固体车间清洁验证方案.doc

1 41 上海金冀商务咨询有限公司上海金冀商务咨询有限公司 Shanghai Jinji Business Consulting Co Ltd 文件编号 固体车间清洁固体车间清洁验证方案验证方案 Cleaning validation Master Plan for Solid Dosage Workshop 立项部门 立项部门 质量保证部 Initiation Department Quality Assurance Department 工艺验证小组负责人 工艺验证小组负责人 Leader of validation teem 方案制订日期 方案制订日期 年 月 日 Date Year Month Day 2 41 目目 录录 List of Content 一一 验证概述验证概述 OVERVIEW OF VALIDATION 二二 验证组织机构及人员安排验证组织机构及人员安排 VALIDATION ORGANIZAGION AND MEMBERS 三三 应用范围应用范围 AREAS OF APPLICATION 四四 风险评估风险评估 RISK EVALUATION 五五 验证方案表格验证方案表格 VALIDATION MATRIX 六六 清洁溶剂清洁溶剂 CLEANSING AGENTS 七七 可接受标准的确定可接受标准的确定 ACCEPTANCE CRITERIA 八八 清洁验证取样清洁验证取样 CLEANING VALIATION AND SAMPLING 九清洁验证的实施九清洁验证的实施 IMPLEMENTATION OF CLEANING VALIDATION 十十 偏差 变更偏差 变更 DEVIATIONS AND CHANGES 十一十一 再验证再验证 RE VALIDATION 3 41 一一 验证概述验证概述 Overview of Validation 1 验证目的验证目的 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 二二 验证组织机构及人员安排验证组织机构及人员安排 Validation Organization and Team Members 2 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 review 2 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 date QA 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 4 41 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 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 report 2 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 5 41 制造部 Production Dept 技术员 Technician QCQC 主管 QC Supervisor QC 理化 1 组组长 Leader of physicochemical team 1 QC 微生物组组长 Leader of Microbial team QC微生物检验员 Analyzer QAQA 检查员 QA inspector QAQA 检查员 QA inspector QAQA 检查员 QA inspector QA 验证管理员 Validation administrator 6 41 三三 应用范围应用范围 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 Specification A B C D E F G H I 7 41 四四 风险评估风险评估 Risk Evaluation 1 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 Yes QA 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 8 41 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 SOP Personnel should be trained for related SOP for hygiene management 是 Yes 是 Yes 9 41 2 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 产品产品 Product 溶解性组溶解性组 Solubility risk group Active pharmaceutical ingredient is practically insoluble API 成分不溶于水 药理学组药理学组 Pharmacology risk group Therapeutic dose is 100mg 治疗剂量 100mg 处方风险组处方风险组 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 validation 10 41 Product 产品产品 溶解性组溶解性组 Solubility risk group Active pharmaceutical ingredient is practically insoluble 活性成分不溶于水 药理学药理学 Pharmacology risk group Therapeutic dose is 100mg 治疗剂量 100mg 此处也可以 MTDD 计算 活性成分含量活性成分含量 Content of active pharmaceutical ingredient 处方风险组处方风险组 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 11 41 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 产品产品 Product 活性成分含量活性成分含量 Content of active pharmaceuticalin gredient 溶解性溶解性 Solubility 治疗剂量治疗剂量 MTDD Therap dose 最坏情况最坏情况 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 group C 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 F 12 41 Choose 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 it s 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 13 41 五五 验证方案表格验证方案表格 Validation matrix 产品 E Product E 验证方案 Validation protocol 序号 Serial No 设备名称 Equipment name 产品 A Product A摇摆 oscillating 联机 Link up 产品 F Product F 按设备验证 此设 备上所要验证的产 品数 equipment specific Number of products to be validated 1 GHJ 50 高效混和机 High Efficient Mixer 1 2 PMA400 湿法制粒机 不含筛网 Wet Type Granulator excluding screen 2 3 PMA400 湿法制粒机 含筛网 Wet Type Granulator including screen 2 4 DFX400 流化床干燥器 DFX 400 fluid bed dryer 3 5 GEA 联机管道 GEA link up pipes 2 6 SL600 干式整粒机 不含筛网 SL600 dry type straightening granulator excluding screen 2 7 SL600 干式整粒机 1150 m 筛网 SL600 dry type straightening granulator 1150 m screen 1 8 SL600 干式整粒机 1350 m 筛网 SL600 dry type straightening granulator 1350 m screen 1 9 HZD800 自动提升料斗混合机 800L HZD800 Automatic Lifting Hopper Mixer 800L 2 10 HZD800 自动提升料斗混合机 400L HZD800 Automatic Lifting Hopper Mixer 400L 2 11 HZD800 自动提升料斗混合机 200L HZD800 Automatic Lifting Hopper Mixer 200L 1 12 S250 40EU B 压片机 5 5mm S250 40EU B Tablet Press 5 5mm 1 13 S250 40EU B 压片机 8mm S250 40EU B Tablet Press 8mm 1 14 41 14 UPS1030MTI 铝塑包装机 thermoforming machine 3 15 剥药机 Deblistering machine 3 16 YK160A 摇摆颗粒机 oscillating granulator 2 17 CT C 热风循环烘箱 circulating hot air oven 18 ZS 650 型漩涡振荡筛 Eddy type oscillating screen 19 LSH 220 型湿法造粒机 Wet type granulator 20 HLSG 10 湿法混合制粒机 Wet type mixing granulator 21 FL 5 沸腾制粒机 Fluid bed dryer 22 GFK2000 胶囊充填机 Gelatine Capsule Filling and Closing Machine 1 23 DXDP350 双铝遮光包装机 Double aluminum packaging machine 24 4S1000 四封小袋包装机 Automatic Packaging Machine For Single dose Sachet 25 BGB 10C 包衣机 Coating machine 26 GSHP150F 包衣机 Coating machine 1 27 FL 350 风冷式粉碎机 Cooling air crusher 1 28 称量设备 Weighing facility 29 周转桶 A Container type A 30 周转桶 B Container 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 15 41 六六 清洁溶剂清洁溶剂 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 SOP Equipment cleaning SOP 所用清洁溶剂 Cleansing agents used GHJ 50 高效混和 机 High Efficient Mixer GHJ 50 高效混和机清洁规程 SOP for Cleaning High Efficient Mixer 纯化水 PW 75 乙醇 75 Ethanol PMA400 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 PW 75 乙醇 75 Ethanol DFX400 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 PW 75 乙醇 75 Ethanol SL600 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 PW 75 乙醇 75 Ethanol HZD800 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 PW 75 乙醇 75 Ethanol S250 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 PW 75 乙醇 75 Ethanol GS HP 包衣机GS HP 包衣机清洁规程 SOP for Cleaning GS HP Coating Machine 纯化水 PW 75 乙醇 75 Ethanol GFK2000 胶囊充 填机 GFK2000 胶囊充填机清洁规程 Gelatine Capsule Filling and Closing Machine 纯化水 PW 75 乙醇 75 Ethanol UPS1030MTI 铝塑 包装机 UPS1030MTI 铝塑包装机清洁规 程 SOP for Cleaning UPS1030MTI Thermoforming Machine 纯化水 PW 75 乙醇 75 Ethanol FL 350 风冷式粉 碎机 Cooling air crusher FL 350 风冷式粉碎机 SOP for Cleaning Cooling air crusher 纯化水 PW 75 乙醇 75 Ethanol 以上设备均用纯化水和乙醇清洁 无其他溶剂 All the equipments are cleaned with purified water and ethanol no other cleansing agents or solvent are used 16 41 七七 可接受标准的确定可接受标准的确定 Acceptance Criteria 1 目检 Visual Check 各设备按照相应 SOP 清洁后 目检无残留 如设备用乙醇清洗 则需过半小时后进行目检 确保设备内表 面无残留 There should be no residual after visual check after equipment cleaning according to the related SOP If the ethanol is used for cleaning visual check after half hour to ensure there s no residual on the surface of the equipment 2 化学残留可接受标准的确定 Calculation of Maximum Acceptance Residue MAR 1 1 1000 原则 下一产品的最大日剂量中含有的上一产品残留物不得多于上一产品最低有效量的千分之 一 No more than 0 1 criterion no more than 0 1 of the minimal effective dose of any product will appear in the maximum daily dose of the following product 千分之一原则 No more than1 1000 criterion 硝苯地平允许在设备内表面上的最大残留量总和 R allowable total maximum residue of Nifedipine left on inner surface of equipment R 最大允许残留总量 先生产产品最低日服用剂量 MTDD 1000 x 后续生产产品批量 后续产品每日最 大剂量 MAR minimum daily dose of previous product 1000 x batch size of subsequent product Maximum daily dose of subsequent product 2 10ppm 原则 上一产品的主药在下一产品中的含量不得超过 10ppm No more than 10ppm criterion no more than 10ppm of main drug of any product will appear in the content of the following product 最大允许残留总量 10 x10 6 x 后续生产产品批量 MAR 10 x10 6 x batch size of subsequent product 按下表分别计算最大允许残留总量 选取最小的一个 17 41 产品性质 表格内容请厂家以自己情况填写自行填写 产品名称 Product name 最低日服用 剂量 mg MTDD Minimum daily dose 批量 Kg Batch size 单位制剂质量 Mass of dose form mg 日最多使用制剂数 Maximum daily intake A B C D E F G H I 分别计算先前产品为 A E 和 F 的最大允许残留总量 在模版中此处省略计算内容 实际请厂家自行 计算并列表 1 1 1000 原则 1 1000 criterion 后续生产品种 Subsequent product 先生产品种 previous product ABCDEFGHI A E F 2 10 ppm 原则 后续生产品种 Subsequent product 先生产品种 previous product ABCDEFGHI A E F 18 41 结论 Conclusion 模板中仅为示例数据 产品产品 Product 千分之一原则千分之一原则 1 1000 criteria mg 10ppm 原则原则 ppm criteria mg 最最大大允允许许残残留留总总量量 MAR mg A10 0001 0001 000 E2001 000200 F1 5001 0001 000 19 41 与所选产品接触面积表 Table for the contact area 产品 E序号 Serial No 设备名称 Equipment name 表面积 cm2 Surface area产品 A 摇摆 oscillating 联机 Link up 产品 F 1 GHJ 50 高效混和机 High Efficient Mixer 8063 2 PMA400 湿法制粒机 不含筛网 Wet Type Granulator excluding screen 46810 3 PMA400 湿法制粒机 含筛网 Wet Type Granulator including screen 48214 4 DFX400 流化床干燥器 DFX 400 fluid bed dryer 47491 5 GEA 联机管道 GEA link up pipes 6572 6 SL600 干式整粒机 不含筛网 SL600 dry type straightening granulator excluding screen 20302 7 SL600 干式整粒机 1150 m 筛网 SL600 dry type straightening granulator 1150 m screen 21706 8 SL600 干式整粒机 1350 m 筛网 SL600 dry type straightening granulator 1350 m screen 21706 9 HZD800 自动提升料斗混合机 800L HZD800 Automatic Lifting Hopper Mixer 800L 45748 10 HZD800 自动提升料斗混合机 400L HZD800 Automatic Lifting Hopper Mixer 400L 29153 11 HZD800 自动提升料斗混合机 200L HZD800 Automatic Lifting Hopper Mixer 200L 19040 12 S250 40EU B 压片机 5 5mm S250 40EU B Tablet Press 5 5mm 30325 13 S250 40EU B 压片机 8mm S250 40EU B Tablet Press 8mm 30541 14 UPS1030MTI 铝塑包装机 thermoforming machine 10125 15 剥药机 Deblistering machine 1191 16 YK160A 摇摆颗粒机 oscillating granulator 12268 20 41 17 CT C 热风循环烘箱 circulating hot air oven 328944 18 ZS 650 型漩涡振荡筛 Eddy type oscillating screen 41855 19 LSH 220 型湿法造粒机 Wet type granulator 11830 20 HLSG 10 湿法混合制粒机 Wet type mixing granulator 5282 21 FL 5 沸腾制粒机 Fluid bed dryer 15622 22 GFK2000 胶囊充填机 Gelatine Capsule Filling and Closing Machine 42938 23 DXDP350 双铝遮光包装机 Double aluminum packaging machine 6954 24 4S1000 四封小袋包装机 Automatic Packaging Machine For Single dose Sachet 6510 25 BGB 10C 包衣机 Coating machine 8190 26 GSHP150F 包衣机 Coating machine 55727 27 FL 350 风冷式粉碎机 Cooling air crusher 19904 28 称量设备 Weighing facility 29 周转桶 A Container type A 30 周转桶 B Container type B 各产品总接触面积 Total contact area for each product 269 760222 323202 840246 777 备注 表示产品每批生产只与对应的设备直接接触一次 无 表示产品与对应的设备无直接接触 Remark means product has direct contact with equipment involved for one time no means product has no direct contact with equipment involved 21 41 3 7 单位面积残留限度 擦拭法 swab test 产品产品 Product 最最大大允允许许残残留留总总量量 MAR mg 设设备备面面积积cm2 单单位位面面积积残残留留限限度度 g cm2 A1 000269 7603 71 摇摆 oscillating 联机 Link up 摇摆 oscillating 联机 Link up E200 222 323202 8400 900 99 F1 000246 7774 05 3 微生物可接受限度为 50CFU 25cm 2 50 25CFU 25cm 2 其中 50 为微生物取样回收率 因此微 生物可接受限度为 25CFU 25cm 2 Acceptable microbial limit is 50CFU 25cm 2 50 25CFU 25cm 2 50 of it is microbial sampling recovery therefore acceptable microbial limit is 25CFU 25cm 2 22 41 八八 清洁验证取样清洁验证取样 Sampling of Clea