Bulk Drug Substances Used in Compounding Under Section 503A of the FD&C Act

State-licensed physicians and pharmacists that compound under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) may only compound drug products using bulk drug substances that:

1. comply with an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph if one exists, and the USP chapter on pharmacy compounding;
2. are components of FDA-approved drug products if an applicable USP or NF monograph does not exist; or
3. appear on FDA’s list of bulk drug substances that can be used in compounding (the 503A bulks list) if such a monograph does not exist and the substance is not a component of an FDA-approved drug product.

In addition, bulk drug substances must be accompanied by a valid certificate of analysis and must have been manufactured by an establishment registered with FDA under section 510 of the FD&C Act. The agency urges compounders to know your bulks supplier.

Developing the 503A Bulks List

FDA solicited nominations for bulk drug substances in 2015 to include on the 503A bulks list and is consulting with the Pharmacy Compounding Advisory Committee for and the U.S. Pharmacopeia Convention for input as it evaluates them.

FDA issued a final regulation in February 2019, List of Bulk Drug Substances That Can Be Used To Compound Drug Products, in which it placed six nominated substances on the list and did not place four other substances on the list, and established the criteria it will use to evaluate substances for inclusion on the list.

FDA also issued a proposed regulation in September 2019, Amendments to the List of Bulk Drug Substances That Can Be Used to Compound Drug Products, in which it proposed to place five nominated substances on the list and not to place 26 other substances on the list. After considering public comments, the agency will issue a final regulation. The agency also will continue to evaluate bulk drug substances that have been nominated with sufficient supporting information, and address those substances on a rolling basis through notice-and-comment rulemaking.

Interim Policy on Compounding Drugs Using Bulk Drug Substances

FDA issued a revised final guidance in January 2017, Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry, which is in place while FDA develops the 503A bulks list. The guidance describes conditions under which the agency does not intend to take action against state-licensed pharmacies, federal facilities, and licensed physicians for compounding drug products from bulk drug substances that cannot otherwise be used under section 503A. The agency issued this guidance document to avoid unnecessary disruption to patient treatment while FDA evaluates the bulk drug substances nominated for inclusion on the 503A bulks list.

The guidance document describes three categories of bulk drug substances nominated by the public for use in compounding. The categories are:

• Category 1 – These substances may be eligible for inclusion on the list of bulk drug substances that can be used in compounding under section 503A, were nominated with sufficient information for FDA to evaluate them, and do not appear on any other list. FDA does not intend to take action against a compounder for compounding drugs using bulk drug substances listed in Category 1, provided that the conditions described in the guidance document are met.
• Category 2 – These are bulk drug substances that were nominated with sufficient supporting information for FDA to evaluate them and they may be eligible for inclusion on the 503A bulks list. However, FDA has identified significant safety risks relating to the use of these substances in compounding, and therefore, pending further evaluation, drug products compounded using these substances are not eligible for the policy described for the substances in Category 1. FDA would consider taking action against a compounder for compounding drug products with this bulk drug substance under its general enforcement policies. Visit Safety Risks Associated with Certain Bulk Drug Substances Nominated for Use in Compounding for the substances and a summary of the identified safety risks.
• Category 3 – These substances may be eligible for inclusion on the 503A bulks list, but were nominated without sufficient supporting information for FDA to evaluate them. These substances are not eligible for the policy that applies to substances in Category 1. FDA would consider taking action against a compounder for compounding drug products with this bulk drug substance under its general enforcement policies. These substances can be re-nominated with sufficient supporting information through Bulk Drug Substances That Can Be Used To Compound Drug Products in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic Act; Establishment of a Public Docket.

FDA intends to update these categories to reflect any new nominations or other changes on a periodic basis.

New Draft Guidance: Interim Policy on Compounding Using Bulk Drug Substances

FDA issued a new draft guidance in December 2023 describing the agency’s interim policy regarding compounding using certain bulk drug substances that have been nominated for use in compounding under section 503A of the FD&C Act. If the guidance document is finalized in its current form, a bulk drug substance nominated on or after the date the agency issues the final guidance document would not be categorized, as described in the guidance, and would not be within the scope of the interim enforcement policy described in FDA’s guidance.

Bulk drug substances that appear in category 1, as described in the draft guidance document, before the guidance is finalized would not be affected by this change. These bulk drug substances may continue to be within the scope of the interim enforcement policy until the agency decides on inclusion of these substances on the 503A list or unless the agency removes the substances from category 1 based on, for example, information about safety risks.

FDA continues to evaluate sufficiently supported nominations for the 503A bulks lists in accordance with the processes and criteria described in the FD&C Act.