ISPE Good Practice Guide Critical Utilities GMP Compliance

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2.2      Compendial Water Pretreatment 药典用水的预处理

The term pretreatment typically indicates unit operations chosen toprepare drinking water forconversion to a higher quality by aprimary treatment method. Pretreatment most oftenisused to either reducethe contaminant load on primary treatment equipment or to extend the interval betweenequipment servicing.

“预处理”一词通常指通过一种初级处理方法将饮用水转换为更高质量水的单元操作。预处理大多数常用于减少关键处理设备的污染物负荷或延长设备保养间隔。

Hence, pretreated water is not required tomeet drinking water nor PW chemical or microbial standards; it is simply an interim quality that allows for primary treatment equipment tooperate under less demanding conditions andat reduced operational costs. Pretreatment is significantly less costly tooperate than primary treatment equipment and extends the timebetweenservice events for theprimary treatment components. Pretreatment systems must receive a similar level of care as compendial systems proper in terms of their maintenance (leaks or other dysfunctions) as they are anintegralpart of the overall treatment. From a compliance perspective, a poorly maintained pretreatment system is a poorly maintained compendial water treatment system.

因此，预处理水不需要满足饮用水或纯化水化学方面或微生物方面的标准；它只是一种质量过渡，所以允许初级处理设备在要求较低的条件和较低运行成本的状态下运行。预处理比初级处理设备的操作成本要低得多，并且延长了初级处理部件维护活动之间的间隔。预处理系统作为整体处理系统的一个组成部分，在维护(泄漏或其他功能障碍)方面必须得到与药典水系统相类似的维护。从合规性的角度来看，一个维护不善的预处理系统就是一个维护不善的药典水处理系统。

Pretreatment systems that are not properly maintainedmayforce primary treatment components tobear the additional load resultingin greater downtime, unscheduledoutages, and increased cost. Each typeof unit operationselected for use as pretreatment requires PreventiveMaintenance(PM) andpossibly routineservice specific toits function.

预处理系统如果没有得到充分地维护会导致初级处理组件承担额外的负载，从而导致更长的停机时间、计划外停机，然后增加成本。选择用于预处理的每一种操作单元都需要预防性维护(PM)，针对其特定功能可能还要进行日常维护。

For example, softeners typically need maintenance at aminimum annually for proper operation; however, dependingon the water quality and age of the system may require morefrequent maintenance. Nonetheless, in additionto regular maintenance, softeners needconstant monitoring of salt usedforregeneration, often needingadditional salt every few days.Failure to maintain salt levels could result inhardness foulinga downstream Reverse Osmosis (RO) system and anunplanned outage.

例如，软化剂通常需要至少每年维护一次才能正常运行；然而，根据水质和系统使用年限的不同，可能需要更频繁的维护。尽管如此，除了定期维护外，软化剂需要不断监测用于再生盐的含量，通常每隔几天就需要额外添加盐。如果不能保持盐水平，可能导致下游反渗透(RO)系统硬度污染和计划外停机。

Thepretreatment system water may not meet therequirements of drinking water, but in order for the system to be GMP compliant, it shouldbe operated ina state of control; that is, parameters are maintained withinspecified ranges. The nature of theparameters tobe monitored depends onthe technologies deployedin thepretreatment (e.g., hardness testing toverify softenerperformance).

预处理系统水可能不符合饮用水的要求，但为了使系统符合 GMP 要求，必须在受控状态下运行；也就是参数维持在特定的范围内。所监控的参数性质取决于在预处理中所采用的技术(例如，软化剂性能的硬度测试)。

Proper maintenance andoperation of pretreatment equipment help toensure optimal overallsystem operation, and helpto reduce events that could jeopardizethe compliance of the system.

对预处理设备进行适当的维护和运行，有助于保证整体系统的最佳运行状态，有助于减少危及系统合规性的事件发生。

2.3      Purified Water 纯化水

2.3.1              General 通则

PW is normally used incleaningoperations as well as inthe manufacture of APIs, oral solutions,topicals, oral solid dosage products, and medical devices. Inmost of these cases, PW is araw material that requires testing todemonstrate quality and compliance.

纯化水通常用于清洁操作，同时用于原料药、口服液、外用药、口服固体制剂产品和医疗器械的生产。在大多数情况下，纯化水是一种原料，需要通过测试来证明其质量及合规性。

2.3.2              Applicable Requirements 适用的要求

PW, as defined by compendial monographs, requires compliance with specifications for chemical andmicrobial quality. Chemical quality requirements aredefined by conductivity and TOC specifications. Microbialquality requirements for PW areusually defined inpublishedstandards. Severalpharmacopeias specify a variety of other parameters, which aresummarized in Appendix 4.

纯化水，按药典各论中的定义，要求符合化学和微生物质量方面的标准。化学质量要求由电导率和TOC 标准确定。微生物标准通常在已发布的标准中明确。附录 4 总结了几部药典规定的其他各种参数。

2.4      Water for Injection 注射水

2.4.1              General 通则

WFI is typically used incleaningoperations, and in themanufacture of inhaledproducts and injectableproducts. It is araw material, and therefore requires adequatetestingto demonstrate quality andcompliance.

注射水通常用于清洁，以及用于吸入性产品和注射类产品的生产。它是一种原料，因此需要充分的测试来证明其质量和合规性。

2.4.2              Applicable Requirements 适用的要求

WFI, as defined by compendial monographs, requires compliance with specifications for chemical andmicrobial quality. Chemical quality requirements aredefined by conductivity and TOC specifications. Microbialrequirements for WFI areusually definedin publishedstandards. Endotoxinlimits arealsoapplicable toWFI. Appendix 4summarizes therequirements for most of the major pharmacopeias.

注射水，按照药典各论的定义，要求符合化学和微生物质量方面的标准。化学质量要求由电导率和TOC 标准确定。微生物标准通常在已公布的标准中明确。内毒素限度也适用于注射水。附录 4 总结了多数药典的要求。

WFI is theproduct of drinking water that has been pretreated andprimary treatedto meet thefinal requiredchemicaland microbialspecifications.There is inconsistency worldwideabout the allowedtreatment techniques and the water that may beused as the feed water toa WFI generationprocess. Europe [13], North America [12], and Japan [18] allow for the use of non-distillation based techniques for thegeneration of WFI, and for the useof potable water as thestarting material. The Chinese Pharmacopoeia [19] specifies that distillation must be usedwith PW as the startingmaterial, but is currently considering allowing generation techniques other thandistillation.

注射水是饮用水经过预处理和初级处理以满足最终要求的化学和微生物标准的产物。在世界范围内，允许使用的处理技术和可能用于注射水制备过程的源水均存在差异。欧洲[13]、北美[12]和日本[18]允许使用非蒸馏技术生产的注射水，也允许使用饮用水作为起始物料。中国药典[19]规定必须以纯化水 为源水进行蒸馏，但目前正在考虑允许衍生蒸馏以外的生产技术。

2.5      Pure Steam 纯蒸汽

2.5.1              General 通则

Steam is classifiedasPure Steam whenitis intended tobe used for direct andindirect product contact, for sterilizationof product or material, or for sanitizationof surfaces.

当蒸汽直接和间接接触产品、用于产品或物料的灭菌或用于表面的灭菌时，它被归类为纯蒸汽。

2.5.2              Applicable Requirements 适用的要求

PureSteam should meet therequirements of theapplicable pharmacopeia(i.e., USP [12], Ph. Eur. [13]).

纯蒸汽应符合适用的药典(即 USP [12]， Ph. Eur[13])的要求。)

Many pharmacopeias do not includea PureSteam monograph; therefore, often therelevant WFImonograph Specifications are applied. Theseare, for instance, therequirements for the feed water,a builtin component toretain droplets,and the required test parameters for WFI that may betestedon the Pure Steam condensate. Dueto thelethality of PureSteam,culturingof microbial samples isnot required, although endotoxintesting is required.

许多药典中不包括纯蒸汽专论；因此，通常采用相关的注射水各论的标准。例如，这个供水的要求，保持液滴的内置部件，以及在纯蒸汽冷凝水上测试 WFI 所要求的测试项目。由于纯蒸汽具有灭菌作用，所以不需要检测微生物，但仍需要做内毒素检验。

Pharmacopeias may not define certainparameters such assteam saturation, dryness, and non- condensablegases; however, guidance is provided by the EN285[20] and the British HTM 01-01 Part C [21] standards. It is recommended toconduct a risk analysis that includes specifics related tothese qualities. EN285 may support adecisionas to whether or not these parameters are applicable, and to define limits and test procedures.

药典可能没有规定某些参数，如蒸汽饱和度、干燥度和不冷凝性气体；然而，EN285[20]和英国 HTM01-01 Part C[21]标准提供了指导值。建议对这些质量相关的细节进行风险评估。EN285提供了支持这些参数是否适用的决定，并确定限度和测试方法。

The testingforsteam quality is most oftendone at the POU toan autoclaveunit and requiresspecialized test elbows andequipment. If futurequality testing is likely, considerations duringthe design phase should bemade to providethe necessary spoolpieces.

蒸汽质量的测试通常在灭菌柜的使用点处进行，需要专门的测试弯头和设备。如果将来品质测试有可能进行的话，在设计阶段应考虑提供必要的控制阀。

2.6      Clean Compressed Air 洁净压缩空气

2.6.1              General 通则

Compressedair intended for use inproduct-impact applications include:

影响产品的压缩空气包括：

•      Steam sterilizer overpressure 高压蒸汽灭菌器

•       Pressureequilibrationafter steam sanitizationof piping andequipment管道及设备蒸汽消毒后的压力平衡

•      Transfer of product 产品转移

•      Blow downof equipment after clean inplace/steam inplace for drying设备清洁后在线吹干/蒸汽烘干

•      Air supply tofermenters 发酵罐供应气体

Inaddition, compressed air is used whenever thereisair contact witha product-contact surfacenot cleaned in a subsequent operation, and in allclassified manufacturingspace into which theprocess compressedair is exhausted.

此外，当与后续操作中未清洁的产品接触表面与空气接时触、以及在所有级别的生产空间内都可以使用压缩空气。

Compressed air may be obtained incylinders based onvolume needs, althoughitis typicallyproduced on siteusingcompressors. This puts it intoa category different than most other gases and justifies its descriptionseparate from other gases.

压缩空气可根据需求量从储气罐中获得，尽管通常是在现场使用压缩机制备。这使它成为一个不同于其他大多数气体的类别，而且它的描述也不同于其他气体。

       2.6.2              Applications 用途

Some pharmacopeias include monographs for medicalair. Standards such as “breathing air” (forexample, theNFPA 99Standard [22]) are available. ISO 8573 [23] is sometimes employed by manufacturers as astandard.

一些药典包括医用气体的专著。可使用如“呼吸空气”(例如，NFPA 99 标准[22])的标准。ISO 8573[23]有时被生产企业作为标准使用。

In most cases medicalgradegases are not required inpharmaceuticalmanufacturing sincemedicalgases and breathing gases are typically intendedfordirect use by people or animals. Thegeneand cell therapy medicines industry alongwith biotechnology manufacturing utilizemedicalgases and process air for product contact.

在大多数情况下，医药生产不需要用到医用气体，因为医用气体和呼吸气体通常是人或动物直接使用的。基因和细胞治疗药品行业和生物技术生产使用医用气体和工艺气体与产品接触。

When used ina pharmaceutical process withdirect product contact, the purity requirements should be basedon product and process needs. Theseproduct requirements areusually defined in themanufacturer’s regulatory filings.

当用于与产品直接接触的制药工艺时，其纯度要求应基于产品和工艺的需要。这些产品要求通常在生产者的监管文件中明确描述。

When applicable, preparation of a risk analysis is prudent.

如适用，准备做一个风险评估更为明智。

It is generally acceptedthat a criticalquality parameter for clean compressed air is the dewpoint/relative humidity with theexpectation that the level of humidity in theair will be non-condensable in thetemperatureranges to which the compressedair piping is exposed. Maintaining dryness essentially eliminates thepossibility for microbialgrowthsince without water, bacteria arenot able to reproduce.

一般认为，洁净压缩空气的一个关键质量参数是露点/相对湿度，期望空气中的湿度水平在压缩空气管道暴露的温度范围内是不可冷凝的。保持干燥，从根本上消除了微生物生长的可能性，因为没有水，细菌无法繁殖。

In addition, requirements applied toenvironmental air can beused to support decisions documented inthe risk analysis. This is especially true in cases where theairis used and exhausted within a classified space. As such, a reasonforthe decisionon the maximum allowed amount of particles or microbes inthe compressed air may bebased on Table 2.1.

此外，适用于环境空气的要求可以用于支持风险分析中记录的决策。在一定洁净级别的空间使用和耗尽空气时尤其如此。因此，决定压缩空气中允许的最大粒子数或微生物数量的理由可以根据表 2.1 来定。

Table2.1: CleanRoom andClean Air Device Classification 洁净室和洁净空气设备分类

(Adaptedfrom EU Guidelines to Good Manufacturing PracticeMedicinalProducts for Human and

Veterinary Use, Annex 1 “Manufactureof Sterile Medicinal Products” [24])

(改编自欧盟人用和兽用药品生产质量管理规范指南 附录 1“无菌药品的生产”[24])

Classification    分类	Nonoperational 静态			Operational 动态
	Maximum permitted number of particles of tabulated size/m3    最大允许的粒子数					Maximum    最大值
Grade    级别	≥ 0.5  μm	≥ 5.0  μm	≥ 0.5  μm		≥ 5.0  μm	Allowed amount of viable    microbes/m3    微生物限度
A	3 520	20	3 520		20	<1
B	3 520	29	352 000		2 900	10
C	352 000	2 900	3520 000		29 000	100
D	3 520 000	29 000	*		*	200
*Annex 1  does not have limits defined  for these cases; nevertheless, it is recommended to  determine limits according to  respective working  procedures.    附录 1 对这些情况没有规定限度;不过，建议大家根据各自的工作程序确定限度。

A risk analysis should consider theneedfor POU filters or decentralizedfilters for each productionroom, whether the use of an oiler or other equipment necessitates the needfor backflowprevention, andif air should beexhausted from the room.

风险评估应该考虑是否需要为最远使用点或分散到每个生产房间的使用点安装过滤器，是否需要使用注油器或其他设备防止回流，以及是否需要将空气从房间排出。

To adequately address complianceitmay be necessary, confirmed by risk analysis, to monitor andrecord important parameters from properly defined sampling points using proper equipment, such asinstruments tomeasure particles, humidity, oil, and temperature, as well as a system andprocedure to test for microbes. Oftenthe limits inISO 8573 [23] areapplied for humidity and oil content testing.

为了充分符合法规要求，有必要通过风险分析确认并使用适当的设备监控和记录确定的取样点样品的重要的参数，比如测量尘埃粒子数、水分、油分和温度的测试仪器，以及微生物测试系统和程序。通常采用 ISO 8573[23]中的水分和油分含量检测限度。

It is ultimately the responsibility of the userto determine theneeds for their product and situations.This should consider and document the requirements of the product and appropriate andapplicable regulatory requirements respective limits and tests as necessary.

用户最终负责确定产品和状况的需求。应考虑并记录产品的要求和适当的、适用的法规要求、各自的限度和必要的测试项目。

During the risk analysis, it may beappropriate toevaluate theoriginof thecompressed air, howitis produced, why compressedairis being used, critical characteristics/quality of thecompressed air andwhy they havebeendefined (as applicable), whichparameters willbe tested and why, wherefilters areinstalled inthe system, which parameters tocontrol, precisionof instruments, redundancyof measurements, recordingof data, etc.

在进行风险评估时，应适当评估压缩空气的来源、制备方式、使用压缩空气的原因、 压缩空气的关键特性/质量和定义的原因(如适用)、要测试哪些参数和为什么要测试、过滤器安装在系统中的什么位置、需要控制哪些参数、仪器的精度、测量值的误差、数据记录等。

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