清洁验证的10个关键点

2018-04-28 来源:bc体育 点击:558

文章来源:PDA TRA49

1.  清洁工艺生命周期流程

2.  前提条件
在制订验证方案前需准备的文件包括:
Validationstrategy, including rationale for product and/or equipment grouping
验证策略,包括产品和/或设备分组的基本原理
Draft cleaningSOP, including CPPs
清洁SOP 草案,包括关键工艺参数
Acceptancecriteria and how those criteria were established
可接受标准,以及这些标准建立的依据
Analyticalmethods and their validation
使用的分析方法和分析方法的验证
Samplingmethods and sampling sites (locations)
取样方法和取样点(位置)
Samplingrecovery studies
取样回收率的研究
Selection of protocolchallenges, including hold times
挑战方案的选择,包括保持时间
Rationale forthe selection of number of validation (PPQ) runs
验证(PPQ)运行次数选择的理由
How equipmentcleaning is to documented
设备清洁的记录方法
Responsibilitiesfor execution of the protocol
方案执行的责任
Training ofoperators, samplers and analysts on applicable procedures
操作者、取样人员和分析人员的培训记录
Plans forvalidation maintenance
验证维护计划
Plansfor equipment and product disposition during the protocol execution.
方案执行过程中设备和产品的处置计划
 3.        清洁工艺的设计与开发
The operational parameters that describe the cleaning process include:描述清洁工艺的运行参数包括:
Cleaning agent清洁剂
Concentration浓度
Contact time接触时间
Temperature温度
Factors which affect the cleaning process include:影响清洁工艺的因素包括:
Product characteristics产品性质
Product condition产品状态
Relevant specifics about the cleaning equipment include:清洁设备相关特性包括:
Automated cleaning pathways自动化的清洗方法
The sequence of manual or automatedcleaning steps各手工或自动化清洁步骤的顺序
Flow rates during each step每一步骤时的流速
4.        残留与限度的确定
10ppm;
日剂量1/1000;
基于毒理学数据的计算;
不同给药途径,不同用药人群,如儿童和老人,不同清洗难易程度的设备表面,专用与多用途设备的不同考虑。
5.      取样方法的开发
Direct surface sampling直接表面取样
Rinse sampling冲洗取样
Swabbing擦拭法
Placebo sampling.安慰剂取样法
6.       取样回收率的研究
微生物和理化取样回收率
擦拭取样回收率,冲洗取样回收率以及“目检”回收率,回收率通常要求70%或更高。
注意取样人员的培训,保证取样工作的一致性。
取样点的选取。
7.      清洁验证分析方法的开发
无论是选用专属性方法还是非专属性方法,均应基于风险的方法根据实际情况来选择。例如,如果不知道清洁过程中活性会发生降解,就可能错误地使用专属性方法;如果非专属性响应不完全源自目标残留物,则可能误用非专属性的方法。
Additional considerations in selecting methods are listed below:选择方法还要考虑以下内容:
? Availability of instrumentation可用的仪器
? Speed of analysis检测的速度
? Specificity of technique检测技术的专属性
? Sampling limitations (including sampling solvents)取样限制(包括取样溶剂)
? Detection/quantitation limit检测限/定量限
? Linearity of response响应值的线性
? Online adaptability能否在线检测
? Cost费用
具体分析方法的验证与确认流程见分析方法验证和确认。
8.       清洁工艺的转移
清洁工艺与清洁验证分析方法的转移具体见技术转移。(技术转移的编制将在后续发布)
9.      清洁验证文件
The master plan should address each important aspect of the cleaningvalidation program. Elements of a master plan and the appropriate detailsprovided for those elements will depend on the practices of the specific facility.One approach is to include more detail in the master plan while anotherapproach is to include that level of detail for procedures consistent with themaster plan. Elements of a master plan may include, but are not limited to, thefollowing topics:
清洁验证主计划应涵盖清洁验证计划的各个重要方面。一个主计划的要素和这些要素的适当细节将取决于各公司的具体操作。一种方法是将更多细节描述在主计划中,而另一种方法是将同等细节写入程序中,而主计划则引用这些程序。主计划的要素可以包括,但不限于:
?Purpose of the plan主计划的目的
?Scope of the cleaning validation program清洁验证程序的范围
?Designation of responsibilities职责的划分
?List of equipment to be validated待验证的设备清单
?Definitions and glossary of terms定义和术语表
?Means of cleaning documentation (e.g., procedures andrecords)清洁文件(例如,程序和记录)
?Prerequisites to cleaning validation (e.g., equipmentand utility qualifications)清洁验证的先决条件(例如,设备与设施的确认)
?Spray device coverage testing喷淋装置覆盖测试
?Use of various cleaning systems (e.g., CIP, COP,mechanical washers or manual cleaning)各种清洁系统(如,在线清洗,离线清洗,机械清洗机或手动清洗)的使用
?Cleaning reagents and mechanisms清洁剂和作用机理
?Cleaning cycle development requirements清洁行程开发要求
?Cleaning equipment lists清洗设备清单
?Product list产品列表
?Cleaning SOPs清洁标准操作规程
?Pre-cleaning methods预清洗方法
?Conditions for use of artificial or surrogate soils人工或替代污物的使用条件
?Definition and use of “worst-case conditions” associatedwith a cleaning process (e.g., flow rates or step
durations)清洁工艺的“最差条件”(例如,流速或操作步骤的持续时间)的定义和使用
?Description of family approach and grouping ofproducts/equipment/systems based on similarities,
including an approach to determine “worst-case product”based upon attributes that impact cleaning (e.g.,
solubility of all components in the “soil”)根据产品/设备/系统的相似性对其分类/分组进行描述,包括根据影响清洁的特性来定义“最差条件产品”的方法。(例如,污物中各组分的溶解度)
?Use of dedicated or shared equipment; single use(disposable) equipment使用专用或共用的设备,一次性使用(一次性)的设备
?Definition of circumstances in which cleaningverification is preferred or acceptable (e.g., clinical stages)定义首选或接受“清洁效果确认”的条件(例如,临床阶段)
?Strategies and definitions for indirect product contactsurfaces间接接触产品表面的策略和定义
?Cleaning of components and single-use equipment组件和一次性设备的清洗
?Use of quality risk management to determine the scopeand extent of validation activities使用质量风险管理来确定验证活动的范围和程度的
?Establishment of design space based on cleaningparameters and use in ongoing monitoring基于清洁参数建立设计空间,并用于持续监测中
?Use of mock, blank, or placebo runs使用模拟,空白或安慰剂进行验证
?Equipment hold study approaches (e.g., dirty hold, cleanhold or storage hold)研究设备保持时间的方法(例如,生产后保持时间,清洁保持时间或储存效期)
?Microbial contamination (e.g., bioburden and endotoxin)微生物污染(如生物负载和内毒素)
?Sampling techniques (e.g., visual inspection, rinsesampling or swab sampling)取样技术(如目视检查,冲洗取样或棉签擦拭取样)
?Training/qualification for sampling techniques取样技术培训/资格确认
?Analytical methods (e.g., validation and recoveryrequirements)分析方法(例如,验证和回收率要求)
?Rationale for the use of product-specific assays andnonspecific assays选择专属性和/或非专属性含量检测方法的理由
?Rationales and formulas for limits for process residues,microbial contaminants and cleaning agents工艺残留、微生物污染和清洁剂限度的制订原理和公式
?Validation maintenance (including routine monitoring,change control, and periodic review)验证维护(包括日常监测,变更控制和定期回顾)
?Attachments/appendices (e.g., various tables or lists ofitems within the realm of the plan such as a
responsibility matrix)附件/附录(例如,在主计划中的不同表格或项目清单,如职责矩阵)
?Requirement for reassessment of cleaning validationmaster plan清洁验证主计划的再评估要求
?Roadmap or summary of current status and upcoming plans现状和计划的路线图或摘要
?References参考 
10.       验证状态的维护
Documentation for the validation maintenance stage will depend onactivities selected for this stage. It should include reports related to thefollowing activities, as applicable:验证维护阶段的文件取决于这个阶段选择进行的活动。它应该包括以下活动相关的报告(如适用):
?Alarms and alerts, including investigations and corrective/preventiveactions报警和警报,包括调查和纠正/预防措施
?Routine monitoring, including trending of data and evaluation of suchtrending (may include statistical
evaluation)例行监控,包括数据趋势和对这些趋势的评估(可包括统计分析)
?Change control变更控制
?Deviations, including investigation and corrective/preventive actions偏差,包括调查和纠正/预防措施
?Evaluations of cumulative changes (which might be as a result of adeviation investigation or a periodic
review)评估累积的变更(这可能是偏差调查或定期回顾的结果所致)
?Training and retraining培训和再培训
?Periodic cleaning process review清洁工艺的定期回顾
?Risk assessments relating to any process changes or shifts.对任何相关的工艺变更或漂移进行风险评估

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