27 February 2014
EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1
Committee for Medicinal Products for Human Use (CHMP)
Committee for Medicinal Products for Veterinary Use (CVMP)
Guideline on process validation for finished products-information and data to be provided in regulatory submissions
Draft agreed by CHMP / CVMP Quality Working Party  2 February 2012 Adoption by CVMP for release for consultation8 March 2012 Adoption by CHMP for release for consultation15 March 2012 End of consultation (deadline for comments)31 October 2012 Agreed by QWP8 November 2013 Agreed by BWP13 November 2013 Adoption by CHMP19 December 2013 Adoption by CVMP15 January 2014 Date for coming into effect  6 months after publication This guideline replaces the note for guidance on process validation (CPMP/QWP/848/96,
EMEA/CVMP/598/99)including annex II–non-standard processes (CPMP/QWP/2054/03).
Keywords Process validation, continuous process verification, on-going
process verification, critical process parameter, critical quality
attribute, lifecycle, change control
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Table of contents
Executive summary (3)
1. Introduction (background) (3)
2. Scope (3)
3. Legal basis (4)
4. General considerations (4)
5. Process validation (4)
5.1. Traditional process validation (4)
5.2. Continuous process verification (5)
5.3. Hybrid approach (6)
5.4. Design space verification (7)
6. Scale-up (7)
7. Post approval change control (7)
8. Standard vs. non-standard methods of manufacture (8)
Definitions (8)
References (10)
Annex I: Process validation scheme (12)
Annex II: Standard/non-standard processes (14)
Executive summary
This guideline replaces the previous note for guidance on process validation (CPMP/QWP/848/96, EMEA/CVMP/598/99). The guideline is brought into line with ICH Q8, Q9 and Q10 documents and the possibility to use continuous process verification in addition to, or instead of, traditional process validation described in the previous guideline has been added and is encouraged. This guideline does not introduce new requirements on medicinal products already authorised and on the market, but clarifies how companies can take advantage of the new possibilities given when applying enhanced process understanding coupled with risk management tools under an efficient quality system as described by ICH Q8, Q9 and Q10.
1. Introduction (background)
Process validation can be defined as documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes (ICH Q7). Continuous process verification has been introduced to cover an alternative approach to process validation based on a continuous monitoring of manufacturing performance. This approach is based on the knowledge from product and process development studies and / or previous manufacturing experience. Continuous process verification may be applicable to both a traditional and enhanced approach to pharmaceutical
development. It may use extensive in-line, on-line or at-line monitoring and / or controls to evaluate process performance. It is intended that the combination of the advice provided in the Note for Guidance on Development Pharmaceutics (CPMP/QWP/155/96) and the Note for Guidance on Pharmaceutical Development (ICH Q8R2) together with this guideline should cover all of the critical elements in manufacturing process for inclusion in the dossier for regulatory submission for a pharmaceutical product for human use. For veterinary medicinal products, the applicable guidance is that provided in the Note for Guidance on Development Pharmaceutics for Veterinary Medicinal Products (EMEA/CVMP/315/98) together with this guideline. Although the ICH Q8 guideline is not applicable to veterinary medicinal products the principles detailed in this guideline may be applied to veterinary medicinal products should an applicant choose to apply an enhanced approach to pharmaceutical development and process validation.
Process validation should not be viewed as a one-off event. Process validation incorporates a lifecycle approach 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.
2. Scope
This document is intended to provide guidance on the process validation information and data to be provided in regulatory submissions for the finished dosage forms of chemical medicinal products for human and veterinary use. The general principles also apply to active substances. However, information on validation of non-sterile active substances is not required in the dossier. In addition, expectations for active substances are contained in ICH Q11 and so the information is not repeated in this document.
The principles described are also applicable to biological medicinal products. However, these should be considered on a case by case basis in view of the complex nature and inherent variability of the biological substance.
It is expected that the information / data requested in this guideline be present in the dossier at the time of regulatory submission.
This document provides guidance on the validation of the manufacturing process, which can be considered as the second stage in the product lifecycle. The first stage (process design) is covered in the note for guidance on pharmaceutical development (ICH Q8R2/ EMEA/CVMP/315/98) and the third stage (on-going process verification) is covered under GMP (Annex 15).
3. Legal basis
This guideline has to be read in conjunction with the introduction and general principles section (4) of Annex I to Directive 2001/83/EC as amended and the introduction and general principles section (2) of Annex I to Directive 2001/82/EC as amended.
4. General considerations
Irrespective of whether a medicinal product is developed by a traditional approach or an enhanced approach, the manufacturing process should be validated before the product is placed on the market. In exceptional circumstances concurrent validation may be accepted. Please refer to GMP Annex 15 for further guidance.
Process validation should confirm that the control strategy is adequate to the process design and the quality of the product. The validation should cover all manufactured strengths and all manufacturing sites used for production of the marketed product. A bracketing approach may be acceptable for different strengths, batch sizes and pack sizes. However, validation must cover all proposed sites. Process validation data should be generated for all products to demonstrate the adequacy of the manufacturing process at each site of manufacture. Validation should be carried out in accordance wit
h GMP and data should be held at the manufacturing location and made available for inspection if not required in the dossier (see section 8).
Process validation can be performed in a traditional way, as described below, regardless of the approach to development taken. However, there is also the possibility to implement continuous process verification if an enhanced approach to development has been performed or where a substantial amount of product and process knowledge and understanding has been gained through historical data and manufacturing experience. A combination of traditional process validation and continuous process verification may be employed. The in-line, on-line or at-line monitoring that is often utilised for continuous process verification (discussed in section 5.2) provides substantially more information and knowledge about the process and might facilitate process improvements.
5. Process validation
5.1. Traditional process validation
Traditional process validation is normally performed when the pharmaceutical development and/or process development is concluded, after scale-up to production scale and prior to marketing of the finished product.As part of the process validation lifecycle, some process validation studies mayvalidation verification
be conducted on pilot scale batches if the process has not yet been scaled up to production scale. It should be noted that pilot batch size should correspond to at least 10% of the production scale batch (i.e. such that the multiplication factor for the scale-up does not exceed 10). For solid oral dosage forms this size should generally be 10% of the maximum production scale or 100,000 units whichever is the greater1. Where the intended batch size is less than 100,000 units, the predictive value of the pilot batches may be limited and a justified approach should be followed. For other dosage forms the pilot batch size should be justified taking into account risk to the patient of failure of the dosage form. Since it is not generally considered useful to conduct full validation studies on pilot scale batches, the process validation scheme outlined in Annex I of this guideline should be completed for each product for subsequent execution at production scale; bracketing may be acceptable. The process validation scheme to be followed should be included in the dossier. The scheme should include a description of the manufacturing process, the tests to be performed and acceptance criteria, a description of the additional controls in place and the data to be collected. A justification for the chosen process validation scheme should be presented in Module 3 and the Quality Overall Summary for human medicines and in Part 2.B and the Pharmaceutical Detailed and Critical Summary for veterinary medicines.
In certain cases however, it is considered necessary to provide production scale validation data in the marketing authorisation dossier at the time of regulatory submission, for example when the product is a biological / biotech product or where the applicant is proposing a non-standard method of manufacture (see section 8 and Annex II).In these cases, data should be provided in the dossier on a number of consecutive batches at production scale prior to approval. The number of batches should be based on the variability of the process, the complexity of the process / product, process knowledge gained during development, supportive data at commercial scale during technology transfer and the overall experience of the manufacturer.  Data on a minimum of 3 production scale batches should be submitted unless otherwise justified. Data on 1 or 2 production scale batches may suffice where these are supported by pilot scale batches and a justification as highlighted above.
The studies should address critical steps of manufacture, by conducting additional testing as necessary.
5.2. Continuous process verification
Continuous process verification is an alternative approach to traditional process validation in which manufacturing process performance is continuously monitored and evaluated (ICH Q8). Continuous process verification can be used in addition to, or instead of, traditional process validation.
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. In order to enable continuous process verification, companies should perform, as relevant, extensive in-line, on-line
or at-line controls and monitor process performance and product quality on each batch. Relevant data on quality attributes of incoming materials or components, in-process material and finished products 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
1In the case of veterinary medicinal products, the minimum pilot batch size may be smaller than 100,000 units where justified.

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