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【转载】ICH Q8(CH&EN) 4  

2012-11-27 16:08:56|  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) 4》
2.3 Manufacturing Process Development制造工艺开发
The selection, the control, and any improvement of the manufacturing process described in 3.2.P.3.3 (i.e., intended for commercial production batches) should be explained. It is important to consider the critical formulation attributes, together with the available manufacturing process options, in order to address the selection of the manufacturing process and confirm the appropriateness of the components. Appropriateness of the equipment used for the intended products should be discussed. Process development studies should provide the basis for process improvement, process validation, continuous process verification* (where applicable), and any process control requirements. Where appropriate, such studies should address microbiological as well as physical and chemical attributes. The knowledge gained from process development studies can be used, as appropriate, to justify the drug product specification (3.2.P.5.6). 关于 3.2.P.3.3 中所述的生产工艺(拟用于市售生产批次),应解释其选择、控制和优化。对关键的配方属性及可获得的生产工艺选项(如:干式制粒法VS 湿式制粒法,终端灭菌VS 无菌工艺)进行考虑是很重要的,这样可以说明生产工艺的选择并确认各组分(例如辅料)的合适性。应讨论用于产品生产的设备的合适性。工艺研究开发要为工艺优化,工艺验证和工艺控制要求提供基础。在合适的情况下,这些研究需要说明微生物学,物理和化学属性。工艺开发研究中所获得的知识,可被适当地用于制剂质量标准的合理性说明(3.2.P.5.6)。
The manufacturing process development programme or process improvement programme should identify any critical process parameters that should be monitored or controlled (e.g., granulation end point) to ensure that the product is of the desired quality.   应当要对工艺能在不同的工艺条件下,在不同的生产规模下,或使用不同的设备这些情况下,能可靠地生产出有指定质量的产品的能力进行评估。生产工艺开发程序应确认需要进行监测和控制的以确保产品有理想质量的那些关键工艺参数。
For those products intended to be sterile an appropriate method of sterilization for the drug product and primary packaging material should be chosen and the choice justified.对于无菌制剂,应当要选择合适的灭菌方法和初级包装材料,并论证说明选择的理由。
Significant differences between the manufacturing processes used to produce batches for pivotal clinical trials (safety, efficacy, bioavailability, bioequivalence) or primary stability studies and the process described in 3.2.P.3.3 should be discussed. The discussion should summarise the influence of the differences on the performance, manufacturability and quality of the product. The information should be presented in a way that facilitates comparison of the processes and the corresponding batch analyses information (3.2.P.5.4). The information should include, for example, (1) the identity (e.g., batch number) and use of the batches produced (e.g., bioequivalence study batch number), (2) the manufacturing site, (3) the batch size, and (4) any significant equipment differences (e.g., different design, operating principle, size). 生产临床安全性和有效性、生物利用度、生物等效性、或初始稳定性实验批次的生产工艺与第3.2.P.3.3 章中所述生产工艺之间有明显差异的话,应对其进行讨论。该讨论应简述这些差异对产品的性能和工艺性能的影响。资料的编排方式应当要便于比较工艺和其相对应的批分析信息(3.2.P.5.4)。这些信息应当包括,比如说,(1)标识(如批号)和使用指定设备生产出来的批次的使用(如生物等效性研究的批号),(2)生产地点,(3)批量和(4)明显的设备差异(如不同的设计,不同的操作原理和不同的尺寸)。
In order to provide flexibility for future process improvement, when describing the development of the manufacturing process, it is useful to describe measurement systems that allow monitoring of critical attributes or process end-points. Collection of process monitoring data during the development of the manufacturing process can provide useful information to enhance process understanding. The process control strategies that provide process adjustment capabilities to ensure control of all critical attributes should be described.  为了给将来的工艺优化提供灵活性,在叙述生产工艺的开发时,对用于关键属性或工艺终点监控的测量系统进行叙述是有用的。收集生产工艺开发过程中的工艺监控资料可以提供有用的资料以增强对工艺的理解。应叙述能提供工艺控制能力以确保了所有关键属性控制的工艺控制。这些为风险控制策略提供了方法。
An assessment of the ability of the process to reliably produce a product of the intended quality (e.g., the performance of the manufacturing process under different operating conditions, at different scales, or with different equipment) can be provided. An understanding of process robustness* can be useful in risk assessment and risk reduction (see ICH Q9 Quality Risk Management glossary for definition) and to support future manufacturing and process improvement, especially in conjunction with the use of risk management tools (see ICH Q9 Quality Risk Management). 工艺耐用性的评估是有助于风险评估和风险降低的,能支持将来的生产和工艺优化,特别是结构化的风险管理工具的联合使用。
2.4 Container Closure System容器系统
The choice and rationale for selection of the container closure system for the commercial product (described in 3.2.P.7) should be discussed. Consideration should be given to the intended use of the drug product and the suitability of the container closure system for storage and transportation (shipping), including the storage and shipping container for bulk drug product, where appropriate. 应对市售产品的包装系统(3.2.P.7)的选择及选择理由进行讨论。应考虑制剂的用途和包装系统的储存及运输适宜性,包括大包装制剂的储存和运输包装。
The choice of materials for primary packaging should be justified. The discussion should describe studies performed to demonstrate the integrity of the container and closure. A possible interaction between product and container or label should be considered. 内包材的选择应恰当。对内包材的讨论应叙述为了论证包装系统的完整性而开展的研究。应考虑产品和包装或标签之间可能存在的相互作用。
The choice of primary packaging materials should consider, e.g., choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching), and safety of materials of construction. Justification for secondary packaging materials should be included, when relevant. 内包装材料的选择应考虑,比如,材质的选择,防潮和避光,材质和剂型的兼容性(包括包装的吸附和浸析),材质的安全性。
If a dosing device is used (e.g., dropper pipette, pen injection device, dry powder inhaler), it is important to demonstrate that a reproducible and accurate dose of the product is delivered under testing conditions which, as far as possible, simulate the use of the product. 如果使用了定量装置(如滴管、笔式注射器、干粉吸入器),论证产品在测试条件下(尽可能地模拟产品使用时的条件)能重复得到准确的剂量非常重要。
2.5 Microbiological Attributes微生物属性
Where appropriate, the microbiological attributes of the drug product should be discussed in this section (3.2.P.2.5). The discussion should include, for example: 在适当的情况下,本章节(3.2.P.2.5)还应论述制剂产品的微生物属性。该讨论应包括如:
? The rationale for performing or not performing microbial limits testing for non sterile drug products (e.g., Decision Tree #8 in ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances and ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products); 是否对非无菌制剂进行微生物限度检测的理由(如,ICH Q6A 质量标准:新原料药和新制剂可接受标准和检测程序:化学原料药,和ICH Q6B 质量标准:生物技术/生物药品的检测程序和可接受标准的决策树#8);
? The selection and effectiveness of preservative systems in products containing antimicrobial preservative or the antimicrobial effectiveness of products that are inherently antimicrobial; 产品中防腐系统的选择和效果,包括抗菌防腐剂或本身就有抗菌作用的产品的抗菌效果;
? For sterile products, the integrity of the container closure system as it relates to preventing microbial contamination. 无菌产品包装系统的完整性,因其关系到能否防止微生物污染。
Although chemical testing for preservative content is the attribute normally included in the drug product specification, antimicrobial preservative effectiveness should be demonstrated during development. The lowest specified concentration of antimicrobial preservative should be demonstrated to be effective in controlling micro-organisms by using an antimicrobial preservative effectiveness test. The concentration used should be justified in terms of efficacy and safety, such that the minimum concentration of preservative that gives the required level of efficacy throughout the intended shelf life of the product is used. Where relevant, microbial challenge testing under testing conditions that, as far as possible, simulate patient use should be performed during development and documented in this section. 尽管通常制剂的质量标准中会有防腐剂含量的化学检测,但在开发中还是应该要对抗菌防腐剂的效果进行论述。需通过抗菌防腐剂效果实验论述抗菌防腐剂在所规定的最低浓度下能有效地控制微生物。使用的浓度应根据效果和安全进行判断,以采用可以保证指定的保存期限内均维持有效防腐水平的最低浓度。相应地,开发过程中应进行检测条件下的微生物挑战性试验(尽可能模拟病人使用情况)并写入本部分的文件。
2.6 Compatibility兼容性
The compatibility of the drug product with reconstitution diluents (e.g., precipitation, stability) should be addressed to provide appropriate and supportive information for the labelling. This information should cover the recommended in-use shelf life, at the recommended storage temperature and at the likely extremes of concentration. Similarly, admixture or dilution of products prior to administration (e.g., product added to large volume infusion containers) might need to be addressed. 应说明制剂与稀释剂或定量装置之间的兼容性(如:原料药在溶液中沉淀,注射装置的吸附性,稳定性等),以便在标签上提供适当的支持性信息。这些信息需包含整个建议的保质期,所建议的储存温度,可能的极限浓度。如果标签上建议在使用之前对固体剂型进行稀释或混合(如,饮用药物),则需要对适当的兼容性实验进行叙述。
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