In a GMP News of 27 January 2010 we had referred to a questions-and-answers document by the FDA. One of the questions in that paper was if, according to cGMP, the manufacture of 3 successful process validation batches is necessary before a new active pharmaceutical ingredient (API) or a new medicinal product can be released for the market.
The FDA's answer is: No
What is highly interesting, however, is the corresponding reason. Neither the cGMP/ICH Q7 rules, nor an FDA policy requires a minimum number of runs for proving the validity of a process. The FDA considers a reduction to 3 runs as too simple for being able to prove validity. Yet, the Agency admits that the idea of having 3 runs is widespread - and can in part also be traced back to its own guidance documents.
However, it currently sees itself in a phase of clarification with regard to its present expectations. In this respect, the FDA points out that the focus is nowadays on process design and the development studies, which are then meant to be transferred to production scale in a reproducible way. Even though, strictly speaking, this aim has always been expected. The number of 'conformance batches' (aka 'validation batches') shall be determined on the basis of knowledge.
The answer also references a Compliance Policy Guide (490.100) of 2004 on the topic of process validation, and in this context the possibility of a concurrent validation is mentioned (however, normally a prospective validation is expected). Nevertheless, the document refers to enhanced tests in this 'short supply situation', which should also be listed in the validation plan. In addition, enhanced sampling and, if necessary, tests for additional attributes could reinforce confidence in the API manufacturing process. For the analytical tests, validated methods are required. Furthermore, the FDA expects a validation protocol including a review and a final report after the production of multiple batches, even if the early batches have already been marketed. That sounds a bit strange. It probably means that a review and a report should already be provided for in the plan, which will later on comprise the concluding evaluation. That does make sense.
Final conclusion: The answer to the question if 3 successfully manufactured validation batches are necessary as the basis for marketing a new API or medicinal product is: no. Even though the new FDA Draft Guidance on Process Validation is not mentioned in the references, the answer aims directly at this document. The number of runs should be performed in a knowledge-based way in order to be able to show the transfer of the process design and of the development studies to commercial scale. A conspicuous feature is the exemplary mention of a 'concurrent validation' and the somewhat confusing mention of a review and report in a 'validation protocol'.
The complete document can be found here.
In view of the present situation, the European Compliance Academy offers the event "The new FDA/EU Approach to Validation" in Prague on 8-9 June 2010. At this event, FDA's new validation approach is explicitly discussed. And an EU inspector explains the new way of seeing process validation in Europe.
On behalf of the European Compliance Academy (ECA)
Source: FDA Webpage, Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2