学术讨论—世界卫生组织HVAC非无菌制药指南(中英对照)WHO-937.docx

WHO 937 Annex 附件2Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms在GMP的根底上补充指导药剂生产的供暖，通风，空调系统的指导条例。1. Introduction 介绍2. Scope of document 文本范围3. Glossary 术语表4. Protection 保护4.1 Products and personnel 产品和人员4.2 Air filtration 空气过滤4.3 Unidirectional airflow 单向空气流4.4 Infiltration 渗透4.5 Cross-contamination 交叉污染4.6 Temperature and relative humidity 温度和相对湿度5. Dust control 固体颗粒污染物控制6. Protection of the environment 环境保护6.1 Dust in exhaust air 排气中的固体颗粒6.2 Fume removal 烟尘的祛除7. Systems and components 系统和构造7.1 General 概论7.2 Recirculation system 循环系统7.3 Full fresh air systems 送风系统8. Commissioning, qualification and maintenance 运转，资格和维护8.1 Commissioning 运转8.2 Qualification 资格8.3 Maintenance 维护References 文献451. Introduction 介绍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.加热，通风，空调HVAC系统在保证药品质量的生产上起着至关重要的作用。同时，设计完善的系统也会给操作人员提供舒适的工作环境。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 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.这些条例主要是针对固体药剂生产车间而提出的。但同时在涉及到与固体药剂生产无关的其它生产中，这些条例可以比拟固体药剂生产车间和其它车间生产规格上的具体要求。HVAC system design infl uences 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. HVAC系统的设计与建筑规划有关，比方气阀、门口、出入口。这些物件的设计对房间气压差的形成和交叉污染的控制都起着重要作用。The prevention of contamination and cross-contamination is an essential design consideration of the HVAC system.污染和交叉污染的防制是HVAC系统设计的重点考虑因素。 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.鉴于这些关键点，在药品生产车间的设计阶段，HVAC系统的设计规划就应被考虑进去。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.适当的温度、相对湿度和良好的通风条件无论是在药品的生产和储藏阶段，都会影响药品质量。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. 本文献的目的是给药品生产和质检人员提供便利，在HVAC系统的设计、设备安装、资质条件以及系统维护方面。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.这些条例也是药品生产GMP1的补充说明，在总条例的中也会读到。The additional standards addressed by the present guidelines should therefore be considered supplementary to the general requirements set out in the parent guide.现在这些增加的标准也应考虑作为制定总条例的重要补充局部。2. Scope of document 文献范围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.这些条例主要是便利固体药剂生产的设计和HVAC系统GMP生产要求。大多数系统的设计原理是为固体药剂生产提供便利，同时也给液体、悬浮剂、膏剂提供便利。这些条理不仅仅是中间体药物生产的标准，同时也是GMP检查者的根本指导条目。These guidelines are intended as a basic guide for use by GMP inspectors. 这些条例并不能给具体生产和参数设计指导，说明性的意义。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(制定) the specific requirements for one particular parameter in isolation.各种不同的参数才能影响一个环境，因此，很难在仅有一个参数的条件下制定出具体的生产要求。46Many manufacturers have their own engineering design and qualifi cation standards and requirements may vary from one manufacturer to the next. 不同的药品生产都有它们自己的工艺设计、质量标准以及产品要求。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.在符合调整标准、能够保证药品生产质量和平安的情况下，为创造出最有效的生产环境，参数的设计因针对不同药品而有所不同。The three primary aspects addressed in this manual are the roles that the HVAC system plays in product protection, personnel protection and environmental protection (Fig. 1).这本指南上，HVAC系统在药品保护、人员保护以及环境保护这三个主要方面起着重要作用。Figure 1 图1The guidelines address the various system criteria according to the sequence set out in this diagram根据下面表格的顺序，不同的系统标准有不同的生产条例。473. Glossary 术语表The definitions given below apply to terms used in these guidelines. They may have different meanings in other contexts. 以下给出条例中使用的术语的解释，这些术语可能在不同文章中有不同意思。acceptance criteria 合理的标准Measurable terms under which a test result will be considered acceptable.由实验结果得出的测量值将视为合理的。action limit 行为限制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. 行为限制就是不能超出一个关键参数的合理标准，超出这些限制的行为必须要有具体的调查。air-handling unit (AHU) 空气处理单元The air-handling unit serves to condition the air and provide the required air movement within a facility. 空气处理单元提供便利在所需空气流动上。Airlock 空气阀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. 有两个或多个门的封闭的空间，也可指两个或多个房间，比方说不同等级的洁净区，送风口的设计是为了控制空气流动。An airlock is designed for and used by either people or goods (PAL, personnel airlock; MAL, material airlock).空气阀门可以为人也可以为药品设计、使用。alert limit 警报极限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.警报极限是超过一个重要参数的正常操作范围，在这里包括阻止超过操作极限的正确方法。as-built 建立状态Condition where the installation is complete with all services connected and functioning but with no production equipment, materials or personnel present. 所有设施已安装，并已运转，但没有生产设备，物料和操作人员。at-rest 暂停状态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.设备安装调试后到达操作者和客户的要求，但没有操作人员现场操作。central air-conditioning unit (see air-handling unit)中心空调单元见空气处理单元change control 改变控制A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status.一旦改变将会影响正常状态的操作系统。The intent is to determine the need for action that would ensure that the system is maintained in a validated state.如果确需要改变操作状态，要保证不影响系统的正常操作。48clean area (clean room) 1 洁净区1An 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. 一个洁净区或房间有着规定的微粒、微生物污染的环境要求，它的建造是为了在这个特定区域里减少污染物的带入、生成。Commissioning 试生产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.试生产是在有理论支持的下，它是根据具体操作需要安装装置和设定系统，保证所有装备都能运转。试运转是工程建设规划的总结。Containment 污染A process or device to contain product, dust or contaminants in one zone, preventing it from escaping to another zone.防止产品、灰尘及污染物从一个区域扩散到另一区域的过程。Contamination 污染物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. 在生产、取样、包装、重新包装、储存和运输阶段，原料和媒介引入化学、微生物或其它外界物质。critical parameter or component 重要参量和组成成分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.参数温度、湿度的设定将会影响到药品的质量，组成成分也将同样会影响到产品的质量。cross-contamination 交叉污染Contamination of a starting material, intermediate product or finished product with another starting material or material during production.交叉污染是指原料药、中间体或成品药在生产过程中与其它的原料药、物料相混。design condition 设计条件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.设计条件是指设计者对可控制变量的变化范围以及精确性的把握，它是操作系统性能的决定因素。design qualifcation (DQ) 质量控制DQ is the documented check of planning documents and technical specifications for conformity of the design with the process, manufacturing GMP and regulatory requirements.质量控制是有理论支持的、有方案性、技术性的文档，它符合产品设计、GMP生产以及药品生产修正需求。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.注意：清洁区的标准规定，例如IS14611-4规定的根据空气中的粒子浓度划分清洁区标准，然而GMP提供了当药物在生产操作状态下和暂停状态中的空气洁净等级。GMP和清洁区标准规定可以一起使用来定义和分类不同的生产环境。49direct impact system 直接影响系统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.这种系统对药品质量有直接的影响。直接影响系统是根据GEP、质量操作来设计和运做的。Facility 设备The built environment within which the clean area installation and associated controlled environments operate together with their supporting infrastructure. 在生产操作中，清洁区的设备安装、生产环境控制，以及相应的操作间构造。good engineering practice (GEP) 优效工程条例Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions.通过工程周期，建立工程方法和标准，到达有效运做、合理花费的效果。indirect impact system 间接影响系统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.间接影响系统对药品质量没有直接影响，但是对直接影响系统有间接意义。这种系统仅仅根据GEP来设计和运转的。infiltration 渗透Infiltration is the ingress of contaminated air from an external zone into a clean area. 渗透是指含污染物的空气有外部区域进入洁净区的过程。installation qualification (IQ) 安装验证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.安装验证在文件支持的前提下，HVAC系统设备、仪器的安装与设计规划相一致.no-impact system 无影响系统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.无影响系统对生产的药品质量没有间接或直接的影响。这个系统仅仅通过GEP来设计和运做的。non-critical parameter or component 不重要参数及组成成分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.系统内的操作参数和组成成分，比方操作、接触、数据控制、警报及失误对药品质量有间接或无任何影响。normal operating range 正常操作范围The range that the manufacturer selects as the acceptable values for a parameter during normal operations. This range must be within the operating range.在正常操作状态下，有生产者选择参数的可操作值的范围。operating limits 操作极限The minimum and/or maximum values that will ensure that product and safety requirements are met.保证产品和平安所需 最小、最大值。50operating range 操作范围Operating range is the range of validated critical parameters within which acceptable products can be manufactured.操作范围指的是在合格产品质量范围内，一个重要的有效参数的变化值。operational condition 操作环境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. 操作环境指的是在生产设备运转和人员操作的环境中，正常物料生产过程操作环境的分类。operational qualification (OQ) 操作条件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.操作条件是备有文件规定的，验证在正常操作范围内，与药物生产规定相一致的设备操作。在预期的操作范围内有效的实施。oral solid dosage (OSD) 口服片剂Usually refers to an OSD plant that manufactures medicinal products such as tablets, capsules and powders to be taken orally. 通常指的是仅生产口服药片、胶囊、粉末的生产车间。performance qualifi cation (PQ) 性能条件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. PQ是指系统完成所有预期操作范围的过程，理论支持的。point extraction 过滤点Air extraction to remove dust with the extraction point located as close as possible to the source of the dust. 空气过滤是指尽可能的去除空气中的尘埃，已尽可能到达尘埃点。pressure cascade 气压层A process whereby air fl ows from one area, which is maintained at a higher pressure, to another area at a lower pressure.气流从从高压区向低压区流动的过程。Qualification 资质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.资质是在设备、系统上进行方案、实施、测试记录，并且是有效操作过程的组成成分，并且保证了生产能如预期打算中完成。relative humidity 相对密度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 is the ratio of the mass of moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature.在一定温度下，空气的实际气压和其饱和气压的比值叫相对密度。更简单的说，就是在指定温度下，饱和水分子的质量和实际空气中存在的水分子的质量的比值。standard operating procedure (SOP) 标准操作规程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 51inspection). Certain SOPs may be used to supplement product-specific master and batch productio