inclusion on the list.
---------------------------------------------------------------------------
\3\ As referenced above, a list of the substances in this
category is available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM467373.pdf.
---------------------------------------------------------------------------
For efficient consolidation and review of nominations, nominators
are encouraged to submit their nominations in an editable Excel file.
Specifically, nominators are encouraged to format their nominations as
follows:
------------------------------------------------------------------------
Column A--What information is Column B--Put data specific to
requested? the nominated substance
------------------------------------------------------------------------
What is the name of the nominated Provide the ingredient name.
ingredient?
Is the ingredient an active ingredient Provide an explanation for why
that meets the definition of ``bulk it is considered an active
drug substance'' in Sec. ingredient when it is used in
207.3(a)(4)? specific compounded drug
products, and provide
citations to specific sources
that describe its active
properties.
Is the ingredient listed in any of the Confirm whether the ingredient
three sections of the Orange Book? is a component of an FDA-
approved product.
Were any drug monographs for the Confirm whether the ingredient
ingredient found in the USP or NF is the subject of an
monographs? applicable USP or NF
monograph.
What is the chemical name of the Chemical name.
substance?
What is the common name of the Common name.
substance?
Does the substance have a UNII code? UNII code.
[[Page 65768]]
What is the chemical grade of the Provide the chemical grade.
substance?
What is the strength, quality, Provide the strength, quality,
stability, and purity of the stability, and purity
ingredient? information and attach a
certificate of analysis.
How is the ingredient supplied? Describe how the ingredient is
supplied (e.g., powder,
liquid).
Is the substance recognized in foreign List the foreign pharmacopeias
pharmacopeias or registered in other or other countries in which it
countries? is registered.
Has information been submitted about Put yes, no, or unknown. If
the substance to the USP for yes, state the status of the
consideration of drug monograph monograph, if known.
development?
What dosage form(s) will be compounded State the dosage form(s).
using the bulk drug substance?
What strength(s) will be compounded List the strength(s) of the
from the nominated substance? drug product(s) that will be
compounded from the nominated
substance, or a range of
strengths, if known.
What are the anticipated route(s) of List the route(s) of
administration of the compounded drug administration of the
product(s)? compounded drug product(s).
Are there safety and efficacy data on Provide a bibliography of
compounded drugs using the nominated safety and efficacy data for
substance? the drug compounded using the
nominated substance, if
available, including any
relevant peer-reviewed medical
literature.
Has the bulk drug substance been used Describe past uses of the bulk
previously to compound drug drug substance in compounding.
product(s)?
What is the proposed use for the drug Provide information on the
product(s) to be compounded with the proposed use of the compounded
nominated substance? drug product.
What is the reason for use of a Provide a rationale for the use
compounded drug product rather than an of a compounded drug product.
FDA-approved product?
Is there any other relevant Provide any other information
information? you would like FDA to consider
in evaluating the nomination.
------------------------------------------------------------------------
In addition to nominating new substances or renominating substances
previously nominated without sufficient supporting information,
individuals and organizations will be able to comment via the docket
established by this notice on substances nominated for the 503A bulks
list that have not yet been addressed in a Notice of Proposed
Rulemaking (NPRM). Comments may be submitted regarding nominations
submitted to both this docket and Docket No. FDA-2013-N-1525. Comments
may provide any relevant information about particular bulk drug
substances, including that in support of, or in opposition to, the
placement of a nominated bulk drug substance on the 503A bulks list.
However, comments submitted should not address the 503A bulks list
generally or other matters related to the Agency's regulation of
compounding. Comments about nominated substances that have been
addressed by the Agency in an NPRM should be submitted to the docket
for the proposed rulemaking in which the substance is addressed.
Please do not submit comments that have already been submitted to
other dockets. Such submissions are duplicative and not helpful to the
Agency. If comments on particular documents or issues are submitted to
this docket rather than the docket specifically opened for the
particular document or issue, the comment might not be considered as
the specific documents are being finalized and issues considered. FDA
will not respond to questions submitted to this docket.
Information in the docket will be publicly available. Therefore, we
remind nominators and commenters not to submit personal or confidential
information.
Dated: October 21, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-27271 Filed 10-26-15; 8:45 am]
BILLING CODE 4164-01-P
