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自2006年WHO发布第一版非无菌制剂暖通空调系统GMP指南，后于2010年、2011年、2015年、2016年、2017年分别发布五版征求意见稿，结构与收录内容几经变更，WHO药物制剂规格专家委员会（ECSPP）于2017年10月第51次会议上商定，非无菌制剂的暖通空调系统指南修订稿将被收录于GMP第一部分。 2018年2月发布《非无菌制剂暖通空调系统GMP指南：第二部分》，在征求公众意见后，将会考虑补充收录。 据WHO发布的修订时间表，2018年5月进行第一次意见整合与评审，2018年7月进行药品和检查工具GXP的讨论，于2018年8月进行第二次公示咨询。现将此文件进行翻译，希望可以为国内药企进行WHO的GMP验证时提供参考。若翻译内容有不当之处，还望不吝赐教。  GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS: PART 2 非无菌制剂暖通空调系统GMP：第二部分
INTERPRETATION OF PART 1 – GMP FOR HVAC SYSTEMS 第一部分说明-暖通空调系统GMP Contents 目录 Section 1 and 2. Introduction and Scope 第一、二节 简介与范围 Section 3. Glossary 第三节 术语 Section 4. Premises 第四节 厂房 Section 5. Design of HVAC systems and components 第五节 暖通空调系统和部件的设计 Section 6. Full fresh air and recirculation systems 第六节 全新风及再循环系统 Section 7. Air filtration, airflow direction and pressure differentials 第七节 空气过滤、气流方向和压差 Section 8. Temperature and relative humidity 第八节 温度和相对湿度 Section 9. Dust, vapour and fume control 第九节 粉尘、蒸汽和烟雾控制 Section 10. Protection of the environment 第十节 环境保护 Section 11. Commissioning 第十一节 试车 Section 12. Qualification 第十二节 确认 Section 13. Maintenance 第十三节 维护 Section 1 and 2 : Introduction and Scope 第一、二节 简介与范围 This document represents Part 2 of the HVAC systems guidelines. It contains non-binding examples, drawings, technical representations and interpretation in support of Part 1 of the HVAC systems guidelines. 本文件代表第二部分的暖通空调系统指南。它包含非强制性的示例、图纸、技术描述及说明，作为第一部分暖通空调系统指南的支撑。 It is intended to be a basic and explanatory guide for use by pharmaceutical manufacturers and GMP inspectors. It is not intended to be prescriptive in specifying requirements and design parameters but it attempts to facilitate a harmonized understanding of expectations for HVAC systems for manufacturers of non-sterile products. 本文件旨在成为供药品生产企业和GMP检查员使用基础和说明性指南。并非是为了就具体要求和设计参数方面进行规定，而是为了能促进非无菌产品制造商期望的暖通空调系统的共同认知。 Part 1 and Part 2 focus on good practices for HVAC systems for non-sterile products. Where applicable, some of the principles referred to may be considered in the HVAC design and approach for other dosage forms. These two documents are, however, not intended to be used as enforceable criteria for the design or review of HVAC systems for, e.g. APIs or sterile products. 第一和第二部分重点在非无菌产品的暖通空调系统良好操作规程。在适当的地方，在其他剂型的暖通空调设计和方法中，可考虑其中一些原则。但是，这两个文件并不作为设计或审查暖通空调系统的强制标准，例如原料药或无菌产品。 Other relevant national and international standards, as applicable, should be considered when Part 1 and Part 2 are used. These include, but are not limited to, the current publications such as ISO 14644 and ASHRAE standards. 当使用第一部分和第二部分时，应考虑适用的其他国家和国际标准。这些标准包括但不限于当前已发布的ISO 14644和ASHRAE标准。 In general, HVAC systems can play an important role in facilitating a suitable environment for the manufacture of quality pharmaceutical products. Therefore careful consideration should be given to the design of the HVAC system. When designing an HVAC system, careful consideration should also be given to the building design and layout of areas as these may influence the decision and design relating to, for example, the number of air handling units (AHUs), components in AHUs, room pressure, pressure differentials, pressure cascades, levels of filtration, humidification, dehumidification, heating and cooling of air. These may in turn have an impact on the quality of materials and products as well as the functioning of equipment and instruments. 一般来说，暖通空调系统在为促进生产高质量药品创造适当环境方面起着至关重要的作用。因此，暖通空调系统的设计应慎重考虑。在设计暖通空调系统时，也应仔细考虑建筑设计和布局区域，因为这些可能会影响与之相关的决策和设计，例如，空气处理机组(AHUS)的数量、空气处理机组(AHUS)的构成、房间压力、压差、压力级联、过滤等级、加湿、除湿、加热和冷却空气，这些可能反过来对原料和产品的质量以及设备和仪器的功能产生影响。 The conditions of areas should be defined and should be appropriate for the storage, manufacturing and use, as appropriate, for equipment, instruments, materials and products. It should further ensure that comfortable conditions are maintained for operators. 应确定适合于设备、仪器、原料和产品的储存、生产和使用的区域环境。它应进一步确保为操作者提供舒适的环境。 Risk assessment 风险评估 In line with the current approach in GMP, risk identification should be done for utilities such as HVAC systems. A science-based, comprehensive exercise of risk assessment should be used to determine risks related to possible failure of the HVAC system and AHUs (including their components and subcomponents). An appropriate risk assessment tool such as failure modes and effects analysis (FMEA) or fault tree analysis (FTA) should be selected. Controls should be identified to eliminate the risks, or minimize the risk to an acceptable level. For example, the effect of the failure of one or more AHUs in the HVAC system; the failure of dust extraction systems; the failure of AHU components such as filters, heating coils, cooling coils and fans should be assessed and appropriate controls should be identified and implemented. 与现行GMP一致，为保证暖通空调系统的效用应进行风险评估。以科学为基础，应进行广泛的风险评估测试来确定HVAC系统与AHUs（包括他们的组件和子组件）可能存在的问题。合适的风险评估工具，例如可选择失效模式、影响分析（FMEA）和故障树分析（FTA）。应明确控制措施以消除风险，或把风险降到可接受的最低限度。例如，暖通空调系统中的一个或多个空调机组失效的影响；除尘系统失效；对过滤器、加热管、冷却管、风扇等空调系统组件进行评估，并确定和实施适当的控制措施。 For more information on risk assessment, refer the current WHO guidelines on Quality risk management. 有关风险评估的更多内容，请参考现行WHO指南中的质量风险管理。 Design parameters 设计参数 Manufacturers should define the design parameters of the HVAC system to ensure appropriate operation and functioning of the system that is needed for all the areas. Special consideration should be given to the required conditions for storage and handling of materials and products, equipment and instrument functioning, personnel requirements and contamination control. 制造商应确定暖通空调系统的设计参数，以确保该系统在所有区域的适当操作并起作用。应特别考虑原料以及产品的储存和处理，设备和仪器的运作，人员要求和污染控制等所需的条件。
Section 3. Glossary 第三节 术语 For definitions and abbreviations, see Part 1. 定义及缩写见第一部分
Section 4. Premises 第四节 厂房 Premises design 厂房设计 Both the architectural design of the building and that of the HVAC system should be carefully considered when attempting to achieve the general objectives of preventing contamination, cross-contamination and ensuring an appropriate environment for the production and control of pharmaceutical products. The layout of the premises should facilitate unidirectional flow of material and personnel; building finishes should not result in contamination (e.g. through shedding of particles) and should ensure that the required environmental conditions, cleanliness and containment are achieved and maintained. 为达到防止污染、交叉污染以及确保药品的生产和控制有一个合适的环境的总体要求时，应谨慎考虑厂房的建筑设计和HVAC系统的设计。厂房布局应有利于人流以及物流的单向流动；建筑完成面不应造成污染(例如，颗粒脱落造成污染)，并应确保达到要求的环境条件，达到并保持洁净等级和密闭性。 Air infiltration of unfiltered air into production areas should be prevented. Manufacturing facilities should normally be maintained at a positive pressure relative to the outside, to limit the ingress of contaminants. Where facilities are to be maintained at negative pressures relative to the ambient pressure, special precautions should be taken。 应避免未经过滤的空气渗入生产区域。生产设备应相对于外部环境保持正压，来防止污染物的进入。如果设备在相对环境压力保持负压状态时，则应采取特殊的预防措施。 Where necessary, air locks, change rooms and pass-through hatches may be considered and provided with effective ventilation and filtered air. Special attention should be given to door design as gaps between doors and floors, doors opening into low pressure areas and sliding doors can result in changes in pressure differential between areas. An interlocking system and a visual and/or audible warning system may be used to prevent the opening of more than one door at a time where required. 必要时，可以考虑气闸室、更衣室和缓冲室，并提供有效的通风和过滤空气。应特别注意门的设计，因为门和地板之间的缝隙，门朝低压区打开和移门都可能导致不同区域间压差的变化。在必要的地方可以使用互锁系统和可视和/或有声报警系统来防止同时打开一个门以上。 In addition to the design of the premises, general controls should be in place to ensure protection of materials, products and personnel. The HVAC system can play a role in achieving this objective. Where identified, areas should be maintained within defined limits for temperature, relative humidity, viable and non-viable particles. In such cases, the areas are considered to be “clean areas” (also referred to as “zones, rooms”, etc.). To ensure that the clean area is maintained at the defined limits, areas are normally classified. When classifying the area, the manufacturer should state whether the classification is for the “as built”, “at rest” or “in operation” condition. For details including definitions, see ISO 14644. 除了厂房设计，用来保护原材料、产品和人的一般控制也应到位。HVAC系统在实现这一目标方面起着至关重要的作用。可以确定的是，区域的温度、相对湿度、活性及非活性粒子保持在限定的范围内。在这种情况下，这种区域被认为是“洁净区”（也可称为“区域、房间”等）。为了保证洁净区维持在确定的范围内，区域通常要进行分类。在对区域进行分类时，制造商应说明该分类是针对“建立状态”、“暂停状态”还是“运行中”条件进行的。定义的等详细信息请参阅ISO 14644。 The following describes approaches (and illustrations by means of diagrams) of different room arrangements and room pressures. 以下描述了实现不同房间布局和房间压力的方法（以及图解）。 Weighing/dispensing and sampling areas 称量/配药和取样区域 A room for weighing (e.g. dispensing of materials), should be of appropriate design. It is often advantageous to have several rooms associated with the weighing activity. These may include a pre-weighing staging area, personnel airlock, material airlock, weighing area with a containment booth, post-weighing staging area, washing area and provision for waste removal. The HVAC system for such areas should ensure that the areas have at least the same area classification as other production areas where materials and products are exposed to the environment, logical flow of material and personnel, appropriate number of AHUs, pressure differentials, containment, dust control, and air exchange rate. 称量室（例如，原料的分配）应进行恰当设计。有几个房间与称重活动相关通常是有利的。这些可能包括称量前室、人员气闸室、物料气闸室、称重密闭区、称量后室、清洗区和出废料设施。这些区域的暖通空调系统应确保至少与其他原材料和产品暴露在环境中的生产区域保持一致的区域分类、合理的物流与人流、空调机组的适当数量、压差、密封性、粉尘控制和换气效率。 The objective of having a booth in a weighing room is to provide dust containment and operator protection. For example, the dust generated at the weighing location should be extracted through a perforated worktop, thus protecting the operator from dust inhalation, but at the same time protecting the product from contamination by the operator by means of the vertical airflow stream. The airflow velocity should be such that it does not disrupt the sensitivity of balances. The operator should neither obstruct the airflow nor become a source of contamination of the materials or products. 在称重室配备一个称量密闭区的目的在于粉尘控制和对操作员的保护。例如，称重位置产生的灰尘应该通过一个穿孔的工作台排出，从而使操作者免受吸尘的影响，同时通过垂直气流保护产品免受操作员的污染。气流速度应该不会影响天平的灵敏度。操作人员既不应阻塞气流，也不应成为原料或产品的污染源。  Figure 1. Example of a weighing area 图一 称量区域示例图  Figure 2. Example of a weighing area 图二 称量区域示例图 Similar aspects may be considered when designing a sampling area, as materials and primary components may be exposed to the environment during sampling. 设计取样区时可能会考虑类似的方面，因为原料和主要成分可能在采样过程中暴露在环境中。 Sampling of materials such as starting materials, primary packaging materials and products, should be carried out in the same environmental conditions that are required for the further processing of the product. 原材料，初级包装材料和产品等的取样应在进一步加工产品所需的相同环境条件下进行。  Figure 3. Example of a sampling area 图三 取样区示例图  Figure 4. Example of a sampling area 图四 取样区示例图 A clean corridor concept is usually recommended for non-sterile oral solid dosage form production areas where there is then a higher pressure in the corridor compared to airlocks or production rooms. This is to facilitate containment of dust and contaminants that may have been generated in production rooms (see also the principles mentioned in the section on sampling and dispensing). 洁净走廊概念通常建议用于非无菌口服固体剂型的生产区域，与气闸室或生产间相比，走廊的压力较高。这是为了便于控制生产室内可能产生的灰尘和污染物(另见取样和分配一节中提到的原则)。 To further support containment, consideration may also be given to have material airlocks (MAL) and personnel airlocks (PAL), where needed, for entry and exiting processing areas. Appropriately designed airlocks can assist in ensuring containment. Additional controls such as pressure differentials between areas, an appropriate number of air changes in an area and sufficient filtration of air should be in place. 为了进一步提高密闭性，还可考虑在需要时为进入和退出生产区域设置物料气闸室（MAL）和人员气闸室（PAL）。 适当设计的气闸室有助于确保密闭性。 额外的控制措施，如区域之间的压力差，适当数量的区域内的空气变化和充足的空气过滤应当到位。  Figure 5. Example of a change room and some production areas图五 更衣室和一些生产区的示例图  Figure 6. Example of a compression cubicle with MAL and PAL (also used as an area to change garments) 图六 带有物料气闸室和人员气闸室（也用做更衣间）的压力间的示例图 Washing areas should be designed and used in such a manner that equipment and components will not be re-contaminated after cleaning. The system supplying and extracting air from the area(s) should be suitably designed to ensure that this objective is achieved. Principles that may be considered include (but are not limited to) filtration of air, pressure differentials between areas and airflow directions. 清洗区域的设计和使用应确保清洗后设备和配件不会再次受到污染。 应适当设计从该区域输送和抽出空气的系统以确保实现此目标。可能考虑的原则包括（但不限于）空气过滤，区域之间的压差和气流方向。  Figure 7. Example of a washing area 图七 清洗区域示例图 Section 5. Design of HVAC systems and components 第五节 暖通空调系统和部件的设计 The HVAC system should be appropriately designed, taking into consideration the design of the facility with various rooms or areas for the storage of materials and in-process materials or products, processing, movement of materials, products and personnel. The required cleanliness classification should be achieved, as well as other parameters such as airflow direction, air filtration, air exchange rate, airflow velocity, air volumes, pressure differentials, temperature and relative humidity, viable and non-viable particle counts and containment. Conditions and limits should be specified based on need. Manufacturers should determine and define limits for these. These should be realistic, appropriate and scientifically justifiable. In determining these, relevant factors and risks should be considered including but not limited to possible failures of AHUs, seasonal variations, properties and types of materials and products, number of personnel and risks of cross-contamination. HVAC系统应适当设计，同时考虑到设备的设计，不同房间或区域的原料和中间品或产品的存储、加工以及原料、产品和人员的移动。应达到要求的洁净等级以及其他参数，如气流方向、空气过滤、换气率、气流速度、风量、压差、温度和相对湿度，活性及非活性粒子计数和密闭性，应根据需要规定条件和限度。制造商应该确定和定义这些限度。这些应该是结合现实的、适当的和在科学上合理的。在确定这些因素时，应考虑相关因素和风险，包括但不限于空调机组可能产生的失效，季节变化，原料和产品的性质和种类，人员数量和交叉污染的风险。 Other aspects such as the number of AHUs, dust collecting or dust extraction systems, the need for recirculation of air, percentage of fresh air (in the case of recirculated air) and the level of filtration of air should be defined by the manufacturer when considering the design of the facility and activities in different areas and rooms. 考虑不同区域和房间的设施和活动的设计，在其他方面，例如空调机组的数量、集尘或除尘系统、空气再循环需求、新风占比（在循环空气情况下）和空气过滤水平应由生产商设定。 Manufacturers should maintain schematic drawings of the HVAC system, AHUs and components. These should reflect the initial design and installation, as well as the current situation. Changes made during the life cycle of the system should be reflected in change control records and qualification protocols and reports as appropriate. 制造商应保存HVAC系统，AHUs和组件的设计图。 这些应该反映最初的设计和安装以及目前的情况。在系统生命周期中所做的更改应适当反映在变更控制记录、资格协议和报告中。 The components selected in an HVAC system should be of sufficient capacity to ensure that the design objectives are met (e.g. for heating, cooling, humidification, dehumidification, air flow volumes), taking impacting factors into consideration such as loss of air due to leakage and seasonal variations. Materials of construction for components and their placement should be such that these do not become the source of contamination. For example, components should not shed particles and the sequence of components should be logical, e.g. filters should be placed in such a manner that any possible contaminants generated in the system can be retained by filters and not be introduced into the production area. 在HVAC系统中选择的组件应足以确保设计目标得到满足（例如加热、冷却、加湿、除湿、空气流量），考虑影响因素（例如由于泄漏造成的空气损失）和季节性变化。 组件的结构材料和放置位置应该保证其不会成为污染源。例如，组件不应该脱落颗粒，组件的顺序应该是合乎逻辑的；例如， 过滤器的安装方式应使得系统中产生的任何可能的污染物都能被过滤器过滤下来，而不会进入生产区域。 To prevent contamination of areas, access to components such as ventilation dampers, filters and other services should be accessible from outside the manufacturing areas (such as service corridors). 为防止污染区域，通风口的节气阀、过滤及其它装置的安装尽可能在生产车间的外部（如走廊）。 The overall design should be such that there is no possibility of undesired, unfiltered air or contaminants entering into manufacturing areas. 总体设计应确保不希望有的、未经过滤的空气或污染物无法进入生产区域。 Containment 密闭性 Manufacturers should ensure that appropriate measures are taken to contain product dust in a manufacturing area, thus preventing or minimizing the risk of contamination of other areas and possible cross-contamination. In some cases, it may be advisable to have airlocks or pass through hatches between rooms or areas. In addition, sufficient dilution, pressure differentials (recommended minimum values of 5 to 15 Pa) and airflow directions can further support containment in an area. 制造商应确保采取适当措施，在生产区域内控制产品粉尘，从而防止或尽量减少其他区域污染的风险和可能的交叉污染。在某些情况下，有必要在不同房间或区域之间设置气闸室或缓冲室。此外，充分的稀释，压差（建议最小值为5-15Pa），气流方向都可进一步加强某一区域的密闭性。 Cleanliness 清洁 Areas should be maintained at the defined levels of cleanliness and classifications. The HVAC system can support this through, e.g. appropriate levels of filtration of air, airflow directions, dilution, dust removal and air exchange rate. Equipment, containers, personnel and other related components should be appropriately located or placed in areas so as not to obstruct airflow and effectiveness of the HVAC system. 区域应保持在规定的洁净度和等级，HVAC系统可以通过适当的空气过滤水平、气流方向、稀释程度、除尘和换气速率等为其提供支持。设备、容器、人员和其他相关部件应适当放置或放置在一定区域内，以免妨碍空气流动和HVAC系统的效能。 Recontamination should be prevented by ensuring that material and personnel movement is within the same area classification and not back and forth between areas of different classification. Where such back-and-forth movement is unavoidable, appropriate controls should be identified and implemented to ensure that moving from a higher class to a lower classified area and back to a higher classified area will not result in contaminants being brought into the cleaner classified area. 防止再污染的办法是确保物流和人流在同一洁净等级区域内，而不是在不同洁净等级之间来回流动。在来回移动不可避免的地方，应确定和实施适当的控制措施，以确保从较高级别移动到较低级别区域并回到较高级别区域时不会导致污染物进入高洁净区。 Automated monitoring systems 自动监测系统 The performance of the HVAC system achieving and maintaining the desired results for parameters such as temperature, relative humidity, airflow and pressure differential should be carefully controlled and monitored. This is to ensure that there is no departure from these limits during manufacturing. Monitoring systems should be in place to ensure that the system operates within its design limits. Manual or automated (computerized) systems may be used. 应着重控制和监控HVAC系统达到并维持温度、相对湿度、气流和压差等参数在预定值的性能。这是为了确保在生产过程中不会偏离这些参数值范围。应建立监测系统，以确保该系统在其设计参数范围内运作。可以使用人工或自动化(计算机化)系统。 Manual systems of monitoring may not always provide sufficient proof that the system is able to maintain all conditions throughout the manufacturing period. 人工监测系统可能无法持续实时提供充分的证据，证明该系统能够在整个生产期间保持所有条件。 Automated monitoring systems may provide ongoing monitoring possibilities with better assurance of compliance with the defined limits. Where these automated systems are considered to be GXP systems, these should be appropriately validated. The scope and extent of validation of the computerized system should be determined, be justifiable and appropriately executed. This includes, but is not limited to, access and privileges to the software, setting of limits, monitoring and acknowledging alarms, audit trails, controls, monitoring and reporting. 自动监测系统可以提供持续监测的可能性，更好地保证维持在规定条件范围内。如果这些自动化系统被认为是GXP系统，则应对这些系统进行适当的验证。计算机系统验证的范围和程度应该确定，合理并适当的执行。这包括但不限于对软件的访问和特权、设置权限、监测和确认警报、核查记录、控制、监测和报告。 Switching off of AHUs 关闭空气处理装置 It is recommended that the HVAC system be operational on an ongoing basis. Where a manufacturer decides to use energy saving modes or switch some selected AHUs off at specified intervals such as overnight, weekends or extended periods of time, care should be taken to ensure that materials and products are not affected. In such cases, the decision, procedures and records should be sufficiently documented and should include risk assessment, standard operating procedures (SOPs), records and validation. This includes procedures and records for the start-up and shut-down sequence of air handling units. 建议暖通空调系统持续运转。如果制造商决定使用节能模式或在指定的时间段如隔夜、周末或延长时间关闭某些特定的空气处理装置，则应注意确保原料和产品不受影响。在这种情况下，决定、程序和记录应有充分的文件记录，并应包括风险评估、标准操作规程（SOP）、记录和验证。这包括空气处理设备启动和关闭顺序的规程和记录。 It will continue.未完待续 素材 / 李佳雯 原文请登录WHO官网查询 |
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