In January 2014 the "new" FDA process validation guide celebrated its 3 years anniversary - and in February the European Commission launched EMA's draft to a new European Annex 15 for Validation and Qualification in the GMPs. However, although Annex 15 is only a draft, we already know enough to prepare our validation and qualification approach for the future. Actually some of the new practices are already becoming regulatory expectations - sometimes with significant impact on observations or even warning letters for pharmaceutical companies.
The final version of the new European Annex 15 for Qualification and Validation is not expected until late 2014 or maybe 2015. But we can now start to see the big picture and can prepare our qualification and validation approach for the future. I have been involved in several training courses and conferences on process validation over the last few years, both in USA and Europe and it strikes me how many companies are not even today well prepared to implement the new principles. Many have not understood that they should start to evaluate the performance of their manufacturing processes after the "three validation batches" and should include both risk management aspects and statistical evaluation, - also for their legacy products.
FDA Process Validation guide
The “new” FDA Process Validation guide has a life cycle approach of three stages: 1. Process Design, 2. Process Qualification and 3. Continued Process Verification. The first is about the process knowledge gathered during the process development and scale-up, the second about qualifying the manufacturing system for commercial manufacturing and the third about monitoring on an ongoing basis the process performance throughout the lifetime of the commercial production. The core principles are simple and make lots of sense, because they follow the life cycle of the product and ensure product quality through process performance during the whole life of the product.
EMA’s new Annex 15
The European draft for a new Annex 15 is similar, but it is written very differently, so it is not easy to see the many shared principles between FDA’s new guide and EMA’s new Annex 15. Probably EMA wanted to maintain some compatibility between the existing Annex 15 and the new draft, so that the enhancements become more clearly. This is a great service for those regulated companies that mainly serve the European market, but for the many, many companies that both operate and sell products internationally it is more confusing than helpful. They may end up having different procedures for FDA and EMA validation, although the two essentially share the same validation paradigm.
A new approach?
Some of the confusion comes from the terminology. FDA’s Continued Process Verification (stage 3) corresponds to the intent of EMA Annex 15’s Ongoing Process Verification. FDA’s Process Qualification term is used for all stage 2 activities, which build the case for a release to commercial production, whereas EMA calls this Process Validation. EMA is very explicit and elaborates on qualification activities and has enhanced its specific terms from DQ/IQ/OQ/PQ into URS/DQ/FAT/SAT/IQ/OQ/PQ whereas FDA made it clear that the strict concept of IQ/OQ/PQ etc. was an industry invention and not a FDA requirement. FDA even makes it very clear that other approaches, including the science and risk based verification standard called ASTM E-2500, are fully acceptable. And there are several other examples of potential confusion.
These differences make the issue of validation more complex than necessary and it is a pity for the industry because the intent of the two is really the same - and because most companies have to comply with both. The era of the “three batches and done” is over. If pharmaceutical manufacturers still just do three validation batches, they will have to be able to demonstrate why they think “three” is enough - and will have to establish ongoing monitoring of process performance after the process validation activities are completed.
The bottom line is that despite the differences in guidance wording, the intentions are essentially the same. EMA and FDA have also increased cooperation and shared knowledge about their process validation guides as they were developed. They share regulatory compliance data increasingly and look for many of the same things, despite differences in approaches. And they do of course share ICH Q10 where many of the new principles were introduced originally.
So if pharmaceutical companies have not started building the process validation for the future, it is about time. And if they do it smart, they can do it as one approach that fits both guides!
Gert Moelgaard is Head of Strategic Development at
NNE Pharmaplan, an
engineering and consulting
company focused on the life