(PATRICK KALYANAPU/GETTY IMAGES)
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In the pharmaceutical industry, a change and deviation management system (CMS) is a central part of the overall quality management
system for drug product manufacture — often referred to as the pharmaceutical quality system. In accordance with the ICH Q10
guideline, also supported by the FDA, CMS is one of the four key elements that make up a pharmaceutical quality system (the
remaining three elements include process performance and product quality monitoring system; corrective action and preventive
action (CAPA) system; management review of process performance and product quality).
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 failures
Although 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:
- The failure to evaluate FDA filing requirements; i.e., whether to file for a prior approval or changes being effected, or
to report the change in the next annual report.
- The failure to file changes with the FDA.
- The failure to evaluate and/or justify whether equipment/system requalification is needed to support an equipment/system change,
and whether process revalidation, stability studies or equivalency studies are required to support a process and/or processing
parameter change.
- The inadequate review and approval of the change by the quality control unit.
- The FDA expects the intimate involvement of the quality control unit in the change control review and approval process, and
usually holds the quality control unit responsible for deficiencies regarding change control, which again can be evidenced
in several Warning Letters issued in the past years. One example of this FDA expectation was documented in a Warning Letter
issued by the FDA in 2003. A company performed a routine replacement of the filling pump pistons, without filing a change
request because it was a "like to like" replacement (which has been a typical industry practice). Although the replacement
pistons had the same part number as the original pistons, they were slightly longer. This longer dimension caused the pistons
to come into contact with the bottom of the filling blocks, resulting in the generation of metal particles, which contaminated
the product batches. This metal contamination resulted in the recall of several product batches and the FDA's issuance of
a Warning Letter. The Warning Letter stated that: "Prior to changing the filling line pump parts on the…line, the quality
control unit failed to properly assess the impact that the change may have on the product. It is the quality control unit's
responsibility to review any change to your manufacturing process and to assure the change will not adversely affect the drug
product".
