Pharmaceutical Compounding: A US FDA Perspective

Ian Deveau

Deputy Office Director

FDA

Background

Drug compounding involves licensed pharmacists or physicians combining, mixing, or altering ingredients to create medications tailored to individual patient needs. Compounded drugs are not US FDA-approved and are exempt from certain provisions of the Federal Food, Drug, and Cosmetic (FD&C) Act if specific conditions are met. These drugs can be crucial for patients with unique clinical needs that FDA-approved drugs cannot meet.

The Food and Drug Administration Modernization Act of 1997 introduced Section 503A to the FD&C Act, establishing conditions under which compounded drugs can qualify for exemptions from new drug approval requirements, labeling with adequate directions for use, and current good manufacturing practice (CGMP) requirements. This section aims to ensure the availability of compounded drugs while preventing manufacturing under the guise of compounding.

Historical Context and Challenges

From 1998 to 2011, Section 503A faced legal challenges regarding restrictions on advertising and promotion, leading to ambiguity about its applicability. During this period, the US FDA encountered significant challenges in regulating compounders. Serious adverse events linked to poor-quality compounded drugs, such as deaths and infections highlighted the risks associated with compounding.

A pivotal moment in compounding regulation was the 2012 fungal meningitis outbreak caused by contaminated drugs from the New England Compounding Center (NECC). This incident, which resulted in numerous deaths and infections, underscored the need for stricter oversight and led to renewed US FDA inspectional activities and the enactment of the Drug Quality and Security Act in 2013.

The current US FDA framework for compounding focuses on Sections 503A and 503B of the FD&C Act. Section 503A applies to state-licensed pharmacies, federal facilities, and physicians, while Section 503B pertains to outsourcing facilities that compound sterile drugs and elect to register with the US FDA. Outsourcing facilities are subject to increased federal oversight, CGMP requirements, and must report adverse events to the US FDA.

Frequent inspection findings and common regulatory violations in 2024 include unsanitary conditions, CGMP violations, and non-compliance with Sections 503A and 503B. These violations can lead to compounded drugs being subject to all requirements applicable to conventional drug manufacturers, including new drug approval and labeling requirements. The US FDA has increased the frequency and thoroughness of inspections for both 503A and 503B facilities. These inspections help identify and rectify potential issues before they can lead to patient harm. Enhanced environmental monitoring protocols have been implemented to ensure that compounding facilities maintain sterile conditions. This includes regular testing of air and surfaces for microbial contamination. The US FDA has taken legal action against facilities that fail to comply with safety standards. Penalties for non-compliance have been increased to deter facilities from cutting corners on safety. This includes higher fines and the potential for facility shutdowns.

US FDA’s Office of Compounding Quality and Compliance (OCQC)

The OCQC addresses compounding quality concerns, conducts inspections, tracks incidents, and develops policies. The office’s activities include pre-operational meetings, policy documents, and outreach efforts. The OCQC also manages compounding incident reports and conducts follow-up investigations to ensure public health safety.

The US FDA has established the Compounding Quality Center of Excellence to support outsourcing facilities and stakeholders in providing high-quality drugs. The center offers training, research, and engagement efforts, including live virtual training, self-guided online courses, and an annual conference. These initiatives aim to enhance the quality and safety of compounded drugs.

Outsourcing facilities are now required to report adverse events to the US FDA. This helps the agency track and respond to potential safety issues more quickly.

Conclusion

503B outsourcing facilities are subject to specific requirements under the Federal Food, Drug, and Cosmetic Act (FD&C Act) to ensure the safety and quality of compounded drugs. Facilities must register with the FDA as an outsourcing facility and this registration must be renewed annually. Compounding must be performed by or under the direct supervision of a licensed pharmacist. Compounded drugs must be labeled with specific information, including the statement “This is a compounded drug” and other details such as the facility’s name, address, and lot or batch number. Outsourcing facilities must comply with current good manufacturing practice (CGMP) requirements. This ensures that drugs are produced in a controlled environment to prevent contamination and ensure quality.

The US FDA’s regulatory framework for drug compounding is designed to balance the need for individualized therapies with the necessity of ensuring drug safety and quality. The OCQC’s ongoing efforts and the establishment of the Compounding Quality Center of Excellence demonstrate the US FDA’s commitment to improving compounding practices and protecting public health. The US FDA issues public alerts and guidance documents to inform healthcare providers and the public about safety concerns related to compounded drugs. This transparency helps prevent the use of potentially harmful products. The US FDA conducts outreach programs to educate compounders about regulatory requirements and safety standards.1^, 2^, 3