Guideline on Process Validation

1 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail Website An agency of the European Union European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged. 1 2 3 4 5 6 29 March 2012 EMA/CHMP/CVMP/QWP/70278/2012-Rev1 Committee for Medicinal Products for Human Use (CHMP) Committee for Medicinal Products for Veterinary Use (CVMP) Guideline on Process Validation Draft Draft Agreed by CHMP / CVMP Quality Working Party 2 February 2012 Adoption by CVMP for release for consultation 8 March 2012 Adoption by CHMP for release for consultation 15 March 2012 End of consultation (deadline for comments)

2 31 October 2012 Agreed by QWP <Month YYYY> Adoption by CHMP <DD Month YYYY> Adoption by CVMP <DD Month YYYY> Date for coming into effect <DD Month YYYY> 7 8 9 10 This Guideline replaces the Note for Guidance on Process Validation (CPMP/QWP/848/96, EMEA/CVMP/598/99) Comments should be provided using this template. The completed comments form should be sent to 11 Keywords Process Validation , continuous Process verification, continued Process verification, critical Process parameter, critical quality attribute, lifecycle, change control Guideline on Process Validation EMA/CHMP/CVMP/QWP/70278/2012-Rev1 Page 2/11 Guideline on Process Validation 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Table of contents Executive summary.

3 3 1. Introduction (background).. 3 2. 3 3. Legal basis .. 4 4. General 4 5. Process 4 Traditional Process Validation .. 4 Continuous Process verification .. 5 Hybrid approach .. 6 Continued Process Verification during the 7 6. Scale 7 7. Post approval change 7 8. Standard vs. non-standard methods of manufacture .. 7 Definitions .. 9 References .. 10 ANNEX I: Process Validation 10 Guideline on Process Validation EMA/CHMP/CVMP/QWP/70278/2012-Rev1 Page 3/11 Executive summary 30 31 32 33 34 35 36 37 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 60 61 62 63 64 65 66 67 68 This Guideline replaces the previous Guideline on Process Validation .

4 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 verification described in the previous Guideline has been added. 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 and efficient quality system as described by ICH Q8, Q9 and Q10. 1. Introduction (background) 38 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.

5 Continuous Process verification (CPV) 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. CPV 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 guidance 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 guidance should cover all of the critical elements in manufacturing Process for a pharmaceutical product for human use.

6 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 guidance. 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. 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.

7 2. Scope 59 This note for guidance is intended to apply to data generated to validate the manufacturing Process of the intended commercial dosage form only. It is not directly relevant to the manufacture of the active substance or other starting materials, although it may contain information useful for such activities. It is intended to apply to medicinal products for human and veterinary use. The fundamental principles described in this document are 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 the biological substance.

8 The document provides guidance on the information to be considered for dossier submission and as such is mainly aimed at industry and assessors; however the information may also be useful for inspectors. Guideline on Process Validation EMA/CHMP/CVMP/QWP/70278/2012-Rev1 Page 4/11 3. Legal basis 69 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 Directive 2001/82/EC as amended. 70 71 72 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 4.

9 General Considerations 73 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. Process Validation should confirm that the control strategy is sufficient to support 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 matrix approach may be acceptable. Process Validation can be performed in a traditional way as described below; however there is also the possibility to implement continuous Process verification if an enhanced approach to development has been employed or where a substantial amount of product and Process knowledge and understanding has been gained through historical data and manufacturing experience.

10 A combination of 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 ) provides substantially more information and knowledge about the Process and might facilitate Process improvements. When feed-forward or feedback loops are employed then it is possible to adjust the Process during manufacture to maintain finished product quality. 5. Process Validation 89 Traditional Process Validation 90 Process Validation data should be generated for all products to demonstrate the adequacy of the manufacturing Process at each site of manufacture.