On April 12, 2012, EMA (European Medicines Agency) published a new draft for the process validation GMP guideline.
The comment period is going to end on October 31, 2012.
The new guideline will supersede the current Note for Guidance on Process Validation that came into practice on September 2001. In the last ten years a lot of ICH guidelines (Q8, Q9, Q10) were published and new interpretations on GMPs were discussed.
The publication of the process validation guideline of the FDA (US Food and Drug Administration) in January 2011 already anticipated some of the principles laied down in this European draft.
The Continuous Process Verification (CPV) has been introduced by FDA and is now also discussed in the EMA draft as an additional way to validate manufacturing processes. The EMA emphasizes that the guideline shall not set new requirements. But the agency wants to show the potential that comes with implementing a risk and science based approach in an efficient quality management.
„Continuous Process Verification (CPV) has been introduced to cover an alternative approach to process validation based on a continuous monitoring of manufacturing performance”.
The Continuous Process Verification shall not replace but replenish the current approach.
The process validation is not seen anymore as a one-off event. The EMA promotes, as well as the FDA, the life cycle approach, which links the product and process development, the validation of commercial manufacturing process and the maintenance of the process in a state of control during routine production.
It is the goal to build bridges between the development and commercial manufacturing to improve communication between these important departments with expert knowledge.
The scope of this guideline focuses on finished drug products and is not intended for Active Pharmaceutical Ingredients (APIs). Biologicals are expressly mentioned in the guideline and can also be validated under the CPV approach with adequate changes. Explicitly noted is that this guideline is written for the dossier submission and as that aimes at industry and assessors but it may also be helpful for GMP inspectors and auditors.
Traditional Process Validation
EMA stressed several times, that the traditional approach of process validation is still appropriate. And it is accentuated that the number of validation batches should depend on
- process variability,
- process complexity,
- product complexity and
- manufacturing experience.
The previous Note for Guidance defined 3 validation batches to be appropriate. The new draft refers to a minimum of 3 batches.
„The number of batches (minimum of 3) should be based on the variability of the process, the complexity of the process/product and the experience of the manufacturer”.
The requirements of the batch size and the content of a validation study (summarised in the annex) remain the same as in the present guidance.
Continuous Process Verification
It is necessary to have in-line and at-line controls in place and to monitor process and product quality in a timely manner to apply Continuous Process Verification (CPV).
Process Quality Attributes (PQA) of incoming materials or components, in-process material and finished products should be implemented and collected. This should include the verification of attributes, parameters and endpoints and assessment of CQA and Critical Process Parameter (CPP) trends.
„It is a science and risk-based real-time approach to verify and demonstrate that a process that operates within the predefined specified parameters consistently produces material which meets all its Critical Quality Attributes (CQAs)and control strategy requirements.“
A reference to PAT, NIR Spectroscopy and multivariate SPC as enablers are made.
But it is also discussed that CPV depends on multiple factors:
- know-how in development and manufacturing of similar products or processes
- process understanding
- product complexity
- process complexity
- level of process automation and analytical technology used
- process robustness
- manufacturing history
„Continuous Process Verification can be introduced at any time of the lifecycle of the product: it can be used to design process validation protocols for the initial commercial production, to re-validate commercialised products as part of process changes or to support continual improvement throughout the remainder of the lifecycle.“
The chapter scale-up was slightly reviewed and change control refers to EU Variations Guideline (2010/C17/01) and Regulation (1234/2008/EC).
A new chapter standard vs. non-standard methods of manufacturing was introduced. If not following the CPV approach additional data must be submitted for non-standard processes.
A brief glossary, a reference part and the already known annex complete the document.
With this draft EMA presents a concept that in total accepts the previous traditional approach. Nevertheless, the Continuous Process Verification (CPV) approach is introduced as a new method, which is also compatible with the FDA process validation guidance. The presented method is a modern and future orientated method to make process validation efficient and compatible with a life-cycle approach.
Until now the industry was hesitant to implement the FDA model. Now a European interpretation is available and will probably make it easier for pharmaceutical manufacturers to implement a new approach which promises a clear efficiency increase. We are looking forward to the draft comments.
1. EMA, Guideline on Process Validation, Draft,EMA/CHMP/CVMP/QWP/70278/2012-Rev1, April 2012
2. EMA, Note for Guidance on Process Validation, CPMP/QWP/848/96, EMEA/CVMP/598/99, March 2001
3. FDA Guidance for Industry, Process Validation: General Principles and Practices, January 2011
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