Warning Letter: Deficiencies in Validation and OOS

Recommendation

17-19 September 2024

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Again, an Indian pharmaceutical manufacturer has received a Warning Letter from the US FDA due to deficiencies discovered during an inspection. The Letter focuses on deficiencies in the validation process and the handling of OOS results in the laboratory.

Execution of process validation

The FDA criticises the non-compliance with the company's validation plan. The reason for the validation was the qualification of a new API to be used for production. The validation plan was to produce three consecutive validation batches. However, the first three validation batches failed in the test points content and dissolution, so that the manufacturer produced a fourth validation batch, which also had quality defects. Numerous OOS investigations were started and the quality unit rejected all four batches. The manufacturer then drew up a document allowing the new API to be used for commercial production without the original validation plan. This made it possible to release batches for the US market, even though the manufacturer was aware that the new API would not produce a specification-compliant product. In addition, numerous batch recalls followed due to increased nitrosamine content. In a response to these inspection deficiencies, the manufacturer stated that the use of the new API had no impact on the manufacturing process or the quality of the final product, which of course did not satisfy the FDA.

Handling of OOS results

The handling of OOS results in the laboratory was also criticized by the FDA. Numerous OOS investigations were completed without indicating the reason for the error and the affected batches were released. The FDA lists examples in which neither a manufacturing nor a laboratory error could be determined as the cause, but the batches were nevertheless released. According to the FDA, this is an inadequate handling of OOS results which has already been criticized in two previous inspections at other sites of the manufacturer. The FDA now expects an independent review of all invalidated OOS results (IPC, release and stability tests) of products currently on the US market.
If OOS results are found during this review without evidence of a laboratory error, the FDA will expect a detailed review of the manufacture of these batches, taking into account manufacturing protocols, manufacturing equipment, raw materials, process capability, deviation history, etc. For each batch, the potential causes should be listed, together with improvement measures.

The original Warning Letter to the Indian API manufacturer can be found on the FDA website.