503B Has Genesis in Food, Drug, and Cosmetic Act

The drug quality and Security Act (DQSA) was established in 2013 in response to contaminated steroid injections intended for intrathecal use that had caused a fungal meningitis outbreak.¹

The outbreak infected a confirmed 753 individuals and led to the deaths of 64.² The contaminated steroid injections were manufactured by the New England Compounding Center. Title I of the DQSA, the Compounding Quality Act, amends the Federal Food, Drug, and Cosmetic Act regarding the compounding of drug products. Out of this amendment, section 503B was born.³

503B outsourcing facilities can produce large batches of medication for distribution to clinics, doctor’s offices, and health care centers, with or without prescriptions, whereas 503A pharmacies produce limited amounts of anticipatory compounding and patient-specific medication. 503B facilities are subject to stricter regulations than traditional 503A compounding pharmacies. Registration with the Drug Enforcement Administration, the FDA, and state boards of pharmacy is a requirement for 503B outsourcing facilities, as well as compliance with United States Pharmacopeia (USP) general chapters <795>, <797>, and current Good Manufacturing Practices (cGMP) (21 Code of Federal Regulations, Parts 210 & 211).

503B facilities are also subject to inspection by the FDA. cGMP regulations define the minimum requirements needed during the processing, testing, packaging, and distributing of drug products.⁴ To comply with cGMP, facilities establish a quality system, which provides the structure to ensure the quality and safety of products.⁵ An important aspect of a quality system is an independent quality unit that is responsible for creating procedures, investigating deviations, reviewing records, and ultimately approving and releasing, or rejecting, compounded products (see Figure).

A quality system is a checks and balances system in which the quality unit oversees all aspects of a 503B outsourcing facility, from incoming raw materials to the release
of the final product. In addition to having an independent quality unit, there are many other critical aspects to a quality system in a 503B facility, including standard operating procedures (SOPs), which provide clear, consistent instructions for performing tasks.

503B facilities are required to have SOPs for compounding drug products and executing the myriad other activities performed under the quality system. SOPs eliminate or reduce ambiguity in the facility’s processes and are a key tool in training personnel.

Release of Raw Materials and Supplies

Releasing raw materials and supplies confirms the identity and quality of raw materials used in the drug compounding processes. Samples are taken of raw materials and tested to ensure that they meet predetermined specifications prior to use. Certificates of analysis are obtained for each lot of components and raw materials to ensure they meet quality standards and specifications. Environmental monitoring of air cleanliness standards exists in 503B facilities such that facilities are designed in a manner that minimizes the level of contaminants, thereby preventing microbiological contamination of drug products.

Regular testing of the environment is required for ensuring the cleanliness of drug compounding areas. International Organization for Standardization (ISO) 5 areas are tested minimally each production shift, whereas ISO 7 or 8 areas must be tested at least weekly to ensure that the requirements of air cleanliness are being met.

Training

Training programs at 503B compounding facilities need to encompass training in regulations and standards, such as cGMP and USP <797>, in addition to job-specific training in aseptic technique and garbing, among others. Various methods, such as proficiency evaluations and written exams, are used to ensure that personnel are qualified to perform their job functions.

Validation

Validation is the collection and evaluation of data that establishes scientific evidence that a desired result with predetermined criteria will be achieved each time. Process validation significantly contributes to ensuring drug quality. Each step of the drug compounding process is controlled so that the finished product meets its quality attributes and specifications. Test method validation ensures that tests comply with USP standards. All product batches are thoroughly tested using validated methods prior to being released for use.

Equipment Calibration and Maintenance

A high degree of accuracy is needed in drug compounding. Equipment used in a 503B facility must be calibrated regularly to ensure exact measurements. In addition, a preventive maintenance program keeps equipment operating optimally. Supplier qualification suppliers of goods and services are vetted and approved prior to the purchase of their products. The qualification process is a means of ensuring that the supplier can provide consistent quality components, packaging, materials, packaging, and services in compliance with regulatory requirements.

Summary 503B outsourcing facilities came about as a result of the DQSA. The establishment of section 503B allows health care centers to obtain sterile drug products produced with high levels of compliance and quality. Because 503B facilities operate on a larger scale compared with 503A traditional compounding pharmacies, they are mandated to follow cGMP regulations. 503B facilities play a key role in health care because of their bulk production, stringent quality standards, and wide distribution. They fill a gap between 503A pharmaceutical manufacturers and pharmacies, and ensure that the public has access to effective and safe medications.

Sharyl Zaccaglino, MS, is director of research quality
and compliance at the University of Rochester Medical Center in New York.

References

1. Goldman TR. Regulating compounding pharmacies. HealthAffairs. May 1, 2014. Accessed October 31, 20219. http://healthaffairs.org/healthpolicybriefs/brief_pdfs/healthpolicybrief_114.pdf

2. Multistate outbreak of fungal meningitis and other infections – case count. October 30, 2015. Updated May 9, 2019. Accessed October 31, 2021. CDC. https://www.cdc.gov/hai/outbreaks/ meningitis-map-large.html

3. Drug Quality and Security Act, HR 3204, 113th Cong, 1st Sess, §102 (2013).

4. Food and Drugs. 21 CFR §210-§211 (1978).

5. Quality systems approach to pharmaceutical current good manufacturing regulations. FDA. October 2006. Updated April 16, 2020. Accessed October 31, 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations