[Federal Register Volume 84, Number 42 (Monday, March 4, 2019)]
[Notices]
[Pages 7383-7388]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-03810]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-3240]


List of Bulk Drug Substances for Which There Is a Clinical Need 
Under Section 503B of the Federal Food, Drug, and Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is evaluating 
substances that have been nominated for inclusion on a list of bulk 
drug substances (active pharmaceutical ingredients) for which there is 
a clinical need (the 503B Bulks List). Drug products that outsourcing 
facilities compound using bulk drug substances on the 503B Bulks List 
can qualify for certain exemptions from the Federal Food, Drug, and 
Cosmetic Act (FD&C Act) provided certain conditions are met. This 
notice identifies two bulk drug substances that FDA has considered and 
is not including on the list at this time: Nicardipine hydrochloride 
and vasopressin. Additional bulk drug substances nominated by the 
public for inclusion on this list are currently under consideration and 
will be the subject of future notices.

DATES: The announcement of the notice is published in the Federal 
Register on March 4, 2019.

ADDRESSES: Submit electronic comments on bulk drug substances nominated 
for the 503B Bulks List to Docket No. FDA-2015-N-3469. Submit written 
comments on bulk drug substances nominated for the 503B Bulks List to 
the Dockets Management Staff (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should 
be identified with the docket number found in brackets in the heading 
of this document.

FOR FURTHER INFORMATION CONTACT: Elizabeth Hankla, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5216,

[[Page 7384]]

Silver Spring, MD 20993, 301-796-3110.

SUPPLEMENTARY INFORMATION: 

I. Background

A. Drug Compounding

    Compounded drug products can serve an important role for patients 
for whom an FDA-approved drug product is not appropriate, such as 
patients who have an allergy and need a medication to be made without a 
certain dye or hospital inpatients who need infusions of a drug 
combined with a particular diluent not specified in the approved 
product labeling. However, they also pose a higher risk to patients 
than FDA-approved drugs. In 2012, contaminated injectable drug products 
that a State-licensed compounding pharmacy shipped to patients and 
healthcare practitioners across the country caused a fungal meningitis 
outbreak that resulted in more than 60 deaths and 750 cases of 
infection.\1\ This was the most serious of a long history of outbreaks 
and other serious adverse events associated with contaminated, 
superpotent, or otherwise poor quality compounded drugs.
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    \1\ See https://www.cdc.gov/HAI/outbreaks/meningitis.html.
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    In response to this outbreak, Congress enacted the Drug Quality and 
Security Act (Pub. L. 113-54), which, among other things, added new 
section 503B to the FD&C Act (21 U.S.C. 353b) and created a new 
category of compounders known as outsourcing facilities.\2\ Drug 
products compounded by outsourcing facilities in accordance with the 
conditions of section 503B are exempt from the following three sections 
of the FD&C Act: Section 505 (21 U.S.C. 355) (concerning the approval 
of drugs under new drug applications (NDAs) or abbreviated new drug 
applications (ANDAs)); section 502(f)(1) (21 U.S.C. 352(f)(1)) 
(concerning the labeling of drugs with adequate directions for use); 
and section 582 (21 U.S.C. 360eee-1) (concerning drug supply chain 
security requirements).\3\
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    \2\ See Public Law 113-54, section 102(a), 127 Stat. 587, 587-
588 (2013). Other compounders, which are not the subject of this 
notice, are regulated under section 503A of the FD&C Act (21 U.S.C. 
353a). These include licensed pharmacists in State-licensed 
pharmacies or Federal facilities, and licensed physicians, who have 
not registered an outsourcing facility with FDA. Drug products 
compounded by section 503A compounders are exempt from sections 505 
(new drug approval requirements), 502(f)(1) (labeling with adequate 
directions for use), and 501(a)(2)(B) (CGMP requirements) if the 
conditions of section 503A are met, including that compounding is 
based on the receipt of valid prescriptions for identified 
individual patients (section 503A(a)). In general, section 503A 
compounders do not register with and are not routinely inspected by 
FDA and are primarily overseen by the States.
    \3\ Section 503B(a) of the FD&C Act.
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    Drug products compounded under the conditions in section 503B are 
not exempt from current good manufacturing practice (CGMP) requirements 
in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).\4\ 
Outsourcing facilities are also subject to FDA inspections according to 
a risk-based schedule, specific adverse event reporting requirements, 
and other conditions that help to mitigate the risks of the drug 
products they compound.\5\ Outsourcing facilities may or may not obtain 
prescriptions for identified individual patients and may, therefore, 
distribute compounded drugs to healthcare practitioners for ``office 
stock'' to hold in their offices in advance of patient need.\6\
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    \4\ Compare section 503A(a) of the FD&C Act (exempting drugs 
compounded in accordance with section 503A from CGMP requirements) 
with section 503B(a) of the FD&C Act (not exempting drugs compounded 
in accordance with section 503B from CGMP requirements).
    \5\ Section 503B(b)(4) and (5) of the FD&C Act.
    \6\ Section 503B(d)(4)(C) of the FD&C Act.
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    Because compounded drug products are not FDA-approved, they have 
not undergone FDA premarket review for safety, effectiveness, and 
quality. Although outsourcing facilities must comply with CGMP 
requirements and are inspected by FDA according to a risk-based 
schedule, their drug products have not been determined to be safe or 
effective for the conditions of use reflected in drug product labeling 
and have not been subjected to a premarket inspection or associated 
with a finding of manufacturing quality, all of which are part of the 
drug approval process. Because compounded drug products are subject to 
a lower regulatory standard than FDA-approved drug products, they 
should only be used by patients who could not use an FDA-approved drug 
product.
    When a compounded drug is appropriate for a patient, outsourcing 
facilities may be able to prepare that drug using an FDA-approved drug 
product as the starting material. On other occasions it may be 
necessary to compound the drug from a bulk drug substance.\7\ Section 
503B limits the bulk drug substances that outsourcing facilities can 
use in compounding to those that are used to compound drugs in shortage 
or that appear on a list developed by FDA of bulk drug substances for 
which there is a clinical need. Section 503B includes this limitation, 
among others, to help prevent outsourcing facilities from growing into 
conventional manufacturing operations making unapproved new drug 
products. Allowing outsourcing facilities to compound a drug product 
from a bulk drug substance that is a component of an FDA-approved drug 
product because of, for instance, economic incentives, when a patient's 
clinical needs could be met by the approved drug product or a drug 
product compounded from the approved drug product would reduce the 
incentive for applicants to seek FDA approval of drug products and to 
continue to market them. The drug approval process is critical to 
ensure pharmaceuticals meet regulatory standards established for 
quality, safety, and effectiveness. In addition, when it is feasible to 
compound a drug product by starting with an approved drug product, 
there are certain benefits of doing so over starting with a bulk drug 
substance, including benefits relating to the assurances associated 
with premarket review by FDA for safety, effectiveness, and quality.
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    \7\ For a fuller discussion of these issues, see FDA's guidance 
for industry entitled ``Evaluation of Bulk Drug Substances Nominated 
for Use in Compounding Under Section 503B of the Federal Food, Drug, 
and Cosmetic Act'' (503B Bulks Evaluation Guidance), particularly 
sections II.B. and C., available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM602276.pdf.
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    In sum, section 503B's limitation on the 503B Bulks List to bulk 
drug substances for which there is a clinical need serves important 
public health functions. First, it helps to limit patient exposure to 
compounded drug products, which have not been demonstrated to be safe 
and effective, to those situations in which the compounded drug product 
is necessary for patient treatment. Second, it preserves the incentives 
for applicants to invest in the research and testing required to obtain 
FDA approval and to continue to manufacture FDA-approved drug products, 
thereby helping to maintain a supply of high-quality, safe, and 
effective drugs.

B. Statutory and Regulatory Background

    Section 503B of the FD&C Act describes the conditions that must be 
satisfied for drug products compounded by an outsourcing facility to be 
exempt from the approval, labeling, and drug supply chain security 
requirements cited above.\8\ One of the conditions that must be met for 
a drug product compounded by an outsourcing facility to qualify for 
exemptions under section 503B is that the outsourcing facility may not 
compound a drug using a bulk drug substance unless the bulk drug 
substance appears on a list established by the Secretary of Health and 
Human

[[Page 7385]]

Services identifying bulk drug substances for which there is a clinical 
need (the 503B Bulks List); or the drug compounded from such bulk drug 
substances appears on the drug shortage list in effect under section 
506E of the FD&C Act (FDA's drug shortage list) (21 U.S.C. 356e) at the 
time of compounding, distribution, and dispensing.\9\
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    \8\ Section 503B(a) of the FD&C Act.
    \9\ Section 503B(a)(2)(A) of the FD&C Act.
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    Section 503B directs FDA to establish the 503B Bulks List by (1) 
publishing a notice in the Federal Register proposing bulk drug 
substances to be included on the list, including the rationale for such 
proposal; (2) providing a period of not less than 60 calendar days for 
comment on the notice; and (3) publishing a notice in the Federal 
Register designating bulk drug substances for inclusion on the 
list.\10\
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    \10\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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    For purposes of section 503B, bulk drug substance means an active 
pharmaceutical ingredient as defined in 21 CFR 207.1(b).\11\ Active 
pharmaceutical ingredient means any substance that is intended for 
incorporation into a finished drug product and is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease, or to affect the 
structure or any function of the body, but the term does not include 
intermediates used in the synthesis of the substance.12 13
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    \11\ 21 CFR 207.3.
    \12\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
    \13\ Inactive ingredients are not subject to section 503B(a)(2) 
of the FD&C Act and will not be included in the 503B Bulks List 
because they are not included within the definition of a bulk drug 
substance. Pursuant to section 503B(a)(3), inactive ingredients used 
in compounding must comply with the standards of an applicable 
United States Pharmacopeia or National Formulary monograph, if a 
monograph exists.
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II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

    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 inclusion on the 503B Bulks List. In response to that 
request, interested groups and individuals nominated a wide variety of 
substances. However, many of those nominations were not for substances 
used in compounding as active pharmaceutical ingredients or did not 
include sufficient information to allow FDA to evaluate the nominated 
substance. To improve the efficiency of the process for the development 
of the list of bulk drug substances, FDA reopened the nomination 
process in the Federal Register of July 2, 2014 (79 FR 37750) and 
provided more detailed information on what it needs to evaluate 
nominations for the list. On October 27, 2015 (80 FR 65770), the Agency 
opened a new docket, FDA-2015-N-3469, to provide an opportunity for 
interested persons to submit new nominations of bulk drug substances or 
to renominate substances with sufficient information.
    As FDA evaluates bulk drug substances, it intends to publish 
notices for public comment in the Federal Register that describe its 
proposed position on each substance along with the rationale for that 
position.\14\ After considering any comments on FDA's proposals 
regarding whether to include nominated substances on the 503B Bulks 
List, FDA intends to consider whether input from the Pharmacy 
Compounding Advisory Committee (PCAC) on the nominations would be 
helpful to the Agency in making its determination, and if so, it will 
seek PCAC input.\15\ Depending on its review of the docket comments and 
other relevant information before the Agency, FDA may finalize its 
proposed determination without change, or it may finalize a 
modification to its proposal to reflect new evidence or analysis 
regarding clinical need. FDA will then publish in the Federal Register 
a final determination identifying the bulk drug substances for which it 
has determined there is a clinical need and FDA's rationale in making 
that final determination. FDA will also publish in the Federal Register 
a final determination regarding those substances it considered but 
found that there is no clinical need to use in compounding and FDA's 
rationale in making this decision.
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    \14\ This is consistent with procedures set forth in section 
503B(a)(2)(A)(i). Although the statute only directs FDA to issue a 
Federal Register notice and seek public comment when it proposes to 
include bulk drug substances on the 503B Bulks List, we intend to 
seek comment when the Agency has evaluated a nominated substance and 
proposes either to include or not to include the substance on the 
list.
    \15\ Section 503B does not require FDA to consult the PCAC 
before developing a 503B Bulks List.
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    FDA intends to maintain a current list of all bulk drug substances 
it has evaluated on its website, with separate lists for bulk drug 
substances it has placed on the 503B Bulks List and those it has 
decided not to place on the 503B Bulks List. FDA will only place a bulk 
drug substance on the 503B Bulks List where it has determined there is 
a clinical need for outsourcing facilities to compound drug products 
using the bulk drug substance. If a clinical need to compound drug 
products using the bulk drug substance has not been demonstrated, based 
on the information submitted by the nominator and any other information 
considered by the Agency, FDA will not place a bulk drug substance on 
the 503B Bulks List.
    FDA intends to evaluate the bulk drug substances nominated for the 
503B Bulks List on a rolling basis. FDA will evaluate and publish in 
the Federal Register its proposed and final determinations in groups of 
bulk drug substances until all nominated substances that were 
sufficiently supported have been evaluated and either placed on the 
503B Bulks List or identified as bulk drug substances that were 
considered but determined not to be appropriate for inclusion on the 
503B Bulks List.\16\
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    \16\ On June 10, 2016 (81 FR 37502), FDA announced the 
availability of a guidance for industry (revised January 2017) 
entitled ``Interim Policy on Compounding Using Bulk Drug Substances 
Under Section 503B of the Federal Food, Drug, and Cosmetic Act''; 
available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469122.pdf. 
This guidance provides additional information regarding FDA's 
policies for bulk drug substances nominated for the 503B Bulks List 
pending our review of nominated substances under the ``clinical 
need'' standard.
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B. Analysis of Substances Nominated for the List

    As noted above, section 503B(a)(2)(A)(i) provides that the 503B 
Bulks List is to include ``bulk drug substances for which there is a 
clinical need.'' The Agency is evaluating bulk drug substances that 
were nominated for inclusion on the 503B Bulks List, proceeding case by 
case, under the standard provided by the statute.\17\ In applying this 
standard to make determinations regarding the substances set forth in 
this notice, FDA interprets the phrase ``bulk drug substances for which 
there is a clinical need'' to mean that the 503B Bulks List may include 
a bulk drug substance if: (1) There is a clinical need for an 
outsourcing facility to compound a drug product, and (2) the drug 
product must be compounded using the bulk drug substance. FDA is not 
interpreting supply issues, such as backorders, to be within the 
meaning of ``clinical need'' for compounding with a bulk drug 
substance. Section 503B separately provides for compounding from bulk 
drug substances under the exemptions from the FD&C Act discussed above 
if the drug product compounded from the bulk drug

[[Page 7386]]

substance is on the FDA drug shortage list at the time of compounding, 
distribution, and dispensing. Additionally, we are not considering cost 
of the compounded drug product as compared with an FDA-approved drug 
product when assessing ``clinical need.''
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    \17\ See 503B Bulks Evaluation Guidance, supra n.7 (describing 
FDA's policies for developing the 503B Bulks List, including the 
interpretation of the phrase ``bulk drug substances for which there 
is a clinical need,'' as it is used in section 503B).
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    The bulk drug substances that we are addressing in this notice are 
components of FDA-approved drug products, and we evaluated them by 
asking the following questions:
    (1) Is there a basis to conclude, for each FDA-approved product 
that includes the nominated bulk drug substance, that (a) an attribute 
of the FDA-approved drug product makes it medically unsuitable to treat 
certain patients for a condition that FDA has identified for 
evaluation, and (b) the drug product proposed to be compounded is 
intended to address that attribute?
    (2) Is there a basis to conclude that the drug product proposed to 
be compounded must be produced from a bulk drug substance rather than 
from an FDA-approved drug product?
    The reason for question (1) is that unless an attribute of the FDA-
approved drug is medically unsuitable for certain patients, and the 
drug product to be compounded is intended to address that attribute, we 
do not expect that there will be a clinical need for a patient to use a 
compounded drug product. Rather, such compounding would unnecessarily 
expose patients to the risks associated with drug products that have 
not been shown to meet the standards applicable to FDA-approved drug 
products for safety, effectiveness, quality, and labeling and would 
undermine the drug approval process. The reason for question (2) is 
that to place a bulk drug substance on the 503B Bulks List, FDA must 
determine that there is a clinical need for outsourcing facilities to 
compound a drug product using the bulk drug substance rather than 
starting with an FDA-approved drug product.
    If the answer to both of these questions is ``yes,'' there may be 
clinical need for outsourcing facilities to compound using the bulk 
drug substance, and we would analyze the question further.\18\ If the 
answer to either of these questions is ``no,'' there generally would 
not be a basis to conclude that there is a clinical need to compound 
drug products using the bulk drug substance instead of administering or 
starting with an approved drug product, and we would generally not 
include the bulk drug substance on the 503B Bulks List.
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    \18\ Under the analysis described in FDA's 503B Bulks Evaluation 
Guidance, the additional analysis would consist of the consideration 
of four additional factors. We did not answer ``yes'' to both of the 
threshold questions for nicardipine hydrochloride or vasopressin, so 
we did not consider these additional factors in our determination 
not to include nicardipine hydrochloride or vasopressin on the 503B 
Bulks List.
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III. Substances Proposed for the 503B Bulks List

    In August 2018, the Agency issued a Federal Register notice in 
which it evaluated three nominated bulk drug substances under the 
statutory standard--bumetanide, nicardipine hydrochloride, and 
vasopressin--and proposed not to include them on the 503B Bulks List 
(the August notice). In this notice, after review of the comments 
submitted to the docket for the August notice, FDA is making its final 
determination with regard to nicardipine hydrochloride and vasopressin. 
At this time, FDA is not making a final determination regarding 
bumetanide. This substance remains under consideration by FDA.

1. Nicardipine Hydrochloride

    Nicardipine hydrochloride has been nominated for inclusion on the 
503B Bulks List.\19\ The proposed route of administration is 
intravenous, the proposed dosage form is injection, and the proposed 
strength is 0.1 to 2.5 milligrams per milliliter (mg/mL). This 
nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., NDAs 022276 and 019734). FDA has approved nicardipine 
hydrochloride drug products as 0.1 mg/mL and 0.2 mg/mL solutions ready 
for intravenous administration (or ``ready to use'') and as a 2.5 mg/mL 
single-dose vial that must be diluted prior to 
infusion.20 21 The single dose vial (NDA 022276) contains an 
excipient, benzoic acid; the ready-to-use solutions (NDA 019734) do not 
contain benzoic acid.
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    \19\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0002.
    \20\ See, e.g., labeling available as of the date of this notice 
at https://www.accessdata.fda.gov/spl/data/32756b4e-a977-47ac-9620-0c1ed74d7606/32756b4e-a977-47ac-9620-0c1ed74d7606.xml (ready-to-use) 
and https://www.accessdata.fda.gov/spl/data/5444784f-fefe-4352-afd1-b4c487165f3a/5444784f-fefe-4352-afd1-b4c487165f3a.xml (for 
dilution).
    \21\ Nicardipine hydrochloride is also approved as an oral 
capsule. See, e.g., ANDA 074642.
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    Because nicardipine hydrochloride is a component of FDA-approved 
drug products, we considered whether (1) there is a basis to conclude 
that an attribute of each FDA-approved drug product makes each one 
medically unsuitable to treat certain patients for a condition that FDA 
has identified for evaluation, and the nicardipine hydrochloride drug 
product proposed to be compounded is intended to address that attribute 
in each FDA-approved drug product; and (2) whether the drug product 
proposed to be compounded must be compounded using a bulk drug 
substance.
a. Suitability of FDA-Approved Drug Products.
    The nomination proposed to include on the list nicardipine 
hydrochloride injection compounded to concentrations of 0.1 mg/mL 
through 2.5 mg/mL. The nomination does not identify attributes of the 
approved nicardipine hydrochloride products that make them medically 
unsuitable to treat certain patients and that the proposed compounded 
drug products are intended to address. Specifically, the nomination did 
not explain why ready-to-use nicardipine hydrochloride injection at 0.1 
mg/mL and 0.2 mg/mL, and the 2.5 mg/mL single dose vial (for dilution) 
are medically unsuitable for certain patients.
    A commenter on FDA's proposal not to include nicardipine 
hydrochloride on the 503B Bulks List indicated that an attribute of 
approved nicardipine hydrochloride injections, the presence of the 
excipient benzoic acid, makes those approved drug products medically 
unsuitable for patients who have an allergy to benzoic acid and that 
drug products would be compounded from the bulk drug substance 
nicardipine hydrochloride without benzoic acid. However, the commenter 
did not acknowledge the availability of FDA-approved benzoic acid-free 
nicardipine hydrochloride ready-to-use solutions for intravenous 
administration or explain why these approved drug products would be 
medically unsuitable for patients who have an allergy to benzoic 
acid.\22\
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    \22\ See NDAs 022276 and 019734.
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    Accordingly, with respect to the nicardipine hydrochloride drug 
products proposed to be compounded, FDA finds no basis to conclude that 
an attribute of each of the approved drug products makes each one 
medically unsuitable to treat certain patients for a condition that FDA 
has identified for evaluation.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination provided no basis to conclude that drug products 
containing nicardipine hydrochloride must be compounded using a bulk 
drug substance rather than using an FDA-approved drug product. The 
nomination

[[Page 7387]]

and a related comment assert that it would be preferable to compound a 
drug product using a bulk drug substance than using an approved drug 
product that requires dilution. However, the nomination and comment do 
not take the position or provide support for the position that a bulk 
drug substance must be used to prepare the proposed concentrations of 
nicardipine hydrochloride. For example, the nomination does not 
indicate that the desired concentrations of nicardipine hydrochloride 
could not be prepared by diluting the approved drug product in a form 
that is suitable for patient administration. Nor is FDA aware of data 
or information suggesting this cannot be done. We note that the 
approved labeling of a nicardipine hydrochloride drug product directs 
the drug product to be diluted to a concentration within that range. We 
do not consider whether a benzoic acid-free nicardipine hydrochloride 
drug product must be compounded using the bulk drug substance because 
benzoic acid-free nicardipine hydrochloride product is FDA-approved at 
concentrations of 0.1 mg/mL and 0.2 mg/mL and because patients for whom 
these FDA-approved drug products may be medically unsuitable were not 
identified in section III.1.a. In sum, FDA finds no basis to conclude 
that drug products must be compounded using a bulk drug substance 
rather than the approved drug product.

2. Vasopressin

    Vasopressin was nominated for inclusion on the 503B Bulks List to 
compound drug products that treat septic shock, post-cardiotomy shock, 
diabetes insipidus, and hypotension.\23\ The proposed route of 
administration is intravenous; the proposed dosage form is injection. 
The nominators proposed a range of specific concentrations (0.1, 0.2, 
0.4, and 1 units/mL (U/mL)) and concentrations above that range without 
identifying any specific concentration. This nominated bulk drug 
substance is the active ingredient of the FDA-approved drug VASOSTRICT 
(NDA 204485). VASOSTRICT is approved as a 20 U/mL intravenous infusion 
that, per its labeling, should be diluted with normal saline or 5 
percent dextrose in water to either 0.1 U/mL or 1 U/mL for intravenous 
administration.\24\
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    \23\ See Docket No. FDA-2015-N-3469, documents No. FDA-2015-N-
3469-0012 and -0023.
    \24\ The labeling as of the date of this notice is available at 
https://www.accessdata.fda.gov/spl/data/4166e423-659e-4fe4-8a3c-2394434d00dd/4166e423-659e-4fe4-8a3c-2394434d00dd.xml.
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    VASOSTRICT is available in a multidose vial that contains the 
preservative agent chlorobutanol and in a single dose vial that does 
not contain chlorobutanol. The VASOSTRICT labeling includes a 
contraindication regarding chlorobutanol that applies to the 
chlorobutanol-containing product.\25\ Because vasopressin is a 
component of an FDA-approved drug product, we considered whether (1) 
there is a basis to conclude that an attribute of each FDA-approved 
drug product containing vasopressin makes each one medically unsuitable 
to treat certain patients for a condition that FDA has identified for 
evaluation, and the vasopressin drug product proposed to be compounded 
is intended to address that attribute; and (2) whether the drug product 
proposed to be compounded must be compounded using a bulk drug 
substance.
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    \25\ The labeling states that VASOSTRICT is ``contraindicated in 
patients with known allergy or hypersensitivity to 8-L-arginine 
vasopressin or chlorobutanol.'' However, this contraindication is 
not applicable to the formulation of VASOSTRICT marketed without 
chlorobutanol. As described in the package insert, the VASOSTRICT 10 
mL solution contains chlorobutanol, while the 1 mL solution does 
not.
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a. Suitability of FDA-Approved Drug Product
    The nominations propose vasopressin for the 503B Bulks List so that 
it can be used to compound drug product at various concentrations, some 
lower than undiluted VASOSTRICT and others higher. However, the 
nominations and the comments do not identify an attribute of VASOSTRICT 
that makes it medically unsuitable for patients and that the compounded 
products are intended to address.
    The nomination that refers to products with a higher concentration 
than VASOSTRICT does not identify any data or information as to the 
need for a higher concentration than the approved product, nor does the 
nomination identify specific higher concentrations it proposes to 
compound. In addition, the nomination does not identify patients for 
whom a concentration at or below 20 U/mL is medically unsuitable and 
who would therefore require a higher concentration, and FDA is not 
aware of patients who would need concentrations above 20 U/mL.
    Both nominations also propose to compound vasopressin at specific 
concentrations lower than undiluted VASOSTRICT. However, the proposed 
concentrations are within the range described in the labeling for the 
FDA-approved drug product, and the proposed route of administration 
(intravenous) is the same as that of VASOSTRICT. The nominations do not 
identify an attribute of the approved drug product that would make it 
medically unsuitable for patients or show that the compounded drug 
product would address that attribute.
    Commenters on FDA's proposal not to include vasopressin on the 503B 
Bulks List assert that an attribute of VASOSTRICT that makes it 
medically unsuitable to treat patients is that it contains a 
preservative, chlorobutanol. Chlorobutanol-containing VASOSTRICT is 
contraindicated in patients who have an allergy or hypersensitivity to 
this excipient. However, the commenters fail to acknowledge that the 
preservative-free formulation of VASOSTRICT is also marketed and fail 
to explain why that formulation would be medically unsuitable for 
patients who have an allergy to chlorobutanol.
    Accordingly, with respect to the vasopressin drug products proposed 
to be compounded, FDA finds no basis to conclude that an attribute of 
VASOSTRICT makes it medically unsuitable to treat certain patients.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    As noted previously, the nominations propose to compound drug 
products containing vasopressin at concentrations that are lower than 
undiluted VASOSTRICT, but that are within the range of VASOSTRICT's 
final, post-dilution concentrations. The nominations do not take the 
position or provide support for the position that a bulk drug substance 
rather than the FDA-approved drug product must be used to prepare these 
lower concentrations. For example, the nominations do not explain, or 
even suggest, that the desired concentration of vasopressin cannot be 
prepared by diluting the approved drug product.\26\ We do not consider 
whether a chlorobutanol-free vasopressin drug product must be 
compounded using the bulk drug substance because a chlorobutanol-free 
vasopressin product is FDA-approved and because patients for whom this 
FDA-approved drug product may be medically unsuitable were not 
identified in section III.2.a. In addition, in light of the analysis in 
section III.2.a. above, we do not

[[Page 7388]]

consider whether a bulk drug substance must be used to compound a 
vasopressin drug product at concentrations higher than 20 U/mL. In sum, 
FDA finds no basis to conclude that drug products must be compounded 
using a bulk drug substance rather than the approved drug product.
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    \26\ For example, the nomination does not take the position or 
provide support for a position that a drug product prepared by 
starting with the approved drug product would be unsuitable for 
patient administration. We also note that outsourcing facilities 
often prepare ready-to-use forms of drug products for healthcare 
practitioners by compounding (e.g., diluting) approved drug 
products, including VASOSTRICT.
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IV. Other Issues Raised in Nominations and Comments

    The nominations for nicardipine hydrochloride and vasopressin and 
some comments state that there could be a benefit in the availability 
of drug products containing each of these bulk drug substances that do 
not require dilution prior to administration. We note first, with 
respect to nicardipine hydrochloride, that two ready-to-use nicardipine 
drug products are FDA-approved, and the comments do not identify 
patients for whom these products are medically unsuitable. More 
broadly, as explained above, when a bulk drug substance is a component 
of an approved drug, FDA asks whether there is a basis to conclude that 
an attribute of each approved drug product makes each one medically 
unsuitable to treat certain patients for their condition, an 
interpretation that protects patients and the integrity of the drug 
approval process. The nominations and comments do not show that the 
approved drug product, when not manufactured in the ready-to-use form, 
is medically unsuitable for certain patients. Nor do the nominations 
and comments establish that drug products in the relevant 
concentrations, including ready-to-use products, cannot be prepared 
from the approved nicardipine and vasopressin drug products.\27\ 
Rather, they propose to compound a ready-to-use product from bulk drug 
substances to seek improved efficiency for prescribers or healthcare 
providers, or to address the possibility that the approved drug might 
be mishandled by a medical professional. That is not clinical need to 
compound a drug product using a bulk drug substance.
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    \27\ With respect to vasopressin specifically, a comment states 
that vasopressin cannot be produced in ready-to-use form because the 
approved drug product is labeled with an in-use time of 18 hours 
room temperature or 24 hours refrigerated once diluted. In contrast, 
the commenter says that it could compound a ``pre-diluted'' drug 
product from bulk vasopressin with a beyond-use-date (BUD) of 60 
days. We note that, in accordance with CGMP provisions, outsourcing 
facilities can conduct stability studies on vasopressin compounded 
using the approved drug product to assign a BUD based on data.
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    The nominations for nicardipine hydrochloride and vasopressin and 
some comments also include statements that these substances should be 
added to the 503B Bulks List because compounding from the bulk drug 
substance could help outsourcing facilities to address drug shortages 
and disruptions in supply of approved drugs intended for injection. As 
noted above, section 503B contains a separate provision for compounding 
from bulk drug substances to address a drug shortage, and we do not 
interpret the other price- and supply-related issues advanced by the 
nomination to be within the meaning of ``clinical need'' for 
compounding with a bulk drug substance.

V. Conclusion

    For the reasons stated above, we find no clinical need for an 
outsourcing facility to compound using the bulk drug substances 
nicardipine hydrochloride and vasopressin and, therefore, we are not 
including nicardipine hydrochloride and vasopressin on the 503B Bulks 
List.

    Dated: February 26, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-03810 Filed 3-1-19; 8:45 am]
 BILLING CODE 4164-01-P