来源:http://zhuyujiao1972.blog.163.com/blog/static/98694727201512535424837/
FDA & EMA
10 December 2014
EMA/59240/2014
Questions and answers on level of detail in the regulatory submissions
法规申报文件详细程度问答
What types of risk assessments (RAs) can be included in a regulatory submission?
哪些风险评估（RA）类型可以包括在法规申报文件中？
It is up to the applicant to determine what RAs are included in the submission. This information can be useful to aid the assessor/reviewer for determining how the applicant selected the specific formulation, manufacturing process and controls. For example, the Agencies have seen risk assessments related to selection of formulation variables, delineation of impact of various process parameters and selection of in-process controls.
应由申报者来决定在申报文件中包括哪些风险评估。这些信息可能有助于评审员确认申报者是如何来选择特定的配方、生产工艺和控制。例如，药监局看到了与配方变量选择相关的风险评估，不同工艺参数影响和中控选择的描述。
What level of detail should be considered for an RA related to process design in a regulatory submission?
在法规申报文件中工艺设计相关的风险评估要考虑到何种详细程度？
The level of detail should be commensurate with the significance of the outcome of the RA to the commercial manufacturing process and to the control strategy. For example, a risk assessment pertaining to identification of critical process parameters in a process or to the establishment of a design space for an important unit operation would normally be considered of high significance. The information that should be provided in such cases could include:
详细程度应与商业生产工艺和控制策略RA结果的重要性相等同。例如，一个用于识别工艺中关键工艺参数，或建立一个重要操作单元的设计空间的风险评估一般会被认为是很重要的。这种情况下所提供内容可包括以下：
? A statement of which RA tool was used; or if a novel RA tool was used, a definition of the RA tool along with sample output from the tool.
? 一份使用了哪些风险评估工具的声明，或如果使用了一个新的RA工具，该RA工具与工具中输出样品的定义
? A comprehensive qualitative or quantitative summary of the outcome of the RA (e.g. RPN (Risk Priority Number), threshold value for RPN (and an explanation for why such a threshold was chosen) and final list of all RPNs) supporting and explaining the applicant’s rationale for the selection of variables/parameters that warranted further study and those which were not further studied. Information on the way in which risk assessment activities were used to determine which process parameters and quality attributes are to be considered critical or non-critical.
? RA结果的定性或定量综述（例如，RPN（风险优先号）、RPN阈值（和一个为什么选择该阈值的解释）和所有RPN的最终清单），用于支持和解释申报者选择一些变更/参数来保证进一步研究，以及不再进行研究的合理性。使用风险评估活动来决定哪些工艺参数和质量属性被认为是关键的或非关键的信息。
Both agencies acknowledge that regulators should take the following into consideration when requesting additional details regarding an RA in a submission: complexity of the dosage form, the commonality of the risks identified relative to products of the same type (i.e., available prior knowledge), and the amount of commercial scale manufacturing data available at the time of submission (i.e., state of knowledge).
FDA和EMA都知道法规人员在要求一份申报资料中关于RA的更多详细内容时应考虑以下内容：剂型的复杂性、相对于同类药品所识别的风险的普通程度（即，之前的知识），以及在提交申报时可能获得的商业规模生产数据的多少（即，知识状态）。
What level of detail should be considered for an RA related to product design in a regulatory submission?
法规申报中产品设计相关的RA要考虑的内容详细程度应如何？
The level of detail should be commensurate with the level of risk presented by the formulation and dosage form, as it is intended to be used by the patient. The information provided can include how the risk assessment approach was used to optimize and select the formulation, and/or to rank or prioritize formulation variables (e.g., raw material attributes) based on their potential effects on finished product Critical Quality Attributes (CQA). The factors considered can also include how the drug product could be unintentionally or intentionally misused. For example, a risk assessment pertaining to a solid modified release oral formulation for an opioid would normally include an analysis of the potential for dose dumping. The factors discussed can also include considerations such as physical and chemical stability over shelf life.
详细程度应与处方和剂型，以及患者使用的用途所代表的风险程度相称。所提交的资料可以包括这些风险评估方法如何用于优化和选择处方，和/或根据其对制剂的关键质量属性（CQA）的潜在影响来排列或优先排序处方变量（例如，原料属性）。考虑的因素还可以包括药品可能被如何有意无意地误天。例如，类鸦片的固体改释口服剂型的风险评估一般包括一份超剂量使用可能性的分析。讨论的因素还可以包括对整个货架期的物理和化学稳定性的考虑。
What level of detail should be considered for design of experiments (DOEs) in a regulatory submission?
法规申报文件中实验设计（DOE）要考虑详细到何种程度？
The level of detail should be commensurate with the significance of the outcome of the DOE to the selection of the product design, commercial manufacturing process and control strategy. For example, a DOE to define operating ranges for an important unit operation would normally be considered of high significance. The information to be provided in such cases could include:
详细程度应与产品设计、商业生产工艺和控制策略选择DOE的结果的重要性相等同。例如，用于界定一个重要操作单元的操作范围的DOE一般会被认为是较为重要的。这种情况下，可以包括以下内容：
? Type of experimental design and parameter ranges studied. Justification for choice of design could be useful, in particular if the design is not fully balanced.
? 实施设计类型和所研究的参数范围。
? Tables summarizing inputs and outputs, including batch size.
? 投料量和收量总结表，包括批量
? Summary of parameters that were kept constant during the DOE.
? 实验设计中保持不变的参数总结
? Delineation of factors as scale dependent or independent, with justification (for example experimental results, scientific rationale, prior knowledge).
? 因素划分为相互依赖的和独立的，包括论证（例如，实验结果、科学理论、之前的知识）
? Description of main effects and interactions on response variables, including statistical significance of parameters (p-value).
? 主要影响和相互反应响应变量描述，包括参数的统计学显著性（p值）
? Discussion of regression model validation parameters (e.g. table of coefficients, output from ANOVA regression analysis, residual plots, goodness of fit (R2), goodness of prediction, table of predicted response values with confidence intervals), if applicable.
? 适用时，回归模式验证参数（例如，因子表、ANOVA回归分析结果、残差图、拟合性（R2）、预测符合性、预测返回值与置信区间表格）的讨论
What level of detail should be considered for justifying and describing a design space in a regulatory submission?
在法规申报资料中设计空间的论证和描述应考虑详细到何种程度？
The level of detail in the information used to support the proposed design space should be commensurate with both the significance of the design space (i.e. role of the design space in the overall control strategy) and its extent. (The extent refers to the degree of additional operational flexibility provided by the design space as compared to fixed set points and normal operating ranges). Other factors can include the ability of the control strategy to detect failures and the degree of commercial scale experience in multiple regions of the design space.
用于支持所提议的设计空间的资料的详细程度应与设计空间（即，设计空间在总体控制策略中的作用）的重要性和其程度相当。（程度指与固定的设定点和常规操作范围相比，设计空间所允许的额外操作灵活性的程度）其它因素可以包括控制策略能发现失败的能力，以及设计空间多区域商业规模试验的程度。
Additionally, both agencies are of the opinion that there are circumstances where a mathematical regression model representing the design space need not be submitted. This is generally the case if the design space is presented as a linear combination of material inputs and process parameters. In situations where a design space presentation includes a surface (e.g. as represented by quadratic terms), the regression model representing the surface should be provided.
另外，FDA和EMA均认为，不提交代表设计空间的数学回归模式是有条件的。如果设计空间是原料投料和工艺参数的线性组合，则不需要提交。如果设计空间表达包括了一个平面（例如，二次项表达），则应提交代表平面的回归模型。
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