6过滤器验证

Access Services & Considerations for Filter Validation ACCESS验证服务＆过滤器验证要点 Objectives目标 • Why filter validation is important? 过滤器验证的重要性何在? • Who is responsible for validation? 谁将对验证负责? • What needs to be validated? 需要验证哪些内容？ • How Millipore can help？ 密理博将如何帮助您？ x1 幻灯片 2 x1 xdun, 2006-9-15 Why is filter validation important? 过滤器验证的重要性 • Filter Validation is a Good Business Practice which ensures 过滤器验证是良好的生产实践，能保证： – Consistent 生产的连续稳定性 – reproducible results生产批次重复性好 • It is a regulatory requirement. 法规的要求 Filter Validation is Required Worldwide by GMP 世界各国ＧＭＰ法规要求进行过滤器验证 • US GMP 21 CFR Parts 210 & 211 美国GMP • Appropriate written procedures…shall be established and followed. Such procedures shall include validation of any sterilization process 必须建立和跟进相应的证明性文件….,，这些文件中包括所有的除菌工 艺的验证文件． • EU GMP Annex 1 Sterile Medicinal Products 欧盟GMP 无菌药品附录 • All sterilization processes should be validated 所有除菌 工艺 钢结构制作工艺流程车尿素生产工艺流程自动玻璃钢生产工艺2工艺纪律检查制度q345焊接工艺规程 必须进行验证 • Australian TGA GMP 澳大利亚 TGA GMP • Filtration processes used as the sterilizing step for products should be validated 出于除菌目的过滤工艺应该验证 • Health Canada GMP 加拿大GMP • Documented evidence is available establishing validation and validity of each sterilization process 每步除菌工艺必须要有验证其有效性的证明性文件 Filter Validation in Regulatory and Industry Guidelines 法规及行业指南对过滤验证的要求 • FDA Aseptic Processing Guidelines (1987 & 2004, www.fda.gov) FDA无菌工艺指南 – Correlate filter performance with filter integrity testing Include microbiological challenges to simulate ‘worst case’ production conditions 与过滤器完整性相关的性能测试应包括：模拟生产条件，在最苛刻生产环境下进 行微生物挑战试验。 • PDA Technical Report 26 (1998, www.pda.org) – “Early, careful screening of potential filter types and configuration can result in fewer technical and regulatory problems, fewer delays, more efficient product processing, and greater sterility assurance” 更早地，更细致地选用过滤器的规格和类型可减少技术和法规方面的问题，避免 延误，更有效的生产，更好的无菌保障． • ISO/DIS 13408-2 Aseptic Processing (2003, www.iso.ch) ISO/DIS 无菌工艺 – Filter Pre-selection shall take into account chemical and physical characteristics of the filter, as established by the filter manufacturer. – Bacterial retention performance of filters shall be validated in a fluid-specific manner or for fluid groups under worst case conditions in production. 选择过滤器前向生产商确认，仔细考虑过滤器的物理，化学性能。 细菌截留性能验证：１）需要在生产过程中可能遇到的最差的条件下进行， ２）使用产品或模拟液进行验证。 Other Sources of Guidance 其它相关指南 • FDA 483 and warning letters Show regulatory trend法规发展方向 • Site Lack of Validation for缺陷常发生在： • Filter Compatibility with product过滤器与产品间的兼 容性 • Filter Extractables过滤器的溶出物 • Actual Filtration Process Conditions used实际过滤操 作条件 • Filter Integrity Testing Methods/Fluids过滤器完整性测 试方法／测试流体 • Equivalency of alternate filters过滤器的一致性 Benefits of Filter Validation 过滤器验证的好处 Validation Ensures 验证能够确保 • Correct Filter Selection正确的过滤器选型 – Chemically Compatible with product与产品的化学兼容 性 – Process Conditions (such as temperature & pressure) are compatible 对生产条件（如温度＆压力）耐受性 – Verification of Sterilizing-grade performance 无菌性能的 验证 • Optimized Filter Configuration优化过滤器的配置 – Robust system design可靠的系统 设计 领导形象设计圆作业设计ao工艺污水处理厂设计附属工程施工组织设计清扫机器人结构设计 • Consistent Operation运行稳定 – Validate Cleaning清洁验证 – Validate Sterilization灭菌验证 – Test Filter Integrity完整性测试 – Trained Operators操作人员培训 Who is Responsible? 谁对验证负责 • Filter User Responsibilities:用户的职责： – Filter Selection (w/manufacturer’s assistance) 过滤器的选型（生产商协助） – Filter/Product Specific Validation Studies 过滤器／产品特性验证研究 – Process Validation 生产工艺验证 • Filter Vendor Responsibilities: 生产商的职责： – Filter Design Qualification – Filter Fabrication Qualification – Filter Quality & Testing 过滤器设计合理性确认 过滤器制造材料性能确认 过滤器本身质量测试 Filter User Responsibilities 用户的职责 • According to the guidelines, the filter user is ultimately responsible for the filter validation.根据指南，用户应最终对过滤器的验证负责 • When validating filter use, be sure to:当过滤器选定后，必须： – test in your drug product whenever possible 尽可能以产品进行验证 – test your “worst-case” process conditions 在最差条件下进行验证／测试 最苛刻环境下过滤器性能 • Using outside testing laboratories is acceptable according to: 在经授权认定的实验机构进行相关实验是允许的： – Aseptic Processing Guidelines 1987 ※ 2004无菌工艺指南 • Data may be generated by outside labs, filter suppliers, or the user 数据可由第三方实验机构＼过滤器生产商＼或用户提供 – Human Drug cGMP Notes, December 1995 人类用药cGMP注释，1995年12月 • The drug product manufacturer’s ultimate responsibility is to ensure that “worst-case forumulation and processing parameters are adequately studied, evaluated, and documented.” 药品生产商应最终负责保证最差的条件下对过滤器性能充分的测试， 评估，并有相应证明文件 • Audit the outside laboratory. 考核实验机构 Filter User-Auditing审核 • When auditing the outside laboratory: evaluate the facility adequacy, quality of the equipment, documentation, quality systems and training of operators. 核查实验机构：仪器设备的齐备，仪器的性能可靠，证明文件，质量验 证体系，及操作人员的培训。 • Ensure each validation test has a protocol 保证每个验证测试均有相应实验 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 • Review your protocols prior to testing 测试前核查实验方案 • Ensure that protocols cover your process 保证实验方案能代表您的生产工艺过程 – Meet guideline requirements满足指南要求 – Signed prior to testing实验前签字确认 Responsibilities of the Filter Vendor 过滤器供应商职能 • Validate filter claims and manufacturing process 过滤器的验证证明及过滤器生产工艺 • Establish specifications and operating limits 建立说明书及操作条件限制 – Integrity specifications – BP and diffusion 完整测试 标准 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 – 起泡点及扩散流 – Use Temperature – maximum 最大操作温度 – Use Pressure – maximum 最大操作压力 – Sterilization cycle maximum - cycle #, temp, time 可以最多灭菌的次数－次数，温度，时间 Responsibilities of the Filter Vendor 过滤器供应商的职责 Ensure that its filters meet regulatory and compendial requirements 确保其过滤器符合法规要求 – Non-Fiber releasing - defined 21 CFR 210.3 无纤维脱落 – Endotoxin - <0.5 Eu/mL by LAL 内毒素- <0.5 Eu/mL 鲎试剂法 – In vivo/In vitro Toxicity - Class VI and Mouse Safety 体内体外毒性试验符合六级材料标准，大鼠安全试验 – Sterilizing-grade performance – ASTM 除菌级过滤器的性能 – Evaluate Extractables 溶出物评估 Responsibilities of the Filter Vendor 过滤器供应商职责 • To meet filter vendor regulatory requirements, Millipore offers Filter Validation Guides which include: 为满足法规要求，密理博公司提供的过滤器验证指南包括： – Product specifications产品说明书 – Qualification test results for: 产品性能测试结果： • Retention testing-using ASTM methodology 按美国试验材料协会制定方法执行的截留实验 • Integrity testing: diffusion, forward and reverse 完整性测试：扩散流，正反相起泡点 • USP biological safety testing results USP生物安全测试结果 • USP bacterial endotoxin test results USP细菌内毒素测试结果 • Water flow rate 水流速 • Hydraulic stress resistance 耐水压性能 • Thermal stress resistance (to sterilization cycles) 耐热性（灭菌次 数） • Extractables 溶出物 • USP Oxidizable substances test results 氧化物测试结果 • Particulates and fiber shedding data 颗粒及纤维脱落 Additional Testing Is Still Required 其他需要的的附加实验 • Filter testing for validation guides is generic using standard methodologies. 验证指南中过滤器检测使用常规的实验方法 – Parameters are chosen to test limits. 各项参数是检测极限 – Fluids used are not drug products. 不是基于产品制定的。 • In addition to the validation guide, product and process specific filter validation testing is required. 除了验证指南，产品适用性验证和工艺适应性验证也是必须的。 • Millipore offers product and process specific filter validation testing through its Access SM Services contract laboratory. 密理博ACCESS验证实验室可提供产品和工艺适用性验证服务。 验证流程 Protocol 方案 VMP验证 总体计划 Access Questionnaire 调查表 Report 报告 Validation Master file 验证总文件 Process design 过滤设计 Filter Sterilisation 过滤器的灭菌 Tester IQ OQ检测仪的安 装运行确认 Bioburden Sterility 生物负荷的降低 Training Education培训 Bacteria retention细菌截留 Extractables 析出物 Adsorption吸附性 Product specific parameters 产品规格参数 Filter integrity Test过滤器的完 整性检测 Filter performance过 滤器性能 Compatibility 兼容性 Filter integrity test operator certification 滤器操作者资格证书 Design, SOP validation for filter sterilisation灭菌 过程设计,标准操作程 序的制定, Steritest school 项目 Sampling Equipment 取样设备 IQ OQ 安装确认,运行确认 Microbiological method validation 微生物方法验证 PQ性能确认 air surfaces fluids SIP validation 在线灭菌验证 Filterability studies 过滤性研究 Engineering 加工 RegulatoryRegulatory ComplianceCompliance法规法规 Sterility AssuranceSterility Assurance 无菌保证无菌保证 除菌过滤器验证流程 定义工艺条件及流程 确定操作条件 完整性检测方法析出物，兼容性，吸附 微生物挑战 试验，毒性 压力，流速， 温度 验证指南产品 使用说明 爱威a9效果器使用图word使用说明在哪儿钻床数控系统用户手册玻璃钢风机使用说明书控制器用户说明书 Validation Guide 验证指南 What is Access Services? ACCESS服务内容 A group of Contract Laboratory and filtration services for Millipore products 多家签约实验室为密理博公司的过滤产品提供服务 Dedicated laboratory facilities in Millipore’s Billerica， US, Molshiem ，France， Yonezawa， Japan and Bangalore，India, 密理博生物制药技术中心拥有专业实验仪器 Dedicated Personnel: – Pharmacists 药师 – Microbiologists 微生物学家 – Biochemists 生化学家 – Engineers 位研发人员＆工程师 Highly trained to test Millipore product 良好的专业培训 Dedicated Laboratories and Validated Equipment 专业科研人员及经过验证的实验设备 Access Services Filter Test Offerings Biological生物性能 – Microbial Retention 微生物截留 • Customized to客户 定制 Flow Rate流速 Throughput产量 Process temperature 操作温度 Pressure压力 System Size系统尺寸 大小 Physical物理性能 – Integrity完整性 • Product/water BP ratio产品／水起跑点 • Diffusion ratio扩散流 – Binding吸附 4000 3500 3000 2500 2000 1500 1000 W avenumber cm-1 FTIR Reference Spectrum of Polycarbonate Chemical化学性能 – Compatibility – Extractables 兼容性＼析出物 Compatibility Testing 兼容性测试 Filter/Product Compatibility Testing 过滤器与产品兼容性测试 • Is the filter membrane compatible with the drug product?滤膜与产品兼容吗？ • Static soak in actual drug product for process time (24 hr minimum). 将滤膜浸泡在料液中。浸泡时间不短于生产 时间（最小24小时） • Inspect for visible changes 察看有无可见的变化 • Evaluate for physical change in 检测物理性能的变化： – Water Flow Rate水流速 – Membrane Weight滤膜重量 – Product Bubble Point产品起泡点 Extractables Evaluation 析出物评估 Filter Extractables Evaluation 过滤器析出物评估 • Filter Extractables evaluation is mentioned in both PDA Technical Reports 15 and 26. 在注射剂管理委员会的15及26号报告中描述了过滤器析出物评估方法。 • Knowledge of Extractables level is important in relation to: 了解析出物水平有利于： – Filter flush volume determination决定过滤器预先冲洗体积 – Small volume applications-where dilution of extractables is minimal决定 过滤器能否用于小体积过滤（无法冲淡和稀释析出物） – Direct filling-where extractables levels are highest in first vials filled直接 灌装（这时第一瓶的析出物含量最高） • 2 methods to consider:考虑使用两种方法： – Determination of Extractables in Actual Drug在实际药物中的析出物 – Use Model Solvent Stream Approach用溶剂来模拟，检测析出物 Filter Extractables Evaluation 过滤器析出物评估 • Use of Actual Drug problem:使用实际产品会造成： – Solutes in the drug can cause interference with analytical methods used to detect filter extractables – 药物中的溶质有可能影响对最终析出物的检测。 – Filter Extractable levels in extract solutions will be small as compared to product solute levels – 在提取液中，滤器析出物水平可能会远低于溶质浓度。（不容易检测） – Filter Extractables would be masked by drug product ingredients – 析出物可能被药物成分掩盖（不容易检测到） • Avoid detection issue:如果要避免出现这些问题： – Use Model Solvent Stream Approach使用模拟溶剂方法 • Review drug formulation information 查看药液配方信息 • Determine solvent to model drug决定模拟溶剂 • Extract in that solvent (or solvents)用一种或多种溶剂进行提取 • Evaluate filter extractables only 评估析出物水平 – Widely used and acceptable analysis approach – 被广泛使用和接受的分析方法 Binding Studies 吸附研究 Why Binding Studies? 为什么对吸附进行研究 • A filter should neither add nor remove any ingredients from a fluid. • 一个滤器既不应该对流体添加成分，也不应减少流体中的成分。 • However, preservatives and proteins still may bind in small quantities. • 然而，防腐剂和蛋白仍会有少部分损失 • When the concentration of an ingredient is critical, it is important to understand how filtration my affect concentration in the final product. • 当流体中的成分浓度很关键时，了解滤器对产品的吸附程度就显 得非常重要了。 Millipore Binding Studies 密理博的吸附研究 • Conducted when Filter User has concern about critical component concentration • 当客户对关键成分非常在意时，执行吸附验证 试验。 • Procedure:程序 – Conduct scale down filtration – 作小样试验 – Collect first filtrate samples in fractions – 收集首先过滤出来的流体 – Filter User: analyze for component concentration – 过滤器使用者对料液中的成分进行分析 0 20 40 60 80 100 % R e c o v e r y Filtrate Volume Binding Study Binding Data 吸附数据 • Allows Filter User to determine if there is a filter saturation point. • 由滤器使用者判断滤器对料液有无吸附饱和点。 • If yes, binding can be compensated for by pre-use saturation with the binding ingredient. • 如果有，可以事先添加使吸附位点饱和的成分，补偿吸附造成的损失。 • The product volume up to saturation point –can be discarded or returned to the upstream reservoir for reprocessing (if is determined that this return will not cause unacceptable dilution of the batch). • 对于饱和点以上的多余那部分料也可以抛弃或将他们返回到储罐中再处 理（如果稀释不影响工艺）。 Product Specific Bubble Point 产品起泡点 Product Bubble Point Specification 产品泡点标准 • Pre-use integrity testing is recommended. • 最好在滤器使用前检测完整性 – Use the recommended wetting fluid (that has a corresponding bubble point specification) to determine integrity of the filter. – 使用推荐的液体润湿滤器，然后检测过滤器完整性（工艺上提供 标准） • Post-use integrity testing is required • 过滤后必须检测完整性 – If post-use integrity testing in Product, a Product bubble point specification is required – 如果过滤后直接检测，就需要产品泡点标准 – Determine a Product/Water bubble point ratio – 通过验证，确定产品/水起泡点比值 – Use ratio to establish product bubble point specification – 用这个比值建立产品泡点标准 When to Use a Product Bubble Point Specification? 什么时候使用产品泡点 • Post filtration flushing with the BP wetting fluid of choice is impractical • 过滤后使用标准润湿液不现实 • Can’t risk dilution of valuable product • 产品不允许稀释 • Product is incompatible/immiscible with the specified wetting fluid • 产品与标准润湿液不兼容或无法完全混合。 Note: After establishing a product bubble point specification, the Filter User must continually collect data to detect if there is product bubble point drift over time 注：产品起泡点建立好以后，过滤器的使用中要不断收集数据，判断产 品泡点是否有漂移。 Microbial Retention Testing 微生物截留试验 What is a Sterilizing-Grade Filter? 什么是除菌级过滤器？ • Defined by ASTM F838-83 (1993) 给出定义 • A filter which, when challenged with the bacterium Brevundimonas diminuta, at a minimum concentration of >107 cfu per cm2 of filter surface area, will produce a sterile effluent. 除菌级过滤器是指符合以下标准的过滤器：用每平方厘米 >107CFU的缺陷性假单胞菌进行挑战这一滤器，下游液体 无菌。 What is a Sterilizing-Grade Filter? 什么是除菌级过滤器？ • Definition is further refined to include product-specific bacterial retention testing as noted in:在下面的法规中，除菌过滤器的定义包括滤器能满足 料液中的细菌截留要求： – Aseptic Processing Guideline, FDA 1987 & 2004 无菌工 艺指南，FDA，1987 & 2004 – PDA Technical Report 26, 1998 注射剂管理委员会，26号技术报告 Note: the definition does not include a filter type or pore size recommendation. This must be determined by product/process specific bacterial retention testing. 注意：定义中并不要求滤膜的孔径，而是要求对产品中细菌的截留指标。 Product/Process Specific Bacterial Retention Testing产品中细菌截留试验 • Millipore uses the standard ASTM method and applies recommendations of PDA Technical Report 26 to simulate actual Filter User conditions on a laboratory scale using actual drug product. • 密理博根据ASTM的标准和PDA的要求，在试验室种用实际料液进行细菌挑战试验。 • Filter User过滤器的使用者 – Supplies product and confirms their conditions – 提供产品和确认过滤工艺操作条件 • Disclose ingredients list and Chemical Attributes 提供产品成分列表和化学属性 • Actual processing conditions 实际操作条件 • Bioburden organisms 可能的生物负荷（微生物种类数量等） Bacterial Retention Test Method 细菌截留检测方法 • Use Standard Challenge Organism 使用标准的挑战微生物 – Brevundimonas diminuta缺陷性假单胞菌 – ATCC 19146 菌种 • With Standard Culturing Method使用标准的培养方法 – Saline lactose broth 肉汤培养基（含乳糖） – Size in SLB = 0.68 µm x 0.31 µm缺陷性假单胞菌的尺寸 • And Standard Test Design标准试验设计 – Laboratory-scale simulation of the manufacturing and processing conditions including:在试验室模拟生产工艺条件 • Time, Temperature过滤时间及温度 • Differential Pressure or压差 • Flow Rate流速 • Intermittent or Continuous Flow间歇或连续过滤 – Tested on Membrane Discs膜收集法检测 • Using Customer’s Test Fluid使用客户提供的检测料液 – Actual drug product when possible如果可能，使用实际料液 Summary总结 • Each drug-filtration process must be validated. • 应针对所过滤的每种产品进行验证 • There are several critical components in the validation of sterilizing filters. • 无菌过滤器验证的几个关键因素 – Determine Compatibility of filter, drug & process – 首先决定滤器，产品，工艺的兼容性 – Establish Complete Microbial Retention in drug at processing conditions – 在实际生产条件下，验证对微生物截留性能 – Evaluate Filter Extractables-sterilizing and upstream – 评估过滤器的析出物水平 – Determine the Product-Filter Integrity Specification when necessary – 若有必要，确定基于产品的完整性测试标准。 Summary总结 • Filter Validation uses a combination of tests and techniques to achieve a complete validation package • 使用不同的工具和技术相结合去完成验证 • Millipore can assist with validation by: • 密理博可提供的帮助如下： – Recommending appropriate filters推荐最适合的过滤器 – Optimizing filtration trains优化过滤系列（多个滤器的组合） – Offering filter validation guides提供验证指南 – Filtration and integrity test training过滤以及完整性培训 • Millipore Access SM Services can conduct your product/process specific validation tests for you 密理博验证部门可指导或直接提供验证相关试验 What we have covered today • Why filter validation is important? 过滤器验证的重要性何在? • Who is responsible for validation? 谁将对验证负责? • What needs to be validated? 需要验证哪些内容？ • How Millipore can help？ 密理博将如何帮助您？ MILLIPORE’s Thank You and any Questions? Access Services & Considerations for Filter Validation�ACCESS验证服务＆过滤器验证要点 Objectives目标 Why is filter validation important? �过滤器验证的重要性 Filter Validation is Required Worldwide by GMP�世界各国ＧＭＰ法规要求进行过滤器验证 Filter Validation in Regulatory and Industry Guidelines�法规及行业指南对过滤验证的要求 Other Sources of Guidance�其它相关指南 Benefits of Filter Validation�过滤器验证的好处 Validation Ensures�验证能够确保 Who is Responsible?�谁对验证负责 Filter User Responsibilities�用户的职责 Filter User-Auditing审核 Responsibilities of the Filter Vendor�过滤器供应商职能 Responsibilities of the Filter Vendor�过滤器供应商的职责 Responsibilities of the Filter Vendor�过滤器供应商职责 Additional Testing Is Still Required�其他需要的的附加实验 验证流程 þÿ 除菌过滤器验证流程 Validation Guide What is Access Services?�ACCESS服务内容 Dedicated Laboratories and Validated Equipment�专业科研人员及经过验证的实验设备 Access Services Filter Test Offerings Compatibility Testing� 兼容性测试 Filter/Product Compatibility Testing�过滤器与产品兼容性测试 Extractables Evaluation Filter Extractables Evaluation�过滤器析出物评估 Filter Extractables Evaluation�过滤器析出物评估 Binding Studies Why Binding Studies?�为什么对吸附进行研究 Millipore Binding Studies�密理博的吸附研究 Binding Data�吸附数据 Product Specific Bubble Point Product Bubble Point Specification�产品泡点标准 When to Use a Product Bubble Point Specification?什么时候使用产品泡点 Microbial Retention Testing What is a Sterilizing-Grade Filter? �什么是除菌级过滤器？ What is a Sterilizing-Grade Filter? �什么是除菌级过滤器？ Product/Process Specific Bacterial Retention Testing产品中细菌截留试验 Bacterial Retention Test Method �细菌截留检测方法 Summary总结 Summary总结 What we have covered today MILLIPORE’s