Almost a year and a half after adoption of the Drug Quality and Security Act (DQSA) in November 2013, which revised federal oversight of drug compounding, the Food and Drug Administration (FDA) continues to roll out guidance documents detailing its view on assorted issues concerning implementation of the statute. The FDA’s most recent offering is four draft guidance documents addressing issues related to compounding. These draft guidance documents address when a facility should consider registering as a so-called “Outsourcing Facility” under the DQSA’s Section 503B, when and how an Outsourcing Facility must report adverse events and policies regarding repackaging human drugs and mixing, diluting and repackaging biological products. 

The public is invited to submit comments in response to each draft guidance. Comments are due May 20, 2015. 

Each is summarized below:

Draft Guidance for Entities Considering Whether to Register as Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act 

This Draft Guidance was prepared by the FDA in response to questions regarding whether certain entities engaged in limited activities must register as an Outsourcing Facility. The Draft Guidance provides information regarding the regulatory impact of registering as an Outsourcing Facility under Section 503B of the Federal Food, Drug, and Cosmetic Act (FFDCA), as implemented by the DQSA, including recommendations as to whether certain entities should or should not register as Outsourcing Facilities. The FDA specifies that a facility engaged in only certain activities, including repackaging human drugs and compounding non-sterile drugs, should not register as an Outsourcing Facility because its compounded drug products will not qualify for the exemptions provided in Section 503B, including exemptions from the new drug approval requirements. Not surprisingly, the FDA noted that registration as an Outsourcing Facility indicates a compounding facility’s intent for the compounded drugs to be regulated under Section 503B. In this Draft Guidance, the FDA clarified that an Outsourcing Facility must compound at least one sterile product. In other words, an Outsourcing Facility can compound non-sterile products but it must compound at least one sterile product to qualify for the exemptions under Section 503B. It is also worth noting that a compounded drug can only qualify for the exemptions under Sections 502(f)(1) (requiring certain labeling with adequate directions for use), 505 (requiring a New Drug Application) and 582 (the Drug Supply Chain Security Act) if all of the facility’s compounded drugs are compounded in accordance with Section 503B. In other words, the non-sterile product compounded also must meet current good manufacturing practice (cGMP) standards. The Draft Guidance also notes that Outsourcing Facilities are subject to cGMP requirements, among other FFDCA requirements, including inspection by the FDA on a risk-based schedule. 

Draft Guidance on Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the FFDCA 

Among the requirements applicable to Outsourcing Facilities under Section 503B of the FFDCA is a requirement that Outsourcing Facilities submit adverse event reports to the FDA following any “unexpected, serious adverse drug experience” involving compounded prescription drug products regardless of whether the Outsourcing Facility distributes them pursuant to prescriptions. An adverse drug experience is considered “serious” if it results in death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, or a congenital anomaly or birth defect. Medical events that do not result in death, life-threatening situations, or hospitalization can still be considered “serious” if, based on appropriate medical judgment, they may jeopardize the patient or require medical intervention to prevent such outcomes. Examples of such events include the development of drug dependency or abuse, allergic bronchospasm requiring emergency intervention or convulsions. Such experiences are “unexpected” if they are not listed in the current labeling for the drug product—that is, if they have not been observed as opposed to whether they could be anticipated pharmacologically. 

According to the Draft Guidance, Outsourcing Facilities must report these adverse events to the FDA as soon as possible but in no case later than 15 calendar days from first receiving information about the adverse event. Specifically, Outsourcing Facilities should submit a 15-day “Alert report” when they have information regarding any one of the following: an identifiable patient, an identifiable reporter, a suspect drug or a serious adverse event. Information regarding an identifiable patient includes various identifiers, such as names, dates of birth, etc., but also includes general description of a patient, such as “an elderly woman who suffered anaphylaxis.” Information regarding an identifiable reporter includes the name, contact information and/or professional identifier (e.g., “nurse”) of the patient, consumer, family member, healthcare practitioner or other person initiating the report. Outsourcing Facilities must promptly investigate adverse events and attempt to locate information regarding all four elements and submit a follow-up report to the FDA within 15 days of receiving new information about the event or as requested by the FDA. The Draft Guidance also specifies that adverse event reports should be submitted via Form FDA 3500A in hard copy until the FDA completes modifications to its electronic submissions process. If the compounded drug product contains multiple components, each component should be listed in the report along with the component’s manufacturer and any other drug product being taken by the patient at the time of the event. Reports should also include a copy of the current labeling for the compounded drug product that is the subject of the report. Reports should not identify patients by name or address.

Draft Guidance for Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities 

This Draft Guidance describes the conditions where the FDA will not take action against facilities repackaging human drug products for violating three sections of the FFDCA: 505 (requiring a New Drug Application), 502(f)(1) (requiring certain labeling with adequate directions for use), and 501(a)(2)(B) (concerning cGMP). The Draft Guidance applies to state-licensed pharmacies, federal facilities and Outsourcing Facilities registered under Section 503B of the FFDCA that take finished drug products from the container in which they were distributed by the manufacturer and put them in different containers without further manipulating the drug. It does not address repackaging non-prescription drugs, those intended for use in animals or biological products. The Draft Guidance also clarifies that repackaged drugs are not eligible for the exemptions provided by FFDCA Sections 503A and 503B. 

The FDA makes clear that repackaged drugs typically are not exempt from any provisions of the FFDCA related to the production of drugs. However, improper repackaging can cause serious adverse events. Specifically, the FDA notes that repackaging is of particular concern when it involves sterile drugs, which are susceptible to contamination and degradation. Accordingly, the Draft Guidance spells out 11 requirements, including that the drug be repackaged: by or under the direct supervision of a licensed pharmacist; in a way that does not conflict with the approved drug product labeling (other than an exception for a single-dose vial); and that its beyond-use date (BUD) complies with requirements detailed in the Draft Guidance. The repackaged drug product must be sold only by the entity that did the repackaging, although this does not include administration of a repackaged drug product in a healthcare setting. Certain labeling requirements will apply for drugs repackaged by an Outsourcing Facility. 

Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application 

This Draft Guidance details the conditions that must be met for the FDA to not take action against certain facilities for violations of Section 351 of the Public Health Service (PHS) Act (mandating a biologics license application (BLA) and certain labeling) and FFDCA Section 501(a)(2)(B) (concerning cGMP) for the dilution, mixing or repackaging of certain biological products without having first obtained a BLA. The Draft Guidance only applies to state-licensed pharmacists, federal facilities and Outsourcing Facilities and does not apply to blood and blood components for transfusion, vaccines, cell therapy products and gene therapy products or for products intended for use in animals. 

The Draft Guidance details 10 conditions, some of which are similar to those in the Draft Guidance on repackaging certain human drug products, including: complying with the prescribed BUD requirements; that the product be sold (which does not include administration in a healthcare setting) only by the entity that mixed, diluted or repackaged it; and certain labeling requirements for those products handled by an Outsourcing Facility. 

The Draft Guidance also discusses the preparation of licensed allergenic extracts that are mixed and diluted to provide subcutaneous immunotherapy to an individual patient, otherwise known as prescription sets. It notes that the FDA will not take action for violation of Section 351 of the PHS Act or Section 502(f)(1) of the FFDCA if a state licensed pharmacy, federal facility, Outsourcing Facility or physician prepares the prescription sets in accordance with 10 conditions. Conditions include that the prescription set: is prepared from FDA-licensed allergenic extracts and appropriate diluents; is prepared in a way that it does not conflict with approved labeling of the licensed biological products that are part of the prescription set; and is not sold or transferred by an entity other than the one that prepared it. Finally, additional labeling requirements will apply for a prescription set prepared by an Outsourcing Facility.