Top Ten FDA Warning Letter Observations

An anecdotal review of recent FDA warning letters provides key insights to pharmaceutical companies about how they can improve their quality systems, their manufacturing processes and most importantly, manage future FDA inspections.

Some surprising information culled from the GMP warning letters issued recently include the following:
• Approximately 80 percent of the the FDA-issued GMP warning letters went to domestic facilities, notwithstanding the numerous concerns that have been raised in years past about the increasingly global nature of pharmaceutical manufacturing
• A similar majority of FDA-issued GMP warning letters also went to finished product manufacturers – rather than API manufacturers – again highlighting the fact that the FDA is still primarily focused on final production instead of the global supply chain for pharmaceutical manufacturing
• Additionally, several warning letters incorporated other compliance issues, including: allegations of unapproved new drugs, misbranded drugs, promotional issues and pharmacy compounding, which demonstrates that the FDA is taking a more holistic approach to enforcement when it identifies violate conduct;
•The warning letters that we reviewed clearly show that the FDA is taking a more systemic and risk-based approach to assessing GMP compliance, and paying particularly close attention to such areas as the quality control unit, manufacturing process validation, CAPA, and laboratory out of specification (OOS) test results and investigations.

We believe that pharmaceutical companies, by carefully assessing FDA GMP warning letters from the past year, and thereby understand what the FDA was
looking for in other inspections — can enhance their quality systems and improve their manufacturing processes, and therefore more effectively manage future FDA establishment inspections.
Shown below are the top 10 issues found in the FDA warning letters:
1. Failure to adequately establish a system/process for investigating systemic issues (about 80% of it about the CAPA Process).
2. Failure to both document and then fully perform the responsibilities applicable to the quality control unit in procedures.
3. Failure to provide adequate documentation to prove the training of the personnel performing laboratory tests.
4. Failure to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products.
5. Failure to fully perform and/or document the review of production batch records to determine compliance with all established, approved written procedures before a batch is released.
6. Failure to ensure that all tests are in conformance with the established specifications and that these are met prior to the release of drug products for distribution.
7. Failure to review production records to assure that no errors had either a) occurred or, b) if errors had occurred, that they were fully investigated, conclusions reached, and then followed-up upon.
8. Failure to investigate complaints involving the possible failure of a drug product to meet any of its specifications.
9. Failure to submit NDA-Field Alert Reports (FARs) within three (3) working days of receipt of information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug products
10. Failure to establish a designated Quality Unit with autonomous authority to review, approve/reject results.

Given the potentially significant consequences of GMP non-compliance, we strongly encourage our clients to make every effort to ensure that their written responses demonstrate a commitment to manufacture high-quality drug products and to implement aggressive corrective action as part of a robust pharmaceutical quality system.

What your organization’s most recent warning letter included?