FDA发布《行业指南：非无菌药品生产中的微生物质量考量》草案！

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).

C.    MicrobiologicalConcerns for Specific Dosage Forms and Special Cases

特殊剂型的微生物关切和特殊案例

1.    Solid Dosage Forms

固体制剂

Comparedto other NSDs, solid dosage forms represent a lower microbiological risk topatients due to their low water activity. Therefore, the microbiologicalcontrols associated with their manufacture are generally not expected to be asstringent as those associated with the manufacture of other NSDs.

相比于其它 NSD，固体制剂由于其低水活性而呈现出对患者更低的微生物风险。因此，与其生产有关的微生物控制一般来说不会比其它 NSD生产相关的控制更为严格。

Themicrobiological quality of the finished solid dosage form is also monitoredthrough finished product testing⁵⁹.Microbial enumeration testing of the finished drug product can be performed bymethods described in the USP for Total Aerobic Microbial Counts (TAMC), TotalCombined Yeast and Mold Count (TYMC), and specified organisms, as appropriate⁶⁰⁶¹. Iftesting is performed using compendial methods, method suitability testingshould be performed using the drug product. Other test methods, including rapidmicrobiological methods, may be used for product testing, but will requirevalidation to demonstrate their suitability and equivalence to the compendialmethods⁶².

固体剂型的微生物质量亦通过制剂成品检测进行监测。可执行 USP中所述的 TAMC、TYMC和指定微生物（适用时）方法测定微生物计数。如果使用药典方法进行检测，需使用药品进行方法适用性测试。其它检验方法，包括快速微生物检测方法，均可用于产品检测，但会需要进行验证以证明其适用性和与药典方法的等同性。

Althoughthe USP contains recommended acceptance criteria for microbial control, andspecifies the absence of certain objectionable microorganisms⁶³,manufacturers may develop alternativeapproaches to microbiologicalcontrol, including limits/release criteria. For example, many finished solidoral dosage forms have a water activity that does not permit growth orpersistence of many vegetative cells. Therefore, it is possible that wateractivity determination during product development, in conjunction within-process controls designed to limit objectionable microorganisms, can serveas justification for the reduction or elimination of microbiological testingfor release of certain types of solid oral finished products. If there aresufficient data to demonstrate that in-process microbiological controls aresuccessful, finished product water activity is acceptable, and component lotbioburden test results remain consistently in control, the microbialenumeration testing of the finished product may be reduced or eliminated (seesection below titled “Potentially Reducing Microbiological Release Testing forSolid Dosage Forms Based on Risk-Based Impact Assessment”). If such surrogatecriteria are used in lieu of a product release test, it is important toestablish and document appropriate process and facility controls, includingtesting of incoming component lots and controls in the manufacturing process,as these controls serve to limit the bioburden in the final product.

虽然 USP含有建议的微生物控制可接受标准，并指明了特定致病菌不得检出，但生产商可建立替代方法进行微生物控制，包括限度/放行标准。例如，许多固体口服制剂有水活性，但并不会提供条件让许多营养细胞的生长或持续存在。因此有可能在产品开发期间测定水活性，结合限制致病菌的中控设计，作为减少或删除特定类别固体口服制剂放行检测中微生物检测的理由。如果有足够的数据证明中间体微生物控制是成功的，制剂水活性是可接受的，并且组份生物负载检测结果保持持续受控，则可减少或删除成品的微生物计数检测（参见下节题为“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”）。如果使用该替代标准取代产品放行测试，则建立并记录适当的工艺和设施控制（包括测试进厂组份批次和生产工艺控制）非常重要，因为这些控制措施是用于来限制最终产品的生物负载的。

⁵⁶See 21 CFR 211.110(a)(6).

⁵⁷USP<61> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: MICROBIAL ENUMERATION TESTS.

USP <61>“非无菌药品的微生物检测：微生物计数检测”

⁵⁸USP <62>MICROBIOLOGICALEXAMINATION OFNONSTERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS.

USP <62>“非无菌药品的微生物检测：指定微生物的检测”

⁵⁹See 21CFR 211.165(b).

⁶⁰USP<61> MICROBIOLOGICALEXAMINATIONOFNONSTERILE PRODUCTS: MICROBIAL ENUMERATION TESTS. USP <61>“非无菌药品的微生物检测：微生物计数检测”

⁶¹USP <62>MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS.

USP <62>“非无菌药品的微生物检测：指定微生物的检测”

 ⁶²See 21 CFR 211.194(a)(2).

USP<1111> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS:  ACCEPTANCE CRITERIAFOR PHARMACEUTICALPREPARATIONSANDSUBSTANCESFOR 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。

 

PotentiallyReducing Microbiological Release Testing f or Solid Dosage Forms Based onRisk-Based Impact Assessment

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

Soliddosage forms with a water activity that will not support vegetative microbialgrowth are excellent candidates for reduced microbial testing for productrelease and stability. ICH Q6A TestProcedures and Acceptance Criteria for New Drug Substances and New DrugProducts: Chemical Substances includes recommendations for conditions underwhich “periodic or skip testing” with regard to microbial enumeration testingmay be considered. The recommendations in ICH Q6A are based on productcharacteristics and provide a logical approach to determining an appropriatemicrobiological testing schedule. To support the reduction or elimination ofmicrobiological release testing for solid dosage forms, manufacturers shouldconduct a risk-based impact assessment, as recommended in section IV.B of thisguidance.

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。ICH Q6A“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。ICH Q6A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。

Microbiologicaltesting in a stability program may be reduced or eliminated for lower risksolid dosage forms with appropriate justification, including the manufacturer’shistorical experience in manufacturing the NSD, such as the amount ofmicrobiological release and stability data, anyadverse findings, and the extentof process, facility, and component bioburden controls. Note that some soliddosage forms that contain growth-supporting components, such as proteinaceouscomponents⁶⁴, should undergoa risk assessment to determine if they are candidates for reducing oreliminating the need for microbiological testing in stability protocols.

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。

2.   Non-Solid Dosage Forms

非固体制剂

Typically,non-solid dosage forms (e.g., solutions, suspensions, lotions, creams, and someointments) have higher water activity than solid dosage forms and thus a higherrisk of supporting microbial growth. The capacity of non-solid dosage forms tosupport microbial growth is largely dependent on the water activity of the drugproduct components. Many contamination events have been associated withproducts with water activity levels that support microbial growth, andtherefore we recommend that non-solid dosage form manufacturers focus onmicrobiological quality when evaluating the overall manufacturing process.Understanding a product’s water activity throughout the manufacturing processcan aid in decisions related to manufacturing, in-process holding times, andstorage conditions. For products, components, and in-process materials withwater activities that are known to support microbial proliferation, greaterscrutiny should be placed on process controls throughout the operation. Thisincludes in-process and finished product microbiological monitoring methods andacceptance criteria, validation of in-process holding periods⁶⁵, and anymanufacturing step that is vulnerable to microbial proliferation. For example,naturally occurring ingredients with low water activity may have high intrinsicbioburdens and require special attention. Also, the presence of objectionablemicroorganisms in the manufacturing steps for topical drugs has resulted inmicrobial contamination of such products, which typically have low wateractivity. Additionally, suspensions can present an additional challenge inmanaging objectionable microorganisms⁶⁶.

通常，非固体剂型（例如溶液、悬浮液、洗剂、乳膏和一些软膏）比固体剂型具有更高的水分活度，因此支持微生物生长的风险更高。非固体剂型支持微生物生长的能力在很大程度上取决于药品成分的水分活度。许多污染事件与具有支持微生物生长的水分活度水平的产品有关，因此我们建议非固体剂型生产商在评估整个生产过程时关注微生物质量。了解产品在整个生产过程中的水分活度有助于做出与生产、中间体放置时间和储存条件相关的决策。对于已知具有支持微生物增殖的水分活度的产品、组份和中间体，应在整个操作过程中对工艺控制进行更严格的审查。这包括中间体和成品微生物监测方法和验收标准、中间体放置时长的验证以及任何易受微生物增殖影响的生产步骤。例如，具有低水分活度的天然成分可能本身具有高生物负载，需要特别注意。此外，在通常具有低水活度的外用药物的生产步骤中存在有害微生物已导致此类产品受到微生物污染。此外，混悬液在有害微生物管理方面可能会带来额外的挑战。

Productstability studies should take into account that suspensions may separate intodifferent phases, during storage and distribution, that may result in thesegregation of formulation ingredients and cause an unequal distribution ofpreservatives. The phase with insufficient preservatives may have high wateractivity resulting in microbial growth.

产品稳定性研究应考虑到混悬液在存贮和分配过程中可能会分离成不同的相，这可能会导致配方成分分离并导致防腐剂分布不均。防腐剂不足的相可能具有高水分活度，导致微生物生长。

Inaddition to evaluating the overall manufacturing process, it is also importantto ensure that manufacturing equipment is cleaned and maintained such thatwater residue does not remain on equipment while it is stored, unused, orunprotected⁶⁷. Waterresidue can promote microbial growth. Equipment surfaces, including those thatmay not contact product directly, should be dried or stored in manner thatpermits rapid drying as soon as possible after cleaning and sanitization.

除了评估整个生产过程之外，确保生产设备得到清洁和维护也很重要，这样在设备存储、未使用或未保护时，水不会残留在设备上。残留水可以促进微生物的生长。设备表面，包括那些可能不直接接触产品的表面，应在清洁和消毒之后尽快干燥或储存。

Non-solidproducts with low water activities nonetheless can harbor objectionablecontamination due to introduction of contamination during manufacturing or fromraw materials. However, microbial proliferation during shelf-life is lesscommon. For non-solid products with synthetic components and water activitiesthat are well below those that are known to support microbial proliferation,less frequent microbiological testing conducted in the finished productstability program may be supportable. Batches placed in a stability testingprogram are typically sampled and tested at multiple time points over theirlabeled shelf life, including beginning and end and several interim points. Tosupport reduced (i.e., fewer stability time points) microbiological testing offinished product lots in the stability program, a risk-based impact assessmentshould be performed that includes water activity data, microbiologicalmonitoring information related to the manufacturing process, bioburdenpotential of the components, manufacturing history (with attention to anyfailures and deviations), and an understanding of the processing steps that maycontribute positively or negatively to microbiological quality (see previoussubsection on “Potentially Reducing Microbiological Release Testing for SolidDosage Forms Based on Risk-Based Impact Assessment”).

尽管如此，由于在生产过程中或从原材料引入污染，具有低水分活度的非固体产品可能会受到致病菌污染。然而，货架期内的微生物增殖不太常见。如果非固体药品的合成成分和水分活度远低于已知支持微生物增殖的药品，在成品稳定性计划中进行较少频率的微生物测试可能是可行的。放置在稳定性测试计划中的批次通常在其标记的保质期内的多个时间点进行采样和测试，包括开始和结束以及几个中间点。为了支持稳定性计划中对成品批次减少（即更少的稳定性时间点）微生物测试，应进行基于风险的影响评估，其中包括水分活度数据、与生产过程相关的微生物监测信息、产品的生物负载潜力。组份、生产历史（注意任何故障和偏差），以及可能对微生物质量产生积极或消极影响的工艺步骤的理解（参见前面 “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”）。

⁶⁴Solid oral dosage forms with certain naturally-derived a ctive ingredients (e.g., pancreatic enzymes) a nd soft gela tin capsules have a higher likelihoodof harboring objectionable contamination.

有某些天然衍生活性成分（例如，胰酶）和软明胶胶囊的固体口服制剂更有可能藏有有害污染。

⁶⁵See 21 CFR 211.111.

66   Seefootnote 6.

3.  Microbiological Consideration –Special Cases

微生物考量—特殊案例

Thissection discusses examples of NSD product formulations and intended uses thatinherently pose greater relative risk for objectionable microorganisms orbioburden to harm the patient population (e.g., administration of NSD to skinprior to medical procedures that break the skin). This example demonstratesthat more rigorous identification and assessment of the bioburden in theseproducts is critical to understand product hazard. Appropriate laboratorymethods must be used, and qualified staff must review the results to determineif the product is contaminated with objectionable microorganisms⁶⁸⁶⁹. Thesemethods should differentiate and identify objectionablemicroorganisms. Such batchquality information is critical to prevent distribution of an objectionablycontaminated product that poses a hazard to consumers, and to facilitate aninvestigation of the cause(s) to correct or prevent a quality problem.

本节讨论 NSD产品配方和预期用途的示例，这些产品本身对有害微生物或生物负载对患者群体造成更大的相对风险（例如，在破坏皮肤的医疗程序之前将 NSD施用于皮肤）。此例表明，对这些产品中的生物负载进行更严格的鉴别和评估对于了解产品危害至关重要。必须使用适当的实验室方法，并由合格的人员审核结果以确定产品是否被致病菌污染。这些方法应该区分和鉴别致病微生物。此类批次质量信息对于防止销售对消费者造成危害的被污染产品至关重要，并有助于调查原因以纠正或防止质量问题。

a.          Burkholderiacepacia Complex and Aqueous Drug Products

洋葱伯克霍尔德菌复合物和水性药物制剂

Non-sterileaqueous drug products have the potential to be contaminated with BCC organismsbecause of the potential for these microorganisms to be present inpharmaceutical water systems. (Refs. 2, 18, 19, 21). Burkholderia cepacia is now considered part of a complex of atleast 17 genomovars, or closely related species (Refs. 2, 8, 14).

非无菌水性药品有可能被 BCC微生物污染，因为这些微生物可能存在于制药用水系统中。（参考文献 2、18、19、21）。洋葱伯克霍尔德菌现在被认为是至少 17种基因型或近缘物种复合体的一部分（参考文献 2、8、14）。

Theseorganisms are opportunistic human pathogens that can cause severelife-threatening infections (Refs. 2, 14, 24). It is important that non-sterileaqueous drug products not contain BCC organisms because of their uniquecharacteristics and the safety risk they pose. BCC strains have awell-documented ability to utilize a wide variety of substrates as energysources, many of which are traditional preservative systems (Refs. 1-4, 12,13). Thus, despite the presence of an otherwise adequate preservative system ina non-sterile drug product, BCC strains can survive and proliferate in anon-sterile product over its shelf life. While microbial enumeration testingfor finished product release may demonstrate an acceptable level for the totalaerobic microbial count, BCC can proliferate to unsafe levels by the time theproduct reaches the patient. In May 2016, the FDA was notified by the Centersfor Disease Control and Prevention (CDC) of severe illnesses and deathsassociated with BCC in patients in 13 hospitals across 9 states. This promptedthe recall of a non-sterile OTC liquid stool softener due to BCC contamination(Ref. 17). In a series of cases from 2000 to 2002, involving a medical device(an ultrasound gel), intrinsic contamination by BCC led to serious bloodinfections after the gel was used in association with transrectal prostatebiopsies (Ref. 6).

这些微生物是机会性人类病原体，可导致严重的致命感染（参考文献 2、14、24）。重要的是，非无菌水性药物产品不含 BCC微生物，因为它们具有独特的特性和安全风险。BCC菌株具有利用多种底物作为能源的能力，其中许多是传统的防腐剂系统（参考文献1-4、12、13）。因此，尽管在非无菌药物产品中存在足够的防腐剂系统，但 BCC菌株可以在非无菌产品的货架期内存活和增殖。虽然成品放行的微生物计数测试可以证明TAMC达到可接受水平，但当产品到达患者时，BCC可能会繁殖到不安全的水平。2016年 5月，美国疾病控制和预防中心（CDC）向 FDA通报了 9个州 13家医院中与 BCC相关的严重疾病和死亡。BCC污染导致了非无菌 OTC液体粪便软化剂召回（参考文献 17）。在 2000年至 2002年涉及医疗器械（超声波凝胶）的一系列病例中，在凝胶与经直肠前列腺活检联合使用后，BCC的固有污染导致了严重的血液感染（参考文献 6）。

Pharmaceuticalwater and naturally-derived components used in the manufacturing process arethe most likely sources of BCC in drug products. Therefore, a robustimplementation of the CGMPs is essential to ensure product quality and patientsafety, including:

制药用水和生产过程中使用的天然衍生成分是药品中 BCC的最可能来源。因此，CGMPs的稳健实施对于确保产品质量和患者安全至关重要，包括：

• establishing a risk managementprogram for the design and control of operations to prevent BCC contamination⁷⁰
• 建立风险管理计划对操作进行设计和控制，从而预防 BCC污染
• using robust water systems⁷¹
• 使用稳健的水系统
• ensuring components meetappropriate specifications for bioburden ⁷²
• 确保组份满足适当的生物负载标准
• appropriately sanitizing andcleaning equipment⁷³, and
• 恰当地消毒和清洁设备，以及
• validated sampling procedures⁷⁴ toroutinely perform in-process monitoring and finished product testing for thepresence of BCC
• 采用经过验证的取样程序执行 BCC日常中控监测和成品检测

Unless amanufacturer performs validated manufacturing steps (e.g., microbial retentivefiltration of the bulk product formulation with a sterilizing filter rightbefore filling) that render a drug product free from BCC, release testing isessential as the last in a series of controls that helps demonstrate that thenon-sterile aqueous drug product is free from BCC (Ref. 7).

除非生产商执行经过验证的生产步骤（例如，在灌装前使用灭菌过滤器对散装产品配方进行微生物截留过滤）使药品不含 BCC，否则放行测试是一系列控制中必不可少的最后一步，有助于证明非无菌水性药品不含 BCC（参考文献 7）。

The USPprovides a compendial test for BCC that became official on December 1, 2019,entitled〈60〉 MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS—TESTS FOR BURKHOLDERIA CEPACIA COMPLEX. FDArecommends that manufacturers use the USP method described in this USP chapterto test drug products for the presence of BCC. If a manufacturer chooses todevelop an alternative in-house method, the alternative method or proceduremust be fully validated and must produce comparable results to the compendialmethod⁷⁵.Additionally, any applicant choosing to develop an alternative method should beaware that test methods can be complicated by the fact that BCC are highlyadaptable and variable in their ability to survive and grow in a variety ofenvironments (Refs. 1, 8). There can be difficulties detecting and correctlyidentifying and classifying BCC (Refs. 1, 15) and, consideration of the diversephenotypes exhibited by BCC members is essential for recovery methoddevelopment (Ref. 3).

USP提供了一项于 2019年 12月 1日正式生效的 BCC药典检测方法，题为<60>非无菌药品的微生物检查—洋葱伯克霍尔德菌复合体（BCC）检测。 FDA建议生产商使用本 USP章节中描述的 USP方法来测试药品是否存在 BCC。如果生产商选择开发替代的内部方法，则替代方法或程序必须经过充分验证，并且必须产生与药典方法相当的结果。此外，任何选择开发替代方法的申请人都应该意识到，由于 BCC具有高度的适应性和在各种环境中生存和生长的能力，测试方法可能会变得复杂（参考文献 1、8）。BCC的检测、正确鉴别和分类可能存在困难（参考文献 1、15），考虑 BCC成分表现出的不同表型对于开发回收方法至关重要（参考文献 3）。

⁶⁷See 21CFR 211.67.

⁶⁸See 21CFR 211.160(b).

69 See 21CFR 211.25(a).

⁷⁰See 21 CFR 211.100(a), 21 CFR211.113(a).

⁷¹See 21CFR 211.42(a).

⁷²See 21CFR 211.80(a), 211.84(d)(6).

⁷³See 21CFR 211.67(a).

⁷⁴See 21CFR 211.110(a), 21 CFR 211.165(a).

75 See 21CFR 211.194(a)(2), 21 CFR 211.194(a)(6), USP <1223>.

b.PreoperativeSkin Preparation Drug Products (Topical Antiseptics)

术前备皮药品（局部防腐剂）

Patientpreoperative skin preparations are topical antiseptic drug products used toreduce the number of microorganisms on the skin prior to medical procedures orinjections, as the skin is typically covered with microorganisms (Ref. 16).Some of these products are not manufactured as sterile products (Ref. 16).However, there have been a number of published reports of infection outbreaksassociated with antiseptic products due to microbial contamination (Refs. 9,10, 11, 21). Notably, contaminated antiseptic products made up a majority ofnon-sterile product recalls that occurred between 2009 and 2013. There wereeight recalls due to microbial contamination of alcohol or povidone-iodine preppads.

患者术前备皮药品是局部消毒药物产品，用于在医疗程序或注射之前减少皮肤上微生物的数量，因为皮肤通常被微生物覆盖（参考文献 16）。其中一些产品不是作为无菌产品生产的（参考文献 16）。然而，已经有许多已发表的报告称，由于微生物污染，与消毒产品相关的感染爆发（参考文献 9、10、11、21）。值得注意的是，在 2009年至 2013年期间发生的非无菌产品召回中，大部分是受污染的防腐剂产品。有 8起召回是由于酒精或聚维酮碘备垫受到微生物污染。

Theproduct indication alone (application to a body surface that is about to besurgically compromised), as well as recent infection outbreaks and productrecalls, suggest that the sterility of the product may be an important riskmitigation or have an important impact on clinical outcomes. In 2011, the FDApublished a news release reminding health care professionals to check thelabeling on alcohol prep pads to determine if they are sterile or non-steriledue to recent contamination events⁷⁶. FDArecommended that only sterile pads be used for procedures requiring strictsterility measures (Ref. 19). FDA encourages manufacturers of patientpre-operative antiseptic products to explore manufacturing processes for theseproducts that render them sterile, whether the product is under development orcurrently marketed. FDA welcomes questions regarding development of sterilizationprocesses for these products, and is committed to working with applicants andother stakeholders on options for sterilization of pre-operative antisepticproducts⁷⁷.

单独的产品适应症（应用于即将手术受损的体表），以及最近的感染爆发和产品召回，表明产品的无菌性可能是一个重要的风险缓解因素或对临床结果有重要影响。2011年， FDA发布了一份新闻稿，由于最近的污染事件，提醒医疗保健专业人员检查酒精备垫上的标签，以确定它们是无菌的还是非无菌的。FDA建议在需要严格无菌措施的程序中仅使用无菌垫（参考文献 19）。 FDA鼓励患者术前消毒产品（无论该产品是在开发中还是目前已上市）的生产商探索这些产品的生产工艺，使其无菌。 FDA欢迎提出与这些产品灭菌工艺开发有关的问题，并致力于与申请人和其他利益相关者合作，研究术前消毒产品的灭菌选择。

76      FDA Press Announcement “FDAreminds health care professionals a bout safe use of non-sterile a lcohol prep pa ds,”February 1, 2011, https://wayback.archive-it.org/7993/2017 01130738 26/http://www.fda.gov /NewsEvents/Newsroom/PressAnnouncements/ucm241 750.htm. See a lso “FDA Drug Sa fety Communication: FDA requests la bel changes a ndsingle-use packaging for some over- the-countertopical a ntiseptic products to decrease risk of infection,” November 13, 2013,https://www.fda.go v/Drugs/DrugSaf ety/ucm374 711.htm.

FDA新闻公告“FDA提醒医疗保健专业人员安全使用非无菌酒精准备垫”，20110201。亦可参见“FDA药品安全沟通：FDA要求有些 OTC局部用消毒药品修改标签和使用单次使用包装以降低污染风险”，20131113。

77   Requests not a ssociated with aspecific a pplication can be sent toCDER-OPQ-I nqu iries@fda .hhs.gov.不与特定申报有关的请求可发送到上述邮箱

c.  Transdermal Products

透皮制剂

Traditionaltransdermal and topical delivery systems (collectively TDS) pose limitedmicrobial risk when used on intact skin⁷⁸.However, as the technology for these products continues to evolve, thepotential risk to patients should be re-assessed to determine the need foradditional manufacturing controls.

传统的透皮和局部给药系统（统称为 TDS）在完整皮肤上使用时造成的微生物风险有限。然而，随着这些产品的技术不断发展，应重新评估对患者的潜在风险，以确定是否需要额外的生产控制。

TDSdesigned with a physical mechanism to abrade or penetrate the skin increase thepotential for infections, especially given that skin thickness varies acrossindividuals, body sites, and by patient age. During development manufacturersof such TDS should consider the risks and determine whether the TDS should bemanufactured as sterile or with a bioburden level below that normally seen withTDS designs that rely on chemical permeation enhancers⁷⁹. The FDAencourages these manufacturers to contact the Agency in the early phase ofplanning and product development⁸⁰.

TDS设计有物理机制，会磨损或穿透皮肤，增加感染的可能性，特别是考虑到皮肤厚度因个体、身体部位和患者年龄而异。在此类 TDS的开发过程中，生产商应考虑风险并确定 TDS是否应生产为无菌或生物负载水平低于通常看到依赖化学渗透促进剂的 TDS设计的水平。FDA鼓励这些生产商在规划和产品开发的早期阶段联系 FDA。

D.  Updating Approved Drug ProductSpecifications

更新已批准的药品质量标准

FDA doesnot expect application holders of approved drug products to amend the productspecification in cases where it is inconsistent with the recommendationsdiscussed in this guidance. If a new supplemental application proposing amanufacturing change that may impact the risk of increased microbiologicalgrowth (e.g., new manufacturing process, relaxation of critical processparameters) is submitted, FDA assessors may request that application holdersupdate the microbiological testing information in the product specificationduring assessment and before approval. Application holders may wish to considerupdating a given drug product specification as recommended in this guidance.This could help to expedite approval of future supplements for othermanufacturing changes⁸¹. Table 1provides guidance regarding the filing category for submission of supplementsthat propose changes to the microbiological testing program of non-sterile drugproducts.

如果申请持有人的已批准产品与本指南中讨论的建议不一致，FDA不要求其修改产品标准。如果提交了新的补充申请，提出了可能影响微生物生长增加风险的生产变更（例如，新的生产工艺、放宽关键工艺参数），FDA审评员可能会在评估期间和批准之前要求申请持有人更新产品规格中的微生物检测信息。申请持有者可能希望按照本指南的建议考虑更新给定的药品质量标准。这可能有助于加快未来其他生产变化补充的批准。表 1提供了变更非无菌药品微生物检测程序的补充资料提交类别的指南。

⁷⁸Technicalconsiderations (beyond microbiological a spects) for traditional tra nsdermalsystems are a ddressed in FDA’s dra ft guidance for industry Transdermal and Topical Delivery Systems -Product Development and Quality  Considerations

(November2019). When final, this guida ncewill represent the FDA’s current thinking on this topic.传

统贴剂系统的技术考量（超出微生物方面）在 FDA行业指南草案“贴剂和透皮给药系统—产品开发和质量考量（201911）”。定稿时，该指南将代表 FDA当前对该问题的看法。

⁷⁹See FDA’s guida nce for industry Chronic Cutaneous Ulcer and Burn Wounds — DevelopingProducts for  Treatment

(June 2006).参见 FDA行业指南“慢性皮肤溃疡和烧伤—开发治疗药品”（200606）。

⁸⁰When the submission is for a nNDA, contact the specific drug product’s review division with questions. Whenthe product under development is a n ANDA, the Office of Pharmaceutical Quality(OPQ) a nd Office of Generic Drugs (OGD) ma y be contacted through generalcorrespondence, controlled correspondence, or request for a Pre-ANDA Meeting, a sa pplica ble.如果为 NDA提交资料，请联系专用药品服务中心。如果正在开发的产品是 ANDA，通过一般通信、受控通信或 ANDA预备会议（适用时）联系 OPQ和 OGD。

81   FDA a lso recommends thatnon-application drug products consider updating drug product specifications as maintained by the pharmaceutical quality system as recommended in this guida nce.FDA亦建议非申报药品考虑按本指南中所建议的药物质量体系维护时更新药品质量标准。

Table 1.Regulatory Filing Strategy for Proposed Changes to the Microbiological Testingof Non-Sterile Drugs

表 1：非无菌药品微生物检测拟定变更的注册提交策略

APPENDIX: Case Study Examples ofMicrobiological Contamination of NSD Products; Impact on Product Quality andManufacturing Process

附录：NSD产品微生物污染的案例研究示例；对产品质量和生产过程的影响

Thefollowing seven case studies summarize incidents of NSDs contaminated withmicroorganisms leading to infections, and ultimately product recalls. In eachof the cases below, the manufacturer of the product initiated voluntary recallactions to mitigate the impact of the contaminated product on patients andend-users, and instituted new processes and corrective measures to preventfuture microbial contamination of their product. Of particular significance arethe root cause analyses and corrective/preventative strategies thatmanufacturers took to address microbiological contamination. These examplessuggest that risk assessments should be an integral part of strategies toprevent the microbiological contamination of NSDs.

以下七个案例研究总结了 NSD被微生物污染导致感染和最终产品召回的事件。在以下每种情况下，产品生产商都发起了自愿召回行动，以减轻受污染产品对患者和最终用户的影响，并制定了新的流程和纠正措施，以防止其产品在未来受到微生物污染。特别重要的是生产商为解决微生物污染而采取的根本原因分析和纠正/预防策略。这些例子表明，风险评估应该是防止 NSD微生物污染战略的一个组成部分。

Case 1: Contamination of an oralsolution with Burkholderia cepaciacomplex (BCC)

案例 1：洋葱伯克霍尔德菌复合物（BCC）污染口服溶液

In 2016,an OTC product (oral liquid docusate sodium) indicated for constipation wascontract manufactured for a customer who marketed the products under its ownlabel. FDA investigated a multistate outbreak of serious BCC infections in 108 patients, including multiple associatedpatient deaths. Testing by FDA and CDC revealed that more than 10 lots of oralliquid product were contaminated with BCC.The BCC clinical isolates matchedwith the product isolates. The investigation also detected BCC in the water system used by the firm to manufacture theproduct.

2016年，有一种用于便秘的 OTC产品（口服液多库酯钠）的自有品牌销售商将该产品委外加工。 FDA调查了多州爆发的 108名患者严重 BCC感染事件，其中多例相关患者死亡。 FDA和 CDC的检测显示，超过 10批口服液体产品被 BCC污染。BCC临床分离株与产品分离株相匹配。调查还在该公司用于生产产品的水系统中检测到 BCC。

FDA andCDC identified the contract manufacturer as the source of the outbreak. Thepoorly designed water system (cold system; not continuously circulating),inadequate monitoring of the system, poor manufacturing controls, andinadequate microbiological testing methods all contributed to severe risks tothe consumer. All lots of liquid products made by the contract manufacturerwere ultimately recalled.

FDA和 CDC将合同生产商确定为爆发的源头。设计不佳的水系统（冷系统；不连续循环）、系统监控不充分、生产控制不力以及微生物检测方法不当都对消费者造成了严重的风险。合同生产商生产的所有液体产品最终都被召回。

Case 2: Contamination of aqueous-basedthroat spray and liquid antacid with Escherichiacoli

案例 2：水基咽喉喷雾剂和液体抗酸剂被大肠杆菌污染

In 2014,a manufacturer of an aqueous-based, non-sterile spray to relieve throat drynessand to restore throat comfort was determined to be contaminated with Escherichia coli (E.coli). Thecontamination was discovered when a microbial assay of the product returnedresults that indicated the bacterial count to be too numerous to count (TNTC).Although the root cause was not fully determined by the firm, several manufacturingpractices were corrected as a result of the event, including new processes andprocedures for cleaning and storage of equipment, and physicalseparation between used equipment and equipment that had been sanitized. Over20,000 units of this product were distributed nationally.

2014年，一家生产用于缓解喉咙干燥和恢复喉咙舒适度的水性非无菌喷雾剂的生产商被确定有大肠杆菌 (E.coli)污染。污染是在得到产品的微生物检测结果是细菌计数过多而无法计数 (TNTC)时才发现的。尽管该公司并未完全确定根本原因，但作该事件的结果，公司纠正了一些生产实践，包括用于清洁和存储设备的新流程和程序，以及将使用过的设备和经过消毒的设备之间进行物理分离。该产品在全国销售超过 20,000台。

Aseparate case of E.coli contaminationof an antacid liquid occurred in 2013, in which over 10,000 units of thecontaminated product were distributed nationally prior to completion of qualityassurance testing. When the microbial assay for the product returned with E.coli counts greater than 3000 CFU/g,the product was immediately recalled by the manufacturer. After themanufacturer’s investigation, the quality assurance procedures were updated andemployee training was conducted. However, the root cause of the contaminationwas not determined. In this instance, there were no reported injuries orillnesses that were attributed to the contaminated product.

2013年发生了另一起抗酸液被大肠杆菌污染的案例，在完成质量保证测试之前，全国已销售了 10,000多件受污染的产品。当产品微生物检测结果报告其中大肠杆菌大于 3000CFU/g时，生产商立即召回了该产品。在调查之后，生产商更新了质量保证程序并进行了员工培训。然而，污染的根本原因尚未确定。在该案例中，未报告因在受污染产品导致的伤害或疾病。

A reviewof FDA’s recall database between 2012 and 2017 demonstrates that at least fourother separate events have occurred with non-sterile aqueous based productsresulting in E. coli contamination.

对 2012年至 2017年间 FDA召回数据库的回顾表明，至少发生了四起其他非无菌水基药品导致大肠杆菌污染的独立事件。

Case 3: Contamination ofmoisturizing cream with Pseudomonasand Staphylococcus

案例 3：保湿霜被假单胞菌和葡萄球菌污染

In 2017,a manufacturer of a baby eczema moisturizing cream reported that their productwas contaminated with Pseudomonasaeruginosa and Staphylococcus aureus.Over 15,000 units of the product were distributed nationally. The microbialassay determined that the bacterial load in the products was 87,500 CFU/g,despite presence of a preservative in the formulation. The root cause for themicrobiological contamination appeared to be a raw material of natural originthat became contaminated due to improper storage at the firm, and apparentlyresulted in microbiological growth in finished product.

2017年，一家婴儿湿疹保湿霜的生产商报告称，他们的产品被铜绿假单胞菌和金黄色葡萄球菌污染。该产品在全国销售超过 15,000件。尽管配方中存在防腐剂，但微生物测定显示产品中的细菌负载为 87,500 CFU/g。微生物污染的根本原因似乎是一种天然来源的原材料，由于公司储存不当而受到污染，显然导致发成品中微生物的生长。

Similarly,in 2015, a distributor of a liquid antacid determined that over 100,000 unitsof their nationally distributed product was objectionably contaminated. Productcontamination included Pseudomonasaeruginosa, as well as high yeast and mold counts. The recall scope wasbased on assessment of retentionsamples spanning 12 months. The root cause of the contamination appeared to berelated to issues in the contract manufacturing process, but the ultimate rootcause was not identified.

同样，在 2015年，一家液体抗酸剂经销商确定其全国销售的 100,000多件产品受到了有害污染。产品污染包括铜绿假单胞菌，以及高酵母和霉菌数量。根据跨越 12个月的留样所做的评估决定了召回范围。污染的根本原因似乎与合同生产过程中的问题有关，但最终的根本原因并未确定。

Case 4: Excessive contaminationof a non-aqueous-based cream indicated for infants

案例 4：婴儿用非水性乳膏过度污染

In 2018,a zinc oxide diaper rash cream, indicated for infants, was imported by a USdistributor who intended to market it as an OTC product. When tested, it wasfound to be objectionably contaminated. Although the product was notaqueous-based, and had a low intrinsic water activity, it contained excessivenumbers of bacteria and fungi. Samples included units with several very highaerobic microbial counts including values such as 3.5 million CFU Total AerobicMicrobial Count (TAMC)/mL and 27,000 CFU TAMC/mL. Many of the bacteria werespore formers of the Bacillus, spp.Yeast and mold count levels were also very high, including 2700 Total Combined Yeast and Mold Count (TYMC)/mL, 39000TYMC/mL, and 200 TYMC/mL. The manufacturer recalled all lots of the product andceased shipping to the US.

2018年，一家美国经销商进口了一种适用于婴儿的氧化锌尿布疹霜，该经销商打算将其作为 OTC产品进行销售。经过测试，发现它受到了致病菌污染。尽管该产品不是水基的，并且固有的水分活度很低，但它含有过多的细菌和真菌。有几件样品的需氧微生物计数值特别高，包括 350万 CFU总需氧微生物计数 (TAMC)/mL和 27,000 CFU TAMC/mL等值。许多细菌是芽孢杆菌属的孢子形成者。酵母菌和霉菌计数水平也非常高，包括 2700酵母菌和霉菌总数 (TYMC)/mL、39000 TYMC/mL和 200 TYMC/mL。生产商召回了所有批次的产品并停止向美国发货。

Case 5: Topical creamcontaminated with Enterobacter, sp.

案例 5：受肠杆菌污染的外用乳膏。

In 2018 amanufacturer of a topical cream-based drug became aware that several lots oftheir product were contaminated with Enterobacter,sp. The product was inadvertently shipped prior to the completion of themicrobial assay, which resulted in a microbial count that was TNTC. In additionto the assay, there was an unusually strong odor not typically associated withthe product. After the recall was initiated, the manufacturer received customercomplaints regarding a strong odor from the product. The potential root causefor the microbiological contamination was suspected to be improper changeovercleaning of the filling equipment. Several corrective actions were taken toprevent future microbial contamination of product, including revision of preventativemaintenance and release testing procedures and employee re-training.

2018年，一家外用乳膏型药物的生产商意识到他们的几批产品被肠杆菌属污染。该产品在微生物测定完成之前被无意运出，导致微生物计数为 TNTC。除了分析结果之外，还有一种产品通常并不会有的异常强烈气味。召回开始后，生产商收到了客户关于产品气味强烈的投诉。微生物污染的潜在根本原因被怀疑是灌装设备的转换清洁不当。生产商采取了多项纠正措施以防止产品未来受到微生物污染，包括修订预防性维护和放行测试程序以及员工再培训。

Case 6: Alcohol antisepticscontaminated with Bacillus cereus

案例 6：酒精防腐剂被蜡样芽孢杆菌污染

In 2011,an alcohol-based antiseptic product was produced under poor manufacturingconditions and the product was found to be contaminated with Bacillus, spp., including Bacillus cereus.

2011年，有一种酒精类防腐剂产品生产条件恶劣，结果该产品被发现受到芽孢杆菌属的污染，包括蜡状芽孢杆菌。

Adverseevents were reported to be associated with the contaminated antiseptics.Inspection of the firm found lack of appropriate controls to preventcontamination during formulation, filling, and storage of the drug products.Equipment was also observed to be insufficiently cleaned.

据报道，不良事件与受污染的防腐剂有关。对该公司的检查发现，在配制、灌装和储存过程中缺乏适当的控制措施来防止污染，还发现设备清洁不充分。

Thesedeficient conditions likely contributed to the contamination events. Themanufacturer issued a voluntary nationwide recall of all lots of alcohol preppads, alcohol swabs, and alcohol swab sticks, due to confirmed and potentialmicrobial contamination.

这些缺陷条件可能导致了污染事件。鉴于已确认的和潜在的微生物污染，生产商在全国范围内自愿召回了所有批次的酒精准备垫、酒精棉签和酒精棉签棒。

Case 7: Contamination of an APIwith Aspergillus, sp. and Enterobacter, sp.

案例 7：原料药被曲霉属和肠杆菌属污染。

In 2016,a manufacturer of an API that is further utilized by other manufacturers toderive oral and injectable finished pharmaceuticals became aware of customercomplaints that their API contained TNTC/g levels of fungal contamination byvarious Aspergillus species. The rootcause for this microbiological contamination appeared to be related to parts ofthe drying equipment used to dry the API. As corrective action, the APImanufacturer replaced defective drying equipment ductwork to prevent trappedmoisture from collecting within it, and revised existing preventivemaintenance/monitoring procedures to enable a more robust control againstmicrobiological contamination. The API manufacturer initiated a voluntaryrecall that impacted several API lots over the course of one year, and severalmanufacturers of finished drug products. There were no reported injuries orillnesses associated with the contaminated product.

2016年，一家 API生产商被其他生产商进一步用于生产口服和注射成品药物，他们意识到客户抱怨他们的 API含有 TNTC/g水平的各种曲霉属真菌污染。这种微生物污染的根本原因似乎与 API的干燥设备部件有关。作为纠正措施，API生产商更换了有缺陷的干燥设备管道系统，以防止水分聚集在其中，并修改了现有的预防性维护/监控程序，以便对微生物污染进行更有效的控制。 API生产商发起了一项自愿召回，一年生产的多批 API和几个制剂生产商受到影响。未报告与受污染产品相关的伤害或疾病。

In 2014,another manufacturer of a bulk cream base used to compound topical drugsrecalled several lots of its bulk cream due to high counts of mold andbacteria, and specifically high counts of Aspergillus,sp. and Penicillium, sp. (among other microorganisms). The root cause ofthe microbial growth was insufficient manufacturing instructions that resultedin personnel adding lower amounts of preservatives than needed to ensureuniform distribution throughout each of the affected batches. When the final productswere manufactured, enclosing the cream in its final container/closure resultedin the development of moisture as the product cooled. The moisture enabled moldto grow. Microbial assays of impacted lots all demonstrated mold growth, andcorresponding microbial identity testing demonstrated lower preservativeamounts in impacted batches. To mitigate future errors, the bulk creammanufacturer modified their manufacturing procedures and processes to ensureuniform distribution of the preservatives in each bulk cream batch.

2014年，另一家用于配制外用药物的散装乳膏基质生产商召回了多批散装乳膏，原因是霉菌和细菌数量过多，特别是其中的曲霉属和青霉菌属。微生物生长的根本原因是生产说明不充分，导致人员添加的防腐剂量低于确保每个受影响批次均匀分布所需的防腐剂量。在生产最终产品时，将膏剂封闭在其最终容器/密封件中导致产品冷却时产生了水分，而水分使霉菌得以生长。受影响批次的微生物检测均表明有霉菌生长，相应的微生物鉴定测试表明受影响批次的防腐剂含量较低。为了减少未来的错误，散装膏剂生产商修改了他们的生产程序和流程，以确保防腐剂在每个散装膏剂批次中的均匀分布。

Case 8: Fungal contaminationtraced to excipient

案例 8：真菌污染追踪到赋形剂

In 2001, a manufacturer recalled 45 lots of Glyburide tabletsfor fungal contamination. The source of the contamination was traced to afiller/binder excipient used in the formulation. A subsequent FDA WarningLetter cited the firm for not conducting an adequate investigation to determinethe sources of the fungal contaminants and identify other Glyburide tablet lotsmanufactured which used the same excipient lots as well as the failure toappropriately sample and test the excipient. Additional investigation foundthat the air used in the drying process of the excipient was contaminated withseasonal fungal spores during the chemical synthesis of excipient at the excipientmanufacturing facility.

2001年，一家生产商因真菌污染召回了 45批格列本脲片。污染源被追溯到配方中使用的填充剂/粘合剂辅料。随后的 FDA警告信指出，该公司没有进行充分的调查，以确定真菌污染物的来源，并确定使用相同辅料批次生产的其他格列本脲片批次，以及未能对辅料进行适当取样和测试。进一步调查发现，在辅料生产设施进行辅料化学合成期间，辅料干燥过程中使用的空气被季节性真菌孢子污染。

Case 9: Contamination of eletriptan hydrobromide with Pseudomonas, sp. And

Burkholderia, sp.

案例 9：氢溴酸依来曲坦被假单胞菌和伯克霍尔德菌污染。

In 2019, a firm recalled two lots of eletriptan hydrobromidebecause these product lots failed microbiological specifications for thepotential presence of Pseudomonas,sp. and Burkholderia, sp. For thegeneral population these risks are low, and may include temporarygastrointestinal distress without serious infection. However, for certainvulnerable patient populations (such as patients with compromised immunesystems, cystic fibrosis and chronic granulomatous disease) this objectionablecontamination may pose the potential for serious adverse events includinglife-threatening infections.

2019年，一家公司召回了两批氢溴酸依曲普坦，因为这些产品批次不符合可能存在假单胞菌和伯克霍尔德菌属的微生物标准。对于一般人群而言，这些风险较低，可能包括无严重感染的暂时性胃肠不适。然而，对于某些易损患者群体（例如免疫系统受损、囊性纤维化和慢性肉芽肿病的患者），这种有害污染可能会导致严重的不良事件，包括危及生命的感染。