April 6, 2018

FDA Issues Draft Guidance on Bulk Substances for Compounding by Outsourcing Facilities

Holland & Knight Healthcare Blog
Andrew I. Namkung | Benjamin T. Tso

On March 23, 2018, the U.S. Food and Drug Administration (FDA) released draft guidance regarding the process through which it proposes to evaluate bulk drug substances nominated for use in compounding by outsourcing facilities registered under section 503B of the Federal Food, Drug and Cosmetic Act (FD&C Act). The FDA is accepting comments and suggestions on the draft guidance until May 25, 2018.

Section 503B permits the compounding of sterile drugs by registered "outsourcing facilities." Under Section 503B, outsourcing facilities may not compound a drug using a "bulk drug substance" (or, the active pharmaceutical ingredient that is intended for incorporation into a finished drug product) unless: (a) the bulk drug substance appears on a list established by the FDA ("Bulk List"), or (b) the drug to be compounded appears on the drug shortage list under the FD&C Act. The proposed guidance addresses the process that the FDA proposes to use to create the Bulk List.

The FDA's stated policy objective underlying the proposed process is to assess whether there is truly a need to allow a bulk drug substance to be compounded in light of the health and safety risks associated with compounding. For example, the FDA pointed to the meningitis outbreak originating from the New England Compounding Center allegedly due to contamination during the compounding of certain injectable products.

The draft guidance proposes a two-step analysis. The first step would consider whether the bulk drug substance is currently the active pharmaceutical ingredient in an FDA-approved drug product. If not, the FDA would use a balancing test under step 2. If so, the FDA would further evaluate whether (a) all of the FDA-approved products have attributes that make them unsuitable for patient populations that the compounded drug product would address, and (b) there is a need for the drug product to be compounded from the bulk drug substance and not from a currently FDA-approved drug product.

For bulk drug products that meet both requirements and for those that are not a component of an FDA-approved drug product, the FDA would apply a 4-factor balancing test under step 2 to assess the safety and efficacy of the bulk substance:

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

Although the FDA explains how it would interpret each of the four factors, it does not provide any guidance about how the factors will be weighed or what would be sufficient to satisfy the test under step 2.

The draft guidance also appears to leave a number of other questions unanswered:

  • How will the FDA define "FDA-approved" drugs? Would DESI and Grandfathered drugs qualify or will the FDA only consider drugs currently on the market that has passed through the NDA process?
  • Will the FDA consider off-label uses in determining whether there is the FDA-approved drug products containing the bulk substances are unsuitable for a given patient population?
  • How soon will the FDA begin adding bulk substances into the Bulk List? Moreover, given that FDA has stated that the Bulk List will be updated on a rolling basis, will 503B outsourcing facilities be immediately limited to using only those substances on the Bulk List immediately or will there be a future implementation date?

The FDA's proposed process, if adopted, may limit the number of products that Section 503B outsourcing facilities are permitted to compound, given that that the bulk substance (and the drug product that is compounded using the bulk substance) must not only be safe and effective, but also address a unique issue for a patient population that the current FDA-approved drugs cannot.

In light of the potential limitations that this proposed guidance could place on the products eligible for Section 503B compounding by an outsourcing facility, and the open questions presented by the draft guidance, outsourcing facilities, manufacturers, providers who rely on outsourcing facilities and other participants in the supply chain should closely monitor future developments.

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