ICHM7step4基因毒性杂质评估和控制中英(7)

根据TTC制订的可接受摄入量要用单独应用于各个杂质。如果有两个2类或3类杂质，则限度是针对单个杂质的。如果原料药质量标准中有3个或更多3类或3类杂质，临床研发和已上市药品中的总诱变性杂质应根据表3所列进行限制。

For combination products each active ingredient should be regulated separately. 对于复方药品，每个活性成分要分别规定。

Table 3: Acceptable Total Daily Intakes for Multiple Impurities Duration treatment Total intake (μg/day) 表 3: 多个杂质的可接受日总摄入量 治疗期 日总摄入量 (μg/天) Only specified Class 2 and 3 impurities on the drug substance specification are included in the calculation of the total limit. However, impurities with compound-specific or class-related acceptable intake limits (Class 1) should not be included in the total limits of Class 2 and Class 3 impurities. Also, degradation products which form in the drug product would be controlled individually and a total limit would not be applied. 在原料药质量标准中，只有列出的2类和3类杂质才会被包括在总限度计算中，而特定化合物或按可接受摄入限度分类（第1类）的杂质不应计入第2类和第3类杂质总限度。还有，原料药中形成的降解产物要单独控制，不能计入总限度。 7.5 Exceptions and Flexibility in Approaches 方法特例和灵活性

31

of ≤1month >1-12months >1-10years >10 years to lifetime Daily 120 60 30 5 ≤1月 120 >1-12月 60 >1-10年 30 >10 年到终生 5 ? Higher acceptable intakes may be justified when human exposure to the impurity will be much greater from other sources e.g., food, or endogenous metabolism (e.g., formaldehyde).

如果人们暴露于其它杂质其它来源，如，食品或内源性代谢物（例如甲醛） 的可能性非常大，则可以考虑判定较高的可接受摄入量。

? Case-by-case exceptions to the use of the appropriate acceptable intake can be justified in cases of severe disease, reduced life expectancy, late onset but chronic disease, or with limited therapeutic alternatives.

使用适当的可接受摄入量可以用于以下各案例外情况：病情严重、降低生命期望、发病迟但长期疾病，或其它治疗方法有限的情况。

? Compounds from some structural classes of mutagens can display extremely high carcinogenic potency (cohort of concern), i.e., aflatoxin-like-, N-nitroso-, and alkyl-azoxy structures. If these compounds are found as impurities in pharmaceuticals, acceptable intakes for these high-potency carcinogens would likely be significantly lower than the acceptable intakes defined in this guideline. Although the principles of this guideline can be used, a case-by-case approach using e.g., carcinogenicity data from closely related structures, if available, should usually be developed to justify acceptable intakes for pharmaceutical development and marketed products.

有些诱变结构类别的化合物可能会显示出非常高的诱变性（关注的队列），例如，黄曲霉毒素类、N-亚硝基化合物、以及烷基-氧化偶氮结构。如果在药物的杂质中存在杂质是这样的化合物，则这些高效价诱变物的可接受摄入量很可能要显著低于本指南中定义的可接受摄入量。尽管如果，也还是能使用本指南的原则，一般要研究一种针对各案采用，例如，已有的近似的相关结构的基因致癌数据，的方法来判定药品研发和上市药品中的可接受摄入量。 The above risk approaches described in Section 7 are applicable to all routes of administration and no corrections to acceptable intakes are generally warranted. Exceptions to consider may include situations where data justify route-specific concerns that should be evaluated case-by-case. These approaches are also applicable

32

to all patient populations based upon the conservative nature of the risk approaches being applied.

在第7部分中所描述的上述风险方法可以应用于所有摄入途径，不需要修正可接受摄入量。对例外情况的考虑可能包括需要各案评价的特定摄入途径数据判定。由于所采用的风险方法是较为保守的，因此这些方法也适用于所有患者人群， 8. CONTROL 控制

A control strategy is a planned set of controls, derived from current product and process understanding that assures process performance and product quality (ICH Q10, Ref. 8). A control strategy can include, but is not limited to, the following: 控制策略是指从现行产品和工艺知识中获得的，保证工艺性能和产品质量的一套有计划的控制方法。一个控制策略可以包括，但不限于以下：

— Controls on material attributes (including raw materials, starting

materials, intermediates, reagents, solvents, primary packaging materials); — 物料特性控制（包括原料、起始物料、中间体、试剂、溶剂、内包材） — Facility and equipment operating conditions; — 设施和设备操作条件

— Controls implicit in the design of the manufacturing process; — 生产工艺设计中的控制内涵

— In-process controls (including in-process tests and process

parameters);

— 中控（包括中控检测和工艺参数）

— Controls on drug substance and drug product (e.g., release

testing).

— 原料药和制剂控制（例如，放行检测）

33

When an impurity has been characterized as Classes 1, 2, or 3 in Table 1, it is important to develop a control strategy that assures that the level of this impurity in the drug substance and drug product is below the acceptable limit. A thorough knowledge of the chemistry associated with the drug substance manufacturing process, and of the drug product manufacturing process, along with an understanding of the overall stability of the drug substance and drug product is fundamental to developing the appropriate controls. Developing a strategy to control mutagenic impurities in the drug product is consistent with risk management processes identified in ICH Q9 (Ref. 9). A control strategy that is based on product and process understanding and utilisation of risk management principles will lead to a combination of process design and control and appropriate analytical testing, which can also provide an opportunity to shift controls upstream and minimize the need for end-product testing.

如果一个杂质已根据表1进行了定性分类为1、2或3类，则研究一种控制策略来保证该杂质在原料药和制剂中存在的水平低于可接受限度是很重要的。在建立适当的控制策略时，对原料工生产工艺的化学方面的深入理解、对制剂生产工艺的了解、对原料药和制剂全面稳定性的了解是很必要的。建立一种策略来控制原料药中的诱变性杂质是与ICH Q9（参考文献9）中定义的风险管理过程相一致的。控制策略应该是根据对产品和工艺的理解，利用风险管理原则进行综合的工艺设计和控制，以及适当的分析检测。这也能提供一个机会来转移对上游进行控制，并将最终产品检测的必要性降至最小。

8.1 Control of Process Related Impurities 工艺相关杂质的控制

There are 4 potential approaches to development of a control strategy for drug substance:

有4种方法可供选择用作原料药控制策略： Option 1 第1种方法

Include a test for the impurity in the drug substance specification with an acceptance criterion at or below the acceptable limit using an appropriate analytical procedure.

34

在原料药质量标准中加入杂质检测并制订质量标准，标准不高于采用适当的分析方法时的可接受限度。

For an Option 1 control approach, it is possible to apply periodic verification testing per ICH Q6A (Ref. 10). Periodic verification testing is justified when it can be shown that levels of the mutagenic impurity in the drug substance are less than 30% of the acceptable limit for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the drug substance specification is recommended. See Section 8.3 for additional considerations.

根据ICH Q6A（参考文献 10），方法1控制方式可以适用定期检测。如果原料药中的诱变性杂质在至少6个连续的中试批次或3个连续的生产批次中，测得结果均低于可接受限度的30%，则可以论述进行定期检测。如果不满足该条件，则建议对原料药进行常规检测。参见8.3中更多考虑因素。 Option 2 第2种方法

Include a test for the impurity in the specification for a raw material, starting material or intermediate, or as an in-process control, with an acceptance criterion at or below the acceptable limit using an appropriate analytical procedure. 在原料、起始物料或中间体的质量标准中包括对杂质的检测，或作为中控检测，同时制订可接受标准，或采用适当的分析方法，将杂质控制在可接受限度以下。 Option 3 第3种方法

Include a test for the impurity in the specification for a raw material, starting material or intermediate, or as an in-process control, with an acceptance criterion above the acceptable limit of the impurity in the drug substance, using an appropriate analytical procedure coupled with demonstrated understanding of fate and purge and associated process controls that assure the level in the drug substance is below the acceptable limit without the need for any additional testing later in the process.

35

百度搜索“77cn”或“免费范文网”即可找到本站免费阅读全部范文。收藏本站方便下次阅读，免费范文网，提供经典小说综合文库ICHM7step4基因毒性杂质评估和控制中英(7)在线全文阅读。