FDA warning letter tells Spanish API firm to up its validation game

A Spanish producer of active pharmaceutical ingredients (API) was chastised by the US Food and Drug Administration (FDA) in a June 30 warning letter for its spotty approach to validation and ensuring that manufacturing processes remain in a state of control and can consistently produce a quality product.

The letter to Bioiberica SAU in Barcelona, Spain, which makes heparin-based products, in addition to APIs, follows an inspection between 31 January and 4 February this year.

FDA told the company that “your firm does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.”

Inspectors found that the firm failed to establish appropriate monitoring and control process for ensuring product quality after reworking batches of the API. In 2020 and 2021, the firm needed to rework approximately 23 batches of API due to microbiological contamination after high levels of a class 3 residual solvent were found in the product.

These rework steps were performed on multiple batches until acceptable results were obtained. Yet no studies were performed to establish the effectiveness of these rework steps, and these steps were not part of the company’s established process validation program.

FDA told the company that “an ongoing program for monitoring process controls to ensure your rework operations can maintain consistent drug quality is essential.” In addition, “because of the narrow therapeutic range of these products, proper blending, and manufacture of your product, appropriately evaluated through process validation, is essential to prevent patients from receiving insufficient or excessive doses.”

The firm agreed there was inadequate control and monitoring and committed to validating its microbiological contamination reduction processes.

The firm also failed to evaluate and conduct stability testing on the reworked batches to show that these batches were of equivalent quality to the batches produced by the original process.

FDA states that “these batches were reworked because of microbiological out-of-specification or non-conforming high [redacted] results. None of the reworked batches were place on stability to ensure they were of quality equivalent to that produced by the validated process.”

In response, the company planned to develop impurity profile parameters and stability-indicating analytical methods for reworked batches. Yet this response was inadequate, said FDA, because it “failed to provide interim measures until your proposed actions are complete.” Also, the stability of the reworked batches currently on the market have not been evaluated.

FDA advised the company to hire a GMP consultant, and to correct the deviations promptly or the agency would withhold approval of new applications or supplements from the firm.

Warning letter

FDA warning letter tells Spanish API firm to up its validation game

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