近日，FDA发布了《行业指南：非无菌药品生产中的微生物质量考量》指南草案，用以帮助生产商确保其非无菌药品（NSD）的微生物质量。适用于固体非无菌制剂，以及半固体和液体非无菌制剂（例如，局部使用的膏剂和乳剂和擦剂，以及口服溶液和混悬液）。也有助于生产商符合制剂和API的CGMP要求。
文件提及非无菌药品微生物风险评估方法并给出详细的指导
基于风险的影响评估

产品特定要素

剂型：液体制剂一般比其它类别制剂更有可能生长微生物，半固体制剂则一般比固体更有可能生长微生物

水活度

非水性NSD的水活性应该低到足以抑制微生物生长

如果NSD有更高的水活性，则微生物生长的可能性更高，因此需要额外的生产控制

所拟用途

考虑患者人群—可能暴露于药品的患者群和最脆弱的用药患者疾病状态

考虑给药途径

考虑可能摄入NSD的身体部位（例如，皮肤、呼吸道、胃肠道或泌尿道），以及组织是否可能受损或患病，从而更易于被感染

考虑产品使用设置（例如，手术间，NICU）

包装

确保容器/密闭器提供足够的保护，不受可能导致微生物污染的可预见外来因素影响（例如，水或微生物侵入）

在选择NSD包装时考虑单剂量VS多剂量容器密闭器的适当性。对于特定剂型，单剂量容器/密闭器可提供更高安全性，防止外来微生物侵入制剂成品

产品组分和比例

考虑选择适当的防腐剂，确保防止货架期微生物繁殖的有效性

确保所有批次进厂原料适合于其既定用途，包括可接受微生物质量

微生物测试—产品特定考量

为组份、中间体和成品建立适当的微生物限度

确保取样计划能发现批内差异

确保方法有适当的灵敏度，能检出可能出现在组份和成品中的不同微生物，以及可能对患者或产品稳定性有风险的微生物

对用作组份的水（包括用作工艺助剂的水）执行适当的行动限和检测方法。USP建议固体口服制剂用纯化水不超出100CFU/ml。其它制剂可能适用更严格的微生物质量标准。

生产要素

o生产工艺步骤：某些工艺步骤可能比其它步骤在提高或降低生物负载方面有更大影响。

散装存贮步骤，尤其是那些水基生产工艺，可能会创造条件让微生物可以繁殖，尤其是在延长的中间体保存时间段内（即，不同单元操作之间的时间）。其它生产步骤可能会引入致病菌。因此，不建议延长水基中间体的保存时长（例如，包衣混悬液/溶液、添加防腐剂之前的液体混合物）。必须建立保存时限以保持产品质量。

设备清洁工艺不充分，例如，延长清洁之前的放置时长，以及设备清洁之后干燥不充分，亦有可能增加微生物污染。

环境控制不充分，例如生产区域向自然环境敞开、不受控，或当产品或产品接触表面暴露时环境控制不充分可能会增加微生物污染。

有些生产步骤（例如，涉及过滤、高温、极端pH值或有机溶剂的那些步骤）可能会使得中间体生物负载降低。

o组份：非无菌组份在生产工艺中可能是致病菌的来源。必须建立这些组份的适当质量标准，以及监测、控制、预防致病菌的策略。特别要注意纯化水和天然组份，因为其属性具备污染风险。

o水系统：用作组份的水（或用作工艺助剂）必须像其它组份一样，具备适当的质量，适合其既定工艺和配方用途。如果水是公司自制，用作一种组份，则纯化水系统必须设计优良，受到严格控制和维护。水纯化系统的维护和控制应包括主动更换部件以预防老化，进行常规监测以确保系统可持续产出满足其既定质量特性的水。监测程序应结合适当的行动限和警戒限，包括在关键水处理步骤之后，水处理设备和传送系统后及时取样，包括所有使用点。用作清洁剂的水，根据其使用条件和设备，应予以监测从而确保其符合既定用途的适当质量。

o环境：生产商必须确保设施、设备和环境条件足以确保生产空气质量受控，如防止引入可能对所生产的特殊NSD有害的微生物污染或生物负载。生产商应定期识别生产设施中出现的微生物，这些微生物有可能导致NSD污染，确保其控制措施有效降低这些微生物对其NSD的影响。

o设备：通过适当设计（例如，容器、管道）、维护、清洁和消毒来限制生物负载，维护设备的卫生条件至关重要。

o清洁和消毒剂：生产商必须使用合适的清洁/消毒剂，确保以清洁和卫生的方式对建筑物和设施进行维护，其中应包括确保它们不会成为致病菌港湾。适当的设备清洁对于防止致病菌污染组份、容器、密闭器、包材和药品来说至关重要。

o人员：生产商应采取措施建立和维护适当的粒子，将人员引入致病菌到生产工艺的潜在影响降至最低。他们必须确保人员遵守优良卫生规范。

o中控检测：生产商需要建立程序确保中间体质量与制剂成品的既定标准相一致，其中包括评估生产过程中是否满足微生物属性要求。

o微生物放行测试（适当时）

文件提出根据基于风险的影响性评估减少固体剂型微生物放行检测的可能性：有水活性但不支持营养微生物生长的固体制剂是降低产品放行和稳定性测试中微生物项目的优秀候选对象。ICHQ6A“新原料药和新制剂检验方法和可接受标准：化学物质”包括有在何条件下可考虑“定期执行或跳检”微生物计数检测的条件。ICHQ6A中的建议是基于产品特性的，同时提供了确定适当的微生物检测计划的逻辑方法。要支持删除或减少固体制剂的微生物放行检测，生产商应按本指南节IV.B所建议的执行基于风险的影响性评估。经过适当的论证，包括生产商在NSD生产中的历史经验，例如微生物放行和稳定性数据的数量、所有负面发现和工艺、设施和组份生物负载控制的程度，可删除或减少低风险固体制剂稳定性计划中的微生物检测。注意有些固体制剂含有支持生长的组份，如蛋白类组份，则应进行风险评估以确定其是否可以降低或删除稳定性方案中的微生物测试。

全文翻译如下：
TABLEOFCONTENTS
目录
I.INTRODUCTION
前言
II.BACKGROUND
背景
III.STATUTORYANDREGULATORYFRAMEWORK
法律法规框架
IV.MICROORGANISMSANDLIFECYCLEPRODUCTQUALITY
微生物和生命周期产品质量
A.General─MicrobiologicalConcernsRegardingNSDs
概述--NSD的微生物关切
B.Risk-BasedImpactAssessment
基于风险的影响评估
1.ProductSpecificElements
产品特定要素
2.ManufacturingElements
生产要素
C.MicrobiologicalConcernsforSpecificDosageFormsandSpecialCases
特定剂型的微生物关切和特殊案例
1.SolidDosageForms
固体剂型
2.Non-SolidDosageForms
非固体剂型
3.MicrobiologicalConsideration–SpecialCases
微生物考量—特殊案例
D.UpdatingApprovedDrugProductSpecifications
更新已批准药品质量标准
APPENDIX:CASESTUDYEXAMPLESOFMICROBIOLOGICALCONTAMINATIONOFNSDPRODUCTS;IMPACTONPRODUCTQUALITYANDMANUFACTURINGPROCESS
附录：案例研究：NSD产品的微生物污染示例；对产品质量和生产工艺的影响
MicrobiologicalQualityConsiderationsinNon-sterileDrugManufacturingGuidanceforIndustry
行业指南：非无菌药品生产中的微生物质量考量

ⅠINTRODUCTION
前言
Thisguidance is intended to assist manufacturers in assuring the control ofmicrobiological2 qualityof their non-sterile drugs (NSDs3). Therecommendations herein apply to solid non-sterile dosage forms, as well assemi-solid, and liquid non-sterile dosage forms (e.g., topically appliedcreams, lotions and swabs, and oral solutions and suspensions). NSDs can beprescription or nonprescription drugs, including those marketed under approvednew drug applications (NDAs) or abbreviated new drug applications (ANDAs), andnonprescription drugs without approved new drug applications which are governedby the provisions of section 505G of the FD&C Act (often referred to asover-the-counter (OTC) monograph drugs4). Theserecommendations, if followed, will also assist manufacturers in complying withthe current good manufacturing practice (CGMP) requirements for finishedpharmaceuticals and active pharmaceutical ingredients (APIs5).
本指南意在协助生产商确保其非无菌药品（NSD）的微生物质量。此处的建议适用于固体非无菌制剂，以及半固体和液体非无菌制剂（例如，局部使用的膏剂和乳剂和擦剂，以及口服溶液和混悬液）。NSD可以是处方药亦可以是非处方药，它包括以 NDA或 ANDA批准上市的药品，以及没有 NDA批准受 FDCA第 505G条规定管理的非处方药（通常称为 OTC各论药）。这些建议（如得到遵守）亦有助于生产商符合制剂和 API的 CGMP要求。

This guidance discusses product development considerations, risk assessments, andcertain CGMPs that are particularly relevant to microbiological control in amanufacturing operation for a NSD. It also provides recommendations to helpmanufacturers assess the risk of contamination of their NSDs with objectionablemicroorganisms in order to establish appropriate specifications and manufacturingcontrols that prevent such contaminations and assure the safety, quality,identity, purity, and efficacy of the NSD6.
本指南讨论的是产品开发考量、风险评估和特定的 CGMP，特别是与 NSD生产操作中的微生物控制有关的部分。它还提供了建议帮助生产商评估其 NSD受致病菌的污染风险，从而建立适当的质量标准和生产控制，防止此类污染，确保 NSD的安全性、质量、鉴别、纯度和有效性。

For application products (i.e., NDAs, ANDAs) this guidance also explains howapplicants should submit NSD controls in original submissions and reportchanges in microbiological specifications and testing programs to the FDA, inaccordance with current Agency guidances regarding changes to an approvedapplication.
对于申报产品（即 NDA、ANDA），本指南亦解释了申报人应在原始申报中提交 NSD控制措施，并向 FDA报告微生物质量标准和检测方法变更，满足 FDA关于已批准申报的现行变更指南。

Toillustrate the importance of a microbiological risk assessment and controlstrategy, this guidance discusses incidents of Burkholderia cepacia complex (BCC) and other microorganismcontamination in non-sterile dosage forms that resulted in adverse events andrecalls of the drug products. The guidance describes proper prevention of andtesting for BCC in aqueous dosage forms of NSDs.
为了说明微生物风险评估和控制策略的重要性，本指南讨论了洋葱伯克霍尔德菌复合体（BCC）事件和其它非无菌制剂的微生物污染导致不良事件和产品召回的情况。本指南阐述了 NSD水性制剂中 BCC的恰当预防和检测。

The guidancedescribes the Agency’s current thinking on microbiological contamination oftopical antiseptic drugs intended for use by health care professionals in ahospital setting or other health care situations outside the hospital7, whichare used prior to medical procedures to reduce the number of bacteria on theskin and that in some cases are not manufactured as sterile products.
本指南描述了 FDA目前对供专业医疗人员在医院环境或医院外其他卫生保健情况下使用的外用抗菌药物的微生物污染的看法。这些药品是在医疗程序之前使用以减少皮肤上细菌数量的。它们在某些情况下不是作为无菌产品生产的。

Thecontents of this document do not have the force and effect of law and are notmeant to bind the public in any way, unless specifically incorporated into acontract. This document is intended only to provide clarity to the publicregarding existing requirements under the law.
本指南的内容并没有强制法律效力，不会以任何形式对公众形成约束力，签订在合同的条款除外。本文仅意在向公众澄清现有法律下的要求。

FDA’sguidance documents should be viewed only as recommendations, unless specificregulatory or statutory requirements are cited. The use of the word should in Agency guidances means thatsomething is suggested or recommended, but not required.
FDA的指南文件应仅看作是建议，其中引用的具体法律法规要求除外。SHOULD一词在 FDA指南中表示建议某事，但并非强制。

1 This guidance has been preparedby the Office of Pharmaceutical Quality in the Center for Drug Evaluation andResearch (CDER) a t the Food and Drug Administration.
本指南由 FDA的 CDER的 OPQ起草。
2 For thepurposes of this guidance, the terms “microbiological” and “microbial” are usedinterchangeably.
本指南中，术语“microbiological”和“microbial”均为微生物，意思相同。
3 For the purposes of thisguidance, non-sterile drugs (NSDs) refers to non-sterile finished dosage forms.
本指南中，非无菌药品（NSD）指非无菌制剂。
4 The term ‘OTC monograph drug’means a nonprescription drug without an approved new drug application which isgoverned by the provisions of section 505G. See FD&C Act section 744L(5).
术语“OTC各论药”指没有已批准 NDA的非处方药，它根据 FDCA第 505G章 744L(5)节进行管理。
5 See 21CFR parts 210 and 211, CGMP for Finished Pharmaceuticals, a nd FD&C Actsection 501(a)(2)(B) for APIs.
参见 21 CFR第 210和 211节，制剂 CGMP，和 FDCA法案节 501(a)(2)(B)的 API内容。
6 The term “objectionablemicroorganisms” as used here refers to organisms that are objectionable due totheir detrimental effect on products or potential ha rmto patients or objectionable due to the total number of organisms. See43 FR45053 (Sep. 29, 1978).
术语“致病菌”在此指由于其对产品或患者有不良影响因而有害的菌，或者是由于其总微生物数量而有害的菌。参见 43 FR 45053 (19780929)。
7 Suchproducts include health care personnel hand washes, health care personnel handrubs, surgical hand scrubs, surgicalhand rubs, and patient antiseptic skin preparations (i.e., patient preoperativeand pre-injection skin preparations).
此类产品包括卫生健康护理人员洗手液、卫生护理人员消毒液、外科手术用手消毒液、外科手术用手洗手液，以及患者备皮用消毒液（即患者术前和注射前皮肤准备）。


II. BACKGROUND背景

Thisguidance was developed, in part, as a result of the Agency’s review of FDAAdverse Event Reports (FAERs8) andrecalls involving contamination of non-sterile dosage forms. A review of FAERsthat occurred between 2014 and 2017 revealed 197 FAERs associated withintrinsic9microbiological or fungal contamination, and of those, 32 reported seriousadverse events.
制定本指南有部分原因是因为 FDA对 FDA不良事件报告（FAER）和涉及非无菌剂型污染的召回的审查。对 2014年至 2017年间发生的 FAER的审查显示，有 197起 FAER与内在微生物或真菌污染有关，其中 32起报告了严重的不良事件。

Becausespontaneous reports10 in FAERsare voluntary by definition, the Agency anticipates a degree of underreporting.The actual number of incidents associated with microbiological contamination islikely significantly higher than the number of events reported11.
由于 FAER中的自发报告根据定义是自愿的，因此 FDA预计会有一定程度的漏报。与微生物污染相关的实际事件数量可能明显高于已报告的事件数量 。

Thereview of voluntary recall actions during the same time period revealed over 50events associated with objectionable microbiologically contaminated NSDs12. Therecalls showed that a wide range of objectionable microorganisms were found inboth aqueous and non-aqueous NSDs13.
对同一时期自愿召回行动的审查显示，超过 50起事件与有害微生物污染 NSD相关。召回表明，在水性和非水性 NSD中都发现了广泛的有害微生物 。

TheAgency is also aware of specific concerns regarding BCC and its associationwith contamination of aqueous-based NSDs that resulted in a number of seriousadverse events, i.e., infections and deaths14. In May2017, FDA released a statement15 alertingdrug manufacturers of the recent product recalls associated with the presenceof BCC in NSDs. The statement also reminded drug manufacturers of theirresponsibilities to prevent objectionable microorganisms from adverselyimpacting their NSD manufacturing processes, as well as the productsthemselves.
FDA还意识到 BCC及其与导致一系列严重不良事件（即感染和死亡）的水基 NSD污染的关联引发的担忧。2017年 5月，FDA发布了一份声明，提醒药品生产商注意最近的产品召回与 NSD中存在 BCC相关。该声明还提醒药品生产商他们有责任防止有害微生物对其 NSD生产过程以及产品本身产生不利影响。

Analysisof these events, combined with FDA’s experience conducting microbiologyassessments of non-sterile drugs for NDA and ANDA products and complianceactions, helped to inform the recommendations in this guidance16.
对这些事件的分析，结合 FDA对 NDA和 ANDA产品的非无菌药物进行微生物学评估和合规行动的经验，为本指南中的建议提供了信息。

8FDA Adverse Event ReportingSystem (FAERS) La test Quarterly Da ta Files -https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEff ects/ucm082 193.htm.
FDA不良事件报告系统（FAERS）最新季度数据文件链接。
9Intrinsic means the microbial or fungalcontamination origina ted with the manufacture, packaging, shipping, or storage of thedrug, not from extrinsic sources, (e.g., consumer or health care provider useerrors). “内在”是指微生物或真菌污染源于药物的生产、包装、运输或储存，而不是来自外在来源（例如，消费者或医疗保健提供者的使用错误）。
10 For definition of spontaneous report see FDA’s The Public’sSta ke In Adverse Event Reporting -https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveilla nce/AdverseDrugEff ects/ucm179586.htm.关于“自发报告”的定义参见 FDA公众对不良事件报告的关注。
11 Accordingto FDA’s Question a nd Answers on FAERs, “FDA does not receive reports forevery a dverse event ormedication error that occurs with a product…There are a lso duplicatereports where the same report was submitted by the consumer a nd by the sponsor[drug manufacturer].”https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/.根据 FDA的 FAER问答“FDA不会收到一个产品的不良事件或错误用药情况报告……如果患者和申报人【药品生产商】提交了相同的报告，则会有两份报告”
12 Seefootnote 6.
参见脚注 6.
13 FDA Recalls, Ma rket Withdrawals, & Sa fety Alerts -https:/ /www.f da.gov/Safety /Recalls/default .htm.FDA的召回、上市撤回和安全警示链接。
14Glowicz J et a l, 2018, A multistate investigationof health care–associated Burkholderia cepacia complex infectionsrela ted to liquid docusate sodium contamination, Ja nuary-October 2016, Am JInfection Control, Vol 46:649-665,https://www.ajic jo urnal.org/a rtic le/S0196-6553(17)31 287-7/fullt ext.Glowicz J et a l, 2018,与液体多库酯钠污染相关的医疗保健相关洋葱伯克霍尔德菌复合感染的多州调查，2016年 1月至 10月，Am J感染控制，第 46卷：649-665
14 FDA advises drug manufacturers that Burkholderia cepacia complex poses acontamination risk in non-sterile, wa ter-based drug products, May 2017,https://www.fda.go v/Drugs/DrugSafety/ucm559508 .htm.FDA告知药品生产商关于洋葱伯克霍尔德菌复合物对非无菌水基药品造成污染风险，2017年 5月


III. STATUTORYAND REGULATORY FRAMEWORK
法律法规框架

Undersection 501(a)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act17), a drugwill be deemed adulterated if:
根据《联邦食品、药品和化妆品法案》（FD&C法案）第 501(a)(2)条，如果出现以下情况，药物将被视为掺假：

“themethods used in, or the facilities or controls used for, its manufacture,processing, packing, or holding do not conform to or are not operated oradministered in conformity with current good manufacturing practice to assurethat such drug meets the requirements of this Act as to safety and has theidentity and strength, and meets the quality and purity characteristics, whichit purports or is represented to possess,” or “if it has been prepared, packed,or held under insanitary conditions whereby it may have been contaminated withfilth, or whereby it may have been rendered injurious to health.”
“用于其生产、加工、包装或保存的方法，或用于其生产、加工、包装或保存的设施或控制不符合或未按照 CGMP操作或管理，以确保此类药物符合本法的安全要求，具有鉴别和含量，并符合其声称或理当具备的质量和纯度特征”，或“如果它在不卫生的条件下制备、包装或保存，可能已被脏物污染，或有可能损害健康。”

Forfinished pharmaceuticals, the CGMP regulations described in 21 CFR parts 210and 211 address prevention of objectionable microorganisms in non-sterile drugproducts, bioburden specifications, and in-process testing. Specifically:
对于成品药物，21 CFR第 210和 211部分中描述的 CGMP法规涉及预防非无菌药品、生物负载标准和中控测试中的有害微生物。具体来说：

21 CFR211.113(a), Control of microbiological contamination, states that appropriatewritten procedures, designed to prevent objectionable microorganisms in drugproducts not required to be sterile, shall be established and followed.
21 CFR 211.113(a)，微生物污染的控制，指出应建立并遵循适当的书面程序，旨在防止不需要无菌的药品中出现有害微生物。

21 CFR211.110(a)(6), (b), (c), Sampling and testing of in-process materials and drugproduct, requires (where appropriate) in-process bioburden testing and validin-process specifications to assure the drug product meets its microbiologicalspecifications. In-process testing shall occur during the product process,e.g., at commencement or completion of significant phases or after storage forlong periods.
21 CFR 211.110(a)(6)、(b)、(c)，中间体和成品的取样和测试，要求（在适当的情况下）中间体生物负载测试和有效的中控标准以确保成品符合其微生物标准。中控测试应在产品工艺过程中进行，例如，在重要阶段的开始或完成时，或在长期储存后。

16CDER began chemistry, manufacturing a nd controls (CMC) microbiology reviews of NSD inthe mid-1990s with a focus on a queous based NSDs. CDER在 1990年代中期开始 CMC微生物审评，侧重于水基 NSD。
17 See 21 U.S.C. 351(a)(2).

21 CFR211.84(d)(4) and (6), When appropriate, components shall be microscopicallyexamined. Each lot of a component, drug product container, or closure withpotential for microbiological contamination that is objectionable in view ofits intended use shall be subjected to microbiological tests before use.
21 CFR 211.84(d)(4)和 (6)，适当时，应对组件进行显微镜检查。考虑到其预期用途，具有潜在微生物污染的每个批次的组件、药品容器或密封件都应在使用前进行微生物测试。

To assurethe microbiological quality of NSDs subject to premarket approval, applicantsmust propose appropriate drug substance and product specifications (i.e.,tests, analytical procedures, and acceptance criteria) in their submissions inaccordance with 21 CFR 314.50(d)(1) [NDAs] and 21 CFR 314.94(a)(9) [ANDAs]18.
为了确保需要上市前批准的 NSD的微生物质量，申请人必须根据 21CFR 314.50(d)(1)【NDA】和 21CFR 314.94(a)(9)【ANDA】提出适当的原料药和制剂质量标准（即检测项目、分析方法和可接受标准）。

Ingeneral, a drug with a name recognized in an official compendium must complywith the United States Pharmacopeia (USP) compendial standards for identity,strength, quality, and purity, or be deemed adulterated, misbranded, or both19. If USPhas established a monograph for a drug, the USP monograph will identify theofficial tests, procedures, acceptance criteria, and other requirements. WhenUSP monographs include a test or specification referencing “Applicable GeneralChapters20,”20 theapplicant should ensure that their monograph product complies with the testingrequirement, or it could be deemed adulterated. Some of the USP GeneralChapters that are more commonly referenced in drug monographs, as they apply tocontrolling microbiological activity in NSDs, include, for example:
一般而言，具有官方药典认可名称的药物必须符合美国药典 (USP)药典标准关于鉴别、含量、质量和纯度，否则会被视为掺假、贴错标签，或两者兼而有之。如果 USP为药物制定了各论，USP各论将确定官方检测项目、检验方法、可接受标准和其他要求。当 USP各论有引用“适用通则”的测试或标准时，申请人应确保其各论产品符合测试要求，否则可能被视为掺假。有些 USP通则在药物各论中被引用的更为频繁，因为它们适用于控制 NSD中的微生物活动，例如：

USP <60> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS TESTS FOR BURKHOLDERIA CEPACIA COMPLEX
USP <60>非无菌产品的微生物学检查：伯克霍尔德氏菌复合物
USP <61> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS:MicrobialEnumeration Tests
USP <61>非无菌产品的微生物检验：微生物计数检测
USP <62> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: Testsfor Specified Microorganisms
USP <62>非无菌产品微生物检验：特定微生物检测

Inaddition to USP monograph requirements, further microbiological tests are oftenperformed as part of batch release requirements as described in 21 CFR part 21121.
除了 USP各论要求，通常如 21 CFR第 211部分所述，将进一步的微生物测试作为批次放行要求的一部分执行。

Objectionablemicroorganisms and bioburden in non-sterile APIs should be controlled. FDAguidance for industry Q7 GoodManufacturing Practice Guidance for Active Pharmaceutical Ingredients (September2016) states:
应控制非无菌原料药中的有害微生物和生物负载。 FDA行业指南 Q7 API的 GMP指南（2016年 9月）指出：

“Appropriatespecifications should be established for APIs in accordance with acceptedstandards and consistent with the manufacturing process. The specificationsshould include control of impurities (e.g., organic impurities, inorganicimpurities, and residual solvents). If the API has a specification formicrobiological purity, appropriate action limits for total microbial countsand objectionable microorganisms should be established and met.”
“应根据公认的标准为 API制定适当的标准并与生产过程一致。标准应包括对杂质（例如有机杂质、无机杂质和残留溶剂）的控制。如果 API有微生物纯度标准，则应建立并满足总微生物计数和有害微生物的适当行动限制。”

18For thedefinition of specification, see 21 CFR 314.3(b) a nd also ICH guidance forindustry Q6A Specifications: TestProcedures and Acceptance Criteria for New Drug Substances and New DrugProducts: Chemical Substances (December 2000).
关于【质量标准 specification】的定义，参见 21 CFR 314.3(b)和 ICH Q6A“质量标准：新原料药和新制剂的检验方法和可接受标准：化学物质（200012）”。
19FD&C Act 501(b) a nd502(e)(3)(B) a nd (g); a lso 21 CFR 299.5.
20See USP,Conformance to Standards, 3.10, “Applicable general chapters” means generalchapters numbered below 1000 or a bove 2000 that a re madeapplicable to a n a rticle through reference in General Notices, a monograph, or another applicable general chapter numbered below 1000.”
参见 USP<3.10>“标准符合性”，“适用通则”指1000号以内的通则，或大于 2000通过在范例、各论或另一个编号小于 1000的适用通则中的引用让其适用于某物的通则。


IV. MICROORGANISMS AND LIFECYCLEPRODUCT QUALITY
微生物和生命周期产品质量

A. General ─Microbiological Concerns Regarding NSDs
关于 NSD的微生物担忧—概况

Prevention,control, and monitoring of the microbiological population in non-sterile drugcomponents and drug products are necessary to minimize the risk of:
为了将以下风险降至最低，有必要对非无菌药品组份和制剂中微生物群进行预防、控制和监测：

patient exposure to significantnumbers or harmful species of microorganisms, especially in immunocompromisedpatients22
患者，尤其是免疫缺陷患者暴露于大量或有害微生物中
patient exposure to harmfulmicrobial metabolites and/or toxins
患者暴露于有害微生物代谢物和/或毒素
drug spoilage or degradation
药品变质或降解

Thestatutory and regulatory framework described in section III above, coupled withsound scientific rationale, provides the foundation for establishing a programto monitor and control the manufacturing process to prevent objectionablemicroorganisms from affecting the quality of a NSD.
在上面第三章中所述的法律法规框架，配以科学合理的原理，提供了建立程序对生产工艺进行监测和控制，从而防止致病菌影响 NSD质量的基础。

To ensureproduct quality and patient safety, it is essential to limit the level and typeof microorganisms in NSDs during manufacturing and over product shelf life.While a NSD is not required to be sterile, there is a threshold ofmicrobiological content above which safety and efficacy of a given NSD may beadversely impacted.
为确保产品质量和患者安全，有必要限制生产及产品货架期间 NSD中微生物的水平和类型。虽然不要求 NSD是无菌的，但存在一个微生物含量的阈值，高于该阈值可能会对指定 NSD的安全性和有效性产生不利影响。

The CGMPregulations require that components are sampled, tested, or examined prior torelease by the manufacturer’s quality control unit23.Naturally-derived components (e.g., plant or animal derived ingredients, andnaturally occurring ingredients such as water) may contribute significantly tothe total bioburden of the drug product and must be subjected tomicrobiological testing in accordance with established procedures24. Forinstance, water is a common component used in NSD manufacturing. However, watersystem control deviations can be difficult to detect due to limitations ofsampling25. Thesedeviations may lead to the formation of biofilms and have been shown to have aprofound impact on microbial quality of an aqueous-based drug.
CGMP法规要求将放行组份之前由生产商的质量控制部门对其取样检测或检查。天然组份（例如植物或动物来源成分，和天然产生的成分如水）可能会对药品的总生物负载贡献巨大，必须根据既定程序进行微生物检测。例如，水是 NSD生产中常用成分，但是由于取样局限性，可能难以发现水系统控制偏差，而这些偏差有可能导致形成生物膜，已证明这些偏差对水基药品的微生物质量有深远影响。

Consequently,proper water system design and control, appropriate microbial action limits26, androutine water quality testing is critical to assuring that microbial levels arebelow established limits, and that the water is free of objectionablemicroorganisms27.Therefore, it is important for manufacturers to have a robust design for watersystems, including controls designed to prevent objectionable microorganismsand procedures for monitoring, cleaning, and maintenance28.
因此，适当的水系统设计和控制、恰当的微生物行动限，以及日常水质量检测对于确保微生物水平低于既定限度，并且水中没有致病微生物是至关重要的。所以生产商具备稳健的水系统设计，包括设计用于防止致病微生物的控制措施和监测、清洁及维护程序是非常重要的。

21CGMPs are not limited to drugs marketed under a pproved a pplications. See FD&CAct section 501(a) a nd 21 CFR pa rts 210 a nd 211.CGMP并不仅限于通过已批准申报上市的药品。参见 FDCA第 501(a)节和 21CFR节 210和211。
22For the purposes of thisguidance, we define immunocompromised patients as those who have a weakened immune system, which may be due to trauma, surgery, illness, or chronic disease. It a lso includes vulnerable populations, such asinfants a nd the elderly.
在本指南中，我们定义“免疫功能低下患者”为免疫系统减弱的患者，这可能是由于外伤、手术、疾病或慢性病所致。它还包括弱势群体，例如婴儿和老人。患者暴露于有害的微生物代谢物和/或毒素中
23See 21 CFR 211.84.
24See 21CFR 211.84(d) a nd 211.113(a).
25Aneffective a nd ongoing monitoring program is important in determining if wa terused to support batch ma nufacture continues to meet predetermined qualitycharacteristics. For products that include wa ter in ma nufacturing operations, more sensitive wa tersampling stra tegies a re generally a ppropriate, a nd should include use ofla rger sa mple sizes (e.g., 100 mL) with membrane filtration.
在确定所用水是否支持批生产持续满足预定质量属性时，执行有效的持续监测程序是很重要的。对于生产操作中有水的药品，一般适用更为灵敏的取样策略，应该包括使用更大样品数量（例如 100ml）采用膜过滤法检测。
26Microbial action limits shouldbe established based on the risk-based impact assessment, a s described insection IV.B.
应按节 IV.B所述根据基于风险的影响性评估建立“微生物行动限”。
27See 21 CFR 211.84(d).
28 See 21CFR 211.63, 211.67, 211.100.

Aqueousnon-sterile products, which may support microbial growth during the productshelf life due to their water activity (aw)29, shouldbe designed to prevent microbial proliferation of intrinsic microorganisms orthose inadvertently introduced during use.
在产品货架期内由于具备水活性（aw）所以可支持微生物生长的水基非无菌药品的设计应该能够防止内含微生物或在使用中被无意引入的微生物的繁殖。

While thepotential for microbial growth during the manufacturing process or over storagethrough the shelf life can be partially mitigated by a properly designedpreservative system or formulation, antimicrobial preservatives can provide afalse sense of product safety regarding the presence or growth ofmicroorganisms. Two purposes of a preservative are to counteract possibleincidental microbial contamination during multiple uses of a product by aconsumer and maintain microbial control over the shelf life of the product.Preservatives are not a substitute for a comprehensive approach to preventingobjectionable microorganisms from contaminating NSDs, and should not bepresumed to reduce in-process bioburden during manufacturing. Certainmicroorganisms have been found to degrade commonly used preservatives, despitethe drug having previously met antimicrobial effectiveness testing acceptancecriteria. Consequently, non-sterile drug manufacturers should be aware of thepotential for the development of preservative resistance. This potentialdecrease in preservative effectiveness should be investigated (root cause analysisand corrective action to eliminate the source of contamination) in cases ofobjectionable microbes or an upward trend in total microbial enumerationcounts. This issue is discussed as a special case study regarding Burkholderia cepacia complex and AqueousDrug Products in section IV.C.3.a Microbial Considerations – Special Cases ofthis guidance.
虽然生产过程中或整个生命周期存贮期间的微生物生长可能性可能会因为设计有适当的防腐系统或配方而有部分降低，但抗菌防腐剂可能会在微生物存在或生长方面导致产品安全假象。防腐剂的 2个目的是对抗患者多次使用药品期间可能的意外微生物污染，以及在产品生命周期中保持对微生物的控制。防腐剂并不能全面取代防止致病菌污染 NSD的所有方法，不应认为其可降低生产期间中控生物负载。已经发现有些微生物可使得常用防腐剂降解，即使这些药品之前是满足抗菌有效性测试可接受标准的。因此非无菌药品生产商应该明白防腐剂耐受性发展的可能性。如果检出致病菌或总微生物计数有上升趋势，则应该调查防腐剂有效性降低的这种可能性（根本原因分析和纠正措施，以消除污染来源）。这个问题作为关于洋葱伯克霍尔德菌复合物和水性药物产品的特殊案例研究在第 IV.C.3.a节微生物注意事项 -本指南的特殊案例中进行了讨论。

In contrast, many non-sterile liquid products thatare not aqueous-based, such as those containing high percentages of alcohol orother non-aqueous solvents, can potentially pose lower risk of microbialproliferation during processing, holding of in-process materials, and storageover shelf life30. Also,non-sterile solid drug products, such as tablets and capsules, have a low wateractivity that usually does not allow for microbial growth during product shelflife. However, it should be noted that although microorganisms that are presentin a non-sterile drug product with low water activity will not proliferate,they can persist in non-aqueous liquids and dry products throughout the shelflife of the product. The CGMP regulations require that written procedures beestablished to prevent introduction of objectionable microbiologicalcontamination in the manufacture of drug products not required to be sterile,and that a program be designed to assess the stability characteristics of drugproducts, including NSD31.Consequently, it is important to provide for appropriate microbiologicalcontrol of the components (e.g., excipients and APIs) of non-sterile drugproducts, even if the components possess a low water activity.
相反，许多非无菌液体药品并不是水基的，例如那些含有高比例乙醇或其它非水性溶剂，在中间物料加工、保存和货架期存贮期间的微生物滋生风险可能较低。非无菌固体制剂，如片剂和胶囊的水活性亦较低，通常在产品货架期内不允许微生物生长。但是，要注意虽然出现在低水活性非无菌药品中的微生物不会繁殖，但它们可能在非水性液体和干燥药品中在其整个货架期内都顽固存在。CGMP法规要求制订书面程序防止引入致病菌污染到不要求无菌的药品生产中，并设计有程序评估药品（包括 NSD）的稳定性。因此，即使该组份水活性很低，为非无菌药品组份（例如，辅料和 API）提供适当的微生物控制非常重要。

Non-sterilesolid drug products also can be at risk for microbial proliferation throughcontamination during manufacturing. For example, extended in-process hold timesof aqueous solutions or slurries at various points in the manufacturing processof a solid drug product could allow for microbial proliferation exceeding theappropriate levels for such dosage forms.
非无菌固体制剂还可能在生产期间通过污染产生微生物滋长风险。例如，延长固体制剂的水性溶液或浆料中间体在不同生产工艺点放置时长，可能会使得微生物滋生超出此类剂型的适当水平。

Consequently,procedures that establish time limits are essential to assure product quality,including control of microbiological quality, at each process step used in themanufacture of both liquid and solid NSDs to prevent objectionablemicroorganisms32.
因此，制定时限的程序对于确保液体和固体 NSD生产过程中使用的每个工艺步骤的产品质量（包括微生物质量控制）从而防止存在致病菌至关重要。

While notexhaustive, the USP provides a widely accepted set of microbiological testmethods for non-sterile drug products33. USPalso recommends the establishment of acceptance criteria regarding totalnumbers of microorganisms, in addition to selected specified microorganisms inNSDs34.However, the USP does not provide a comprehensive list of objectionablemicroorganisms; therefore, firms should identify any additional controls andacceptance criteria that are necessary. The need for additional controls ofobjectionable microorganisms should be determined for each product. Forexample, the presence of BCC in aqueous non-sterile drug products may lead toboth drug product degradation and patient infection. The intended patientpopulation, drug product indication, and route of administration should beconsidered when establishing a microbial specification and determining if aspecific microorganism is objectionable in the drug product.
虽然并不完全，但 USP提供了被广泛接受的一套非无菌药品微生物检测方法。USP亦建议除了所选择的 NSD中指定微生物外，制订微生物总计数可接受标准。但是，USP并未提供完整的致病菌清单，因此公司应识别所有额外控制措施和必要的可接受标准。应为每种产品确定是否需要对致病菌制订更多控制措施。例如，BCC存在于水性非无菌药品中有可能导致药品降解和患者感染。在建立微生物质量标准，确定一个特定的微生物在一个药品中是否致病时，应考虑目标患者人群、药品适应症以及给药途径。

29It is important to note thatwater activity is different from water content. USP <1112> defines wateractivity as the ratio of the vapor pressure of water in the drug, when in acompletely undisturbed balance with the surrounding air media , to the vaporpressure of distilled water under identical conditions. See USP <1112>APPLICATION OF WATER ACTIVITY INDETERMINATION TO NONSTERILE PHARMACEUTICAL PRODUCTS. In contrast, water contentis the amount of moisture in the drug.
需要注意的是，水分活度与水分含量不同。 USP <1112>将水分活度定义为药物中水蒸气压与周围空气介质完全不受干扰时的蒸汽压与相同条件下蒸馏水蒸气压的比值。参见 USP <1112>水活度测定在非无菌药物产品的应用。相反，水含量是药物中的水分含量。
30 There havebeen recalls in a lcohol based products. Refer to Appendix, Case 6.
乙醇基药品曾有过召回，参见附录案例 6。
31See, e.g., 21 CFR 211.113 and211.166(a).
32See 21CFR 211.111 a nd 211.113(a).
33USP<61> MICROBIAL ENUMERATION TESTS and USP <62> TESTS FOR SPECIFIEDORGANISMS.
USP<61>微生物计数测试和 USP<62>指定微生物检测。
34USP<1111> MICROBIOLOGICALEXAMINATIONOFNONSTERILE PRODUCTS: ACCEPTANCE CRITERIA FOR PHARMACEUTICALPREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE.
USP<1111>非无菌药品的微生物检查：制剂和药用物质的可接受标准。

B. Risk-Based Impact Assessment
基于风险的影响性评估

Thecontrols necessary to prevent objectionable microorganisms will depend on therisk (probability and hazard potential) of microbiological contamination in theNSD, including the characteristics of the NSD (e.g., formulation, componentselection, conditions of use, and route of administration), the NSDmanufacturing process, and the impact of the manufacturing environment.Well-designed and appropriately controlled manufacturing processes presentfewer opportunities for introducing objectionable microorganisms and theirproliferation or growth. For certain low-risk manufacturing operations (e.g.,tablet manufacture), reduction in microbiological monitoring and testing may bejustified using a risk assessment (see section C below).
防止致病菌所需控制措施取决于 NSD的微生物污染风险（可能性和危害潜力），包括 NSD特性（例如，配方、成分选择、使用条件和给药途径）、NDS生产工艺，以及生产环境的影响。如果生产工艺经过良好设计并受到恰当控制，则引入致病菌及其繁殖或生长的机会就会很小。对于特定的低风险生产操作（例如，片剂生产），可使用风险评估支持减少微生物监测和检测（参见以下节 C）。

A risk-basedimpact assessment helps manufacturers identify product-specific characteristicsand manufacturing process elements that are more likely to introduce bioburdenor objectionable microorganisms into the NSD. Systems designed to mitigaterisks based on this risk-based impact assessment are more likely to preventobjectionable microorganisms in NSDs. The elements listed below, while not anexhaustive list, should be considered in the risk management plan to reduceobjectionable microorganisms, where relevant.
基于风险的影响性评估有助于生产商识别更有可能引入生物负载或致病菌至 NSD的产品特有属性和生产工艺要素。根据这个基于风险的影响性评估设计的风险缓解系统更有可能预防 NSD中的致病菌。下列要素虽然并不是完全清单，但在风险管理计划中应予以考虑，以降低致病菌（如相关）。

1. Product Specific Elements
产品特有要素

o DosageForm
剂型

Liquid products typically have ahigher potential for microbial growth than other types, and semi-solidstypically have a higher potential for microbial growth than solids35.
液体制剂一般比其它类别制剂更有可能生长微生物，半固体制剂则一般比固体更有可能生长微生物

35 Dosa geform will dicta te the type of and extent to which microbial enumerationtesting should be performed on the finished product. Generalenumeration testing is described in USP <61> a nd USP <62>. Forsolid dosa ge forms, ICH Q6A Test Procedures and Acceptance Criteriafor New Drug Substances and New Drug Products: Chemical Substances includesrecommendations for conditions under which “periodic or skip testing” with regard to microbial enumeration testing may be considered.
剂型将决定对成品进行微生物计数测试的类型和程度。USP <61>和USP <62>中描述了通用的计数检测。对于固体剂型，ICH Q6A《新原料药和新药产品的检验方法和可接受标准：化学物质》包括关于微生物计数测试的“定期或跳过测试”条件的建议。

o WaterActivity36
水活度

Water activity of non-aqueousNSDs should be low enough to inhibit microbial growth.
非水性 NSD的水活性应该低到足以抑制微生物生长
When NSDs have a higher wateractivity, there is higher potential for microbial growth and additionalmanufacturing controls may be needed.
如果 NSD有更高的水活性，则微生物生长的可能性更高，因此需要额外的生产控制

o ProposedUse
所拟用途

Consider the patient population–thespectrum of patients that could be exposed to the drug and disease state of themost vulnerable patients taking the drug.
考虑患者人群—可能暴露于药品的患者群和最脆弱的用药患者疾病状态
Consider the route ofadministration.
考虑给药途径
Consider the body site to whichthe NSD may be administered (e.g., the skin, the respiratory tract, thegastrointestinal tract, or the urinary tract), and whether the tissue may beinjured or diseased, and therefore more susceptible to infection.
考虑可能摄入 NSD的身体部位（例如，皮肤、呼吸道、胃肠道或泌尿道），以及组织是否可能受损或患病，从而更易于被感染
Consider the setting in which theproduct is used (e.g., operating room, NICU).
考虑产品使用设置（例如，手术间，NICU）

o Packaging
包装

Ensure container/closure providesadequate protection from foreseeable external factors that can lead tomicrobial contamination (e.g., water or microbial ingress37).
确保容器/密闭器提供足够的保护，不受可能导致微生物污染的可预见外来因素影响（例如，水或微生物侵入）
Consider the appropriateness of asingle-dose versus a multiple-dose container-closure when selecting the NSDpackaging38. Forcertain dosage forms, a single-dose container/closure might provide superiorsafety with respect to preventing extrinsic microbial ingress into the finishedproduct.
在选择 NSD包装时考虑单剂量 VS多剂量容器密闭器的适当性。对于特定剂型，单剂量容器/密闭器可提供更高安全性，防止外来微生物侵入制剂成品

o ProductComponents and Composition
产品组分和比例

Consider selection of appropriatepreservatives that assure effectiveness to prevent
考虑选择适当的防腐剂，确保防止货架期微生物繁殖的有效性
Assure all incoming lots of rawmaterials are suitable for their intended use, including acceptablemicrobiological quality39.
确保所有批次进厂原料适合于其既定用途，包括可接受微生物质量

o MicrobiologicalTesting–Product Specific Considerations
微生物测试—产品特定考量

Establish appropriate microbiallimits for components, in-process materials, and finished products40.
为组份、中间体和成品建立适当的微生物限度
Ensure the sampling plan detectsvariation within a batch41.
确保取样计划能发现批内差异
Ensure appropriate sensitivity ofmethods for detecting a variety of microbes that could be in components or thefinished product and that could pose a risk to patients or product stability42.
确保方法有适当的灵敏度，能检出可能出现在组份和成品中的不同微生物，以及可能对患者或产品稳定性有风险的微生物
Implement appropriate actionlimits and test methods for water that is used as a component, including use asa processing aid43.Purified water, USP, that does not exceed 100 CFU/ml is recommended for use insolid oral dosage forms. More stringent microbiological quality standards maybe appropriate for other dosage forms44.
对用作组份的水（包括用作工艺助剂的水）执行适当的行动限和检测方法。USP建议固体口服制剂用纯化水不超出 100CFU/ml。其它制剂可能适用更严格的微生物质量标准。

2. Manufacturing Elements
生产要素

o ManufacturingProcess Steps: Certain processing steps may have a greater impact than othersin either promoting or reducing bioburden.
o 生产工艺步骤：某些工艺步骤可能比其它步骤在提高或降低生物负载方面有更大影响。

Bulk storage steps, especiallythose that are aqueous-based in the manufacturing process, may createconditions in which microorganisms can proliferate, particularly duringextended in-process holding periods (i.e., time between different unitoperations). Other manufacturing steps might introduce objectionablemicroorganisms. Therefore, extended holding of aqueous in-process materials(e.g., coating suspensions/solutions, liquid mixtures prior to the addition ofa preservative) is not advisable. Holding time limits must be established topreserve product quality45.
散装存贮步骤，尤其是那些水基生产工艺，可能会创造条件让微生物可以繁殖，尤其是在延长的中间体保存时间段内（即，不同单元操作之间的时间）。其它生产步骤可能会引入致病菌。因此，不建议延长水基中间体的保存时长（例如，包衣混悬液/溶液、添加防腐剂之前的液体混合物）。必须建立保存时限以保持产品质量。
Inadequate equipment cleaningprocesses, such as extended hold times before cleaning and insufficient dryingafter equipment has been cleaned, may also promote microbiologicalcontamination.
设备清洁工艺不充分，例如，延长清洁之前的放置时长，以及设备清洁之后干燥不充分，亦有可能增加微生物污染。
Inadequate environmentalcontrols, such as production areas open to a natural, uncontrolled, orinsufficiently controlled environment when product or product contact surfacesare exposed may promote microbiological contamination.
环境控制不充分，例如生产区域向自然环境敞开、不受控，或当产品或产品接触表面暴露时环境控制不充分可能会增加微生物污染。
Some manufacturing steps (e.g.,those that involve filtration, high temperature, extreme pH, or organicsolvents) might result in an in- process material that has a reduced bioburden.
有些生产步骤（例如，涉及过滤 、高温、极端 pH值或有机溶剂的那些步骤）可能会使得中间体生物负载降低。

36USP <1112>APPLICATIONOFWATER ACTIVITY DETERMINATIONTONONSTERILE PHARMACEUTICALPRODUCTS - Reducedwa ter activity (a w) willgrea tly a ssist in the prevention of microbial prolifera tion in pharmaceuticalproducts; the formulation, manufacturing steps, a nd testing of nonsteriledosage forms should reflect this parameter.
USP<1112>水活性检测在非活性药品中的应用—降低后的水活性（aw）很大程度上能帮助防止微生物在药品中的滋生，因此非无菌药品的配方、生产步骤和检测过程应反映出该参数。
37CFR211.94(b).
38 USP <659> PACKAGING ANDSTORAGEREQUIREMENTS. USP <659>“包装和存贮要求”。microbiologicalproliferation throughout the shelf life.
39See 21 CFR 211.84(d)(6).
40See 21CFR 211.113(a).
41See 21CFR 211.110(a).
42See 21CFR 211.160(b).
43See 21CFR 211.84(d)(6).
44USP <1231> WATER FORPHARMACEUTICAL PURPOSES.
USP <1231>“制药用水”。
See 21 CFR 211.111.

o Components:Non-sterile components can be a source of objectionable microorganisms in themanufacturing process. Appropriate specifications46 forthese components, as well as strategies for monitoring, controlling, preventingobjectionable microorganisms must be established47. Specialattention should be given to purified water48 andnaturally-derived components due to their intrinsic risk for contamination.
o 组份：非无菌组份在生产工艺中可能是致病菌的来源。必须建立这些组份的适当质量标准，以及监测、控制、预防致病菌的策略。特别要注意纯化水和天然组份，因为其属性具备污染风险。

o WaterSystem: Water used as a component (or as a processing aid) must be, as for anyother component, of appropriate quality for its intended use in processing andin the formulation4950. Whenwater used as a component is processed in-house, the purification system mustbe well-designed and rigorously controlled and maintained51.Maintenance and control of water purification systems should include proactivereplacement of parts to prevent deterioration and routine monitoring to assurethe system can consistently produce water meeting its predetermined qualitycharacteristics. The procedure for monitoring should incorporate appropriateaction and alert limits and include timely sampling after key water processingsteps and equipment used in the water processing and delivery system, includingall points-of-use. Water used as a cleaning agent, depending on conditions ofuse and equipment, should be monitored to ensure it meets appropriate qualityfor its intended use.
o 水系统：用作组份的水（或用作工艺助剂）必须像其它组份一样，具备适当的质量，适合其既定工艺和配方用途。如果水是公司自制，用作一种组份，则纯化水系统必须设计优良，受到严格控制和维护。水纯化系统的维护和控制应包括主动更换部件以预防老化，进行常规监测以确保系统可持续产出满足其既定质量特性的水。监测程序应结合适当的行动限和警戒限，包括在关键水处理步骤之后，水处理设备和传送系统后及时取样，包括所有使用点。用作清洁剂的水，根据其使用条件和设备，应予以监测从而确保其符合既定用途的适当质量。

o Environment:Manufacturers must ensure that facilities, equipment, and environmentalconditions are adequate to ensure control of air quality for manufacture, suchas preventing introduction of microbiological contaminants or bioburden thatwould be objectionable to the particular NSD being produced52.Manufacturers should periodically identify microorganisms present in themanufacturing facility which might lead to contamination of the NSD, and ensurethat their controls effectively mitigate the impact of these microorganisms ontheir NSD.
o 环境：生产商必须确保设施、设备和环境条件足以确保生产空气质量受控，如防止引入可能对所生产的特殊 NSD有害的微生物污染或生物负载。生产商应定期识别生产设施中出现的微生物，这些微生物有可能导致 NSD污染，确保其控制措施有效降低这些微生物对其 NSD的影响。

o Equipment:It is important to maintain the sanitary condition of equipment by limitingbioburden through proper design (e.g., vessels, piping), maintenance, cleaning,and sanitization.
o 设备：通过适当设计（例如，容器、管道）、维护、清洁和消毒来限制生物负载，维护设备的卫生条件至关重要。

o Cleaningand Sanitizing Agents: Manufacturers must use cleaning/sanitizing agentsappropriate to assure that buildings and facilities are maintained in a cleanand sanitary manner, which should include ensuring that they do not harborobjectionable microorganisms53. Appropriateequipment cleaning is essential to prevent objectional microbiologicalcontamination of components, containers, closures, packaging materials, anddrugs54.
o 清洁和消毒剂：生产商必须使用合适的清洁/消毒剂，确保以清洁和卫生的方式对建筑物和设施进行维护，其中应包括确保它们不会成为致病菌港湾。适当的设备清洁对于防止致病菌污染组份、容器、密闭器、包材和药品来说至关重要。

o Personnel:Manufacturers should take steps to establish and maintain appropriate practicesto minimize the potential impact of personnel introducing objectionablemicroorganisms into the manufacturing process. They must ensure that personnelfollow good hygiene practices55.
o 人员：生产商应采取措施建立和维护适当的粒子，将人员引入致病菌到生产工艺的潜在影响降至最低。他们必须确保人员遵守优良卫生规范。

In-Process Testing: Manufacturers are required toestablish procedures to assure the quality of in-process materials isconsistent with the finished product’s established specifications, whichincludes evaluating whether microbial attributes are met during processing56.
o 中控检测：生产商需要建立程序确保中间体质量与制剂成品的既定标准相一致，其中包括评估生产过程中是否满足微生物属性要求。

o MicrobiologicalRelease Testing (as appropriate):
o 微生物放行测试（适当时）

Total microbial content(microbiological enumeration testing57)
总微生物含量（微生物计数）
Specified organism testing andidentification program to identify other objectionable microorganisms58
特定微生物测试和鉴别程序，以鉴别其它致病菌

46See 21CFR 211.160(b).
47See 21CFR 211.100(a), 211.113(a).
48USP <1231> WATER FORPHARMACEUTICAL PURPOSES.
USP <1231>“制药用水”。
49See 21CFR 211.80, 211.84, 211.160(b).
50USP<1231> WATER FOR PHARMACEUTICAL PURPOSES classifies different waterquality gra des to indica te relative purity a nd a bsence ofmicroorganisms. USP <1231>“制药用水”对不同水质进行了分类，以显示相关纯度和微生物质量。
51 See 21CFR 211.63, 211.67.
52See 21 CFR 211.46(b), 211.56.
53See 21CFR 211.56.
54See 21CFR 211.56, 211.67.
55 See 21CFR 211.28(b).

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