In July 2014, the U.S. Food and Drug Administration (FDA) released five documents containing policies and proposals that affect both traditional compounding pharmacies and outsourcing facilities that compound drugs for human use. These documents are:
- Draft Interim Guidance setting forth FDA's current thinking as to its interim expectations for outsourcing facilities regarding compliance with Current Good Manufacturing Practices (CGMP) until regulations are developed;
- A Proposed Rule adding 25 new drug products to the "do-not-compound" list, for both traditional compounders and outsourcing facilities;
- Final Guidance for traditional compounders; and
- Two separate requests, one for 503A and one for 503B, to nominate bulk drug substances for FDA lists of active bulk substances that traditional compounders and outsourcing facilities are permitted to use.
As detailed in an earlier Duane Morris Alert, Title I of the Drug Quality and Security Act (DQSA)—referred to as the Compounding Quality Act (CQA)—allows FDA to oversee drug compounding in human health. The DQSA amended and reinstated Section 503A, which sets out certain requirements for traditional compounding, and it created a new FDA-regulated entity called an "outsourcing facility" in Section 503B. These guidance documents and the proposed regulation flesh out FDA's current thinking and enforcement priorities for both traditional compounders and outsourcing facilities under the CQA.
Outsourcing Facilities—Draft Interim Guidance on CGMP Requirements
Unlike traditional compounding pharmacies, outsourcing facilities are required to comply with CGMP. Although FDA intends to develop specific CGMP regulations that apply to outsourcing facilities, until these regulations are promulgated, FDA issued draft interim guidance that sets out its CGMP expectations for outsourcing facilities during this interim period. In this Draft Interim Guidance, FDA expresses its intent to recognize the difference in its CGMP expectations between outsourcing facilities and conventional drug manufacturers.
FDA focuses on the CGMP requirements that relate to sterility assurance and safety of compounded drug products with respect to strength (sub and super potency), labeling and drug product mix-up. FDA sets out its CGMP expectations for the following areas:
- Facility design, including air quality requirements for sterile drugs;
- Control systems requiring separate or defined areas for facility operations to prevent contamination;
- A system for environmental and personnel monitoring in aseptic processing areas;
- Controls over equipment used to compound and containers and closures in which a compounded drug product is packaged;
- Control over the source and quality of components;
- Production and process controls (essential for sterile compounds);
- Release testing (compounds tested for final product specification before distribution);
- Laboratory controls for testing components and finished drug products;
- A program for stability/expiration dating;
- Packaging requirements for sterile drugs; and
- A quality control unit to oversee various aspects of sterile production.
Comments to the Draft Guidance may be submitted by September 2, 2014. FDA is accepting comments electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting comments to the Draft Guidance are available on the FDA's notice in the Federal Register. In the Draft Interim Guidance, FDA specifically seeks public comment on alternative approaches on: (1) Reducing the need for laboratory testing of incoming components; and (2) minimizing the need for facilities to have an in-house laboratory.
Proposed Rule Adding 25 Drug Products to the Do-Not-Compound List
Both Sections 503A and 503B direct FDA to publish a list of drugs or drug components that cannot be compounded because they have been withdrawn or removed from the market as unsafe or not effective. The Proposed Rule is FDA's proposal to amend this list, found at 21 CFR Part 216, to add 25 additional drug products. As set forth in the Proposed Rule, FDA intends to prohibit all drug products for a certain molecule, possibly even if only one or a few dosage forms have been found either unsafe or not effective.
Comments to the Proposed Rule may be submitted by September 2, 2014. FDA is accepting comments electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting comments to the Draft Guidance are available on the FDA's notice in the Federal Register.
Final Guidance for Traditional Pharmacies Operating Under Section 503A
After soliciting public comment, FDA has published its Final Guidance, which reflects FDA's current thinking on the enforcement of Section 503A. It is important to note that, in the Final Guidance, FDA has changed its position on when it will begin to enforce the 5-percent limit on out-of-state distribution for pharmacies located in states that have not entered into the Memorandum of Understanding (MOU). As directed by Section 503A, FDA is currently working in collaboration with the National Association of Boards of Pharmacy on the MOU to address interstate distribution of compounded drugs. FDA now states that the Federal Register notice that announces the availability of the draft MOU will specify a time period during which the MOU will be made available for the states to sign. Only after this time period expires does FDA intend to enforce the 5-percent limit on interstate distribution of compounded drugs from traditional compounders in states that have not signed the MOU.
FDA Reopens Nominations for Bulk Drug Substances Lists Under Sections 503A and 503B
FDA issued two notices, one relating to the 503B bulk substances list and another relating to the 503A bulk substances list. FDA has indicated in both of these notices that the bulk substances required to appear on this list are for active ingredients only. Both of these notices reopened and restarted the nomination process for bulk substances drugs to appear on these respective lists. Both notices allow 90 days for bulk substances to be nominated for these respective lists.
Section 503B limits outsourcing facilities to using only bulk chemicals that appear on a positive list developed by FDA "identifying bulk drug substances for which there is a clinical need." 21 U.S.C. 353b(a)(2)(A)(i). In this notice, FDA takes the position that it needs the following information to evaluate this "clinical need": a statement describing the medical condition the product made from the substances would treat; if there is an FDA-approved drug to treat the condition; if so, why the compounded drug is necessary (why the approved drug is not suitable); an estimate of the size of the population that needs the compounded drug (due to an allergy or intolerance); bibliography of safety and efficacy data if available, including peer reviewed medical literature; and if an FDA-approved drug includes the bulk drug substance, an explanation of why the bulk drug substance needs to be used, and not the FDA-approved product. Information regarding the bulk drug substance's active ingredients, the dosage form, strengths and anticipated routes of administration is also required.
In contrast, under 503A, a bulk drug substance can be used if it has a United States Pharmacopeia (USP) or National Formulary (NF). Only if it has neither of these things is it required to appear on FDA's approved list. FDA is proposing to examine four criteria for a bulk substance to appear on the 503A list: (1) physical and chemical characterization of the substance; (2) safety issues raised by use of it in compounded drug products; (3) historical use of the substance in drug products, including information about medical conditions it has been used to treat and references in peer-reviewed medical literature; and (4) the available evidence of effectiveness or ineffectiveness of a drug product compounded with the substance, if any exists.
Nominations for the 503B or 503A bulk drug substances lists may be submitted by September 30, 2014. FDA is accepting nominations electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting nominations are available on the FDA's notices (503A list and 503B list) in the Federal Register.
These FDA guidance documents and proposed rule are the latest FDA action to implement its new authority under the CQA to regulate the compounding of drugs for human use. FDA's current thinking, its proposed regulation and Final Guidance are key guideposts for entities compounding for human use under either Section 503A, Section 503B, or both.