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FDA發(fā)布《行業(yè)指南：非無(wú)菌藥品生產(chǎn)中的微生物質(zhì)量考量》草案

嘉峪檢測(cè)網(wǎng) 2021-10-08 00:41

近日，F(xiàn)DA發(fā)布了《行業(yè)指南：非無(wú)菌藥品生產(chǎn)中的微生物質(zhì)量考量》指南草案，用以幫助生產(chǎn)商確保其非無(wú)菌藥品（NSD）的微生物質(zhì)量。適用于固體非無(wú)菌制劑，以及半固體和液體非無(wú)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(chǎn)商符合制劑和 API的 CGMP要求。

文件提及非無(wú)菌藥品微生物風(fēng)險(xiǎn)評(píng)估方法并給出詳細(xì)的指導(dǎo)

基于風(fēng)險(xiǎn)的影響評(píng)估

產(chǎn)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(zhǎng)微生物，半固體制劑則一般比固體更有可能生長(zhǎng)微生物

水活度

非水性 NSD的水活性應(yīng)該低到足以抑制微生物生長(zhǎng)

如果 NSD有更高的水活性，則微生物生長(zhǎng)的可能性更高，因此需要額外的生產(chǎn)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(tài)

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(chǎn)品使用設(shè)置（例如，手術(shù)間，NICU）

包裝

確保容器/密閉器提供足夠的保護(hù)，不受可能導(dǎo)致微生物污染的可預(yù)見(jiàn)外來(lái)因素影響（例如，水或微生物侵入）

在選擇 NSD包裝時(shí)考慮單劑量 VS多劑量容器密閉器的適當(dāng)性。對(duì)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(lái)微生物侵入制劑成品

產(chǎn)品組分和比例

考慮選擇適當(dāng)?shù)姆栏瘎?，確保防止貨架期微生物繁殖的有效性

確保所有批次進(jìn)廠原料適合于其既定用途，包括可接受微生物質(zhì)量

微生物測(cè)試—產(chǎn)品特定考量

為組份、中間體和成品建立適當(dāng)?shù)奈⑸锵薅?/span>

確保取樣計(jì)劃能發(fā)現(xiàn)批內(nèi)差異

確保方法有適當(dāng)?shù)撵`敏度，能檢出可能出現(xiàn)在組份和成品中的不同微生物，以及可能對(duì)患者或產(chǎn)品穩(wěn)定性有風(fēng)險(xiǎn)的微生物

對(duì)用作組份的水（包括用作工藝助劑的水）執(zhí)行適當(dāng)?shù)男袆?dòng)限和檢測(cè)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(yán)格的微生物質(zhì)量標(biāo)準(zhǔn)。

2. 生產(chǎn)要素

o 生產(chǎn)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(fù)載方面有更大影響。

散裝存貯步驟，尤其是那些水基生產(chǎn)工藝，可能會(huì)創(chuàng)造條件讓微生物可以繁殖，尤其是在延長(zhǎng)的中間體保存時(shí)間段內(nèi)（即，不同單元操作之間的時(shí)間）。其它生產(chǎn)步驟可能會(huì)引入致病菌。因此，不建議延長(zhǎng)水基中間體的保存時(shí)長(zhǎng)（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(shí)限以保持產(chǎn)品質(zhì)量。

設(shè)備清潔工藝不充分，例如，延長(zhǎng)清潔之前的放置時(shí)長(zhǎng)，以及設(shè)備清潔之后干燥不充分，亦有可能增加微生物污染。

環(huán)境控制不充分，例如生產(chǎn)區(qū)域向自然環(huán)境敞開(kāi)、不受控，或當(dāng)產(chǎn)品或產(chǎn)品接觸表面暴露時(shí)環(huán)境控制不充分可能會(huì)增加微生物污染。

有些生產(chǎn)步驟（例如，涉及過(guò)濾、高溫、極端 pH值或有機(jī)溶劑的那些步驟）可能會(huì)使得中間體生物負(fù)載降低。

o 組份：非無(wú)菌組份在生產(chǎn)工藝中可能是致病菌的來(lái)源。必須建立這些組份的適當(dāng)質(zhì)量標(biāo)準(zhǔn)，以及監(jiān)測(cè)、控制、預(yù)防致病菌的策略。特別要注意純化水和天然組份，因?yàn)槠鋵傩跃邆湮廴撅L(fēng)險(xiǎn)。

o 水系統(tǒng)：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(dāng)?shù)馁|(zhì)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(tǒng)必須設(shè)計(jì)優(yōu)良，受到嚴(yán)格控制和維護(hù)。水純化系統(tǒng)的維護(hù)和控制應(yīng)包括主動(dòng)更換部件以預(yù)防老化，進(jìn)行常規(guī)監(jiān)測(cè)以確保系統(tǒng)可持續(xù)產(chǎn)出滿足其既定質(zhì)量特性的水。監(jiān)測(cè)程序應(yīng)結(jié)合適當(dāng)?shù)男袆?dòng)限和警戒限，包括在關(guān)鍵水處理步驟之后，水處理設(shè)備和傳送系統(tǒng)后及時(shí)取樣，包括所有使用點(diǎn)。用作清潔劑的水，根據(jù)其使用條件和設(shè)備，應(yīng)予以監(jiān)測(cè)從而確保其符合既定用途的適當(dāng)質(zhì)量。

o 環(huán)境：生產(chǎn)商必須確保設(shè)施、設(shè)備和環(huán)境條件足以確保生產(chǎn)空氣質(zhì)量受控，如防止引入可能對(duì)所生產(chǎn)的特殊 NSD有害的微生物污染或生物負(fù)載。生產(chǎn)商應(yīng)定期識(shí)別生產(chǎn)設(shè)施中出現(xiàn)的微生物，這些微生物有可能導(dǎo)致 NSD污染，確保其控制措施有效降低這些微生物對(duì)其 NSD的影響。

o 設(shè)備：通過(guò)適當(dāng)設(shè)計(jì)（例如，容器、管道）、維護(hù)、清潔和消毒來(lái)限制生物負(fù)載，維護(hù)設(shè)備的衛(wèi)生條件至關(guān)重要。

o 清潔和消毒劑：生產(chǎn)商必須使用合適的清潔/消毒劑，確保以清潔和衛(wèi)生的方式對(duì)建筑物和設(shè)施進(jìn)行維護(hù)，其中應(yīng)包括確保它們不會(huì)成為致病菌港灣。適當(dāng)?shù)脑O(shè)備清潔對(duì)于防止致病菌污染組份、容器、密閉器、包材和藥品來(lái)說(shuō)至關(guān)重要。

o 人員：生產(chǎn)商應(yīng)采取措施建立和維護(hù)適當(dāng)?shù)牧Ｗ?，將人員引入致病菌到生產(chǎn)工藝的潛在影響降至最低。他們必須確保人員遵守優(yōu)良衛(wèi)生規(guī)范。

o 中控檢測(cè)：生產(chǎn)商需要建立程序確保中間體質(zhì)量與制劑成品的既定標(biāo)準(zhǔn)相一致，其中包括評(píng)估生產(chǎn)過(guò)程中是否滿足微生物屬性要求。

o 微生物放行測(cè)試（適當(dāng)時(shí)）

文件提出根據(jù)基于風(fēng)險(xiǎn)的影響性評(píng)估減少固體劑型微生物放行檢測(cè)的可能性：有水活性但不支持營(yíng)養(yǎng)微生物生長(zhǎng)的固體制劑是降低產(chǎn)品放行和穩(wěn)定性測(cè)試中微生物項(xiàng)目的優(yōu)秀候選對(duì)象。ICH Q6A“新原料藥和新制劑檢驗(yàn)方法和可接受標(biāo)準(zhǔn)：化學(xué)物質(zhì)”包括有在何條件下可考慮“定期執(zhí)行或跳檢”微生物計(jì)數(shù)檢測(cè)的條件。ICH Q6A中的建議是基于產(chǎn)品特性的，同時(shí)提供了確定適當(dāng)?shù)奈⑸餀z測(cè)計(jì)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(cè)，生產(chǎn)商應(yīng)按本指南節(jié) IV.B所建議的執(zhí)行基于風(fēng)險(xiǎn)的影響性評(píng)估。經(jīng)過(guò)適當(dāng)?shù)恼撟C，包括生產(chǎn)商在 NSD生產(chǎn)中的歷史經(jīng)驗(yàn)，例如微生物放行和穩(wěn)定性數(shù)據(jù)的數(shù)量、所有負(fù)面發(fā)現(xiàn)和工藝、設(shè)施和組份生物負(fù)載控制的程度，可刪除或減少低風(fēng)險(xiǎn)固體制劑穩(wěn)定性計(jì)劃中的微生物檢測(cè)。注意有些固體制劑含有支持生長(zhǎng)的組份，如蛋白類組份，則應(yīng)進(jìn)行風(fēng)險(xiǎn)評(píng)估以確定其是否可以降低或刪除穩(wěn)定性方案中的微生物測(cè)試。

全文翻譯如下：

TABLE OF CONTENTS

I. INTRODUCTION

前言

II. BACKGROUND

背景

III. STATUTORYAND REGULATORY FRAMEWORK

法律法規(guī)框架

IV. MICROORGANISMS AND LIFECYCLEPRODUCT QUALITY

微生物和生命周期產(chǎn)品質(zhì)量

A. General ─Microbiological Concerns Regarding NSDs

概述--NSD的微生物關(guān)切

B. Risk-BasedImpact Assessment

基于風(fēng)險(xiǎn)的影響評(píng)估

1. ProductSpecific Elements

產(chǎn)品特定要素

2. Manufacturing Elements

生產(chǎn)要素

C. MicrobiologicalConcerns for Specific Dosage Forms and Special Cases

特定劑型的微生物關(guān)切和特殊案例

1. SolidDosage Forms

固體劑型

2. Non-SolidDosage Forms

非固體劑型

3. MicrobiologicalConsideration – Special Cases

微生物考量—特殊案例

D. UpdatingApproved Drug Product Specifications

更新已批準(zhǔn)藥品質(zhì)量標(biāo)準(zhǔn)

APPENDIX: CASE STUDYEXAMPLES OF MICROBIOLOGICAL CONTAMINATION OF NSD PRODUCTS; IMPACT ON PRODUCTQUALITY AND MANUFACTURINGPROCESS

附錄：案例研究：NSD產(chǎn)品的微生物污染示例；對(duì)產(chǎn)品質(zhì)量和生產(chǎn)工藝的影響

Microbiological Quality Considerations in Non-sterile Drug ManufacturingGuidance for Industry

行業(yè)指南：非無(wú)菌藥品生產(chǎn)中的微生物質(zhì)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(xié)助生產(chǎn)商確保其非無(wú)菌藥品（NSD）的微生物質(zhì)量。此處的建議適用于固體非無(wú)菌制劑，以及半固體和液體非無(wú)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(zhǔn)上市的藥品，以及沒(méi)有 NDA批準(zhǔn)受 FDCA第 505G條規(guī)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(chǎn)商符合制劑和 API的 CGMP要求。

Thisguidance 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(chǎn)品開(kāi)發(fā)考量、風(fēng)險(xiǎn)評(píng)估和特定的 CGMP，特別是與 NSD生產(chǎn)操作中的微生物控制有關(guān)的部分。它還提供了建議幫助生產(chǎn)商評(píng)估其 NSD受致病菌的污染風(fēng)險(xiǎn)，從而建立適當(dāng)?shù)馁|(zhì)量標(biāo)準(zhǔn)和生產(chǎn)控制，防止此類污染，確保 NSD的安全性、質(zhì)量、鑒別、純度和有效性。

Forapplication 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(duì)于申報(bào)產(chǎn)品（即 NDA、ANDA），本指南亦解釋了申報(bào)人應(yīng)在原始申報(bào)中提交 NSD控制措施，并向 FDA報(bào)告微生物質(zhì)量標(biāo)準(zhǔn)和檢測(cè)方法變更，滿足 FDA關(guān)于已批準(zhǔn)申報(bào)的現(xiàn)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(shuō)明微生物風(fēng)險(xiǎn)評(píng)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(fù)合體（BCC）事件和其它非無(wú)菌制劑的微生物污染導(dǎo)致不良事件和產(chǎn)品召回的情況。本指南闡述了 NSD水性制劑中 BCC的恰當(dāng)預(yù)防和檢測(cè)。

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(duì)供專業(yè)醫(yī)療人員在醫(yī)院環(huán)境或醫(yī)院外其他衛(wèi)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(yī)療程序之前使用以減少皮膚上細(xì)菌數(shù)量的。它們?cè)谀承┣闆r下不是作為無(wú)菌產(chǎn)品生產(chǎn)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(nèi)容并沒(méi)有強(qiáng)制法律效力，不會(huì)以任何形式對(duì)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(xiàn)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(yīng)僅看作是建議，其中引用的具體法律法規(guī)要求除外。SHOULD一詞在 FDA指南中表示建議某事，但并非強(qiáng)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(shù)語(yǔ)“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(wú)菌藥品（NSD）指非無(wú)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(shù)語(yǔ)“OTC各論藥”指沒(méi)有已批準(zhǔn) NDA的非處方藥，它根據(jù) FDCA第 505G章 744L(5)節(jié)進(jìn)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(jiàn) 21 CFR第 210和 211節(jié)，制劑 CGMP，和 FDCA法案節(jié) 501(a)(2)(B)的 API內(nèi)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(shù)語(yǔ)“致病菌”在此指由于其對(duì)產(chǎn)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(shù)量而有害的菌。參見(jiàn) 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(chǎn)品包括衛(wèi)生健康護(hù)理人員洗手液、衛(wèi)生護(hù)理人員消毒液、外科手術(shù)用手消毒液、外科手術(shù)用手洗手液，以及患者備皮用消毒液（即患者術(shù)前和注射前皮膚準(zhǔn)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?yàn)?FDA對(duì) FDA不良事件報(bào)告（FAER）和涉及非無(wú)菌劑型污染的召回的審查。對(duì) 2014年至 2017年間發(fā)生的 FAER的審查顯示，有 197起 FAER與內(nèi)在微生物或真菌污染有關(guān)，其中 32起報(bào)告了嚴(yán)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(fā)報(bào)告根據(jù)定義是自愿的，因此 FDA預(yù)計(jì)會(huì)有一定程度的漏報(bào)。與微生物污染相關(guān)的實(shí)際事件數(shù)量可能明顯高于已報(bào)告的事件數(shù)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(duì)同一時(shí)期自愿召回行動(dòng)的審查顯示，超過(guò) 50起事件與有害微生物污染 NSD相關(guān)。召回表明，在水性和非水性 NSD中都發(fā)現(xiàn)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(shí)到 BCC及其與導(dǎo)致一系列嚴(yán)重不良事件（即感染和死亡）的水基 NSD污染的關(guān)聯(lián)引發(fā)的擔(dān)憂。2017年 5月，F(xiàn)DA發(fā)布了一份聲明，提醒藥品生產(chǎn)商注意最近的產(chǎn)品召回與 NSD中存在 BCC相關(guān)。該聲明還提醒藥品生產(chǎn)商他們有責(zé)任防止有害微生物對(duì)其 NSD生產(chǎn)過(guò)程以及產(chǎn)品本身產(chǎn)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(duì)這些事件的分析，結(jié)合 FDA對(duì) NDA和 ANDA產(chǎn)品的非無(wú)菌藥物進(jìn)行微生物學(xué)評(píng)估和合規(guī)行動(dòng)的經(jīng)驗(yàn)，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(bào)告系統(tǒng)（FAERS）最新季度數(shù)據(jù)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(nèi)在”是指微生物或真菌污染源于藥物的生產(chǎn)、包裝、運(yùn)輸或儲(chǔ)存，而不是來(lái)自外在來(lái)源（例如，消費(fèi)者或醫(yī)療保健提供者的使用錯(cuò)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(guān)于“自發(fā)報(bào)告”的定義參見(jiàn) FDA公眾對(duì)不良事件報(bào)告的關(guān)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(jù) FDA的 FAER問(wèn)答“FDA不會(huì)收到一個(gè)產(chǎn)品的不良事件或錯(cuò)誤用藥情況報(bào)告……如果患者和申報(bào)人【藥品生產(chǎn)商】提交了相同的報(bào)告，則會(huì)有兩份報(bào)告”

12 Seefootnote 6.

參見(jiàn)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(kù)酯鈉污染相關(guān)的醫(yī)療保健相關(guān)洋蔥伯克霍爾德菌復(fù)合感染的多州調(diào)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(chǎn)商關(guān)于洋蔥伯克霍爾德菌復(fù)合物對(duì)非無(wú)菌水基藥品造成污染風(fēng)險(xiǎn)，2017年 5月

III. STATUTORYAND REGULATORY FRAMEWORK

法律法規(guī)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(jù)《聯(lián)邦食品、藥品和化妝品法案》（FD&C法案）第 501(a)(2)條，如果出現(xiàn)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(chǎn)、加工、包裝或保存的方法，或用于其生產(chǎn)、加工、包裝或保存的設(shè)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(dāng)具備的質(zhì)量和純度特征”，或“如果它在不衛(wèi)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(duì)于成品藥物，21 CFR第 210和 211部分中描述的 CGMP法規(guī)涉及預(yù)防非無(wú)菌藥品、生物負(fù)載標(biāo)準(zhǔn)和中控測(cè)試中的有害微生物。具體來(lái)說(shuō)：

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(yīng)建立并遵循適當(dāng)?shù)臅?shū)面程序，旨在防止不需要無(wú)菌的藥品中出現(xiàn)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(cè)試，要求（在適當(dāng)?shù)那闆r下）中間體生物負(fù)載測(cè)試和有效的中控標(biāo)準(zhǔn)以確保成品符合其微生物標(biāo)準(zhǔn)。中控測(cè)試應(yīng)在產(chǎn)品工藝過(guò)程中進(jìn)行，例如，在重要階段的開(kāi)始或完成時(shí)，或在長(zhǎng)期儲(chǔ)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(kāi)始 CMC微生物審評(píng)，側(cè)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(dāng)時(shí)，應(yīng)對(duì)組件進(jìn)行顯微鏡檢查?？紤]到其預(yù)期用途，具有潛在微生物污染的每個(gè)批次的組件、藥品容器或密封件都應(yīng)在使用前進(jìn)行微生物測(cè)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(zhǔn)的 NSD的微生物質(zhì)量，申請(qǐng)人必須根據(jù) 21CFR 314.50(d)(1)【NDA】和 21CFR 314.94(a)(9)【ANDA】提出適當(dāng)?shù)脑纤幒椭苿┵|(zhì)量標(biāo)準(zhǔn)（即檢測(cè)項(xiàng)目、分析方法和可接受標(biāo)準(zhǔn)）。

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(rèn)可名稱的藥物必須符合美國(guó)藥典 (USP)藥典標(biāo)準(zhǔn)關(guān)于鑒別、含量、質(zhì)量和純度，否則會(huì)被視為摻假、貼錯(cuò)標(biāo)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(cè)項(xiàng)目、檢驗(yàn)方法、可接受標(biāo)準(zhǔn)和其他要求。當(dāng) USP各論有引用“適用通則”的測(cè)試或標(biāo)準(zhǔn)時(shí)，申請(qǐng)人應(yīng)確保其各論產(chǎn)品符合測(cè)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?yàn)樗鼈冞m用于控制 NSD中的微生物活動(dòng)，例如：

USP <60> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS TESTS FOR BURKHOLDERIA CEPACIA COMPLEX

USP <60>非無(wú)菌產(chǎn)品的微生物學(xué)檢查：伯克霍爾德氏菌復(fù)合物

USP <61> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS:MicrobialEnumeration Tests

USP <61>非無(wú)菌產(chǎn)品的微生物檢驗(yàn)：微生物計(jì)數(shù)檢測(cè)

USP <62> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: Testsfor Specified Microorganisms

USP <62>非無(wú)菌產(chǎn)品微生物檢驗(yàn)：特定微生物檢測(cè)

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(jìn)一步的微生物測(cè)試作為批次放行要求的一部分執(zhí)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(yīng)控制非無(wú)菌原料藥中的有害微生物和生物負(fù)載。 FDA行業(yè)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(yīng)根據(jù)公認(rèn)的標(biāo)準(zhǔn)為 API制定適當(dāng)?shù)臉?biāo)準(zhǔn)并與生產(chǎn)過(guò)程一致。標(biāo)準(zhǔn)應(yīng)包括對(duì)雜質(zhì)（例如有機(jī)雜質(zhì)、無(wú)機(jī)雜質(zhì)和殘留溶劑）的控制。如果 API有微生物純度標(biāo)準(zhǔn)，則應(yīng)建立并滿足總微生物計(jì)數(shù)和有害微生物的適當(dāng)行動(dòng)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(guān)于【質(zhì)量標(biāo)準(zhǔn) specification】的定義，參見(jiàn) 21 CFR 314.3(b)和 ICH Q6A“質(zhì)量標(biāo)準(zhǔn)：新原料藥和新制劑的檢驗(yàn)方法和可接受標(biāo)準(zhǔn)：化學(xué)物質(zhì)（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(jiàn) USP<3.10>“標(biāo)準(zhǔn)符合性”，“適用通則”指1000號(hào)以內(nèi)的通則，或大于 2000通過(guò)在范例、各論或另一個(gè)編號(hào)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(chǎn)品質(zhì)量

A. General ─Microbiological Concerns Regarding NSDs

關(guān)于 NSD的微生物擔(dān)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(fēng)險(xiǎn)降至最低，有必要對(duì)非無(wú)菌藥品組份和制劑中微生物群進(jìn)行預(yù)防、控制和監(jiān)測(cè)：

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(zhì)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(guī)框架，配以科學(xué)合理的原理，提供了建立程序?qū)ιa(chǎn)工藝進(jìn)行監(jiān)測(cè)和控制，從而防止致病菌影響 NSD質(zhì)量的基礎(chǔ)。

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(chǎn)品質(zhì)量和患者安全，有必要限制生產(chǎn)及產(chǎn)品貨架期間 NSD中微生物的水平和類型。雖然不要求 NSD是無(wú)菌的，但存在一個(gè)微生物含量的閾值，高于該閾值可能會(huì)對(duì)指定 NSD的安全性和有效性產(chǎn)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(guī)要求將放行組份之前由生產(chǎn)商的質(zhì)量控制部門對(duì)其取樣檢測(cè)或檢查。天然組份（例如植物或動(dòng)物來(lái)源成分，和天然產(chǎn)生的成分如水）可能會(huì)對(duì)藥品的總生物負(fù)載貢獻(xiàn)巨大，必須根據(jù)既定程序進(jìn)行微生物檢測(cè)。例如，水是 NSD生產(chǎn)中常用成分，但是由于取樣局限性，可能難以發(fā)現(xiàn)水系統(tǒng)控制偏差，而這些偏差有可能導(dǎo)致形成生物膜，已證明這些偏差對(duì)水基藥品的微生物質(zhì)量有深遠(yuǎn)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(dāng)?shù)乃到y(tǒng)設(shè)計(jì)和控制、恰當(dāng)?shù)奈⑸镄袆?dòng)限，以及日常水質(zhì)量檢測(cè)對(duì)于確保微生物水平低于既定限度，并且水中沒(méi)有致病微生物是至關(guān)重要的。所以生產(chǎn)商具備穩(wěn)健的水系統(tǒng)設(shè)計(jì)，包括設(shè)計(jì)用于防止致病微生物的控制措施和監(jiān)測(cè)、清潔及維護(hù)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(guò)已批準(zhǔn)申報(bào)上市的藥品。參見(jiàn) FDCA第 501(a)節(jié)和 21CFR節(jié) 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(tǒng)減弱的患者，這可能是由于外傷、手術(shù)、疾病或慢性病所致。它還包括弱勢(shì)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(chǎn)持續(xù)滿足預(yù)定質(zhì)量屬性時(shí)，執(zhí)行有效的持續(xù)監(jiān)測(cè)程序是很重要的。對(duì)于生產(chǎn)操作中有水的藥品，一般適用更為靈敏的取樣策略，應(yīng)該包括使用更大樣品數(shù)量（例如 100ml）采用膜過(guò)濾法檢測(cè)。

26Microbial action limits shouldbe established based on the risk-based impact assessment, a s described insection IV.B.

應(yīng)按節(jié) IV.B所述根據(jù)基于風(fēng)險(xiǎn)的影響性評(píng)估建立“微生物行動(dòng)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(chǎn)品貨架期內(nèi)由于具備水活性（aw）所以可支持微生物生長(zhǎng)的水基非無(wú)菌藥品的設(shè)計(jì)應(yīng)該能夠防止內(nèi)含微生物或在使用中被無(wú)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(chǎn)過(guò)程中或整個(gè)生命周期存貯期間的微生物生長(zhǎng)可能性可能會(huì)因?yàn)樵O(shè)計(jì)有適當(dāng)?shù)姆栏到y(tǒng)或配方而有部分降低，但抗菌防腐劑可能會(huì)在微生物存在或生長(zhǎng)方面導(dǎo)致產(chǎn)品安全假象。防腐劑的 2個(gè)目的是對(duì)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(chǎn)品生命周期中保持對(duì)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(yīng)認(rèn)為其可降低生產(chǎn)期間中控生物負(fù)載。已經(jīng)發(fā)現(xiàn)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(cè)試可接受標(biāo)準(zhǔn)的。因此非無(wú)菌藥品生產(chǎn)商應(yīng)該明白防腐劑耐受性發(fā)展的可能性。如果檢出致病菌或總微生物計(jì)數(shù)有上升趨勢(shì)，則應(yīng)該調(diào)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(lái)源）。這個(gè)問(wèn)題作為關(guān)于洋蔥伯克霍爾德菌復(fù)合物和水性藥物產(chǎn)品的特殊案例研究在第 IV.C.3.a節(jié)微生物注意事項(xiàng) -本指南的特殊案例中進(jìn)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(wú)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(fēng)險(xiǎn)可能較低。非無(wú)菌固體制劑，如片劑和膠囊的水活性亦較低，通常在產(chǎn)品貨架期內(nèi)不允許微生物生長(zhǎng)。但是，要注意雖然出現(xiàn)在低水活性非無(wú)菌藥品中的微生物不會(huì)繁殖，但它們可能在非水性液體和干燥藥品中在其整個(gè)貨架期內(nèi)都頑固存在。CGMP法規(guī)要求制訂書(shū)面程序防止引入致病菌污染到不要求無(wú)菌的藥品生產(chǎn)中，并設(shè)計(jì)有程序評(píng)估藥品（包括 NSD）的穩(wěn)定性。因此，即使該組份水活性很低，為非無(wú)菌藥品組份（例如，輔料和 API）提供適當(dāng)?shù)奈⑸锟刂品浅Ｖ匾?/span>

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(wú)菌固體制劑還可能在生產(chǎn)期間通過(guò)污染產(chǎn)生微生物滋長(zhǎng)風(fēng)險(xiǎn)。例如，延長(zhǎng)固體制劑的水性溶液或漿料中間體在不同生產(chǎn)工藝點(diǎn)放置時(shí)長(zhǎng)，可能會(huì)使得微生物滋生超出此類劑型的適當(dāng)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(shí)限的程序?qū)τ诖_保液體和固體 NSD生產(chǎn)過(guò)程中使用的每個(gè)工藝步驟的產(chǎn)品質(zhì)量（包括微生物質(zhì)量控制）從而防止存在致病菌至關(guān)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(wú)菌藥品微生物檢測(cè)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(jì)數(shù)可接受標(biāo)準(zhǔn)。但是，USP并未提供完整的致病菌清單，因此公司應(yīng)識(shí)別所有額外控制措施和必要的可接受標(biāo)準(zhǔn)。應(yīng)為每種產(chǎn)品確定是否需要對(duì)致病菌制訂更多控制措施。例如，BCC存在于水性非無(wú)菌藥品中有可能導(dǎo)致藥品降解和患者感染。在建立微生物質(zhì)量標(biāo)準(zhǔn)，確定一個(gè)特定的微生物在一個(gè)藥品中是否致病時(shí)，應(yīng)考慮目標(biāo)患者人群、藥品適應(yīng)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(zhì)完全不受干擾時(shí)的蒸汽壓與相同條件下蒸餾水蒸氣壓的比值。參見(jiàn) USP <1112>水活度測(cè)定在非無(wú)菌藥物產(chǎn)品的應(yīng)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(guò)召回，參見(jiàn)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(jì)數(shù)測(cè)試和 USP<62>指定微生物檢測(cè)。

34USP<1111> MICROBIOLOGICALEXAMINATIONOFNONSTERILE PRODUCTS: ACCEPTANCE CRITERIA FOR PHARMACEUTICALPREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE.

USP<1111>非無(wú)菌藥品的微生物檢查：制劑和藥用物質(zhì)的可接受標(biāo)準(zhǔn)。

B. Risk-Based Impact Assessment

基于風(fēng)險(xiǎn)的影響性評(píng)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(fēng)險(xiǎn)（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(chǎn)工藝，以及生產(chǎn)環(huán)境的影響。如果生產(chǎn)工藝經(jīng)過(guò)良好設(shè)計(jì)并受到恰當(dāng)控制，則引入致病菌及其繁殖或生長(zhǎng)的機(jī)會(huì)就會(huì)很小。對(duì)于特定的低風(fēng)險(xiǎn)生產(chǎn)操作（例如，片劑生產(chǎn)），可使用風(fēng)險(xiǎn)評(píng)估支持減少微生物監(jiān)測(cè)和檢測(cè)（參見(jiàn)以下節(jié) 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(fēng)險(xiǎn)的影響性評(píng)估有助于生產(chǎn)商識(shí)別更有可能引入生物負(fù)載或致病菌至 NSD的產(chǎn)品特有屬性和生產(chǎn)工藝要素。根據(jù)這個(gè)基于風(fēng)險(xiǎn)的影響性評(píng)估設(shè)計(jì)的風(fēng)險(xiǎn)緩解系統(tǒng)更有可能預(yù)防 NSD中的致病菌。下列要素雖然并不是完全清單，但在風(fēng)險(xiǎn)管理計(jì)劃中應(yīng)予以考慮，以降低致病菌（如相關(guān)）。

1. Product Specific Elements

產(chǎn)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(zhǎng)微生物，半固體制劑則一般比固體更有可能生長(zhǎng)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(duì)成品進(jìn)行微生物計(jì)數(shù)測(cè)試的類型和程度。USP <61>和USP <62>中描述了通用的計(jì)數(shù)檢測(cè)。對(duì)于固體劑型，ICH Q6A《新原料藥和新藥產(chǎn)品的檢驗(yàn)方法和可接受標(biāo)準(zhǔn)：化學(xué)物質(zhì)》包括關(guān)于微生物計(jì)數(shù)測(cè)試的“定期或跳過(guò)測(cè)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(yīng)該低到足以抑制微生物生長(zhǎng)

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(zhǎng)的可能性更高，因此需要額外的生產(chǎn)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(tài)

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(chǎn)品使用設(shè)置（例如，手術(shù)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(hù)，不受可能導(dǎo)致微生物污染的可預(yù)見(jiàn)外來(lái)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.

o ProductComponents and Composition

產(chǎn)品組分和比例

Consider selection of appropriatepreservatives that assure effectiveness to prevent

考慮選擇適當(dāng)?shù)姆栏瘎?，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(jìn)廠原料適合于其既定用途，包括可接受微生物質(zhì)量

o MicrobiologicalTesting–Product Specific Considerations

微生物測(cè)試—產(chǎn)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(dāng)?shù)奈⑸锵薅?/span>

Ensure the sampling plan detectsvariation within a batch41.

確保取樣計(jì)劃能發(fā)現(xiàn)批內(nèi)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.

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.

2. Manufacturing Elements

生產(chǎn)要素

o ManufacturingProcess Steps: Certain processing steps may have a greater impact than othersin either promoting or reducing bioburden.

o 生產(chǎn)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(fù)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.

Inadequate equipment cleaningprocesses, such as extended hold times before cleaning and insufficient dryingafter equipment has been cleaned, may also promote microbiologicalcontamination.

設(shè)備清潔工藝不充分，例如，延長(zhǎng)清潔之前的放置時(shí)長(zhǎng)，以及設(shè)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.

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(chǎn)步驟（例如，涉及過(guò)濾、高溫、極端 pH值或有機(jī)溶劑的那些步驟）可能會(huì)使得中間體生物負(fù)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(cè)在非活性藥品中的應(yīng)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(wú)菌藥品的配方、生產(chǎn)步驟和檢測(cè)過(guò)程應(yīng)反映出該參數(shù)。

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 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 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 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 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 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.

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 MicrobiologicalRelease Testing (as appropriate):

o 微生物放行測(cè)試（適當(dāng)時(shí)）

Total microbial content(microbiological enumeration testing57)

總微生物含量（微生物計(jì)數(shù)）

Specified organism testing andidentification program to identify other objectionable microorganisms58

特定微生物測(cè)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(duì)不同水質(zhì)進(jìn)行了分類，以顯示相關(guān)純度和微生物質(zhì)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

特殊劑型的微生物關(guān)切和特殊案例

1. Solid Dosage Forms

固體制劑

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，固體制劑由于其低水活性而呈現(xiàn)出對(duì)患者更低的微生物風(fēng)險(xiǎn)。因此，與其生產(chǎn)有關(guān)的微生物控制一般來(lái)說(shuō)不會(huì)比其它 NSD生產(chǎn)相關(guān)的控制更為嚴(yán)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.

固體劑型的微生物質(zhì)量亦通過(guò)制劑成品檢測(cè)進(jìn)行監(jiān)測(cè)。可執(zhí)行 USP中所述的 TAMC、TYMC和指定微生物（適用時(shí)）方法測(cè)定微生物計(jì)數(shù)。如果使用藥典方法進(jìn)行檢測(cè)，需使用藥品進(jìn)行方法適用性測(cè)試。其它檢驗(yàn)方法，包括快速微生物檢測(cè)方法，均可用于產(chǎn)品檢測(cè)，但會(huì)需要進(jìn)行驗(yàn)證以證明其適用性和與藥典方法的等同性。

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.

雖然 USP含有建議的微生物控制可接受標(biāo)準(zhǔn)，并指明了特定致病菌不得檢出，但生產(chǎn)商可建立替代方法進(jìn)行微生物控制，包括限度/放行標(biāo)準(zhǔn)。例如，許多固體口服制劑有水活性，但并不會(huì)提供條件讓許多營(yíng)養(yǎng)細(xì)胞的生長(zhǎng)或持續(xù)存在。因此有可能在產(chǎn)品開(kāi)發(fā)期間測(cè)定水活性，結(jié)合限制致病菌的中控設(shè)計(jì)，作為減少或刪除特定類別固體口服制劑放行檢測(cè)中微生物檢測(cè)的理由。如果有足夠的數(shù)據(jù)證明中間體微生物控制是成功的，制劑水活性是可接受的，并且組份生物負(fù)載檢測(cè)結(jié)果保持持續(xù)受控，則可減少或刪除成品的微生物計(jì)數(shù)檢測(cè)（參見(jiàn)下節(jié)題為“根據(jù)基于風(fēng)險(xiǎn)的影響性評(píng)估減少固體劑型微生物放行檢測(cè)的可能性”）。如果使用該替代標(biāo)準(zhǔn)取代產(chǎn)品放行測(cè)試，則建立并記錄適當(dāng)?shù)墓に嚭驮O(shè)施控制（包括測(cè)試進(jìn)廠組份批次和生產(chǎn)工藝控制）非常重要，因?yàn)檫@些控制措施是用于來(lái)限制最終產(chǎn)品的生物負(fù)載的。

56See 21 CFR 211.110(a)(6).

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

USP <61>“非無(wú)菌藥品的微生物檢測(cè)：微生物計(jì)數(shù)檢測(cè)”

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

USP <62>“非無(wú)菌藥品的微生物檢測(cè)：指定微生物的檢測(cè)”

59See 21CFR 211.165(b).

60USP<61> MICROBIOLOGICALEXAMINATIONOFNONSTERILE PRODUCTS: MICROBIAL ENUMERATION TESTS. USP <61>“非無(wú)菌藥品的微生物檢測(cè)：微生物計(jì)數(shù)檢測(cè)”

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

USP <62>“非無(wú)菌藥品的微生物檢測(cè)：指定微生物的檢測(cè)”

62See 21 CFR 211.194(a)(2).

USP<1111> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: ACCEPTANCE CRITERIAFOR PHARMACEUTICALPREPARATIONSANDSUBSTANCESFOR PHARMACEUTICAL USE.

USP<1111>非無(wú)菌藥品的微生物檢查：制劑和藥用物質(zhì)的可接受標(biāo)準(zhǔn)。

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

根據(jù)基于風(fēng)險(xiǎn)的影響性評(píng)估減少固體劑型微生物放行檢測(cè)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.

有水活性但不支持營(yíng)養(yǎng)微生物生長(zhǎng)的固體制劑是降低產(chǎn)品放行和穩(wěn)定性測(cè)試中微生物項(xiàng)目的優(yōu)秀候選對(duì)象。ICH Q6A“新原料藥和新制劑檢驗(yàn)方法和可接受標(biāo)準(zhǔn)：化學(xué)物質(zhì)”包括有在何條件下可考慮“定期執(zhí)行或跳檢”微生物計(jì)數(shù)檢測(cè)的條件。ICH Q6A中的建議是基于產(chǎn)品特性的，同時(shí)提供了確定適當(dāng)?shù)奈⑸餀z測(cè)計(jì)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(cè)，生產(chǎn)商應(yīng)按本指南節(jié) IV.B所建議的執(zhí)行基于風(fēng)險(xiǎn)的影響性評(píng)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.

經(jīng)過(guò)適當(dāng)?shù)恼撟C，包括生產(chǎn)商在 NSD生產(chǎn)中的歷史經(jīng)驗(yàn)，例如微生物放行和穩(wěn)定性數(shù)據(jù)的數(shù)量、所有負(fù)面發(fā)現(xiàn)和工藝、設(shè)施和組份生物負(fù)載控制的程度，可刪除或減少低風(fēng)險(xiǎn)固體制劑穩(wěn)定性計(jì)劃中的微生物檢測(cè)。注意有些固體制劑含有支持生長(zhǎng)的組份，如蛋白類組份，則應(yīng)進(jìn)行風(fēng)險(xiǎn)評(píng)估以確定其是否可以降低或刪除穩(wěn)定性方案中的微生物測(cè)試。

2. Non-Solid Dosage Forms

非固體制劑

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，非固體劑型（例如溶液、懸浮液、洗劑、乳膏和一些軟膏）比固體劑型具有更高的水分活度，因此支持微生物生長(zhǎng)的風(fēng)險(xiǎn)更高。非固體劑型支持微生物生長(zhǎng)的能力在很大程度上取決于藥品成分的水分活度。許多污染事件與具有支持微生物生長(zhǎng)的水分活度水平的產(chǎn)品有關(guān)，因此我們建議非固體劑型生產(chǎn)商在評(píng)估整個(gè)生產(chǎn)過(guò)程時(shí)關(guān)注微生物質(zhì)量。了解產(chǎn)品在整個(gè)生產(chǎn)過(guò)程中的水分活度有助于做出與生產(chǎn)、中間體放置時(shí)間和儲(chǔ)存條件相關(guān)的決策。對(duì)于已知具有支持微生物增殖的水分活度的產(chǎn)品、組份和中間體，應(yīng)在整個(gè)操作過(guò)程中對(duì)工藝控制進(jìn)行更嚴(yán)格的審查。這包括中間體和成品微生物監(jiān)測(cè)方法和驗(yàn)收標(biāo)準(zhǔn)、中間體放置時(shí)長(zhǎng)的驗(yàn)證以及任何易受微生物增殖影響的生產(chǎn)步驟。例如，具有低水分活度的天然成分可能本身具有高生物負(fù)載，需要特別注意。此外，在通常具有低水活度的外用藥物的生產(chǎn)步驟中存在有害微生物已導(dǎo)致此類產(chǎn)品受到微生物污染。此外，混懸液在有害微生物管理方面可能會(huì)帶來(lái)額外的挑戰(zhàn)。

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.

產(chǎn)品穩(wěn)定性研究應(yīng)考慮到混懸液在存貯和分配過(guò)程中可能會(huì)分離成不同的相，這可能會(huì)導(dǎo)致配方成分分離并導(dǎo)致防腐劑分布不均。防腐劑不足的相可能具有高水分活度，導(dǎo)致微生物生長(zhǎng)。

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.

除了評(píng)估整個(gè)生產(chǎn)過(guò)程之外，確保生產(chǎn)設(shè)備得到清潔和維護(hù)也很重要，這樣在設(shè)備存儲(chǔ)、未使用或未保護(hù)時(shí)，水不會(huì)殘留在設(shè)備上。殘留水可以促進(jìn)微生物的生長(zhǎng)。設(shè)備表面，包括那些可能不直接接觸產(chǎn)品的表面，應(yīng)在清潔和消毒之后盡快干燥或儲(chǔ)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”).

盡管如此，由于在生產(chǎn)過(guò)程中或從原材料引入污染，具有低水分活度的非固體產(chǎn)品可能會(huì)受到致病菌污染。然而，貨架期內(nèi)的微生物增殖不太常見(jiàn)。如果非固體藥品的合成成分和水分活度遠(yuǎn)低于已知支持微生物增殖的藥品，在成品穩(wěn)定性計(jì)劃中進(jìn)行較少頻率的微生物測(cè)試可能是可行的。放置在穩(wěn)定性測(cè)試計(jì)劃中的批次通常在其標(biāo)記的保質(zhì)期內(nèi)的多個(gè)時(shí)間點(diǎn)進(jìn)行采樣和測(cè)試，包括開(kāi)始和結(jié)束以及幾個(gè)中間點(diǎn)。為了支持穩(wěn)定性計(jì)劃中對(duì)成品批次減少（即更少的穩(wěn)定性時(shí)間點(diǎn)）微生物測(cè)試，應(yīng)進(jìn)行基于風(fēng)險(xiǎn)的影響評(píng)估，其中包括水分活度數(shù)據(jù)、與生產(chǎn)過(guò)程相關(guān)的微生物監(jiān)測(cè)信息、產(chǎn)品的生物負(fù)載潛力。組份、生產(chǎn)歷史（注意任何故障和偏差），以及可能對(duì)微生物質(zhì)量產(chǎn)生積極或消極影響的工藝步驟的理解（參見(jiàn)前面 “根據(jù)基于風(fēng)險(xiǎn)的影響性評(píng)估減少固體劑型微生物放行檢測(cè)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）和軟明膠膠囊的固體口服制劑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.

本節(jié)討論 NSD產(chǎn)品配方和預(yù)期用途的示例，這些產(chǎn)品本身對(duì)有害微生物或生物負(fù)載對(duì)患者群體造成更大的相對(duì)風(fēng)險(xiǎn)（例如，在破壞皮膚的醫(yī)療程序之前將 NSD施用于皮膚）。此例表明，對(duì)這些產(chǎn)品中的生物負(fù)載進(jìn)行更嚴(yán)格的鑒別和評(píng)估對(duì)于了解產(chǎn)品危害至關(guān)重要。必須使用適當(dāng)?shù)膶?shí)驗(yàn)室方法，并由合格的人員審核結(jié)果以確定產(chǎn)品是否被致病菌污染。這些方法應(yīng)該區(qū)分和鑒別致病微生物。此類批次質(zhì)量信息對(duì)于防止銷售對(duì)消費(fèi)者造成危害的被污染產(chǎn)品至關(guān)重要，并有助于調(diào)查原因以糾正或防止質(zhì)量問(wèn)題。

a. Burkholderiacepacia Complex and Aqueous Drug Products

洋蔥伯克霍爾德菌復(fù)合物和水性藥物制劑

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).

非無(wú)菌水性藥品有可能被 BCC微生物污染，因?yàn)檫@些微生物可能存在于制藥用水系統(tǒng)中。（參考文獻(xiàn) 2、18、19、21）。洋蔥伯克霍爾德菌現(xiàn)在被認(rèn)為是至少 17種基因型或近緣物種復(fù)合體的一部分（參考文獻(xiàn) 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).

這些微生物是機(jī)會(huì)性人類病原體，可導(dǎo)致嚴(yán)重的致命感染（參考文獻(xiàn) 2、14、24）。重要的是，非無(wú)菌水性藥物產(chǎn)品不含 BCC微生物，因?yàn)樗鼈兙哂歇?dú)特的特性和安全風(fēng)險(xiǎn)。BCC菌株具有利用多種底物作為能源的能力，其中許多是傳統(tǒng)的防腐劑系統(tǒng)（參考文獻(xiàn)1-4、12、13）。因此，盡管在非無(wú)菌藥物產(chǎn)品中存在足夠的防腐劑系統(tǒng)，但 BCC菌株可以在非無(wú)菌產(chǎn)品的貨架期內(nèi)存活和增殖。雖然成品放行的微生物計(jì)數(shù)測(cè)試可以證明TAMC達(dá)到可接受水平，但當(dāng)產(chǎn)品到達(dá)患者時(shí)，BCC可能會(huì)繁殖到不安全的水平。2016年 5月，美國(guó)疾病控制和預(yù)防中心（CDC）向 FDA通報(bào)了 9個(gè)州 13家醫(yī)院中與 BCC相關(guān)的嚴(yán)重疾病和死亡。BCC污染導(dǎo)致了非無(wú)菌 OTC液體糞便軟化劑召回（參考文獻(xiàn) 17）。在 2000年至 2002年涉及醫(yī)療器械（超聲波凝膠）的一系列病例中，在凝膠與經(jīng)直腸前列腺活檢聯(lián)合使用后，BCC的固有污染導(dǎo)致了嚴(yán)重的血液感染（參考文獻(xiàn) 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:

制藥用水和生產(chǎn)過(guò)程中使用的天然衍生成分是藥品中 BCC的最可能來(lái)源。因此，CGMPs的穩(wěn)健實(shí)施對(duì)于確保產(chǎn)品質(zhì)量和患者安全至關(guān)重要，包括：

establishing a risk managementprogram for the design and control of operations to prevent BCC contamination70

建立風(fēng)險(xiǎn)管理計(jì)劃對(duì)操作進(jìn)行設(shè)計(jì)和控制，從而預(yù)防 BCC污染

using robust water systems71

使用穩(wěn)健的水系統(tǒng)

ensuring components meetappropriate specifications for bioburden 72

確保組份滿足適當(dāng)?shù)纳镓?fù)載標(biāo)準(zhǔn)

appropriately sanitizing andcleaning equipment73, and

恰當(dāng)?shù)叵竞颓鍧嵲O(shè)備，以及

validated sampling procedures74 toroutinely perform in-process monitoring and finished product testing for thepresence of BCC

采用經(jīng)過(guò)驗(yàn)證的取樣程序執(zhí)行 BCC日常中控監(jiān)測(cè)和成品檢測(cè)

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).

除非生產(chǎn)商執(zhí)行經(jīng)過(guò)驗(yàn)證的生產(chǎn)步驟（例如，在灌裝前使用滅菌過(guò)濾器對(duì)散裝產(chǎn)品配方進(jìn)行微生物截留過(guò)濾）使藥品不含 BCC，否則放行測(cè)試是一系列控制中必不可少的最后一步，有助于證明非無(wú)菌水性藥品不含 BCC（參考文獻(xiàn) 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提供了一項(xiàng)于 2019年 12月 1日正式生效的 BCC藥典檢測(cè)方法，題為<60>非無(wú)菌藥品的微生物檢查—洋蔥伯克霍爾德菌復(fù)合體（BCC）檢測(cè)。 FDA建議生產(chǎn)商使用本 USP章節(jié)中描述的 USP方法來(lái)測(cè)試藥品是否存在 BCC。如果生產(chǎn)商選擇開(kāi)發(fā)替代的內(nèi)部方法，則替代方法或程序必須經(jīng)過(guò)充分驗(yàn)證，并且必須產(chǎn)生與藥典方法相當(dāng)?shù)慕Y(jié)果。此外，任何選擇開(kāi)發(fā)替代方法的申請(qǐng)人都應(yīng)該意識(shí)到，由于 BCC具有高度的適應(yīng)性和在各種環(huán)境中生存和生長(zhǎng)的能力，測(cè)試方法可能會(huì)變得復(fù)雜（參考文獻(xiàn) 1、8）。BCC的檢測(cè)、正確鑒別和分類可能存在困難（參考文獻(xiàn) 1、15），考慮 BCC成分表現(xiàn)出的不同表型對(duì)于開(kāi)發(fā)回收方法至關(guān)重要（參考文獻(xiàn) 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)

術(shù)前備皮藥品（局部防腐劑）

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.

患者術(shù)前備皮藥品是局部消毒藥物產(chǎn)品，用于在醫(yī)療程序或注射之前減少皮膚上微生物的數(shù)量，因?yàn)槠つw通常被微生物覆蓋（參考文獻(xiàn) 16）。其中一些產(chǎn)品不是作為無(wú)菌產(chǎn)品生產(chǎn)的（參考文獻(xiàn) 16）。然而，已經(jīng)有許多已發(fā)表的報(bào)告稱，由于微生物污染，與消毒產(chǎn)品相關(guān)的感染爆發(fā)（參考文獻(xiàn) 9、10、11、21）。值得注意的是，在 2009年至 2013年期間發(fā)生的非無(wú)菌產(chǎn)品召回中，大部分是受污染的防腐劑產(chǎn)品。有 8起召回是由于酒精或聚維酮碘備墊受到微生物污染。

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.

單獨(dú)的產(chǎn)品適應(yīng)癥（應(yīng)用于即將手術(shù)受損的體表），以及最近的感染爆發(fā)和產(chǎn)品召回，表明產(chǎn)品的無(wú)菌性可能是一個(gè)重要的風(fēng)險(xiǎn)緩解因素或?qū)εR床結(jié)果有重要影響。2011年， FDA發(fā)布了一份新聞稿，由于最近的污染事件，提醒醫(yī)療保健專業(yè)人員檢查酒精備墊上的標(biāo)簽，以確定它們是無(wú)菌的還是非無(wú)菌的。FDA建議在需要嚴(yán)格無(wú)菌措施的程序中僅使用無(wú)菌墊（參考文獻(xiàn) 19）。 FDA鼓勵(lì)患者術(shù)前消毒產(chǎn)品（無(wú)論該產(chǎn)品是在開(kāi)發(fā)中還是目前已上市）的生產(chǎn)商探索這些產(chǎn)品的生產(chǎn)工藝，使其無(wú)菌。 FDA歡迎提出與這些產(chǎn)品滅菌工藝開(kāi)發(fā)有關(guān)的問(wèn)題，并致力于與申請(qǐng)人和其他利益相關(guān)者合作，研究術(shù)前消毒產(chǎn)品的滅菌選擇。

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新聞公告“FDA提醒醫(yī)療保健專業(yè)人員安全使用非無(wú)菌酒精準(zhǔn)備墊”，20110201。亦可參見(jiàn)“FDA藥品安全溝通：FDA要求有些 OTC局部用消毒藥品修改標(biāo)簽和使用單次使用包裝以降低污染風(fēng)險(xiǎn)”，20131113。

77 Requests not a ssociated with aspecific a pplication can be sent toCDER-OPQ-I nqu iries@fda .hhs.gov.不與特定申報(bào)有關(guān)的請(qǐng)求可發(fā)送到上述郵箱。

c. Transdermal Products

透皮制劑

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.

傳統(tǒng)的透皮和局部給藥系統(tǒng)（統(tǒng)稱為 TDS）在完整皮膚上使用時(shí)造成的微生物風(fēng)險(xiǎn)有限。然而，隨著這些產(chǎn)品的技術(shù)不斷發(fā)展，應(yīng)重新評(píng)估對(duì)患者的潛在風(fēng)險(xiǎn)，以確定是否需要額外的生產(chǎn)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設(shè)計(jì)有物理機(jī)制，會(huì)磨損或穿透皮膚，增加感染的可能性，特別是考慮到皮膚厚度因個(gè)體、身體部位和患者年齡而異。在此類 TDS的開(kāi)發(fā)過(guò)程中，生產(chǎn)商應(yīng)考慮風(fēng)險(xiǎn)并確定 TDS是否應(yīng)生產(chǎn)為無(wú)菌或生物負(fù)載水平低于通常看到依賴化學(xué)滲透促進(jìn)劑的 TDS設(shè)計(jì)的水平。FDA鼓勵(lì)這些生產(chǎn)商在規(guī)劃和產(chǎn)品開(kāi)發(fā)的早期階段聯(lián)系 FDA。

D. Updating Approved Drug ProductSpecifications

更新已批準(zhǔn)的藥品質(zhì)量標(biāo)準(zhǔn)

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.

如果申請(qǐng)持有人的已批準(zhǔn)產(chǎn)品與本指南中討論的建議不一致，F(xiàn)DA不要求其修改產(chǎn)品標(biāo)準(zhǔn)。如果提交了新的補(bǔ)充申請(qǐng)，提出了可能影響微生物生長(zhǎng)增加風(fēng)險(xiǎn)的生產(chǎn)變更（例如，新的生產(chǎn)工藝、放寬關(guān)鍵工藝參數(shù)），F(xiàn)DA審評(píng)員可能會(huì)在評(píng)估期間和批準(zhǔn)之前要求申請(qǐng)持有人更新產(chǎn)品規(guī)格中的微生物檢測(cè)信息。申請(qǐng)持有者可能希望按照本指南的建議考慮更新給定的藥品質(zhì)量標(biāo)準(zhǔn)。這可能有助于加快未來(lái)其他生產(chǎn)變化補(bǔ)充的批準(zhǔn)。表 1提供了變更非無(wú)菌藥品微生物檢測(cè)程序的補(bǔ)充資料提交類別的指南。

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.傳

統(tǒng)貼劑系統(tǒng)的技術(shù)考量（超出微生物方面）在 FDA行業(yè)指南草案“貼劑和透皮給藥系統(tǒng)—產(chǎn)品開(kāi)發(fā)和質(zhì)量考量（201911）”。定稿時(shí)，該指南將代表 FDA當(dāng)前對(duì)該問(wèn)題的看法。

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

(June 2006).參見(jiàn) FDA行業(yè)指南“慢性皮膚潰瘍和燒傷—開(kāi)發(fā)治療藥品”（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.如果為 NDA提交資料，請(qǐng)聯(lián)系專用藥品服務(wù)中心。如果正在開(kāi)發(fā)的產(chǎn)品是 ANDA，通過(guò)一般通信、受控通信或 ANDA預(yù)備會(huì)議（適用時(shí)）聯(lián)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亦建議非申報(bào)藥品考慮按本指南中所建議的藥物質(zhì)量體系維護(hù)時(shí)更新藥品質(zhì)量標(biāo)準(zhǔn)。

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

表 1：非無(wú)菌藥品微生物檢測(cè)擬定變更的注冊(cè)提交策略

FDA發(fā)布《行業(yè)指南：非無(wú)菌藥品生產(chǎn)中的微生物質(zhì)量考量》草案

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

附錄：NSD產(chǎn)品微生物污染的案例研究示例；對(duì)產(chǎn)品質(zhì)量和生產(chǎn)過(guò)程的影響

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.

以下七個(gè)案例研究總結(jié)了 NSD被微生物污染導(dǎo)致感染和最終產(chǎn)品召回的事件。在以下每種情況下，產(chǎn)品生產(chǎn)商都發(fā)起了自愿召回行動(dòng)，以減輕受污染產(chǎn)品對(duì)患者和最終用戶的影響，并制定了新的流程和糾正措施，以防止其產(chǎn)品在未來(lái)受到微生物污染。特別重要的是生產(chǎn)商為解決微生物污染而采取的根本原因分析和糾正/預(yù)防策略。這些例子表明，風(fēng)險(xiǎn)評(píng)估應(yīng)該是防止 NSD微生物污染戰(zhàn)略的一個(gè)組成部分。

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

案例 1：洋蔥伯克霍爾德菌復(fù)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，有一種用于便秘的 OTC產(chǎn)品（口服液多庫(kù)酯鈉）的自有品牌銷售商將該產(chǎn)品委外加工。 FDA調(diào)查了多州爆發(fā)的 108名患者嚴(yán)重 BCC感染事件，其中多例相關(guān)患者死亡。 FDA和 CDC的檢測(cè)顯示，超過(guò) 10批口服液體產(chǎn)品被 BCC污染。BCC臨床分離株與產(chǎn)品分離株相匹配。調(diào)查還在該公司用于生產(chǎn)產(chǎn)品的水系統(tǒng)中檢測(cè)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將合同生產(chǎn)商確定為爆發(fā)的源頭。設(shè)計(jì)不佳的水系統(tǒng)（冷系統(tǒng)；不連續(xù)循環(huán)）、系統(tǒng)監(jiān)控不充分、生產(chǎn)控制不力以及微生物檢測(cè)方法不當(dāng)都對(duì)消費(fèi)者造成了嚴(yán)重的風(fēng)險(xiǎn)。合同生產(chǎn)商生產(chǎn)的所有液體產(chǎn)品最終都被召回。

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

案例 2：水基咽喉噴霧劑和液體抗酸劑被大腸桿菌污染

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，一家生產(chǎn)用于緩解喉嚨干燥和恢復(fù)喉嚨舒適度的水性非無(wú)菌噴霧劑的生產(chǎn)商被確定有大腸桿菌 (E.coli)污染。污染是在得到產(chǎn)品的微生物檢測(cè)結(jié)果是細(xì)菌計(jì)數(shù)過(guò)多而無(wú)法計(jì)數(shù) (TNTC)時(shí)才發(fā)現(xiàn)的。盡管該公司并未完全確定根本原因，但作該事件的結(jié)果，公司糾正了一些生產(chǎn)實(shí)踐，包括用于清潔和存儲(chǔ)設(shè)備的新流程和程序，以及將使用過(guò)的設(shè)備和經(jīng)過(guò)消毒的設(shè)備之間進(jìn)行物理分離。該產(chǎn)品在全國(guó)銷售超過(guò) 20,000臺(tái)。

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年發(fā)生了另一起抗酸液被大腸桿菌污染的案例，在完成質(zhì)量保證測(cè)試之前，全國(guó)已銷售了 10,000多件受污染的產(chǎn)品。當(dāng)產(chǎn)品微生物檢測(cè)結(jié)果報(bào)告其中大腸桿菌大于 3000CFU/g時(shí)，生產(chǎn)商立即召回了該產(chǎn)品。在調(diào)查之后，生產(chǎn)商更新了質(zhì)量保證程序并進(jìn)行了員工培訓(xùn)。然而，污染的根本原因尚未確定。在該案例中，未報(bào)告因在受污染產(chǎn)品導(dǎo)致的傷害或疾病。

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.

對(duì) 2012年至 2017年間 FDA召回?cái)?shù)據(jù)庫(kù)的回顧表明，至少發(fā)生了四起其他非無(wú)菌水基藥品導(dǎo)致大腸桿菌污染的獨(dú)立事件。

Case 3: Contamination ofmoisturizing cream with Pseudomonasand Staphylococcus

案例 3：保濕霜被假單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，一家嬰兒濕疹保濕霜的生產(chǎn)商報(bào)告稱，他們的產(chǎn)品被銅綠假單胞菌和金黃色葡萄球菌污染。該產(chǎn)品在全國(guó)銷售超過(guò) 15,000件。盡管配方中存在防腐劑，但微生物測(cè)定顯示產(chǎn)品中的細(xì)菌負(fù)載為 87,500 CFU/g。微生物污染的根本原因似乎是一種天然來(lái)源的原材料，由于公司儲(chǔ)存不當(dāng)而受到污染，顯然導(dǎo)致發(fā)成品中微生物的生長(zhǎng)。

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.

同樣，在 2015年，一家液體抗酸劑經(jīng)銷商確定其全國(guó)銷售的 100,000多件產(chǎn)品受到了有害污染。產(chǎn)品污染包括銅綠假單胞菌，以及高酵母和霉菌數(shù)量。根據(jù)跨越 12個(gè)月的留樣所做的評(píng)估決定了召回范圍。污染的根本原因似乎與合同生產(chǎn)過(guò)程中的問(wèn)題有關(guān)，但最終的根本原因并未確定。

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

案例 4：嬰兒用非水性乳膏過(guò)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，一家美國(guó)經(jīng)銷商進(jìn)口了一種適用于嬰兒的氧化鋅尿布疹霜，該經(jīng)銷商打算將其作為 OTC產(chǎn)品進(jìn)行銷售。經(jīng)過(guò)測(cè)試，發(fā)現(xiàn)它受到了致病菌污染。盡管該產(chǎn)品不是水基的，并且固有的水分活度很低，但它含有過(guò)多的細(xì)菌和真菌。有幾件樣品的需氧微生物計(jì)數(shù)值特別高，包括 350萬(wàn) CFU總需氧微生物計(jì)數(shù) (TAMC)/mL和 27,000 CFU TAMC/mL等值。許多細(xì)菌是芽孢桿菌屬的孢子形成者。酵母菌和霉菌計(jì)數(shù)水平也非常高，包括 2700酵母菌和霉菌總數(shù) (TYMC)/mL、39000 TYMC/mL和 200 TYMC/mL。生產(chǎn)商召回了所有批次的產(chǎn)品并停止向美國(guó)發(fā)貨。

Case 5: Topical creamcontaminated with Enterobacter, sp.

案例 5：受腸桿菌污染的外用乳膏。

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，一家外用乳膏型藥物的生產(chǎn)商意識(shí)到他們的幾批產(chǎn)品被腸桿菌屬污染。該產(chǎn)品在微生物測(cè)定完成之前被無(wú)意運(yùn)出，導(dǎo)致微生物計(jì)數(shù)為 TNTC。除了分析結(jié)果之外，還有一種產(chǎn)品通常并不會(huì)有的異常強(qiáng)烈氣味。召回開(kāi)始后，生產(chǎn)商收到了客戶關(guān)于產(chǎn)品氣味強(qiáng)烈的投訴。微生物污染的潛在根本原因被懷疑是灌裝設(shè)備的轉(zhuǎn)換清潔不當(dāng)。生產(chǎn)商采取了多項(xiàng)糾正措施以防止產(chǎn)品未來(lái)受到微生物污染，包括修訂預(yù)防性維護(hù)和放行測(cè)試程序以及員工再培訓(xùn)。

Case 6: Alcohol antisepticscontaminated with Bacillus cereus

案例 6：酒精防腐劑被蠟樣芽孢桿菌污染

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，有一種酒精類防腐劑產(chǎn)品生產(chǎn)條件惡劣，結(jié)果該產(chǎn)品被發(fā)現(xiàn)受到芽孢桿菌屬的污染，包括蠟狀芽孢桿菌。

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.

據(jù)報(bào)道，不良事件與受污染的防腐劑有關(guān)。對(duì)該公司的檢查發(fā)現(xiàn)，在配制、灌裝和儲(chǔ)存過(guò)程中缺乏適當(dāng)?shù)目刂拼胧﹣?lái)防止污染，還發(fā)現(xiàn)設(shè)備清潔不充分。

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.

這些缺陷條件可能導(dǎo)致了污染事件。鑒于已確認(rèn)的和潛在的微生物污染，生產(chǎn)商在全國(guó)范圍內(nèi)自愿召回了所有批次的酒精準(zhǔn)備墊、酒精棉簽和酒精棉簽棒。

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

案例 7：原料藥被曲霉屬和腸桿菌屬污染。

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生產(chǎn)商被其他生產(chǎn)商進(jìn)一步用于生產(chǎn)口服和注射成品藥物，他們意識(shí)到客戶抱怨他們的 API含有 TNTC/g水平的各種曲霉屬真菌污染。這種微生物污染的根本原因似乎與 API的干燥設(shè)備部件有關(guān)。作為糾正措施，API生產(chǎn)商更換了有缺陷的干燥設(shè)備管道系統(tǒng)，以防止水分聚集在其中，并修改了現(xiàn)有的預(yù)防性維護(hù)/監(jiān)控程序，以便對(duì)微生物污染進(jìn)行更有效的控制。 API生產(chǎn)商發(fā)起了一項(xiàng)自愿召回，一年生產(chǎn)的多批 API和幾個(gè)制劑生產(chǎn)商受到影響。未報(bào)告與受污染產(chǎn)品相關(guān)的傷害或疾病。

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藥物的散裝乳膏基質(zhì)生產(chǎn)商召回了多批散裝乳膏，原因是霉菌和細(xì)菌數(shù)量過(guò)多，特別是其中的曲霉屬和青霉菌屬。微生物生長(zhǎng)的根本原因是生產(chǎn)說(shuō)明不充分，導(dǎo)致人員添加的防腐劑量低于確保每個(gè)受影響批次均勻分布所需的防腐劑量。在生產(chǎn)最終產(chǎn)品時(shí)，將膏劑封閉在其最終容器/密封件中導(dǎo)致產(chǎn)品冷卻時(shí)產(chǎn)生了水分，而水分使霉菌得以生長(zhǎng)。受影響批次的微生物檢測(cè)均表明有霉菌生長(zhǎng)，相應(yīng)的微生物鑒定測(cè)試表明受影響批次的防腐劑含量較低。為了減少未來(lái)的錯(cuò)誤，散裝膏劑生產(chǎn)商修改了他們的生產(chǎn)程序和流程，以確保防腐劑在每個(gè)散裝膏劑批次中的均勻分布。

Case 8: Fungal contaminationtraced to excipient

案例 8：真菌污染追蹤到賦形劑

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，一家生產(chǎn)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劑/粘合劑輔料。隨后的 FDA警告信指出，該公司沒(méi)有進(jìn)行充分的調(diào)查，以確定真菌污染物的來(lái)源，并確定使用相同輔料批次生產(chǎn)的其他格列本脲片批次，以及未能對(duì)輔料進(jìn)行適當(dāng)取樣和測(cè)試。進(jìn)一步調(diào)查發(fā)現(xiàn)，在輔料生產(chǎn)設(shè)施進(jìn)行輔料化學(xué)合成期間，輔料干燥過(guò)程中使用的空氣被季節(jié)性真菌孢子污染。

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

案例 9：氫溴酸依來(lái)曲坦被假單胞菌和伯克霍爾德菌污染。

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，一家公司召回了兩批氫溴酸依曲普坦，因?yàn)檫@些產(chǎn)品批次不符合可能存在假單胞菌和伯克霍爾德菌屬的微生物標(biāo)準(zhǔn)。對(duì)于一般人群而言，這些風(fēng)險(xiǎn)較低，可能包括無(wú)嚴(yán)重感染的暫時(shí)性胃腸不適。然而，對(duì)于某些易損患者群體（例如免疫系統(tǒng)受損、囊性纖維化和慢性肉芽腫病的患者），這種有害污染可能會(huì)導(dǎo)致嚴(yán)重的不良事件，包括危及生命的感染。

來(lái)源：Internet

FDA發(fā)布《行業(yè)指南：非無(wú)菌藥品生產(chǎn)中的微生物質(zhì)量考量》草案

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