According to the FDA and International Conference on Harmonisation (ICH), a formal CMS should be established to evaluate all changes that could affect the production and control of the drug product, intermediate or API in a pharmaceutical manufacturing company. In addition, some level of CMS is also expected by the FDA for the production of clinical supplies; any changes in the production process and product formulation after the production of the phase III clinical batch must be tightly controlled and carefully evaluated from a product equivalency perspective. Significant process, formulation or equipment changes after the production and use of the phase III clinical batch could result in the performance of lengthy and costly bioequivalency and safety studies, and cause a delay in FDA product approval.
FDA requirements and typical failuresAlthough the cGMP regulation for drug products (21 CFR 211) has no direct reference to change control, change control is implied in 211.100(a) and 211.160(a). 211.100(a) requires that changes in production procedures and process controls be reviewed and approved by the appropriate organisation units and the quality control unit. This was a major component of Warning Letters issued by the FDA between 2007 and 2009. 211.160(a) requires a similar review and approval for changes related to laboratory controls, sampling plans, specifications, and analytical test methods.
The FDA considers change control a very critical GMP compliance issue; therefore it has been one of the main criteria used by the agency in determining their drug inspection depth and coverage, and their decision for follow-up regulatory actions (e.g., Warning Letter issuance). The FDA's strategy for drug inspection and follow-up is evidenced in their systems inspection programme introduced in 2002 for drug product inspection, and in 2006 for API inspection. The FDA compliance programme for drug product inspection (CP7356.002) instructs the FDA investigator to select the comprehensive inspection option when changes have been made that could impact cross-contamination control, or when there had been changes in technology, new facilities or equipment. The FDA compliance programme for API inspection (CP7356.002F) has the same requirements for the performance of a comprehensive inspection, along with additional criteria for changes related to starting materials, intermediates, equipment, facilities, support systems, processing steps, packaging materials or computer software. Both compliance programmes instruct the FDA district office to recommend regulatory actions when there is a pattern of the failure to establish or to follow a CMS.
Typical major GMP deficiencies related to CMS include: