An Example of Process Understanding Directed Risk Based CMC Regulatory Oversight of Post-Approval Change
Ajaz S. Hussain, Ph.D.
Deputy Director
Office of Pharmaceutical Science, CDER, FDA
Process Understanding
Physical, chemical, microbiological, and engineering focus
Critical attributes and causal links to quality
Process control strategy (including environmental conditions)
Limitations of analytical methods
Quality system capabilities
QC/QA, IQ, OQ, PQ….
Change control
Training
OOS investigations - Continuous learning
Other aspects
Risk-Based
Risks of uncontrolled post approval changes
New impurities, shorter shelf-life, bio-in-equivalence
Risk of too restrictive post approval change policies
Low efficiency and high cost of manufacturing
Questionable and possibly minimal difference between quality of acceptable and rejected batches
Potential for eroding credibility of pharmaceutical quality system
Likelihood of occurrence, severity of consequence, mitigation strategies
CMC Regulatory Oversight
Prior Approval Supplement (PAS)
High risk
Changes Being Effected in 30 Days (CBE-30) and Changes Being Effected (CBE)
Moderate risk
Annual Report
Low risk
Post-Approval Changes
Scale-Up, site of manufacturing, equipment and process, components and composition
Levels of changes
Analytical methods, packaging, and other types of changes
Why change
Marketing needs, mergers and acquisitions,..
Improving the process (voluntary, a good thing, but..)
Improvement demanded by FDA (e.g., consent decrees)
Process
Understanding
Post

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