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【转载】ICH Q8 (CH&EN)3  

2012-11-27 16:06:41|  分类: 生物医药产业 |  标签: |举报 |字号 订阅

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本文转载自Julia《ICH Q8 (CH&EN)3》

2.1 Components of the Drug Product制剂产品的组分
      2.1.1 Drug Substance活性成分


      The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g., solid state properties), should be identified and discussed.  Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability. These properties could be inter-related and might need to be considered in combination.  应当要对原料药的能对制剂的性质及其生产能力产生影响的,或是已被专门设计在原料药方面的(如:晶体工程学)物化性质和生物学特性进行说明和讨论。可能需要检查的物化属性和生物特性有:溶解性、水分、粒径、晶体特性、生物活性、和渗透性等。这些性质可能相互之间是有联系的,因此可能需要综合起来考虑。有些性质会随着时间而改变的,或是和供应商相关。


    To evaluate the potential effect of drug substance physicochemical properties on the performance of the drug product, studies on drug product might be warranted. For example, the ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances describes some of the circumstances in which drug product studies are recommended (e.g., Decision Tree #3 and #4 (Part 2)). This approach applies equally for the ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The knowledge gained from the studies investigating the potential effect of drug substance properties on drug product performance can be used, as appropriate, to justify elements of the drug substance specification (3.2.S.4.5). 为了评估原料药的物理化学性质对制剂产品性能的潜在影响,应当要提供制剂的研究资料。比如说,ICH Q6A 质量标准:新化学原料药及新制剂的检验方法及合格标准中建议的一些情况下需要进行制剂研究(如决策树#3 和#4(第2 部分))。对原料药性质可能会对制剂性能产生的影响进行研究所获得的知识,如果合适,可被用于论证原料药的质量标准建立的原因(3.2.S.4.5)。


    The compatibility of the drug substance with excipients listed in 3.2.P.1 should be evaluated. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated. 需讨论原料药与第 3.2.P.1 章中所列辅料的兼容性。对于含有多个原料药的制剂,还应讨论各原料药间的兼容性。


    2.1.2 Excipients辅料
The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient. This should include all substances used in the manufacture of the drug product, whether they appear in the finished product or not (e.g., processing aids). Compatibility of excipients with other excipients, where relevant (for example, combination of preservatives in a dual preservative system), should be established. The ability of excipients (e.g., antioxidants, penetration enhancers, disintegrants, release controlling agents) to provide their intended functionality, and to perform throughout the intended drug product shelf life, should also be demonstrated. The information on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the excipient, and to support the justification of the drug product specification (3.2.P.5.6). 可以影响制剂产品的性能(例如,稳定性和生物利用度)或是制剂产品的工艺性的辅料选择,辅料的浓度和特性必须按各自的功效逐一讨论。在相关的情况下(比如双防腐剂系统中的防腐剂),还需确定各赋形剂间的兼容性。还应阐述各种辅料(如防氧化剂、穿透增强剂、分解质、释放控制剂)在整个制剂保质期内实现其预期作用的能力。可适当应用辅料性能方面的资料来论证辅料选择及其质量特性的合理性,以支持制剂质量标准的合理性说明(3.2.P.5.6)。
    Information to support the safety of excipients, when appropriate, should be cross-referenced (3.2.P.4.6).适当时,还应交叉引用相关资料以支持辅料的安全性论证(3.2.P.4.6)。


2.2 Drug Product制剂
2.2.1 Formulation Development处方开发

    A summary should be provided describing the development of the formulation, including identification of those attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration. Information from formal experimental designs can be useful in identifying critical or interacting variables that might be important to ensure the quality of the drug product. 应综述配方的开发过程,包括那些对制剂产品质量很重要的属性,并考虑拟定用途和给药途径。
    The summary should highlight the evolution of the formulation design from initial concept up to the final design. This summary should also take into consideration the choice of drug product components (e.g., the properties of the drug substance, excipients, container closure system, any relevant dosing device), the manufacturing process, and, if appropriate, knowledge gained from the development of similar drug product(s). 该综述应着重说明配方设计从最初概念到最终设计的发展过程。该综述还应当要考虑各制剂组分的选择(如:原料药,赋形剂,包装系统和相关剂型装置),生产工艺和类似制剂产品开发过程中所获得的经验(如果合适的话)。
    Any excipient ranges included in the batch formula (3.2.P.3.2) should be justified in this section of the application; this justification can often be based on the experience gained during development or manufacture.  正式的实验设计所获得的资料可用于确定关键的或有相互作用的变量,这些变量对于确保制剂产品的质量可能是重要的。在申请文件的此章节中应对批配方(3.2.P.3.2)中的辅料范围进行合理性说明。通常,该合理性说明会建立在配方和生产工艺的开发所获得的经验这个基础上。


    A summary of formulations used in clinical safety and efficacy and in any relevant bioavailability or bioequivalence studies should be provided. Any changes between the proposed commercial formulation and those formulations used in pivotal clinical batches and primary stability batches should be clearly described and the rationale for the changes provided. 应综述在临床安全性和有效性,生物利用度研究或生物等效性研究中所用到的所有配方。对于拟定的市售配方和临床研究与稳定性实验所用批次的配方间的变更都应当进行明确地说明,并提供这些变更的合理性说明。


    Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) that links clinical formulations to the proposed commercial formulation described in 3.2.P.1 should be summarized and a cross-reference to the studies (with study numbers) should be provided. Where attempts have been made to establish an in vitro/in vivo correlation, the results of those studies, and a cross-reference to the studies (with study numbers), should be provided in this section. A successful correlation can assist in the selection of appropriate dissolution acceptance criteria, and can potentially reduce the need for further bioequivalence studies following changes to the product or its manufacturing process. 应综述和市售配方(如3.2.P.1 中所描述)相关联的对比性体外研究(如:溶出度)或对比性体内研究(如:生物等效性)所获得的信息,并参引这些研究(研究序号)。如果已试图确立体外实验和体内实验之间的相关性,则在此章节中应提供这些研究的结果并参引这些研究(研究序号)。成功的相关性有助于合适的溶出度可接受标准的选择,并可能减少在产品和生产工艺出现变更的情况下,进一步进行生物等效性研究的需要。


    Any special design features of the drug product (e.g., tablet score line, overfill, anti-counterfeiting measure as it affects the drug product) should be identified and a rationale provided for their use. 需应标明制剂的所有设计特性(如:药片标记线、过度充填、反伪造措施),并提供使用他们的理由。应提供这些特性的适宜性的支持信息。


2.2.2 Overages超量
In general, use of an overage of a drug substance to compensate for degradation during manufacture or a product’s shelf life, or to extend shelf life, is discouraged. 总体来说,不鼓励加入过量原料药以补偿生产过程或产品存贮期中原料药的降解,或用以延长保存期。
Any overages in the manufacture of the drug product, whether they appear in the final formulated product or not, should be justified considering the safety and efficacy of the product. Information should be provided on the 1) amount of overage, 2) reason for the overage (e.g., to compensate for expected and documented manufacturing losses), and 3) justification for the amount of overage. The overage should be included in the amount of drug substance listed in the batch formula (3.2.P.3.2).对于制剂生产过程中出现的过量现象,无论其是否是出现在最终制剂中,都应当要从产品的安全性和有效性方面对其进行合理性说明。应提供如下信息:1)过量的量;2)过量的原因(如,补偿生产过程中出现的损失);3)超出量的合理性说明。在典型批配方(3.2.P.3.2)所列的原料药量中应包括超出量。


2.2.3 Physicochemical and Biological Properties物化和生化性质
The physicochemical and biological properties relevant to the safety, performance or manufacturability of the drug product should be identified and discussed. This includes the physiological implications of drug substance and formulation attributes. Studies could include, for example, the development of a test for respirable fraction of an inhaled product. Similarly, information supporting the selection of dissolution vs. disintegration testing, or other means to assure drug release, and the development and suitability of the chosen test, could be provided in this section. See also ICH Q6A Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances; Decision Tree #4 (Part 3) and Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The discussion should cross-reference any relevant stability data in 3.2.P.8.3. 应确定和制剂产品的性能或工艺性能相关的物理化学特性和生物学特性,并对它们进行讨论。可以包括如下配方属性:pH 值、摩尔渗透压浓度、离子浓度、亲油性、溶出度、再分散作用、重构、粒径分布、颗粒形状、聚集作用、多晶形、流变性质、乳剂的颗粒尺寸、生物活性/功效、和/或免疫活性。配方属性的生理性质如pH 值也应当要说明。需参引3.2.P.8.3 中的相关稳定性资料。在申请文件中的此章节(3.2.P.2.2.3)中,应综述为了研究物理化学特性和生物学性质对制剂的潜在影响及制剂可接受限度的合适性开展的开发研究。这些研究包括:比如,溶出度实验或释放度实验的开发,吸入制剂的可吸入组分的实验开发。应说明原料药的生理适应性和配方属性。比如说可以包括研究是否需要在制剂质量标准中加入多晶型的合格标准所获得的信息。类似的,关于溶出度VS 崩解实验或其他确保制剂释放的方法的选择,以支持配方和生产工艺的耐用性的信息也可以包括在该章节。也可参见ICH Q6A 质量标准:新原料药和新制剂的测试方法和认可标准:化学物质。决策树#4(Part 3)和决策树#7(Part 1)。

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