On October 27, 2015, the U.S. Food and Drug Administration (FDA) published notice of two draft guidance documents in the Federal Register[1]: “Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act”[2] and “Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act.”[3] These draft guidance documents provide insight into the FDA’s intention to exercise enforcement discretion over compounding with certain bulk drug substances while it develops final lists to publish in the Federal Register.

Draft Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act

Section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) describes the conditions that must be satisfied for compounded human drug products to be exempt from Sections 505, 502 (f)(1) and 501(a)(2)(B) of the FD&C Act.[4] Under Section 503A, a compound can be prepared from bulk substances if it has an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph and is a component of an FDA-approved drug. If the bulk substance meets none of these criteria, it must appear on an FDA list of approved bulk drug substances under section 503A(b)(1)(A)(i)(III).

FDA is currently developing this bulk substances list, which it will publish in the Federal Register and promulgate as a regulation pursuant to section 503A(b)(1)(A)(i)(III) of the FD&C Act.[5] However, until the list is finalized as a regulation, FDA has proposed this draft guidance, which, when finalized, will let the industry know how FDA intends to use its enforcement discretion. The draft guidance describes the conditions under which FDA does not intend to take action against a licensed pharmacist or licensed physician for compounding a drug product from a bulk drug substance that has a USP or an NF, or is not a component of a commercially available drug product.[6]

FDA has created four lists for nominated bulk drug substances,[7] which categorize approximately 740 nominated substances in the following categories:

  • 503A List 1 – Bulk Drug Substances Under Evaluation: FDA states that these bulk drug substances may be eligible for inclusion on the 503A bulks list as they were nominated with sufficient supporting information for FDA to evaluate them and they do not appear on any other list.[8]
  • 503A List 2 – Bulk Drug Substances That Raise Safety Concerns: FDA states that these bulk drug substances may be eligible for inclusion on the 503A bulks list as they were nominated with sufficient supporting information to allow FDA to evaluate them. However, FDA has identified safety concerns relating to these substances, so it has placed the substances on a list that may not be used in compounding under section 503A until FDA publishes a final rule authorizing their use under 503A.[9]
  • Section 503A List 3 – Bulk Drug Substances Nominated Without Adequate Support: FDA states that these bulk drug substances may be eligible for inclusion on the 503A bulks list, but FDA found there was not enough supporting information to evaluate them. These substances may be renominated with sufficient supporting information through an FDA docket.[10]
  • Section 503A List 4 – Bulk Drug Substances That May Not Be Used to Compound Drug Products Under Section 503A (to be developed): FDA considered these bulk substances for inclusion on the 503A list, but after notice-and-comment rulemaking, FDA determined that they should not be used.[11]

In this draft guidance, FDA proposes that it will not take action against a state-licensed pharmacy, federal facility or licensed physician compounding a drug product using a bulk drug substance that is not a component of an FDA-approved drug product and that is not the subject of an applicable USP or NF monograph if the following conditions are met:

  1. the bulk substance appears on the 503A List 1;
  2. the bulk drug substance was originally manufactured by an establishment that is registered under Section 510 of the FD&C Act and is accompanied by a valid certificate of analysis from the original manufacturer; and
  3.  the drug is compounded in compliance with all other conditions of Section 503A.[12]

Draft Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act

Section 503B of the FD&C Act describes the conditions that must be satisfied for human drug products compounded by an outsourcing facility to be exempt from Sections 505, 502(f)(1) and 582 of the FD&C Act.[13] Section 503B only allows an entity to compound from bulk substances that appear on an FDA-approved positive list.

FDA is currently developing this bulk substances list for Section 503B facilities that it will publish in the Federal Register and promulgate as a regulation pursuant to section 503B(a)(2)(A) of the FD&C Act.[14] However, until the list is finalized as a regulation, the draft guidance informs the industry of how FDA intends to exercise its enforcement discretion over 503B entities compounding from bulk substances. The 503B draft guidance proposes conditions under which, if finalized, FDA does not intend to take action against an outsourcing facility for compounding a drug product from a bulk drug substance, while FDA develops the list of bulk drug substances that can be used in compounding under section 503B(a)(2)(A)(i) of the FD&C Act.[15]

FDA also published four lists of 503B bulk drug substances to explain how it intends to exercise its enforcement discretion while developing the final Section 503B positive list.[16] The lists categorize approximately 2,590 nominated substances in the following categories:

  • 503B List 1 – Bulk Drug Substances Under Evaluation: FDA states that these bulk drug substances may be eligible for inclusion on the 503B bulks list as they were nominated with sufficient supporting information for FDA to evaluate them and they do not appear on any other list.[17]
  • 503B List 2 – Bulk Drug Substances That Raise Safety Concerns: FDA states that these bulk drug substances may be eligible for inclusion on the 503B bulks list as they were nominated with sufficient supporting information to allow FDA to evaluate them. However, FDA has identified safety concerns relating to these substances, so it has placed the substances on a list that may not be used in compounding under section 503B until FDA publishes a final rule authorizing their use under 503B.[18]
  • Section 503B List 3 – Bulk Drug Substances Nominated Without Adequate Support: FDA states that these bulk drug substances may be eligible for inclusion on the 503B bulks list, but FDA found there was not enough supporting information to evaluate them. These substances may be renominated with sufficient supporting information through an FDA docket.[19]
  • Section 503B List 4 – Bulk Drug Substances That May Not Be Used to Compound Drug Products under Section 503B (to be developed): FDA considered these bulk substances for inclusion on the 503B list, but after notice-and-comment rulemaking, FDA determined that they should not be used.[20]

Similar to 503A bulk substances, FDA states that it will not take action against an outsourcing facility for compounding a drug product using a bulk drug substance if the following conditions are met:

  1. the bulk substance appears on the 503B List 1;
  2. the bulk drug substance was originally manufactured by an establishment that is registered under Section 510 of the FD&C Act and is accompanied by a valid certificate of analysis from the original manufacturer;
  3. the bulk drug substance is the subject of a USP or NF monograph and the bulk drug substance complies with the monograph; and
  4. The drug product is compounded in compliance with all other provisions of Section 503B. [21]

Comment

Interested parties may submit comments regarding the draft guidance documents to FDA by December 28, 2015.