For compounded drugs to be exempt from certain drug requirements, drugs must be compounded using bulk substances that (1) comply with monograph standards; (2) are components of previously approved drugs; or (3) appear on particular lists issued by the FDA, which are currently undergoing consideration. Outsourcing facilities must not use bulk drug substances, unless the substances are on a particular list or are used to compound a drug that is on the drug shortage list. The FDA clarified its regulatory policy concerning sections 503A and 503B of the federal Food, Drug, and Cosmetic Act (FDC) (21 U.S.C. §301) in interim guidances that will stand until the agency develops final bulk substances lists (Notice, 81 FR 37500, June 10, 2016; Notice, 81 FR 37502, June 10, 2016).
503A. Compounded drugs that meet certain criteria are exempt from drug approval, labeling, and current good manufacturing practice requirements. These drugs must use bulk substances that:
- comply with standards of a United States Pharmacopeia (USP) or National Formulary (NF) monograph;
- if no monograph exists, be components of approved drugs; or
- appear on a list developed through regulations.
A bulk drug substance "becomes an active ingredient or a finished dosage form of the drug, but does not include intermediates used in the synthesis of such substances" (21 C.F.R. sec. 207.3(4)). These substances must be manufactured by a registered establishment and have a valid certificate of analysis (COA). While the FDA considers bulk drug substances that were nominated for the bulk substance list, it does not intend to take regulatory action against those compounding drug products using substances that are not on a monograph or part of an approved drug if the nomination included adequate information for evaluation, and if the substance does not seem to present safety risks. The FDA will ultimately publish its list of approved 503A bulk substances in a Final rule.
503B. Compounding facilities registered as outsourcing facilities are restricted in their use of bulk drug substances, and the FDA is developing a separate 503B bulks list. For outsourcing facilities to be exempt from approval, labeling, and drug supply chain security requirements, it must only use bulk substances that appear on a list identifying substances for which exists a clinical need, or the drug compounded is on the FDA’s drug shortage list. These substances must also comply with an appropriate monograph, be manufactured by a registered establishment, and be accompanied by a COA.
The FDA received over 2,000 nominations in its initial process, and reopened the nomination process with clearer instructions after determining that many of the nominations were either ineligible or inadequately supported. After the second round of nominations, the agency identified that 1,740 of the substances were biologics that are not eligible for 503B compounding exemptions. The FDA will continue to consider nominated substances, and publish regular notices regarding its position on each substance. In the meantime, the agency does not intent to take action on a facility for compounding a drug using a bulk substance that is not on the list, as long as the drug appeared on the FDA’s drug shortage list within 60 days of dispensing and was to fill an order that was received while the drug was on the shortage list. If these conditions are not met, the agency still does not intend to take action as long as:
- the substance is a category one substance;
- the manufacturers are registered;
- there is a valid COA;
- the substance complies with applicable monographs; and
- it is compounded in compliance with 503B.
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