6/7 October 2021
It didn't really come as a surprise that EMA published its revised Guideline on Process Validation on 27 February 2014 after the publication of the draft on the revision of Annex 15 at the beginning of February. EMA had announced the revision in a concept paper already a long time ago. The aim was to include modern aspects of GMP such as ICH Q8-11, PAT, QdB, RTRT. Another goal mentioned was a harmonization with the FDA Guidance on Process Validation. Fortunately, the document was now also attuned to the draft of Annex 15.
The following is a detailed analysis concerning the original draft of the revision from March 2012.
The Note for Guidance on Process Validation which in the beginning only comprised seven pages now has more than doubled its content (15 pages). Even the original draft for the revision only consisted of 11 pages. It is striking that the title was changed into "Guideline on process validation for finished products- information and data to be provided in regulatory submissions". This states already clearly that the document concerns authorisational affairs.
After the publication of the draft of Annex 15 at the beginning of February 2014 EMA now followed suit with the revision of its Guideline on Process Validation. The final document was published on 27 February 2014. EMA had announced the revision in a concept paper already a long time ago. As aim of the revision the inclusion of modern aspects of GMP was mentioned.
Just like the draft, the document is divided into eight numbered chapters, an executive summary, definitions, references, an Annex I (Process validation scheme) and an Annex II concerning the topic standard/non standard processes. Annex II is new as compared to the draft. The sub-chapter "Design space verification" in the chapter Process validation also is new.
In comparison with the draft there are only few changes in the content of the executive summary. The executive summary still explains that the draft serves for bringing the guideline into line with the ICH Guidelines Q8, Q9 and Q 10 and that it is possible to use continuous process verifications (CPV). The indication that the document does not introduce new requirements on medicinal products already authorised also remained unchanged.
The first chapter also contains only very few changes as compared to the draft. New elements are the reference to ICH Q7 in the term "quality attribute" and the reference that all the critical elements in the manufacturing process should be covered and included in the dossier for regulatory submission. Apart from that, the possibility of a CPV based on the knowledge from product and process development and the corresponding process and / or previous manufacturing experience is addressed just as before. CPV may be applied in addition to the "traditional approach" as described in the current guideline or independently in the sense of an "enhanced approach". The draft mentions the possibility to use in-line, on-line or at-line monitoring to evaluate process performance. It is stated that the combination of the contents of EMA's guideline "Note for guidance on development pharmaceutics" (CPMP/QWP/155/96) and ICH Q8(R2) with the current document covers all the critical elements in the manufacturing process. A separate reference is made to veterinary medicinal products to which ICH Q8(R2) does not apply. But the principles detailed in the draft may, in principle, also be applied to veterinary medicinal products. Hence, there is nothing new compared to the draft.
The indication that process validation is no one-off event and that a lifecycle approach (product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production) continues to be valid unchanged.
Chapter 2 now points out more frequently that the document refers to the commercial dosage form of chemical medicinal products. Just as in the draft it is indicated, furthermore, that the general principles also apply to active substances. However, information on the validation of non-sterile active substances is not required in the dossier. Now, reference is made to ICH Q11 concerning further details on active substances. It has remained unchanged in the document that the principles are also applicable to biological products and that these should, however, be considered on a case-by-case basis in view of the complex nature and inherent variability of such products. The part that the document provides guidance on the information to be considered for dossier submission and as such is mainly aimed at industry and assessors and that the information may, however, also be useful for inspectors was deleted. The expectation is new that the information / data requested in this guideline be present in the dossier at the time of regulatory submission. In conclusion, reference is now made to the product lifecycle and the data required in this document is assigned to the second stage (validation of the manufacturing process). Regarding the first stage (process design) reference is made to the "Note for Guidance on pharmaceutical Development" (ICH Q8R2/EMEA/CVMP/315/98) and concerning the third stage (on-going process verification) to GMP (Annex 15).
3. Legal basis
This chapter refers to individual sections of Directives 2001/83/EC and 2001/82/EC - without any changes as compared to the draft.
4. General Considerations
This chapter mentions once again that validation is generally required before the product is placed on the market. This corresponds exactly to the draft. But now there is a reference to Annex 15 if in exceptional circumstances concurrent validation may be accepted. The requirement that validation should cover all manufactured strengths and all manufacturing sites used for production of the marketed product has remained unchanged. The reference made to the bracketing approach (still called matrix-approach in the draft) and to its use in the case of different strengths, batch sizes and pack sizes is new. But each site has to be taken into consideration. This list is comparable to point 4.4 in the revision draft of Annex 15. This is followed by the indication that validation should be carried out in accordance with GMP and that data should be held at the manufacturing location and made available for inspection if not required in the dossier. This part was taken over from chapter 5.1 of the draft into this chapter. Later on there is the - new - indication that the traditional way can be performed regardless of the approach to the development taken. Then continuous process verification and process improvements which could enable a CPV are addressed.
The complete detailed analysis of the new draft is avialable in the ECA´s members area.