The FDA's Outsourcing Facility Designation: What It Means and Why It Matters

A pharmacy that seeks to register as an outsourcing facility will likely need to make investments in infrastructure and training in order to comply with the Drug Quality and Security Act.

Looking back at the history of federal oversight of all types of prescription drugs, it becomes clear that legislation is often enacted in response to serious adverse events and safety issues. An example of this is the 2013 passage of the Drug Quality and Security Act (DQSA), which followed a 2012 outbreak of life-threatening and fatal infections in patients who had received spinal injections from contaminated vials supplied from an unaccredited compounding facility, according to the FDA. In December 2014, a criminal investigation revealed that significant safety and quality violations occurred at this pharmacy, including false documentation of expiration dates, failure to properly sterilize drugs, and failure to comply with disinfecting practices.

While such incidents are thankfully rare, this event caused serious concern in the health care community and led to a call for greater government oversight of compounding practices. In response, Congress passed the DQSA, which includes more stringent requirements for facilities that compound drugs. Specifically, the DQSA updated the Section 503A exemption to the Federal Food, Drug, and Cosmetic Act to apply only to small compounding pharmacies that produce medications in limited quantities for specific patient prescriptions. A larger pharmacy that distributes a high volume of compounded drugs can now register as a designated outsourcing facility through the DQSA’s 503B exemption. This designation is required for entities that need the ability to manufacture large batches of compounded sterile preparations without specific prescriptions for individual patients and/or to ship these products across state lines.

For pharmacies already maintaining both strict quality controls and third-party accreditations, this new designation provides an opportunity to reassure providers that patient safety is a top priority. In fact, the FDA has sent letters to many purchasers of compounded products encouraging them to require that their vendors comply with this new legislation. However, a pharmacy that wants to register as an outsourcing facility will likely have to make some investments in infrastructure, training, and personnel in order to comply with the legislation. These requirements are outlined below, while greater detail can be found within “Guidance for Industry: Current Good Manufacturing Practice—Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act,” the FDA’s latest guidance document for Section 503B.

Maintenance of Current Good Manufacturing Processes

Outsourcing facilities are subject to increased government oversight and must comply with current good manufacturing processes (CGMPs) as defined by the FDA. CGMPs are a series of strict, detailed guidelines that must be observed during the preparation of compounded medications. These principles are designed to eliminate contamination of compounded medications, deviation from protocols, and the use of incorrect ingredients, and to address other safety and quality issues. Among other requirements, the DQSA outlines the following practices as mandatory for all outsourcing facilities:

Facility Design and Clean Room Standards

Preparing compounded medications in a sophisticated, state-of-the-art clean room is a must for compliance with CGMPs. According to the DQSA, “Certain elements of facility design are considered critical to ensuring the quality of compounded sterile drug products.”

Clean room standards include maintaining air quality and proper levels of humidity and temperature, reducing particulates, and testing of high-energy particulate arrestance filters.

To prevent contamination or mix-ups during the course of operations, the FDA also requires separate or defined areas for certain functions and other control systems for a facility’s operations.

Environmental and Personnel Monitoring

Guidance issued by the FDA with regard to 503B states that “environmental monitoring should consist of a well-defined program that evaluates the potential routes of microbial contamination of the human drug that could arise from the air, surfaces, process, operation, and personnel practices.” This includes ensuring coverage of all production shifts and, at minimum, daily monitoring of the ISO 5 zone during operations. Facilities must also document their use of sample and testing methods to ensure they are detecting environmental contaminants.

Strict Controls over the Source and Quality of Drug Components

Also critical to CGMPs are testing procedures that ensure the quality and safety of components. For instance, facilities must verify that a component was purchased directly from a manufacturer registered with the FDA, and that the component conforms to appropriate specifications, and, if needed, that it has maintained sterility before use in compounding.

Cleaning and Sanitation

Outsourcing facilities must establish and follow procedures for proper sanitation. Specifically, they must detail the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.

Production and Process Controls

These controls include written procedures for documentation of production for each batch of drug product, as well as requirements for aseptic drug processing techniques. For example, these controls ensure that sterile materials are handled only with sterile instruments and that proper procedures for gowning storage and use are followed.

Laboratory Controls

Laboratory controls must be in place to ensure the reliability of testing for all components, in-process materials, and finished drug products. This includes the development and compliance of written procedures for testing and sampling. These CGMPs also require the use of the right methods and equipment to ensure that testing results are valid.

Proper Labeling

New labeling requirements for compounded drugs are required under Section 503B. All labels must include information about the facility of origin and pertinent details about the drug, including expiration date, active and inactive ingredients, manufacturing date, and storage/handling instructions.

In addition to these requirements, facilities must adhere to the use of proper equipment and containers, ensure proper release testing, and have an established quality control unit that both maintains ongoing quality assurance activities and complaint handling procedures.

Ongoing Inspections for Outsourcing Facilities

Registered outsourcing facilities are required to be inspected by the FDA. According to the FDA, after an initial inspection has been completed, outsourcing facilities will be regularly assessed based on the following factors:

• Compliance history
• Record, history, and nature of recalls linked to the facility
• Inherent risk of the compounded drugs
• Inspection frequency and history of the facility
• Whether the facility has registered that it intends to compound a drug that appears on the list in effect under Section 506E (the FDA’s drug shortage list)
• Any other criteria determined by the secretary of the FDA

Reporting Requirements

An outsourcing facility must submit a drug product report to the FDA upon its initial registration and twice each year thereafter. This report lists all drugs compounded at the facility during the previous 6-month period. It must include information such as the active ingredient and strength, the National Drug Code, the dosage form, and the source of the active ingredient. These reports allow the FDA to improve its tracking of drugs across the supply chain, which in turn makes it possible for the government to more quickly identify the source of any drugs that may have caused adverse events or safety issues.

Additional information about the reporting requirements for outsourcing facilities can be found in “Electronic Drug Product Reporting for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” a guidance document issued by the FDA.

The Expected Impact of 503B

While it is certainly complex and may seem cumbersome to some, the DQSA could have long-lasting positive implications for the entire health care industry. It allows reputable pharmacies to showcase their commitment to quality while weeding out those facilities that take dangerous shortcuts and risk patients’ lives. It will also make it easier for providers to identify a supplier with the highest standards for quality assurance, testing, and sterility. This is especially important as pharmacies look to overcome concerns from providers based on the 2012 compounding contamination tragedy. In spite of this event, our industry is filled with many highly experienced and reputable facilities that go above and beyond established quality requirements to ensure patient safety.

This new outsourcing facilities designation will help reinforce those efforts and communicate the value of dedicated compounding professionals to the marketplace. Just like the doctors they serve, these experts take great pride in their ability to improve patient health and, most importantly, to “do no harm.” SPT

About the Author

Eric Sredzinksi, PharmD, AAHIVP, is executive vice president, clinical affairs and quality assurance, for Avella Specialty Pharmacy, where he is responsible for clinical management, disease state management, training, and implementation of patient adherence and persistence programs. Working closely with the company’s oncology, infectious disease, and transplant teams, Dr. Sredzinski is also responsible for the management of manufacturer contracted data sets. Sredzinski received his doctor of pharmacy degree from the University of Arizona College of Pharmacy (2000) and completed his pharmacy practice residency at the Southern Arizona VA Medical Center in Tucson. Prior to joining Avella, Dr. Sredzinski worked as the clinical pharmacist for Arizona Oncology’s autologous PSCT team where he assisted in the medication management of all pre- and post transplant patients.