All Mixed Up: FDA Issues Two Guidances Relating to Compounding Using Bulk Drug Substances

When we think of compounding, which is the process of combining, mixing, or altering ingredients to create a medication specific to the needs of an individual patient, we think of the Cars’ 1978 classic, “It’s All Mixed Up.” Well, that’s how some of us think.

Earlier this month, the Food and Drug Administration published two draft guidance documents relating to compounding under section 503A and section 503B of the Federal Food, Drug, and Cosmetic Act (“FD&C Act” or “the Act”) (21 U.S.C. § 353a and 21 U.S.C. § 353b).¹ These guidances seek to replace current guidance documents and revise the categorization of certain substances nominated for inclusion on each section’s associated bulk substance lists.² Some members of industry found the existing categorizations confusing.

In this Bulletin, for context, we will provide a high-level background on these statutory sections and the associated bulks lists. We will also explain the proposed revisions to existing guidance. The public can provide comments on these draft guidance documents until January 8, 2024.³

Overview of Sections 503A and 503B of the FD&C Act

Sections 503A and 503B of the Act both address human drug compounding. However, the sections differ in their applicability, in the exemptions granted from certain requirements under the Act, and in the conditions for which bulk substances are acceptable.

Applicability of 503A and 503B

• Section 503A applies to human drug compounding by a licensed pharmacist within a state-licensed pharmacy or federal facility, or by a licensed physician, that is not registered with FDA as an outsourcing facility.
• Section 503B applies to human drug compounding within an outsourcing facility. An “outsourcing facility” is defined as a facility engaged in the compounding of sterile drugs that elects to register as an outsourcing facility with FDA to comply with certain statutory requirements. An outsourcing facility does not need to be a licensed pharmacy and may obtain prescriptions for identified individual patients.

Exemptions to Requirements Under the Act

• Section 503A describes the conditions under which compounded products are exempt from the following three sections of the Act:
  1. section 505 – concerning the approval of drugs under new drug applications or abbreviated new drug applications;
  2. section 502(f)(1) – concerning the labeling of drugs with adequate directions for use and misbranding; and
  3. section 501(a)(2)(B) – concerning current good manufacturing practice requirements and adulteration.
• Section 503B describes the conditions under which compounded drugs by an outsourcing facility are exempt from the following three sections of the FD&C Act:
  1. the aforementioned section 505 and drug approval;
  2. the aforementioned section 502(f)(1) and adequate directions for use and misbranding; and
  3. section 582 – concerning drug supply chain security requirements.

Bulk Substances Allowed Under These Sections

• State-licensed physicians and pharmacists who compound under section 503A 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 (i.e., the 503A bulks list), if such a monograph does not exist and the substance is not a component of an FDA-approved drug product.
• Outsourcing facilities that compound under section 503B may only compound drug products using bulk drug substances that: (1) appear on a list developed by FDA of bulk drug substances that can be used in compounding under section 503B (i.e., the 503B bulks list); or (2) appear on FDA’s drug shortage list at the time of compounding, distribution, and dispensing.⁴ In addition, if an applicable USP, NF, or any other compendium or pharmacopeia monograph recognized by FDA exists, bulk drug substances must comply with the monograph.
• Both sections 503A and 503B restrict compounding drug products that are essentially a copy of a commercially available drug product or an approved drug product.

Bulks Lists Under the 2017 Guidance Documents

• The current guidance documents contain categorization of certain substances nominated for inclusion on the 503A and 503B bulks lists.⁵
• According to the 2017 guidance documents, once a substance is nominated for inclusion into a bulks list, FDA classifies the nomination into one of three categories:
  • Category 1: FDA found that the substance’s nomination had sufficient information for evaluation, and the substance does 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 under the applicable section (503A or 503B) are met.
  • Category 2: FDA found that the substance’s nomination had sufficient supporting information for FDA to evaluate it. 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 non-enforcement 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.
  • Category 3: FDA found that the substance’s nomination did not have sufficient supporting information for FDA to evaluate it. These substances are not eligible for the non-enforcement 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.

Proposed 2023 Changes

• FDA issued the proposed revisions to the 2017 guidance because:

FDA has determined that ongoing categorization of newly nominated substances, as described in the 2017 [503A/503B] Interim Policy Guidance, no longer serves the interim policy’s stated objective of avoiding unnecessary disruption to patient treatment and does not otherwise benefit public health. Categorizing substances nominated on or after the date of finalization of this guidance would unnecessarily expose patients to the risks associated with drugs compounded from such bulk drug substances.

• If finalized, the 2023 guidance documents would remove the categorization of bulk drug substances (Categories 1, 2, or 3), as outlined above.
• Rather, for a substance nominated on or after the date of publication of the final guidance for inclusion on the 503A bulks list, FDA would consider the substance’s inclusion in accordance with the process and criteria established in the law.⁶
• For a substance nominated on or after the date of publication of the final guidance for inclusion on the 503B bulks list, FDA would consider the substance’s inclusion in accordance with the process and clinical need standard established in the Act.⁷
• Substances currently listed in Category 1 may continue to be eligible for the non-enforcement policy that applies to Category 1 substances, as described in the 2017 guidance documents, until FDA makes a final determination of whether they will be placed on the 503A or 503B bulks list in accordance with applicable section of the Act, or unless the Agency removes the substances from Category 1 based on, for example, information about safety risks.
  • More specifically, FDA does not intend to take action against a state-licensed pharmacy, federal facility, or licensed physician compounding a drug product using a bulk drug substance otherwise prohibited under section 503A, so long as:
    1. the bulk drug substance appears on the 503A Category 1 list for bulk drug substances (i.e., FDA has not identified a significant safety risk in compounding) prior to the publication of this guidance, once finalized;⁸
    2. the original manufacturer and all subsequent manufacturers of the bulk drug substance are registered establishments;
    3. the bulk drug substance is accompanied by a valid Certificate of Analysis; and
    4. the drug product compounded using the bulk drug substance is compounded in compliance with all other conditions of section 503A.
  • Similarly, FDA does not intend to take action against an outsourcing facility for compounding a drug product using a bulk drug substance otherwise prohibited under section 503B so long as:
    1. the bulk drug substance appears on the 503B Category 1 list for bulk drug substances (i.e., FDA has not identified a significant safety risk in compounding) prior to the publication of this guidance, once finalized;⁹
    2. the original manufacturer and all subsequent manufacturers of the bulk drug substance are registered establishments;
    3. the bulk drug substance is accompanied by a valid Certificate of Analysis;
    4. if the bulk drug substance is the subject of an applicable USP or NF monograph, the bulk drug substance complies with the monograph; and
    5. the drug product compounded using the bulk drug substance is compounded in compliance with all other provisions of section 503B.
• Substances listed in Category 3 prior to finalization of the guidance may be re-nominated with sufficient supporting information.
• If a nominator believes that its substance was miscategorized prior to finalization of the guidance, that party can submit a comment to the relevant 503A or 503B docket.

AGG Observations

• The current categorization of substances on these lists has caused some confusion within industry, trying to understand FDA enforcement discretion and the availabilities of certain bulk substances. FDA is now removing these categories, stating that the categorization no longer serves the “objective of avoiding unnecessary disruption to patient treatment, and does not other benefit the public health.” Public comment may help in determining whether industry agrees with this view, and whether the parallel change in policies for sections 503A and 503B help achieve these safety objectives.
• It would appear that anyone who wants to nominate any new bulk substances or offer new nominations of the bulk substances currently in Category 3 of the interim 503A list should do so soon. After the final guidance is published, FDA will not consider new nominations for inclusion on the interim 503A Bulks List.
• To borrow more references from the Cars, you might think your input is foolish and crazy, but it might be just what FDA (and you) need.

[1] The draft guidance for industry, “Interim Policy on Compounding Using Bulk Drug Substances Under section 503A of the Federal Food, Drug, and Cosmetic Act,” is available here: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/interim-policy-compounding-using-bulk-drug-substances-under-section-503a-federal-food-drug-and-0; the draft guidance for industry, “Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” is available here: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/interim-policy-compounding-using-bulk-drug-substances-under-section-503b-federal-food-drug-and-0; see 21 U.S.C. §§ 353a and 353b.

[2] Docket for the 2023 503A Interim Policy Draft Guidance is available here: https://www.regulations.gov/docket/FDA-2015-D-3517; docket for the 2023 503B Interim Policy Draft Guidance is available here: https://www.regulations.gov/docket/FDA-2015-D-3539.

[3] We prepared a Bulletin on the previous guidances, which can be accessed at: https://www.agg.com/news-insights/publications/fda-releases-draft-guidances-on-compounded-drugs-helps-to-answer-when-are-they-copies-07-19-2016/.

[4] 21 U.S.C. § 353b(a)(2). The 503B bulks list can be found here: https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503b-fdc-act.

[5] FDA, Bulk Drug Substances Used in Compounding Under Section 503A of the FD&C Act, available here: https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503a-fdc-act; and Bulk Drug Substances Used in Compounding Under Section 503B of the FD&C Act, available here: https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503b-fdc-act.

[6] See 21 U.S.C. § 353a(b)(1)(A) and 21 C.F.R. § 216.23(c).

[7] See 21 U.S.C. § 353b(a)(2)(A)(i).

[8] This list is available here: https://www.fda.gov/media/94155/download.

[9] This list is available here: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM467374.pdf.