503A and 503B Compounding Regulations by FDA Regulatory Body | Newsletter | Issue 10 | 2022

In 2013, the Drug High Quality and Security Act (DQSA) was enacted as retort to instances of infections like the contamination of steroid injections produced by New England Compounding Facility in Framingham, Massachusetts, which included 64 fatalities and more than 700 injuries. The DQSA has enhanced monitoring and traceability of manufacturing and disbursement of compounded drugs along with supply chain logistics and increased the overall quality of compounding procedures with the Compounding Quality Act (CQA). The CQA offers the FDA more oversight authority over compounding drug facilities, specifically establishing the 503B classification of the Federal Food, Drug, and Cosmetics Act (FDCA) for outsourcing facilities to operate within prescribed standards of current good manufacturing practices (cGMP). The act reiterates that 503A Compounding Pharmacies in the FDCA, allows a compounding facility to operate under United States Pharmacopeia (USP) standards rather than the more strenuous cGMP.

Healthcare Systems Drugs Delivered by both 503A and 503B

503A classification remains by the FDA for oversight and responsibility of sterile compounding by a qualified pharmacist within a state-licensed facility. Compounding requires a patient prescription from a medical practitioner or service provider for dispersement. With oversight by State Boards of Pharmacy, USP criteria specify beyond-use dates (BUDs) and environmental monitoring requirements for clean room activities for sterile compounding.

The newer designated 503B outsourcing facilities are more aligned with federal cGMP, typically manufacture in larger commercial batches and are non-patient prescriptive. BUDs are set by required stability testing on all commercialized products. All methods and procedures need to be documented and validated including stability testing, sterilization validation, container closure and other microbiology and analytical chemistry testing executed by a licensed contract research laboratory.

The 503B manufacturing location along with all personnel are subject to inspection by the FDA. Most inspections are triggered by adverse event reporting and the majority result in 483’s due to them being predicated on a medical practitioner or patient complaint to the regulatory body.

FDA Guidance

The increased FDA oversight has also generated several guidance documents. These publications are not legally enforceable regulations. They represent recommendations by the FDA for compliance with existing regulations and are intended to clarify the path to compliance. It is important to note however that many State Pharmacy Boards use guidance to draft and implement guidelines that then become enforceable to 503A compounding pharmacies. For example, there is guidance related to compounding “Essentially Copies of Approved Drug Products” https://www.fda.gov/regulatory-information/search-fda-guidance-documents/compounded-drug-products-are-essentially-copies-approved-drug-products-under-section-503b-federal which bars attempts to duplicate a drug product with the same active pharmaceutical ingredient. The guidance also indicates the copy does not have to be identical, because “essential” provides for nearly similar changes that might be viewed as clinically insignificant by doctors. Compounded products change route of administration, concentrations, APIs, and excipients to manufacture a drug product that achieves the clinical effectiveness required by the patient and the medical community.

There are also draft guidance documents that are being finalized but represent the FDA’s thought process. One example that received a great deal of attention around sterile compounding is “Hospital and Health System Compounding Under the Federal Food, Drug, and Cosmetic Act”, where a criterion for a 503A compounding pharmacy is that it must be within a 1-mile radius of the health care facility. This has created concern for some hospitals. The draft guidance clarifies that this is an attempt to limit production to a hospital health system rather than allowing a 503A facility to distribute across a larger geographic location and function as a manufacturer without applying the standards to ensure a higher level of quality. The FDA has not yet released final guidance around this topic and is currently in draft form https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hospital-and-health-system-compounding-under-section-503a-federal-food-drug-and-cosmetic-act.

Considerations of moving to 503A+ or to 503B

Business continuity planning has owners/pharmacists debating the pros and cons connected with a move from 503A compounding pharmacy to a registered 503B facility as a complex challenge that many health care systems (HCSs) face. The advantages of moving to a registered 503B can be attractive. From a quality perspective, applying cGMP standards (defined by us as 503A+) can improve quality, safety and mitigate risk. This also includes a more extensive environmental monitoring and reporting program. Larger-scale manufacturing can reach outside the health care system, serving a large territory, even interstate. This can also result in improved efficiencies with larger and less frequent batches for a specific drug therapy. BUDs may also be extended, and with future anticipated changes to USP General Chapter <797> in limiting BUDs, this may become more important. There is also extensive reporting required, including adverse event documentation, which improves safety profiles and tracking for compounded medications.

All of this must be evaluated as a financial business model because many of these advantages come with significantly increased costs in research & development, operations, contract laboratory testing, personnel, and document control. Health systems must be able to financially sustain this large-scale operation, which can be challenging and may result in a much larger, volume-driven expansion than what might be part of the strategic vision of a healthcare organization. There are restrictions to the drug products that can be produced under 503B, as well, including limitations to bulk source materials, essential copies of an FDA-approved medication, and medications previously removed from the market.

The advantages of remaining in a 503A designation should also be vetted. Although production would have to remain within the health care system network, this allows for direct control over adherence to USP quality standards, as well as for application of some cGMP standards to further improve safety, exceeding the 503A requirements. This may include a robust environmental monitoring program, more aggressive potency and stability testing than required, and many other components of cGMP. Because compounding sterile products always carries a level of risk, limiting the distribution network can reduce the extent of potential recall. Medication shortage management can also be handled within the HCS, allowing for more nimble reaction to changes in the market and patient demand.

MediZap created the term 503A+ which is a 503A investing in terminal sterilization by irradiation to operate like it’s under cGMP; moreover, HCS’ now can ship with no geolocation constraints reinforcing MediZap value proposition. 503B’s can deliver the most safe and effective drugs using our terminal sterilization services allowing for manufacturing margin of error that is mitigated by our 10-6 sterility assurance levels.

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