FDA Briefing Document Pharmacy Compounding Advisory Committee

429 Pages·2016·15.84 MB·English

by  James Flahive

FDA Briefing Document

Pharmacy Compounding Advisory Committee (PCAC)

Meeting

March 8 and 9, 2016

The attached package contains background information prepared by the Food and Drug
Administration (FDA) for the panel members of the Pharmacy Compounding Advisory
Committee (advisory committee). We are bringing certain compounding issues to this advisory
committee to obtain the committee’s advice. The background package may not include all issues
relevant to the final regulatory recommendation and instead is intended to focus on issues
identified by the Agency for discussion by the advisory committee. The FDA background
package often contains assessments and/or conclusions and recommendations written by
individual FDA reviewers. Such conclusions and recommendations do not necessarily represent
the final position of the individual reviewers, nor do they necessarily represent the final position
of the Review Division or Office. The FDA does not intend to issue a final determination on the
issues at hand until input from the advisory committee process has been considered and all
reviews have been finalized. The final determination may be affected by issues not discussed at
the advisory committee meeting.
Table of Contents

I. Introduction ................................................................................................................... 3

A. Bulk Drug Substances That Can Be Used by Compounders under Section 503A

.............................................................................................................................. 3

B. Difficult to Compound ......................................................................................... 4

II. Substances Nominated for Inclusion on the Section 503A Bulk Drug Substances List

(in order of discussion at the meeting) .......................................................................... 5

III. Drug Products That Present Demonstrable Difficulties for Compounding ................. 6

A. Metered Dose Inhalers (MDIs) ......................................................................... 6

B. Dry Powder Inhalers (DPIs) ............................................................................. 7

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I. Introduction

Section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) describes the
conditions that must be satisfied for human drug products compounded by a licensed
pharmacist in a State-licensed pharmacy or Federal facility, or by a licensed physician, to
be exempt from the following three sections of the FD&C Act: section 505 (concerning
the approval of drugs under new drug applications or abbreviated new drug applications);
section 502(f)(1) (concerning the labeling of drugs with adequate directions for use); and
section 501(a)(2)(B) (concerning current good manufacturing practice requirements).

On November 27, 2013, President Obama signed the Drug Quality and Security Act,
legislation that contains important provisions relating to the oversight of compounding of
human drugs. Title I of this law, the Compounding Quality Act, created a new section
503B of the FD&C Act under which a compounder can elect to register as an outsourcing
facility. Registered outsourcing facilities can compound drugs without receiving patient
specific prescriptions or orders. If the conditions under section 503B of the FD&C Act
are satisfied, drugs compounded by or under the direct supervision of a licensed
pharmacist in a registered outsourcing facility may qualify for exemptions from the new
drug approval requirements (section 505 of the FD&C Act), the requirement to label
products with adequate directions for use (section 502(f)(1) of the FD&C Act), and the
Drug Supply Chain Security Act (section 582 of the FD&C Act). Outsourcing facilities
remain subject to current good manufacturing practice (CGMP) requirements.

A. Bulk Drug Substances That Can Be Used by Compounders
under Section 503A

One of the conditions that must be met for a compounded drug product to qualify for the
exemptions in section 503A of the FD&C Act is that a licensed pharmacist or licensed
physician compounds the drug product using bulk drug substances that:

(1) Comply with the standards of an applicable United States Pharmacopeia
(USP) or National Formulary (NF) monograph, if a monograph exists, and the
USP chapter on pharmacy compounding;
(2) If such a monograph does not exist, are drug substances that are components
of drugs approved by the Secretary; or
(3) If such a monograph does not exist and the drug substance is not a component
of a drug approved by the Secretary, appears on a list developed by the
Secretary through regulations issued by the Secretary under subsection (c) of
section 503A.

(See section 503A(b)(1)(A)(i) of the FD&C Act).

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FDA is considering those substances nominated for inclusion on the list of bulk drug
substances that may be used to compound drug products under section 503A of the
FD&C Act. As discussed at the February 2015 PCAC meeting, in the July 2014 Federal
Register notice (79 FR 37747) (July 2, 2014) soliciting nominations for the section 503A
bulk drug substances list, FDA proposed the following criteria to evaluate the nominated
substances:

(1) The physical and chemical characterization of the substance;
(2) Any safety issues raised by the use of the substance in compounded drug
products;
(3) Historical use of the substance in compounded drug products, including
information about the medical condition(s) the substance has been used to
treat and any references in peer-reviewed medical literature; and
(4) The available evidence of effectiveness or lack of effectiveness of a drug
product compounded with the substance, if any such evidence exists.

No single one of these criteria is dispositive. Rather, the agency is considering each
criterion in the context of the others and balancing them, on a substance-by-substance
basis, in deciding whether a particular substance is appropriate for inclusion on the list.

B. Difficult to Compound

Both sections 503A and 503B of the FD&C Act require compounded drug products to

satisfy several requirements to qualify for the statutory exemptions from the FD&C Act.

One of those requirements is that the compounded drug product is not one that the

Agency has

identified as being demonstrably difficult to compound. See sections 503A(b)(3)(A);

503B(a)(6).

Specifically, section 503A states that the compounded drug product may not be one that

“presents demonstrable difficulties for compounding that reasonably demonstrate an

adverse effect on the safety or effectiveness of that drug product.” See section

503A(b)(3).

Similarly, section 503B states that the compounded drug, or category of drugs, either is

not one that “present[s] demonstrable difficulties for compounding that are reasonably

likely to lead to an adverse effect on the safety or effectiveness of the drug or category of

drugs, taking into the account the risks and benefits to patients,” or is compounded in

accordance with “conditions that are necessary to prevent the drug or category of drugs

from presenting [such] demonstrable difficulties.” See section 503B(a)(6).

FDA presented criteria to the advisory committee at its June 2015 meeting. These

criteria included the following criteria which were described in more detail in the briefing

materials for the meeting:

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1. Complex Formulation
2. Complex Drug Delivery Mechanism
3. Complex Dosage Form
4. Bioavailability
5. Compounding Process Complexity
6. Physiocochemical or Analytical Testing Complexity

The committee provided the following recommendations which we have incorporated
into the criteria for evaluation of whether drug products are demonstrably difficult to
compound under sections 503A and 503B of the FD&C Act. Specifically, the committee
recommended consideration of: (1) the compatibility and/or stability of the active
pharmaceutical ingredients in the final dosage form (now incorporated under revised
factor 1) and (2) the container closure system which may interact with the compounded
drug (now incorporated into revised factor 3). In addition, the Agency has revised the
document to clarify the description of each factor to more specifically track the statutory
language. Attached at Tab 7 is a revised set of proposed criteria.
II. Substances Nominated for Inclusion on the Section 503A
Bulk Drug Substances List (in order of discussion at the
meeting)

A. Quinacrine Hydrochloride (Tab 1)

1. Nominations (Tab 1a)
(a) Professional Compounding Centers of America
(b) National Community Pharmacists Association
(c) Fagron

2. FDA Reviews (Tab 1b)

B. Boswellia (Tab 2)

1. Nominations (Tab 2a)
(a) McGuff
(b) American Association of Naturopathic Physicians
(c) Alliance for Natural Health USA
(d) Integrative Medical Consortium
(e) American College for Advancement in Medicine
(f) Fagron

2. FDA Review (Tab 2b)

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C. Aloe Vera 200:1 Freeze Dried (Tab 3)

1. Nominations (Tab 3a)
(a) International Academy of Compounding Pharmacists
(b) Fagron

2. FDA Review (Tab 3b)

D. D-Ribose (Tab 4)

1. Nominations (Tab 4a)
(a) Fagron

2. FDA Reviews (Tab 4b)

E. Chondroitin Sulfate (Tab 5)

1. Nominations (Tab 5a)
(a) National Community Pharmacists Association
(b) International Academy of Compounding Pharmacists

2. FDA Review (Tab 5b)

F. Acetyl-L-Carnitine (Tab6)

1. Nominations (Tab 6a)
(a) Alliance for Natural Health USA
(b) Integrative Medical Consortium
(c) McGuff
(d) American Association of Naturopathic Physicians
(e) American College for Advancement in Medicine
(f) National Community Pharmacists Association
(g) Professional Compounding Centers of America
(h) International Academy of Compounding Pharmacists

2. FDA Review (Tab 6b)
III. Drug Products That Present Demonstrable Difficulties for
Compounding

The revised proposed criteria for determining whether a drug product or category of drug
products is demonstrably difficult to compound are found within the document attached
at Tab 7.
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A. Metered Dose Inhalers (MDIs) (Tab 8)

1. Nominations (Tab 8a)
(a) GlaxoSmithKline
(b) Public Citizen’s Health Research Group

2. FDA Review (Tab 8b)

B. Dry Powder Inhalers (DPIs) (Tab 9)

1. Nominations (Tab 9a)
(a) GlaxoSmithKline
(b) Public Citizen’s Health Research Group

2. FDA Review (Tab 9b)

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Tab 1

Quinacrine Hydrochloride
Tab 1a

Quinacrine Hydrochloride

Nominations