(May 2016) 3 DRAFT FOR COMMENTS - WHO

1 Working document May 2016 . DRAFT document for comment 1. 2 GUIDELINES ON VALIDATION. 3 (May 2016 ). 4 DRAFT FOR COMMENTS . Should you have any COMMENTS on the attached text, please send these to Dr S. Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms with a copy to Ms Marie Gaspard by 12 July 2016 . Medicines Quality Assurance working documents will be sent out electronically only and will also be placed on the Medicines website for comment under Current projects . If you do not already receive our DRAFT working documents please let us have your email address (to and we will add it to our electronic mailing list. 5. 6 World Health Organization 2016 . 7 . All rights reserved. 8 This DRAFT is intended for a restricted audience only, the individuals and organizations having 9 received this DRAFT . The DRAFT may not be reviewed, abstracted, quoted, reproduced, transmitted, 10 distributed, translated or adapted, in part or in whole, in any form or by any means outside these 11 individuals and organizations (including the organizations' concerned staff and member 12 organizations) without the permission of the World Health Organization.)

2 The DRAFT should not be 13 displayed on any website. 14 Please send any request for permission to: 15 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, 16 Regulation of Medicines and other Health Technologies, Department of Essential Medicines and 17 Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. 18 Fax: (41-22) 791 4730; email: 19 The designations employed and the presentation of the material in this DRAFT do not imply the 20 expression of any opinion whatsoever on the part of the World Health Organization concerning the 21 legal status of any country, territory, city or area or of its authorities, or concerning the delimitation 22 of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which 23 there may not yet be full agreement. 24 The mention of specific companies or of certain manufacturers' products does not imply that they 25 are endorsed or recommended by the World Health Organization in preference to others of a similar 26 nature that are not mentioned.

3 Errors and omissions excepted, the names of proprietary products are 27 distinguished by initial capital letters. 28 All reasonable precautions have been taken by the World Health Organization to verify the 29 information contained in this DRAFT . However, the printed material is being distributed without 30 warranty of any kind, either expressed or implied. The responsibility for the interpretation and use 31 of the material lies with the reader. In no event shall the World Health Organization be liable for 32 damages arising from its use. 33 This DRAFT does not necessarily represent the decisions or the stated policy of the World Health Working document page 2. 34 Organization. 35 SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT. 36 : 37 Guidelines on validation 38. 39. Discussion of proposed need for revision in view of the 29 June . current trends in validation during informal consultation 1 July 2015. on data management, bioequivalence, GMP and medicines' inspection Preparation of DRAFT proposal for revision of the main text July 2015.

4 And several appendices by specialists in collaboration April 2016 . with the Medicines Quality Assurance Group and Prequalification Team (PQT)-Inspections, based on the feedback received during the meeting and from PQT- Inspections, DRAFT proposals developed on the various topics by specialists, as identified in the individual working documents. Presentation of the progress made to the fiftieth meeting 12 16 October 2015. of the WHO Expert Committee on Specifications for Pharmaceutical Preparations Discussion at the informal consultation on good 4 6 April 2016 . practices for health products manufacture and inspection, Geneva, Preparation of revision by Dr van Zyl, a participant May 2016 . at the above-mentioned consultation, based on his initial proposal and the feedback received during and after the informal consultation by the meeting participants and members of PQT-Inspections. Circulation of revised working document for public May 2016 . consultation Consolidation of COMMENTS received and review of August September feedback 2016 .

5 Presentation to the fifty-first meeting of the WHO Expert 17 21 October 2016 . Committee on Specifications for Pharmaceutical Preparations Any other follow-up action as required . 40. 2. Working document page 3. 41 Background information 42. 43. 44 The need for revision of the published Supplementary guidelines on good 45 manufacturing practices: validation (WHO Technical Report Series, No. 46 937, 2006, Annex 4) (1) had been identified by the Prequalification of 47 Medicines Programme and a DRAFT document was circulated for comment in 48 early 2013. The focus of the revision was the Appendix on non-sterile 49 process validation (Appendix 7), which had been revised and was adopted 50 by the Committee at its forty-ninth meeting in October 2014. 51. 52 The main text included in this working document constitutes the 53 general principles of the new guidance on validation. 54. 55 The DRAFT on the specific topics, the appendices to this main text, will 56 follow.

6 57. 58 The following is an overview on the appendices that are intended to 59 complement the text in this working document: 60. 61 Appendix 1. 62 Validation of heating, ventilation and air-conditioning systems 63 will be replaced by cross-reference to WHO Guidelines 64 on GMP for HVAC systems for considerations in 65 qualification of HVAC systems 66 (update - working document ) (2). 67. 68 Appendix 2. 69 Validation of water systems for pharmaceutical use 70 will be replaced by cross-reference to WHO Guidelines on 71 water for pharmaceutical use for consideration in qualification of 72 water purification systems (3). 73. 74 Appendix 3. 75 Cleaning validation consensus to retain 76. 77 Appendix 4. 78 Analytical method validation update in process 79. 3. Working document page 4. 80 Appendix 5. 81 Validation of computerized systems update in process 82. 83 Appendix 6. 84 Qualification of systems and equipment update in process 85. 86 Appendix 7. 87 Non-sterile process validation update already published as Annex 88 3, WHO Technical Report Series, No.

7 992, 2015. 4. Working document page 5. 89 Guidelines on validation 90. 91. 92 1. Introduction 93 2. Scope 94 3. Glossary 95 4. Relationship between validation and quali cation 96 5. Validation 97 6. Documentation 98 7. Validation master plan 99 8. Quali cation and validation protocols 100 9. Quali cation and validation reports 101 10. Quali cation 102 User requirement specifications 103 Factory acceptance test (FAT) and site acceptance test 104 (SAT). 105 Design quali cation 106 Installation quali cation 107 Operational quali cation 108 Performance quali cation 109 Requali cation 110 Revalidation 111 Process validation 112 11. Change management 113 12. Deviation management 114 13. Calibration and veri cation 115 References 116. 117. 118. 119 1. INTRODUCTION. 120. 121 Validation is an essential part of good practices including good 122 manufacturing practices (GMP) (4) and good clinical practices (GCP). It is 123 therefore an element of the pharmaceutical quality system.

8 Validation, as a 124 concept, incorporates qualification and should be applied over the life 125 cycle of, the applicable product, process, system, equipment or utility. 126. 127 These guidelines cover the general principles of validation and 128 quali cation. In addition to the main part, appendices on validation and 129 quali cation ( cleaning, computer and computerized systems, 5. Working document page 6. 130 equipment, utilities and systems, and analytical methods) are included. 131. 132 The following principles apply: 133. 134 the execution of validation should be in compliance with 135 regulatory expectations;. 136 quality, safety and ef cacy must be designed and built into the 137 product;. 138 quality cannot be inspected or tested into the product;. 139 quality risk management principles should be applied in 140 determining the need, scope and extent of validation;. 141 ongoing review should take place to ensure that the validated state 142 is maintained and opportunities for continuing improvement are 143 identified.

9 144. 145 The implementation of validation work requires considerable 146 resources such as: 147. 148 time: generally validation work is subject to rigorous time 149 schedules;. 150 financial: validation often requires the time of specialized 151 personnel and expensive technology. 152 human: validation requires the collaboration of experts from 153 various disciplines ( a multidisciplinary team, comprising 154 quality assurance, engineering, information technology, 155 manufacturing and other disciplines, as appropriate.). 156. 157 2. SCOPE. 158. 159 These guidelines focus mainly on the overall concept of validation 160 and are not intended to be prescriptive in speci c validation requirements. 161 This document serves as general guidance only and the principles may be 162 considered useful in its application in the manufacture and control of 163 starting materials and nished pharmaceutical products (FPPs), as well as 164 other areas. Validation of speci c processes and systems, for example, in 165 sterile product manufacture, requires much more consideration and a 166 detailed approach that is beyond the scope of this document.

10 167. 168 There are many factors affecting the different types of validation 169 and it is, therefore, not intended to de ne and address all aspects related to 170 one particular type of validation here. 6. Working document page 7. 171. 172 The general text in the main part of these guidelines may be 173 applicable to validation and quali cation of premises, equipment, utilities, 174 systems, processes and procedures. 175. 176 3. GLOSSARY. 177. 178 The de nitions given below apply to the terms used in these guidelines. 179 They may have different meanings in other contexts. 180. 181 calibration. The set of operations that establish, under speci ed 182 conditions, the relationship between values indicated by an instrument or 183 system for measuring (for example, weight, temperature and pH), 184 recording, and controlling, or the values represented by a material 185 measure, and the corresponding known values of a reference standard. 186 Limits for acceptance of the results of measuring should be established.