SUPPLEMENTARY GUIDELINES ON GOOD …

1 Working document RESTRICTED WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE SUPPLEMENTARY GUIDELINES ON good MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING (HVAC) SYSTEMS FOR NON- sterile DOSAGE FORMS World Health Organization 2005 All rights reserved. This draft is intended for a restricted audience only, 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 WHO. The draft should not be displayed on any website. Please send any request for permission to: Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards (PSM), World Health Organization, CH-1211 Geneva 27, Switzerland.

2 Fax: (41-22) 791 4730; e-mails: 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.

3 The World Health Organization does not warrant that the information contained in this draft is complete and correct and shall not be liable for any damages incurred as a result of its use. The first revision of this document was reviewed during a consultation held in May 2005, further to which a second revision has been drafted by Dr van Zyl, South Africa. Please address any comments you may have thereon to Dr S. Kopp, Quality Assurance and Safety: Medicines, Medicines Policy and Standards, World Health Organization, 1211 Geneva 27, Switzerland; fax: +41-22 781 4730; e-mail: (with a copy to by 15 October 2005. Working document page 2 TENTATIVE SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT : SUPPLEMENTARY GUIDELINES ON good MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR CONDITIONING (HVAC))

4 SYSTEMS FOR NON- sterile DOSAGE FORMS Deadline First draft prepared and mailed for comments March 2003 Deadline for receipt of comments 15 April 2003 Collation of comments May 2003 Revision of draft document October 2004 Presentation to Thirty-ninth WHO Expert Committee on Specifications for Pharmaceutical Preparations October 2004 Mailing of first revision for comment March 2005 Collation of comments April 2005 Discussion in consultation May 2005 Revision of draft document June-July 2005 Mailing of second revision for comment August 2005 Collation of comments September-October 2005 Presentation to Fortieth WHO Expert Committee on Specifications for Pharmaceutical Preparations 24-28 October 2005 Working document page 3 SUPPLEMENTARY GUIDELINES ON good MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR CONDITIONING (HVAC) SYSTEMS FOR NON- sterile DOSAGE FORMS CONTENTS 1.

5 Introduction .. 4 2. Glossary .. 4 3. List of abbreviations used .. 8 4. Scope of 9 5. 9 Products and 9 Air 11 Unidirectional airflow (UDAF).. 13 14 14 Temperature and relative 17 6. Dust 18 7. Protection of the 19 Exhaust air 19 Fume 20 8. HVAC systems and 20 21 Recirculation 22 Full fresh air 22 9. Commissioning, qualification and 23 23 23 26 10. References .. 26 Appendix: Figures are given in a separate document entitled "Figures to SUPPLEMENTARY GUIDELINES on GMP for HVAC systems for non- sterile dosage forms.

6 Appendix to main GUIDELINES " (Working document ). Working document page 4 1. INTRODUCTION Heating, Ventilation and Air-Conditioning (HVAC) play an important role in ensuring the manufacture of quality pharmaceutical products. A well designed HVAC system will also result in operator comfort. This guideline mainly focuses on recommendations for systems for manufacturers of solid dosage forms. Reference in this guideline is also made to other systems or components which are not relevant to solid dosage form manufacturing plants as these references may assist in providing a comparison between the requirements for solid dosage plants and other systems. HVAC system design influences architectural layouts with regard to items such as airlock positions, doorways and lobbies. The architectural components have an effect on room pressure differential cascades and cross-contamination control.

7 The prevention of contamination and cross-contamination is an essential design consideration of the HVAC system. In view of these critical aspects the design of the HVAC system should be considered at the concept design stage of a pharmaceutical manufacturing plant. Temperature, relative humidity and ventilation should be appropriate and should not adversely affect the quality of pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment. This document aims to give guidance to inspectors of pharmaceutical manufacturing facilities and pharmaceutical manufacturers, on the design, installation, qualification and maintenance of the HVAC systems. 2. GLOSSARY The definitions given below apply to terms used in this guideline. They may have different meanings in other contexts.

8 Acceptance criteria Measurable terms under which a test result will be considered acceptable. Action limit Action limit is reached when the acceptance criteria of a critical parameter have been exceeded. Results outside theses limits will require specified action and investigation. Air Handling Unit (AHU) Air handling unit which serves to condition the air and provide the required air movement within a facility. Airlock An enclosed space with two or more doors, which is interposed between two or more rooms, of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An airlock is designed for and used by either people or goods (PAL = Personnel airlock and MAL = Material airlock). Alert limit Alert limit is reached when the normal operating range of a critical parameter has been exceeded, indicating that corrective measures may need to be taken to prevent the action limit being reached.

9 Working document page 5 API Active pharmaceutical ingredient As-built Condition where the installation is complete with all services connected and functioning but with no production equipment, materials, or personnel present. ASHRAE American Society of Heating, Refrigeration and Air Conditioning Engineers. At-rest Condition where the installation is complete with equipment installed and operating in a manner agreed upon by the customer and supplier, but with no personnel present. Central Air-Conditioning Unit (See "air-handling unit") Change control A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status.

10 The intent is to determine the need for action that would ensure that the system is maintained in a validated state. Clean area (clean room) An area (or room) with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area. Commissioning Commissioning is the documented process of verifying that the equipment and systems are installed according to specifications, placing the equipment into active service and verifying its proper action. Commissioning takes place at the conclusion of project construction but prior to validation. Containment A process or device to contain product, dust or contaminants in one zone, preventing it from escaping to another zone.