2015年9月起CEP申报文件要求更新

                      20150923 ECA新闻：2015年9月起CEP申报文件要求更新  

As of September 2015, updated Requirements apply to the Application of a CEP!
2015年9月起CEP申报文件要求更新
The EDQM recently published a revised version of its certification policy document titled "Content of the dossier for chemical purity and microbiological quality". The revision takes into account the new regulatory developments in Europe that are reflected in many revised and, to some extent, new guidelines of the EMA, ICH as well as in some revised general chapters and monographs of the European Pharmacopoeia (see the summary of these guidance documents under "References" at the end of the policy document).
EDQM最近公布了其认证政策文件“化学纯度和微生物质量申报文件内容”的修订版本。修订考虑了欧洲EMA、ICH新的和修订的指南以及EP里通论和各论修订中反映的新的法规发展情况（参见政策文件结束处“参考文献”项下这些指南文件的汇总）。
The aim of the policy document is to provide CEP applicants with a guideline for preparing the authorisation dossier and for compiling all the documents required for this. The dossier is to be divided into 3 modules:
政策文件的目的是向CEP申报人提供如何准备上市批准文档的指南，以及所有要求文件的汇总要求。文档分为三个模块：
Module 1: The authorisation history of the products is to be described which contain the active ingredient for which a CEP application is submitted. The following declarations are also to be submitted:
模块1：描述含有要申报CEP的活性成份的药品上市历史。还要提交以下声明：
a declaration of GMP conformity from all manufacturers involved in the manufacture of intermediate products and the final active ingredient,
声明所有中间体和原料药生产场所符合GMP要求
a declaration from these manufacturers that they are willing to be inspected before and after being granted a certificate of suitability,
上述生产商声明他们在CEP颁发前和颁发后均愿意接受现场检查
a declaration of the CEP applicant/holder about the use/non-use of material of human or animal origin. In cases where such material is used, compliance with the provisions of the EDQM Guideline "Content of the dossier for a substance for TSE risk assessment (PA/PH/CEP (06) 2)" should be demonstrated.
CEP申报人/持有人声明人体或动物源物料的使用/未使用情况。如果使用了这类物料，则应证明符合EDQM指南“TSE风险评估物质申报文件内容（PA/PH/CEP(06)2）”。
a commitment to provide the EDQM, upon request, with samples of the final active ingredient and/or its impurities,
承诺在EDQM索取时向其提交最终活性成分和/或其杂质的样品
a declaration to acknowledge the provisions of the Certification procedure and to agree to the exchange of assessment reports between the national competent authorities of the European Member States as well as the EMA experts.
声明已知晓认证程序的条款，同意欧盟成员国国家药监局及EMA专家之间交换评审报告
Module 2: Part of this module (analogous to the CTD structure) is the Quality Overall Summary (QOS). The EDQM published a ready-to-use Word template for this. The template can be accessed on the EDQM website "Submit a new application" which contains the most important facts regarding the submission of a new application for a CEP together with links for the relevant documents. With the description of the active ingredient in the QOS, evidence must be provided that the pharmacopoeia monograph is suitable to control the quality of the active ingredient, particularly with regard to the impurity profile of the substance. Plausible justification is important for the cases where testing for possible impurities is omitted.
模块2：本模块一部分（相似于CTD结构）是质量综述（QOS）。EDQM公布了可直接套用的WORD模板。该模板可以在EDQM网站“提交新申报”栏目下找到，这个栏目里包括了提交新的CEP申报时最重要的内容，并链接至相关的文件。在QOS的活性成分描述中，要提交证据证明药典各论适用于控制活性成分的质量，尤其是物质的杂质概况。如果省略了对可能杂质的测试，则合理的论证尤为重要。
Module 3: Also this Module reflects the CTD structure, i.e. the content of subchapter 3.2.S.1 to 3.2.S.7 with further subdivisions corresponds to the content of a standard authorisation application for a medicinal product. Here are some examples of important points that must be considered in light of the regulatory developments:
模块3：此模块反映的是CTD结构，即子项3.2.S.1至3.2.S.7的内容，对应药品标准上市申报资料内容进一步细分。这里是一些重要内容的例子，必须考虑法规发展情况：
A CEP that covers different grades of active ingredient (different physical properties, such as particle size or certain polymorphic forms) cannot be issued if these grades also have different limits for impurities and if different analytical methods of determination are required for their control. A CEP for different grades of freedom from pyrogens or bacterial endotoxins is only possible when the relevant monograph foresees this. Otherwise, separate applications must be submitted for grades of the active ingredient that do and do not contain pyrogens or endotoxins ("General properties"; 3.2.S.1.3).
如果要在一份CEP包括不同原料药级别（不同物理特性，例如颗粒度、特定的晶型），而这些级别也具有不同的杂质限度，且用于控制的检验方法不同则不能颁发CEP。如果一份CEP中有不同热源或细菌内毒素级别，则只有当相关的各论已注明此情况时可以申请。否则，必须为有和没有热源和内毒素规格的不同级别原料药分别提交申报。
Different production sites and manufacturing processes may only be described in one and the same application if it can be proven in a plausible manner that the quality (specifications and impurity profiles) of the relevant intermediate products and the final active ingredient is not significantly changed. Reprocessing steps are to be clearly described; reworking is not normally accepted ("Description of the manufacturing process and process controls"; 3.2.S.2.2).
一份申报资料中如果需要包括不同的生产场所和生产工艺，则必须有合理方式证明相关中间体产品和最终活性成分的质量（质量标准和杂质概况）没有显著改变。返工步骤要清楚描述，再加工一般是不被接受的（3.2.S.2.2.生产工艺和工艺控制描述）。
The selection of the starting material is to be justified as per the regulations of ICH Q11 and the EMA Reflection Pager on Starting Materials (EMA/448443/2014). Single step synthesis is generally not accepted unless the starting material itself has a CEP (see EDQM Guideline "Use of a CEP to describe a starting material in an application for another CEP"). Testing for impurities including solvents, catalysts and reactants and absence of a possible carryover into the final product is to be described ("Control of materials"; 3.2.S.2.3).
起始物料的选择也要根据 ICH Q11和EMA关于起始物料的概念文件（EMA/448443/2014）的要求进行论述。一步合成一般来说是不会被接受的，除非起始物料本身具有CEP（参见EDQM指南“使用一份CEP来描述另一份CEP申报中的起始物料”）。杂质检测，包括溶剂、催化剂和反应物，以及可能的残留不会被带入最终产品的情况要说明（3.2.S.2.3物料控制）。
Validation data for manufacturing sterile substances is to be submitted; the complete validation data (protocols and reports) is to be presented for the sterilisation process. Part 2 of the EU GMP guidelines applies to the manufacture of the active ingredient until immediately before the sterilisation stage; sterilisation and aseptic processing should be carried out according to Annex 1 of the guideline ("Process validation and/or evaluation" 3.2.S.2.5).
要提交无菌物质生产的验证数据，要提交灭菌工艺完整的验证数据（方案和报告）。EU GMP指南的第二部分适用于原料药的生产，直到灭菌步骤。灭菌和无菌工艺要根据指南的附录1实施（3.2.S.2.5工艺验证和/或评估）。
Testing for all kinds of impurities (reagents, catalysts, solvents, by-products etc.) and their potential sources are to be described, particularly if the monograph does not contain suitable test methods. Analytical data and a minimum of significant validation data (incl. LOD/LOQ values) are to be presented ("Impurities"; 3.2.S.3.2).
所有类别杂质（试剂、催化剂、溶剂、副产物等）的测试和其潜在来源要进行描述，尤其是如果各论中没有适当的检测方法来控制时。要提交分析数据和重大验证数据（包括LOD/LOQ值）（3.2.S.3.2杂质）。
Data from formal stability studies are not normally required for active ingredients. However, when a retest period is requested to be mentioned on the certificate, these data must be collected and submitted as per the guideline "Stability testing of existing active substances and related finished products" and itsAnnexes ("Stability"; 3.2.S.7).
正式稳定性研究数据一般不要求提交。但是，如果申请在证书上载明复验期，则必须根据指南“已有活性物质和相关制剂的稳定性测试”及其附录收集并提交这些数据（3.2.S.7稳定性试验）。
Overall the provisions of the new certification policy document are rather extensive. As mentioned at the start, the pharmacopoeia authority has reacted to the increased requirements in the newly published and revised ICH and EU guidelines. The policy document is now applicable with no transition period, which means CEP applicants who submitted their application without knowing about this document may receive from the EDQM a particularly long list of deficiencies along with the request to submit the relevant information required.
新的认证政策文件的条款总体来说相关广泛。正如开始时提到的，药典官方已对新公布和修订的ICH和EU指南中日益增加的要求做出反应。政策文件现在直接生效没有过渡期，这表示不知道此文件的而已提交资料的CEP申报者可能会收到EDQM很长的缺陷清单，要求提交所需的相关资料。

来源：http://zhuyujiao1972.blog.163.com/blog/static/98694727201598112857545/