Working document QAS/13.527 April 2013 RESTRICTED
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PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE PROCESS VALIDATION
(APRIL 2013) DRAFT FOR COMMENT
validation verificationPlease address any comments on this proposal by 24 May 2013 to Dr S. Kopp, Medicines Quality Assurance Programme, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730 or e-mail: kopps@who.int with a copy to gaspardm@who.int. We are sending out our working documents electronically only and they are also placed on the Medicines web site for comment. If you do not already receive our documents please let us have your e-mail address (to bonnyw@who.int) and we will add it to our electronic mailing list.
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© World Health Organization 2013 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any web site. Please send any request for permission to: Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; e-mail: kopps@who.int. The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to v
erify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/13.527: PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINE ON GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE PROCESS VALIDATION
Need for revision of published good manufacturing practices: validation identified by Prequalification of Medicines Programme Wide circulation of draft document for comment Compilation of feedback received Discussion of feedback during informal consultation on quality assurance guidelines Mailing of revision for comment Presentation to forty-eighth meeting of the WHO Expert Committee on Specifi
cations for Pharmaceutical Preparations Any further action as necessary
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March 2013
April 2013 June 2013 July 2013 August 2013 October 2013
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Working document QAS/13.527 page 3
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PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINE ON GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE PROCESS VALIDATION
Note from Secretariat: The current text of the Supplementary Guideline on Good Manufacturing Practic
es: Validation (Ref: World Health Organization, WHO Technical Report Series, No. 937, 2006, Annex 4) is available on the following web site:
www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/index.html
Moreover, comments are being sought at the same time, if the Appendix 3 on Cleaning validation be revised in line with the current developments on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities; if yes concrete proposals for revision would be appreciated.
The Appendixes of the Supplementary Guideline on Good Manufacturing Practices:
Validation are currently as follows:
Appendix 1- Validation of heating, ventilation and air-conditioning systems Appendix 2 -Validation of water systems for pharmaceutical use
Appendix 3 - Cleaning validation
– need for revision?
Appendix 4 - Analytical method validation
Appendix 5 - Validation of computerized systems
Appendix 6 - Qualification of systems and equipment
Appendix 7 - Non-sterile process validation – proposed to be revised
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Proposal for revision of the Supplementary Guideline on Good Manufacturing Practices: Validation, Appendix 7: Non-sterile process validation
Contents page 1. Background and scope 2. Glossary 3. Introduction 4. Phase I. Process design 5. Phase II. Qualification and process verification 6. Phase III. Continued process verification 7. Change control References
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BACKGROUND AND SCOPE
Further to the Supplementary Guideline on good manufacturing practices: validation, as published in the World Health Organization (WHO) Technical Report, No. 937,1 additional guidelines to support current approaches in GMP are published herewith to further support the scope of process validation (also referred to as process qualification) linked to quality risk management and quality by design principles as described by WHO and the International Conference on Harmonisation (ICH).
This guideline allows for different approaches in process validation. The principles described in this guideline are applicable to non-sterile finished pharmaceutical dosage forms. Thorough knowledge of product and process development studies; previous manufacturing experience; and quality risk management (QRM) principles are essential in the all approaches to process validation as the focus is now on the life-cycle approach. The life-cycle approach
Supplementary guidelines on good manufacturing practices: validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization. WHO Technical Report Series, No. 937 (Annex 5), 2006.
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links product and process development, validation of the commercial manufacturing process and maintenance of the process during routine commercial production.
A risk based approach to validation is recommended, linked to in-line or on-line controls and monitoring to ensure that a process is in a state of control during routine manufacture.
2.
GLOSSARY
control strategy
A planned set of controls, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and pharmaceutical product materials and components, facility and equipment oper
ating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
continued process verification (CPV) Continued process verification (CPV) can be defined as continuous monitoring of manufacturing performance by using extensive in-line, on-line or at-line monitoring and/or controls to evaluate process performance. 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.
continuous process verification An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated.
critical process parameter (CPP) A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
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critical quality attribute (CQA) A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality. life-cycle All phases in the life of a product from the initial development through marketing until the product’s discontinuation (ICH Q8).
pharmaceutical quality system (PQS) Management system to direct and control a pharmaceutical company with regard to quality.
process validation Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets its predetermined specifications and quality characteristics.
3.
INTRODUCTION
Process validation data should be generated for all products to demonstrate the adequacy of the manu
facturing process at each site of manufacture. The validation should be carried out in accordance with good manufacturing practices (GMP) and data should be held at the manufacturing location and made available for inspection. Manufacturers should confirm that a manufacturing process is under control before a product is placed on the market.
Process validation is associated with the collection and evaluation of data, from the process design stage through commercial production, which provides scientific evidence that a process is capable of consistently delivering a quality product. Process validation provides documented evidence that a process is capable of reliably and repeatedly rendering a product of the required quality. A risk assessment approach should be used to determine the scope and extent to which process(es) and starting material variability may affect product quality. The critical steps and

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