The Food and Drug Administration (“FDA”) has released draft interim guidance documents that impact the use of bulk drug substances in compounding under Sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (“FDCA”). Both documents provide a detailed overview of the historical development of FDA’s position pertaining to the use of bulk products, as well as a draft position statement on its current thinking. These new draft interim guidance documents represent a significant departure from FDA’s past policy. In these documents, FDA states that any new bulk drug substance nominated after the applicable guidance is finalized cannot be used until FDA has completed its review and included the substance on a list of ingredients permitted for compounding. This alert summarizes these documents and the implications they will have for compounding entities.

Background and Context

Section 503A of the FDCA established conditions under which compounded drugs could be exempted from certain FDA regulations pertaining to human drugs, including the need for new drug approval, compliance with good manufacturing practices, and standardized labeling. This section specifically targets compounding by licensed pharmacists and physicians for specific patients.

Section 503B, introduced by the Drug Quality and Security Act of 2013 (“DQSA”), created a new category of compounding entities known as “outsourcing facilities,” designed to facilitate large-scale compounding, often without patient-specific prescriptions.

Under both sections, compounders are restricted to using substances included in the United States Pharmacopeia (“USP”) or those with a National Formulary (“NF”) monograph, components approved by the Secretary of the Department of Health and Human Services (“DHS”), or bulk substances developed under Section 503A or 503B if other options are not applicable.

Originally, FDA required the use of either USP/NF substances or components approved by DHS, excluding bulk substances on the interim list from compounding use until FDA could finalize a list of suitable bulk materials. However, due to the complexity involved in creating this finalized list (and a 2002 Supreme Court case that set things back a bit), the final list continued to be delayed, leading to concerns about patient care disruption for those needing drugs compounded with these bulk materials.

Responding to these concerns, FDA issued a series of guidance documents that culminated in a categorization method allowing for the limited use of certain unapproved bulk substances with low safety risks and sufficient scientific support.

FDA’s Current Thinking on Unapproved Bulk Substances

These new guidance documents provide additional transparency to FDA’s thought process regarding which bulk substances may be used for compounding in the absence of a final list issued by the FDA. Importantly, these policies only apply to substances nominated before the final policy is implemented. Therefore, if compounding entities are relying on the inclusion of a certain bulk compounding substance in this interim list, the substance should be nominated as soon as possible to ensure it is included before this draft policy is finalized. The comment period for this draft policy closed January 8, 2024, though FDA will need additional time to finalize the policy after reviewing the comments.

           1. Policy for 503A Bulk Substances

For substances in the 503A bulk list, FDA indicated it will slot nominated substances into three categories depending on safety considerations and supporting information. These categories are:

• Category 1: Substances under evaluation, with adequate supporting information and no significant safety risks identified.
• Category 2: Substances identified with significant safety risks, which are not recommended for use in compounding.
• Category 3: Substances with insufficient supporting information, indicating a need for more research or data.

FDA indicates it will not enforce action against compounding pharmacies or physicians for using a Category 1 bulk drug substance, provided certain conditions are met. These conditions are inclusion of the substance on FDA’s website as a Category 1 substance, registration of all manufacturers under Section 510 of the FDCA, possession of a valid Certificate of Analysis (COA), and compliance with all other conditions of Section 503A.

          2. Policy for Outsourcing Facilities

Similar to the 503A guidance, the 503B document introduces categorizations for bulk drug substances, but with a focus on the distinct regulatory environment of outsourcing facilities. The emphasis is on ensuring these substances meet specific criteria, such as being necessary for patient care where no equivalent, FDA-approved drug exists.

Per this new draft guidance, FDA will not enforce action against an outsourcing facility for compounding a drug product using a bulk substance not on the final 503B bulks list if: (1) the substance appeared on FDA’s drug shortage list within 60 days of distribution and dispensing; and (2) was to fill an order that the outsourcing facility received for the drug while it was on the drug shortage list.

Additionally, FDA will permit compounding with bulk substances drugs that do not appear on FDA’s shortage list if the following conditions are met:

• The bulk substance is included on “Category 1” of FDA’s website;
• The manufacturers of the substance are all registered under Section 510 of the FDCA;
• The bulk substance is accompanied by a valid COA;
• If the bulk substance is the subject of an applicable USP or NF monograph, it complies with said monograph; and
• The bulk substance is compounded in compliance with all other provisions of Section 503B of the FDCA.

For both 503A and 503B bulk substances that do not meet their respective requirements in these guidance documents, FDA may still take enforcement action against facilities that use such substances in their compounding practices.