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Process validation data should be generated for all products to demonstrate the adequacy of the manufacturing process at each site of production. It is recognized that, at the time of submission, process validation data may not always be available. It is nevertheless essential that valid manufacturing processes are always used. Validation should be done in accordance with GMP and data should be kept at the production location and made available for inspection. As part of the process validation life cycle some process validation studies may be conducted in pilot scale batches if the process has not yet been scaled up to production scale. It should be noted that the pilot batch size should correspond to at least 10% of the production scale batch (ie the multiplication factor for scale-up should not exceed 10). For solid oral dosage forms this size is usually 10% of the maximum production scale or 100,000 units whichever is greater. Where the intended batch size is less than 100,000 units, the predictive value of pilot batches may be limited and a judicious approach should be followed. Competent authority may decide on limitation for approval after increase in batch size.
Since it is not generally considered useful to conduct full validation studies on pilot scale batches, the process validation scheme described in Appendix I of this guideline should be completed for each product for subsequent production scale execution. The process by which the validation scheme will be followed should be included in the dossier. The scheme should include a description of the manufacturing process, the tests that will be carried out and the acceptance criteria, a description of the additional controls in place and the data to be collected. A justification for the selected process validation project should be presented in Module 3 and the Quality Overall Summary and Part 2.B for Human Medicines and in the Pharmaceutical Detail and Critical Summary for Veterinary Medicines.
Process validation should focus on control techniques, including primarily critical process parameters and other relevant studies that demonstrate that the process is capable of delivering the desired product quality.
However, in some cases, it is considered necessary to provide production scale validation data in the marketing authorization dossier, such as in situations where the product is a biological / biotech product, where the applicant is proposing a non-standard method, where pilot scale data may not be predictive of production scale. , or for special products such as medicinal products for human use for certain modified release preparations, see the note for guidance on the quality of modified release products; For veterinary use, see note for guidance on quality of modified release dosage forms for veterinary use). Where non-standard sterilization methods or aseptic processing are employed, data on several consecutive batches at production scale should be provided prior to approval. The number of batches (minimum 3) should be based on process variability, process/product complexity and manufacturer’s experience. For other specialized non-standard processes (described in Section 8), data from 1 or 2 production scale batches may be sufficient where these are supported by pilot scale batches and a history of continuous production of products by substantially equivalent processes.
Studies should address those phases of production, particularly critical phases that will not be adequately addressed by the application of finished product specifications alone by conducting additional testing as needed. A justification for the selected process validation study should be presented in Module 3 and Quality of Human Medicines Overall Summary and Part 2.B and Pharmaceutical Detail and Critical Summary for Veterinary Medicines.
If a design space is applied, the applicant should provide production scale validation techniques to ensure that the models used at pilot scale to determine the design space are still valid at production scale. Verification at production scale can be conducted step by step as the manufacturer moves to different areas of the design space.
