Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires all drugs to be manufactured in conformance with CGMP. The CGMP regulations in 21 CFR parts 210 and 211 for finished pharmaceuticals apply equally to over-the-er (OTC) and prescription (Rx) drug products (see Compliance Policy Guide Sec. 450.100).
The CGMP regulations provide the minimum legal requirements for conducting reliable operations (see 21 CFR part 211). Some relevant CGMP regulations, with a brief description, are given below:
Manufacturing Design and Control: CGMP Requirements and Recommended Guidance for Manufacturers
- Design manufacturing facilities (§ 211.42) and processes (see below) to prevent microbial contamination:
- For nonsterile drug products, establish control procedures to monitor output and validate processes to include bioburden testing (§§ 211.110(a)(6)), 211.111) and establish and follow written procedures designed to prevent the introduction of objectionable microorganisms (§ 211.113(a)).
- For sterile drug products, establish and follow written procedures designed to prevent microbial contamination (§ 211.113(b)). See the guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice.
- Conduct process validation studies to ensure acceptable output (e.g., with topical antiseptics, particularly product microbiological quality) (§ 211.110(a)). Implement and validate needed changes when deficient manufacturing steps, equipment, or raw materials may be adversely affecting process control. See the guidance for industry Process Validation: General Principles and Practices.
- Ensure that operating procedures will consistently produce a quality product (§ 211.100). Review and evaluate any deviations or discrepancies documented during manufacturing and testing to determine if a product lacks assurance of sterility (for sterile antiseptics) or may be contaminated with objectionable microorganisms (for nonsterile antiseptics). Document and implement any corrective actions deriving the evaluation (§ 211.192).
- Ensure that all equipment, including water systems, operates consistently and is clean, sanitary, and suitable for its intended use (§§ 211.63, 211.65, 211.67, and 211.68).
- Establish and follow in-process bioburden testing procedures to help monitor in-process control, including understanding the bioburden challenge to a final sterilization process (§ 211.110(a)(6)).
Components, In-Process Materials, Containers or Closures, and Finished Product Testing: CGMP Requirements for Manufacturers
- Establish appropriate written testing standards/specifications and sampling plans for components, in-process materials, containers or closures, and finished products (§ 211.160).
- Establish procedures for testing and approval or rejection of components, drug product containers, and closures (§ 211.80). Test each lot of a drug product component and container or closure, including those that may be vulnerable to microbiological contamination (§ 211.84)(d)(4-5), including applicator material (e.g., cotton pads) and water used as an ingredient in the product.
- Conduct appropriate microbiological tests before a batch disposition decision is made. Test each batch of a sterile product for sterility (§ 211.167). Test each batch of a non-sterile product to ensure absence of objectionable microorganisms (§ 211.165(b)).
Management
The CGMPs require that the management of a manufacturing facility maintains a well-functioning quality system, which includes an effective quality unit vested with the responsibilities and authorities required under CGMP (§ 211.22). See ICH guidances for industry Q9 Quality Risk Management and Q10 Pharmaceutical Quality System.
