[Federal Register Volume 84, Number 170 (Tuesday, September 3, 2019)]
[Notices]
[Pages 46014-46021]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-18932]


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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

[[Page 46015]]

developing 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 nine bulk drug 
substances that FDA has considered and is proposing not to include on 
the list: Dipyridamole, ephedrine sulfate, famotidine, hydralazine 
hydrochloride, methacholine chloride, sodium bicarbonate, sodium 
tetradecyl sulfate, trypan blue, and vecuronium bromide. 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: Submit either electronic or written comments on the notice by 
November 4, 2019 to ensure that the Agency considers your comment on 
this notice before it begins work on a notice reflecting the Agency's 
final decision about whether to include these substances on the 503B 
Bulks List.

ADDRESSES: You may submit comments at any time as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2018-N-3240 for ``List of Bulk Drug Substances For Which There Is a 
Clinical Need Under Section 503B of the Federal Food, Drug, and 
Cosmetic Act.'' Received comments will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or at the Dockets Management 
Staff between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Elizabeth Hankla, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5216, Silver Spring, MD 20993, 301-796-
3110.

SUPPLEMENTARY INFORMATION:

I. Background

A. Statutory and Regulatory Background

    Section 503B of the FD&C Act (21 U.S.C. 353b) describes the 
conditions that must be satisfied for drug products compounded by an 
outsourcing facility to be exempt from 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).\1\
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    \1\ 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)).\2\ 
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.\3\ Outsourcing facilities may or may not obtain 
prescriptions for identified individual patients and can, therefore, 
distribute compounded drugs to healthcare practitioners for ``office 
stock,'' to hold in their offices in advance of patient need.\4\
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    \2\ Compare section 503A(a) of the FD&C Act (exempting drugs 
compounded in accordance with that section) with section 503B(a) of 
the FD&C Act (not providing the exemption from CGMP requirements).
    \3\ Section 503B(b)(4) and (5) of the FD&C Act.
    \4\ Section 503B(d)(4)(C) of the FD&C Act.
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    One of the conditions that must be met for a drug product 
compounded by an outsourcing facility to qualify for exemptions under 
section 503B of the FD&C Act is that the outsourcing facility may not 
compound a drug using a bulk drug substance unless: (1) The bulk drug 
substance appears on a list established

[[Page 46016]]

by the Secretary of Health and Human Services identifying bulk drug 
substances for which there is a clinical need (the 503B Bulks List) or 
(2) 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.\5\
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    \5\ Section 503B(a)(2)(A) of the FD&C Act.
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    Section 503B of the FD&C Act 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.\6\
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    \6\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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    In March 2019, FDA published a notice that identified two bulk drug 
substances, nicardipine hydrochloride and vasopressin, that were 
nominated for inclusion on the 503B Bulks List, and that, after 
consideration, FDA did not include on that list (84 FR 7383). The March 
2019 notice stated that additional bulk drug substances were under 
evaluation, and that additional substances would be the subject of 
future notices. This notice identifies nine nominated substances that 
FDA has evaluated and proposes not to include on the 503B Bulks List.
    For purposes of section 503B, bulk drug substance means an active 
pharmaceutical ingredient as defined in 21 CFR 207.1.\7\ 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.8 9
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    \7\ 21 CFR 207.3.
    \8\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
    \9\ 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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    For further information about drug compounding and the background 
for the 503B Bulks List, see 83 FR 43877 (August 28, 2018).

II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

    FDA requested nominations for specific bulk drug substances for the 
Agency to consider for inclusion on the 503B Bulks List in the Federal 
Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination 
process in the Federal Register of July 2, 2014 (79 FR 37750), and 
provided more detailed information on what FDA 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 the 
FDA's proposed position on each substance along with the rationale for 
that position.\10\ 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.\11\ 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 list 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 list of 
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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    \10\ This is consistent with procedure set forth in section 
503B(a)(2)(A)(i) of the FD&C Act. 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.
    \11\ Section 503B of the FD&C Act 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, and separately identify 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.\12\
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    \12\ On January 13, 2017, FDA announced the availability of a 
revised final guidance for industry that 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 entitled ``Interim 
Policy on Compounding Using Bulk Drug Substances Under Section 503B 
of the Federal Food, Drug, and Cosmetic Act'' (81 FR 37502); 
available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469122.pdf.
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B. Analysis of Substances Nominated for the List

    As noted above, the 503B Bulks List will include bulk drug 
substances for which there is a clinical need. The Agency is beginning 
its evaluation of some of the bulk drug substances that were nominated 
for inclusion on the 503B Bulks List, proceeding case by case, under 
the clinical need standard provided by the statute.\13\ In applying 
this standard to develop the proposals in this notice, FDA is 
interpreting the phrase ``bulk drug substances for which there is a 
clinical need'' to mean that the 503B Bulks List may include a bulk

[[Page 46017]]

drug substance if: (1) There is a clinical need for an outsourcing 
facility to compound the 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 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 to be within the 
meaning of ``clinical need.''
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    \13\ On March 4, 2019, FDA announced the availability of a final 
guidance 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) (84 FR 7390); 
available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM602276.pdf. 
This guidance describes FDA policies for developing the 503B Bulks 
List, including the Agency's interpretation of the phrase ``bulk 
drug substances for which there is a clinical need,'' as it is used 
in section 503B of the FD&C Act.
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    The bulk drug substances that we are addressing in this notice are 
components of FDA-approved drug products, and we therefore began our 
evaluation 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 a drug 
product compounded using a bulk drug substance that is a component of 
the approved drug is intended to address that attribute, there is no 
clinical need to compound a drug product using that bulk drug 
substance. Rather, such compounding would unnecessarily expose patients 
to the risks associated with drug products that do not 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 a 
clinical need for outsourcing facilities to compound using the bulk 
drug substance, and we would analyze the question further.\14\ If the 
answer to either of these questions is ``no,'' we generally would not 
include the bulk drug substance on the 503B Bulks List, because there 
would not be a basis to conclude that there may be a clinical need to 
compound drug products using the bulk drug substance instead of 
administering or starting with an approved drug product.
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    \14\ FDA's 503B Bulks Evaluation Guidance sets forth four 
additional factors that the Agency generally intends to consider in 
such an analysis. Because we did not answer ``yes'' to both of the 
threshold questions for dipyridamole, ephedrine sulfate, famotidine, 
hydralazine hydrochloride, methacholine chloride, sodium 
bicarbonate, sodium tetradecyl sulfate, trypan blue, or vecuronium 
bromide, we did not consider these four additional factors in this 
proposal.
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III. Substances Proposed for the 503B Bulks List

    Because the substances in this notice are components of FDA-
approved drug products, we considered whether: (1) There is a basis to 
conclude that an attribute of each FDA-approved drug product containing 
the bulk drug substance makes each one medically unsuitable to treat 
certain patients for a condition that FDA has identified for 
evaluation, and the 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.
    The nine bulk drug substances that have been evaluated and that FDA 
is proposing not to place on the list are as follows: dipyridamole, 
ephedrine sulfate, famotidine, hydralazine hydrochloride, methacholine 
chloride, sodium bicarbonate, sodium tetradecyl sulfate, trypan blue, 
and vecuronium bromide. The reasons for FDA's proposals are included 
below.

A. Dipyridamole

    Dipyridamole has been nominated for inclusion on the 503B Bulks 
List to compound drug products that are used for thallium myocardial 
perfusion imaging for the evaluation of coronary artery disease in 
patients who cannot exercise adequately.\15\ The proposed route of 
administration is intravenous, the proposed dosage form is an 
injection, and the proposed strength is 1 milligram per milliliter (mg/
mL) in a 50 mL and 60 mL syringe. The nominated bulk drug substance is 
a component of FDA-approved drug products (e.g., ANDAs 074521 and 
074939). FDA-approved dipyridamole is available as a 5 mg/mL injection 
for intravenous administration.16 17 Per its labeling, it 
should be diluted to a final concentration of less than or equal to 2.5 
mg/mL.\18\
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    \15\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0031.
    \16\ See, e.g., ANDA 074521 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175.xml.
    \17\ Dipyridamole is also approved as an oral tablet and in 
combination with aspirin as an extended release capsule.
    \18\ According to the label for ANDA 074521, dipyridamole 
injection should be diluted in at least a 1:2 ratio with with sodium 
chloride injection 0.45%, sodium chloride injection 0.9% or dextrose 
injection 5% for a total volume of approximately 20 to 50 mL.
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1. Suitability of FDA-Approved Drug Product
    The nomination does not identify an attribute of the FDA-approved 
drug products that makes them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nomination does not explain why the 5 mg/mL 
injection (for dilution) is medically unsuitable for certain patients. 
Accordingly, with respect to the dipyridamole drug products proposed to 
be compounded, FDA finds no basis to conclude that an attribute of the 
FDA-approved product makes it medically unsuitable to treat certain 
patients for a condition that FDA has identified for evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not take the position or provide support for 
the position that drug products containing dipyridamole must be 
compounded from bulk drug substances rather than by diluting the 
approved drug product. FDA finds no basis to conclude that the 
dipyridamole drug products proposed in the nominations must be 
compounded using a bulk drug substance rather than the approved drug 
product.

B. Ephedrine Sulfate

    Ephedrine sulfate has been nominated for inclusion on the 503B 
Bulks List to compound drug products that treat acute bronchospasm, 
drug induced hypotension due to anesthesia, and nasal congestion.\19\ 
The proposed route of administration is intravenous, the proposed 
dosage form is a preservative-

[[Page 46018]]

free solution, and the proposed strengths are 5 mg/mL and 10 mg/mL.\20\ 
The nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., NDAs 208943 and 208289). FDA-approved ephedrine sulfate 
is available as a single-dose, preservative-free 50 mg/mL solution for 
intravenous administration.21 22 Per its labeling, ephedrine 
sulfate must be diluted before administration to achieve the desired 
concentration as an intravenous bolus or intravenous infusion. The 
labeling includes preparation instructions for making a solution 
containing a final concentration of 5 mg/mL of ephedrine sulfate 
injection for bolus intravenous administration.
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    \19\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \20\ Nominator(s) proposed to compound a preservative-free 
solution. However, they failed to acknowledge that there is a 
preservative-free formulation of ephedrine sulfate that is marketed 
or explain why that formulation would be medically unsuitable for 
certain patients.
    \21\ See, e.g., NDA 208943 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/6df5e5f1-6375-45ff-9905-f19927e92ee2/6df5e5f1-6375-45ff-9905-f19927e92ee2.xml.
    \22\ Per the label for NDA 208943, each mL contains ephedrine 
sulfate 50 mg in water for injection as a single-dose product.
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1. Suitability of FDA-Approved Drug Product
    The nominations do not identify an attribute of the FDA-approved 
drug products that make them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nominations do not explain why the single-
dose, preservative-free 50 mg/mL solution (for dilution) is medically 
unsuitable for certain patients. Accordingly, with respect to the 
ephedrine sulfate drug products proposed to be compounded, FDA finds no 
basis to conclude that an attribute of the FDA-approved product makes 
it medically unsuitable to treat certain patients for a condition that 
FDA has identified for evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not take the position or provide support for the 
position that drug products containing ephedrine sulfate must be 
compounded from bulk drug substances rather than by diluting the 
approved drug product. FDA finds no basis to conclude that the 
ephedrine sulfate drug products proposed in the nominations must be 
compounded using a bulk drug substance rather than the approved drug 
product.

C. Famotidine

    Famotidine has been nominated for inclusion on the 503B Bulks List 
to compound drug products that treat duodenal ulcer disease, 
esophagitis, gastrointestinal reflux disease, and gastric ulcer 
disease, among other conditions.\23\ The proposed route of 
administration is intravenous, the proposed dosage form is a 
preservative-free solution and a diluted injection solution, and the 
proposed strengths range from 2 mg/mL to 10 mg/mL.\24\ The nominated 
bulk drug substance is a component of FDA-approved drug products (e.g., 
ANDAs 078641 and 078642). FDA-approved famotidine is available as a 
single-dose, preservative-free 10 mg/mL solution for intravenous 
administration.25 26 27 Per its labeling, famotidine may be 
diluted to a final concentration of 4 mg/mL or 2 mg/mL for bolus 
administration.\28\
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    \23\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \24\ Nominator(s) proposed to compound a preservative-free 
solution. However, they failed to acknowledge that there is a 
preservative-free formulation of famotidine that is marketed or 
explain why that formulation would be medically unsuitable for 
certain patients.
    \25\ See, e.g., ANDAs 079641 and 079641 labeling available as of 
the date of this notice at https://www.accessdata.fda.gov/spl/data/99bd2efa-ef75-4daf-ae24-ab574adf1a1e/99bd2efa-ef75-4daf-ae24-ab574adf1a1e.xml.
    \26\ Per the label for ANDA 079641, famotine injection is 
available in a non-preserved single-dose vial.
    \27\ Famotidine is also approved as an oral tablet and a powder 
for suspension for oral administration.
    \28\ According to the label for ANDA 078642, to prepare 
famotidine intravenous solutions, aseptically dilute 2 mL of 
famotidine injection, USP (solution containing 10 mg/mL) with 0.9% 
Sodium Chloride Injection or other compatible intravenous solution 
(see Stability, Famotidine Injection, USP) to a total volume of 
either 5 mL or 10 mL and inject over a period of not less than 2 
minutes. In addition, to prepare famotidine intravenous infusion 
solutions, aseptically dilute 2 mL of famotidine injection, USP with 
100 mL of 5% dextrose or other compatible solution (see Stability, 
Famotidine Injection, USP), and infuse over a 15- to 30-minute 
period.
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1. Suitability of FDA-Approved Drug Product
    The nominations do not identify an attribute of the FDA-approved 
drug products that make them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nominations do not explain why the single-
dose, preservative-free 10 mg/mL solution (for dilution) is medically 
unsuitable for certain patients. Accordingly, with respect to the 
famotidine drug products proposed to be compounded, FDA finds no basis 
to conclude that an attribute of the FDA-approved product makes it 
medically unsuitable to treat certain patients for a condition that FDA 
has identified for evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not take the position or provide support for the 
position that drug products containing famotidine must be compounded 
from bulk drug substances rather than by diluting the approved drug 
product. FDA finds no basis to conclude that the famotidine drug 
products proposed in the nominations must be compounded using a bulk 
drug substance rather than the approved drug product.

D. Hydralazine Hydrochloride (HCl)

    Hydralazine HCl has been nominated for inclusion on the 503B Bulks 
List to compound drug products that treat essential hypertension.\29\ 
The proposed routes of administration are intravenous and 
intramuscular, the proposed dosage form is a preservative-free 
solution, and the proposed strengths are 0.2 mg/mL and 20 mg/mL.\30\ 
The nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., ANDAs 204680 and 040730). FDA-approved hydralazine HCl 
is available as a preservative-free 20 mg/mL solution for intravenous 
and intramuscular administration.31 32 33
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    \29\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \30\ Nominator(s) proposed to compound a preservative-free 
solution. However, they failed to acknowledge that there is a 
preservative-free formulation of hydralazine HCl that is marketed or 
explain why that formulation would be medically unsuitable for 
certain patients.
    \31\ See, e.g., ANDA 204680 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/92e234dc-d44e-4e81-b305-4a47b1cfe2c3/92e234dc-d44e-4e81-b305-4a47b1cfe2c3.xml.
    \32\ Per the label for ANDA 204680, hydralazine HCl is available 
in a preservative-free, single-dose vial.
    \33\ Hydralazine HCl is also approved as an oral tablet, as an 
oral capsule in combination with hydrochlorothiazide, and as an oral 
tablet in combination with isosorbide dinitrate.
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1. Suitability of FDA-Approved Drug Product
    The nominations do not identify an attribute of the FDA-approved 
drug products that make them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nominations do not explain why the 
preservative-free 20 mg/mL solution is medically unsuitable for certain 
patients. Accordingly, with respect to the hydralazine HCl drug

[[Page 46019]]

products proposed to be compounded, FDA finds no basis to conclude that 
an attribute of the FDA-approved product makes it medically unsuitable 
to treat certain patients for a condition that FDA has identified for 
evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not take the position or provide support for the 
position that drug products containing hydralazine HCl must be 
compounded from bulk drug substances rather than by diluting the 
approved drug product. FDA finds no basis to conclude that hydralazine 
HCl drug products proposed in the nominations must be compounded using 
a bulk drug substance rather than the approved drug product.

E. Methacholine Chloride

    Methacholine chloride has been nominated for inclusion on the 503B 
Bulks List to compound drug products that aid in the diagnosis of 
bronchial airway hyperactivity.\34\ The proposed route of 
administration is inhalation tapering dose kits, the proposed dosage 
form is an inhalant, and the proposed strengths are as follows: 8 
dilutions (0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/
mL, 8 mg/mL, 16 mg/mL) and 10 dilutions (0.031 mg/mL, 0.0625 mg/mL, 
0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL, 
16 mg/mL). The nominated bulk drug substance is a component of an FDA-
approved drug product (NDA 019193). FDA-approved methacholine chloride 
is available as a 100 mg/vial powder for solution to be administered 
only by inhalation.\35\ Per its labeling, methacholine chloride is 
reconstituted and diluted to the following concentrations with 0.9% 
sodium chloride injection or 0.9% sodium chloride injection containing 
0.4% phenol (pH 7.0): 0.025 mg/mL, 0.25 mg/mL, 2.5 mg/mL, 10 mg/mL, and 
25 mg/mL.
---------------------------------------------------------------------------

    \34\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
    \35\ See, e.g., NDA 208943 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/7f538d73-80e2-4c00-911a-df2637e5a4d1/7f538d73-80e2-4c00-911a-df2637e5a4d1.xml.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product
    The nomination does not identify an attribute of the FDA-approved 
drug product that makes it medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nomination does not explain why the 100 mg/
vial powder for solution (for reconstitution) is medically unsuitable 
for certain patients. Accordingly, with respect to the methacholine 
chloride drug products proposed to be compounded, FDA finds no basis to 
conclude that an attribute of the FDA-approved product makes it 
medically unsuitable to treat certain patients for a condition that FDA 
has identified for evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not take the position or provide support for 
the position that drug products containing methacholine chloride must 
be compounded from bulk drug substances rather than by diluting the 
approved drug product. FDA finds no basis to conclude that the 
methacholine chloride drug products proposed in the nominations must be 
compounded using a bulk drug substance rather than the approved drug 
product.

F. Sodium Bicarbonate

    Sodium bicarbonate has been nominated for inclusion on the 503B 
Bulks List to compound drug products that treat various conditions, 
including metabolic acidosis, certain drug intoxications, severe 
diarrhea, and indigestion.\36\ The proposed route of administration is 
intravenous, the proposed dosage forms are an injectable, preservative-
free solution, and injection solutions, and the proposed strengths 
range from 4.2% to 8.4%, as well as unspecified higher 
concentrations.\37\ The nominated bulk drug substance is a component of 
FDA-approved drug products (e.g., ANDAs 203449 and 202494). FDA-
approved sodium bicarbonate is available as a single-dose, 
preservative-free 1 milliequivalent (mEq/mL) (8.4%) solution for 
intravenous administration.38 39 40
---------------------------------------------------------------------------

    \36\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298. Also, see Docket No. FDA-2015-N-
3469, document no. FDA-2015-N-3469-0095.
    \37\ Nominator(s) proposed to compound a preservative-free 
solution. However, they failed to acknowledge that there is a 
preservative-free formulation of sodium bicarbonate that is marketed 
or explain why that formulation would be medically unsuitable for 
certain patients.
    \38\ See, e.g., ANDA 203449 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/0e955d36-928c-4f09-9b34-0cc954e5b1f4/0e955d36-928c-4f09-9b34-0cc954e5b1f4.xml.
    \39\ Per the label for ANDA 203449, the solutions contain no 
bacteriostat, antimicrobial agent, or added buffer and are intended 
only for use as a single-dose injection.
    \40\ Sodium bicarbonate is also approved in combination with 
other ingredients as an injectable, solution for irrigation, and 
various oral formulations.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product
    The nominations do not identify an attribute of the FDA-approved 
drug products that make them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nominations do not explain why the single-
dose, preservative-free 1 mEq/mL (8.4%) solution is medically 
unsuitable for certain patients. A nomination submitted by the 
Outsourcing Facilities Association states that it may be necessary to 
compound a product with greater concentration than is commercially 
available, but the nomination does not identify specific higher 
concentrations that the nominator proposes to compound or provide any 
data or information supporting the need for a higher concentration. 
Accordingly, with respect to the sodium bicarbonate drug products 
proposed to be compounded, FDA finds no basis to conclude that an 
attribute of the FDA-approved product makes it medically unsuitable to 
treat certain patients for a condition that FDA has identified for 
evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not take the position or provide support for the 
position that the proposed sodium bicarbonate products with 
concentrations at or below 8.4% (1 mEQ/mL) must be compounded from bulk 
drug substances rather than by diluting the approved drug product. In 
light of the analysis in section III.6.a. above, we do not consider 
whether a bulk drug substance must be used to compound a sodium 
bicarbonate drug product at concentrations higher than 8.4%. FDA finds 
no basis to conclude that the sodium bicarbonate drug products proposed 
in the nominations must be compounded using a bulk drug substance 
rather than the approved drug product.

G. Sodium Tetradecyl Sulfate

    Sodium tetradecyl sulfate has been nominated for inclusion on the 
503B Bulks List to compound drug products that treat varicose 
veins.\41\ The proposed route of administration is intravenous, the 
proposed dosage form is an injection solution, and the proposed 
strengths range from 0.1% to 3%. The nominated

[[Page 46020]]

bulk drug substance is a component of an FDA-approved drug product 
(ANDA 040541). FDA-approved sodium tetradecyl sulfate is available as a 
20 mg/2 mL (10 mg/mL; 1%) and 60 mg/2 mL (30 mg/mL; 3%) solution for 
intravenous administration.\42\
---------------------------------------------------------------------------

    \41\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
    \42\ See, e.g., ANDA 040541 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/5450f902-fb17-44b8-8c4b-4fefeed1908e/5450f902-fb17-44b8-8c4b-4fefeed1908e.xml.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product
    The nomination does not identify an attribute of the FDA-approved 
drug product that makes it medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nomination does not explain why the 20 mg/2 
mL (10 mg/mL; 1%) and 60 mg/2 mL (30 mg/mL; 3%) solutions are medically 
unsuitable for certain patients. Accordingly, with respect to the 
sodium tetradecyl sulfate drug products proposed to be compounded, FDA 
finds no basis to conclude that an attribute of the FDA-approved 
product makes it medically unsuitable to treat certain patients for a 
condition that FDA has identified for evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not take the position or provide support for 
the position that drug products containing sodium tetradecyl sulfate 
must be compounded from bulk drug substances rather than by diluting 
the approved drug product. FDA finds no basis to conclude that the 
sodium tetradecyl sulfate drug products proposed in the nominations 
must be compounded using a bulk drug substance rather than the approved 
drug product.

H. Trypan Blue

    Trypan blue has been nominated for inclusion on the 503B Bulks List 
to compound drug products that aid in staining the eye for cataract 
surgery and vitrectomy.\43\ The proposed route of administration is 
intraocular,\44\ the proposed dosage form is a preservative-free 
solution, and the proposed strengths are 0.05%, 0.06%, and 0.15%.\45\ 
The nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., NDAs 021670 and 022278). FDA-approved trypan blue is 
available as a single-dose, preservative-free 0.06% and 0.15% solution 
for intraocular administration.46 47
---------------------------------------------------------------------------

    \43\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \44\ One nominator proposed the following route of 
administration and dosage form: Ophthalmic solution; injection. 
Thus, FDA determined that the proposed route of administration is 
intraocular.
    \45\ Nominator(s) proposed to compound a preservative-free 
solution. However, they failed to acknowledge that there is a 
preservative-free formulation of trypan blue that is marketed or 
explain why that formulation would be medically unsuitable for 
certain patients.
    \46\ See, e.g., NDA 021670 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/7c57aaf4-e1a1-d191-e053-2a91aa0a757a/7c57aaf4-e1a1-d191-e053-2a91aa0a757a.xml 
and NDA 022278 labeling available as of the date of this notice at 
https://www.accessdata.fda.gov/spl/data/7c57f83d-da8f-2499-e053-2a91aa0afe8e/7c57f83d-da8f-2499-e053-2a91aa0afe8e.xml.
    \47\ Per the label for NDA 021670, each mL contains: 0.6 mg 
trypan blue, 1.9 mg sodium mono-hydrogen orthophosphate, 0.3 mg 
sodium di-hydrogen orthophosphate, 8.2 mg sodium chloride, and water 
for injection. Per the label for NDA 022278, each mL contains: 1.5 
mg trypan blue, 1.9 mg sodium mono-hydrogen orthophosphate, 0.3 mg 
sodium di-hydrogen orthophosphate, 8.2 mg sodium chloride, and water 
for injection.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product
    The nominations do not identify an attribute of the FDA-approved 
drug products that make them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nominations do not explain why the single-
dose, preservative-free 0.06% and 0.15% solutions are medically 
unsuitable for certain patients. Accordingly, with respect to trypan 
blue drug products proposed to be compounded, FDA finds no basis to 
conclude that an attribute of the FDA-approved product makes it 
medically unsuitable to treat certain patients for a condition that FDA 
has identified for evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not take the position or provide support for the 
position that drug product containing trypan blue must be compounded 
from bulk drug substances rather than by diluting the approved drug 
product. FDA finds no basis to conclude that the trypan blue drug 
products proposed in the nominations must be compounded using a bulk 
drug substance rather than the approved drug product.

I. Vecuronium Bromide

    Vecuronium bromide has been nominated for inclusion on the 503B 
Bulks List to compound drug products that facilitate endotracheal 
intubation.\48\ The proposed route of administration is rapid 
intravenous injection or by intravenous infusion using an infusion 
control device, the proposed dosage form is an injection, and the 
propose strengths are 10 mg/10 mL (1 mg/mL) in sterile water for 
injection and 100 mg/100 mL (1 mg/mL) in 0.9% sodium chloride solution. 
The nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., ANDAs 079001 and 206670). FDA-approved vecuronium 
bromide is available as a 10 mg/vial and 20 mg/vial lyophilized powder 
for solution for intravenous administration (bolus dosing or continuous 
infusion).\49\ Per its labeling, vecuronium bromide is 1 mg/mL after 
reconstitution with either 10 mL (10 mg/vial) or 20 mL (20 mg/vial) of 
diluent.\50\
---------------------------------------------------------------------------

    \48\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0011.
    \49\ See, e.g., ANDA 079001 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/82d6bc45-04a5-409a-9223-da1884b2468f/82d6bc45-04a5-409a-9223-da1884b2468f.xml.
    \50\ In addition, the labeling contains infusion rate 
information for two separate strength solutions: 0.1 mg/mL (10 mg of 
vecuronium bromide in 100 mL solution) and 0.2 mg/mL (20 mg of 
vecuronium bromide in 100 mL solution).
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product
    The nomination does not identify an attribute of the FDA-approved 
drug products that make them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nomination does not explain why the 10 mg/
vial and 20 mg/vial lyophilized powders for solution (for 
reconstitution) are medically unsuitable for certain patients. 
Accordingly, with respect to the vecuronium bromide drug products 
proposed to be compounded, FDA finds no basis to conclude that an 
attribute of the FDA-approved product makes it medically unsuitable to 
treat certain patients for a condition that FDA has identified for 
evaluation.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not take the position or provide support for 
the position that drug products containing vecuronium bromide must be 
compounded from bulk drug substances rather than by diluting the 
approved drug product. FDA finds no basis to conclude that the 
vecuronium bromide drug products proposed in the

[[Page 46021]]

nominations must be compounded using a bulk drug substance rather than 
the approved drug product.

IV. Other Issues Raised in Nominations

    Some of the bulk drug substance nominations included in this notice 
state that there could be a benefit gained from providing drug products 
containing each of these bulk drug substances that do not require 
dilution or reconstitution prior to administration. 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 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 establish that 
drug products in the relevant concentrations, including ready-to-use 
products, cannot be prepared from the approved drug products. 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, neither of which falls within 
the meaning of clinical need to compound a drug product using a bulk 
drug substance.
    Some of the nominations for the substances in this notice include 
statements that these substances should be added to the 503B Bulks List 
because compounding from the bulk drug substance could help outsourcing 
facilities address drug shortages and supply disruptions of approved 
drugs. As noted above, section 503B of the FD&C Act 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 nominations to be within the meaning of 
``clinical need'' for compounding with a bulk drug substance.\51\
---------------------------------------------------------------------------

    \51\ Please see the final guidance 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) (84 FR 7390); available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM602276.pdf and the Federal Register notice entitled ``List of 
Bulk Drug Substances for Which There Is a Clinical Need Under 
Section 503B of the Federal Food, Drug, and Cosmetic Act'' available 
at https://www.federalregister.gov/documents/2019/03/04/2019-03810/list-of-bulk-drug-substances-for-which-there-is-a-clinical-need-under-section-503b-of-the-federal.
---------------------------------------------------------------------------

    Some of the nominations for the substances in this notice assert 
that it would be preferable to compound a drug product using a bulk 
drug substance rather than using an approved drug product; however, 
they do not take the position or provide support for the position that 
a bulk drug substance must be used to prepare these concentrations.\52\
---------------------------------------------------------------------------

    \52\ For example, the nominations do not take the position or 
provide support for the position that a drug product prepared by 
starting with the approved drug would be unsuitable for 
administration.
---------------------------------------------------------------------------

V. Conclusion

    For the reasons stated above, we find no basis to conclude that 
there is a clinical need for outsourcing facilities to compound drug 
products using the bulk drug substances dipyridamole, ephedrine 
sulfate, famotidine, hydralazine hydrochloride, methacholine chloride, 
sodium bicarbonate, sodium tetradecyl sulfate, trypan blue, and 
vecuronium bromide. We therefore propose to not include dipyridamole, 
ephedrine sulfate, famotidine, hydralazine hydrochloride, methacholine 
chloride, sodium bicarbonate, sodium tetradecyl sulfate, trypan blue, 
and vecuronium bromide on the 503B Bulks List.

    Dated: August 27, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-18932 Filed 8-30-19; 8:45 am]
 BILLING CODE 4164-01-P


