FDA Requirements for Process Validation

Inspection results often help with the interpretation of regulatory requirements. The FDA Warning Letters are a very good source for that purpose. A recent Warning Letter criticises deficiencies in process validation.

In the Warning Letter, the FDA criticised the fact that no microbiological tests were named in the validation protocol and that the active ingredient specification did not correspond to the current process. Process validation studies were also missing for other medicinal products with regard to different active ingredients and dosage forms.

In the company's response letter, the FDA lacked a detailed description of how the company will ensure in future that the manufacturing process consistently produces medicinal products of suitable quality. The FDA refers to the validation life cycle and specifically mentions the importance of developing the manufacturing process and monitoring after the actual validation. Each significant stage of a manufacturing process must be adequately developed and ensure the quality of the starting materials used, the in-process materials and the finished drug product. Process qualification studies include intensive monitoring and testing of all significant process steps to characterise within-batch variation and evaluate batches to determine whether an initial control state has been achieved.

Successful process qualification studies are required prior to commercial distribution, according to the FDA. Referring to its process validation guidance, the FDA writes that without adequate process validation that considers all production factors and parameters that may affect product quality, the company lacks the basic assurance that it can reproducibly deliver products that meet specifications.

Specifically, the FDA requires:

  • A detailed summary of the validation programme to ensure that a "state of control" is maintained 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 to assess intra-batch and inter-batch variability to ensure state of control
  • A schedule for the implementation of PPQ for each of the marketed medicinal products.
  • A detailed programme for the development, validation, maintenance, control and monitoring of each manufacturing process, with regard to intra- and inter-batch variability, with the aim of achieving a state of control
  • A programme for the qualification of facilities and equipment.
  • A comprehensive, independent assessment of the change management system. This assessment should include procedures to ensure that changes are justified, reviewed and approved by your quality unit. Your change management programme should also include requirements for determining the effectiveness of changes.

You can find the entire Warning Letter on the FDA website.

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