Detailed Analysis of EMA's new Draft on Process Validation

EMA published the long-announced revision of its Guideline on Process Validation as draft on 15 March 2012. Initially, publication was planned already for the third quarter of 2010. The final version will replace the current guideline "Note for Guidance on Process Validation (CPMP/QWP/848/96, EMEA/CVMP/598/99). EMA has announced the revision in a concept paper. The aim was to include modern aspects of GMP. The concept paper has mentioned ICH Guidelines Q8, Q9 and Q10, Process Analytical Technology (PAT), Quality by Design (QbD), Real-Time Release Testing (RTRT). It has already announced that the revision will add an "enhanced" approach and "continuous process verification" to the current traditional approach as described in ICH Q8. The annexes of the current Note for Guidance will be included in the revised guideline and a harmonisation with the current FDA Guidance on Process Validation is recommended.

The draft consists of eleven pages subdivided into eight numbered chapters and an executive summary, definitions, references and Annex 1 (Process validation scheme).

The executive summary explains the draft's aims to bring the guideline into line with the ICH Guidelines Q8, Q9 and Q 10 and that the possibilities of continuous process verifications have been added. The draft explicitly points out that it does not introduce new requirements on medicinal products already authorised and on the market.

1. Introduction (background): Chapter 1 comments on the possibilities of a continuous process verification (CPV). It is based on the knowledge from product and process development and / or previous manufacturing experience. 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 states that the combination of the contents of EMA's Guideline "Note for guidance on development pharmaceutics" (CPMP/QWP/155/96) and ICH Q8(R2) together with the current draft should cover all 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.

It is particularly interesting that process validation should not be viewed as a one-off event and that a lifecycle approach should be applied. This includes product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.

2. Scope: The draft describes the data that should be generated to validate the manufacturing process of dosage forms. It is not directly relevant for manufacturers of active substances or other starting materials. Nevertheless, it is pointed out that the draft may also contain information useful for such activities. The principles are also applicable to biological products, however, these should be considered on a case-by-case basis in view of the complex nature and inherent variability of such products. The draft is mainly aimed at industry and assessors to provide guidance for dossier submission. But according to the draft the information may also be useful for inspectors.

3. Legal basis: This chapter refers to individual sections of Directives 2001/83/EC and 2001/82/EC.

4. General Considerations: This chapter mentions the general requirement of validation before the product is placed on the market once again. Interestingly, the draft requires process validation to confirm that the control strategy (as described in ICH Q10) is sufficient to support the process design and the quality of the product. And that is a slightly different definition of process validation. It can also be found in the draft's section "Definitions". According to the draft concurrent validation may be accepted in exceptional circumstances. The validation should cover all strengths of the medicinal product and all manufacturing sites used for production of the marketed product. According to the draft a matrix approach may also be acceptable. Then, continuous process verification is again addressed in addition to the traditional approach. In principle, it is a more in-depth discussion of the issues in Chapter 1. The draft also mentions the possibility of process improvements by utilising CPV.

Chapter 5 (Process validation) is subdivided into four sub-chapters (Traditional process validation, Continuous process verification (CPV), Hybrid approach and Continued Process Verification during the Lifecycle).

In sub-chapter 5.1 (Traditional process validation) the draft lists many points of the currently still valid EMA Guideline on Process Validation. It states that at the time of submission process validation data may not always be available. Some process validation studies may be conducted on pilot scale batches if the process has not yet been scaled up to production scale. Here, the (old) 10% or 100,000 units rule is mentioned once more. For the data to be conclusive, a justified approach is required in the case of smaller scales. However the process validation scheme outlined in Annex I of this guideline should then be completed at the production scale. Then the draft points out where justifications for the chosen process validation scheme should be presented in the authorisation documentation. It is stressed again that process validation should focus on the control strategy which includes critical process parameters. The process should be capable of delivering the desired product quality. In certain cases however, the draft considers it necessary to provide production scale validation data, e.g. for biological / biotech products. The draft also mentions non-standard methods such as non-standard sterilisation methods or aseptic processing. For these two methods reference is made to the magical three as minimum number for consecutive batches. But the number of batches should be based on the variability of the process and the complexity of the process / product. The sub-chapter closes with references to validation if a design space has been implemented. The objective is to show that the model is still valid at production scale. In this case, a step-wise validation is considered to be possible.

In chapter 5.2 "Continuous process verification" CPV is defined as an alternative approach to traditional process validation in which manufacturing process performance is continuously monitored and evaluated (ICH Q8). It is a science and risk-based real-time approach to verify and demonstrate that a process that operates within the predefined specified parameters produces material which meets all its Critical Quality Attributes (CQAs) and control strategy requirements. Again, the focus is put explicitly on extensive in-line or at-line controls and on monitoring process performance and product quality in a timely manner. Relevant process quality attributes of incoming materials or components should be collected. This should include the verification of attributes, parameters and end points, and assessment of CQA and Critical Process Parameter (CPP) trends. Process analytical technology applications such as NIR spectroscopy (with application examples) and multivariate statistical process control (MSPC) can be viewed as enablers. Sufficient knowledge and understanding of the process is required for a CPV. Scope and extent of CPV are influenced by a number of factors including:

• development and manufacturing knowledge from similar products and/or processes;
• the extent of process understanding gained from development studies and commercial manufacturing experience; 
• the complexity of the product and/or manufacturing process; 
• the level of process automation and analytical technologies used; 
• with reference to the product lifecycle, process robustness and manufacturing history since point of commercialization as appropriate.

The process should be verified on commercial scale batches prior to marketing.

A discussion on the appropriateness and feasibility of the CPV strategy should be included in the development section of the dossier and should be supported with data from at least lab or pilot scale batches. A description of the CPV strategy including the process parameters and material attributes that will be monitored as well as the analytical methods that will be employed should be included (reference to Annex 1), with cross reference in the validation section of the dossier. Actual CPV data generated at commercial scale should be held at the site for inspection. The applicant should define the stage at which the product is considered to be validated and the basis on which that decision was made. This rationale should include a justification for the number of batches used based on the complexity and expected variability of the process and existing manufacturing experience of the company.

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 as part of process changes or to support continual improvement throughout the lifecycle. Continuous process verification performance depends strongly on compliance with GMP, if necessary complemented by Pharmaceutical quality systems (PQS) as described in ICH Q10. GMP matters and PQS should not be included in the submission. According to the draft they are assessed and handled by GMP inspectors.

Sub-chapter 5.3  "Hybrid approach" states that it may be necessary to use either the traditional approach or CPV for different steps within the manufacturing process. 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. The validation requirements in terms of batch size and number of batches would depend on the extent to which continuous process verification has been used. For non-standard processes (as defined in section 8) reference is made to the requirements highlighted in section 5.1 (traditional approach).

Chapter 5.4 ("Continued Process Verification during the Lifecycle") requires that subsequent to process validation and during commercial manufacture, product quality should be monitored to ensure a state of control is maintained. This will provide assurance of the continued capability of the process and the product quality and possibilities to identify changes that may improve product quality or performance. Relevant process trends e.g. quality of incoming materials or components, in-process and finished product results, non-conformances and defect reporting should be collected and assessed in order to verify the validity of the original process validation or to identify required changes to the control strategy. The extent and frequency of ongoing process validation should be reviewed periodically. Moreover, it should be modified if appropriate throughout the product lifecycle considering the level of process understanding and process performance at any point in time. The draft states that, if appropriate, the product may benefit from a defined period of enhanced sampling and monitoring to help increase process understanding as part of continuous improvement. If high impact models (the term is new and explained in the Definitions) are used as part of continued process verification during the lifecycle a general discussion of this should be included in the dossier.

6. Chapter 6 "Scale up" is almost identical with the relevant chapter in the current Note for Guidance. If the process has been proven to be scale independent the parameters listed in the process validation scheme (Annex I) will not generally have to be re-validated in the case of scale-up after authorisation.

Chapter 7 "Post approval change control" also adopts some parts of the chapter "Change Control" of the current Note for Guidance, but it is shorter. This chapter explicitly states that change control is part of GMP and is not normally specified in the dossier. Reference is made to the European Commission guidance on Type I and Type II variations and to Regulation 1234/2008/EC.

Chapter 8 (Standard vs. non-standard methods for manufacture) is only relevant for processes which have not been validated using continuous process verification. The requirements described correspond - mainly in the same words - to the actual Annex II CPMP/QWP/2054/03, EMEA/CVMP/395/03) of the currently valid Note for Guidance on Process Validation which also refers to non-standard processes.

The definitions are taken mainly from ICH Guidelines Q8 and Q10 but none from ICH Q9.

Annex I (Process validation scheme) is almost identical to Annex I of the current Note for Guidance. But there are some exceptions: The draft points out that the number of batches used depends on the variability of the process, the complexity of the process or product and the experience of the manufacturer and that it would (usually) be a minimum of three consecutive batches. The currently valid Note for Guidance does not mention a minimum but speaks only of "usually three consecutive batches". The draft also contains a section on CPV which naturally could not already be in the currently valid Guidance. In cases where continuous process verification is applied the draft requires additional monitoring for the first commercial batches. The process validation scheme should provide details on the number of batches for which additional monitoring is proposed, the type of monitoring to be performed, the acceptance criteria to be applied and how the data will be evaluated. This is also applicable to statistical models or tools used. If continuous processing is employed, the stage where the process is considered to be validated should be stated based on the complexity of the process, expected variability and manufacturing experience of the company.

Deadline for comments on the draft "Guideline on Process Validation" is 31 October 2012.

Conclusions: The draft is quite difficult to read and remains general in many parts. It is an authorisation document and is mainly aimed at assessors and the regulatory affairs departments in the pharmaceutical industry. The document applies only to medicinal products, but also comprises useful information for active substances, starting materials or biological products. It does not apply to legacy products, though. The integration of continued process verification (CPV) is a novelty, even though this approach is already known from ICH Q8. The "traditional approach" remains accepted. Even the "magical" three for the number of batches is mentioned twice in the draft. Here the draft differs from FDA's Guidance on Process Validation. According to the draft validation is not a one-off event and the lifecycle approach mentioned has three stages, comparable with the FDA Guidance. Unfortunately this validation lifecycle is not much further extended in the draft. It rather emphasises the product itself. The continuous process of improvement is considered quite important, and, in this respect, CPV to be helpful. The term "high impact models" as possibility for a part of the CPV is new. The reference that CPV may be introduced in each product phase remains a little theoretical such as the implementation of a hybrid approach of traditional process validation and continuous process verification. The draft's aim to integrate modern elements from ICH Q8 and ICH Q10 has been reached successfully, such as the integration of the former Annexes. But there are only few concrete references to ICH Q9. The adjustment to the FDA Guidance on Process Validation could have been more extensive. The FDA Guidance is valid also for APIs and biological substances and the process validation lifecycle runs like a red thread through the complete FDA document. In addition, the FDA Guidance contains GMP aspects. The FDA Guidance further refers explicitly to legacy products which are to be integrated in the lifecycle in step 3. Moreover, there is another big difference. In contrast to the FDA Guidance the EMA draft does not strongly emphasise statistical methods. There may be room to substantiate this aspect and further harmonise the final document. For this, industry could use the period of consultation till the end of October.

It is quite unfortunate that a draft of Annex 15 to the EU- GMP-Guideline which was actually already announced by EMA was not prepared at the same time. Maybe the Inspectors Working Group will be able to publish this draft still during the period of consultation of the Note for Guidance on Process Validation. This would make it possible to concurrently coordinate requirements for authorisation and GMP aspects laid down in Annex 15. Otherwise Annex 15 will lag behind the Note for Guidance, and GMP issues - e.g. with regard to CPV - remain unsolved.

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