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WHO1002-draft HVAC-Rev-QAS10-342-25012010-TrChange-highlighted Working document QAS/10.342 January 2010 RESTRICTED SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS PROPOSAL FOR REVISION ...

WHO1002-draft HVAC-Rev-QAS10-342-25012010-TrChange-highlighted
Working document QAS/10.342 January 2010 RESTRICTED SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS PROPOSAL FOR REVISION ______________________________________________________________________________________________________________ © World Health Organization 2010 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 Pharmaceutical Policies, 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 verify 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. Please address comments on this proposal, by 10 April 2010 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 and to bonnyw@who.int. All insertions and deletions have been left in track-change format and highlighted for easy reference. As these supplementary guidelines have already been published it would be appreciated if you would send comments on these new parts only please. During the past few years we have moved more towards an electronic system for sending out our working documents for comment, for convenience and in order to speed up the process. If you do not already receive our documents electronically, please let us have your e-mail address (to bonnyw@who.int) and we will add it to our electronic mailing list. Working document QAS/10.342 page 2 SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/10.342: SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS PROPOSAL FOR REVISION WHO Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms. In. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report (WHO Technical Report Series, No. 937, Annex 2), 2006. The need for an update of the above-mentioned supplementary guidelines was identified during the meeting of inspectors collaborating in the WHO Prequalification Programme. 2006 2-3 April 2009 Recommendation regarding update made by the WHO Expert Committee on Specifications for Pharmaceutical Preparations 12-16 October 2009 A first draft proposal for revision was prepared by Mr D. Smith, South Africa November-December 2009 The above-mentioned proposal reviewed by the WHO Prequalification Inspection team January 2010 Mailing (wide distribution) of document for comments February 2010 Discussion during informal consultation on Quality assurance systems, medicines and risk analysis, Geneva 4-6 May 2010 Review of comments received and further mailing of working document June 2010 Further review of comments received August-September 2010 Discussion during WHO Expert Committee on Specifications for Pharmaceutical Preparations 18-22 October 2010 Any follow-up action, as needed … Working document QAS/10.342 page 3 c World Health Organization WHO Technical Report Series, No. 937, 2006 Annex 2 Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms Proposal for revision 1. Introduction 2. Scope of document 3. Glossary 4. Protection 4.1 Products and personnel 4.2 Air filtration 4.3 Unidirectional airflow 4.4 Infiltration 4.5 Cross-contamination 4.6 Temperature and relative humidity 5. Dust control 6. Protection of the environment 6.1 Dust in exhaust air 6.2 Fume removal 7. HVAC Systems and components 7.1 General 7.2 Air distribution 7.3 Recirculation system 7.4 Full fresh air systems 7.5 Additional system components 8. Commissioning, qualification and maintenance 8.1 Commissioning 8.2 Qualification 8.3 Maintenance 9. Premises References 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 provide comfortable conditions for operators. These guidelines mainly focus on recommendations for systems for manufacturers of solid dosage forms. The guidelines also refer to other systems or components which are Working document QAS/10.342 page 4 not relevant to solid dosage form manufacturing plants, but which may assist in providing a comparison between the requirements for solid dosage-form 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. 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 pharmaceutical manufacturers and inspectors of pharmaceutical manufacturing facilities on the design, installation, qualification and maintenance of the HVAC systems. These guidelines are intended to complement those provided in Good manufacturing practices for pharmaceutical products (1) and should be read in conjunction with the parent guide. The additional standards addressed by the present guidelines should therefore be considered supplementary to the general requirements set out in the parent guide. 2. Scope of document These guidelines focus primarily on the design and good manufacturing practices (GMP) requirements for HVAC systems for facilities for the manufacture of solid dosage forms. Most of the system design principles for facilities manufacturing solid dosage forms also apply to other facilities such as those manufacturing liquids, creams and ointments. These guidelines do not cover requirements for manufacturing sites for the production of sterile pharmaceutical products. These guidelines are intended as a basic guide for use by pharmaceutical manufacturers and GMP inspectors. They are not intended to be prescriptive in specifying requirements and design parameters. There are many parameters affecting a clean area condition and it is, therefore, difficult to lay down the specific requirements for one particular parameter in isolation. Many manufacturers have their own engineering design and qualification standards and requirements may vary from one manufacturer to the next. Design parameters should, therefore, be set realistically for each project, with a view to creating a cost-effective design, yet still complying with all regulatory standards and ensuring that product quality and safety are not compromised. The three primary aspects addressed in this manual are the roles that the HVAC system plays in product protection, personnel protection and environmental protection (Figure 1). Working document QAS/10.342 page 5 These guidelines do not cover the specific requirements relating to facilities handling hazardous products. Guidelines for hazardous product facilities are covered in a separate WHO guideline. Figure 1 The guidelines address the various system criteria according to the sequence set out in this diagram 3. Glossary The definitions given below apply to terms used in these guidelines. They may have different meanings in other contexts. acceptance criteria Measurable terms under which a test result will be considered acceptable. action limit The action limit is reached when the acceptance criteria of a critical parameter have been exceeded. Results outside these limits will require specified action and investigation. air changes per hour (ACH) The volume of air supplied to a room, in m3/hr, divided by the room volume, in m3. air-handling unit (AHU) The air-handling unit 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, e.g. 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; MAL, material airlock). alert limit The 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. as-built Condition where the installation is complete with all services connected and functioning but with no production equipment, materials or personnel present. 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. Working document QAS/10.342 page 6 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. 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)1 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. contamination The undesired introduction of impurities of a chemical or microbial nature, or of foreign matter, into or on to a starting material or intermediate, during production, sampling, packaging or repackaging, storage or transport. critical parameter or component A processing parameter (such as temperature or humidity) that affects the quality of a product, or a component that may have a direct impact on the quality of the product. cross-contamination Contamination of a starting material, intermediate product or finished product with another starting material or material during production. design condition Design condition relates to the specified range or accuracy of a controlled variable used by the designer as a basis for determining the performance requirements of an engineered system. 1 Note: Clean area standards, such as ISO 14644-1 provide details on how to classify air cleanliness by means of particle concentrations, whereas the GMP standards provide a grading for air cleanliness in terms of the condition (at-rest or operational), the permissible microbial concentrations, as well as other factors such as gowning requirements. GMP and clean area standards should be used in conjunction with each other to define and classify the different manufacturing environments. Working document QAS/10.342 page 7 design qualification (DQ) DQ is the documented check of planning documents and technical specifications for conformity of the design with the process, manufacturing, GMP and regulatory requirements. direct impact system A system that is expected to have a direct impact on product quality. These systems are designed and commissioned in line with good engineering practice (GEP) and, in addition, are subject to qualification practices. facility The built environment within which the clean area installation and associated controlled environments operate together with their supporting infrastructure. good engineering practice (GEP) Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions. indirect impact system This is a system that is not expected to have a direct impact on product quality, but typically will support a direct impact system. These systems are designed and commissioned according to GEP only. infiltration Infiltration is the ingress of contaminated air from an external zone into a clean area. installation qualification (IQ) IQ is documented verification that the premises, HVAC system, supporting utilities and equipment have been built and installed in compliance with their approved design specification. no-impact system This is a system that will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned according to GEP only. non-critical parameter or component A processing parameter or component within a system where the operation, contact, data control, alarm or failure will have an indirect impact or no impact on the quality of the product. normal operating range The range that the manufacturer selects as the acceptable values for a parameter during normal operations. This range must be within the operating range. Working document QAS/10.342 page 8 operating limits The minimum and/or maximum values that will ensure that product and safety requirements are met. operating range Operating range is the range of validated critical parameters within which acceptable products can be manufactured. operational condition This condition relates to carrying out room classification tests with the normal production process with equipment in operation, and the normal staff present in the room. operational qualification (OQ) OQ is the documentary evidence to verify that the equipment operates in accordance with its design specifications in its normal operating range and performs as intended throughout all anticipated operating ranges. oral solid dosage (OSD) Usually refers to an OSD plant that manufactures medicinal products such as tablets, capsules and powders to be taken orally. pass-through-hatch (PTH) or pass box (PB) A cabinet with two or more doors for passing equipment or product, whilst maintaining the pressure cascade and segregation. performance qualification (PQ) PQ is the documented verification that the process and/or the total process related to the system performs as intended throughout all anticipated operating ranges. point extraction Air extraction to remove dust with the extraction point located as close as possible to the source of the dust. pressure cascade A process whereby air flows from one area, which is maintained at a higher pressure, to another area at a lower pressure. qualification Qualification is the planning, carrying out and recording of tests on equipment and a system, which forms part of the validated process, to demonstrate that it will perform as intended. relative humidity The ratio of the actual water vapour pressure of the air to the saturated water vapour pressure of the air at the same temperature expressed as a percentage. More simply put, it Working document QAS/10.342 page 9 is the ratio of the mass of moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature. standard operating procedure (SOP) An authorized written procedure, giving instructions for performing operations, not necessarily specific to a given product or material, but of a more general nature (e.g. operation of equipment, maintenance and cleaning, validation, cleaning of premises and environmental control, sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation. turbulent flow Turbulent flow, or non-unidirectional airflow, is air distribution that is introduced into the controlled space and then mixes with room air by means of induction. unidirectional airflow (UDAF) Unidirectional airflow is a rectified airflow over the entire cross-sectional area of a clean zone with a steady velocity and approximately parallel streamlines (see also turbulent flow). (Modern standards no longer refer to laminar flow, but have adopted the term unidirectional airflow.) validation The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results. validation master plan (VMP) VMP is a high-level document which establishes an umbrella validation plan for the entire project, and is used as guidance by the project team for resource and technical planning (also referred to as master qualification plan). 4. Protection 4.1 Products and personnel 4.1.1 Areas for the manufacture of pharmaceuticals, where pharmaceutical starting materials and products, utensils and equipment are exposed to the environment, should be classified as “clean areas”. 4.1.2 The achievement of a particular clean area classification depends on a number of criteria that should be addressed at the design and qualification stages. A suitable balance between the different criteria will be required in order to create an efficient clean area. 4.1.3 Some of the basic criteria to be considered sh
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