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GOOD PRACTICE GUIDE: Critical Utilities GMP Compliance 2020版本

时间:2020年09月15日 ⁄ 分类: GMP 评论:0
1 Introduction介绍

ISPE Critical Utilities GMP Compliance.jpg



1.1         Overview概述

Regulatory compliance of Critical Utilities (CU) is important tomaintaining overall facility compliance,but due totheir hidden nature, CUcan become vulnerable tononcompliance.CU consistently receive close scrutiny by inspectors primarily because ofthe level ofassociated risk toproduct.Ifcontamination is present in theCU systems,the risk of productcontamination increases significantly since in many cases, one or more of thefollowing are true:
关键公用系统(CU)的合规性对于维持整体设施的合规性很重要,但是由于其隐藏的性质,CU可能容易受到不合规的影响。 CU一直受到检查员的严格审查,主要是因为与产品相关的风险水平。如果CU系统中存在污染,则由于许多情况下存在以下一种或多种情况,产品污染的风险会大大增加:

•   Waterfromthe CU is used as an excipient directly in product
公用工程的水系统直接用作产品中的赋形剂
•   Compressedgas is used in direct contact with product
压缩空气与产品直接接触
•   Waterand/or compressed gas are used in cleaningproduct-contact surfaces
水和/或压缩空气用于清洁或与产品表面接触
•  Clean steamis used in the sterilization ofproductor product-contact surfaces•清洁蒸汽用于产品或与产品表面接触的灭菌

Governmental inspectorates have been largely silent fordecades on their specificexpectations ofusers during an inspection of CU.Aninspection guide was written by the FDAforhigh purity water systems in 1993 (Guide to Inspections of High Purity Water Systems [1]).This guide, although valuable in earlier years, has led to manydiscussions regarding non-contemporary water system designs and validationapproaches, to name a few issues, and does not provide the depth ofscope toprepare organizations foraninspection in today’s pharmaceuticalindustry. Inaddition, there are no compliance or inspection guides issuedby any inspectorate forother CU suchas compressed gases or steam.
几十年来,政府检查机构在对公用系统进行检查时一直对用户的特定期望保持沉默。 FDA在1993年为高纯水系统编写了一份检查指南(《高纯水系统检查指南》 [1])。该指南尽管在前几年很有价值,但引起了许多关于非当代水系统设计和验证方法的讨论,仅列举了几个问题,也没有提供深度的范围,以应对在今天的制药行业检查组织。此外,任何检查机构都没有针对其他公用系统(例如压缩空气或蒸汽)发布合规性或检查指南。

ISPE sees the need in thepharmaceutical industry for guidance in the CU area (specifically water, steam, and compressed gases) forachieving and maintaining GMPcompliance, and fordemonstrating thatcompliance during a regulatory inspection.This Good Practice Guide (GPG) isintended to fill that void by providing knowledge based on the collective experiences ofthe authors gained from operational and regulatory inspections.Tomake this Guide internationally useful, the authors have included informationacquired from experience with the inspectorates of Brazil,Canada,China, theEuropean Union, India, Japan, the United Kingdom, and the United States.
ISPE认为制药行业需要在公用系统方面的指导(特别是水、蒸汽和压缩空气),以实现和维持GMP合规性,并在监管检查期间证明其合规性。本良好实践指南(GPG)旨在通过提供基于科学的方法来填补这一空白,作者从操作和监管检查中获得的经验总结。为了使本指南在国际上的通用性,作者纳入了从巴西、加拿大、中国、欧洲联盟、印度、日本、联合国和美国检查员的经验中获得的信息。

This GPG is not a regulatorydocument, and should not be interpreted to reflect inspectorate guidance.Additionally, it is not the goal of this GPG to provide tips on how to passan inspection; rather the intent is to provide guidance on achieving and maintainingcompliance,and toassistorganizations in preparing the documents, personnel, and meeting rooms to helpensure inspections are efficientlyconducted,making good use of the limited resources of regulators.
本GPG不是监管文件,不应被理解为反映检查机构的指导意见。此外,本GPG的目的不是提供如何通过检查的提示;而是旨在提供实现和维持合规性的指导,并帮助组织准备文件、人员和会议室,以帮助确保有效地进行检查,充分利用监管者有限的资源。


1.2       Purpose目的

The purpose of this GPG istwofold: to help pharmaceutical organizations achieve and maintain their CUsystems in a state of control and to help organizations efficientlydemonstrate these systems’GMPcomplianceto auditors and regulatory inspectors. By making inspections more efficient,our hope is that regulators’limited resources will be deployed morewidely, resulting in enhancedpatient safety.
本GPG的目的有两个:帮助制药企业实现并维持其公用工程系统处于受控状态,并帮助组织有效地向审计员和监管检查员证明这些系统的GMP合规性。提高通过检查效率,我们希望监管者有限的资源将被更广泛地部署,从而提高患者的安全性。

1.3       Scope范围

CU systems are utilities with thepotential to impact product quality or performance in a significant way.Theprimary CU discussed in this GPG is the water system, as it is highly complexand prone to noncompliance. (Appendix 1 contains examples of typical regulatorycitations specific to water systems.)Theother utilities covered are Pure Steam,compressedair, and compressed medical gases.
公用工程系统是一种潜在的可能对产品质量或性能产生重大影响的系统。本GPG讨论的主要公用工程是水系统,因为它非常复杂,容易出现不符合规定的情况。(附录1包含针对水系统的典型管理参考案例)。其他包括纯蒸汽、压缩空气和医用压缩空气。

This GPG provides an overview ofthe processes and documentation needed to implement and maintain a validatedutility system, for example, assessing the risks of upstream noncriticalparameters (Section 3.3), the value of proactively scheduling water systemsanitizations (Section 4.2), and determining a suitable statisticaldistribution model for monitoring water system data (Section 4.5). Furthermore,Chapter 5 discusses the challenges of legacy water systems.
该GPG提供了实施和维护经过验证的公用工程系统所需的活动及文档的概述,例如,评估上游非关键参数的风险(第3.3节),合理安排水系统消毒的价值(第4.2节)以及确定合适的用于监测水系统趋势的统计分布模型(第4.5节)。此外,第5章讨论了遗留水系统的挑战。

Topics such as the importance ofmaintaining up-to-date system drawings (Section 3.4) and sampling water in thesame manner as water use during manufacturing (Appendix 3) provide inspectionpreparation activities specific to CU systems.Also included in this GPGarebroadly applicable best practices, such as inspection hosting and an inspectionreadiness checklist (Appendix 2).Theseare presented here to make the GPG comprehensive, since they are not covered inother ISPE Guides. However,activities pertaining to CU inspections described in depth by other ISPEGuides (such as the ISPEBaseline®Guide: Volume 5 – Commissioning and Qualification[2], and the ISPE Good Practice Guide: Sampling for Pharmaceutical Water,Steam, and Process Gases [3]) are discussed at a higher level in this GPG.The objective of this redundancy is tomake this GPG as stand-alone as possible without sending the user searching tofind other GPGs with the critical content needed during preparation for aninspection.
诸如维护最新系统图纸的重要性(第3.4节)和以生产过程中相同的用水方式取样(附录3)等主题,提供了针对CU系统的应对检查的准备活动。该GPG还包括广泛适用的最佳实践,例如托管检查和检查准备清单(附录2)。此处介绍这些内容是为了使GPG更加全面,因为其他ISPE指南中并未涵盖这些内容。但是,其他ISPE指南(例如ISPEBaseline®指南:第5卷–调试和确认[2]以及ISPE良好实践指南:制药用水,蒸汽和工艺气体的采样)对与CU检查有关的活动进行了深入描述。[3])在此,GPG中进行了更高级别的讨论。冗余的目的是使该GPG尽可能独立,而无需采用搜索的方式来查找在应对检查时需要其他GPG的关键内容。

It is worth noting that compliancebegins with properly engineered systems; however other ISPE Guides fully coverthis aspect.Assuch, this GPGdoes not address the design ofCU systems,but serves as acompanion document to these ISPEGuides(for example, ISPEBaseline®Guide: Volume 4 – Water and Steam Systems [4]).
值得注意的是,合规性源于系统合理的设计。但是其他ISPE指南完全涵盖了这一方面。因此,本GPG并未解决CU系统的设计问题,而是作为这些ISPE指南(例如ISPEBaseline®指南:第4卷–水和蒸汽系统[4])的随同文档。

Although HVAC is considered by many tobe a CU, it is not included in this GPG.Such systemsareoften considered to be an integral part of clean room operations and subject toadditional quality attributes and operational issues, and so tend to beassociated with inspections of aseptic processing operations rather than CU. Inaddition, media supply systemsarenormally considered as an excipient (except compressed air fororal solid dosage forms manufacturing),but HVAC systems are not.Thus, the viewpoint when inspecting HVAC systems is differentcompared to the CU systemsmentioned in this Guide.
尽管许多人认为HVAC是CU,但此GPG中并未包含HVAC。此类系统通常被认为是洁净室运行的组成部分,并受其他质量属性和操作问题的影响,因此往往与无菌处理操作的检查相关联,而不是与CU相关。另外,介质供应系统通常被认为是一种赋形剂(用于口服固体剂型生产的压缩空气除外),而HVAC系统则不是。因此,与本指南中提到的CU系统相比,检查HVAC系统的关注点是不同的。

1.4       KeyTerms关键术语

This section introduces key termsas they are used in the context of this Guide. Refer toAppendix 7 for an expanded listing of definitions.
本节介绍在本指南的上下文中使用的关键术语。有关定义的扩展列表,请参阅附录7。

Critical Utilities(CU)关键公用工程(CU)
Utilities that have the identified potential to impactproduct quality or performance in a significant way.
确定具有潜在重大影响产品质量或性能的公用工程。

Deviation (ICH Q7 [5]) 偏差(ICH Q7 [5])

Departure from an approved instruction or establishedstandard.
偏离批准的说明或建立的标准。

Drinking Water饮用水

Drinking water is not covered by acompendial monograph but must comply with the quality attributes of the US EPA NPDWR1[6] or comparable regulations ofthe European Union (EU) [7], WorldHealth Organization (WHO) [8], or Japan [9]. It may be derived from a varietyof sources including a public water utility,a private water supply (e.g., a well), or a combination of more than one ofthese sources.
饮用水不在本次讨论涵盖的范围内,但必须符合美国EPANPDWR1 [6]的质量属性或欧盟(EU)[7],世界卫生组织(WHO)[8]或日本的类似法规 [9]。它可能有多种来源,包括公共供水公司,私人供水(例如井)或这些来源中的一种以上的组合。

MedicalGases (FDA[10, 11])医用气体(FDA [10,11])

“Compressedmedical gases (CMG or medical gases) include gaseous and liquid (cryogenic)forms stored in high-pressure cylinders that are administered as a gas. Types of compressed medical gases include,but are not limited to, oxygen, carbon dioxide, helium, nitrogen, nitrousoxide, medical air, and combinationsof these gases.”
“医用压缩空气(CMG或医用气体)包括存储在高压气瓶中的气态或液态(低温)形式,并以气体形式管理。医用压缩空气的类型包括但不限于氧气,二氧化碳,氦气,氮气,一氧化二氮,医用压缩空气以及这些气体的组合。”

“The term‘medical gas’means a drug that— (A)is manufactured or stored in a liquefied, nonliquefied, or cryogenic state; and(B) is administered as a gas.”
“医用气体”一词是指以下药物:(A)以液态,非液态或低温状态生产或储存;(B)以气体形式执行。

Potable Water饮用水

Waterthatis suitable fordrinking.
适合饮用的水。
Pure Steam纯蒸汽

Steam that is produced by a steam generator which, whencondensed, meets requirements for Waterfor Injection(WFI).
由蒸汽发生器产生的蒸汽,经冷凝后符合注射用水的要求(WFI)。



Purified Water(PW) 纯化水(PW)

Aclassificationof water according to compendial standards.
根据药典标准对水进行分类。

WaterforInjection(WFI)注射用水(WFI)

As defined in the US Pharmacopeia (USP) [12]
根据美国药典(USP)的定义

“Preparedfrom water complying with the quality attributes of “Drinking Water.”Purified by distillation or a purification process that is equivalent orsuperior to distillation in the removal of chemicals and microorganisms.”
“由符合“饮用水”质量属性的水制备。通过蒸馏或在除去化学物质和微生物方面有等同于或优于蒸馏的纯化工艺进行纯化。”

As defined in European Pharmacopoeia (Ph. Eur.) [13]根据欧洲药典(Ph.Eur.)的定义[13]

“Water for the preparation ofmedicines for parenteral administration when water is used as a vehicle (WFI inbulk) and for dissolving or diluting substances or preparations for parenteraladministration (sterilized Water forInjection).”
“以水作为媒介物(散装WFI)时用于制备肠胃外用药物的水,以及用于溶解或稀释肠胃外用药或制剂的水(注射用无菌水)。
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