
[Federal Register Volume 79, Number 127 (Wednesday, July 2, 2014)]
[Notices]
[Pages 37750-37754]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-15373]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-1524]


Bulk Drug Substances That May Be Used To Compound Drug Products 
in Accordance With Section 503B of the Federal Food, Drug, and Cosmetic 
Act, Concerning Outsourcing Facilities; Revised Request for Nominations

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; revised request for nominations.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is preparing 
to develop a list of bulk drug substances (active ingredients) that may 
be used to compound drug products in accordance with section 503B of 
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) concerning 
outsourcing facilities. In response to a notice published in the 
Federal Register of December 4, 2013, interested groups and individuals 
previously nominated a wide variety of substances for this list. 
However, many of those nominations were not for bulk drug substances 
used in compounding as active ingredients, and none included sufficient 
information to justify inclusion of the nominated substances on the 
list. To improve the efficiency of the process for developing the list 
of bulk drug substances that may be used to compound drug products 
under section 503B of the FD&C Act, FDA is providing more detailed 
information on what it needs to evaluate a nomination. Because the 
deadline for nominations has passed, FDA is reopening the nomination 
process so that interested persons can submit nominations of bulk drug 
substances and provide adequate support to justify placing the 
substances on the list. Bulk drug substances that were previously 
nominated will not be further considered unless they are renominated 
and adequately supported. Substances that are not adequately supported 
will not be placed on the list.

DATES: Submit written or electronic nominations for the bulk drug 
substances list by September 30, 2014.

ADDRESSES: You may submit nominations, identified by Docket No. FDA-
2013-N-1524, by any of the following methods.

Electronic Submissions

    Submit electronic nominations in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

[[Page 37751]]

Written Submissions

    Submit written nominations in the following ways:
     Mail/Hand delivery/Courier (for paper submissions): 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2013-N-1524 for this request for nominations. All 
nominations received may be posted without change to http://www.regulations.gov, including any personal information provided. For 
additional information on submitting nominations, see the ``Request for 
Nominations'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
nominations received, go to http://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: Emily Helms Williams, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6280, Silver Spring, MD 20993-0002, 301-
796-3381.

SUPPLEMENTARY INFORMATION:

I. Background

    Under the Drug Quality and Security Act (Pub. L. 113-54), which 
added section 503B to the Federal Food, Drug, and Cosmetic Act (FD&C 
Act) (21 U.S.C. 353b), outsourcing facilities \1\ may qualify for 
certain exemptions from the FD&C Act if the conditions set forth in the 
statute are satisfied. Those conditions include that an outsourcing 
facility does not compound drug products using a bulk drug substance 
unless the bulk drug substance appears on a list established by the 
Secretary identifying bulk drug substances for which there is a 
clinical need (the 503B list), or the drug product compounded from such 
bulk drug substance appears on the drug shortage list in effect under 
section 506E of the FD&C Act (21 U.S.C. 356e) (FDA drug shortage list) 
at the time of compounding, distribution, and dispensing, and each of 
the following conditions are met: (1) If an applicable monograph exists 
under the United States Pharmacopeia, the National Formulary, or 
another compendium or pharmacopeia recognized by the Secretary for 
purposes of this paragraph, the bulk drug substance complies with the 
monograph; (2) the bulk drug substance is manufactured by an 
establishment that is registered under section 510 of the FD&C Act (21 
U.S.C. 360); and (3) the bulk drug substance is accompanied by a valid 
certificate of analysis (see section 503B(a)(2) of the FD&C Act).
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    \1\ ``Outsourcing facilities'' are facilities that meet certain 
conditions described in section 503B of the FD&C Act, including 
registering with FDA as an outsourcing facility.
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    Section 503B 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 
503B(a)(2) 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, published in the Federal 
Register of December 4, 2013 (78 FR 72838), FDA requested nominations 
for specific bulk drug substances for the Agency to consider for 
placement on the 503B list. In response to that request, 753 comments 
were submitted to the docket, most of which nominated substances for 
inclusion on the bulk drug substances list. Some comments nominated 
several hundred substances, and approximately 10 comments nominated 
thousands of substances, including en bloc nominations of substances 
listed in the United States Pharmacopeia (USP) or National Formulary, 
the British Pharmacopeia, the European Pharmacopeia, the Japanese 
Pharmacopeia, the Food Chemicals Codex, the Homeopathic Pharmacopeia of 
the United States, and the USP Dietary Supplements Compendium. Several 
submissions referenced a spreadsheet entitled ``OTC Active 
Ingredients,'' available on FDA's Web site at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf. Those submissions 
nominated all of the ingredients on the spreadsheet, which numbered 
over 1,700 entries.\2\
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    \2\ The total number of unique ingredients on the spreadsheet 
available on FDA's Web site and the nominations that mirrored that 
document is lower than this total because the same substances were 
listed separately for different indications, according to how they 
are listed in the over-the-counter (OTC) monographs and regulations.
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    However, many of the nominated substances are typically inactive 
ingredients or foods. Some commonly used inactive ingredients are 
occasionally used as the active ingredient in a drug product. See 55 FR 
46914 at 46916, November 7, 1990 (noting that 21 CFR 310.545 only 
affects the use of the listed ingredients as active ingredients for the 
specific indications and that some of the ingredients listed in the 
rule, such as sorbitol, sugars, and eucalyptol, have valid uses as 
inactive ingredients). Ingredients commonly used as inactive 
ingredients in compounded drug products, such as flavorings, dyes, 
diluents, or other excipients, need not appear on the Secretary's list 
of bulk drug substances to be eligible for use as an inactive 
ingredient in compounded drug products, should not be nominated, and 
will not be included on the list. All nominations must demonstrate how 
the ingredient is used as an active ingredient in a particular 
compounded drug product.
    Further, the nominations did not include sufficient information for 
the Agency to evaluate the clinical need for drug products compounded 
using the bulk drug substance. As stated previously, section 503B 
requires FDA to create a list ``identifying bulk drug substances for 
which there is a clinical need . . . .'' Section 503B(a)(2)(A)(i) of 
the FD&C Act. Although this language is ambiguous, the Agency has 
interpreted it to mean that a clinical need to compound with a bulk 
drug substance exists where there is a clinical need for a specific 
drug product to be compounded with the nominated bulk drug substance. 
The Agency believes that this interpretation is consistent with both 
the language and purpose of

[[Page 37752]]

the statute. Therefore, to qualify for placement on the 503B list, it 
is necessary to identify the compounded drug product for which there is 
a clinical need and to demonstrate that the nominated bulk drug 
substance is required to compound that drug product.
    The nominators of the en bloc submissions provided no justification 
for listing any of the specific substances on the list. To the extent 
information about the clinical need for the use of a bulk drug 
substance in compounded drug products was provided at all in individual 
nominations, many of the comments to the docket included a statement 
about the need for the use of bulk drug substances in compounding 
generally rather than information about the specific clinical need for 
drug products compounded using a particular bulk drug substance. For 
example, many nominations included the following standardized language 
as the explanation of clinical need for compounding with the bulk drug 
substance: ``Prescribed dosage forms and strengths not available 
commercially. Manufacturer backorders. Possible patient sensitivities 
to manufactured product dyes, fillers, preservatives and other 
excipients.'' Such statements do not provide sufficient information for 
FDA to determine that there is a clinical need to compound a particular 
drug product from the nominated bulk drug substance. Because the 
information submitted with previous nominations was insufficient, FDA 
is unable to determine whether those substances should be included on 
the list.
    To improve the efficiency of the process for the development of the 
list of bulk drug substances that may be used to compound drug products 
under section 503B of the FD&C Act, and because the deadline for 
submitting nominations has passed, FDA is reopening the nomination 
process so that interested persons have the opportunity to submit 
nominations of bulk drug substances and provide adequate support for 
placing them on the list. FDA will be able to evaluate only those bulk 
drug substances submitted in response to this notice that are supported 
with adequate data and information, as described in section II.
    Bulk drug substances that were previously nominated will not be 
further considered unless they are renominated and adequately 
supported. Substances that are not adequately supported will not be 
placed on the list. FDA expects the submissions for each bulk drug 
substance to provide the information described in section II. For 
example, nominations must include sufficient information to demonstrate 
that a particular ingredient meets the definition of ``bulk drug 
substance,'' as defined in Sec.  207.3(a)(4). See section 503B(a)(2) of 
the FD&C Act. The identification of an ingredient as an ``active 
ingredient'' in a regulation, or on a spreadsheet such as the one 
listing ``OTC Active Ingredients,'' is not sufficient to demonstrate 
that a substance is a bulk drug substance for purposes of the 503B 
List. En bloc nominations of substances listed in compendia, 
pharmacopeia, or similar reference materials cannot be placed on the 
list unless the Agency receives adequate information for each bulk drug 
substance to justify its placement on the list. FDA will only be able 
to consider bulk drug substances that are supported with the 
information requested in section II.
    In section II, FDA identifies the type of information needed to 
support a nomination to the 503B list.

II. Request for Nominations

A. Active Ingredients

    Interested groups and individuals may nominate specific bulk 
substances for inclusion on the list. Nominations will only be 
evaluated if they are for specific active ingredients that meet the 
definition of a bulk drug substance in Sec.  207.3(a)(4). Nominated 
substances that do not meet this definition will not be included on the 
list.
    To fully evaluate a bulk drug substance, FDA needs the following 
information about both the bulk drug substance being nominated and the 
drug product(s) that will be compounded using such substance:
1. Confirmation That the Nominated Substance Is a Bulk Drug Substance
    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 compounded drug products, citing 
to specific sources that describe the active properties of the 
substance.
2. General Background on the Bulk Drug Substance
     Ingredient name;
     chemical name;
     common name(s); and
     identifying codes, as available, from FDA's Unique 
Ingredient Identifiers (UNII) used in the FDA/USP Substance 
Registration System, available at http://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;
     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 USP for 
consideration of monograph development.

B. Clinical Need To Compound

    For FDA to be able to meaningfully evaluate a substance, the 
information provided regarding the clinical need for compounding with a 
bulk drug substance must be specific to the particular substance 
nominated and drug product to be compounded. A ``boilerplate'' or 
general explanation of clinical need for compounding with bulk drug 
substances will not enable FDA to conduct an adequate review. 
Prescribers of the compounded drug products who may be in the best 
position to explain why there is a clinical need for a compounded drug 
product may provide data in support of a nomination. The following 
information about clinical need is necessary to provide adequate 
support for nominations to the 503B list:
     A statement describing the medical condition(s) that the 
drug product to be compounded with the nominated bulk drug substances 
is intended to treat (i.e., what patient need is met by the drug 
product compounded with the bulk drug substance);
     a list of FDA-approved drug products, if any, that address 
the same medical condition;
     if there are FDA-approved drug products that address the 
same medical condition, an explanation of why a compounded drug product 
is necessary (i.e., why the approved drug product is not suitable for a 
particular patient population);
     if the approved drug product is not suitable for a 
particular patient population, an estimate of the size of the 
population that would need a compounded drug product (e.g., for a drug 
product compounded from bulk because of patient allergies or other 
intolerances to excipients in FDA-approved drug products, FDA expects 
the supporting information to include a good faith estimate of the 
patient

[[Page 37753]]

population with the specific medical condition that suffers from the 
allergy or intolerance, with citations to the literature regarding the 
incidence of the condition or a statement that a search was conducted 
and no references were found); \3\
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    \3\ For example, if there is a need to compound a drug product 
from bulk drug substances due to patient sensitivity to a 
preservative or other excipient in the approved drug product, the 
supporting data is expected to set forth the number of patients for 
whom the drug product is prescribed that are allergic or sensitive 
to that particular excipient.
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     a bibliography of safety and efficacy data for the drug 
compounded using the nominated substance,\4\ if available, including 
any relevant peer-reviewed medical literature; and
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    \4\ 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. Note that data regarding 
safety and efficacy, while relevant, is not indicative of a clinical 
need for a particular bulk drug substance, and additional 
information regarding the clinical need must be provided.
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     if there is an FDA-approved drug product that includes the 
bulk drug substance nominated, an explanation of why the drug product 
proposed to be compounded must be compounded from bulk rather than with 
the FDA-approved drug product.
    General or boilerplate statements regarding the need to compound 
from the bulk drug substance or the benefits of compounding generally 
will not be considered sufficient. Note that the Agency does not 
consider supply issues, such as backorders, that do not rise to the 
level of a drug shortage listed on FDA's drug shortage Web site as 
evidence of a clinical need for compounding with a bulk drug substance, 
and section 503B of the FD&C Act already allows compounding from bulk 
drug substances if the compounded drug product is on the FDA drug 
shortage list. Similarly, considerations of cost and convenience will 
not be considered indicators of clinical need.

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 drug product(s); and
     information about the previous use(s) of the compounded 
drug product(s).

D. Nomination Process

    Because the deadline for submitting nominations has passed, FDA is 
reopening the nomination process so that interested persons can submit 
nominations of bulk drug substances and have the opportunity to provide 
adequate support for placing them on the list. Bulk drug substances 
that were previously nominated need to be renominated. 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.
    Individuals and organizations will be able to comment on nominated 
substances after the nomination period has closed or petition FDA to 
make additional list amendments after the list is published, in 
accordance with 21 CFR 10.30.
    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:

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     Column A--What information is        Column B--put data specific to
               requested?                    the nominated substance
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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.
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.
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.
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 monograph               monograph, if known.
 development?
What medical condition(s) is the drug    Describe the medical
 product compounded with the bulk drug    condition(s) that the drug
 substances intended to treat?            product compounded with the
                                          bulk drug substances is
                                          intended to treat.
Are there other drug products approved   List the other approved
 by FDA to treat the same medical         treatments.
 condition?
If there are FDA-approved drug products  Provide a justification for
 that address the same medical            clinical need, including an
 condition, why is there a clinical       estimate of the size of the
 need for a compounded drug product?      population that would need the
                                          compounded drug.
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.
If there is an FDA-approved drug         Provide an explanation of why
 product that includes the bulk drug      it is necessary to compound
 substance nominated, is it necessary     from the bulk drug substance.
 to compound a drug product from the
 bulk drug substance rather than from
 the FDA-approved drug product?
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).

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Has the bulk drug substance been used    Describe previous uses of the
 previously to compound drug              bulk drug substance in
 product(s)?                              compounding.
Is there any other relevant              Provide any other information
 information?.                            you would like FDA to consider
                                          in evaluating the nomination.
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    Interested persons may submit either electronic nominations to 
http://www.regulations.gov or written nominations to the Division of 
Dockets Management (see ADDRESSES). It is only necessary to send one 
set of nominations. Identify nominations with the docket number found 
in the brackets in the heading of this document. Received nominations 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

    Dated: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-15373 Filed 7-1-14; 8:45 am]
BILLING CODE 4164-01-P


