PDA TR60 风险评估和参数关键性设定

Risk Assessment and Parameter Criticality Designation

风险评估和参数关键性设定

Risk assessment plays an important role in the development of a commercial control strategy. Risk assessments are performed by interdisciplinary teams at several points during stage 1 of the lifecycle, and serve a number of purposes. (See Section 6.1 – Application of Risk Management) Risk assessment tools

provide a structured means for documenting data and rationale associated with the risk assessment outcome, and becomes part of the documented process development history.

风险评估在商业化控制策略开发中具有重要作用。风险评估是在生命周期第一阶段的几个点上由跨学科团队实施的，分属于不同目标。（见第6.1节风险管理的应用）风险评估工具提供了一个结构化的方式来记录与风险评估的结果相关的数据和理由，并成为工艺开发历史记录的一部分。

As shown in Figure 3.0-1, the initial identification of critical quality attributes is followed by a quality risk assessment in stage 1. The initial quality risk assessment is a cause and effect type of analysis to identify process input parameters where variability is likely to have the greatest impact to product quality or process performance. This assessment is based primarily on prior knowledge or early development work, and the outcome of this assessment provides the foundation for process characterization studies that follow.

如图3.0-1所示，在第一阶段通过质量风险评估初步识别关键质量属性。初始质量风险评估是识别对产品质量或工艺性能影响最大的工艺输入参数变量的原因和影响分类。这个评估主要是基于已有知识或早期开发工作，评估结果为下述工艺性能研究提供基础。

Understanding the impact of process parameter variability and applying the appropriate controls is a fundamental element in development of the commercial control strategy. ICH Q8 (R2) defines a Critical Process Parameter (CPP) as, “one with variability that has an impact on a CQA, and therefore, should be monitored or controlled to ensure that the process produces the desired quality (3).

了解工艺参数变化的影响和应用适当的控制是商业化控制策略开发的基本要素。ICH Q8 (R2)定义关键工艺参数（CPP）为：“对CQA有影响的可变参数，因此，应该被监测或控制以保证该工艺产生预期的质量”（3）。

Process parameters may be further categorized based on impact to the process. In certain circumstances, process performance is controlled and monitored as an additional means of ensuring a consistent state of

control. Process parameters that have been shown experimentally to impact process performance may be classified as key process parameters (KPP). KPPs may impact process performance attributes (such antibody titer in cell culture processes or yield in downstream purification), but do not impact critical product quality attributes (15). In some processes, identifying and appropriately controlling KPPs is useful since process performance measures may be an important means of demonstrating intra-batch consistency.

根据对工艺的影响，工艺参数可以被进一步分类。在某些情况下，工艺性能的控制和监控是作为一个额外的控制手段，确保控制状态的协调一致。试验显示对工艺性能有影响的工艺参数可以分类为重要工艺参数（KPP）。KPPs可以影响工艺性能属性（如在细胞培养过程中的抗体滴度或下游纯化产量），但不影响产品关键质量属性（15）。在有些工艺中，KPPs的识别和适当控制是有用的，因为工艺性能评估可能是批内一致性证明的一个重要手段。

Beyond the generally recognized definition of a critical process parameter from of ICH Q8 (R2),however, process parameter designations are not standardized and approaches may vary. For this reason, definitions for parameter designations must be clearly documented and understood within the organization. Definitions should remain consistent throughout the process validation lifecycle.

然而，除了普遍认可的定义ICH Q8（R2）的关键工艺参数，工艺参数命名会不规范、方法可能会有所不同。出于这个原因，在组织内参数命名的定义必须清楚地记录并理解。在整个工艺验证生命周期中参数命名的定义应保持一致。

Figure 3.6-1 provides an example of a decision tree developed to guide the assignment of parameter designations in conjunction with the quality risk assessments. The decision tree facilitates categorization of process parameters as critical, key, or non-key (see definitions). Decision making tools can facilitate common understanding among participants, and have the advantage increases consistency in the decision making process as well as consistent documentation of rationales as part of the risk assessment process.

图3.6-1提供了一个决策树示例，以指导结合质量风险评估进行参数命名。决策树有助于将工艺参数分类为关键、重要或非重要（见定义）。决策制定工具可以帮助参与者形成共识，并有利于提高决策过程的一致性，以及作为风险评估过程部分有理由一致的记录文档。

The decision tree can be used for risk assessments both before and after the supporting data from process characterizations studies are available.

决策树可以用于来源于工艺性能研究的支持数据前后的风险评估。

· Parameter or Attribute: Process variables can be outputs from one unit operation and inputs to another.For a given unit operation, each variable is initially established as a parameter or an attribute on the basis of direct controllability

参数或属性：工艺变量可以是单元操作的输出和对另一单元的输入。对一个指定的单元操作，根据每个变量的直接可控性初步设定为参数或属性。

Yes — Directly controllable process input parameters can theoretically contribute to process variability.

是—直接可控的工艺输入参数理论上有利于工艺变异性。

No — Process outputs that are not directly controllable are attributes that are monitored and may be indicative of process performance or product quality.

否—不能直接控制的工艺输出是被监测的属性，可能表示工艺性能或产品质量。

· Process Parameters: Potential impact to critical quality attributes.

工艺参数：对关键质量属性的潜在影响。

Yes — If impact is suspected, or if data show that variability in a parameter could impact a CQA, the parameter is designated as a CPP. Although a parameter may be initially classified as a CPP, data from robustness studies conducted during process characterization may show that CQAs are not impacted despite exaggerated variations in the parameter. In these cases, the second risk assessment serves to change the assessment to non-CPP.

是—如果怀疑参数的变化对CQA有影响，或如果数据显示可能会有影响，则指定这个参数为关键工艺参数（CPP）。

No — Parameter is a non-CPP and is further evaluated

否—参数为非关键工艺参数并进一步评价。

· Non-CPP: Potential to impact process performance or consistency if run outside of defined range.

非关键工艺参数：如果超定义范围运行，潜在影响工艺性能或稳定性。

Yes — Parameter designated a KPP

是—参数指定为重要工艺参数（KPP）。

No — Parameter has little impact to the process over a wide range. Parameter is designated a non-KPP.

否—在较宽的范围参数对工艺无影响。参数被指定为非重要工艺参数（non-KPP）。

Figure 3.6-1 Decision Tree for Designating Parameter Criticality

关键性命名决策树