关键起始原料需要详细的生产工艺?
应该只需提供合成路线图及各步所用到的试剂、溶剂或催化剂等信息即可。
详见:cuturl('http://www.dxy.cn/bbs/topic/22914378')
In order to assess the presence of all potential impurities, including regioisomeric and stereoisomeric impurities, toxic impurities, residual solvents and residues of catalysts in the starting material, a brief narrative description of the synthesis including an outline leading to the starting material beginning with simpler molecules with all the reagents, solvents, and intermediates specified and the flow chart of the synthesis should be provided. Potential for the presence of adventitious agents, including viral and bacterial agents, residual proteins and TSE agents in the starting material selected should be discussed.
A more detailed description of the synthetic process should be provided for steps leading from the starting material to the final drug substance. The additional details should include quantities of raw materials, description of equipment, reaction conditions, in-process controls, percent yields, etc.
这个是加拿大的要求,FDA或EMA也是这样的要求,可以找到原文。作者: hyuu 时间: 2016-1-9 09:00
是不是你们所决定的“起始物料”不合理?作者: hyuu 时间: 2016-1-9 09:00
Since the manufacture of a starting material may often be purchased or contracted out to a supplier and because GMP applies downstream in the synthesis from this material, the correct designation of starting material is crucial. In the United States, it is usual to discuss the choice of starting materials with FDA during review of the IND (e.g., at an end-of-phase II meeting), and thus suitable commercial arrangements for sourcing the material can be put in place well in advance of the registration filing. This allows the timely manufacture of launch stock of the bulk drug substance.
For registration filings in the European Union, the 2003 Committee for Proprietary Medicinal Products (CPMP) “Guideline on the Chemistry of New Active Substances” recommends that the description of the manufacturing process should include a justification for the choice of starting material. A flow chart should be included indicating the synthetic process prior to the introduction of the starting material, as it is felt that this may be useful in evaluating the suitability of the specification. A schematic diagram is suggested as in Figure 2. The European review process has the disadvantage that the acceptability of the choice of starting material is not certain until the MAA has been reviewed.作者: cocacola 时间: 2016-1-9 09:01
关键起始原料需要详细的生产工艺?
应该只需提供合成路线图及各步所用到的试剂、溶剂或催化剂等信息即可。
详见:cuturl('http://www.dxy.cn/bbs/topic/22914378')
In order to assess the presence of all potential impurities, including regioisomeric and stereoisomeric impurities, toxic impurities, residual solvents and residues of catalysts in the starting material, a brief narrative description of the synthesis including an outline leading to the starting material beginning with simpler molecules with all the reagents, solvents, and intermediates specified and the flow chart of the synthesis should be provided. Potential for the presence of adventitious agents, including viral and bacterial agents, residual proteins and TSE agents in the starting material selected should be discussed.
A more detailed description of the synthetic process should be provided for steps leading from the starting material to the final drug substance. The additional details should include quantities of raw materials, description of equipment, reaction conditions, in-process controls, percent yields, etc.
这个是加拿大的要求,FDA或EMA也是这样的要求,可以找到原文。
......
Health Canada的问答
Q): What level ofdetail for submission purposes is required on the starting material of an APIprepared by chemical synthesis?
问:化学合成制备的原料药所提交的CTD资料中起始物料的信息到底要详细到什么程度呢?
A): It is acknowledged that ICH Q7A provides a definition for "APIStarting Material", which may be distinct from the concept of"starting material for synthesis" discussed in this Q&A document.These are considered complementary definitions, since Q7A defines the point atwhich GMP requirements apply to the synthetic process in some jurisdictions,while requirements for "starting material for synthesis" defines thestarting point in the synthetic process for an API which should be provided toHealth Canada to permit the evaluation of the safety and quality of the API. Inmany cases, the "starting material for synthesis" may precede the ICH"API Starting Material" by several steps in the synthetic process.The level of details required concerning reaction conditions and controls willincrease as synthetic steps get closer to the final API.
答:大家所公认的ICH Q7A提供了“原料药起始物料”的定义,这个可能要与本问答文件中所讨论的“合成的起始物料”的概念相区别。这可以被认为是补充定义,因为Q7A定义了某些监管机构所要求合成工艺中执行GMP管理的起点,然而,“合成的起始物料”的要求定义了为允许评价原料药的安全性和质量而提交给加拿大卫生部的原料药合成工艺的起点,在多数情况下,“合成的起始物料”在合成工艺中要领先于“原料药起始物料”好几个步骤,反应条件和控制的详细程度随着合成步骤与最终原料药越接近而变得更详细。
In general, the starting material forsynthesis in drug submissions should:
通常,在药物提交的合成的起始物料应:
be a synthetic precursor one or more synthetic steps prior to the final API intermediate,
是在最终原料药中间体前一步或多步合成步骤的合成前体;
be a well characterised, isolated and purified substance with structure fully elucidated,
是一个结构充分确证的良好特性的、分离的且纯化的物质;
have well defined specifications which include one or more specific identity tests, and tests and limits for potency, specified and unspecified impurities and total impurities.
具有明确的质量标准,包括一个或多个特定的鉴别试验、检测和含量限度,特定和非特定杂质以及总杂质。
Acids, bases, salts, esters and similarderivatives of the API, and the racemate of a single enantiomeric API are notconsidered final intermediates.
原料药的酸、碱、盐、酯及类似的衍生物,以及单一对映体原料药的消旋体不能作为最终的中间体。
The selection of a particular compound as thestarting material for synthesis and its specifications should be justified.
用作为合成的起始物料的特定化合物的选择及其质量标准应经过确认。
In order to assess the presence of allpotential impurities, including regioisomeric and stereoisomericimpurities, toxic impurities, residual solvents and residues of catalysts inthe starting material, a brief narrative description of the synthesis includingan outline leading to the starting material beginningwith simpler molecules with all the reagents, solvents, and intermediatesspecified and the flow chart of the synthesis should be provided. Potential forthe presence of adventitious agents, including viral and bacterial agents,residual proteins and TSE agents in the starting material selected should bediscussed.
为了评价起始物料中可能存在的包括几何异构体和立体异构体杂质、毒性杂质、残留溶剂以及残留催化剂的杂质,应提供从更简单的分子至起始物料的包括反应图在内的合成简述,以及所有的试剂、溶剂和特定的中间体,合成的流程图。对所选择的起始物料中存在病毒和细菌、残留蛋白质和TSE等异物的可能性应进行讨论。
A more detailed description of the syntheticprocess should be provided for steps leading from the starting material to thefinal drug substance. The additional details should include quantities of rawmaterials, description of equipment, reaction conditions, in-process controls,percent yields, etc.
从起始物料至最终原料药的合成步骤应提供更为详细的合成工艺描述,应包括原料的用量、设备描述、反应条件、工艺控制和收率等。
编译如下:
问:化学合成制备的原料药所提交的CTD资料中起始物料的信息到底要详细到什么程度呢?
答:大家所公认的ICH Q7A提供了“原料药起始物料”的定义,这个可能要与本问答文件中所讨论的“合成的起始物料”的概念相区别。这可以被认为是补充定义,因为Q7A定义了某些监管机构所要求合成工艺中执行GMP管理的起点,然而,“合成的起始物料”的要求定义了为允许评价原料药的安全性和质量而提交给加拿大卫生部的原料药合成工艺的起点,在多数情况下,“合成的起始物料”在合成工艺中要领先于“原料药起始物料”好几个步骤,反应条件和控制的详细程度随着合成步骤与最终原料药越接近而变得更详细。
通常,在药物提交的合成的起始物料应:
是在最终原料药中间体前一步或多步合成步骤的合成前体;
是一个结构充分确证的良好特性的、分离的且纯化的物质;
具有明确的质量标准,包括一个或多个特定的鉴别试验、检测和含量限度,特定和非特定杂质以及总杂质。
原料药的酸、碱、盐、酯及类似的衍生物,以及单一对映体原料药的消旋体不能作为最终的中间体。
用作为合成的起始物料的特定化合物的选择及其质量标准应经过确认。
为了评价起始物料中可能存在的包括几何异构体和立体异构体杂质、毒性杂质、残留溶剂以及残留催化剂的杂质,应提供从更简单的分子至起始物料的包括反应图在内的合成简述,以及所有的试剂、溶剂和特定的中间体,合成的流程图。对所选择的起始物料中存在病毒和细菌、残留蛋白质和TSE等异物的可能性应进行讨论。
从起始物料至最终原料药的合成步骤应提供更为详细的合成工艺描述,应包括原料的用量、设备描述、反应条件、工艺控制和收率等。作者: xiaoxiaoniao 时间: 2016-1-9 09:54
EDQM对于起始物料选择的指导原则:
More and more frequently, applicants propose short synthesis, with complex products proposed as starting materials in the application. This is generally not acceptable and the complex material is considered by the assessors as an intermediate in the synthesis.
Applicants are reminded that the approved starting material is the starting point for GMP and variations, and must be representative of the overall synthetic process and not just a late intermediate resulting in a shortened synthesis. The proposed starting material should be justified. Proposing a complex molecule as starting material may lead to a request for redefinition of the starting material further back in the synthesis.
The policy for definition of Starting Materials for APIs applied at EDQM is the following:
— The proposed starting materials should generally not have a structure that is very close to that of the final substance in relative size and complexity (but will depend on the number of steps to the final active substance).
— Multiple synthesis steps should separate the starting material(s) and the active substance. A synthesis step is a step in the synthesis where covalent bonds are formed or broken. A process consisting of only 1-2 steps is generally not sufficient to ensure full control of the quality of the final substance. Fewer steps may be acceptable in some cases, for example for simple molecules, or when the proposed starting material is the subject of a CEP.
— The full description of the process should cover all the synthetic steps critical for safety (impurities) and/or efficacy; such as steps in which a genotoxic substance is used or formed, step contributing to the overall stereochemistry of the active substance or steps such as biocatalytic transformations.
— Commercial availability is an insufficient justification to accept a starting material. Starting materials produced by custom synthesis and those available commercially are not accepted unless supported by additional criteria as described above.
— It is the combination of the number of chemical synthetic transformation steps carried out under GMP and the control strategy applied to these steps, which provides assurance of quality of the active substance.
— The name and address of manufacturers of starting materials should be stated in the dossier.
— In order to justify the specifications of the starting material information on the manufacture of the starting material should be provided. This should include a flow diagram outlining enough steps of the synthesis and information on the solvents, reagents and catalysts used during its synthesis.
— Any declaration on GMP and/or on willingness to be inspected presented by starting material manufacturers will in effect have no influence on which substance will be accepted as an appropriate starting point for the part of the synthesis since GMP cannot be imposed for the manufacture of a starting material.
— An appropriate control strategy should be proposed to ensure the robustness and consistency of the manufacturing process.作者: moonlight 时间: 2016-1-9 09:56
EDQM对于起始物料选择的指导原则:
More and more frequently, applicants propose short synthesis, with complex products proposed as starting materials in the application. This is generally not acceptable and the complex material is considered by the assessors as an intermediate in the synthesis.
Applicants are reminded that the approved starting material is the starting point for GMP and variations, and must be representative of the overall synthetic process and not just a late intermediate resulting in a shortened synthesis. The proposed starting material should be justified. Proposing a complex molecule as starting material may lead to a request for redefinition of the starting material further back in the synthesis.
The policy for definition of Starting Materials for APIs applied at EDQM is the following:
— The proposed starting materials should generally not have a structure that is very close to that of the final substance in relative size and complexity (but will depend on the number of steps to the final active substance).
— Multiple synthesis steps should separate the starting material(s) and the active substance. A synthesis step is a step in the synthesis where covalent bonds are formed or broken. A process consisting of only 1-2 steps is generally not sufficient to ensure full control of the quality of the final substance. Fewer steps may be acceptable in some cases, for example for simple molecules, or when the proposed starting material is the subject of a CEP.
— The full description of the process should cover all the synthetic steps critical for safety (impurities) and/or efficacy; such as steps in which a genotoxic substance is used or formed, step contributing to the overall stereochemistry of the active substance or steps such as biocatalytic transformations.
— Commercial availability is an insufficient justification to accept a starting material. Starting materials produced by custom synthesis and those available commercially are not accepted unless supported by additional criteria as described above.
— It is the combination of the number of chemical synthetic transformation steps carried out under GMP and the control strategy applied to these steps, which provides assurance of quality of the active substance.
— The name and address of manufacturers of starting materials should be stated in the dossier.
— In order to justify the specifications of the starting material information on the manufacture of the starting material should be provided. This should include a flow diagram outlining enough steps of the synthesis and information on the solvents, reagents and catalysts used during its synthesis.
— Any declaration on GMP and/or on willingness to be inspected presented by starting material manufacturers will in effect have no influence on which substance will be accepted as an appropriate starting point for the part of the synthesis since GMP cannot be imposed for the manufacture of a starting material.
— An appropriate control strategy should be proposed to ensure the robustness and consistency of the manufacturing process.
......
这是针对起始物料是通过有机合成的情况。那如果我从起始物料到原料药只有一步合成反应,而我的起始物料目前商业化的只有植物提取的,生产过程基本上就是溶解,过滤,结晶等,全是物理处理,没有涉及到合成反应;那我申报资料里面只有一步合成就从起始物料到原料药了,这样能接受吗?我没办法往起始物料的 further back in the synthesis追溯啊,因为压根就没有synthesis啊!版主有相关的资料说明没呢?作者: qhyu 时间: 2016-1-9 10:00