Warning letter due to non-validated Analytical Methods

Recommendation

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Suitable analytical methods to assess AAV quality during development and manufacturing

The utilisation of validated analytical methods is one of the basic requirements for laboratories in a GMP-regulated environment. If a company's quality control unit works without proof of reliability and reproducibility of their analytical procedures, it violates these requirements. If this happens at a contract laboratory, which performs analyses for various customers, the consequences are all the more extensive and troublesome for all parties involved.

During their visit at the French contract laboratory Quali-Controle in September 2017, FDA inspectors were faced with this exact situation. Since the laboratories' response to the complaints was not convincing, a Warning Letter followed half a year later.

The company was accused of the following GMP violations:

Non-validated test methods

Analytical methods, which are not part of the pharmacopoeia monographs, are used for analysing GMP-liable products and thus lay the foundation for release decisions.

Invalidation of OOS results

Out of three consecutively performed analysis runs, two were outside of and one was within the specification. Both the OOS results had subsequently been invalidated without justification or documented root cause analysis. The reason given in the response that the OOS results had been caused by unclean glassware, was not accepted by the FDA since there was no evidence provided for this. Furthermore, the FDA wasn't presented with a CAPA plan showing how such error sources are to be prevented in the future.

Non-Compliance with quality agreements

Quali-Controle violated the obligations laid down in the quality agreement with the customer. Instead of the utilisation of USP procedures as described, alternative (non-validated) methods had been used. The customers had neither been informed about this beforehand, nor had their consent been obtained.

The FDA views all facilities performing production steps or, as in this case, analyses on a customers behalf as an extension of the pharmaceutical manufacturer. Contract laboratories therefore have to take full (GMP) responsibility and are affected by the consequences in the same way as the manufacturer. The additional claims of the FDA against Quali-Control regarding GMP documents which should exist in a GMP-regulated business are therefore extensive.

Source: FDA Warning Letter to Quali Controle & Qual-Controle-C.E.Bac.