What is a GMP Warning Letter, Anyway?

 The regulatory bodies – FDA and European Medicine Agency (EMA) require pharmaceutical companies to comply with cGMP standards. If FDA investigators observe any violation these will be put down on a FDA 483 form. If these GMP violations are regarded as critical or the response letter was unsatisfactory, FDA may take an formal step by sending a warning letter to the manufacturer.

Corrective Measures

Upon receipt of the 483, FDA wants you to take instant and adequate measures to correct the violations. You can’t fool authorities by only showing that you have planned to take action. They expect you to demonstrate that adequate steps have been taken to eliminate the discrepancies.

All warning letters should be taken seriously, some of them can potentially have more dangerous consequences than others. For example, if FDA warns you of a misleading advertisement violating the regulations, you can more easily resolve the issue by stopping that advertisement. On the contrary, in case you have found to be violating cGMP for drugs or Quality System Regulations (QSR) for medical device production, the inconsistencies may have immediate as well as long –term consequences. It’s because the company has to take long-term corrective measures to resolve the issue. 

Follow up Evaluation

Once you apprise FDA that the required changes have been made, FDA may perform a follow-up evaluation to verify the changes made in response to the warning letter. Are the violations now fully  addressed resolved?. FDA may withhold the approval of pending applications if it observes the same violations again.

Trends in GMP Warning Letters

Having the knowledge about recent trends in GMP warning letters can provide pharmaceutical and medical devices manufacturers valuable hints to improve their quality systems, manufacturing process.

A detailed review of over a dozen warning letters issued by FDA in the past 12 months yields a number of useful insights about the focus points of FDA and where FDA place greater emphasis when assessing GMP compliance.

  • Majority of GMP warning letters were issued to finished product manufacturers as compared to API producers. It’s evidence that regulatory authorities still focus heavily on the end product more than anything else.

  • Many GMP warning letters were linked with the promotional issues, misbranded medicines. It demonstrates a holistic approach by FDA to take enforcement measures upon violation of rules.

  • The GMP warning letters clearly reflect that FDA is paying a systematic and particularly close attention to process validation, out of specification (OOS) results and quality control.

Along with the above listed observations, FDA is likely to focus on the adverse event reporting and pharmacovigilance systems as well, especially because of its heightened sensitivity to drug safety.

In fact, almost all the GMP warning letters mentioned their concern over the inadequacies in company’s response to inspection observations. When crafting a response, you should make every effort to demonstrate that your firm is committed to produce high quality pharmaceutical products and implement the most appropriate corrective actions to achieve GMP compliance.