无菌检查之风险评估及规避_Olivier
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Method 方法
Device & Hardware 设备及硬件
Media 培养基
Failure may bring false positive results with the risk of batch rejection and false negative results with safety hazard to the recipients!
实验失败可能会带来导致实验批报废风险的假阳性结果和导致用户使用危害 的假阴性结果。
False POSITIVES: What consequences?
假阳性：什么后果？
Regulation forbids to just redo the test without finding first the root cause of the contamination法规禁止不以发现造成污染的根本原因 为目的而只是重复测试的行为。
Water
In-process
Support Data Product Release
Sterility Testing - Method principle
无菌检查—方法原理
Test from Pharmacopeias (compendial method)药典方法
Sterility is demonstrated by growth and reproduction (Growth Based test) 无菌性通过生长和繁殖来证明（基于生长实 验）
Alternative tests (under development and implementation) 可替代方法（开发和实施中）
Sterility Testing – Guidelines
指导方针
European Pharmacopoeia US Pharmacopoeia, <71> Japanese Pharmacopoeia ICH (International Committee Harmonization) Regulatory Guidelines/Guidance
Sterility Testing Programs in Pharmaceutical MicrobiEnvironmental Monitoring
Microbiology Laboratory
Sterility Testing
Final Product
Raw Materials
Brief look at 21 CFR 610.12 Revision
21 CFR 610.12修订版简要介绍
• Revision is applicable for Biologic based drugs only 修订只适用于生物制药 • This proposed rule is intended to provide manufacturers of biological
2.6.1 Sterility
5.1.9 Guidelines for using the test for Sterility
TGA : Therapeutic Good Administration from Australia – September 2006澳大利亚
治疗用品管理条例 PIC/S : Pharmaceutical Impection Convention / Pharmaceutical Impection
products greater flexibility and to encourage use of the most appropriate and state-of-the-art test methods for assuring the safety of biological products 本协议的原则是给生物制品生产商提供更大的灵活性，确保生物制品
的安全性，并鼓励使用最适当的检查方法
1. Eliminate references to specific test methods and culture media 去除使用特定检查方法 和培养基的指导方法
2. Use of a sterility test method that is appropriate to the material being tested such that the material does not interfere with or otherwise hinder the test 使用对该实验材料恰当 的无菌检查方法以防止干扰或妨碍实验，
3. Validation studies to demonstrate that the sterility test method used is capable of consistently detecting the presence of viable contaminating microorganisms 验证研究用 以表明该无菌检查方法能够检测出污染微生物的存在。
“对于每一批认为是无菌/无热源的药品，需要通过适当的 实验室检查来确定” 21CFR211.167 (a)
EP7/USP33 „The test is applied to substances, preparations or articles which, according to the Pharmacopoeia, are required to be sterile.“
1. Sterility testing introduction无菌检查介绍
2. Risks assessment风险评估
Environmental considerations环境因素 Method considerations方法因素 Device & Hardware设备及硬件 Media considerations培养基因素
Risk Assessment & Risk Mitigation in Sterility testing 无菌检查之风险评估及规避
Olivier MAZILLE, Global Product Manager - Sterility testing Gilles Aubut, Head of Product Management – Sterility testing
假阴性：什么后果？
Test passed and contaminated product is released检查通过，污染产品放行 o Patient injury risks 病人生命危险 o Recalls 召回 o Branding damages 品牌受损 o Plant shutdown risks 工厂关闭风险
Sterility Testing - General implications
无菌检查 - 基本概念
Users must undergo training programs! 用户必须经过严格培训！
“Because sterility testing is a very exact procedure, where asepsis of the procedure must be ensured for a correct interpretation of results, it is important that personnel be properly trained and qualified” (USP 31)由于无菌检查是非常 精确的实验，为保证实验的无菌过程和正确的结果判断，操作人员必须经过专 门的培训并通过资格认证。 (USP 31)
False POSITIVES: What consequences?
假阳性：什么后果？
Heavy investigation to find out the root cause大量的调查以找到问 题根本原因。 o Time and resource consuming耗费时间和资源 o Potential inspection by regulatory法规部门的审查
False POSITIVES: What consequences?
假阳性：什么后果？
Batch scrap 批报废 o If no root cause is proven 无可证明的根本原因 o High loss of money possible 可能的巨大损失
False NEGATIVES: What consequences?
代表一组数据有助于我们判断产品是否达到所要求的那样soleproductreleasetest并不作为唯一的产品放行检查的标准sterilitytestingwhat什么是无菌检查什么是无菌检查什么是无菌检查什么是无菌检查sterilitytestingprogramspharmaceuticalmicrobiology制药微生物中无菌检查程序制药微生物中无菌检查程序制药微生物中无菌检查程序制药微生物中无菌检查程序microbiologylaboratoryenvironmentalmonitoringwaterinprocessfinalproductrawmaterialssupportdataproductreleasesterilitytestingsterilitytestingmethodprinciple无菌检查无菌检查无菌检查无菌检查方法原理方法原理方法原理方法原理testfrompharmacopeiascompendialmethod药典方法reproductiongrowthbasedtest无菌性通过生长和繁殖来证明基于生长实alternativetestsunderdevelopmentimplementation可替代方法开发和实施中sterilitytestingguidelines指导方针指导方针指导方针指导方针europeanpharmacopoeiauspharmacopoeia71japanesepharmacopoeiaichinternationalcommitteeharmonizationregulatoryguidelinesguidancetherapeuticgoodadministrationfromaustraliaseptember2006澳大利亚治疗用品管理条例pharmaceuticalimpectionconventionpharmaceuticalimpectioncooperationschemeseptember2007药品检验药品检验合作公约drugadministration食品及药物管理局europeanagencymedicinalproducts欧洲药品管理局parenteraldrugadministration注射药物管理局medicalinstrumentation医疗仪器促进协会internationalorganizatio
Co-operation Scheme - September 2007 药品检验药品检验合作公约 FDA : Food and Drug Administration食品及药物管理局 EMEA : European Agency for the Evaluation of Medicinal Products欧洲药品管理局 PDA : Parenteral Drug Administration注射药物管理局 AAMI : Association for the Advancement of Medical Instrumentation医疗仪器促进 协会 ISO : International Organization for Standardization国际标准化组织 WHO : World Health Organization世界卫生组织
Sterility Testing - General implications
Considering the requirements and the limitations, each test component is critical! 考虑到要求和限制，每一个实验条件都非常重要！
Environment 环境
3. Conclusions结论
Sterility Testing Introduction 无菌检查介绍
Sterility Testing为何进行无菌检查 Why to conduct a sterility test ?
GMP requirements “For each batch of drug product purporting to be sterile and/or pyrogen free, there shall be appropriate lab testing to determine conformance to such requirements” 21CFR211.167 (a)
“药品无菌检查系用于检查药典要求无菌的药品、 医疗器具、原料、辅料及 其他品种是否无菌的一种方法”
Sterility Testing What is the Test for Sterility ?
什么是无菌检查
Presence / Absence test存在/不存在检查 Reference test参考性测试 Quality assurance requirement 质量保证要求 Represents one set of data which contributes to the decision of whether or not the product lot meets the stated claims. 代表一组数据，有助于我们判断产品是否达到所要求的那样 Not intended as a sole product release test 并不作为唯一的产品放行检查的标准
Risk Assessment: Environmental considerations
4. Verification that the sterility test method and test components used can detect the presence of viable contaminating microorganisms 确认无菌检查方法和实验条件可以检 测出活体污染微生物的存在。
Device & Hardware 设备及硬件
Media 培养基
Failure may bring false positive results with the risk of batch rejection and false negative results with safety hazard to the recipients!
实验失败可能会带来导致实验批报废风险的假阳性结果和导致用户使用危害 的假阴性结果。
False POSITIVES: What consequences?
假阳性：什么后果？
Regulation forbids to just redo the test without finding first the root cause of the contamination法规禁止不以发现造成污染的根本原因 为目的而只是重复测试的行为。
Water
In-process
Support Data Product Release
Sterility Testing - Method principle
无菌检查—方法原理
Test from Pharmacopeias (compendial method)药典方法
Sterility is demonstrated by growth and reproduction (Growth Based test) 无菌性通过生长和繁殖来证明（基于生长实 验）
Alternative tests (under development and implementation) 可替代方法（开发和实施中）
Sterility Testing – Guidelines
指导方针
European Pharmacopoeia US Pharmacopoeia, <71> Japanese Pharmacopoeia ICH (International Committee Harmonization) Regulatory Guidelines/Guidance
Sterility Testing Programs in Pharmaceutical MicrobiEnvironmental Monitoring
Microbiology Laboratory
Sterility Testing
Final Product
Raw Materials
Brief look at 21 CFR 610.12 Revision
21 CFR 610.12修订版简要介绍
• Revision is applicable for Biologic based drugs only 修订只适用于生物制药 • This proposed rule is intended to provide manufacturers of biological
2.6.1 Sterility
5.1.9 Guidelines for using the test for Sterility
TGA : Therapeutic Good Administration from Australia – September 2006澳大利亚
治疗用品管理条例 PIC/S : Pharmaceutical Impection Convention / Pharmaceutical Impection
products greater flexibility and to encourage use of the most appropriate and state-of-the-art test methods for assuring the safety of biological products 本协议的原则是给生物制品生产商提供更大的灵活性，确保生物制品
的安全性，并鼓励使用最适当的检查方法
1. Eliminate references to specific test methods and culture media 去除使用特定检查方法 和培养基的指导方法
2. Use of a sterility test method that is appropriate to the material being tested such that the material does not interfere with or otherwise hinder the test 使用对该实验材料恰当 的无菌检查方法以防止干扰或妨碍实验，
3. Validation studies to demonstrate that the sterility test method used is capable of consistently detecting the presence of viable contaminating microorganisms 验证研究用 以表明该无菌检查方法能够检测出污染微生物的存在。
“对于每一批认为是无菌/无热源的药品，需要通过适当的 实验室检查来确定” 21CFR211.167 (a)
EP7/USP33 „The test is applied to substances, preparations or articles which, according to the Pharmacopoeia, are required to be sterile.“
1. Sterility testing introduction无菌检查介绍
2. Risks assessment风险评估
Environmental considerations环境因素 Method considerations方法因素 Device & Hardware设备及硬件 Media considerations培养基因素
Risk Assessment & Risk Mitigation in Sterility testing 无菌检查之风险评估及规避
Olivier MAZILLE, Global Product Manager - Sterility testing Gilles Aubut, Head of Product Management – Sterility testing
假阴性：什么后果？
Test passed and contaminated product is released检查通过，污染产品放行 o Patient injury risks 病人生命危险 o Recalls 召回 o Branding damages 品牌受损 o Plant shutdown risks 工厂关闭风险
Sterility Testing - General implications
无菌检查 - 基本概念
Users must undergo training programs! 用户必须经过严格培训！
“Because sterility testing is a very exact procedure, where asepsis of the procedure must be ensured for a correct interpretation of results, it is important that personnel be properly trained and qualified” (USP 31)由于无菌检查是非常 精确的实验，为保证实验的无菌过程和正确的结果判断，操作人员必须经过专 门的培训并通过资格认证。 (USP 31)
False POSITIVES: What consequences?
假阳性：什么后果？
Heavy investigation to find out the root cause大量的调查以找到问 题根本原因。 o Time and resource consuming耗费时间和资源 o Potential inspection by regulatory法规部门的审查
False POSITIVES: What consequences?
假阳性：什么后果？
Batch scrap 批报废 o If no root cause is proven 无可证明的根本原因 o High loss of money possible 可能的巨大损失
False NEGATIVES: What consequences?
代表一组数据有助于我们判断产品是否达到所要求的那样soleproductreleasetest并不作为唯一的产品放行检查的标准sterilitytestingwhat什么是无菌检查什么是无菌检查什么是无菌检查什么是无菌检查sterilitytestingprogramspharmaceuticalmicrobiology制药微生物中无菌检查程序制药微生物中无菌检查程序制药微生物中无菌检查程序制药微生物中无菌检查程序microbiologylaboratoryenvironmentalmonitoringwaterinprocessfinalproductrawmaterialssupportdataproductreleasesterilitytestingsterilitytestingmethodprinciple无菌检查无菌检查无菌检查无菌检查方法原理方法原理方法原理方法原理testfrompharmacopeiascompendialmethod药典方法reproductiongrowthbasedtest无菌性通过生长和繁殖来证明基于生长实alternativetestsunderdevelopmentimplementation可替代方法开发和实施中sterilitytestingguidelines指导方针指导方针指导方针指导方针europeanpharmacopoeiauspharmacopoeia71japanesepharmacopoeiaichinternationalcommitteeharmonizationregulatoryguidelinesguidancetherapeuticgoodadministrationfromaustraliaseptember2006澳大利亚治疗用品管理条例pharmaceuticalimpectionconventionpharmaceuticalimpectioncooperationschemeseptember2007药品检验药品检验合作公约drugadministration食品及药物管理局europeanagencymedicinalproducts欧洲药品管理局parenteraldrugadministration注射药物管理局medicalinstrumentation医疗仪器促进协会internationalorganizatio
Co-operation Scheme - September 2007 药品检验药品检验合作公约 FDA : Food and Drug Administration食品及药物管理局 EMEA : European Agency for the Evaluation of Medicinal Products欧洲药品管理局 PDA : Parenteral Drug Administration注射药物管理局 AAMI : Association for the Advancement of Medical Instrumentation医疗仪器促进 协会 ISO : International Organization for Standardization国际标准化组织 WHO : World Health Organization世界卫生组织
Sterility Testing - General implications
Considering the requirements and the limitations, each test component is critical! 考虑到要求和限制，每一个实验条件都非常重要！
Environment 环境
3. Conclusions结论
Sterility Testing Introduction 无菌检查介绍
Sterility Testing为何进行无菌检查 Why to conduct a sterility test ?
GMP requirements “For each batch of drug product purporting to be sterile and/or pyrogen free, there shall be appropriate lab testing to determine conformance to such requirements” 21CFR211.167 (a)
“药品无菌检查系用于检查药典要求无菌的药品、 医疗器具、原料、辅料及 其他品种是否无菌的一种方法”
Sterility Testing What is the Test for Sterility ?
什么是无菌检查
Presence / Absence test存在/不存在检查 Reference test参考性测试 Quality assurance requirement 质量保证要求 Represents one set of data which contributes to the decision of whether or not the product lot meets the stated claims. 代表一组数据，有助于我们判断产品是否达到所要求的那样 Not intended as a sole product release test 并不作为唯一的产品放行检查的标准
Risk Assessment: Environmental considerations
4. Verification that the sterility test method and test components used can detect the presence of viable contaminating microorganisms 确认无菌检查方法和实验条件可以检 测出活体污染微生物的存在。