Does cGMP regulations require three successful process validation batches before a new active pharmaceutical ingredient (API) or a finished drug product is released for distribution?
No. Neither the cGMP regulations nor FDA policy specifies a minimum number of batches to validate a manufacturing process.
The current FDA guidance on APIs (see ICHQ7) also does not specify a specific number of batches for process validation. FDA's process validation guidance now recommends a product lifecycle approach.
The emphasis for demonstrating validated processes is placed on the manufacturer’s process design and development studies in addition to its demonstration of reproducibility at scale, a goal that has always been expected.
However, a minimum number of conformance (a.k.a. validation) batches necessary to validate the manufacturing processes is not specified.
The manufacturer is expected to have a sound rationale for its choices in this regard. The Agency encourages the use of science-based approaches to process validation.
The Compliance Policy Guide (CPG) Sec. 490.100 describes the concept that, after having identified and establishing control of all critical sources of variability, conformance batches are prepared to demonstrate that under normal conditions and operating parameters, the process results in the production of an acceptable product.
Successful completion of the initial conformance batches would normally be expected before commercial distribution begins, but some possible exceptions are described in the CPG.
The conditions outlined in the CPG include expanded testing for each batch intended to address a short supply situation.
Expanded testing conducted according to an established validation protocol could provide added assurance that the batch meets all established and appropriate criteria before the API is used in the finished drug product.
Additionally, confidence in the API manufacturing process may be gained by enhanced sampling and perhaps the testing of additional attributes.
Validated analytical methods are needed for testing every batch, including validation batches.
The Agency would also expect the manufacturer to use a validation protocol that includes a review and final report after multiple batches are completed, even though the earlier batches may have been distributed or used in the finished drug product.
References:
- 21 CFR 211.100: Written procedures; deviations
- 21 CFR 211.110: Sampling and testing of in-process materials and drug products
- Compliance Policy Guide Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval
- ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
- FDA Guidance for Industry, 2011, Process Validation: General Principles and Practices
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