EMA publishes New Process Validation Guideline

After the publication of the Annex 15 draft at the beginning of February 2014, the EMA made a move towards the revision of its process validation guideline. The final document was published on 27 February 2014. For a long time now, the EMA had already announced this revision in a concept paper. The objective of the revision was to integrate modern GMP aspects:

  • Integration of the ICH Q8, Q9 and Q10 Guidelines
  • Incorporation of Process Analytical Technology (PAT), Quality by Design (QbD) and Real-Time Release Testing (RTRT).
  • Extension with regard to an "enhanced approach" and integration of "continuous process verification"
  • Integration of the Annexes to the current Note for Guidance 
  • Harmonisation with the current FDA Guidance on Process Validation 

The deadline for comments on the draft for the revision of the process validation guideline ended in October 2012 already. Now, elements in accordance with the Annex 15 have also flowed into the final document. In the following, you will read a short evaluation of the document with regard to the original draft from March 2012, the (still) applicable Note for Guidance on Process Validation and FDA's Guidance on Process Validation. The GMP relevant aspects of the documents will also be addressed.

The original 7-page long Note for Guidance on Process Validation has more than doubled and now contains 15 pages. Even the original revision draft had only 11 pages. The change in the title to "Guideline on process validation for finished products- information and data to be provided in regulatory submissions" is noticeable. The title itself gives indication about the content of the document, namely marketing authorisation matters. 

Like in the draft, the document is composed of 8 numerated chapters, a summary, definitions, references, an Annex I (Process validation scheme) and an Annex II (Standard/non-standard processes) which is a new part compared to the draft. A sub section on "Design space verification" has been newly added to the chapter on process validation.

There haven't been big changes to the draft document released in 2012. Only the chapter "Design space verification" is brand new, all other parts have been mostly updated. The chapter on ongoing process validation has been removed. Compared to the draft, indications about standard/ non-standard processes are now available in the Annex II - like in the currently applicable Note for Guidance.

What are the changes to the currently applicable Note for Guidance on Process Validation?

Compared to the current Note for Guidance, the revision remains in its final version pretty difficult to read and rather general. This is a marketing authorisation document, which is clearly addressed in the title and only applies to finished dosage forms of chemical medicinal products for human and veterinary use but not for old ones, which are already authorised and on the market. The introduction of a validation life cycle and the integration of continued process verification (CPV) are completely new although this approach is already acquainted from ICH Q8. The "traditional approach" remains accepted. Like in the Annex 15 draft the hybrid approach remains here in the final document "nebulous". The idea to integrate modern elements from ICH Q8, Q10 (and Q11) into the document is clearly noticeable. Yet, far less concrete references are made to ICH Q9.

A stronger overlap of the FDA Guidance would have been desirable. FDA's Guidance also deals with APIs and biologicals, and the process validation life cycle runs like a thread through the whole FDA document. FDA's Guidance also contains GMP aspects. The FDA Guidance explicitly addresses old products which should be integrated to stage 3 of the life cycle. Yet, there is another big difference. The revised document doesn't highlight statistical methods like the FDA Guidance.

Before the finalisation, a comparison with the Annex 15 has been made which is a nice thing. This explains the long period between the publication of the draft (March 2012) and that of the finalisation (February 2014). 

What is significant for the GMP world? On the one hand almost nothing, on the other hand quite a lot:  one may wonder why? Direct references to the Annex 15 can be found with regard to the "ongoing process verification" and "concurrent validation",  which is almost nothing looking at the whole document. Moreover, validation in general is required to be executed according to the GMP regarding "continuous process verification" and "change control"; these are the essential parts of the document, and (almost) the complete document should therefore be seen from a GMP perspective. 

The new EMA guideline on process validation will apply by the end of August 2014.

We will present a detailed analysis of EMA's new process validation guideline next week in another News.

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