液体灭菌过滤
技术报告No.26
目录
1.INTRODUCTION简介 (1)
2.PHARMACEUTICAL FILTRATION:HISTORICAL HIGHLIGHTS药用过滤：历史成果 (1)
3.HOW FILTERS WORK过滤器如何工作 (2)
3.1Size Exclusion体积排阻 (2)
3.2Other Retention Mechanisms其他保留机理 (2)
of3.3Bioburden Retention Probability生物负荷保留概率 (2)
3.4Pore Size Rating孔径大小等级 (3)maintenance翻译
4.FILTER SELECTION AND CHARACTERIZATION过滤器选择和特点 (3)
4.1Filter Types过滤器类型 (3)
4.2Filter Configuration过滤器配置 (3)
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4.3Particle Shedding颗粒脱落 (4)
4.4Extractable萃取物 (4)
4.5Chemical Compatibility化学兼容性 (4)
4.6Adsorption吸附 (4)
4.7Thermal Stress Resistance抗热应力 (4)
4.8Hydraulic Stress Resistance抗液压 (4)
4.9Toxicity Testing毒性试验 (4)
4.10Bacterial Challenge Testing细菌挑战性测试 (5)
4.11Physical Integrity Testing物理完整性测试 (5)
5PHYSICAL AND MECHANICAL CHARACTER-ISTICS物理和机械特性 (5)
5.1Filtration Rate and Clogging(Throughput)过滤流速和堵塞（产量） (5)
5.2Fluid/Piping液体/管道 (6)
5.3Fluid/Filter液体/过滤器 (6)
5.4Physical and Structural Limitations物理和结构极限 (6)
6STERILE FILTER VALIDATION/BACTERIAL RE-TENTION无菌过滤器验证/细菌保留 (6)
6.1Factors Influencing Microbial Retention影响微生物停留的因素 (6)
6.2Considerations for Bacteria1Retention Validation Studie细菌停留验证研究需考虑方面 (7)
6.3Challenge Organism Selection Criteria挑战有机物选择标准 (7)
6.4Culture Maintenance培养基保存 (7)
6.5Culture Conditions and Standardizatio培养基状况和标准 (7)
6.6Effective Challenge Concentration有效挑战浓度 (8)
6.7Challenge Level挑战等级 (8)
6.8Aggregation聚合 (8)
6.9Culture Viability培养基存活能力 (8)
6.10Challenge Test Methods挑战性测试方法 (8)
6.11Test Organism Viability测试有机物存活能力 (8)
6.12Testing Procedure and Protocol Development测试程序和方案起草 (8)
6.13Nonbactericidal Process and Fluids无菌工艺和液体 (9)
6.14Surrogate Fluids替代液体 (9)
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6.15Bacteriostatic/Bactericidal/Nondispersive Challenge Fluids细菌抑制/灭菌/非分散挑战液体 (10)
6.15.1Product U at Reduced Exposure Time对比暴露时间内的产品使用 (10)
6.15.2Modify Process修改工艺 (10)
6.15.3Modify Formulation修改剂型 (10)
6.15.4U of Resistant Indigenous Bioburden抗固有生物负荷的使用 (10)
6.16Filter Medium versus Device过滤器介质VS.设备 (11)
6.17Pressure Differential and Flow Rate压差和流速 (11)
6.18Duration持续时间 (11)
6.19Downstream Samplin下游取样 (11)
6.20Assay Membrane Selection检测膜选择 (11)
kirs6.21Results Interpretation结果说明 (11)
6.22Product Bioburden产品生物负荷 (12)
6.23Filter Configuration Change过滤器配置变更 (12)
7INTEGRITY TESTING完整性测试 (12)
7.1Integrity Testing Theory完整性测试理论 (12)
7.2Relationship Between Integrity Test Results and Bacterial Retention完整性测试结果和细菌停留的关系 (14)
7.3Product-Wetted versus Water-Wetted Integrity Testing产品浸湿VS水侵完整性测试 (15)
7.3.1Product-Wetted Bubble Point(Ratio)产品浸湿气泡点（比率） (16)
7.3.2Product-Wetted Bubble Point(Statistical Approach产品浸湿气泡点（统计法） (16)
7.3.3Product-Wetted Diffusive Flow/Forward Flow Test Specifications产品浸湿扩散流/顺流测试说明 (17)
7.4Upstream Testing without Downstream Manipulation Utilizing Automated Integrity Test Instruments自动完整性测试仪进行上游测试，无下游控制 (17)
7.5When a Sterilizing Grade Filter Should Be Integrity Tested灭菌级过滤器何时应进行完整性测试 (17)
7.6Failure Analysis/Troubleshooting故障分析/故障检修 (18)
8FILTER STERILIZATION过滤器灭菌 (19)
trunk8.1Steam Sterilization蒸汽灭菌 (19)
8.1.1Autoclave Sterilization高压蒸汽灭菌 (19)
8.1.2Sterilize-in-Place在线灭菌 (19)
日语三级8.2Irradiation Sterilization辐射灭菌 (19)
8.3Gas Sterilization气体灭菌 (20)
APPENDIX A,PORE SIZE ESTIMATION附件A，孔径估测 (21)
APPENDIX B,TOXICITY AND FILTER EXTRACTABLES TESTING附件B，毒性和过滤器浸出物测试 (22)
APPENDDIX C,FILTER VALIDATION RECOMMENDA-TlONS附件C，过滤器验证建议 (23)
Tests Commonly Performed by Filter Urs and the Filter Manufacturers-General Industry Practices通常由过滤器使用者和过滤器生产商进行的测试一般工业规范 (23)
APPENDIX D,NONDESTRUCTIVE PHYSICAL INTEGRITY TEST METHODS附件D，非破坏性物理完整性测试方法 (24)
Bubble Point Test气泡点测试 (24)
Diffusive Flow/Forward Flow Test扩散流/顺流测试 (24)
Pressure Hold/Decay Test压力保持/衰减测试 (25)
Automated Integrity Test Instruments自动完整性测试仪
Correlation Between Pressure Hold/Decay and Diffusive Flow/Forward Flow压力保留/衰减和扩散流/顺流 (26)
APPENDIX E,STATISTICAL ADJUSTMENT TOTHE CALCULATED PRODUCT-WETTED BUBBLE POINT附件E，所计算产品浸湿气泡点的统计调整 (28)
1.INTRODUCTION简介
Sterilizing filtration is the process of removing all microorganisms,excluding virus,from
a fluid stream.A sterilizing filter must remove all microorganisms prent in a fluid stream
without adverly affecting product quality.This technical report is intended to provide a systematic approach to lecting and validating the most appropriate filter for a sterilizing filtration application.
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灭菌过滤是从液体蒸汽中除去不包括病毒在内的所有微生物的过程。灭菌过滤器必须除去液体蒸汽中的所有微生物，而不能影响产品质量。技术报告旨在提供系统研究法以选择并确认最合适的过滤器。
Early,careful screening of potential filter types and configurations can result in fewer technical and regulatory problems,fewer delays,more efficient product processing and greater sterility assurance
my day作文早期仔细筛选过滤器类型和配置能减少技术和管理问题，减少拖延时间，产品加工效率更高，无菌保证性更高。
This document should be considered as a guide;it is not intended to establish any mandatory or implied standard.
此文件应作为指南，而不是建立任何强制或隐含的标准。
2．PHARMACEUTICAL FILTRATION:HISTORICAL HIGHLIGHTS药用过滤：历史成果In the early1900s,the first parenteral drugs were manufactured on an industrial scale.The need aro to find a suitable sterilization method for heat-nsitive products that could not be autoclaved in the final ,had to be aptically procesd.Later,filtration to remove subvisible particulates from parenteral preparations,particularly solutions introduced intravenously,was found to be important.
20世纪初，注射药物第一次以工业规模生产。对于不能在最终容器中进行高压灭菌的热敏感产品需有合适的灭菌法，即必须进行无菌加工。之后，过滤除去注射剂配液中显微镜的可见颗粒非常重要，特别是进入静脉的溶液。
It is not surprising that pioneering work in the field of germ removal by filtration (sterilization by filtration)also was underway from about1900to1930.In the industrial field,three paths were pursued:porcelain filter cartridges,asbestos-cellulo layers and membrane filters.
过滤灭菌领域的早期工作从1900到1930一直在进行。在工业领域，有3条途径：瓷滤筒，石棉-纤维层和薄膜过滤器。
Initially,porcelain filters by Chamberlain were ud in pharmaceutical production.However, problems
with cleaning the permanent filters and the danger of cross-contamination led to their replacement.The first filter medium to be ud on an industrial scale worldwide for almost50years was a cellulo-asbestos filter known as the Seitz EK Filter(EK-Entkeimung,“germ removal”).Since the mid-1970s this filter has been forced off the market becau of the asbestos fiber issue.Collodion membranes,manufactured by urs themlves,were employed in bacteriological laboratories as early as the first decade of the20th century.The forerunner to the membrane filter was developed by Zsigmondy and Birchmann who patented a graded ries of membranes in1918.The Sartorius-Werke Aktiengellschaft,Gottingen,Germany,refined the Zsigmondy process and in1929 began the commercial production of membrane filters on a small scale.The firsttwo is better than one
membrane disks led to the replacement of porcelain filter cartridges in pharmaceutical production.There still was a lack of efficient,large surface area,inexpensive membrane filters for u in large parenteral batch production.The membrane filter cartridges, especially the pleated cartridges that entered the market in the197Os,were a step in the right direction.
Chamberlain的瓷过滤器最初用于药品生产。然而，清洗这些永久过滤器及交叉污染风险等问题导致其被替换。全球用于工业规模第一个过滤器介质是石棉-纤维过滤器，称为Seitz EK 过滤器，几乎用了50年。从1970s中期开始，由于石棉光纤问题，这种过滤器被迫离开市场。早在20世纪初十年，使用
者将自己生产的火棉胶膜用于细菌实验室中。薄膜过滤器的先驱为Zsigmondy和Birchmann，他们在1918年申请了薄膜等级系列专利。Sartorius-Werke Aktiengellschaft,Gottingen，德国改进了Zsigmondy工艺并在1929年开始小规模生产薄膜过滤器。第一个膜盘的出现导致药品生产中瓷滤筒被替换。但大型注射剂批生产仍缺乏效率高，大面积和便宜的膜过滤器。膜滤筒，特别是1970s进入市场的折叠过滤器，是很大的进步。
There still were problems,as the retention rate for bacteria was unacceptable to the pharmaceutical industry.The problem was examined systematically,and a collaboration between filter manufacturers and pharmaceutical companies developed basic principles that would ensure safety in sterilization by filtration(77).
但仍有很多问题，比如细菌残留率不符合医药工业要求。此问题已系统检验过，过滤器生产商和医药公司的合作确立了基本原则，确保过滤灭菌的安全性。
The homogeneity of the membranes in the sponge-like labyrinth system and the concern about the potential for interfering“large pores”initially led to the u of double-layer membranes.Additionally,defects in the cartridges aro from the folding and welding,or gluing of the membranes,as well as defective als and damage during autoclaving. Newly developed integrity te
st equipment helped,allowing accurate measurements to asss the defects.Improved filter manufacturing techniques eventually eliminated the defects.
最初由于海绵状迷宫式系统的同质性及考虑到其可能会干扰“大孔”，此外还有折叠，焊接或膜之间的粘附引起的滤筒缺陷，高压灭菌过程中的密封缺陷和损坏导致采用了多层膜。最近研发的完整性测试设备能进行精确测量以评估缺陷。改进的过滤器生产技术最终消除了这些缺陷。
Until the late1960s,0.45pm-rated membranes were considered“sterilizing grade”filters, and were ud successfully in the sterilizing filtration of parenterals.Such filters were qualified using0.6x1pm Serrutia marcescens,a standard bacterium for qualifying analytical membranes ud for water quality testing(6).In the mid-1960s,however,Dr. Frances Bowman of the FDA obrved a0.45ym“sterile-filtered”culture medium to be contaminated with an organism,subquently shown to penetrate0.45pm-rated membranes repeatedly in small numbers at challenge levels above104-l06per cm2(9,ll).直到1960s后期，0.45μm级膜被认为是“灭菌级”过滤器，成功用于注射剂灭菌过滤。这些过滤器通过使用0.6xlμm Serratia marcescens来证明，这是水质测试的标准细菌，用以证明分析膜合格。在1960s中期，FDA的Dr.Frances Bowman发现0.45μm“无菌过滤”培养基中有一个有机污染物，最终显示其在挑战等级高于104-106/cm2条件下以少量数目能重复渗透0.45μm级膜。
Bowman also obrved that the next finer grade commercial membrane(nominally0.22
