Sampling: A Crucial Factor in Process Validation

In the past, ECA has highlighted the importance of sampling in process validation in various news articles. You can find another example of this in a recent warning letter from the FDA.

As is usually the case when it comes to process validation, the FDA cites 21 CFR 211.100(a): Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess.

The finding

Among other things, criticism was levelled at the insufficient process validation of the bulk solution, in particular due to the lack of any scientific justification for the sampling methodology. This concerned the concentration in various bulk solutions. The validation report also states that an acceptance criterion had not been met; however, the validation in this case was accepted anyways without any further measures being taken.

The response

The FDA is not satisfied with the response from the company, which is to create new validation protocols for products exported to the US and then carry out the validation. It wants a scientific justification for the specific sampling methodology compared to other sampling methods. The company's commitment to involve a third party to train the head of the quality department in validation principles has also been found insufficient by the FDA. Here, too, it is requesting documented details of what this training will look like to ensure that the validation activities comply with US requirements.

The consequences

The FDA further stipulates:

• A detailed summary of the validation program, including the product life cycle, together with the corresponding procedural instructions.
• A validation life cycle program that also includes monitoring of deviations within and between batches.
• A timeline for the process performance qualification of each product.
• A risk assessment and, if necessary, follow-up measures for products that were distributed without process validation.
• Validation protocols with explanations for each process control parameter and acceptance criteria.
• The qualification program and procedural instructions for the qualification of equipment and premises.

Further deficiencies

In addition to the above-mentioned validation deficiencies, the FDA also criticizes deficiencies in environmental monitoring in clean areas and, with reference to 21 CFR 211.63, deficiencies in equipment qualification and cleaning validation. The FDA points out that as a contract manufacturer, the company must also comply with GMP requirements. Medicinal products from the Australian company were placed on "Import Alert."   

Conclusion: A scientific rationale for sampling as part of process validation is necessary. Contract manufacturers must also comply with GMP requirements.

As always, the entire warning letter is available on the FDA website.