FDA Warning Letter for both missing Process and Cleaning Validation

The current FDA process validation guideline has been in force since 2011. The topic of cross-contamination has been mentioned in 21 CFR 211 since 1978, and the FDA Guide to Inspections on Cleaning Validation dates back to 1993. Process and cleaning validation have therefore been established procedures in the pharmaceutical industry for a long time. But what happens if these two requirements are still not met during an FDA inspection?

During a GMP inspection, the FDA noticed, among other things, that a contract manufacturer had neither process nor cleaning validation in place. The company never responded to the Form 483 that was subsequently issued.

In the subsequent Warning Letter, the FDA now makes it clear what it expects from the inspected company.

Process validation

With reference to its process validation guidance, the FDA explains what it means by process validation and why it is important to it.

Specifically, the FDA requires:

• A detailed summary of the validation programme that ensures that a 'state of control' is achieved throughout the product life cycle, together with the associated procedures
• A description of the process performance qualification (PPQ) programme
• A description of the monitoring activities for evaluating variability within and between batches to ensure the 'state of control'
• A schedule for performing PPQ for each of the marketed medicinal products
• PPQ plans and written procedures for the qualification of premises and equipment
• A detailed programme for the development, validation, maintenance, control and monitoring of each manufacturing process with regard to variations within and between batches with the aim of achieving a 'state of control'
• An assessment of each production process to ensure that there is a data-driven and scientifically sound programme in place to identify and control sources of variability. This includes an assessment of the suitability of equipment, the adequacy of monitoring and testing systems, the quality of raw materials, and the reliability of each manufacturing step and its controls.

Cleaning validation

The same applies to the lack of cleaning validation. Here, the FDA cites the risk of cross-contamination in equipment used to manufacture multiple products. This is particularly relevant given that cosmetics are also manufactured on this equipment.

The agency also calls for improvements in the cleaning validation programme, with particular emphasis on worst-case scenarios in medicinal product manufacturing. This applies in particular to the identification and assessment of worst-case scenarios:

• Medicines with higher toxicity
• Medicines with higher active ingredient content
• Medicines with low solubility in cleaning agents
• Medicines with properties that make them difficult to clean
• Swab sampling points in locations that are most difficult to clean
• Maximum standing times before cleaning

In addition, the FDA requires:

• A description of the steps that still need to be implemented in the change management system before new equipment or a new product is introduced.
• A summary of the updated work instructions that ensure that a suitable programme is in place to verify and validate cleaning procedures for products, processes and equipment.

Conclusion: The above measures required by the FDA describe virtually the entire scope of process and cleaning validation.

You can find all the details and further descriptions of deficiencies in the full Warning Letter on the FDA website.