ICHM7step4基因毒性杂质评估和控制中英(6)

Compound-specific risk assessments to derive acceptable intakes should be applied instead of the TTC-based acceptable intakes where sufficient carcinogenicity data exist. For a known mutagenic carcinogen, a compound-specific acceptable intake can be calculated based on carcinogenic potency and linear extrapolation as a default approach. Alternatively, other established risk assessment practices such as those used by international regulatory bodies may be applied either to calculate acceptable intakes or to use already existing values published by regulatory authorities (Note 4).

如果具备足够的基因致癌性数据，则应采用对特定化合物进行风险评估的方式计算可接受摄入量，取代根据TTC所计算的可接受摄入量。对于已知具有突变致癌性的化合物，可以根据致癌可能性和线性计算可接受摄入量，这时默认采用线性外推法。对应地，其它已实施的风险评估经验，例如，被国际法规实体采用的经验，也可以用于计算可接受摄入量，或采用已由法规当局公布的值（注4）。

Compound-specific calculations for acceptable intakes can be applied case-by-case for impurities which are chemically similar to a known carcinogen compound class (class-specific acceptable intakes) provided that a rationale for chemical similarity and supporting data can be demonstrated (Note 5).

对特定化合物的可接受摄入量的计算方法可以根据实际情况应用于与已知致癌化合物在化学结构上类别较相似的杂质（按类别制订的可接受摄入量），但前提是必须证明该杂质与已知化合物化学结构相似性的合理性及具备支持性数据。

7.2.2 Mutagenic Impurities with Evidence for a Practical Threshold 有实际阈值证据的诱变性杂质

The existence of mechanisms leading to a dose response that is non-linear or has a practical threshold is increasingly recognized, not only for compounds that interact with non-DNA targets but also for DNA-reactive compounds, whose effects may be modulated by, for example, rapid detoxification before coming into contact with DNA, or by effective repair of induced damage. The regulatory approach to such compounds can be based on the identification of a No-Observed Effect Level (NOEL)

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and use of uncertainty factors (ICH Q3C(R5), Ref. 7) to calculate a Permissible Daily Exposure (PDE) when data are available.

大家现在越来越认识到，有一些机理说明对剂量的反应并非线性或实用阈值，不仅仅是与非DNA靶标产生作用的化合物，也包括与DNA有活性反应的化合物，其影响可能会，例如，在与DNA接触前其毒性即被快速清除，或对产生的损伤进行有效修复。针对该类化合物的合规方法可以是根据对无明显反应水平（NOEL）的鉴别，在可以获得数据的情况下，使用不确定性因子（ICH Q3C（R5）参考文献7）计算允许日暴露量（PDE）。

The acceptable intakes derived from compound-specific risk assessments (Section 7.2) can be adjusted for shorter duration of use in the same proportions as defined in the following sections (Section 7.3.1 and 7.3.2) or should be limited to not more than 0.5%, whichever is lower. For example, if the compound specific acceptable intake is 15 μg/day for lifetime exposure, the less than lifetime limits (Table 2) can be increased to a daily intake of 100 μg (> 1-10 years treatment duration), 200 μg (> 1-12 months) or 1200 μg (< 1 month). However, for a drug with a maximum daily dose of, for instance, 100 mg the acceptable daily intake for the < 1 month duration would be limited to 0.5% (500 μg) rather than 1200 μg.

在短期服用时，特定化合物风险分析所获得的可接受服用量（第7.2部分）可以按以下部分所指定的比例进行调整（第7.3.1和7.3.2部分），或限制不超过0.1%，取低者。例如，如果一个特定化合物的可接受服用量为终生暴露期15μg/天，在短于终生时长暴露时的限度（表2）可以增加至100μg（>1-10年治疗进长），200μg（>1-12月）或1200μg（<1个月）。但是，对于具有最大日服用剂量的药物，例如，100mg，则<1个月时长的可接受日服用剂量应受限于0.1%（500μg），而不是1200μg。

7.3 Acceptable Intakes in Relation to LTL Exposure 与LTL暴露有关的可接受摄入量

Standard risk assessments of known carcinogens assume that cancer risk increases as a function of cumulative dose. Thus, cancer risk of a continuous low dose over a lifetime would be equivalent to the cancer risk associated with an identical cumulative exposure averaged over a shorter duration.

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对已知致癌物的标准风险评估假定癌症风险随着给药量的累积而增加，这样，终生以低剂量持续给药时癌症风险则与在短期内大量给药具有相同的累积暴露平均值。

The TTC-based acceptable intake of 1.5μg/day is considered to be protective for a lifetime of daily exposure. To address LTL exposures to mutagenic impurities in pharmaceuticals, an approach is applied in which the acceptable cumulative lifetime dose (1.5μg/day x 25,550 days = 38.3 mg) is uniformly distributed over the total number of exposure days during LTL exposure. This would allow higher daily intake of mutagenic impurities than would be the case for lifetime exposure and still maintain comparable risk levels for daily and non-daily treatment regimens. Table 2 is derived from the above concepts and illustrates the acceptable intakes for LTL to lifetime exposures for clinical development and marketing. In the case of intermittent dosing, the acceptable daily intake should be based on the total number of dosing days instead of the time interval over which the doses were administered and that number of dosing days should be related to the relevant duration category in Table 2. For example, a drug administered once per week for 2 years (i.e., 104 dosing days) would have an acceptable intake per dose of 20μg.

基于TTC计算的可接受日摄入量1.5μg/天被认为是在终生每日暴露情况下可以受到保护的量。在说明药品中诱变性杂质的LTL暴露量时，所采用的方法是假定可接受的累积终生剂量（1.5μg/天X25,550天=38.3mg）在终生摄入期间是均匀分布在这些天数中的，这样诱变性杂质的日摄入量可以高于平均终生日暴露量，而其风险水平仍与每日或非每日治疗方案相持平。表2是从上述概念得到的数据，其中写出了临床研发阶段和上市阶段终生暴露LTL下可接受摄入量数值。如果给药是间歇性的，则可接受日摄入量应根据给药总天数计算，而不是服用药物的总时间长度计算，给药天数与表2中相关时长分类有关。例如，2年期间每周服用一次的药物（即104个服药天数），其可接受摄入剂量为每剂20μg。 Table 2: Acceptable Intakes for an Individual Impurity Duration treatment Total Daily 120 20 10 of ≤1month >1-12months >1-10years >10 years to lifetime 1.5 28

intake (μg/day) 表2:单个杂质的可接受摄入量 治疗期 日总摄入量 (μg/天) ≤1月 120 >1-12月 20 >1-10年 10 >10 年到终生 1.5 7.3.1 Clinical Development 临床研发 Using this LTL concept, acceptable intakes of mutagenic impurities are recommended for limited treatment periods during clinical development of up to 1 month, 1 to 12 months and more than one year up to completion of Phase 3 clinical trials (Table 2). These adjusted acceptable intake values maintain a 10-6 risk level in early clinical development when benefit has not yet been established and a 10-5risk level for later stages in development (Note 6). 采用LTL概念，诱变性杂质的可接受摄入量在临床研究中的治疗期限最高为1个月、1-12个月及长于1年直到完成3期临床试验（表2）。对可接受摄入值的调节在其受益水平尚未不可知时，保持早期临床风险水平为百万分之一，后期临床为十万分之一。 An alternative approach to the strict use of an adjusted acceptable intake for any mutagenic impurity could be applied for Phase 1 clinical trials for dosing up to 14 days. For this approach, only impurities that are known mutagenic carcinogens (Class 1) and known mutagens of unknown carcinogenic potential (Class 2), as well as impurities in the cohort of concern chemical class, should be controlled (see Section 8) to acceptable limits as described in Section 7. All other impurities would be treated as non-mutagenic impurities. This includes impurities which contain structural alerts (Class 3), which alone would not trigger action for an assessment for this limited Phase 1 duration. 29

所有诱变性杂质经过调整的可接受摄入量严格用法的替代方式可以应用于长达14天的一期临床试验阶段。采用该方法时，只有已知诱变性致癌（1类）杂质和致癌性未知的已知诱变物（2类），以及被列入关注化学类别中的杂质要控制（参见第8部分）在第7部分的可接受限度内。所有其它杂质可以作为非诱变性杂质对待，其中包括含有警示结构（3类）的杂质。仅仅只是含有警示结构不需要在一期临床试验期间进行评估。

7.3.2 Marketed Products 已上市药物

The treatment duration categories with acceptable intakes in Table 2 for marketed products are intended to be applied to anticipated exposure durations for the great majority of patients. The proposed intakes along with various scenarios for applying those intakes are described in Table 4, Note 7. In some cases, a subset of the population of patients may extend treatment beyond the marketed drugs categorical upper limit (e.g., treatment exceeding 10 years for an acceptable intake of 10 μg/day, perhaps receiving 15 years of treatment). This would result in a negligible increase (in the example given, a fractional increase to 1.5/100,000) compared to the overall calculated risk for the majority of patients treated for 10 years. 已上市药品的治疗时长分类与可接受摄入量在表2中列中。它可以用来预计绝大部分患者的暴露时长。所拟的摄入量与使用这些摄入量的不同情景在表4注7中已有说明。在有些情况下，患者中一部分人群可能会延长治疗时长，超出上市药物分类的上限（例如，可接受摄入量为10μg/天的药物治疗超出10年，可能会接受15年治疗）。与按绝大部分患者治疗10年计算出的整体风险相比，延长治疗时长导致的风险增加（如上例，增加比例为1.5/100000）可以忽略。

7.4 Acceptable Intakes for Multiple Mutagenic Impurities 多个诱变性杂质可接受摄入量

The TTC-based acceptable intakes should be applied to each individual impurity. When there are two Class 2 or Class 3 impurities, individual limits apply. When there are three or more Class 2 or Class 3 impurities specified on the drug substance specification, total mutagenic impurities should be limited as described in Table 3 for clinical development and marketed products.

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