New draft CHMP Guidance on Process Validation
Wednesday the 18th April 2012
Peter Gough reviews:
In late March 2012 the EMA published a draft CHMP Guideline on Process validation that proposes to replace the existing CHMP Guidance’s on this topic (CPM/QWP/848/96 and EMEA/CVMP/598/99). Comments on this proposal are due to EMA by 31 October 2012. Unlike the 2011 FDA Guidance on process validation this draft states that it does not introduce new requirements for medicinal products already authorised and on the market.
The changes are being proposed to bring EU guidance in line with ICH Q8, 9 & 10 and to also to better align with the 2011 FDA Guidance for Industry on Process Validation.
The scope of this draft revision is both human and veterinary medicinal products. It is also applicable to biological products but these should be considered on a case-by-case basis in view of the complex nature and inherent variability of biological substances. Unlike the FDA Guidance, it is NOT applicable to APIs.
There are several significant changes to the requirements for process validation (PV) in this new draft. One of these is the introduction of what is called “Continuous Process Verification” as an alternative to the traditional approach to PV. It is also important to note the philosophical change to a lifecycle approach to PV, which ever approach is followed, that is contained within this draft where it states:
“Process validation should not be viewed as a one-off event. A lifecycle approach should be applied linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.”
“Process validation should confirm that the control strategy is sufficient to support the process design and the quality of the product.”
The draft allows different approaches to process validation; the traditional approach, what it calls “Continuous Process Verification” or a combination of the two. The guidance on the traditional approach is largely the same as in the previous guidance. The main requirements are set out in Appendix 1 of the guide and are almost identical to the earlier text but where it originally said “usually 3 consecutive batches” the new draft says “the number of batches used would depend on the variability of the process, the complexity of the process / product and the experience of the manufacturer, but would usually be a minimum of 3 consecutive batches”. This does not go as far as the 2011 FDA guidance but by emphasising the link to process variability it does further undermine the former “three batches and you are done” mind-set even where the traditional approach is adopted.
The new approach given in section 5.2 of the draft is called “Continuous Process Verification” and is essentially what has become more generally known as the “Quality by Design (QbD)” approach, following the implementation of ICH Q8. As there is a later section, 5.4, in the draft on “Continued Process Verification during the lifecycle” (the same terminology as is used for stage 3 in the FDA guidance) there must be the opportunity for considerable confusion between these two different but linked concepts. It would be better if the approach given in section 5.2 were called something like the QbD approach.
Section 5.2 seems to be saying approximately the same as stages 1.2 and 2.2 of the 2011 FDA guidance. It says “Process analytical technology applications … and multivariate statistical process control can be viewed as enablers for continuous process verification.” However, this approach appears to be restricted to cases where the control strategy is based on continuous monitoring.
There is no mention in this draft of the qualification of facilities, utilities and equipment as there is in stage 2.1 of the FDA guidance. It appears that this is being left to a revision of Annex 15 of the EU GMP Guide, which is being initiated at a PIC/S meeting in September 2012.
If the continuous process verification approach is utilised, Annex 1 adds the requirement to conduct additional monitoring of the first commercial batches. It states that “The process validation scheme should provide details on the number of batches for which additional monitoring is proposed, the type of testing / monitoring to be performed, the acceptance criteria to be applied and how the data will be evaluated. Any statistical models or tools used should be described. … the stage where the commercial process is considered to be validated should be stated based on the complexity of the process, expected variability and manufacturing experience of the company.”
Section 5.3 is titled “Hybrid approach” and allows for the use of the traditional approach for some steps in a manufacturing process and the continuous process verification approach in others. It states that “A justification for using this hybrid approach should be presented in the dossier and it should be clear which approach to validation has been taken for which part of the manufacturing process.”
Section 5.4 “Continued Process Verification during the lifecycle”, is similar to stage 3 of the 2011 FDA guidance. It would appear to be a new requirement that applies whichever process verification approach is adopted. This section requires that “Subsequent to process validation and during commercial manufacture, companies should monitor product quality to ensure a state of control is maintained throughout the commercial part of the product lifecycle.”
There is also a new section 8 titled “Standard vs. non-standard methods of manufacture”. This section is only relevant for processes which have not been validated using continuous process verification. The section gives examples of several non-standard products and processes that may require non-standard approaches to process validation on a case-by-case basis.
The publication of this draft revision to the EU CHMP Guide to Process Validation marks a convergence with the 2011 FDA Guidance on the same topic but it falls a long way short of complete harmony; e.g. the traditional 3 batch approach is still acceptable. If you follow the FDA Guidance then you should meet these new draft EU expectations but not the other way round. A final version of this guide is not expected until late 2013.
Peter Gough, Partner