EMA发布新指南“活性物质化学部分”

julia朱玉姣

GMP News
21/12/2016

EMAissues new Guideline on "Chemistry of Active Substances"

EMA发布新指南“活性物质化学部分”

A medicinal product authorization application requires comprehensiveinformation on origin and quality of an active substance. What information isrequired was defined in two Guidelines so far: the Guideline "Chemistry of Active Substances" (3AQ5a)from 1987 and the "Guideline on the Chemistry of New ActiveSubstances" from 2004. Because both Guidelines' content do nottake into account the ICH Guidelines Q8-11 issued in the meantime and do thusnot meet the current state of the art in sciences and in regulatory practice,the EMA Quality Working Party (QWP) developed an updated document entitled "Guideline on the chemistry of active substances"(EMA/454576/2016), which was issued on 21 November.

药品上市申报中要求提交活性物质来源和质量的全面信息。之前有两个指南指定了资料中所需的信息：1987年的《活性物质化学部分》（3AQ5a）和2004年的《新活性物质化学部分指南》。由于两个指南的内容都没有考虑ICH指南Q8-11，因此并不符合当前理想的科学状态以及法规规范，EMA质量工作组（QWP）起草了一份题为《活性物质化学部分指南》（EMA/454576/2016）的更新文件，并于2016年11月21日发布。

The new Guideline describes the information on new or already existingactive substances required in an authorization dossier. In the context of thisGuideline "already existing" ingredients are those that are used in aproduct already authorized in the EU.

新指南中描述了上市申报文件中所需的已有和新的活性物质的信息。在该指南中，“已有”成分指已经在EU境内批准的产品中所用的成分。

In detail the information and data regarding the substance have to beincluded in the following chapters of the CTD:

具体来说，在CTD的以下章节中要包括的物质方面信息和数据有：

3.2.S.1: Nomenclature,information on the structural formula, pharmacological relevant physicochemicalproperties.

3.2.S.1：专用名称、结构式信息、药学相关理化特性

3.2.S.2: Information on themanufacturer(s), contractor(s), testing facilities etc.; description of themanufacturing processes (schematic representation with flow diagram as well asnarrative); where appropriate detailed information on alternative manufacturingprocesses, for recovering of solvents and for routine reprocessing. Informationwith regard to re-working should not be included in the authorization dossier.

3.2.S.2：生产商、合同商、检验场所等方面的信息，生产工艺描述（流程图以及工艺叙述），适当时要提交可替代工艺的详细信息，回收溶液和常规返工信息。关于再加工的信息不应包括在申报文件中。

3.2.S.2.3: Information forcontrolling the material used during the manufacture and for its specification(incl. identity test). This paragraph is more comprehensive in the newGuideline compared with its predecessor and takes into account the requirementsof the ICH Guideline Q11. ThisGuideline comprises requirements for the following materials: materials frombiological sources, those used for the chemical synthesis of startingmaterials, materials from herbal origin, excipients like solvents (incl.water), reagents, catalysts etc.

3.2.S.2.3：生产中所用物料的控制信息及其质量标准（包括鉴别测试）。相比于其前版，新指南中的此段更为全面，考虑了ICH指南Q11的要求。此指南包括对以下物料的要求：生物来源的物料、起始物料化学合成用物料、植物来源物料、像溶剂一样的辅料（包括水）、试剂、催化剂等。

3.2.S.2.4: Information on criticalprocess steps (the Guideline comprises examples for these critical steps) aswell as on quality and control of isolated intermediates within the synthesissteps. All information has to be provided with the appropriate justifications.

3.2.S.2.4：关键工艺步骤的信息（指南包括此类关键步骤的举例）以及在合成步骤中被分离出的中间体的质量和控制信息。所有信息都要有适当的论证。

3.2.S.2.5: Information on ProcessValidation

工艺验证信息。

3.2.S.2.6: Information on thedevelopment of the manufacturing process. Here all changes have to be describedthat were performed during the various phases (pre-clinical, clinical,scale-up, pilot and possibly production phase) of the process fornew active substances. For already existing active substances available inproduction scale no information on process development is needed.

生产工艺研发信息。这里要描述新的活性物质的工艺在不同阶段所实施的所有变更（临床前、临床期间、放大生产、中试和可能的生产阶段）。对于可以从生产获得的已有活性物质，则不需要提交工艺研发信息。

3.2.S.3: Information onCharacterisation. Comprehensive information on the elucidation of the structureof the active substance, its physico-chemical properties and its impuritiesprofile have to be provided. Further, the mutagenic potentialof degradation products has to be considered. The analytical methods haveto be described and their suitability has to be justified.

结构确证信息。要提交活性物质结构确证的信息，其理化特性及其杂质谱。另外，必须要考虑降解产物的潜在基因诱变性。要描述分析方法，分析方法的适用性要进行论证。

3.2.S.4: Information on thecontrol of active substances. The analytical procedures and their validationhave to be described. Data for the analytical method development should beprovided if critical aspects of the analysis regarding the activesubstance's specification need to be clarified. Analytical data are necessaryfor batches for pre-clinical and clinical studies as well as for pilot batcheswhich are not less than 10% of the maximum production scale. The substance's specificationand its control strategy have to be justified on the basis of data from thepre-clinical and clinical phase and, if available, from the production phase.

活性物质的控制信息。要描述分析方法及其验证。如果需要澄清活性物质的质量标准方面的分析关键问题，则需要提供分析方法研发数据。需要提交临床前的批分析数据，以及不小于最大生产批量10%规模的中试批次批分析数据。物质的质量标准及其控制策略要根据临床前和临床阶段的数据进行论证，如果有生产阶段数据，也要一并考虑。

3.2.S.5: Information on referencematerials. If no Chemical Reference Substances (CRS) of the EuropeanPharmacopoeia - counting as completely qualified reference standards - areused, comprehensive information on the analytical and physico-chemicalcharacterization are required even for established primary standards.

对照品信息。如果EP没有化学对照品（CRS）---EP的CRS是作为完整确认的对照品的---即使是使用已有基准对照品，也需要提交分析和理化特性方面的全面信息。

3.2.S.6: Information on ContainerClosure System. Here a brief description is sufficient. However, if aContainer-/Closure System is critical for the substance's quality, itssuitability has to be proven and justified. A reference to stability data canbe used as supporting information.

容器密闭系统信息。这里简要描述就够了。但是，如果容器密闭系统对于物质的质量来说很关键的话，则必须证明并论证其适用性。可以引用稳定性数据来作为支持性信息。

3.2.S.7: Information onStability. A detailed description of the stability studies carried out and theprotocol used as well as a summary of the results are expected. Information onstress studies and conclusions on storage conditions and re-test dates orexpiry dates are also to be made. This does not apply to substances monographedin the European Pharmacopoeia. If no re-test period or expiry date of batcheson the production scale is available at the time of submission of theapplication, a stability commitment has to be attached with a post-approvalstability protocol. The analytical methods have to be described.

稳定性信息。详细描述所实施的稳定性研究和所用的研究方案，以及稳定性试验结果。还要提交强降解试验的信息，要做出存贮条件和复验期或有效期的结论。这些不适用于EP里的物质各论。如果在提交申报资料时还没有生产规模批次的复验期或有效期，必须要提交一份承诺，并附上一份批准的稳定性试验方案。必须要描述所用的分析方法。

The Guideline's provisions also apply to an Active Substance Master File(ASMF) or to a Certificate of Suitability (CEP). They apply to activesubstances that have undergone development in a "traditional" way oraccording to the "enhanced" approach. The provisions of the ICHGuidelines Q8-11 have to be taken into account.

指南的条款也适用于ASMF和CEP。它们适用于采用传统方式研发的活性物质，也适用于根据“增强”的方法开发的活性物质。必须要考虑ICH指南Q8-11的条款。

The Guideline is not applicable to active substances of herbal, biologicaland biotechnological origin as well as to radiolabelled products andradiopharmaceuticals.

该指南不适用于植物、生物和生物技术来源的活性物质，不适用于放射性物质示踪药品和放射性药品。

The Guideline "Guideline on the chemistry ofactive substances" (EMA/454576/2016) becomes effective sixmonths after issuing, which means in May 2017.

该指南将于发布后6个月即2017年5月生效。

syhorchid

谢谢分享

静水蓝心

感谢楼主分享

北极的熊猫

很好用，O(∩_∩)O哈哈哈~

月夏柠

太好了，谢谢分享！

预知子

谢谢分享

叶子--

谢谢分享

Gatsby

which website can download policy or acts related to FDA ?

lqthjm

谢谢分享