FDA Publishes Final “Interim Policy” for Both Sections 503A and 503B Compounding from Bulk Substances: Section 503B Bulks

By Karla L. Palmer –

FDA published last week two final “Interim Policies” for compounding using bulk substances under Sections 503A and 503B of the Federal Food, Drug and Cosmetic Act (here and here). FDA first published draft policies back in October 2015 (see our previous post here), and received detailed comments from industry (11 comments addressing the Section 503B draft and 14 comments addressing the Section 503A draft). FDA stated it made several changes to the policies in response to the comments and on its own initiative (but the policies do not seem materially different from their drafts). We address these policies in separate posts.

Section 503B

Like the interim policy for Section 503A bulks, FDA’s final interim policy addressing bulk substances under Section 503B is not all that different from its draft policy published in October 2015. The final guidance describes the conditions that facilities must satisfy to compound preparations in compliance with Section 503B. An outsourcing facility must: (1) compound using bulk substances that appear on a list established by the Secretary for which there is a clinical need, or (2) appear on FDA’s published drug shortage list at the time of compounding, distribution and dispensing. Bulk substances must meet the following additional criteria: (1) if a USP/NF monograph exists, then it must comply with the monograph; (2) it must be manufactured in a FDA-registered facility, and (3) it must be accompanied by a valid certificate of analysis. The final guidance also sets forth the information about clinical need that must be established through the bulks nomination process. (Guidance at 3).

Like the draft policy, the final version includes different “bulks” lists establishing what substances may and may not be used in compounding from the original 2,590 unique nominated substances. Of the nominated substances, 1,740 were allergenic extracts/biological products (which are the subject of a Biologics License Applications (BLAs) and not eligible for the Section 503B the bulks list). The complete three lists are published HERE. As with the Section 503A bulks categories, FDA describes the Section 503B bulks categories as follows:

• List I: Bulk Drug Substances Under Evaluation: These substances may be eligible for the 503B bulks list; they were nominated with sufficient supporting information for FDA to evaluate them and do not appear on any other list.
• List 2: Bulk Drug Substances That Raise Significant Safety Risks: These substances were nominated with sufficient supporting information, but FDA identified “significant safety risks” relating to the use of these substances. If FDA adds to List 2, it will publish that communication on its website, advising the substance is no longer eligible for the policies that apply to substances on List 1. The website is available here. Compounders and outsourcing facilities should also subscribe to FDA’s list serve to receive updates to the list.
• List 3: Bulk Drug Substances Nominated Without Adequate Support: These substances may be eligible for inclusion on the final bulks list, but they were nominated without adequate supporting information for FDA to complete its evaluation. FDA notes these substances maybe renominated through a docket established by FDA, but the substances will not be considered until after FDA makes its way through those substances that were nominated with sufficient support in July 2014.

Unlike Section 503A, there is no obligation FDA to consult the Pharmacy Compounding Advisory Committee (PCAC) before nominating substances, but FDA will consider whether PCAC input on any substances would be helpful to the Agency in its review. It will publish lists identifying substances for which it has determined there is a clinical need, and those substances which it reviewed and determined there is no clinical need for use in compounding.      

FDA also sets forth its “Policy” (at pp. 6- 7) for compounding from bulk substances under section 503B: FDA does not intend to take action against an outsourcing facility for compounding a drug using a bulk substance not on bulks list if the drug (1) appeared on FDA’s shortage list within 60 days of distribution and dispensing and (2) was used to fill and order received when the drug while it was on the shortage list. In addition, FDA does not intend to take action against a facility that compounds using a drug that is not on the 503B bulks list and that is not used to compound a drug on FDA’s shortage list provided the following conditions are met:

1. The bulk substance appears on 503B Category 1 on FDA’s website. Note, however, FDA’s “Summary of Policy” chart at page 10 may create confusion on this point because it states the opposite under the “FDA Policy” Column: “The bulk drug substance is not on the 503B bulks list. However, pending a determination about whether to put the bulk substance on the 503B bulks list , FDA does not intend to take action against an outsourcing facility….” (emphasis added). FDA is likely referring to a substance not appearing on the final bulks list that it will promulgate pursuant to notice-and-comment rulemaking. In addition, the original and subsequent manufacturers of the bulk substance must be registered with FDA, the substance must be accompanied by a valid COA, comply with an applicable USP/NF monograph if one exists, and comply with all other provisions of Section 503B.  
2. Category 2 bulk substances are those that FDA has identified present significant risks in compounding.  
3. Category 3 bulk substances may be eligible for inclusion on the Section 503B bulks list but were nominated with insufficient supporting information for FDA to complete its evaluation. These category 3 substances may only be used to compound a drug that appears on FDA’s drug shortage list. FDA states in a footnote (p. 8) that patients with medical conditions that need to be treated with substances that cannot be used in compounding (i.e., in category 3) “may be able to obtain those drugs through FDA’s expanded access program.” As reflected in comments during PCAC meetings, this can be a burdensome process.