2022年设备清洁验证管理制度 .pdf

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1、File Number:QA-SMP-C06Document name:设备清洁验证管理制度Equipment cleaning validation management systemversion:02Page 1 of 13目的： 本文件旨在提供用于原料药和制剂的生产、包装设备清洁验证的基本原则和基本要求。Aim: The SMP describes general requirements and principles to validate cleaning procedures to clean equipment for packing, API and dosage manuf

2、acturing. 范围： 适用于原料药和制剂的生产和包装设备的清洁验证/ 确认。Scope: Applicable for equipment cleaning validation/qualification for packing, API and dosage manufacturing 责任： 质量保证部、质检科、各生产车间对此程序负责。Responsibility: The QA, QC and other workshops shall be responsible to this SMP. 内容：Contents:1.设备清洁验证类型主要有：Equipment cleaning

3、 validation includes: 1.1 清洁确认：是指清洁方法正在建立过程中（如引入新的设备和产品），或由于偏差超标或清洁验证参数有偏离而进行的确认，每次均应制定相应的清洁确认方案。Cleaning qualification refers to any qualification in the establishment of a cleaning method (e.g.: introduction of new equipment and product), cleaning parameter deviations and deviation out of specific

4、ations. A cleaning plan for qualification shall be prepared accordingly . 1.2 清洁验证 / 再验证：如因为引入的新产品或修订过的清洁程序，再验证要确认设备清洁状态等同于验证状态，应按照清洁验证/ 再验证方案进行。Cleaning validation/re-validation: If new product is introduced or cleaning procedures are revised, cleaning re-validation shall verify that equipment clea

5、ning status equals to validation status and be implemented according to cleaning validation/re-validation protocols. 2.清洁验证评估的执行，应至少考虑以下方面：The following items shall be taken into consideration during the implementation of cleaning validation assessments: 2.1 产品方面 Product -评价某一设备的产品生产过程（特别是多产品生产的设备）以

6、确定设备清洁的最差条件。 Determine the worst condition of equipment cleaning through the assessment of equipment use in manufacturing process (especially for equipment shared in multiple product manufacturing). 名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 1 页，共 13 页 - - - - -

7、- - - - File Number:QA-SMP-C06Document name:设备清洁验证管理制度Equipment cleaning validation management systemversion:02Page 2 of 13-考虑中间体、处方、产品、清洁溶剂的毒性、效力、可溶性和/ 或化学反应，特别要考虑那些着色剂 / 染料，因为他们可能会使随后的产品染色。Take the following factors into consideration: intermediate, formula, product, toxicity , effect, solubility

8、of cleanser, and chemical reaction, especially for coloring agents and dyes that may stain other products subsequently. -考虑最难清洁的残留：特别是要考虑多产品生产的最差条件。Consider residues that are most difficult to clean: especially for consideration of the worst condition of multiple product manufacturing. 2.2 设备方面 Equi

9、pment -重点关注直接接触产品的设备表面：特别关注临近生产的区域有无交叉污染存在的情况；千万不要忽视辅助的一些事物，特别是那些可能吸收产品或清洁溶剂的东西。Emphasized attention shall be paid to equipment surface that contacts products directly: special attention to the area that is close to manufacturing area and see if there is a cross-contamination. Ensure not to ignore s

10、ome parts, especially which can absorb product or cleanser. -定义每个设备的各个产品接触的表面（包括材质）。Define equipment surfaces that contact every product directly (including material type) -重点为主要生产过程中接触的设备表面。Emphasis is the equipment surfaces that contact products during manufacturing -进行各种代表性类型的表面回收率的方法学研究。Methodol

11、ogy research of all representative types of surface recycling factors. -关注于难以清洁的设备部分，特别是多产品使用的设备，例如：对于过滤器系统，可以采用产品专用或单次使用。Focus on equipment parts that are hardest to be cleaned, especially for the equipment for multiple products, eg: filter system, dedicated or single used mode is recommended. -评估应

12、确定难清洁部位和产品容易聚集的部位。Assess hardest cleaning parts and product aggregation parts of equipment -对评估的每一个清洁过程制定一个表面取样计划。Prepare a surface sampling plan for the evaluation of each cleaning process. -提供设备的图纸或照片，描述相关清洗的路径、擦拭位臵以及选择这些取样点的理名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - -

13、- - - 第 2 页，共 13 页 - - - - - - - - - File Number:QA-SMP-C06Document name:设备清洁验证管理制度Equipment cleaning validation management systemversion:02Page 3 of 13由。 Provide equipment drawings and pictures, describe the corresponding cleaning pathway , wiping positions and causes of sampling spot selection. 2.

14、3 清洁程序方面 Cleaning procedures -评价时考虑以下要素：每一步清洁所用的清洁剂和水的质量；清洁剂浓度；在线清洗的应用和自动化程序；清洁过程循环的类型（一次还是再次循环）；参数（温度、压力、流速、接触时间）的标准、数量、洗和冲洗的循环次数；设备使用后至清洁前的最长放臵时间；清洁有效期。The following items shall be taken into consideration: detergent and water quality at every step, detergent concentration, online washing applicat

15、ion and automatic procedures, cycling type in the process of cleaning (once or recycling), parameter standards (temperature, pressure, flow rate, contact time), quantity , washing, rinse recycling times, longest time before cleaning after equipment is used, cleaning expiry date. -在 清 洁 验证 前优 化 清 洁程

16、序。 Optimize cleaning procedures before cleaning validation. -对于多产品使用设备来讲尽可能减少清洁程序的数量，单个的清洁程序可使清洁验证 简 单 化 。 Reduce the number of cleaning procedures as low as possible for equipment to manufacture multiple products. Single cleaning procedure may simplify cleaning validations. -确保清洁程序建立和可重复性。Assure th

17、e establishment of cleaning procedures and the corresponding repeatability. -手动清洁的程序包括详细的文档，能有效的记录清洁过程的关键参数及主要步骤的完 成 情 况 。 Manual cleaning procedures include detailed documents, critical parameters that can effectively record cleaning process and the implementation of main procedures. -评价清洁后程序和设备存放：

18、确保不会引起微生物的增加。Evaluate procedures after cleaning and equipment storage: assure no microbial increase. -在完成清洁验证研究前评估清洁程序的有效性。Assess the validity of cleaning procedures before the accomplishment of cleaning validation research. 2.4 建立残留取样方法和回收率方法Establish residue sampling method and recycling rate meth

19、od 名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 3 页，共 13 页 - - - - - - - - - File Number:QA-SMP-C06Document name:设备清洁验证管理制度Equipment cleaning validation management systemversion:02Page 4 of 13-普通的取样方法是淋洗液取样和擦拭取样，浸提方法有的时候会采用Common sampling methods include eluent sam

20、pling and wiping sampling. Extracting sampling is adopted sometimes. -评价设备的地点，制定每一个的位臵上的设备取样计划Assessment equipment position, establish a sampling plan for equipment at each position -表面进行 目测是清洁验证研究的基本要素Surface visualization is the basic element in cleaning validation research -准确计算表面残留量以建立有效的回收方法 Pr

21、ecisely calculate surface residues to establish effective recycling methods. -计算残留限度时需要运用回收率因子 Recycling factor is needed in the calculation of residue limit. 2.5 确定残留限度 Determine residue limit -残留限度的选择一般基于产品治疗剂量。Selection of residue limit is based on product therapeutic dosage -设立残留限度的方法包括：以一个特定产品的

22、清洁验证代替所有产品的情况；多产品使用时选择最差条件的情况；根据风险程度进行归类（如易容、高毒性、难以检测等）。 Establish residue limit method: use a cleaning validation of one product to replace the validations for all products; select the worst condition when equipment is for multiple products, classify according to risk degree （Soluble, high toxicity

23、, hard to detect ）-对于强效和高毒性的产品，应根据LOQ（lower limit of quantity，定量限下限）计算残留限度。 Calculate residue limit for potent and high toxic products according to LOQ (lower limit of quantity) 2.6 取样和测试方法的验证及建立取样和测试计划Validation of sampling and testing method and establishment of sampling and testing plans -所有残留测试所

24、用的分析方法均需经过验证。All analytic methods to test residues shall be validated. -取样方法应包括取样位臵、取样位臵选择的理由、每一个取样点样品的数量，以及可接受限度。Sampling methods shall include sampling position, selection cause of sampling position, sample number at each sampling position, acceptable limit. 名师资料总结 - - -精品资料欢迎下载 - - - - - - - - -

25、- - - - - - - - - 名师精心整理 - - - - - - - 第 4 页，共 13 页 - - - - - - - - - File Number:QA-SMP-C06Document name:设备清洁验证管理制度Equipment cleaning validation management systemversion:02Page 5 of 13-建立即将要进行验证的清洁取样程序。Establish validation procedures for cleaning and sampling -建立取样和测试计划。 Establish sampling and test

26、ing plans -在清洁记录中记录：设备清洁区域、所用的SOP 、清洁人、清洁时间以及清洁前生产何种产品）。 Record in cleaning records: equipment clean area, SOP , cleaning person, cleaning time and product manufactured before cleaning. -用验证过的方法完成 取样和测 试。Sampling and test according to validated methods 2.7 清洁验证研究的扩展（如确定是否进行一个更全面的清洁验证研究（要求进行连续3次）还是一个

27、水平相当的研究（可以只有一次），同时对清洁有效期的确定进行评估。Extension of cleaning validation research (for example: determine whether a more comprehensive cleaning validation research(request 3 consecutive times) or a competitive research (once ) is needed. Evaluate the determination of cleaning expiry date. 3.建立可接受限度：最常用的三个标准

28、如下（对于专用生产设备且产品质量稳定原料药生产设备的清洁验证/ 确认可采用目检法确定可接受限度）：Establish acceptable limit: three common standards shown as below (cleaning validation/qualification for dedicated API manufacturing equipment can use visualization method to determine acceptable limit. 3.1 目检清洁：清洁后在设备上没有可见残留，可用加样研究来测定活性成分可见时的最低浓度（但不适

29、合高效低剂量药品）。Visualized inspection of clean: no visible residue on the equipment after cleaning. Addition of sample can be used to measure lowest concentration when active ingredients are visible (It is not applicable to high potent and low dose drug) 3.2 残留物浓度限度10ppm ：一个产品在其它产品中比例不大于1010-6。 Residue co

30、ncentration limit 10ppm: one product is no more than 1010-6 of total products. 3.3 生物学活性的限度：按最大日治疗计量计算，前一个产品出现在后续产品中的比例不大于 1/1000 。Biological activity limit: according to maximal daily amount to calculate, the first product is not more than 1/1000 in the subsequent products.3.4 具体的换产品验证的残留限度规定如下：（以产

31、品A 即将换成产品B 为例） Specific 名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 5 页，共 13 页 - - - - - - - - - File Number:QA-SMP-C06Document name:设备清洁验证管理制度Equipment cleaning validation management systemversion:02Page 6 of 13residue limit specification for changed product （Pro

32、duct A will be changed to product B）3.4.1 擦拭或浸提限度 (mg/ 签) Wiping and extracting limit (mg/swab) 3.4.1.1基于生物学活性的限度计算：限度=ADI*SB* 测试面积 *回收率 / （MDD*SSA ）Based on biological activity limit calculation: limit = ADI*SB*test area* recycling factor/(MDD*SSA) 其中： ADI-产品 A的日服剂量 MDD- 产品 B的最大日服剂量acceptable daily

33、 intake (product A) Maximum daily dose (product B) SB-产品 B 的最小批量 SSA- 设备表面积Smallest batch (product B) Specific surface Area 3.4.1.2基于残留限度10ppm：限度 =R*产品 B 最小批量 *测试面积 *回收因子 /SSA based upon residue limit 10ppm: limit = R* product B smallest batch * test area * recycling factor 其中： SSA- 设备表面积Specific su

34、rface area R=10mg 产品 A(product A)/Kg 产品B (product B) =10ppm 3.4.2 淋洗样限度（ mg/L ）Washing sample limit 3.4.2.1基于生物学活性的限度计算：限度=ADI*SB*淋洗面积 / （淋洗体积 *MDD*SSA ）based upon biological activity limit calculation: limit = ADI* SB* washing area/(washing volume*MDD*SSA) 其中： ADI-产品 A的日服剂量 MDD- 产品 B的最大日服剂量acceptab

35、le daily intake (product A) Maximum daily dose (product B) SB-产品 B 的最小批量 SSA- 设备表面积Smallest batch (product B) Specific surface Area 3.4.2.2基于残留限度10ppm：限度 =R*产品 B 最小批量 *淋洗面积 / （SSA* 淋洗体积）based upon residue limit 10ppm: limit = R*product B smallest batch * washing area/(SSA* washing area) 其中： SSA- 设备表

36、面积 R=10mg产品 A/Kg 产品 B=10ppm Specific surface area R=10mg product A/Kg product B= 10ppm 3.5 对于每一个产品，应基于评估确定每次验证的可接受限度Determine acceptable limit of each validation based upon each assessment of every product. 名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 6 页，共 13 页 -

37、- - - - - - - - File Number:QA-SMP-C06Document name:设备清洁验证管理制度Equipment cleaning validation management systemversion:02Page 7 of 134.清洁验证 / 确认方案和报告的形成、审核和批准Cleaning validation/qualification of plan and report form, review and approval 4.1 所有清洁验证 / 确认方案、报告的编号都是唯一的，其编号按照文件分类及编号要求（ QA-SMP-B000 ）程序执行。 N

38、umbering of all clean validation/qualification plan and report is sole, which is numbered according to “document classification and number requirement” (QA-SMP-B000). 4.2 车间准备清洁验证 / 确认方案、报告，内容包括目的、范围、背景、设计（策略和取样测试计划）以及方法学可接受限度等，一份完整的清洁验证/ 确认方案、报告至少应包括以下内容： Workshop shall prepare clean validation/qua

39、lification plans and reports. The corresponding content shall include aim, scope, background, design (strategy and sampling test plan) and acceptable limit of methodology . A complete validation/qualification plan and report shall include the following contents at least: -目的、范围、责任。 Aim, scope and re

40、sponsibility -概述：简明扼要的描述一些关于产品组成、生产过程的相关信息以及设备描述，包括：制 造商 、型 号、 系列号 或其 它唯 一代 码。 Summary: Concisely describe some information related to product composition, production process and equipment description, including manufacturer, model, serial number and sole code. -首要必备的前提条件：提供一些首要必备的要求，诸如设备安装、运行确认；分析方

41、法学已经验证；清洁程序已被批准；验证组织；人员已经培训。Prior and necessary prerequisite: provide some prior and necessary requirements, for example: equipment installation, operation qualification, validated analysis methodology , approved cleaning procedures; validation organization, staffs have been trained. -设备描述：简明描述设备状态，

42、如设备用于单个产品还是多个产品、构造材质，产品 总 的 接 触 表 面 、 最 难 清 洁 部 位 。 Equipment description: concisely describe equipment status, for example: for single product or multiple products, material, total contact surface to product, hardest cleaning parts. -清洁程序描述：概括清洁程序，包括关键清洁参数，提供相关SOP 列表，包括清洁前的设备拆卸程序、清洁间隔时间、日常监测使用的设备（如

43、电导仪、pH 计、总有机碳分析仪）、清洁程序循环次数，所使用的清洁剂（应科学合理的考虑需去除物质的溶解度、需清洁设备的设计、结构以及表面材料、清洁剂的安全性、容易去除的程度、产品名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 - - - - - - - 第 7 页，共 13 页 - - - - - - - - - File Number:QA-SMP-C06Document name:设备清洁验证管理制度Equipment cleaning validation management systemversion:0

44、2Page 8 of 13属性、清洁剂与淋洗液最低温度与体积，以及设备制造商的建议等）。Description of cleaning procedure: summarize cleaning procedures including critical cleaning parameters, provide the corresponding SOP tables and lists including equipment teardown procedures before cleaning, cleaning interval time, equipment for routine m

45、onitoring (conductance instrument, pH meter , total carbon analyzer), cleaning procedure cycle index, detergents （rationally consider: material solubility, cleaning equipment design, structure and surface material, safety of detergents, removable degree, product attributes, lowest temperature and vo

46、lume of detergent and eluent, and suggestions from equipment manufacturers）. -验证评估、方法：应对产品、设备、清洁程序、取样方法等方面进行评估，描述清洁验证策略及其根本原因，一般进行最差条件下的3 批验证。确定可接受限度及取样方法等，包括微生物限度方面的评估考虑及确定。Validation assessment and method: shall make an assessment to product, equipment, cleaning procedures and sampling methods, de

47、scribe cleaning validation strategy and root causes, perform three batch validations at the worst condition, determine the acceptable limit and sampling method including microbial limit assessment and qualification. -取样和测试计划：描述所使用的取样（如直接取样、淋洗取样，中间监测及取样点）和测试策略，清楚描述冲洗路径和擦拭/ 提取部位以及理由。取样方法里应包括取样位臵、各取样位臵

48、的样品数、取样方法、每一个样品的测试方法、所有样品测试的可接受 限 度 。 Sampling and testing plan: describe sampling (direct sampling, washing sampling, interval monitoring and sampling point) and testing strategy , clearly describe cleaning pathway, wiping/extracting parts and reasons. Sampling method shall include sampling positio

49、n, sample number at each sampling position, sampling protocols, testing protocol for each sample, acceptable limit of all sample tests. -可接受标准：基于目测、擦拭、淋洗等进行列表，包括残留活性成分、降解物、不挥发性清洁溶剂的残留标准，残留标准的可接受水平以及其详细的计算过程Acceptable standards: make a list with items: visualization, wiping, and washing. It includes

50、standards for residual active ingredients, degradable materials and non-volatility cleaning solvents, residue standard acceptable level and detailed calculations. -再验证要求 revalidation requirements -偏差与变更处理 deviation and change handling 名师资料总结 - - -精品资料欢迎下载 - - - - - - - - - - - - - - - - - - 名师精心整理 -