Quality by Design, Not Following cGMPs Makes Your Product Adulterated, A Key Regulatory Concept with Supporting Data from Recent CDER Reports and Other Sources
Quality by Design
Not Following cGMPs Makes Your Product Adulterated
A Key Regulatory Concept with Supporting Data from Recent CDER Reports and Other Sources
Have you seen this in an FDA Warning Letter?
“Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug product is adulterated within the meaning of ...the ...FD&C Act…”
Note the FDA provided no evidence something is actually wrong with the product such as an adverse event, or because it failed a lab test. Drug products can be considered adulterated because current Good Manufacturing Practices were not followed.
Some interesting facts jump out of the pages of “FY2024 Report on the State of Pharmaceutical Quality(1)”, recently released by CDER.
On page fifteen you can see recalled drug product counts per year with a breakdown of the reasons for the recalls. For 4 of the last 5 years at least 48% of the drug products were recalled for cGMP deviations, the other reasons consisting of contamination, defective product, temperature abuse, failed specifications, labeling and packaging.
Not only that, all 53 samples collected by the FDA in FY2024 passed laboratory tests. And these samples were targeted, not random. The samples can be reviewed on the “Drug Quality Sampling and Testing Programs(2)” website.
Remember, sample sizes for destructive samples are small and provide limited insight into the quality of a batch as a whole. In fact, if a sample does fail the situation is considered egregious.
“...if a 10,000-unit lot with a 0.1 percent contamination level was sterility tested using 20 units, there is a 98 percent chance that the batch would pass the test.” FDA Guidance(3)
“It should be noted that a sterility test, while a critical final quality control for all aseptically processed products that purport to be sterile, cannot be solely relied upon as justification to release each drug product batch as the test is only the last in a series of design and control provisions intended to protect the consumer from distribution of an unsafe batch. Finished product testing alone does not establish sterility of all units because contamination is typically episodic and not uniformly distributed. Larger contamination problems may go undetected for substantial periods if your firm is placing too much reliance on the final quality control test for sterility to become aware of a problem in aseptic manufacturing. It should also be noted that any positive sterility test result represents a serious CGMP issue that requires a comprehensive investigation into the cause and extent of the problem, and a prompt review of the qualification status of your aseptic process.” FDA Warning Letter(4)
“Analysts should remember that no microbiological sampling plan can prove the absence of microbial contamination, even when no viable contamination is recovered. The absence of growth on a microbiological sample means only that growth was not discovered; it does not mean that the environment is free of contamination.” USP 1116(5)
In summary, in order to take enforcement actions the FDA does not have to prove some one has been injured. It also does not have to prove a product is capable of injuring. Drug products are considered adulterated if they were not manufactured using current Good Manufacturing Practices. “Our product looks great and passed all the tests” is not the metric drug manufacturers should use to determine inspection preparedness or the safety and efficacy of their batches. And of course following the regulations is not just required by law, it’s also a good idea. It provides assurance of the quality of the drug product from the very beginning of the process.
If you enjoyed this article keep TINO Consulting LLC in mind as your first stop for FDA regulatory consulting. TINO, There Is No Other, www.tinoconsultingllc.com
When you think of me, don’t think of cGMP. When you think of cGMP, think of me.
Sources
1 FY2024 Report on the State of Pharmaceutical Quality
https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/report-state-pharmaceutical-quality?utm_medium=email&utm_source=govdelivery
2 Drug Quality Sampling and Testing Programs
https://www.fda.gov/drugs/science-and-research-drugs/drug-quality-sampling-and-testing-programs
3 Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice 2004
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice
4 FDA Warning Letter
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/brassica-pharma-pvt-ltd-679005-07112024
5 You’ll have to use your paid subscription to United Sates Pharmacopeia to view 1116 Microbiological Control and Monitoring of Aseptic Processing Environments