A company recently received the following observation:
…. Process validation does not always include inclusion and establishment of all process parameters that should be controlled for reproducible operations.
Specifically, concerning … manufacturing (used in API manufacturing and the source … for … production, and used in cleaning), operating ranges for process parameters are not fully established, such as determining and monitoring acceptable levels/ranges of pressures and flow for routine production, in order to sufficiently validate and control this manufacturing process. For example, appropriate ranges (upper and lower limits) for the monitoring of flow/pressure for retention time and proper filtering and manufacturing have not been fully established for processing. Also, … do not have sanitization procedures and schedules in order to control microbial proliferations (biofilm growth) and govern a potential source of endotoxins.
According to GMP Trends® Annual Reports, over the last 5 years the observations pertaining to process validations (21 CFR 211.100(a)) have been in the top 10 observations cited by the FDA each year.
Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the following:
A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.
FDA regulations describing current good manufacturing practice (CGMP) for finished pharmaceuticals are provided in 21 CFR parts 210 and 211.
The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so consistently and reliably. Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process validation is provided in § 211.100(a), which states that “[t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess…” (emphasis added). This regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting these attributes.
For more information on process validation, refer to the FDA Guidance Document, Guidance for Industry, Process Validation: General Principles and Practices, January 2011
To view more observations pertaining to process validation, refer to the following GMP Trends® Issues: 1054, 1052, 1046, 1044 and 1040.
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