4-Cleaning-Validation-.ppt

13-01-20101Cleaning Validation清洗验证13-01-20102Module Outcomes模块成果 State the GMP reasons for cleaning validation陈述清洗验证的GMP原因Interpret regulatory requirements and guidelines解释监管需求及指南Outline a strategy for cleaning validation that complies with cGMPs略述符合cGMPs 的清洗验证策略Apply risk management principles to identify cleaning validation parameters应用风险管理原则来确定清洗验证参数13-01-20103Cleaning Validation清洗验证清洗验证Regulatory Compliance Aspects监管和合规方面监管和合规方面13-01-20104Background to Cleaning Validation清洗验证的背景清洗验证的背景FDA published Guide to inspections of Validation of Cleaning Processes-1993 FDA发布情节工艺验证检查指南 1993PIC/S Guideline to Validation-2004PIC/S 验证指南 2004 Biotechnology industry-cross contamination critical生物技术产业 交叉污染的关键More and more potent drugs being manufactured更多更有效的药物正在被制造Issues:How clean is clean?Does cleaning Validation apply to all products，Should all products be Validated?问题：怎么算是清洁？清洗验证是否适用于所有产品？所有产品都要经过验证吗？13-01-20105GMP Requirements Cleaning ValidationGMP要求要求 清洗验证清洗验证Cleaning Validation should be performed in order to confirm the effectiveness of a cleaning procedure.应当实施清洗验证去证实清洗程序的有效性 13-01-20106GMP Requirements:Cleaning ValidationGMP要求要求 清洗验证清洗验证Cleaning validation should confirm the effectiveness of a cleaning procedure.The rationale for selecting limits of carryover for:清洗验证要证实清洗程序的有效性Product residues,cleaning agentsµbial contaminants should be logical,based on the materials involved以相关原料为基础，产品残留物、清洗剂、微生物污染物应该符合逻辑 Limits should be achievable and verifiable所定的限度应该是可以实现的并且可以验证的Suitably sensitive and validated methods should be used to detect residues at the established acceptable level运用恰当的敏感的、经过验证的方法去检测残留物，使其控制在既定的可以接受的水平Validate direct product contact surfaces(but also consider non contact surfaces)验证直接与产品接触的表面（还要考虑非接触表面）Validate the interval from use cleaning(dirty hold time)验证从使用到清洗的间隔时间（脏维持时间）Validate the interval from cleaning to reuse(clean hold time)验证从清洗到再次使用的间隔时间（清洗保持时间）13-01-20107GMP Requirements:Cleaning ValidationGMP 要求要求-清洗验证清洗验证Validation of the worst case of similar materials and cleaning Procedures&processes is allowed相似材料、清洗程序和工艺的最坏情况分析验证是被允许的Validation of 3 consecutive runs of the cleaning procedure should be performed3个连续的清洗程序的验证应当被实施Test until clean is not an appropriate alternative“化验至合格”不能代替清洁验证Products which simulate the physicochemical properties of the substance residues can be used where those materials are toxic or hazardous和残留物具有相似理化性质的产品可用于具有毒性的材料上。13-01-20108GMP Requirements:Cleaning Validation GMP 要求要求-清洗验证清洗验证Facilities,systems,equipment and processes,including cleaning,should be periodically evaluated to confirm that they remain valid.对设施、系统、设备和工艺包括清洗，都要进行定期验证以确保它们维持在验证状态13-01-20109Regulators View监管机构的观点监管机构的观点FDA expects firms to have written general procedures on how cleaning processes will be validated,FDA要求公司有书面的关于清洗验证是如何进行的通用程序FDA expects the general validation procedures to address who is responsible for performing&approving the validation study,the acceptance criteria and when revalidation will be required.FDA要求常规验证程序说明谁负责执行和批准验证研究，谁负责验收标准和什么时候进行再验证FDA expects firms to prepare specific written validation protocols in advance for the studiesFDA要求公司提前为研究提供具体的书面验证方案FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid.FDA要求通过管理而得出的最终的验证报告，该报告说明清洗工艺是否有效FDA Guide to Inspections Validation of Cleaning Processes 1993(section 3,General Requirements)FDA清洗过程验证检查指南 1993（第3部分，常规要求）13-01-201010Other Guidelines&Sources used for Cleaning Validation outside the Regulatory Framework监管框架之外的其它的清洗验证的指南和来源13-01-201011Industry Guidance Documents 行业指导文件行业指导文件 Recommendations on Validation Master Plan,Installation and Operational Qualification,Non-Sterile Process Validation and Cleaning Validation.关于验证主计划、安装和操作确认、非无菌工艺验证和清洁验证的建议 13-01-201012Industry Guidance Documents(2)行业指导文件（行业指导文件（2）Technical Report No.29-Points to Consider for Cleaning Validation技术报告第29 清洗验证要考虑的要点 13-01-201013Cleaning Validation Principle清洗验证原则清洗验证原则Validation of the cleaning methods provides the documented evidence that the use of an approved cleaning procedure will provide clean equipment suitable for use in manufacturing Pharmaceutical products.清洗方法的验证提供了书面证据，证明经验证的清洗程序将为医药产品的生产提供合适的清洁的设备13-01-201014Cleaning Validation Objective清洗验证清洗验证 目标目标 The objective of cleaning validation is to prove that the equipment is consistently cleaned from product,detergent and microbial residues to an acceptable level to prevent possible contamination&cross-contamination.清洗验证的目的就是要证明设备始终是清洁的，从产品、洗洁剂、微生物残留到可接受的水平，以防止可能的污染和交叉污染 The objective of the cleaning validation is the confirmation of a reliable cleaning procedure so that analytical monitoring maybe omitted or reduced to a minimum in the routine phase.“清洗验证的目的就是要证实一个可靠的清洗程序，这样可以将常规阶段的分析检测省略或者降低到最小程度 13-01-201015An Assumption一个假设一个假设The Equipment cleaning process is already defined in sufficient detail and approved for use.设备的清洗工艺已经被详细的定义并且被批准使用If this assumption is not valid then redevelopment of the procedure should be done followed by retraining of personnel responsible for their implementation如果这个假设是无效的程序，然后重建工作应遵循由负责人员实施再培训13-01-201016Types of Cleaning Processes清洗工艺类型清洗工艺类型Automated&Semi Automated Cleaning-such as clean in place(CIP)cleaning processes for:Piping systemsMixers,tanks and blenders(spray ball)GMP component dishwashing machinesLaboratory glassware washersGMP washing machines(fluid bed dryer bags etc)Manual equipment cleaning processesComponent disassembly then manual soak&cleanFree standing equipment;Mixers,tanks and blendersTransfer hoses自动和半自动清洗-例如现场清洗工艺：用于以下清洗：管道系统混频器,水槽和搅拌机(喷涂球)GMP清洗机(流化床干燥机袋等)手动清洗工艺设备组件拆卸然后手动浸泡和清洗浮放设备、混合器、水槽和搅拌机转运软管13-01-201017Cleaning Considerations清洗应注意的问题Cleaning Process清洗过程：1.CIP-repeatable process using a defined control recipes contained in a PLC control systemCIP-用包含在PLC控制系统中的一个确定控制配方的可重复的工艺2.Manual-variable process based on condition of equipment such as bottle brushes,doodlebugs,high pressure Gurney water hose systems.Sink soaking and washing Times by operator手动-随着设备的变化例如瓶子刷子、高压“格尼”水软管系统、水槽浸泡、清洗时间，通过操作者来改变。Considerations注意事项：1.Process&equipment has to be qualified for worst case product and soil load(i.e.solubility index or known historical problems)工艺及设备必须经过最坏情况的确认及土壤负载确认（溶解指数或已知的历史问题）2.Dependent on the individual operator(knowledge,procedure training,attention to detail)依赖于个体操作者（知识、程序培训、细节的注意）13-01-201018Equipment cleaning questions设备清洗的问题How many validation studies are sufficient to determine process repeatability?多少验证能足够的证明工艺的可重复性？What sort of ongoing,routine monitoring is required?需要什么样的持续的、常规的检测？一Failures should be used to improve the SOP&monitor the effectiveness of individual operators失败应该别用来提高SOP和检测个别操作者的有效性一Certain aspects of equipment design may need to be reconsidered(with repeated failures)设备的某些方面可能需要重新考虑Are the proposed cleaning agents compatible with the active&excipient materials being cleaned away?这些清洗剂连同活性物质和赋形剂都一同被清除掉吗？13-01-201019Cleaning validation strategy 清洗验证策略Does cleaning validation have to be done on all products?Usually No Does cleaning validation have to be done on all equipment?Usually YesCan acceptance limits be set for individual pieces of equipment?Usually NoHow do you decide and justify the amount you do?Prepare a Gleaning VMP with clear objectives所有产品都要经过清洗验证吗？通常不是所有的设备都要经过清洗验证吗？通常是可以接受的限度是为设备的各个部分设定的吗？通常不是如何确定你做的多少？准备一个有主要目标的清洗验证主要计划13-01-201020Cleaning Validation-Key Points清洗验证-要点Require a protocol and written report需要一个协议和书面报告Manufacturer to justify the limits selected for clean制造商来确定清洁的限制Must consider the different combinations of:必须考虑以下不同的组合：SOP or cleaning methods used标准操作程序还是所用的清洗方法Equipment mix-common and dedicated设备混合-通用和专用Product mix in common equipment(worst case)产品在通用设备中混合（最坏情况）Distinguish between Manual and Automated Cleaning区分手动清洗和自动清洗Prioritize cleaning validation based on risk of products按照产品的危险性进行清洗验证排序Consider sanitation validation where appropriate在适当情况下考虑卫生验证Post Validation-Ongoing program of monitoring cleaning effectiveness(particularly for manual cleaning)快速验证-检测正在进行的项目的清洗效果（尤其是对人工清洗）Consider the preparation of a VMP for Cleaning Validation依照验证主计划进行清洗验证Change control when modifying cleaning procedures修订清洗程序时要进行变更控制13-01-201021Cleaning Validation-a roadmap(1)清洗验证-路线图(1)Create a Cleaning Validation Plan制定清洗验证计划Identify&review all Equipment Cleaning Procedures(including ones that need to be written)and Agents确定并审查所有设备清洗程序（包括需要被撰写的）和清洗剂Create an Equipment matrix(equipment trains)建立一个设备培训模型Characterise the equipment(product contact surfaces,surface area measurement,hard to clean areas,swab locations)描述设备特征（产品接触表面、表面积测量、难以清洁区、擦拭位置）Create a Product data spreadsheet(active materials,excipients,preservatives,solubility,toxicity,historical knowledge,batch sizes,individual dose size,maximum number of daily does)建立产品数据电子表格（活性物质、赋形剂、防腐剂、溶解性、毒性、历史知识、批量大小、个人剂量大小、最大日剂量）Create a Product index Number based on the Toxicity and Solubility and then order products starting from Low Solubility High Toxicity(higher risk)down to High Solubility Low Toxicity(lower risk)根据产品的溶解度和毒性创建产品索引号，然后从低溶解度且高毒性（高风险）到高溶解度且低毒性（低风险）进行编号。13-01-201022Cleaning Validation-a roadmap(2)清洗验证-路线图(2)Select marker product for each equipment grouping(train)为每个设备行列选择标记产品Set surface limits for each marker product(chemicalµ)为每个标记产品设表面限度（化学的和微生物的）Identify analytical test methods and ensure LOD/LOQ is consistent with the limits you have set鉴定分析测试方法并确保LOD和LOQ没有超出预设的限度Conduct swab recovery and extraction studies进行棉签回收和提取物研究Conduct surface visibly clean studies with Production operators准备、撰写和执行清洗验证方案Prepare,write and execute your cleaning validation protocols和操作人员一起进行表面清洁研究Review all of the data and compile the reports审查所有数据然后汇编成报告Determine the ongoing monitoring program and next revalidation确定持续的检测程序和下一次再验证13-01-201023Validation Planning验证计划Document your policies and rationale to setting limits文件证明你所设置限制的策略和理论基础Include a risk assessment of products(e.g.solubility and toxicity,assessments)包括产品的风险评估（溶解性和毒性评估）Consider grouping strategies for similar equipment and cleaning procedure 考虑相似设备和清洗程序的分组策略Gather product data max daily dose,LD50 etc收集产品数据-最大日剂量，半数致死剂量等List and characterize the common equipment 列出并描绘通用设备Method of testing to be used HPLC,TOC,IMS用于检测的方法-HPLC,TOC,IMS Selection of“worst case”marker products for actual validation protocols实际验证方案最坏情况标记产品的选择Consider the resources to be employed考虑需要耗费的资源13-01-201024Cleaning Procedure Manual Operator dependant 清洗验证清洗验证-依赖手动操作依赖手动操作Identify&review all equipment cleaning procedures and agents.Ask the equipment cleaners the following questions-确定审查所有设备清洗程序和清洗剂，问设备清洁人员以下问题：Is this(the procedure)what you actually do?这是你通常做的吗？Is there sufficient detail and diagrams for you to correctly dismantle and clean the components?是否有正确拆除和清理组件的足够的细节和图表？Is the cleaning agent specified in the SOP being used at the correct dilution ratio?在标准操作规程中所指定的清洗剂是不是按照正确的稀释比例使用的？Is the cleaning agent the most suitable for the material residues being cleaned from the equipment?是不是用了最合适的清洗剂去清洗设备上的残留物？Are soaking times being adhered to?是否严格的按照浸泡时间去做的？Is the correct cleaning equipment being utilised?合适的清洗设备被使用了吗？Has the operator been trained and qualified?清洗人员是否经过培训并合格了？13-01-201025CIP Performance FactorsCIP 性能因素性能因素The reliability of the CIP automated sequences CIP 自动序列的可靠性The time of exposure to cleaning solution清洗液的曝光时间The cleaning agent selected and its concentration清洗液的选择及其浓度The smoothness of the surfaces to be cleaned要清洗的表面的光滑度The degree of turbulence at the surface to be cleaned要清洗的表面的湍流程度The temperature of the cleaning solution清洗液的温度The nature of the contaminating compound(s)被污染的化合物的性质Ease of removal of cleaning solution residues易于去除的清洗液残留13-01-201026CIP Equipment QualificationCIP设备确认设备确认Automated processes must be qualified.Verify the following steps:自动化过程必须合格，需要核实以下步骤：Qualify the control sequences&process steps,确认控制序列和工艺步骤 Perform OQ-check parameters of time,temperature,flow rate&rate of agitation执行OQ 检查时间、温度、流量、转速参数 Perform PQ执行PQ Perform ongoing process monitoring of above parameters执行上述参数进行过程监控 Ensure processes are protected by change control确保工艺收到变更控制的保护Ensure that the correct recipes are used for different material cleaning requirements确保正确的方法用于不同材质的清洗要求13-01-201027Equipment Equivalency设备当量设备当量Are all Tanks the Same?所有的储罐都是相同的吗？所有的储罐都是相同的吗？Set up Equipment Groups based on the following considerations Manufacturer&modelGeometry&shape Materials of construction&surface finish Functionality in the manufacturing process Cleaned in the same way with the same procedure&cleaning agents.i.e.no new cleaning hotspots.Equipment can be a different size but classified as Equivalent providing they are physically the same as above criteria.E.g.Liquid tank.Document your justification of equivalency in a short report and have it approved like any other validation documentation.以考虑的以下几点为基础建立设备群制造商及型号几何学及形状施工材料及表面光洁度制造工艺的功能性用同样的清洗剂同样的程序同样的方法进行清洗，即没有新的清洁热点设备大小有不同，但是作为“等效”分类他们达到了上述标准。例如液体储罐在一个简短的报告里记录下你的等效的理由，并且使它得到批准，就像其它的验证文件一样。13-01-201028Product Master List产品清单产品清单Categorise and identify those finished products which could cause an unacceptable risk(or condition)to a consumer when carried over into another or following product.分类识别一些制成品，当这些产品被持续的运用到其它产品的的时候会对顾客产生不可接受的风险（情况）。You include all materials for each finished product so that you can select one to calculate limits for.核算一下每件制成品所需的所有材料，以便于挑选一种来计算限度。This is usually the API,but it could be another,more toxic or difficult to clean material contained within the formulation.这通常是API，但也有可能是包含在配方中的另一种更有毒的更难清洗的材料。Select worst cases product on the List.在清单上选择“最坏情况”的产品13-01-201029Risk Assess the Products on the List对清单上的产品进行风险评估对清单上的产品进行风险评估Prioritise each group of products into an order that reflects:把每组产品按优先顺序列到一个单上，这个单子能反映：Difficulty of cleaning(based on a solubility assessment of the ingredients).This could be the active material(API)but dont forget to also consider the preservative,excipient,lubricants and even a dye or colouring agent.清洗难度（基于对成分溶解度的评估）。它可能是活性物质，当也不要忘记考虑防腐剂、赋形剂、润滑剂、甚至染料或着色剂。Toxicity of materials(potential harm to patient taking finished dose of the next product made on the same equipment).材料的毒性（当病人服下在同一个设备上制造的同等剂量的下一种产品时所造成的潜在的危害）13-01-201030Scoring the Products for Risk产品风险性评分产品风险性评分Risk Priority=Solubility index X Toxicity index风险系数=溶解指数毒性指数For example:例如：Practically insoluble(in water)material=8(highest score)几乎不溶（水）材料=8（最高分）Freely soluble(in water)material=1(lowest score)极易溶（水）材料=1（最低分）Extremely toxic material(hazardous)=4(highest score)剧毒物质（有害）=4（最高分）Very low toxic material(non hazardous)=1(lowest score)极低的有毒物质（非危险品）=1（最低分）13-01-201031Material(cleaning)risk ratings some ideas材料（清洗）的风险评级一些概念Solubility*ratings溶解度评级级1=Very soluble in water1=非常易溶于水2=Freely soluble in water2=和水互溶3=Soluble in water3=易溶于水4=Sparingly soluble in water4=难溶于水5=Slightly soluble in water5=微溶于水6=Very slightly soluble in water6=极微溶于水7=Practically insoluble in water7=几乎不溶于水8=Insoluble in water8=不溶于水Toxicity ratings毒性等级1=Low hazard rating1=低风险等级2=Medium hazard rating2=中度风险等级3=High hazard rating,toxic3=高危险等级，有毒4=High ha