 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 接上期内容： 收藏！ WHO：非无菌制剂暖通空调GMP指南：第二部分 Section 6. Full fresh air and recirculation systems 第六节 全新风及再循环系统 Manufacturers may select to have full fresh air systems or recirculate treated air supplied to production areas (In a full fresh air system, no air is recirculated. In recirculation systems, a defined percentage of the air is recirculated.). In both cases, the air supplied to the production areas should be appropriately treated to ensure that the environmental conditions specified are met and that the risks for contamination and cross-contamination are controlled. 制造商可以选择全新风系统或再循环处理的空气供应至生产区域（在全新风系统中，空气不会再循环。在再循环系统中，循环空气的比例是特定的）。在这两种系统中，供应至生产区域的空气都应确保得到恰当处理，以确保符合规定的环境条件，并确保污染和交叉污染的风险控制。 Manufacturers using recirculation systems should determine the percentage of fresh air to be supplied to the relevant manufacturing areas, as required by national and international standards. This volume of air should be verified during qualification. 使用再循环系统的制造商应根据国家和国际标准的要求，确定向有关生产区域提供新风的百分比。风量应在资格认定时加以核实。 In both scenarios, appropriate levels of filtration should be applied to prevent contamination and cross-contamination. Manufacturers should ensure that when HEPA filters are used that these are appropriately installed, not damaged and thus suitable for the intended use (see tests described below under the section of qualification). 在两种情况下，应采用适当的过滤水平来防止污染和交叉污染。制造商应确保在使用HEPA过滤器时，这些过滤器安装得当，没有损坏，符合预期的用途（请参阅资格部分下面描述的测试）。  Figure 8. Example of a full fresh-air system 图八 全新风系统 Section 7. Air filtration, airflow direction and pressure differentials 第七节 空气过滤、气流方向和压差 Effective ventilation and appropriate levels of filtration are recommended in basic GMP guidelines. Manufacturers should determine which classes of filters should be used in ensuring that contaminants from outside are not introduced into manufacturing areas and that where recirculation systems are used, filtration of recirculated air should be effectively treated to ensure that there is no risk of cross-contamination. Where different products are manufactured in different rooms in the same facility at the same time, appropriate controls should be in place to ensure containment and the prevention of contamination and cross- contamination. 有效的空气流通和适当的过滤水平在基础GMP指南中有提及。制造商应确定使用哪类过滤器来确保外部污染物不会进入生产区域，并且在使用循环系统的情况下，应有效处理循环空气过滤，确保不存在交叉污染风险。在不同房间的同一设备内同时生产不同的产品时，应制定适当的控制措施确保密闭性，避免产生污染或交叉污染。 Filters selected for air filtration, air changes and airflow direction should be determined and specified. When a manufacturer chooses to install high efficiency particulate air (HEPA) filters to achieve the desired degree of filtration of air, these filters may be placed in the AHU or may be installed terminally near the supply grille. 应确定和指定用于空气过滤、换气和气流方向的过滤器。当制造商选择安装高效空气（HEPA）过滤器以达到所需的空气过滤程度时，这些过滤器可以安装在AHU中，或者可以安装在末端送风格栅附近。 The number of air changes or air exchange rates should be sufficient. A guidance value is between 6 and 20 air changes per hour. Manufacturers should also establish how much time it takes for a room, which is out of its classification, to return within the specified class. This is often referred to as clean-up or recovery time. A guidance time period for clean-up or recovery is about 15 to 20 minutes. 换气量与换气速率应当是足够的。指导值为每小时变化6到20空气变化值。制造商还应该确定一个不同级别的房间需要多少时间才能恢复到指定的级别状态。这通常被称为清洁或恢复时间。清洁或恢复的指导时间约为15至20分钟。 Airflow directions should be specified and proven to promote containment and not be adversely affected or obstructed by equipment, utilities, containers or personnel. The location of supply and return or exhaust air grilles should facilitate appropriate airflow directions in an area. 气流方向需指定并证明可提高密闭性，不会有不利影响或被设备、公用设施、容器、人员遮挡。送风和回风或排气格栅的位置应有助于一个区域内维持适当气流方向。 Figure 9 is a schematic diagram of air-handling system serving rooms with horizontal directional flow, vertical directional flow and turbulent flow, for rooms 3, 4 and 5, respectively. In these room, the HEPA filters are indicate to have been placed terminally mounted at the rooms and not in the AHU. Terminally-mounted HEPA filters can assist with preventing cross-contamination from room to room in the event of a fan failure condition. 图九是空气处理系统为房间3、4、5分别提供水平气流、垂直气流和波动气流的示意图。在这些房间内，HEPA过滤器表明安装在房间末端而不是AHU内。终端安装的HEPA过滤器可以在换气扇故障的情况下防止房间之间产生交叉污染。  Figure 9. Example of horizontal airflow, vertical flow and turbulent flow 图九 水平气流，垂直气流和波动气流示意图 The pressure differential should be of sufficient magnitude to ensure containment and prevention of flow reversal, but should not be so high as to create turbulence problems. It is suggested that pressure differentials of between 5 Pa and 20 Pa be considered. Where the design pressure differential is too low and tolerances are at opposite extremities a flow reversal can take place. There should be no risk of overlap in the acceptable operating range. e.g. 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting in the failure of the pressure cascade. The upper and lower limits for pressure differentials between areas in a facility should be defined by the manufacturer. Where there are inter leading rooms the limits should be appropriate to ensure that there is no overlap in actual values as this may result in loss in pressure differential between areas and even reversal of air flow. 压差应足够大到可以确保密闭性及避免气流逆转，但不应该高到造成气流不稳定问题。建议考虑5~20 Pa的压差。当设计压差太低，限度在相对极值时，气流会发生转向。在可接受的操作范围内不应有重叠的风险，例如在一个房间中为5Pa至15Pa，而在相邻房间中为15Pa至30Pa，导致压力梯级失效。厂房内各区域之间压差的上限和下限应由制造商确定。如果有缓冲室，限值需恰当以确保实际值不会产生重叠，反之则会导致区域之间的压差降低甚至气流逆转。 The pressure control and monitoring devices used should be calibrated and where possible, be linked to an alarm system set according to the determined levels. 所使用的压力控制和监控装备应进行校准，并根据设定的级别连接报警系统。  Figure 10: Examples of pressure cascades 图10 压差形成示例图 Airlocks 气闸室
Airlocks with different pressure cascade regimes include the cascade airlock, sink airlock and bubble airlock: 根据不同压力阶梯增减规则，气闸室包括阶梯气闸室，水槽气闸室和气泡气闸室： · cascade airlock: higher pressure on one side of the airlock and lower pressure on the other; · 阶梯气闸室：气闸室一侧压力较高，另一侧压力较低； · sink airlock: lower pressure inside the airlock and higher pressure on both outer sides; · 水槽气闸室：气闸室内压力较低，外两侧面压力较高。 · bubble airlock: higher pressure inside the airlock and lower pressure on both outer sides. · 气泡气闸室：气闸室内压力较高，外两侧面压力较低。
 Figure 11: Example of cascade airlock 图11：阶梯气闸室示意图 · (在大多数情况下，气闸室的内部压力并不重要。外侧面压差是重要的判据。）  Figure 12: Example of sink airlock 图12：水槽气闸室示意图  Figure 13: Example of bubble airlock 图13：气泡气闸室示意图 Note: The diagrams above and the differential pressures shown here are for illustration purposes only. Pressures indicated in these examples are absolute pressures, whereas the local pressure indication would most likely be pressure differential from room to room. 注：以上图表及压差图仅作说明用途。这些例子中所表示的压力是绝对压力，而局部压力可能是房间之间的压差。 Additional controls should be identified through risk identification and risk assessment. For example, where possible, personnel should not move between different areas during production (such as compression rooms and in process control laboratories) unless there is no risk of contamination of other areas. Personnel often become sources of contamination as they may carry dust from one area to another. Controls may include airlocks or gowning procedures. 通过风险识别和风险评估应确定其他控制措施。例如，人员在生产过程中尽可能避免在不同的区域之间移动 (例如压缩室和过程控制实验室)，除非不存在污染其他区域的风险。人是最常见的污染源，因其可以将灰尘从一个区域带至另一个区域。可以通过气闸室及穿净化服进行控制。 Section 8: Temperature and relative humidity 第八节 温度及相对湿度 Manufacturers should set appropriate upper and lower limits for temperature and relative humidity for different areas. The required storage conditions specified for the materials and products should be considered when the limits are defined. The HVAC system should be designed in such a manner that these limits can be achieved and be maintained through all seasons. 制造商应为不同区域的温度和相对湿度设定适当上下限。规定限度时应考虑材料和产品所需的储存条件。暖通空调系统的设计应使环境保持在这些范围内，并在所有季节都能保持。 Systems for dehumidification or humidification require special considerations due to their contamination risk (e.g. condensate formation, bacterial and fungal contamination, contaminated steam and risks when using mobile systems between different areas). Chemicals such as corrosion inhibitors or chelating agents, which could have a detrimental effect on the product, should not be added to the boiler system. Humidification systems should be well drained. No condensate should accumulate in air-handling systems. Other humidification appliances such as evaporative systems, atomizers and water mist sprays, should not be used because of the potential risk of microbial contamination. Air filters should not be installed immediately downstream of humidifiers as moisture on the filters could lead to bacterial growth. Cold surfaces should be insulated to prevent condensation within the clean area or on air-handling components. Chemical driers using silica gel or lithium chloride are acceptable provided that they do not become sources of contamination. 除湿或加湿系统由于其污染风险（例如冷凝物形成，细菌和真菌污染，污染的蒸汽和在不同区域之间使用移动系统时的风险）而需要特殊考虑。化学品如腐蚀抑制剂或螯合剂可能会对产品产生不利影响，因此不应添加到锅炉系统中。加湿系统应该排水良好。空气处理系统中不应积聚冷凝水。不应使用其他加湿设备如蒸发系统、雾化器和喷雾器，因为存在微生物污染的潜在风险。空气过滤器不应该安装在加湿器的下游，因为过滤器上的水分可能会导致细菌滋生。冷表面应该绝缘处理以防止在清洁区域或空气处理部件上产生冷凝现象。可以使用硅胶或氯化锂的化学干燥剂，只要它们不成为污染源。 Section 9. Dust, vapour and fume control 第九节 粉尘、蒸气、烟雾控制 Manufacturers should ensure that dust-generated vapours and fumes are effectively removed from the manufacturing areas. Extraction or collecting systems should be designed and qualified to demonstrate this. Sufficient air velocity should be maintained in such systems to effectively remove dust and vapours. 制造商应确保粉尘产生的烟雾从生产区域有效清除。应设计排风和捕集系统并确认可行。该系统应维持足够的气流速度以有效清除粉尘和烟雾。 A dust extractor should normally not serve different rooms where different products can be processed at the same time due to the risks such as backflow or flow from room to room resulting in possible contamination and cross-contamination. 当存在同一时间生产不同产品时，一个除尘器通常不应在不同房间工作，因存在从一个房间到另一个房间返流或流动的情况，可能导致污染和交叉污染。 Wherever possible, dust or vapour contamination should be removed at source, i.e. as close as possible to the point where the dust is generated. Dust extraction ducting should be designed with sufficient transfer velocity (determined by the manufacturer depending on materials and products processed) to ensure that dust is carried away, and does not settle in the ducting (a guidance value is 15–20 m/s). As vapours can be problematic, extraction may be supported by directional airflow to assist in the removal. The density of the vapour should be taken into consideration with extract grilles at a high level or possibly at both high and low levels. 如有可能，应在源头清除粉尘或气雾污染，如尽可能靠近产尘区。除尘管道应被设计具备足够的传输速度（由生产商根据所加工的物料和产品决定）以确保粉尘清除，而不滞留在管道内（指导值：15-20m/s）。由于蒸气可能会产生问题，因此可以通过定向空气流来辅助除尘。 应该考虑到蒸气密度，萃取物格栅应该在高处或可能在水平处. Section 10.Protection of the environment 第十节 环境保护 Manufacturers should have controls in place to ensure that air from production areas, including contaminated air from equipment such as fluid bed driers, is passed through appropriate levels of filtration to ensure that the environment is not polluted. Manufacturers should consult national and international environmental legislation. 制造商应对生产区域的空气采取控制措施，包括流化床干燥机等设备产生的污染空气需通过适当级别的过滤确保环境不受污染。制造商应该咨询国内国际的环境立法。 Section 11. Commissioning 第十一节 试车 Where manufacturers perform commissioning, this should be clearly documented. 制造商进行试车的地点应明确记录下来。
Section 12. Qualification 第十二节 确认 Manufacturers should consider all stages of qualification for their HVAC systems. This includes, where appropriate, user requirement specification, design qualification, factory acceptance test, site acceptance test, installation qualification, operational qualification and performance qualification. Qualification to be done over the life cycle of the HVAC system should be described and executed including, e.g. when changes are made to the system. 制造商应考虑对暖通空调系统进行各个阶段的确认。包括用户需求规范（URS）、设计确认、工厂验收测试、现场验收测试、安装确认、运行确认和性能确认。在暖通空调系统生命周期中的确认应进行描述和执行，包括当系统发生变更时。 Validation master plan(s), protocols, reports and source data for tests should be available. The scope and extent of qualification should be determined based on risk assessment. Parameters with limits included in qualification (such as temperature test, airflow direction, viable and non-viable particle counts) should be justified by manufacturers. The procedures followed for the performance of the tests should generally be in line with the standard as described in ISO 14644. 必须有验证主计划、方案、报告和测试源数据。确认的范围和程度应基于风险评估确定。限值参数包括确认（如温度测试、气流方向、活性和非活性粒子计数）等都须由制造商进行修正。测试所遵循的程序通常应与ISO14644所规定的标准保持一致。 Some of the typical HVAC system parameters that should be included in the tests during qualification are listed below. It is recommended that the tests be done at defined intervals. The tests typically cover: 确认期间测试应包括的典型的HVAC系统参数罗列如下。建议测试在规定时间进行。典型的测试包括以下： — temperature; 温度 — relative humidity; 相对湿度 — supply air quantities; 送风量 — return air or exhaust air quantities; 回风或排风量 — room air-change rates; 房间换气次数 — pressure differentials; 压差 — airflow direction test; 气流方向测试 — installed filter leakage tests; 过滤器泄漏测试 — particle counts; 悬浮粒子计数 — clean-up or recovery rates; 自净/恢复时间 — microbiological counts; 微生物计数 — warning/alarm systems. 报警系统
Table 1. Considerations in testing 表1 测试要点   Section 13. Maintenance 第十三节 维护 Manufacturers should maintain current documentation for HVAC systems which include operation and maintenance manuals, schematic drawings, procedures and records. 制造商应保存现有的暖通空调系统文件，包括操作和维护手册、图纸、程序和记录。 Repairs, maintenance and preventive maintenance (including cleaning, replacement of components, changes, qualification) should be executed in accordance with procedures. Records for these should be maintained for an appropriate time. 维修，维护和预防性维护（包括清洁、更换部件、更换、认证）应按照程序执行。这些记录应该保存适当的时间。 素材 / 李佳雯 原文请登录WHO官网查询 |
|
|
