固体车间清洁验证方案.docx

上海金冀商务咨询有限公司, Shanghai Jinji Business Consulting Co., Ltd文件编号：固体车间清洁验证方案Cleaning validation Master Plan for Solid Dosage Workshop立项部门： 质量保证部Initiation Department: Quality Assurance Department工艺验证小组负责人： Leader of validation teem:方案制订日期： 年 月 日 Date: Year Month Day- 1 -目 录List of Content一.验证概述OVERVIEW OF VALIDATION二.验证组织机构及人员安排VALIDATION ORGANIZAGION AND MEMBERS三.应用范围AREAS OF APPLICATION四.风险评估RISK EVALUATION五 验证方案表格VALIDATION MATRIX六 清洁溶剂CLEANSING AGENTS七.可接受标准的确定ACCEPTANCE CRITERIA八.清洁验证取样CLEANING VALIATION AND SAMPLING九清洁验证的实施IMPLEMENTATION OF CLEANING VALIDATION 十. 偏差、变更DEVIATIONS AND CHANGES十一.再验证RE-VALIDATION一. 验证概述 Overview of Validation1. 验证目的根据GMP的要求，在口服固体制剂生产结束后，要对生产设备及操作间进行彻底清洁，以避免造成不同批号或不同品种产品之间的污染和交叉污染。根据各生产设备的操作、清洁及维护保养标准操作规程，进行风险分析，选出最坏情况产品。为了验证清洁方法的稳定性与可靠性，对所选的最坏产品进行三次清洁验证。每批产品生产结束后，对所有在生产中使用的生产设备及容器具进行清洁，清洁后取样检测化学残留及微生物残留，要求残留量低于设定的残留限度要求。According to requirements of GMP, the manufacturing equipments and rooms must be completely cleaned to avoid contamination of different batches of same products or cross-contamination of different products after manufacturing of oral solid dosage. There are two types of cleaning method based on SOPs of Operation/ Cleaning and maintenance for individual equipments: implement the risk analysis assessment to choose the worst case products. Three consecutive cleaning validation will be conducted to validate the stability and reliability of cleaning method. All equipments and utensils used in manufacturing must be completely cleaned once every batch of the worst case products are finished, then sample to test chemical residual and microbial residual, the requirement is the level of residual is less than the limit of residual.二.验证组织机构及人员安排 Validation Organization and Team Members2.1制造部/Production Dept.组织清洁验证方案及报告的起草；Prepare the cleaning validation protocol/report确定设备表面积、清洁方法、取样部位；Determine the surface area of equipments, cleaning method and sampling locations制定清洁操作规程；Establish cleaning procedure按清洁操作规程清洁设备和容器具；Clean equipments and utensils according to cleaning procedure确保清洁记录填写完整；Make sure the completeness of cleaning records将完成的清洁验证文件提交给QA审查；Submit the finalized cleaning documentation to QA review2.2质量保证部/QA Dept. QC审核清洁验证方案/报告；Review the cleaning validation protocol/report 制定清洁验证取样方法和检测方法； Establish sampling method and analytical method of cleaning validation对清洁后设备、容器具进行取样和检测，报告检验结果；Sample and test cleaned equipments and utensils, then report the testing results.使用在校验有效期内的仪器设备进行检测。 Use those instruments within calibration expired dateQA制定清洁验证计划及验证编号；Establish cleaning validation plan and No.负责组织审核清洁验证的方案/报告；Organize the review the cleaning validation protocol/report组织清洁验证相关部门进行清洁验证方案的培训并记录；Organize the training and record for cleaning validation protocol 负责验证实施过程的协调，保证验证项目实施进度；Coordinate the activities of cleaning validation to ensure the performance.验证实施中的监控检查；Supervise the validation activities.保证经验证的参数符合预期的标准；Make sure validated parameters meet pre-determined criteria负责组织验证方案中改变控制、偏差处理的调查；Organize the investigation for the change control and deviation handling.负责将完成的清洁验证文件归档。Archive the completed cleaning validation documentation质量保证部经理：QA Manager批准清洁验证方案、验证报告。Approve the cleaning validation protocol and report2.3设备动力部/Engineering Dept.保证清洁验证过程中，所用到的仪器仪表在校验有效期内；Ensure the instruments and meters involved in the cleaning validation have been calibrated and within calibration due date.保证验证过程中空调、纯化水、压缩空气、热水等的供应，确保清洁验证的实施。Ensure the normal working order and operation of HVAC, purified water system, compressed air, hot water for the cleaning validation.2.4清洁验证小组人员名单/Team Member List组 长 Team Leader部门 Dept.岗位 Position姓名 Name制造部 Production Dept.业务经理 Supervisor小组成员 Team Member部门 Dept.岗位 Position姓名 Name设备动力部 Engineering Dept.业务经理 Supervisor制造部 Production Dept.工艺质量员 Technician制造部 Production Dept.生产协调员 Production Coordinator制造部 Production Dept.工艺质量员Production Coordinator制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员 Technician制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员Technician制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员Technician制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员TechnicianQCQC主管 QC SupervisorQC理化1组组长Leader of physicochemical team 1QC微生物组组长Leader of Microbial teamQC微生物检验员AnalyzerQAQA检查员 QA inspectorQAQA检查员 QA inspectorQAQA检查员 QA inspectorQA验证管理员Validation administrator三 应用范围Areas of application 本清洁验证主计划应用于固体车间所有产品。见产品列表The validation master plan is applied to all the products in the solid workshop. 产品名称Product name主成分API规格SpecificationABCDEFGHI第 41 页 共 41 页四. 风险评估Risk Evaluation1. FMEA 风险项目Item影响/导致结果Influence/Reslult风险级别Risk Level预防措施Precautionary Measures是否可以将风险最小化If the risk can be minimized风险接受(是/否)Risk Acceptance(Yes/No)操作人员对清洁方法不熟悉，清洁操作不规范Operators are not familiar with cleaning method; cleaning operations don't meet standard硝苯地平残留超标Residue of Nifedipine is over specifications 高High培训相关清洁SOP培训；清洁后由生产主管和QA检查确认Operators should be trained for related cleaning SOPs; production supervisor and QA should check after cleaning是Yes是Yes取样方法及取样工具Sampling methods and tools取样方法和工具使用不正确将会影响最终结果Misuse of sampling methods and tools will influence final result.高High对取样人员进行相关培训，明确取样方法以及取样时间。Samplers should be trained for sampling methods and time.是Yes是Yes活性成份残留物检验方法不满足残留限度检测Testing method of API's residue can't meet test of residue limit.不能得到准确的检测结果Inaccurate testing result 高High在本验证实施前进行残留物限度检测方法验证。Performing validation of testing method of residue limit before performing this cleaning validation.是Yes是YesQA人员取样错误Wrong samples are taken by QA.不能得到准确的检测结果Inaccurate testing result高High在清洁验证方案中对取样点进行编号并用图片的方式进行标识。Sampling locations should be numbered and indicated with pictures in the cleaning validation protocol 是Yes是Yes检测人员对残留物检测方法不熟悉Testers are not familiar with testing methods of residue. 不能得到准确的检测结果，清洁评估失败Inaccurate testing result; cleaning evaluation fails中medium对参加样品检测的分析人员进行清洁验证分析方法验证方案和微生物验证方案培训考核。Analyzers involved in testing samples should be trained and assessed for "Validation Protocol of Analytical Method in Cleaning Validation " and "Microbial Validation Protocol".是Yes是Yes人员卫生不符合要求Personnel hygiene doesn't meet requirements.微生物污染Microbial contamination低low培训卫生管理相关SOPPersonnel should be trained for related SOP for hygiene management.是Yes是Yes2 最坏情况产品选择 Worst case product Selection将产品按活性成分溶解性，治疗剂量，处方（颜色，气味，难溶成分）进行分组，首先挑选出无风险的产品。Group all the products according to solubility, therapeutic dose, formulation (colour, flavour, components that are difficult to remove), pick up the no risk products first.2.1产品风险确定表格Assignment of products to risk groups 产品Product溶解性组Solubility risk group Active pharmaceutical ingredient is practically insoluble API成分不溶于水药理学组Pharmacology risk group Therapeutic dose is <100mg 治疗剂量<100mg处方风险组Formulation risk group Product contains dye, flavours or other components that are difficult to remove 产品含有颜色，气味或其他难溶的成分无风险组No risk A - - - B - - - C - - D - - - E - - F - - - G - - - H - - - I - - - 备注：实际操作中，选择低于所有产品治疗剂量范围的第三小的那个。Note: In practice, a value is recommended that is within the lower third of the available dosing range - with respect to the entire product range. 结论：由以上分组可知，产品D和产品I在溶解性，治疗剂量和颜色气味等方面均无风险，归为无风险组。Conclusion: According to the group (see above table), product D and I has no risk in the aspect of solubility, therapeutic dose, color and flavour, they are defined as the no risk product in the cleaning validationProduct产品 溶解性组Solubility risk group Active pharmaceutical ingredient is practically insoluble 活性成分不溶于水药理学Pharmacologyrisk group Therapeutic dose is <100mg 治疗剂量<100mg（此处也可以MTDD计算）活性成分含量Content of activepharmaceuticalingredient处方风险组Formulation risk group Product contains dye, flavours or other components that are difficult to remove 产品含有颜色，气味或其他难容的成分A 几乎不溶于水500mg50%- B 溶于水5025%- C 不溶于水20020%处方中有2%的染料2% dye in the formulation E 几乎不溶于水105%- F 溶于水7550%- G 溶于水15050%包衣层中有1%的颜料1% pigment in film coating H 几乎不溶于水15030%- 分组选择最坏情况Worst case product choosen按活性成分溶解性，治疗剂量和处方（颜色，气味，难溶成分）分组，在每个分组中再按溶解性最差，治疗剂量最低和活性成分含量最高的原则选出最坏情况产品Group all the products according to solubility, therapeutic dose, formulation (colour, flavour, components that are difficult to remove), in each group, choose the products with worst solubility, lowest therap. Dose and highest content of API, defined these products as the worst case products产品Product 活性成分含量Content of active pharmaceuticalin gredient 溶解性Solubility 治疗剂量 （MTDD）Therap.dose 最坏情况Worst case 溶解性组Solubility risk group A 50 % 几乎不溶于水practically insoluble 500 mg 活性成分含量最高Content of active pharmaceutical ingredient, is the highest in this groupC 20 % 不溶于水insoluble 200 mg - E 5 % 几乎不溶于水practically insoluble 10 mg 治疗剂量最低therap. dose H 30 % 几乎不溶于水practically insoluble 150 mg - 此组选择产品A和E Choose product A and E in this group药理组Pharmacology risk group B 25 % 溶于水soluble 50 mg - E 5 % 几乎不溶于水practically insoluble 10 mg 溶解性最差Solubility, therap. dose F 50 % 溶于水Soluble 75 mg 活性成分含量最高Content of active pharmaceutical ingredient 此组选择产品E和FChoose product E and F in this group处方风险组Formulation risk group C 处方中有2%的染料2% dye in the formulation 溶解性染料Soluble dye n.a. 染料Dye G 包衣层中有1%的颜料1% pigment in film coating不溶解颜料Insoluble pigment n.a. 颜料Pigment 对于C产品，其处方中有2%的可溶性染料，虽然不是活性成分，但也会对后续产品产生交叉污染。在此我们采取目视方法，用白色湿抹布在设备关键部位擦拭，肉眼分辨其是否有颜色。 对于G产品，其包衣层中有不溶解的颜料，所以只针对包衣机做目检，方法是用干抹布擦拭设备表面看，肉眼分辨否有颜色残留。 For product C, there is 2% dye in the its formulation, the dye is not the API, but still will affect the subsequent product, increase the risk of cros-contamination. The visually check is used for it. We use the clean wet white tower scrub in the critical part of the equipment, see if the color is on the tower. For product G, the insoluble pigment is in the coating formulation, the visual check method is taken only for the coating machine. We use the clean white dry tower to scrub the scrub in the critical part of the equipment see if the color is on the tower.结论： 通过上表的分析，所选取的最坏情况产品为A，E和F。Conclusion：Through the analysis of the above table, the worst case product are Product A, E and F.五 验证方案表格Validation matrix 序号Serial No.设备名称Equipment name产品AProduct A产品EProduct E产品FProduct F验证方案Validation protocol摇摆oscillating联机Link-up按设备验证（此设备上所要验证的产品数）(equipment-specific): Number of products to be validated1GHJ-50高效混和机High Efficient Mixer-12PMA400湿法制粒机（不含筛网）Wet Type Granulator(excluding screen)-23PMA400湿法制粒机（含筛网）Wet Type Granulator(including screen)-24DFX400流化床干燥器DFX 400 fluid bed dryer35GEA联机管道GEA link-up pipes-26SL600干式整粒机（不含筛网）SL600 dry type straightening granulator(excluding screen)-27SL600干式整粒机（1150m筛网）SL600 dry type straightening granulator( 1150m screen)-18SL600干式整粒机（1350m筛网）SL600 dry type straightening granulator( 1350m screen)-19HZD800自动提升料斗混合机800L)HZD800 Automatic Lifting Hopper Mixer 800L-210HZD800自动提升料斗混合机(400L)HZD800 Automatic Lifting Hopper Mixer 400L-211HZD800自动提升料斗混合机(200L)HZD800 Automatic Lifting Hopper Mixer 200L-112S250/40EU-B压片机（5.5mm）S250/40EU-B Tablet Press（5.5mm）-113S250/40EU-B压片机（8mm）S250/40EU-B Tablet Press（8mm）-114UPS1030MTI铝塑包装机 thermoforming machine315剥药机Deblistering machine316YK160A摇摆颗粒机oscillating granulator-217CT-C-热风循环烘箱circulating hot air oven-18ZS-650型漩涡振荡筛Eddy type oscillating screen-19LSH-220型湿法造粒机Wet type granulator-20HLSG-10湿法混合制粒机Wet type mixing granulator-21FL-5沸腾制粒机Fluid bed dryer-22GFK2000胶囊充填机Gelatine Capsule Filling and Closing Machine-123DXDP350双铝遮光包装机Double aluminum packaging machine-244S1000四封小袋包装机Automatic Packaging Machine For Single-dose Sachet-25BGB-10C包衣机Coating machine-26GSHP150F包衣机Coating machine-127FL-350风冷式粉碎机Cooling air crusher-128称量设备Weighing facility-29周转桶AContainer type A-30周转桶BContainer type B-验证方案Validation protocol 按产品：所涉及的设备(product-specific): Number of production equipment items 10999由上表数据，对三个最坏产品做连续三批的清洁验证。From the data in the table above, the three worst case products is for the continuously three batches cleaning validation.六 清洁溶剂Cleansing agents产品A,E和F所用设备的清洁溶剂如下：The cleansing agent for the product equipments used in product A, E and F are listed:设备名称Equipment name文件编号Document Code设备清洁操作SOPEquipment cleaning SOP所用清洁溶剂Cleansing agents usedGHJ-50高效混和机High Efficient MixerGHJ-50高效混和机清洁规程SOP for Cleaning High Efficient Mixer纯化水 PW75%乙醇 75% EthanolPMA400湿法制粒机PMA400湿法制粒机清洁规程SOP for Cleaning PMA400 Wet Type Granulator纯化水 PW75%乙醇 75% EthanolDFX400流化床干燥器DFX400流化床干燥器清洁规程SOP for Cleaning DFX 400 Fluid Bed Dryer纯化水 PW75%乙醇 75% EthanolSL600干式整粒机SL600干式整粒机清洁规程 SOP for Cleaning SL600 Dry Type Straightening Granulator纯化水 PW75%乙醇 75% EthanolHZD800自动提升料斗混合机HZD800自动提升料斗混合机清洁规程SOP for Cleaning HZD800 Automatic Lifting Hopper Mixer纯化水 PW75%乙醇 75% EthanolS250/40EU-B压片机S250/40EU-B压片机清洁规程SOP for Cleaning S250/40EU-B Tablet Press纯化水 PW75%乙醇 75% EthanolGS HP包衣机GS HP包衣机清洁规程SOP for Cleaning GS HP Coating Machine纯化水 PW75%乙醇 75% EthanolGFK2000胶囊充填机GFK2000胶囊充填机清洁规程Gelatine Capsule Filling and Closing Machine纯化水 PW75%乙醇 75% EthanolUPS1030MTI铝塑包装机UPS1030MTI铝塑包装机清洁规程SOP for Cleaning UPS1030MTI Thermoforming Machine纯化水 PW75%乙醇 75% EthanolFL-350风冷式粉碎机Cooling air crusherFL-350风冷式粉碎机SOP for Cleaning Cooling air crusher纯化水 PW75%