Auditors are starting to ask for a justification for the number of lots used in the PQ. What they are really asking is how do you know three lots are enough? Does anyone know of a methodology to determine how many lots must be run such as in a PQ?
Do CGMPs 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 industry guidance on APIs (see ICH Q7A2 for APIs) also does not specify a specific number of batches for process validation.
FDA recognizes that validating a manufacturing process, or a change to a process, cannot be reduced to so simplistic a formula as the completion of three successful full scale batches. The agency acknowledges that the idea of three validation batches has become prevalent, in part due to language in its own guidance documents. However, FDA is now clarifying current expectations on process validation. The 1987 Guideline of General Principles of Process Validation is currently being revised to address this issue. 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.
In March 2004, FDA revised the Compliance Policy Guide (CPG) (Sec. 490.100) on Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval3. The CPG 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 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. For example, although the CPG does not specifically mention concurrent validation for an API in short supply, the agency would consider the use of concurrent validation when it is necessary to address a true short-supply situation, and if the concurrent validation study conforms to the conditions identified in the CPG (See paragraph 4. a-c).
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 (larger sample size representative of batch) 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 which 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 211.1004: Written procedures; deviations
21 CFR 211.1105: Sampling and testing of in-process materials and drug products
CPG 490.1006 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval.
ICH Q7A7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
I am in medical device. I was hoping someone may have a suggestion on what approach to take to answer this question. One might suggest an f-test to show variability between lots is not different or some other method. Whenever I think of trying to come up with a scheme it seems impractical and overburdensome. If capability is demonstrated with each lot and is above a given threshold value I would think this would show stability in the process and therefore 3 would be sufficient. Any other thoughts?
Hi Bruce,
I Do agree with your approach, The Lot selection in PQ must be based on scientific rational & risk assessment for criticallity of process. There is no as such taylor made no. to PQ lots. One thing should be considered as The objective of PQ should be demonstarted in compliance with selected no. of lots.