Why did FDA change their Guideline on Process Validation?

The 4th European GMP Conference took place on 19/20 May 2011 in Heidelberg. One of the sessions held during the conference dealt with the topic Process Validation. Grace McNally, co-author of the new FDA Guidance on Process Validation, opened the session with a speech on this new Guidance. Her speech was followed by a summary focussed on the rationales regarding the revision of the older Guideline from 1987.

The revision is based on the experience the FDA has been making since 1987 on the topic Process Validation. The FDA has discovered that drugs with lower quality had been marketed while they had been manufactured under "validated" processes. This has led to product recalls and complaints because of missing process understanding and process control. According to McNally, the revision opens out into a Life Cycle Approach (see picture 1) which is rational and scientific and could help to improve to control quality and to secure quality.

Picture 1 - Validation Life Cycle Approach

Showing process knowledge and understanding has become an important aspect. Grace McNally anticipated the most frequently asked question regarding new FDA Guidelines: "Do Field-Investigators on-site know that too?" She showed the present trainings for the new Guidance and presented the training as a prerequisite for the Level III Pharmaceutical Inspectorate Certification. Further training for FDA Investigators is planned for July 2011.

Grace McNally demonstrated very clearly that "Key GMPs" on Process Validation have existed for a very long time. In the current Guidance, she particularly refuted those felt as "new", strongly emphasised statistics with two quotations to 211.110 (b) and its preamble as well as to 211.165 (d), in which demands regarding the need for statistics can be found. She also cited an article from 1966 in which a recommendation for the use of statistical methods is already named. Grace McNally also mentioned expressively that the Process Validation Guidance is not specifically applicable to sterile and cleaning processes.

The new Life Cycle Approach should lead to a relatively stable process in Phase 3 ("continuous process verification"). According to McNally, this - however - will require much more work in the development phase (see picture 2).

Picture 2 - Former vs. new Validation Approach 

She considers that the "entry" of older products into the Life Cycle's Phase 3 may involve the integration of development data and manufacturing experience. This would lead to process improvement. Grace McNally expressively indicated that the new Guidance doesn't contain terms like Prospective, Retrospective and Concurrent Validation, IQ/OQ, Tech Transfer, Critical Quality Attribute, Critical Process Parameter and Worst Case. She ended her speech with 3 questions which need to be answered within a Process Validation. (See picture 3)

Conclusion: The FDA takes the implementation of the new Process Validation approach very seriously and carries on the demands which have actually always been part of the Code of Federal Regulation but have not (always) been rigorously examined: showing process knowledge and understanding based on scientific rationales. Especially regarding older products, the use of the new approach could become a real challenge.

Sven Pommeranz
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)

PS: The ECA event "

The new FDA/EU Approach to Process Validation" taking place on 6/7 December 2011 in Berlin will focus on the new FDA Process Validation Guidance.

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