On February 13, 2015, FDA published four new drug and biological product compounding guidances and a draft memorandum of understanding (MOU) between FDA and states regulating compounding entities. The four new guidances are: “For Entities Considering Whether to Register as Outsourcing Facilities Under Section 503B of the Federal Food, Drug and Cosmetic Act”, “Repackaging of Certain Human Products by Pharmacies and Outsourcing Facilities”, “Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application”, “Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act”. The MOU is entitled “Draft Memorandum of Understanding Addressing Certain Distributions of Compounded Human Drug Products Between the State of [insert State] and the U.S. Food and Drug Administration”.

The first guidance on outsourcing is designed to answer questions about whether entities engaged in various activities, such as compounding only non-sterile drugs or repackaging biological products, should register as an outsourcing facility. Entities that register as outsourcing facilities in FY 2015 must pay certain registration fees, and FDA will not refund these fees. An outsourcing facility is defined as:

[A] facility at one geographic location or address that—(i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of this section.

Outsourcing facilities are not required to be a licensed pharmacy. Sterile drugs is defined by Section 503B(d)(5) as a “drug that is intended for parenteral administration, an ophthalmic or oral inhalation drug in aqueous format, or a drug that is required to be sterile under Federal or State law.” Some outsourcing facilities can qualify for exemptions from the drug approval requirements under Section 505 of the Federal Food, Drug and Cosmetic Act (FD&C Act) if they are compounded under the direct supervision of a licensed pharmacist. The guidance includes the full list of exemptions – many tie to the facility meeting the requirements under Section 503B for ALL of its compounded drugs, and the outsourcing facility may not compound drugs that have been withdrawn for safety or efficacy reason or are essentially a copy of one or more approved drugs. In particular, drugs compounded in accordance with Section 503B must STILL COMPLY with current good manufacturing practices (cGMPs) and will be inspected by FDA periodically.

Some things to think about: 1) registering as an outsourcing facility indicates an intent to compound all drugs at the facility in accordance with Section 503B (not 503A or its exemptions) and cGMPs, 2) an outsourcing facility must be engaged in compounding sterile human drugs, and 3) facilities that only repackage, compound non-sterile or animal drugs, or mix, dilute, or repackage biological products subject to Section 351 of the Public Health Service Act (PHS Act) should not register as an outsourcing facility.

The next guidance on repackaging and outsourcing facilities states that FDA considers repackaging to mean taking a finished drug product from the original container in which it was distributed by the original manufacturer and placing it into a different container with no further manipulation of the drug. Repackaging may also include placing the contents of multiple containers of a finished drug product into another container, assuming the container does not include additional ingredients. FDA is generally concerned with repackaging practices that conflict with approved product labeling the may result in product degradation or adverse events associated with impurities or a lack of efficacy because the active ingredient has deteriorated. Repackaged drugs are generally subject to the adulteration, misbranding, and approval provisions of the FD&C Act. This guidance lists the types of products not addressed in the guidance, e.g., biological products under section 351 of the PHS Act, drug products for use in animals, repackaging by entities that are not state-licensed pharmacies, Federal facilities, or outsourcing facilities, and a licensed pharmacy removing contents from one container of solid oral dosage form drug products to dispense a patient-specific prescription.

Repackaged drugs are not subject to Sections 503A and 503B of the FD&C Act, so drug products repackaged by state-licensed pharmacies, Federal facilities, or outsourcing facilities are not eligible for the exemptions under those sections. The guidance explains that FDA will not take regulatory action for certain repackaging that violates the FD&C Act when practiced by a state-licensed pharmacy, Federal facility, or an outsourcing facility, such as:

  1. Certain hospitals within a health system for registration requirements provided certain conditions are met including that the drugs are on FDA’s drug shortage list and the repackaging is dividing the contents into smaller volumes to extend the supply UNTIL FDA issues final guidance on such hospital pharmacy repackaging for shortages;
  2. The repackaged drug is a prescription drug approved under Section 505 of the FD&C Act (and not a product withdrawn or removed from the market as unsafe or ineffective);
  3. The drug product is repackaged by or under the direct supervision of a licensed pharmacist;
  4. The drug product is repackaged in a way that does not conflict with approved drug product labeling;
  5. The repackaged drug product is assigned a beyond-use-date (BUD) as provided in the guidance;
  6. The drug is not sold or transferred by an entity other than the entity that repackaged such drug product (excludes health care setting repackaging);
  7. The repackaged drugs is distributed only in states in which the facility meets all applicable state requirements; and
  8. Outsourcing facilities have additional requirements for labeling described in the guidance.

The biological product mixing, diluting, repackaging guidance is specific to biological products licensed under 351 of the PHS Act and also excludes certain categories of products, including instances where a marketing application could be or has been submitted under Section 505 of the FD& C Act, cell therapy products, gene therapy products, vaccines, and blood products or components. Biological product as defined by section 351(i)(1) of the PHS means:

[A] virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically-synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

While FDA recognizes that there are valid reasons to repackage biological products, it is concerned about such practices that conflict with approved labeling and may lead to contamination and degradation of these sensitive products, introducing risks such as serious patient injury or death. The shortage provisions for hospitals mentioned in the previous guidance also applies here with the same termination provisions. Manufacturers intending to mix, dilute, or repackage biological products licensed under section 351 of the PHS Act must obtain a license for the product.

The Guidance lists conditions where a state-licensed pharmacy, a Federal facility, or an outsourcing facility may mix, dilute, or repackage a biological product and FDA does not intend to take action for violations under Section 501(a)(2)(B) of the FD&C Act, noting that outsourcing facilities will need to follow cGMPs. The conditions are similar as with the preceding guidance, except there specific provisions such as those directed to BUD are modified to reflect the more sensitive nature of biological products. The Guidance also includes specific guidelines for licensed allergenic extracts being mixed and diluted to provide subcutaneous immunotherapy to an individual patient, called prescription sets.

The adverse event reporting for outsourcing facility guidance is directed to firms that have registered as outsourcing facilities for drug compounding. Outsourcing facilities are required to submit adverse event reports to FDA in accordance with 21 C.F.R. § 310.306 and applicable guidances or other regulations. Adverse events include serious and unexpected adverse drug experiences and may include certain important medical events, such as convulsions or events requiring intensive treatment in an emergency room or at home or the development of drug dependency or drug abuse. Outsourcing facilities must report all serious and unexpected adverse drug experiences associated with their compounded prescription drug products and further investigate key data elements including patient circumstances, an identifiable reporter of the adverse event, the suspect drug, and the nature of the serious adverse event. The guidance further explains how to report adverse events, recordkeeping, and reminds outsourcing facilities that such adverse event reporting is subject to FDA inspection.

The MOU establishes an agreement between FDA and the State party regarding the distribution of inordinate amounts of compounded human drug products interstate and investigation by the State for complaints relating to compounding distributed outside the State. Some of the topics that are addressed in the MOU include the State notifying FDA when a compounding pharmacy, pharmacy or physician is distributing inordinate amounts of compounded human drug products interstate and the sharing of information between the State and FDA of complaints, inspection materials, and other related documents.