Does a Defect Rate of 0.011% justify a Warning Letter?

In a recent Warning Letter from the US FDA, the FDA rebuts the argument of a medicinal product manufacturer that a failure rate of 0.011% does not trigger further action. How does the FDA argue here?

Warning Letters can be the result of an FDA inspection. They are generally freely available on the FDA website. A recent Warning Letter was sent to an Indian manufacturer after the company had responded inadequately to the deficiencies listed in the 483 form.

What did the FDA criticise?

Significant violations of the CGMP regulations for finished medicinal products (21 CFR 210/211) were criticised. In this case, the FDA used the term "adulterated" in relation to the products of the manufacturer Cispla. The FDA also criticised a missing Field Alert Report.

Among other things, inadequate CAPA measures were criticised with reference to 21 CFR 211.192 ("discrepancies"). On the one hand, the timing of the CAPA measures and, on the other, the investigation of other potentially affected batches. In 2.5 years, the company received approximately 3000 discrepancies relating to an inhalation product. Approximately 91% of these defects were classified as "no spray" or empty/low content. Many of these defect reports remained open for a very long time, up to 314 days. Causes cited included particles from the inhaler blocking the outlet and container-closure defects. While the defect was categorised as "critical" during the course of the investigation, the final report contained a "non-critical" classification. A field alert report was therefore not issued.

The FDA refuted Cispla's argument in its response to the 483 that the defects only affected 0.011% of all products delivered by pointing to a further 2,000 defect reports that had only recently been received with the same anomalies. The FDA also pointed out that the ratio of defective products to the total number of products distributed is not an indicator of product quality. The number of defects and the type indicate a critical defect that fundamentally prevents patients from using the product.

In the Warning Letter, the FDA therefore requested, among other things, an assessment of the system for analysing deviations, deficiencies, OOS results and errors. The same should be submitted to the FDA for the CAPA system. In particular, the CAPA system is to be analysed:

• "Root Cause Analyses" 
•  CAPA effectiveness 
• Analyses of trends in investigations 
• Improvements coming from the CAPA system 
• Involvement of the quality unit 
• Support of the programme by senior management

The FDA also requires an independent, retrospective review of all deficiencies and the associated investigations during the period in which the deficiencies were received.

Conclusion: The mere calculation of a defect rate is not a product quality indicator for the FDA. The defects must also be considered in terms of their number and patient relevance.

You can find the entire Warning Letter to Cispla, including deficiencies regarding media fills, environmental monitoring and data integrity, on the FDA website.