The pharmacy compounding industry has been under scrutiny since the New England Compounding Center’s 2012 tragedy where 64 deaths and 751 injured patients occurred due to contaminated medication. This incident was attributed as a direct link to the lack of proper oversight provided by the state boards of pharmacy. As a result, the Food and Drug Administration (FDA) has stepped in as the primary regulatory body for regulating the compounding pharmacies and have divided the pharmacies into two sectors: 503A and 503B facilities.
What is 503A Compounding Pharmacy?
503A facilities are referred to by the FDA as a traditional compounding pharmacy that compounds in accordance to patient specific prescriptions and is required by the state boards of pharmacy to comply with USP <795> and <797> guidelines. In this business model, the facility is prohibited from dispensing for office use which limits the product line to items that the patient can use in their home. In addition, the facility may not compound large batches which can lead to increased product cost. A solution to the presented limitations was to add the ability to create exemptions for a compounding pharmacy as a 503B.
What is a 503B Compounding Pharmacy?
503B facilities are referred to by the FDA as an outsourcing facility that may produce large batches with or without prescriptions to be sold to healthcare facilities as office use only. In this model, pharmacies are able to produce larger scale batches to drive down production cost to provide affordable medication to the consumer. Although not required to provide patient specific medications, the facility is then held to a higher standard as a manufacturer requiring full current good manufacturing practice (CGMP) compliance. The FDA has released several draft and final guidances to assist compounding pharmacies in navigating the new outsourcing facility space, however many guidelines remain unclear as apparent in the recent FDA 483 observations and warning letters. The table below describes the fundamental differences between the 503A and 503B facilities.
503A vs. 503B
A prime difference between 503B and 503A facilities, and a major component of CGMP, is the requirement for every process to be validated in a 503B facility. Before any new product can be brought to market, multiple batches must be made and submitted for testing and stability studies. While this may result in a longer lead time to getting new products to customers, this ensures that every batch made during normal production is consistent in quality and meets the high standards set by the FDA and CGMP. Not only must products be validated, but testing methods must also be validated to ensure accuracy and precision, in accordance to USP standards. All vendors that supply raw materials must be
thoroughly vetted, and on-site inspections are performed by the Quality Assurance team for all critical suppliers.
The Role of the Pharmacist in a 503A vs. 503B Facility
The pharmacist’s role in a 503B also slightly differs from a 503A. In both facilities, pharmacists are still responsible for ensuring the final accuracy of a prescription or drug order. However, in 503B facilities, pharmacists do not perform drug utilization reviews, since pharmacists do not receive patient specific orders in outsourcing facilities. In turn, pharmacists take a much more direct role in the supervision of the manufacturing and compounding process, where there is direct supervision of the technician performing the operations. The pharmacist is also in charge of reviewing all documentation performed by technicians, along with the Quality Assurance team.
Comparison of requirements between compounding facilities
|Complies with USP <795> and <797>||Complies with USP <795> and <797>
Complies with 21 CFR Part 210 and 211 (CGMP)
|Complies with state boards of pharmacy regulations.||Complies with state boards of pharmacy regulations.|
|Human sterile medications must be dispensed as patient specific.||Human sterile medications may or may not be dispensed as patient specific.|
|Environmental Monitoring is performed every 6 months.||A robust Environmental Monitoring program is developed and is performed, at minimum, per production shift in the ISO 5 primary compounding areas and weekly in the secondary compounding areas (ISO 7 and ISO 8).|
|Patient information, medication information, company information, and adequate directions for use of medication.||Labeling requirements per the Drug Quality and Security Act (DQSA).|
|Pharmacists may review their own work and investigate any potential anomalies.||A quality department must be in place that is an independent entity of the operations and sales departments with complete autonomy for investigations and releasing product.|
|Finished Product Dating|
|Beyond Use Dating (BUD) may be assigned based on internal or external scientific literature showing stability.||A robust stability program is required to scientifically confirm the stability of a medication when subjected to degradation variables such as time, temperature, and humidity.|
|Bulk Drug Substances|
|May compound from Category 1 bulk drug substances under the 503A.
May compound from bulk drug substances that have a USP or NF monograph.
May compound with drug substances that are components of drugs approved by the Secretary
|May compound from Category 1 bulk drug substances.|
|Required to register with each state board of pharmacy and DEA||Required to register with each state board of pharmacy, DEA and FDA
Required to report product list to FDA biannually
Although lengthy, the requirements set forth with 503B are defined to give the industry the ability to generate custom product combinations to the public in a unit dose fashion with an extended shelf life while validating the quality and stability of the product. When selecting a 503B facility to customize products, it is important to ensure the quality standards meet the FDA requirements and the commitment to quality standard exists for patient safety.
Author: Melissa Stefko, BS, MS, MBA, CQA is the Senior Director of Quality Assurance for Wells Pharmacy Network, a nationwide 503A Compounding Pharmacy and a 503B Registered Outsourcing Facility. Ms. Stefko has extensive Biotechnology/Pharmaceutical experience within key operational areas of Quality, Facilities, Project Management and Business Development.