The Analytical Procedure Lifecycle
分析方法生命周期
ABSTRACT
An analytical procedure must be demonstrated to be fit for its intended purpose. It is useful to consider the entire lifecycle of an analytical procedure, i.e., its design and development, qualification, and continued verification. The current concepts of validation, verification, and transfer of procedures address portions of the lifecycle but do not consider it holistically. The purpose of this proposed new chapter is to more fully address the entire procedure lifecycle and define concepts that may be useful. This approach is consistent with the concept of quality by design (QbD) as described in International Council for Harmonisation (ICH) Q8-R2, Q9, Q10, and Q11. The lifecycle approach can potentially be applied to all procedures, although the level of effort should be consistent with the complexity and criticality of the procedure.
摘要
分析方法需证明适合其预期目的。分析方法需考虑完整的生命周期，即其设计和开发、确认和持续验证。目前的分析方法确认、验证和转移的理念只涉及生命周期的某些部分，缺乏整体上的考虑。本拟议新章节意在对分析方法全生命周期作更全面地阐述，并定义可能有用的概念。本文理念与ICHQ8、Q9、Q10和Q11中所述质量源于设计（QBD）一致。生命周期理念可应用于所有分析方法，但需根据方法的实际情况调整应用的程度。
INTRODUCTION
This Stimuli article provides the framework for The Analytical Procedure Lifecycle⟨1220⟩. This article describes the current thinking of the USP Validation and Verification Expert Panel which advises the General Chapters—Chemical Analysis Expert Committee with regard to future trends in analytical procedures development, qualification, and continued monitoring. These concepts are described here for the purpose of offering an alternative approach to the classical analytical validation and subsequent verification and transfer, viewing these activities as a continuum and closely interrelated rather than as discrete actions. This enhanced approach potentially offers several advantages, including:
概述
本文提出了分析方法生命周期的框架结构，描述了美国药典验证与确认专家团队当前的想法，该团队就分析方法开发、确认和持续监测的未来趋势向化学分析专家委员会提供建议。此处所述之理念意在是为传统分析验证、确认与转移提供一种新的思维，即将这些活动视为连续、密切相关的而非离散的行为。该新的理念显示出多个优势，包括：
·Improved understanding of the procedure and control of sources of variability, which are linked to the intended use of the procedure as describedin the analytical target profile (ATP)
·Procedures that are more robust, resulting in fewer failures during use and during qualification in a new laboratory
·Reduction of overall resources required for a new or revised procedure. The levels of effort, formality, and documentation should be commensurate with the level of risk
·Identification of adverse trends, allowing proactive measures and facilitation of continued improvements and change control through continued monitoring
·增强对分析方法的理解与对变异源的控制，这些变异源与分析目标概要（ATP）中所述分析方法的预期用途有关
·分析方法更加稳健，在新实验室使用和确认期间故障更少
·减少新或修订的分析方法所需资源。工作、流程及文件级别应与风险级别相称
·查明不利趋势，采取主动措施，通过持续监测促进持续改进和变更控制
The Validation and Verification Expert Panel considers this lifecycle approach to still be evolving, as International Council for Harmonisation (ICH) Q8, Q9, and Q10 concepts are being adopted by the analytical community. Therefore, it is advisable to provide guidance on how to incorporate lifecycle management strategies into analytical procedures, which will increase flexibility in demonstrating the fitness of analytical procedures while leaving the option open to use the classical approach described in Transfer of Analytical Procedures ⟨1224⟩, Validation of Compendial Procedures ⟨1225⟩, and Verification of Compendial Procedures ⟨1226⟩. In addition to offering a preview of the proposed general chapter, the General Chapters—Chemical Analysis Expert Committee and the Validation and Verification Expert Panel are seeking specific input from users in the pharmaceutical industry regarding the following questions:
验证和确认专家团队认为，随着ICHQ8、Q9和Q10概念被分析界采用，生命周期理念不断发展。因此，建议就如何将生命周期管理策略纳入分析方法提供指南，这将扩展分析方法适用方面的灵活性，同时允许选择使用传统理念如分析方法转移<1224>，分析方法验证<1225>，分析方法确认<1226>。除提供拟议的通则的预告外，化学分析专家委员会和验证与确认专家团队正在就以下问题征求制药行业用户的具体意见：
1. Would a general chapter on the lifecycle approach be valuable?
2. Is the information presented herein sufficient for implementation of an analytical procedure under the quality by design (QbD) approach?
3. Would incorporation of references to statistical tools, either in this chapter or in another chapter, be valuable?
4. Can you provide input or approaches that would improve this proposed general chapter?
1.关于生命周期理念的通则有价值吗？
2.本文提供的信息是否足以在质量源于设计（QBD）理念下建立一个分析方法？
3.在本章或另一章中涉及的统计工具是否有价值？
4.你能提供意见或方法来改进拟议的通则吗？
The content and scope of the proposed general chapter will be refined on the basis of responses to this Stimuli article. Because stakeholders may have differing views, the objective of this Stimuli article is to identify and build areas of consensus that may be included in ⟨1220⟩
拟议通则的内容和范围将根据本征求意见稿的反馈加以完善。因为利益相关方可能有不同的观点，本征求意见稿的目的是对可能包含在1220中的某些领域达成共识。
THE LIFECYCLEAPPROACH
Reportable values generated using qualified analytical procedures provide the basis for key decisions regarding compliance of a test article with regulatory,compendial, and manufacturing limits. These values may be applied against decision rules that provide a prescription for the acceptance or rejection of a drug product or drug substance. This is based on the analytical measurement, the uncertainty of the measurement, and the acceptance criteria, taking into account the acceptable level of risk of making a wrong decision.
生命周期理念
使用经确认的分析方法生成的检测结果为待测组分是否符合法规、药典和生产要求的关键决策提供了依据。检测结果可以用于决定原料药或药物是否放行。其决策规则基于对分析测量、测量的不确定度与可接受标准综合评价，并考量做出错误决策的可接受风险水平。
Application of lifecycle management concepts to analytical procedures is based on QbD and provides an opportunity to use the knowledge gained from the application of scientific approaches and apply that knowledge to reportable values generated when using the analytical procedure. The concept of QbD is understood as asystematic approach that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management (ICH Q8). The quality risk management (QRM) for ananalytical procedure is a systematic process for the assessment, control, communication, and review of risk to the quality of the reportable value across the analytical procedure lifecycle. It is important to understand and control sources of variability to ensure that measurement uncertainty is aligned with the decisions that will be made using results generated by an analytical procedure.
生命周期管理概念在分析方法中的应用基于QbD，并提供了一个机会使用从科学理念的应用中获得的知识，并将这些知识应用到使用分析方法时生成的检测结果。QbD的概念被理解为一种系统的方法，它从预定义的目标开始，强调基于可靠的科学和质量风险管理(ICH Q8)的产品和过程理解和过程控制。分析方法的质量风险管理（QRM）是一个系统的过程，用于评估、控制、沟通和审查整个分析方法生命周期中检测结果的质量风险。重要的是要理解和控制变异的来源，以确保测量不确定度与使用分析方法产生的结果做出的决定相一致。
Lifecycle Stages
In order to provide a holistic approach to controlling an analytical procedure throughout its lifecycle, one can use a three-stage concept (see Figure 1) that is aligned with current process validation terminology:
Stage 1:Procedure Design and Development
Stage 2:Procedure Performance Qualification
Stage 3:Continued Procedure Performance Verification
生命周期阶段
为了在分析方法的全生命周期中提供一种整体控制理念，可以使用与当前过程验证术语相一致的三阶段概念（见图1）：
阶段1：方法设计和开发
阶段2：方法性能验证
阶段3：持续方法性能确认
Analytical Target Profile
A fundamental component of the lifecycle approach to analytical procedures is having a predefined objective that stipulates the performance requirements for the analytical procedure. These requirements are described in the ATP. The ATP states the required quality of the reportable value produced by an analytical procedure in terms of the target measurement uncertainty (TMU). ATP criteria are derived from external requirements and not only from the performance of the analytical procedure. The acceptable level of risk of making an incorrect decision is considered when establishing an ATP. The reportable value may bethe mean of multiple analytical results, if there is a defined replication strategy that is documented in the procedure. TMU is the maximum uncertainty that can be associated with a reportable result while still remaining fit forits intended purpose. TMU is a consolidation of the uncertainty from all sources, as illustrated in Figure 2.
分析目标概要
分析方法生命周期理念的一个基本组成部分是有一个预定义的目标，规定分析方法的性能要求。这些要求在ATP中描述。ATP根据目标测量不确定度（TMU）规定了分析方法产生的检测结果所需的质量。ATP标准源于外部要求，而不仅仅源于分析方法的性能。在建立一个ATP时，要考虑做出错误决策的可接受风险水平。如果分析方法中规定了的复测策略，则检测结果可能是多个分析结果的平均值。TMU是与可报告结果相关的最大不确定度，同时仍然适合其预期目的。TMU是来自所有来源的不确定性的综合，如图2所示。
When establishing an ATP, the following should be considered, where relevant:
·Sample to be tested
·Matrix in which the analyte will be present
·Allowable error for the measurement as assessed through accuracy(bias) and precision, both of which make up the TMU
·Allowable risk of the criteria not being met (proportion of results that are expected to be within the acceptance criteria)
·Assurance that the measurement uncertainty and risk criteria aremet
当建立一个ATP时，在相关的情况下，应考虑以下因素：
·待测样品
·含有待测组分的基质
·通过准确度（偏差）和精密度评估测量允许误差，这两者共同构成TMU
·不符合标准的容许风险（预期结果在验收标准范围内的比例）
·确保满足测量不确定度与风险的标准要求
The current ICH and USP validation guidance can be incorporated into an ATP, withemphasis on the quality of the reportable value as shown for a drug product assay
(Example 1).
当前的ICH和USP验证指导原则可纳入到ATP中，重点是药品含量测定所示的检测结果的质量（示例1）。
EXAMPLE 1: ATP #1
The procedure must be able to quantify [analyte] in the [description of test article] in the presence of [x, y, z] with the following requirements for the reportable values: Accuracy = 100%±D% andPrecision≤E%.
The ATP inputs for [analyte], [description of test article] and [x, y, z] (which may be impuritiesor excipients) can be specified. Values for D and E should be specified. For example,D may be expressed as a percentage of label claim and E may be expressed as a percentage of relative standard deviation (%RSD). Alternative units areacceptable as long as they are unambiguous.
例1:ATP #1
该分析方法必须能够在[x，y，z]存在的情况下对[供试品]中的[待测组分]进行量化，并对检测结果提出以下要求：准确度=100%±D%，精密度≤E%。
可规定[待测组分]、[供试品]和[x，y，z]（可能是杂质或辅料）的ATP输入。应指定D和E的值。例如，D可以表示为标签声明的百分比，E可以表示为相对标准偏差的百分比（RSD）。也可采用其他经说明的形式。
Advantages of this approach to an ATP are:
·The ATP is easy to understand, calculations are relatively straight forward, and data are easy to assess for ATP conformance by non-statisticians.
·The ATP includes criteria for accuracy (bias) and precision of thereportable value and is therefore linked to the quality of the reportable values.
·This approach encourages understanding and control of sources of variability(defined control strategy).
这种理念的优点是：
·ATP易于理解，计算相对简单，数据便于非统计人员评估ATP合规性。
·ATP包括检测结果的准确度（偏差）和精密度标准，因此与检测结果的质量相关。
·这种理念鼓励理解和控制变异来源（定义的控制策略）。
Limitations of this approach include:
·Accuracy (bias) and precision are assessed separately so that the TMU of the results is not explicitly defined.
·This approach does not quantify the risk of making a wrong decision by including probability and confidence criteria. However, while the level of risk is not transparent, risk can be controlled through the alignment of specifications and accuracy (bias)/precision criteria such that reportable values that are within specification have a low probability of being on an edge of failure with respect to clinical relevance.
In current approaches, criteria for accuracy (bias) and precision are often established based on generally accepted industry practices using default criteria. However,in a QbD approach, these criteria are aligned with the specification and product and process needs, and the criteria focus on the reportable value.
这种理念的局限性包括：
·准确度（偏差）和精密度单独评估，因此结果的TMU没有明确定义。
·这种方法没有通过包括概率和置信标准来量化做出错误决策的风险。虽然风险水平并不清晰，但可以通过质量标准和准确度（偏差）/精密度标准的一致性来控制风险，以便质量标准的检测结果在临床相关性方面处于失败边缘的概率较低。
现行理念关于准确度（偏差）与精密度的标准通常是基于使用默认标准的普遍接受的行业实践而建立的。然而，在QbD理念中，这些标准与质量标准、产品和过程需求相一致，并且这些标准侧重于检测结果。
EXAMPLE 2: ATP #2
The procedure must be able to quantify [analyte] in the [description of test article] in the presence of [x, y, z] so that the reportable values fall within a TMU of ±C%.
例2:ATP #2
该程序必须能够在[X，Y，Z]存在的情况下量化[供试品]中的[待测组分]，以便报告值在±C%的TMU范围内。
The ATP inputs for [analyte], [description of test article] and [x, y, z] (which may be impurities or excipients) can be specified.
This example contains criteria for the TMU, (±C%), which is directly linked to the results generated by the procedure. The TMU considers the acceptable difference between the measured reportable value and the target value and can be established based on a fraction of the specification range.
可指定[待测组分]、[供试品]和[x，y，z]（可能是杂质或辅料）的ATP输入。
此示例包含TMU的标准（±C%），TMU与程序生成的结果直接相关。TMU考虑测量的检测结果和目标值之间的可接受差异，并可基于质量标准范围的一小部分建立。
The ATP servesas a reference point for assessing the fitness of an analytical procedure, notonly in the development phase but also during all changes within the analytical lifecycle. Note that the ATP is not linked to a specific analytical procedure.Thus, it is conceivable that more than one analytical procedure could meet the requirement of an ATP, and that an alternate procedure that meets therequirement stated in the ATP would be acceptable.
ATP不仅在开发阶段，而且在分析周期内的所有变更中，都是评估分析方法适用性的参考点。请注意，ATP与特定的分析方法没有关联。因此，可以想象不止一个分析方法可以满足ATP的要求，并且可以接受满足ATP中所述要求的替代方法。
For procedures that do not already have an ATP, including existing procedures in compendial monographs, one can be constructed. For instance, the ATP may be based on product acceptance criteria and any existing requirements for the analytical procedure as stated in the monograph.
对于尚无ATP的分析方法，包括现行药典各论中的分析方法，可以为之建立ATP。ATP可以基于产品验收标准和专论中所述分析方法的任何现有要求。
In assessing new or existing procedures for their ability to meet an ATP, analysts may use statistical methods for analyzing prospectively designed studies. In the case of existing procedures for which significant data are available, statistical procedures for retrospective evaluation of historical data, such as stability data, laboratory investigations, check samples/controls, release data, andothers may be used. The level of variability present in the historical data maytrigger additional studies that aim to understand and reduce or eliminate sources of variability and also improve the data quality by means of an optimized control strategy to meet the ATP.
在评估新方法或现行方法满足是否ATP时，分析人员可以使用统计方法分析前瞻性设计的研究。如果现行方法有重要数据可用，则可使用对历史数据进行回顾分析的统计方法，如稳定性数据、实验室调查、检查样品/对照品、放行数据和其他。历史数据中存在的变异水平可能会引发额外的研究，旨在了解、减少或消除变异来源，并通过优化控制策略来提高数据以质量满足ATP的要求。
STAGE 1: PROCEDURE DESIGN AND DEVELOPMENT
Knowledge Gathering
When the need for a procedure is identified, relevant information should be gathered prior to conducting laboratory studies. Such information may include known chemical structures, solubility, reactivity, and stability of the molecules of interest. A literature search may also be useful to understand how the procedure has been applied or modified by others. The intended purpose and fitness for routine use must always be considered. Any relevant information identified during the knowledge-gathering stage—such as the range over which the procedure will beused, criteria for run time, equipment type, and other information—is also considered during the design and development stage. However, this informationis not captured in the ATP.
Once the knowledge-gathering phase is complete, the information is used to select an appropriate technology and procedure likely to meet the requirements defined in the ATP.
阶段1：方法设计与开发
知识收集
当已确定方法的需求，应在进行实验室研究之前收集相关信息。这些信息可以包括已知的化学结构、溶解度、反应性和相应组分的稳定性。文献检索也可能有助于了解其他人如何应用或调整方法。必须始终考虑预期用途和日常使用的适用性。在知识收集阶段确定的任何相关信息，如方法的使用范围、运行时间标准、设备类型和其他信息，也将在设计和开发阶段予以考虑。但是ATP不能提供这些信息。
一旦知识收集阶段完成，信息将用于选择可能满足ATP中规定要求的适当技术与方法。
Risk Assessment Evaluation and Control
The objective of a risk assessment is to develop understanding of procedure variables and their impact on the reportable value, which will assist in the development of a control strategy.
风险评估与控制
风险评估的目的是了解方法变量及其对检测结果的影响，这将有助于制定控制策略。
For example, tools such as process maps and Ishikawa diagrams (fishbone diagrams)may beused, in addition to prior knowledge, to provide structure to a brain storming and information-gathering exercise to identify variables. The attributes shown in Figure 2 may serve as a useful starting point. It is important to consider all steps in the analytical procedure, including development of standard andtest sample preparation. It is important to ensure that the sample preparation step does not cause the analyte to undergo any significant (uncontrolled or unintended) changes in its relevant properties from the moment of sampling tothe time when the actual analysis is carried out. Sample preparation conditions are frequently a source of procedure variability and/or bias and its influence in the performance of the procedure should be investigated. In the case of sample preparation that involves dissolving a sample prior to analysis, systematic extraction studies should be performed to ensure robust, rugged, andcomplete extraction/dissolution. It is also important to investigate sources ofvariability and systematic bias during Stage 1 so that they may be eliminated or controlled during routine use of the procedure.
例如，除了先验知识外，还可以使用过程图和石川图（鱼骨图）等工具，为头脑风暴和信息收集活动提供结构，以识别变量。图2中所示的属性可以作为一个有用的起点。重要的是要考虑分析方法中的所有步骤，包括对照与样品制备。确保样品制备过程不会导致待测组分从取样到实际分析期间的相关性质发生任何重大（不受控制或意外）变化也非常重要。样品制备条件通常是方法变异和/或偏差的来源，应调查其对方法性能的影响。如果样品制备涉及在分析前溶解样品，则应进行系统的提取研究，以确保提取/溶解的结果稳健、坚固和完全。在第1阶段调查变异和系统偏差的来源也很重要，以便在方法的日常使用过程中消除或控制它们。
Besides accuracy(bias) and precision, which are defined in the ATP, experiments may includeother method-specific performance attributes known as traditional validation characteristics (see Figure 2). However, these characteristics are eventually consolidated into the ATP attributes.
除在ATP中定义的准确度（偏差）与精密度外，实验还可以包括其他方法特有的性能属性，即传统的验证参数（见图2）。然而，这些参数最终被整合到ATP属性中。
Risk-assessment tools may be used to prioritize which variables should be studied to evaluate their impact on the reportable results. Results from experiments investigating variables can be used to develop and justify the control strategy.
风险评估工具可用于确定应研究的变量的优先级，以评估其对检测结果的影响。研究变量的实验结果可用于开发与确定控制策略。
Design of experiments (DOE) is a fundamental methodology for the QRM process. It is asystematic method to determine the relationships between variables affecting aprocess, and it is used to find cause-and-effect relationships. This information is needed to manage process inputs in order to optimize the output of the procedure. Multi-factor studies are a powerful way to develop understanding, although single-factor studies are also appropriate in some cases. DOE also utilizes statistical data treatment, which allows clear determinations regarding the significance of a variable and/or its interactions towards the output.
实验设计是QRM过程的基本方法。它是一种确定影响过程的变量之间关系的系统方法，用于寻找因果关系。需要此信息来管理过程输入，以便优化方法的输出。多因素研究是发展理解的有力途径，尽管单因素研究在某些情况下也适用。DOE还利用统计数据处理，允许明确确定变量的重要性和/或其对产出的相互作用。
Analytical Control Strategy
The analytical control strategy is a planned set of controls, which is the output of the QRM process.It is derived from an understanding of both the requirements for the reportable value established in the ATP and the understanding of the analytical procedureas a process.
分析控制策略
分析控制策略是一组有计划的控制，是QRM过程的输出。它源于对atp中确定的检测结果要求的理解，以及对分析方法作为过程的理解。
The variables that need to be controlled and their acceptable ranges (from the riskassessment and subsequent experiments) should be explicitly specified in the procedure. Typical controls may include limits for variability of calibration and between replicates; instructions for environmental controls (light, temperature, and humidity); sample solutionstability; and, for chromatographic methods, system suitability requirements such as sensitivity, resolution, etc. In addition, the controls may include variables and aspects related to the sample, sample preparation, standards, reagents, the facility, equipment operating conditions, the format of the reportable value (i.e., number of replicates), and the frequency of monitoringand control.
分析方法应明确规定需要控制的变量及其可接受的范围（从风险评估和随后的实验开始），典型的控制可包括校准和重复测量的变异范围；环境控制说明（光、温度和湿度）；样品溶液稳定性；对于色谱法，系统适用性要求，如灵敏度、分离度等。此外，控制可包括与样品、样品制备、标准品、试剂、设施、设备操作条件、检测结果的格式（即重复检测次数）相关的变量以及监测和控制的频率。
A replication strategy may be applied to reduce the random variability of the mean(reportable value). It should be noted that increasing the number of replicates will only reduce the random variability corresponding to the step that is replicated. For example, increasing the number of injections will reduce the injection variance, whereas increasing the number of sample preparations will reduce the variance associated with sample preparation.
可以应用重复测定策略来减少平均值（检测结果）的随机误差。应该注意的是，增加重复测定次数只会减少与重复测定步骤相对应的随机误差。例如，增加进样次数将减少进样误差，而增加样品制备次数将减少与样品制备相关的误差。
The analytical control strategy plays a key role in ensuring that the ATP is realized throughout the lifecycle. Different control strategies may be required indifferent labs or when using different equipment.
分析控制策略在保证ATP在整个生命周期内得以实现方面起着关键作用。在不同的实验室或使用不同的设备时，可能需要不同的控制策略。
Knowledge Management
Knowledge management for analytical procedures is a systematic approach to acquiring, analyzing, storing, and disseminating information, and is an important factorin ensuring the ongoing effectiveness of the control strategy. Knowledge management should include, but should not be limited to, development activities, technology transfer activities to internal sites and contract laboratories, qualification and monitoring studies over the lifecycle of theanalytical procedure, and change management activities. The knowledge gathered todevelop the procedure understanding should be collected in a repository and shared as needed to support implementation of the control strategy across sites that use the analytical procedure. Changes and improvements to a qualified analytical procedure should be made through the change control system.
知识管理
分析方法的知识管理是获取、分析、存储和传播信息的系统方法，是确保控制策略持续有效的重要因素。知识管理应包括但不限于开发活动、向内部现场和合同实验室的技术转移活动、分析方法全生命周期内的确认与监测研究以及变更管理活动。为开发方法理解而收集的知识应收集在一个存储库中，并根据需要进行共享，以支持使用分析方法的各现场控制策略的实施。应通过变更控制系统对已确认的分析方法进行变更与改进。
Preparing for Qualification
Before beginning a qualification study, data collected during Stage 1 can be assessed to provide supporting evidence for the absence of significant bias and a confirmation that the precision is at an appropriate level, as well as other pertinent analytical characteristics. Although bias and precision estimates at this stage do not guarantee that a qualification study will be successful, they can flag apotentially problematic procedure.
As an integral part of preparation for laboratory qualification to execute a compendial procedure or a procedure from another site, the process of QRM should becarried out, and the control strategy of the procedure should be verified orexpanded to ensure that the requirements of the ATP are met.
准备确认
在开始确认研究之前，可以对第一阶段收集的数据进行评估，以提供无重大偏差的支持证据，并确认精密度以及其他相关的分析参数处于适当水平。虽然在这个阶段的偏差和精密度估计不能保证确认研究的成功，但它们可以标记出方法潜在的问题。
作为对药典方法或其他来源的分析方法进行实验室确认的一个组成部分，GRM过程应被执行，该方法的控制策略应得到验证或扩展，以确保满足ATP的要求。
STAGE 2: PROCEDUREPERFORMANCE QUALIFICATION
Once an ATP has been established and design activities are completed with appropriate minimization of bias and uncertainty, knowledge is compiled and documented. Aprocedure control strategy is proposed and the performance of the procedure is ready to be qualified. The purpose of qualification is to confirm that theprocedure generates reportable values that meet the ATP criteria and remain appropriate for the testing of the product in the environment where it will be used. The laboratory that will be using the procedure to generate results should perform the qualification study.
阶段2：方法性能确认
一旦建立了一个ATP，并在适当地减少偏差和不确定性的情况下完成了设计活动，就要汇编和记录知识。方法控制策略已具备，方法的性能准备进行确认。方法确认的目的是确认该方法产生的检测结果符合ATP标准，并适用于产品在使用环境中的测试。将使用该方法产生结果的实验室应进行确认研究。
The protocol for the qualification study should be documented and should include (but is notlimited to) the ATP; method-specific performance attributes and acceptance criteria; a description of or reference to the procedure including its control strategy; a description of the experiments including the number of standards, test sample, and series analysis that will be performed; and the statistical approach to be used to analyze the data.
确认研究的方案应记录在案，并应包括（但不限于）ATP；方法特定性能属性与可接受标准；对方法的描述或引用，包括其控制策略；对实验的描述，包括标准数量、试验样品和将要执行的序列分析；以及用于分析数据的统计方法。
The analytical control strategy may be refined and updated as a consequence of any learning from the qualification study. For example, further controls may be added to reduce sources of variability thatare identified in the routine operating environment in an analytical laboratory, or replication levels (multiple preparations, multiple injections, etc.)may be modified based on the uncertainty in the reportable value.
Qualification strategies will depend on the criteria described in the ATP and on the intended use of the procedure.
分析控制策略可根据确认研究中的任何成果进行改进和更新。例如，可以添加进一步的控制，以减少在分析实验室的常规操作环境中识别的误差来源，或者可以基于检测结果的不确定性修改重复测定水平（平行样品、多次进样等）。
确认策略将取决于ATP中描述的标准和程序的预期使用。
STAGE 3: CONTINUED PROCEDURE PERFORMANCE VERIFICATION
Stage 3 of the procedure lifecycle ensures that the analytical procedure remains in control, i.e., this stage maintains the established performance level and thus continues to meet ATP criteria. Therefore, the ATP is used as a reference point for the performance of the procedure during Stage 3 of the lifecycle of the analytical procedure.
This stage includes both routine monitoring and evaluation of the analytical procedure's performance after changes to determine if the analytical procedure continues to be fit for purpose.
阶段3：方法性能持续确认
方法生命周期的第3阶段确保分析方法保持在受控状态，即该阶段保持既定的性能水平，从而继续满足ATP标准。因此，在分析方法生命周期的第3阶段，ATP被用作程序性能的参考点。
这一阶段包括对分析方法进行常规监测，并在变更后对其性能进行评估，以确定分析方法是否继续适用于目的。
Routine Monitoring
Effective monitoring of an analytical procedure provides confidence that thethe reportable value generated is fit for purpose.reportable value generated is fit for purpose.
This stage should include an ongoing program to collect and analyze data that relate to analytical procedure performance. Monitoring may include tracking analytical results, system suitability failures, out-of-specification or out-of-trend investigations, stability trends, or other parameters as appropriate. If the monitoring data indicate that the procedure is not in control, an investigation should be performed with a goal of identifying the root cause. Corrective andpreventive action should be taken to ensure that the analytical control strategy is updated in the analytical procedure.
日常监测
对分析方法有效监控确认了检测结果符合预期目的。
这一阶段应包括一个正在进行的程序，以收集和分析与分析方法性能有关的数据。监测可包括跟踪分析结果、系统适用性故障、超标或超趋势调查、稳定性趋势或其他适宜的参数。如果监测数据表明程序不受控制，则应进行调查，以确定根本原因。应采取纠正和预防措施，以确保分析控制策略在分析方法中得到更新。
A routine monitoring program therefore needs to be designed to:
·Ensure that the performance of the procedure or of appropriate steps (for example, injection and sample preparation variability) maintains anacceptable level over the procedure lifetime. (This is done to conclude that the reportable values produced by the procedure continue to meet the ATP requirement.)
·Provide an early indication of potential procedure performance issues or adverse trends.
·Identify any changes required to the analytical procedure.
因此，需要设计一个常规监测程序，以便：
·确保方法或适当步骤（例如，进样和样品制备误差）的性能在整个方法生命周期内维持在可接受的水平。（以确认方法检测结果持续满足ATP要求。）
·提供潜在方法性能问题或不利趋势的早期指示。
·确定分析方法所需的任何变更。
Changes to an Analytical Procedure
During the lifecycle of a pharmaceutical product, both the manufacturing process and the analytical procedure are likely to experience a number of changes because of continued improvement activities or the need to operate the method and/or process in a different environment (method transfer).
分析方法变更
在药品的生命周期中，由于持续改进活动或需要在不同的环境中操作方法和/或工艺（方法转移），生产工艺与分析方法都可能经历许多变更。
Depending on the degree of change, the actions required to qualify the change will be different. Some examples are given below:
·A change to a procedure variable to a value within the range thatwas previously qualified would not require additional experimentation to qualify the change.
·A change to a procedure variable to a value outside the range that was previously qualified to produce fit-for-purpose data would require performance of a risk assessment. The risk assessment should consider which procedure performance characteristics may be impacted by the change and should then perform an appropriate procedure performance qualification study to confirm that the change does not impact the method's ability to meet the ATP.
·A change to a new laboratory would require review of the risk assessmentand an appropriate qualification study (which might include comparability testing or a reduced or full requalification).
·A change to a new procedure/technique would require performance of appropriate development and qualification activities (Stages 1 and 2) to demonstrate conformance of the new procedure to the ATP.
·A change impacting the ATP, e.g., a specification limit change or aneed to apply the procedure to measure levels of analytes not considered in the original ATP, would require an update to the ATP and a review of the existing procedure design and qualification data (Stages 1 and 2) to determine whether the procedure will still meet the requirements of the new ATP.
根据变更的程度，确认变更所需操作将有所不同。以下是一些例子：
·方法变量在限定范围内的调整不需要额外的实验来确认。
·方法变量在为限定范围外的调整需要进行风险评估。风险评估应考虑变更可能影响哪些方法性能特性，然后应进行适当的方法性能确认研究，以确认变更不会影响方法满足ATP的能力。
·对新实验室的变更将需要审查风险评估和适当的确认研究（可能包括可比性测试或部分或完全重新确认）。
·对新方法/技术的变更将需要执行适当的开发和确认活动（阶段1和阶段2），以证明新方法符合ATP。
·影响ATP的变更，例如质量标准限度变更或需要应用方法测量原始ATP中未考虑的待测组分水平，需要对ATP进行更新，并对现有方法设计和确认数据（阶段1和阶段2）进行审查，以确定程序是否仍然满足新的ATP的要求。
The level of activities required to confirm that a changed analytical procedure is producingfit-for-purpose data will depend on an assessment of 1) the risk associated with the change, 2) the knowledge available about the procedure, and 3) the effectiveness of the control strategy. It is recommended that for all changes,a risk assessment should be carried out to determine the appropriate level ofactivities required. The aim of the exercise is to provide confidence that the modified method will produce results that meet the criteria defined in the ATP.This may be assessed by considering the risk that the change in the method will have on the accuracy (bias) and precision of the reportable value. Risk assessment tools can be used to provide guidance on what actions areappropriate to verify that the method is performing as required.
Applying a lifecycle approach to analytical procedures should ensure that quality objectives for the reportable values are met on a consistent basis.
确认已变更的分析方法能产生符合目的的数据所需的活动水平将取决于对以下方面的评估：1）与变更相关的风险；2）相关方法的可用知识；3）控制策略的有效性。建议对所有变更进行风险评估，以确定所需活动的适当级别。其目的是为变更后的方法能产生符合ATP中定义的标准的结果提供信心。这可以通过考虑方法变更对检测结果的准确度（偏差）和精密度产生的风险来评估。风险评估工具可用于提供指导，以确定哪些措施适合验证方法是否按要求执行。
将生命周期理念应用于分析方法应确保在一致的基础上满足检测结果的质量目标。
【声明】：本文为药事纵横小编编译，请尊重小编的劳动成果，转载本文务必获得药事纵横许可，否则一律视为恶意侵权。
如果觉得《USP&lt;1220&gt;分析方法的生命周期译文》对你有帮助，请点赞、收藏，并留下你的观点哦！
