近日，FDA發布了《行業指南：非無菌藥品生產中的微生物質量考量》指南草案，用以幫助生產商確保其非無菌藥品（NSD）的微生物質量。適用于固體非無菌制劑，以及半固體和液體非無菌制劑（例如，局部使用的膏劑和乳劑和擦劑，以及口服溶液和混懸液）。也有助于生產商符合制劑和API的CGMP要求。
文件提及非無菌藥品微生物風險評估方法并給出詳細的指導
基于風險的影響評估
產品特定要素
劑型：液體制劑一般比其它類別制劑更有可能生長微生物，半固體制劑則一般比固體更有可能生長微生物
水活度
非水性NSD的水活性應該低到足以抑制微生物生長
如果NSD有更高的水活性，則微生物生長的可能性更高，因此需要額外的生產控制
所擬用途
考慮患者人群—可能暴露于藥品的患者群和最脆弱的用藥患者疾病狀態
考慮給藥途徑
考慮可能攝入NSD的身體部位（例如，皮膚、呼吸道、胃腸道或泌尿道），以及組織是否可能受損或患病，從而更易于被感染
考慮產品使用設置（例如，手術間，NICU）
包裝
確保容器/密閉器提供足夠的保護，不受可能導致微生物污染的可預見外來因素影響（例如，水或微生物侵入）
在選擇NSD包裝時考慮單劑量VS多劑量容器密閉器的適當性。對于特定劑型，單劑量容器/密閉器可提供更高安全性，防止外來微生物侵入制劑成品
產品組分和比例
考慮選擇適當的防腐劑，確保防止貨架期微生物繁殖的有效性
確保所有批次進廠原料適合于其既定用途，包括可接受微生物質量
微生物測試—產品特定考量
為組份、中間體和成品建立適當的微生物限度
確保取樣計劃能發現批內差異
確保方法有適當的靈敏度，能檢出可能出現在組份和成品中的不同微生物，以及可能對患者或產品穩定性有風險的微生物
對用作組份的水（包括用作工藝助劑的水）執行適當的行動限和檢測方法。USP建議固體口服制劑用純化水不超出100CFU/ml。其它制劑可能適用更嚴格的微生物質量標準。
生產要素
o生產工藝步驟：某些工藝步驟可能比其它步驟在提高或降低生物負載方面有更大影響。
散裝存貯步驟，尤其是那些水基生產工藝，可能會創造條件讓微生物可以繁殖，尤其是在延長的中間體保存時間段內（即，不同單元操作之間的時間）。其它生產步驟可能會引入致病菌。因此，不建議延長水基中間體的保存時長（例如，包衣混懸液/溶液、添加防腐劑之前的液體混合物）。必須建立保存時限以保持產品質量。
設備清潔工藝不充分，例如，延長清潔之前的放置時長，以及設備清潔之后干燥不充分，亦有可能增加微生物污染。
環境控制不充分，例如生產區域向自然環境敞開、不受控，或當產品或產品接觸表面暴露時環境控制不充分可能會增加微生物污染。
有些生產步驟（例如，涉及過濾、高溫、極端pH值或有機溶劑的那些步驟）可能會使得中間體生物負載降低。
o組份：非無菌組份在生產工藝中可能是致病菌的來源。必須建立這些組份的適當質量標準，以及監測、控制、預防致病菌的策略。特別要注意純化水和天然組份，因為其屬性具備污染風險。
o水系統：用作組份的水（或用作工藝助劑）必須像其它組份一樣，具備適當的質量，適合其既定工藝和配方用途。如果水是公司自制，用作一種組份，則純化水系統必須設計優良，受到嚴格控制和維護。水純化系統的維護和控制應包括主動更換部件以預防老化，進行常規監測以確保系統可持續產出滿足其既定質量特性的水。監測程序應結合適當的行動限和警戒限，包括在關鍵水處理步驟之后，水處理設備和傳送系統后及時取樣，包括所有使用點。用作清潔劑的水，根據其使用條件和設備，應予以監測從而確保其符合既定用途的適當質量。
o環境：生產商必須確保設施、設備和環境條件足以確保生產空氣質量受控，如防止引入可能對所生產的特殊NSD有害的微生物污染或生物負載。生產商應定期識別生產設施中出現的微生物，這些微生物有可能導致NSD污染，確保其控制措施有效降低這些微生物對其NSD的影響。
o設備：通過適當設計（例如，容器、管道）、維護、清潔和消毒來限制生物負載，維護設備的衛生條件至關重要。
o清潔和消毒劑：生產商必須使用合適的清潔/消毒劑，確保以清潔和衛生的方式對建筑物和設施進行維護，其中應包括確保它們不會成為致病菌港灣。適當的設備清潔對于防止致病菌污染組份、容器、密閉器、包材和藥品來說至關重要。
o人員：生產商應采取措施建立和維護適當的粒子，將人員引入致病菌到生產工藝的潛在影響降至最低。他們必須確保人員遵守優良衛生規范。
o中控檢測：生產商需要建立程序確保中間體質量與制劑成品的既定標準相一致，其中包括評估生產過程中是否滿足微生物屬性要求。
o微生物放行測試（適當時）
文件提出根據基于風險的影響性評估減少固體劑型微生物放行檢測的可能性：有水活性但不支持營養微生物生長的固體制劑是降低產品放行和穩定性測試中微生物項目的優秀候選對象。ICHQ6A“新原料藥和新制劑檢驗方法和可接受標準：化學物質”包括有在何條件下可考慮“定期執行或跳檢”微生物計數檢測的條件。ICHQ6A中的建議是基于產品特性的，同時提供了確定適當的微生物檢測計劃的邏輯方法。要支持刪除或減少固體制劑的微生物放行檢測，生產商應按本指南節IV.B所建議的執行基于風險的影響性評估。經過適當的論證，包括生產商在NSD生產中的歷史經驗，例如微生物放行和穩定性數據的數量、所有負面發現和工藝、設施和組份生物負載控制的程度，可刪除或減少低風險固體制劑穩定性計劃中的微生物檢測。注意有些固體制劑含有支持生長的組份，如蛋白類組份，則應進行風險評估以確定其是否可以降低或刪除穩定性方案中的微生物測試。
全文翻譯如下：
TABLEOFCONTENTS
目錄
I.INTRODUCTION
前言
II.BACKGROUND
背景
III.STATUTORYANDREGULATORYFRAMEWORK
法律法規框架
IV.MICROORGANISMSANDLIFECYCLEPRODUCTQUALITY
微生物和生命周期產品質量
A.General─MicrobiologicalConcernsRegardingNSDs
概述--NSD的微生物關切
B.Risk-BasedImpactAssessment
基于風險的影響評估
1.ProductSpecificElements
產品特定要素
2.ManufacturingElements
生產要素
C.MicrobiologicalConcernsforSpecificDosageFormsandSpecialCases
特定劑型的微生物關切和特殊案例
1.SolidDosageForms
固體劑型
2.Non-SolidDosageForms
非固體劑型
3.MicrobiologicalConsideration–SpecialCases
微生物考量—特殊案例
D.UpdatingApprovedDrugProductSpecifications
更新已批準藥品質量標準
APPENDIX:CASESTUDYEXAMPLESOFMICROBIOLOGICALCONTAMINATIONOFNSDPRODUCTS;IMPACTONPRODUCTQUALITYANDMANUFACTURINGPROCESS
附錄：案例研究：NSD產品的微生物污染示例；對產品質量和生產工藝的影響
MicrobiologicalQualityConsiderationsinNon-sterileDrugManufacturingGuidanceforIndustry
行業指南：非無菌藥品生產中的微生物質量考量
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).
本指南意在協助生產商確保其非無菌藥品（NSD）的微生物質量。此處的建議適用于固體非無菌制劑，以及半固體和液體非無菌制劑（例如，局部使用的膏劑和乳劑和擦劑，以及口服溶液和混懸液）。NSD可以是處方藥亦可以是非處方藥，它包括以 NDA或 ANDA批準上市的藥品，以及沒有 NDA批準受 FDCA第 505G條規定管理的非處方藥（通常稱為 OTC各論藥）。這些建議（如得到遵守）亦有助于生產商符合制劑和 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.
本指南討論的是產品開發考量、風險評估和特定的 CGMP，特別是與 NSD生產操作中的微生物控制有關的部分。它還提供了建議幫助生產商評估其 NSD受致病菌的污染風險，從而建立適當的質量標準和生產控制，防止此類污染，確保 NSD的安全性、質量、鑒別、純度和有效性。
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.
對于申報產品（即 NDA、ANDA），本指南亦解釋了申報人應在原始申報中提交 NSD控制措施，并向 FDA報告微生物質量標準和檢測方法變更，滿足 FDA關于已批準申報的現行變更指南。
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.
為了說明微生物風險評估和控制策略的重要性，本指南討論了洋蔥伯克霍爾德菌復合體（BCC）事件和其它非無菌制劑的微生物污染導致不良事件和產品召回的情況。本指南闡述了 NSD水性制劑中 BCC的恰當預防和檢測。
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目前對供專業醫療人員在醫院環境或醫院外其他衛生保健情況下使用的外用抗菌藥物的微生物污染的看法。這些藥品是在醫療程序之前使用以減少皮膚上細菌數量的。它們在某些情況下不是作為無菌產品生產的。
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.
本指南的內容并沒有強制法律效力，不會以任何形式對公眾形成約束力，簽訂在合同的條款除外。本文僅意在向公眾澄清現有法律下的要求。
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的指南文件應僅看作是建議，其中引用的具體法律法規要求除外。SHOULD一詞在 FDA指南中表示建議某事，但并非強制。
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，術語“microbiological”和“microbial”均為微生物，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，非無菌藥品（NSD）指非無菌制劑。
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).
術語“OTC各論藥”指沒有已批準 NDA的非處方藥，它根據 FDCA第 505G章 744L(5)節進行管理。
5 See 21CFR parts 210 and 211, CGMP for Finished Pharmaceuticals, a nd FD&C Actsection 501(a)(2)(B) for APIs.
參見 21 CFR第 210和 211節，制劑 CGMP，和 FDCA法案節 501(a)(2)(B)的 API內容。
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).
術語“致病菌”在此指由于其對產品或患者有不良影響因而有害的菌，或者是由于其總微生物數量而有害的菌。參見 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).
此類產品包括衛生健康護理人員洗手液、衛生護理人員消毒液、外科手術用手消毒液、外科手術用手洗手液，以及患者備皮用消毒液（即患者術前和注射前皮膚準備）。
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為 FDA對 FDA不良事件報告（FAER）和涉及非無菌劑型污染的召回的審查。對 2014年至 2017年間發生的 FAER的審查顯示，有 197起 FAER與內在微生物或真菌污染有關，其中 32起報告了嚴重的不良事件。
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中的自發報告根據定義是自愿的，因此 FDA預計會有一定程度的漏報。與微生物污染相關的實際事件數量可能明顯高于已報告的事件數量 。
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.
對同一時期自愿召回行動的審查顯示，超過 50起事件與有害微生物污染 NSD相關。召回表明，在水性和非水性 NSD中都發現了廣泛的有害微生物 。
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還意識到 BCC及其與導致一系列嚴重不良事件（即感染和死亡）的水基 NSD污染的關聯引發的擔憂。2017年 5月，FDA發布了一份聲明，提醒藥品生產商注意最近的產品召回與 NSD中存在 BCC相關。該聲明還提醒藥品生產商他們有責任防止有害微生物對其 NSD生產過程以及產品本身產生不利影響。
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.
對這些事件的分析，結合 FDA對 NDA和 ANDA產品的非無菌藥物進行微生物學評估和合規行動的經驗，為本指南中的建議提供了信息。
8FDA Adverse Event ReportingSystem (FAERS) La test Quarterly Da ta Files -https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEff ects/ucm082 193.htm.
FDA不良事件報告系統（FAERS）最新季度數據文件鏈接。
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). “內在”是指微生物或真菌污染源于藥物的生產、包裝、運輸或儲存，而不是來自外在來源（例如，消費者或醫療保健提供者的使用錯誤）。
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.關于“自發報告”的定義參見 FDA公眾對不良事件報告的關注。
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/.根據 FDA的 FAER問答“FDA不會收到一個產品的不良事件或錯誤用藥情況報告……如果患者和申報人【藥品生產商】提交了相同的報告，則會有兩份報告”
12 Seefootnote 6.
參見腳注 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鏈接。
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,與液體多庫酯鈉污染相關的醫療保健相關洋蔥伯克霍爾德菌復合感染的多州調查，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告知藥品生產商關于洋蔥伯克霍爾德菌復合物對非無菌水基藥品造成污染風險，2017年 5月
III. STATUTORYAND REGULATORY FRAMEWORK
法律法規框架
Undersection 501(a)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act17), a drugwill be deemed adulterated if:
根據《聯邦食品、藥品和化妝品法案》（FD&C法案）第 501(a)(2)條，如果出現以下情況，藥物將被視為摻假：
“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.”
“用于其生產、加工、包裝或保存的方法，或用于其生產、加工、包裝或保存的設施或控制不符合或未按照 CGMP操作或管理，以確保此類藥物符合本法的安全要求，具有鑒別和含量，并符合其聲稱或理當具備的質量和純度特征”，或“如果它在不衛生的條件下制備、包裝或保存，可能已被臟物污染，或有可能損害健康。”
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:
對于成品藥物，21 CFR第 210和 211部分中描述的 CGMP法規涉及預防非無菌藥品、生物負載標準和中控測試中的有害微生物。具體來說：
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，指出應建立并遵循適當的書面程序，旨在防止不需要無菌的藥品中出現有害微生物。
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)，中間體和成品的取樣和測試，要求（在適當的情況下）中間體生物負載測試和有效的中控標準以確保成品符合其微生物標準。中控測試應在產品工藝過程中進行，例如，在重要階段的開始或完成時，或在長期儲存后。
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年代中期開始 CMC微生物審評，側重于水基 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)，適當時，應對組件進行顯微鏡檢查。考慮到其預期用途，具有潛在微生物污染的每個批次的組件、藥品容器或密封件都應在使用前進行微生物測試。
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.
為了確保需要上市前批準的 NSD的微生物質量，申請人必須根據 21CFR 314.50(d)(1)【NDA】和 21CFR 314.94(a)(9)【ANDA】提出適當的原料藥和制劑質量標準（即檢測項目、分析方法和可接受標準）。
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，具有官方藥典認可名稱的藥物必須符合美國藥典 (USP)藥典標準關于鑒別、含量、質量和純度，否則會被視為摻假、貼錯標簽，或兩者兼而有之。如果 USP為藥物制定了各論，USP各論將確定官方檢測項目、檢驗方法、可接受標準和其他要求。當 USP各論有引用“適用通則”的測試或標準時，申請人應確保其各論產品符合測試要求，否則可能被視為摻假。有些 USP通則在藥物各論中被引用的更為頻繁，因為它們適用于控制 NSD中的微生物活動，例如：
USP <60> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS TESTS FOR BURKHOLDERIA CEPACIA COMPLEX
USP <60>非無菌產品的微生物學檢查：伯克霍爾德氏菌復合物
USP <61> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS:MicrobialEnumeration Tests
USP <61>非無菌產品的微生物檢驗：微生物計數檢測
USP <62> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: Testsfor Specified Microorganisms
USP <62>非無菌產品微生物檢驗：特定微生物檢測
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各論要求，通常如 21 CFR第 211部分所述，將進一步的微生物測試作為批次放行要求的一部分執行。
Objectionablemicroorganisms and bioburden in non-sterile APIs should be controlled. FDAguidance for industry Q7 GoodManufacturing Practice Guidance for Active Pharmaceutical Ingredients (September2016) states:
應控制非無菌原料藥中的有害微生物和生物負載。 FDA行業指南 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.”
“應根據公認的標準為 API制定適當的標準并與生產過程一致。標準應包括對雜質（例如有機雜質、無機雜質和殘留溶劑）的控制。如果 API有微生物純度標準，則應建立并滿足總微生物計數和有害微生物的適當行動限制。”
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).
關于【質量標準 specification】的定義，參見 21 CFR 314.3(b)和 ICH Q6A“質量標準：新原料藥和新制劑的檢驗方法和可接受標準：化學物質（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.”
參見 USP<3.10>“標準符合性”，“適用通則”指1000號以內的通則，或大于 2000通過在范例、各論或另一個編號小于 1000的適用通則中的引用讓其適用于某物的通則。
IV. MICROORGANISMS AND LIFECYCLEPRODUCT QUALITY
微生物和生命周期產品質量
A. General ─Microbiological Concerns Regarding NSDs
關于 NSD的微生物擔憂—概況
Prevention,control, and monitoring of the microbiological population in non-sterile drugcomponents and drug products are necessary to minimize the risk of:
為了將以下風險降至最低，有必要對非無菌藥品組份和制劑中微生物群進行預防、控制和監測：
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謝物和/或毒素
drug spoilage or degradation
藥品變質或降解
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規框架，配以科學合理的原理，提供了建立程序對生產工藝進行監測和控制，從而防止致病菌影響 NSD質量的基礎。
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.
為確保產品質量和患者安全，有必要限制生產及產品貨架期間 NSD中微生物的水平和類型。雖然不要求 NSD是無菌的，但存在一個微生物含量的閾值，高于該閾值可能會對指定 NSD的安全性和有效性產生不利影響。
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法規要求將放行組份之前由生產商的質量控制部門對其取樣檢測或檢查。天然組份（例如植物或動物來源成分，和天然產生的成分如水）可能會對藥品的總生物負載貢獻巨大，必須根據既定程序進行微生物檢測。例如，水是 NSD生產中常用成分，但是由于取樣局限性，可能難以發現水系統控制偏差，而這些偏差有可能導致形成生物膜，已證明這些偏差對水基藥品的微生物質量有深遠影響。
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，適當的水系統設計和控制、恰當的微生物行動限，以及日常水質量檢測對于確保微生物水平低于既定限度，并且水中沒有致病微生物是至關重要的。所以生產商具備穩健的水系統設計，包括設計用于防止致病微生物的控制措施和監測、清潔及維護程序是非常重要的。
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并不僅限于通過已批準申報上市的藥品。參見 FDCA第 501(a)節和 21CFR節 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，我們定義“免疫功能低下患者”為免疫系統減弱的患者，這可能是由于外傷、手術、疾病或慢性病所致。它還包括弱勢群體，例如嬰兒和老人。患者暴露于有害的微生物代謝物和/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.
在確定所用水是否支持批生產持續滿足預定質量屬性時，執行有效的持續監測程序是很重要的。對于生產操作中有水的藥品，一般適用更為靈敏的取樣策略，應該包括使用更大樣品數量（例如 100ml）采用膜過濾法檢測。
26Microbial action limits shouldbe established based on the risk-based impact assessment, a s described insection IV.B.
應按節 IV.B所述根據基于風險的影響性評估建立“微生物行動限”。
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.
在產品貨架期內由于具備水活性（aw）所以可支持微生物生長的水基非無菌藥品的設計應該能夠防止內含微生物或在使用中被無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.
雖然生產過程中或整個生命周期存貯期間的微生物生長可能性可能會因為設計有適當的防腐系統或配方而有部分降低，但抗菌防腐劑可能會在微生物存在或生長方面導致產品安全假象。防腐劑的 2個目的是對抗患者多次使用藥品期間可能的意外微生物污染，以及在產品生命周期中保持對微生物的控制。防腐劑并不能全面取代防止致病菌污染 NSD的所有方法，不應認為其可降低生產期間中控生物負載。已經發現有些微生物可使得常用防腐劑降解，即使這些藥品之前是滿足抗菌有效性測試可接受標準的。因此非無菌藥品生產商應該明白防腐劑耐受性發展的可能性。如果檢出致病菌或總微生物計數有上升趨勢，則應該調查防腐劑有效性降低的這種可能性（根本原因分析和糾正措施，以消除污染來源）。這個問題作為關于洋蔥伯克霍爾德菌復合物和水性藥物產品的特殊案例研究在第 IV.C.3.a節微生物注意事項 -本指南的特殊案例中進行了討論。
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，許多非無菌液體藥品并不是水基的，例如那些含有高比例乙醇或其它非水性溶劑，在中間物料加工、保存和貨架期存貯期間的微生物滋生風險可能較低。非無菌固體制劑，如片劑和膠囊的水活性亦較低，通常在產品貨架期內不允許微生物生長。但是，要注意雖然出現在低水活性非無菌藥品中的微生物不會繁殖，但它們可能在非水性液體和干燥藥品中在其整個貨架期內都頑固存在。CGMP法規要求制訂書面程序防止引入致病菌污染到不要求無菌的藥品生產中，并設計有程序評估藥品（包括 NSD）的穩定性。因此，即使該組份水活性很低，為非無菌藥品組份（例如，輔料和 API）提供適當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.
非無菌固體制劑還可能在生產期間通過污染產生微生物滋長風險。例如，延長固體制劑的水性溶液或漿料中間體在不同生產工藝點放置時長，可能會使得微生物滋生超出此類劑型的適當水平。
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，制定時限的程序對于確保液體和固體 NSD生產過程中使用的每個工藝步驟的產品質量（包括微生物質量控制）從而防止存在致病菌至關重要。
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.
雖然并不完全，但 USP提供了被廣泛接受的一套非無菌藥品微生物檢測方法。USP亦建議除了所選擇的 NSD中指定微生物外，制訂微生物總計數可接受標準。但是，USP并未提供完整的致病菌清單，因此公司應識別所有額外控制措施和必要的可接受標準。應為每種產品確定是否需要對致病菌制訂更多控制措施。例如，BCC存在于水性非無菌藥品中有可能導致藥品降解和患者感染。在建立微生物質量標準，確定一個特定的微生物在一個藥品中是否致病時，應考慮目標患者人群、藥品適應癥以及給藥途徑。
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，水分活度與水分含量不同。 USP <1112>將水分活度定義為藥物中水蒸氣壓與周圍空氣介質完全不受干擾時的蒸汽壓與相同條件下蒸餾水蒸氣壓的比值。參見 USP <1112>水活度測定在非無菌藥物產品的應用。相反，水含量是藥物中的水分含量。
30 There havebeen recalls in a lcohol based products. Refer to Appendix, Case 6.
乙醇基藥品曾有過召回，參見附錄案例 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>微生物計數測試和 USP<62>指定微生物檢測。
34USP<1111> MICROBIOLOGICALEXAMINATIONOFNONSTERILE PRODUCTS: ACCEPTANCE CRITERIA FOR PHARMACEUTICALPREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE.
USP<1111>非無菌藥品的微生物檢查：制劑和藥用物質的可接受標準。
B. Risk-Based Impact Assessment
基于風險的影響性評估
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決于 NSD的微生物污染風險（可能性和危害潛力），包括 NSD特性（例如，配方、成分選擇、使用條件和給藥途徑）、NDS生產工藝，以及生產環境的影響。如果生產工藝經過良好設計并受到恰當控制，則引入致病菌及其繁殖或生長的機會就會很小。對于特定的低風險生產操作（例如，片劑生產），可使用風險評估支持減少微生物監測和檢測（參見以下節 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.
基于風險的影響性評估有助于生產商識別更有可能引入生物負載或致病菌至 NSD的產品特有屬性和生產工藝要素。根據這個基于風險的影響性評估設計的風險緩解系統更有可能預防 NSD中的致病菌。下列要素雖然并不是完全清單，但在風險管理計劃中應予以考慮，以降低致病菌（如相關）。
1. Product Specific Elements
產品特有要素
o DosageForm
劑型
Liquid products typically have ahigher potential for microbial growth than other types, and semi-solidstypically have a higher potential for microbial growth than solids35.
液體制劑一般比其它類別制劑更有可能生長微生物，半固體制劑則一般比固體更有可能生長微生物
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.
劑型將決定對成品進行微生物計數測試的類型和程度。USP <61>和USP <62>中描述了通用的計數檢測。對于固體劑型，ICH Q6A《新原料藥和新藥產品的檢驗方法和可接受標準：化學物質》包括關于微生物計數測試的“定期或跳過測試”條件的建議。
o WaterActivity36
水活度
Water activity of non-aqueousNSDs should be low enough to inhibit microbial growth.
非水性 NSD的水活性應該低到足以抑制微生物生長
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，則微生物生長的可能性更高，因此需要額外的生產控制
o ProposedUse
所擬用途
Consider the patient population–thespectrum of patients that could be exposed to the drug and disease state of themost vulnerable patients taking the drug.
考慮患者人群—可能暴露于藥品的患者群和最脆弱的用藥患者疾病狀態
Consider the route ofadministration.
考慮給藥途徑
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.
考慮可能攝入 NSD的身體部位（例如，皮膚、呼吸道、胃腸道或泌尿道），以及組織是否可能受損或患病，從而更易于被感染
Consider the setting in which theproduct is used (e.g., operating room, NICU).
考慮產品使用設置（例如，手術間，NICU）
o Packaging
包裝
Ensure container/closure providesadequate protection from foreseeable external factors that can lead tomicrobial contamination (e.g., water or microbial ingress37).
確保容器/密閉器提供足夠的保護，不受可能導致微生物污染的可預見外來因素影響（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.
在選擇 NSD包裝時考慮單劑量 VS多劑量容器密閉器的適當性。對于特定劑型，單劑量容器/密閉器可提供更高安全性，防止外來微生物侵入制劑成品
o ProductComponents and Composition
產品組分和比例
Consider selection of appropriatepreservatives that assure effectiveness to prevent
考慮選擇適當的防腐劑，確保防止貨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.
確保所有批次進廠原料適合于其既定用途，包括可接受微生物質量
o MicrobiologicalTesting–Product Specific Considerations
微生物測試—產品特定考量
Establish appropriate microbiallimits for components, in-process materials, and finished products40.
為組份、中間體和成品建立適當的微生物限度
Ensure the sampling plan detectsvariation within a batch41.
確保取樣計劃能發現批內差異
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.
確保方法有適當的靈敏度，能檢出可能出現在組份和成品中的不同微生物，以及可能對患者或產品穩定性有風險的微生物
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.
對用作組份的水（包括用作工藝助劑的水）執行適當的行動限和檢測方法。USP建議固體口服制劑用純化水不超出 100CFU/ml。其它制劑可能適用更嚴格的微生物質量標準。
2. Manufacturing Elements
生產要素
o ManufacturingProcess Steps: Certain processing steps may have a greater impact than othersin either promoting or reducing bioburden.
o 生產工藝步驟：某些工藝步驟可能比其它步驟在提高或降低生物負載方面有更大影響。
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.
散裝存貯步驟，尤其是那些水基生產工藝，可能會創造條件讓微生物可以繁殖，尤其是在延長的中間體保存時間段內（即，不同單元操作之間的時間）。其它生產步驟可能會引入致病菌。因此，不建議延長水基中間體的保存時長（例如，包衣混懸液/溶液、添加防腐劑之前的液體混合物）。必須建立保存時限以保持產品質量。
Inadequate equipment cleaningprocesses, such as extended hold times before cleaning and insufficient dryingafter equipment has been cleaned, may also promote microbiologicalcontamination.
設備清潔工藝不充分，例如，延長清潔之前的放置時長，以及設備清潔之后干燥不充分，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.
環境控制不充分，例如生產區域向自然環境敞開、不受控，或當產品或產品接觸表面暴露時環境控制不充分可能會增加微生物污染。
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.
有些生產步驟（例如，涉及過濾 、高溫、極端 pH值或有機溶劑的那些步驟）可能會使得中間體生物負載降低。
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>水活性檢測在非活性藥品中的應用—降低后的水活性（aw）很大程度上能幫助防止微生物在藥品中的滋生，因此非無菌藥品的配方、生產步驟和檢測過程應反映出該參數。
37CFR211.94(b).
38 USP <659> PACKAGING ANDSTORAGEREQUIREMENTS. USP <659>“包裝和存貯要求”。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>“制藥用水”。
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 組份：非無菌組份在生產工藝中可能是致病菌的來源。必須建立這些組份的適當質量標準，以及監測、控制、預防致病菌的策略。特別要注意純化水和天然組份，因為其屬性具備污染風險。
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 水系統：用作組份的水（或用作工藝助劑）必須像其它組份一樣，具備適當的質量，適合其既定工藝和配方用途。如果水是公司自制，用作一種組份，則純化水系統必須設計優良，受到嚴格控制和維護。水純化系統的維護和控制應包括主動更換部件以預防老化，進行常規監測以確保系統可持續產出滿足其既定質量特性的水。監測程序應結合適當的行動限和警戒限，包括在關鍵水處理步驟之后，水處理設備和傳送系統后及時取樣，包括所有使用點。用作清潔劑的水，根據其使用條件和設備，應予以監測從而確保其符合既定用途的適當質量。
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 環境：生產商必須確保設施、設備和環境條件足以確保生產空氣質量受控，如防止引入可能對所生產的特殊 NSD有害的微生物污染或生物負載。生產商應定期識別生產設施中出現的微生物，這些微生物有可能導致 NSD污染，確保其控制措施有效降低這些微生物對其 NSD的影響。
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 設備：通過適當設計（例如，容器、管道）、維護、清潔和消毒來限制生物負載，維護設備的衛生條件至關重要。
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 清潔和消毒劑：生產商必須使用合適的清潔/消毒劑，確保以清潔和衛生的方式對建筑物和設施進行維護，其中應包括確保它們不會成為致病菌港灣。適當的設備清潔對于防止致病菌污染組份、容器、密閉器、包材和藥品來說至關重要。
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 人員：生產商應采取措施建立和維護適當的粒子，將人員引入致病菌到生產工藝的潛在影響降至最低。他們必須確保人員遵守優良衛生規范。
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 中控檢測：生產商需要建立程序確保中間體質量與制劑成品的既定標準相一致，其中包括評估生產過程中是否滿足微生物屬性要求。
o MicrobiologicalRelease Testing (as appropriate):
o 微生物放行測試（適當時）
Total microbial content(microbiological enumeration testing57)
總微生物含量（微生物計數）
Specified organism testing andidentification program to identify other objectionable microorganisms58
特定微生物測試和鑒別程序，以鑒別其它致病菌
46See 21CFR 211.160(b).
47See 21CFR 211.100(a), 211.113(a).
48USP <1231> WATER FORPHARMACEUTICAL PURPOSES.
USP <1231>“制藥用水”。
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>“制藥用水”對不同水質進行了分類，以顯示相關純度和微生物質量。
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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