FDA Issues New Drug Compounding and Outsourcing Facility Guidance

HIGHLIGHTS:

• The FDA issued multiple policy documents on July 1, 2014, to implement the Compounding Quality Act (CQA). Congress enacted the CQA in November 2013 as part of the Drug Quality and Security Act (DQSA), in response to the deadly fungal meningitis outbreak that took place in late 2012.
• The guidance applies to individual and pharmacy compounders subject to section 503A of the Food, Drug, and Cosmetic Act (FD&C) and to outsourcing facilities governed by section 503B of the FD&C.

The U.S. Food and Drug Administration (FDA) issued multiple policy documents on July 1, 2014, to implement the Compounding Quality Act (CQA), which Congress enacted in November 2013, as part of the Drug Quality and Security Act (DQSA), in response to the deadly fungal meningitis outbreak that took place in late 2012. The guidance applies to individual and pharmacy compounders subject to section 503A of the Food, Drug, and Cosmetic Act (FD&C) and to outsourcing facilities governed by section 503B of the FD&C.

These policy documents aim to clarify FDA's expectations and enable the compounding industry to comply with the CQA. Specifically, FDA policy documents include:

• A Final Guidance for 503A Compounders
• A Draft Interim Guidance for 503B Outsourcing Facilities
• A Proposed Rule Revising the List of Drug Products That May Not Be Compounded
• Two Federal Register Notices Reopening the Nomination Process for Lists of APIs That May Be Used to Compound Drug Products Under Section 503A and 503B

Final Guidance for 503A Compounders¹

The Final Guidance restates the requirements of section 503A of the FD&C and clarifies FDA's interim policies pending the implementation of final regulations. Under section 503A, licensed pharmacists or physicians that satisfy certain compounding requirements can qualify for an exemption from complying with certain "manufacturing" requirements, including current good manufacturing practice (cGMP) standards, certain labeling obligations and the standard drug approval process. In its final guidance, FDA addresses multiple issues relevant to 503A compounders, including:

• FDA expects 503A compounders to comply with the current list of drug products that cannot be compounded because they have been withdrawn or removed from the market due to safety or efficacy concerns.
• Until FDA publishes a list of bulk drug substances that can be used for compounding in the Federal Register (some of which can be utilized in compounding even in the absence of an applicable United States Pharmacopoeia (USP) or National Formulary (NF) monograph), 503A compounders must use only bulk drug substances that have a USP or NF monograph or are components of approved drugs.
• FDA will not yet enforce the FD&C provisions excluding compounded drug products from qualifying for the 503A exemptions if the drug product is on a list of drug products that present demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product.
• FDA will not enforce the 5 percent cap on the distribution of compounded drug products outside of a 503A compounder's state until FDA finalizes a formal memorandum of understanding (MOU) with the states and allows time for the states' consideration and execution of the MOU.

In addition, FDA announced its intent to utilize a risk-based enforcement approach for compounded drugs, prioritizing those drugs that present the greatest threats to public health. However, FDA cautioned that it reserves the right to not identify a particular safety problem prior to initiating enforcement activity. FDA identified a non-exhaustive list of potential FD&C violations that it may enforce and focused on potential problems with sterility, strength, quality, purity and similar cGMP issues, as well as labeling, advertising and promotion. In regards to enforcement mechanisms, FDA noted options such as warning letters, product seizures, injunctions, or criminal prosecution for FD&C violations by compounders.

Draft Interim Guidance for 503B Outsourcing Facilities²

The CQA grants FDA stronger regulatory authority with regard to outsourcing facilities that are engaged in the compounding of sterile drugs for hospitals and providers. In this interim guidance, FDA detailed its expectations for cGMPs at outsourcing facilities, which reflect FDA's position that compounding outsourcing facilities require different cGMPs than conventional drug manufacturers. In brief, the interim guidance addresses the following:

• Facility Design: standards for air filtration, air quality and processing/controlled areas
• Control Systems and Procedures for Maintaining Suitable Facilities: sanitation procedures (e.g., cleaning methods, schedules, equipment and materials to be used)
• Environmental and Personnel Monitoring: systems for monitoring environmental conditions in processing areas as well as personal sanitation practices and gowning
• Equipment, Containers and Closures: requirements for equipment, containers and closures that come into contact with a drug product
• Components: controls over the source and quality of components, including particular detail regarding testing for non-sterile starting materials
• Production and Process Controls: written procedures ensuring identity, strength, quality and purity of drug products, as well as relevant sanitation training
• Release Testing: drug products must satisfy final product specifications before their release for distribution
• Lab Controls: laboratory controls to ensure the quality of sterile drug products
• Stability/Expiration Dating: stability program to assess the stability characteristics of finished drug products and to determine appropriate storage conditions and expiration dates
• Packaging and Labels: packaging system requirements to ensure product integrity
• Quality Assurance Activities/Complaint Handling: independent quality control and individuals designated to handle failure investigations, adverse reactions, and written and oral complaints concerning the drug product quality

Proposed Rule Revising the List of Drug Products That May Not Be Compounded³

In a proposed rule, FDA seeks to amend the list of drug products that may not be compounded. These drug products or components have been withdrawn or removed from the market because they have been found to be unsafe or ineffective. FDA proposed two primary changes. First, FDA aims to broaden the application of the list by proposing that it apply to both 503A compounding pharmacies and 503B outsourcing facilities. Second, FDA proposes adding 25 drug products to the list and amending one drug product already on the list.

Two Federal Register Notices Reopening the Nomination Process for Lists of APIs That May Be Used to Compound Drug Products⁴

In an effort to compile two lists of bulk drug substances (active pharmaceutical ingredients or APIs) that may be used to compound drug products in accordance with sections 503A and 503B, FDA has reopened the nomination process for eligible APIs. FDA proposed that, in evaluating nominations and determining which substances are appropriate for use in compounded drug products under section 503A, it will examine the following four criteria:

1. physical and chemical characterization of the substance
2. safety issues associated with the compounded drug products
3. historical use of the substance in compounded drug products
4. evidence of a compounded drug product's efficacy (if available)

Many previously nominated bulk drug substances were not adequately supported, so FDA was unable to sufficiently evaluate the substance's inclusion on the lists. Accordingly, bulk substances that were previously nominated will not be considered further, unless they are re-nominated and adequately supported.

FDA encourages nominating bulk drug substances utilizing a chart to ensure that all of the following information is provided:

• confirmation that the bulk substance is not already eligible for compounding
• background information about the bulk drug substance
• explanation of clinical need to utilize the bulk drug substance for compounding
• details about the drug product for which the bulk drug substance will be compounded

Next Steps for the Compounding Industry

These policy guidance documents represent FDA's expected next step in regulating the drug compounding industry. If organizations involved in the compounding industry are interested in participating in the regulatory process before FDA finalizes this guidance, most of these policy documents remain open to public comment. Both the draft interim guidance for 503B outsourcing facilities and the proposed rule revising the list of drug products that may not be compounded are open to public comment for 60 days. In addition, the nominations for bulk drugs substances for compounding under both 503A and 503B are open to additional nominations and comments for 90 days.

¹ U.S. Dep't of Health & Human Servs., Food & Drug Admin., Ctr. for Drug Evaluation & Research; Final Guidance: Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act (July 2014). 

² U.S. Dep't of Health & Human Servs., Food & Drug Admin., Ctr. for Drug Evaluation & Research; Draft Guidance: Guidance for Industry, Current Good Manufacturing−Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act, (July 2014).

³ Additions and Modifications to the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness, 79 Fed. Reg. 37687 (proposed July 2, 2014)

⁴ Drug Bulk Substances That May be Used to Compound Drug Products in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic Act; Revised Request for Nominations Notice, 79 Fed. Reg. 37747 (July 2, 2014); Drug Bulk Substances That May be Used to Compound Drug Products in Accordance With Section 503B of the Federal Food, Drug, and Cosmetic Act, Concerning Outsourcing Facilities; Revised Request for Nominations Notice, 79 Fed. Reg. 37750 (July 2, 2014).