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GOOD PRACTICE GUIDE: Critical Utilities GMP Compliance 2020版本(第二章)

时间:2020年09月15日 ⁄ 分类: GMP 评论:0
2   CriticalUtilitiesViewedfroma Regulatory  Perspective从监管角度看关键公用系统

ACritical Utility (CU) is defined by ISPE [14] as: “Utility that has theidentified potential to impact product quality or performance in a significantway.”This GPG focuses on water systems (specifically PW, WFI, and Pure Steam); however it isrelevant to also address some of the systems/utilities that feed water systems,specifically potable water and pretreated water,as these grades of water are important to overall compliance. Process gases aretouched on in this Guide as well, albeit to a lesser extent as they typicallydo not present the same degree of difficultyin maintaining compliance.ISPE [14]

CUs are special in that they canbe considered a raw material, and therefore are subject to GxPrequirements. However, with the continuous generation anddistribution of water and steam, and the constant availability of compressedgases including air, it is notfeasible to take the traditional approach of identifying these materials by adiscrete lot number, testing the lot,and releasing for production. Continuously produced utilities are typicallyused before all results are available.

Additionally, since these CU have a broad impact across multiple productsand processes at a manufacturing site, they are considered to entail asignificantly higher risk to product quality and subsequently, to patient safety.此外,由于这些CU对生产现场的多个产品或工艺具有广泛的影响,因此它们被认为对产品质量以及后期对患者安全的风险显著增加。

For these reasons, regulatoryscrutiny of CU systems often includes more elements of the quality system thataddress monitoring, control, maintenance, and calibration than is seen for anoncritical utility system.

2.1        Drinking/PotableWater饮用水

Drinking water, also referred to as potable water, must comply with appropriate regulatoryrequirements (such as defined by US EPA[6], WHO [8], etc.) and is the minimumquality of water to be used in pharmaceutical manufacturing (i.e., variouspharmacopeias, and GMPs found in the FDA21CFR Parts 210 [15] and 211 [16], andelsewhere2).
直饮水,也称为饮用水,必须符合适当的监管要求(如美国环保署[6]、世界卫生组织[8]等的规定),并且是制药生产中使用的最低水质的水(即,FDA 21 CFR第210[15]和211[16]部分中的各种药典和GMP,以及其他地方标准2)。

Since this is the onlyspecifically mentioned water in the GMPregulations,it is clearly important to regulatory authorities that a lower quality of waternot be used in pharmaceutical manufacturing and that the users have taken stepsto ensure that a lower, potentiallyunsafe quality of water is not inadvertently utilized.This puts the burden of proof on the users of this water toensure the quality meets minimum requirements and is suitable for its intendeduse.

2.1.1Minimum Water Purity Requirements for API and Finished Product Manufacturing原料药和制剂生产最低水纯度要求

According to ICH Q7 [5], theminimum water quality to be used forAPImanufacture and in the pharmaceutical facility in general, is water thatcomplies with WHO Guidelines for Drinking-WaterQuality3[8].
根据ICH Q7[5],原料药生产和制药设施中使用的最低水质是符合世卫组织饮用水质量指南3[8]的水。

Depending on the nature of theAPI processing and its final microbial andchemical attributes, water of a purity level higher than potable quality may beneeded.This is particularlyimportant in the latter stages of synthesis or purification, where removal ofimpurities introduced with the water may not be accomplished by these finalAPI processing steps [5].

Most pharmacopeias require theminimum water quality used forAPIand excipient manufacture to be potable or drinking water. USPGeneral NoticesSection 8.230.20 states4[12]:

“When used in the manufacture of officialsubstances, water shall meet the requirements for drinking wateras set forth in the U.S. Environmental ProtectionAgency National Primary Drinking Water Regulations (NPDWR) or in the drinking water regulationsof the European Union or of Japan, or in the World Health Organization’s Guidelines for Drinking Water Quality.Additionalspecifications may be required in monographs.”

This means that if apharmaceutical manufacturer is in a jurisdiction other than the US, a memberstate of the EU, or Japan, the drinking water quality used in manufacturingmust comply with the one of these jurisdictions’drinking water regulations or WHO drinking water guidelines [8].Compliance with a differentjurisdiction’s drinking water regulations, if not oneof those four, is irrelevant to USPas well as FDA.
The Ph. Eur.[13] defines the minimum quality of water for use inAPI manufacture as:
欧洲药典[13] 将原料药生产中使用的最低水质定义为:

“complieswith the regulations on water intended for human consumption laid down by thecompetent authority.”

Ph. Eur. does not explain who a competent authority is;however, it is understood to be the national entity in charge of the subject.It is the manufacturer’s responsibility to identify the applicable drinkingwater regulations of the country in which the product will be marketed andensure that the drinking water used in manufacturing meets those requirements.


2    Note that at the time of this writing, the EMAdocument “Guideline on the quality ofwater for pharmaceutical use” [17] is pending implementation.请注意,在撰写本文时,EMA文件“药品用水质量指南”[17]正在等待实施。
3   Although the attributes specified in WHO Guidelines for Drinking-Water Quality are considered goals and notnecessarily mandatory for human consumption, compliance with all attributes ismandatory when used inAPImanufacture as well as for general pharmaceutical uses [5].虽然世卫组织饮用水质量指南中规定的属性被视为目标,并不一定是人类饮用的强制性属性,但在用于原料药生产以及用于一般制药用途[5]时,必须遵守所有属性。

2.1.2     SourceWaterforPurification  Systems纯化系统水源

Another important use of drinkingwater is as source water for an on-site purification system that producescompendial grades of water, such asPW or WFI. When starting with one of the pharmacopeial drinking waters, allunsafe levels of impurities have theoretically been removed. So unless there isa possibility that these impurities could be reintroduced into thewater, there is no need to test fortheir absence in the further purified water.Instead, for finished water (i.e., PW or WFI), general non-specific tests forionic and organic impurities, that is, Conductivity and Total Organic Carbon (TOC),can be used to broadly define the finished water quality; however, several jurisdictions mandateadditional tests (seeAppendix 4). Itis noteworthy that the microbial content of the water undergoing purificationis also monitored, and, depending on the treatments selected, it may be thatthe levels of culturable bacteria in the non-compendial pretreatment waterincrease due to certain unit operations, and that this is acceptable.

2.1.3     SourceWaterCompliance  Standards水源符合标准

Similarly to the waterrequirements described forAPIs inUSPGeneral Notices, the USP[12] monographs for PW, WFI, and Pure Steam specify using one ofthe same four regional drinking water specification sets as the source water.

In Europe [13] and Japan [18], aglobally accepted source water quality for purification into PW is WHO DrinkingWater [8]. However some pharmacopeiarequire that PW is used to supply the final purification step that generatesWFI. (SeeAppendix 4 for therequirements of the major pharmacopeias.)

2.1.4     PublicWaterCompliance公共用水合规性

When a public drinking watersource is used, the responsibility for complying with the drinking waterregulations of the region usually falls to the drinking water provider. However,it remains the user’s responsibility to ensure that complianceof all drinking water attributes has been achieved for water used at thepharmaceutical facility; this responsibility includes year-round verificationas there may be seasonal variability in water supply quality.
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