This document is a summary of the top ten deficiencies identified after the initial evaluation of new applications for Certificates of Suitability (CEP) for chemical purity. It is based on the content of a random sample of 30 deficiency letters selected from the year 2023.

本文是對(duì)化學(xué)純度CEP新申請(qǐng)首次評(píng)估中發(fā)現(xiàn)的前10大缺陷問(wèn)題的總結(jié)，本文是基于2023年隨機(jī)抽取的30封缺陷信內(nèi)容進(jìn)行的總結(jié)。

During this period the failure of applicants to satisfactorily address some of the deficiencies described below in their application resulted in an increase in the number of questions raised during requests for additional information by EDQM along with their complexity. Consequently, the timeline for granting of the certificate of suitability was increased.

在申請(qǐng)期間，申請(qǐng)人未能圓滿的解決下面描述的部分缺陷，導(dǎo)致EDQM發(fā)布的補(bǔ)充資料通知中缺陷數(shù)量及缺陷復(fù)雜性相應(yīng)增加，因此CEP證書(shū)的批準(zhǔn)時(shí)間延長(zhǎng)。

This document is intended to help applicants avoid such issues. Expanded details on specific points from each deficiency are provided to inform the users but should always be considered in conjunction with the EDQM guideline “Content of the Dossier for Chemical Purity and Microbiological Quality of Substances for Pharmaceutical Use” which outlines the specific requirements for the submission of CEP applications.

本文旨在幫助CEP申請(qǐng)人避免類似的問(wèn)題。它為使用者提供了每一個(gè)缺陷具體要點(diǎn)的更多詳細(xì)信息，但這些缺陷具體要點(diǎn)的更多詳細(xì)信息應(yīng)與EDQM指南“藥用物質(zhì)化學(xué)純度及微生物質(zhì)量的文檔內(nèi)容”相結(jié)合，該指南概括了CEP申請(qǐng)遞交的具體要求。

 

TOP 1: 3.2.S.2.2

第一大缺陷：在3.2.S.2.2中

Lack of details and/or poor description of the manufacturing process of the substance from the introduction of starting materials (This includes discrepancies noted between the information given in sections S.2.3 and S.2.4). (12% of all questions)

從起始物料引入至原料藥生產(chǎn)工藝缺乏詳細(xì)的信息或者描述的不完整（這包括與S.2.3和S.2.4章節(jié)中信息的差異）。（占總問(wèn)題的12%）

Specific points:

具體要點(diǎn)：

For synthetic and semi synthetic substances, it is expected that a synthetic flow diagram be provided. All synthetic intermediates should be presented, and if non-isolated, they should be presented within square brackets.

期待為合成和半合成的原料藥提供合成流程圖。該合成流程圖應(yīng)該體現(xiàn)所有的合成中間體，如果是非分離中間體，應(yīng)該用方括號(hào)中表示。

When reviewing the route of synthesis, assessors check that the information in S.2.2, S.2.3, and S.2.4 is consistent. Applicants should ensure that all raw materials used (including recovered materials) are addressed both in section S.2.2 and S.2.3 and that no reagents are included in error.

審評(píng)合成路線時(shí)，評(píng)審員會(huì)檢查S.2.2、S.2.3、S.2.4章節(jié)的信息是否一致。申請(qǐng)人應(yīng)確保所有使用的原材料（包括回收物料）在S.2.2和S.2.3章節(jié)中都有說(shuō)明，并且沒(méi)有錯(cuò)誤信息。

The quantities of all raw materials used, and the batch size should be detailed at each stage of the manufacturing process.

在每個(gè)生產(chǎn)工藝階段，都應(yīng)當(dāng)詳細(xì)描述所有使用的原材料的投料量和該階段的生產(chǎn)批量。

If blending of intermediates or the final substance is performed, the process description should make it clear that it is performed in accordance with ICH Q7 and that batches are fully tested prior to blending.

如果中間體或者原料藥需進(jìn)行混合，工藝描述應(yīng)當(dāng)明確此操作符合ICHQ7的要求并且在混合前每個(gè)批次都會(huì)進(jìn)行全面檢測(cè)。

 

TOP 2: 3.2.S.2.4 and TOP 4: 3.2.S.2.3

第二大缺陷：在3.2.S.2.4中及第四大缺陷：在3.2.S.2.3中

Non-adequate or poorly justified specifications proposed to control the quality of isolated intermediates (11% of all questions) and starting materials (7% of all questions).

對(duì)分離中間體（占總問(wèn)題的11%）和起始物料（占總問(wèn)題的7%）的質(zhì)量控制所提議的質(zhì)量標(biāo)準(zhǔn)沒(méi)有充分的合理性論證。

Specific points:

具體要點(diǎn)：

It is expected that the specifications for starting materials and isolated intermediates include appropriate acceptance criteria for specified, unspecified, and total impurities. Acceptance criteria should be justified based on fate and the carryover of the impurity/ies (this may sometimes necessitate spiking studies). Any potential risk to the quality of the final substance should be discussed.

起始物料、分離中間體的質(zhì)量標(biāo)準(zhǔn)應(yīng)該包含特定雜質(zhì)、非特定雜質(zhì)及總雜質(zhì)的適當(dāng)?shù)目山邮軜?biāo)準(zhǔn)。該可接受標(biāo)準(zhǔn)的論證應(yīng)依據(jù)雜質(zhì)的去向及轉(zhuǎn)移（這方面可能有時(shí)候要做加標(biāo)試驗(yàn)）。應(yīng)當(dāng)對(duì)原料藥質(zhì)量的任何潛在的風(fēng)險(xiǎn)進(jìn)行討論。

It is expected by assessors that any major and recurrent impurities;

a) Will be identified and/or characterised.

b) Will be specified individually at justified acceptance criteria based on fate and carryover discussions.

對(duì)于任何主要的和反復(fù)出現(xiàn)的雜質(zhì)，評(píng)審員期望：

a)      進(jìn)行鑒別或結(jié)構(gòu)確證。

b)     應(yīng)當(dāng)基于去向和轉(zhuǎn)移來(lái)單獨(dú)討論其可接受標(biāo)準(zhǔn)的論證。

If the proposed acceptance criteria for unspecified impurities are wider than those proposed for specified impurities, this should be well justified.

如果提議的非特定雜質(zhì)的可接受標(biāo)準(zhǔn)比特定雜質(zhì)的可接受標(biāo)準(zhǔn)更寬，應(yīng)當(dāng)進(jìn)行充分的論證。

Discrepancies in mass balance (sum of assay and total impurities) should be addressed. Where rationales for a discrepancy exist, these should be explained.

應(yīng)闡述質(zhì)量守恒(含量和總雜質(zhì)的和)的問(wèn)題，當(dāng)質(zhì)量不守恒情況存在時(shí)，應(yīng)當(dāng)加以解釋。

 

TOP 3: 3.2.S.3.2

第三大缺陷：在3.2.S.3.2中

Absence or deficient discussion on the risk of having potential mutagenic impurities in the final substance. (7.5% of all questions)

缺乏對(duì)原料藥中潛在致突變雜質(zhì)風(fēng)險(xiǎn)的討論或討論不充分。（占總問(wèn)題的7.5%）

Specific points:

具體要點(diǎn)：

CEP applicants are expected to provide a specific discussion in their dossier regarding potential mutagenic impurities based on their understanding of the manufacturing process for the substance. This should include those:

a) introduced during the manufacturing process (e.g., reagents, starting materials, etc.)

b) arising from the synthesis of the final substance

c) formed as a result of degradation.        

CEP申請(qǐng)人應(yīng)基于對(duì)原料藥生產(chǎn)工藝的理解，在他們提交的資料中針對(duì)潛在致突變雜質(zhì)進(jìn)行詳細(xì)討論。包括：

a)   生產(chǎn)工藝中引入的（如：試劑、起始物料等）

b)   原料藥合成過(guò)程中產(chǎn)生的。

c)   降解產(chǎn)生的。

Such impurities should be listed and classified (class 1 to class 5) in the dossier in accordance with ICH M7. For mutagenic impurities, a suitable control strategy in accordance with the principles of ICH M7 should be proposed.

應(yīng)根據(jù)ICHM7的要求，在申報(bào)資料中列出這些雜質(zhì)并被分類（1至5類）。對(duì)于致突變雜質(zhì)，應(yīng)根據(jù)ICHM7的要求制定適當(dāng)?shù)目刂撇呗浴?/span>

The Threshold of Toxicological Concern (TTC) for an impurity should be determined in accordance with ICH M7. For the calculation of the TTC, the Maximum Daily Dose (MDD) of the drug substance should be based on the Human Medicine European Public Assessment Report (EPAR), Summary of Product Characteristics (SmPCs), or agreed literature such as Martindale, while the appropriate acceptable intake should be based on an appropriate duration of use as described in ICH M7.

應(yīng)該根據(jù)ICHM7制定雜質(zhì)的毒理學(xué)閾值（TTC）。計(jì)算TTC時(shí)，原料藥最大的日劑量（MDD）應(yīng)基于人用藥歐洲公開(kāi)審評(píng)報(bào)告 (EPAR)、產(chǎn)品特性總結(jié)（SmPCs）或者公認(rèn)的文獻(xiàn)如馬丁代爾來(lái)確定，而適當(dāng)?shù)目山邮軘z入量應(yīng)基于ICH M7中所述的適當(dāng)?shù)姆闷趤?lái)確定。

ICH M7 option 3 controls for mutagenic impurities should be justified with suitable spiking and/or carryover studies.

ICHM7選項(xiàng)3，對(duì)于致突變雜質(zhì)的控制應(yīng)通過(guò)適當(dāng)?shù)募訕?biāo)和/或轉(zhuǎn)移研究來(lái)論證。

ICH M7 option 4 controls should be supported by a demonstration that, based on understanding of the process and impact on residual impurity levels (including fate and purge knowledge), the level of the impurity in the drug substance will always be below the acceptable limit. Option 4 controls may additionally need to be supported by analytical data (e.g., spiking and/or carryover studies).

ICHM7選項(xiàng)4的控制，應(yīng)該基于對(duì)工藝的理解及對(duì)殘留雜質(zhì)水平的影響（包括去向及清除知識(shí)），原料藥中雜質(zhì)的水平將會(huì)永遠(yuǎn)低于可接受標(biāo)準(zhǔn)限度的證據(jù)來(lái)證明。選項(xiàng)4控制可能需要有額外的分析數(shù)據(jù)支持（如加標(biāo)研究和/或轉(zhuǎn)移研究）。

 

TOP 5: 3.2.S.2.3

第五大缺陷：在3.2.S.2.3中

Absence or inadequate acceptance criteria (and/or analytical methods) for raw materials (incl. recovered materials) used in the manufacture of the final substance, from the introduction of starting materials. (7.1% of all questions)

缺少自起始物料引入至在原料藥生產(chǎn)中使用的原材料（包括回收物料）的可接受標(biāo)準(zhǔn)（和/或分析方法），或者信息不充分。（占總問(wèn)題的7.1%）

Specific points:

具體要點(diǎn)：

Applicants should ensure that suitable specifications are provided for all raw materials used in the manufacturing process for the final substance.

申請(qǐng)人應(yīng)確保原料藥生產(chǎn)工藝中使用的所有原材料提供了適當(dāng)?shù)馁|(zhì)量標(biāo)準(zhǔn)。

Specifications of raw materials used late in the manufacturing process should not contain wide acceptance criterion without any suitable justification being provided. The impact of the use of these materials (incl. recovered materials) on the impurity profile of the final substance should be addressed.

在沒(méi)有提供任何合適的論證情況下，生產(chǎn)工藝后續(xù)步驟中使用的原材料的質(zhì)量標(biāo)準(zhǔn)應(yīng)不能過(guò)寬。應(yīng)闡述使用的這些物料（包括回收物料）對(duì)原料藥雜質(zhì)概況的影響。

In case material of fish origin or a peptone is used in the manufacturing process, the EDQM requirements should be met.

若生產(chǎn)過(guò)程中使用了魚(yú)源物料或者蛋白胨，則應(yīng)符合EDQM的要求。

 

TOP 6: 3.2.S.2.2

第六大缺陷：在3.2.S.2.2中

The reprocessing and recovery of raw materials are inadequately addressed. (6.1% of all questions)

原料的返工和回收處理沒(méi)有充分地闡述。（占總問(wèn)題的6.1%）

Specific points:

具體要點(diǎn)：

Reprocessing: In accordance with the EU “Guideline on the Chemistry of Active Substances” in Section 3.2.S.2.2 CEP applicants are expected to provide a detailed narrative description of any reprocessing step and to define the triggers for this reprocessing. Statements such as “Reprocessing is a repetition of the approved step X” are not considered appropriate replacements.

返工：根據(jù)EU“活性藥物化學(xué)指南”，CEP申請(qǐng)人應(yīng)在3.2.S.2.2章節(jié)提供任何返工步驟的詳細(xì)描述，并且定義返工的起因。諸如“返工是重復(fù)已批準(zhǔn)的步驟X”這樣的描述是不恰當(dāng)?shù)摹?/span>

Recovery: In Section 3.2.S.2.2 CEP applicants are expected to suitably identify the point in the manufacturing process from where materials are recovered, to describe in detail how they are recovered, and to clearly identify where they are reintroduced in the process.

回收：在3.2.S.2.2章節(jié)中， CEP申請(qǐng)人應(yīng)明確物料是在生產(chǎn)工藝中的哪一步進(jìn)行回收的，詳細(xì)描述其是怎么樣被回收的，并且明確的標(biāo)明在工藝中哪個(gè)生產(chǎn)步驟被重新引入。

 

TOP 7: 3.2.S.3.2

第七大缺陷：在3.2.S.3.2中

Absent or deficient risk assessment related to Nitrosamines. (4% of all questions)

亞硝胺雜質(zhì)的風(fēng)險(xiǎn)評(píng)估缺乏或者評(píng)估不充分的。（占總共問(wèn)題的4%）

Specific points:

具體要點(diǎn)：

New CEP applications (chemical, semi-synthetic, products of fermentation, or herbals) are expected to include a comprehensive risk assessment for the presence of nitrosamines based on the principles outlined in the ICH Q9 and ICH M7 guidelines, as well as the current EMA Q&A document on nitrosamines (incl. its Appendix 1).

根據(jù)ICHQ9和ICH M7指導(dǎo)原則和現(xiàn)行EMA關(guān)于亞硝胺的問(wèn)答（包括它的附件1），CEP新申請(qǐng)（化學(xué)的、半合成的、發(fā)酵產(chǎn)品或者草藥）的申報(bào)資料中應(yīng)包含關(guān)于亞硝胺雜質(zhì)存在的全面風(fēng)險(xiǎn)評(píng)估。

The risk assessment should address not only risks from the manufacturing process but also those from the introduction of materials used in the manufacturing process (starting materials, reagents, solvents – fresh and recovered, etc.) as well as degradation. Any risk concerning the formation and carryover of nitrosamines should be suitably addressed, taking into account the above-mentioned EMA Q&A document.

風(fēng)險(xiǎn)評(píng)估應(yīng)闡述不僅僅來(lái)源于生產(chǎn)過(guò)程的風(fēng)險(xiǎn)，也可能來(lái)源于生產(chǎn)過(guò)程中使用的物料（起始物料、試劑、溶劑-新鮮的或回收的溶劑等）及其降解產(chǎn)物的風(fēng)險(xiǎn)。關(guān)于亞硝胺雜質(zhì)的形成和轉(zhuǎn)移的任何風(fēng)險(xiǎn)都應(yīng)當(dāng)根據(jù)上述EMA的問(wèn)答進(jìn)行適當(dāng)?shù)年U述和討論。

 

TOP 8: 3.2.S.3.2

第八大缺陷：在3.2.S.3.2中

Failure to adequately address the origin, fate, and carryover of related substances into the final substance. (4% of all questions)

沒(méi)有充分闡述原料藥中的有關(guān)物質(zhì)的來(lái)源、去向、轉(zhuǎn)移。（占總問(wèn)題的4%）

 

Specific points：

具體要點(diǎn)：

A discussion based on Ph. Eur. impurities alone is generally not considered as sufficient, and the discussion on related substances should address the formation, carryover and fate of other impurities (e.g., starting materials, intermediates, process related impurities, and degradants).

僅僅基于歐洲藥典的雜質(zhì)進(jìn)行討論一般認(rèn)為是不充分的，對(duì)有關(guān)物質(zhì)的討論應(yīng)闡述其它雜質(zhì)（例如：起始物料、中間體、工藝相關(guān)雜質(zhì)和降解產(chǎn)物）的形成、轉(zhuǎn)移及去向。

The suitability of the Ph. Eur monograph to control impurities, not present in the transparency list of the monograph (i.e., additional in house impurities), for which a control in the final substance is proposed or required (e.g., found above the reporting threshold), should be addressed.

對(duì)于并不存在于各論公開(kāi)雜質(zhì)列表中（例如，額外的內(nèi)控雜質(zhì)）但擬在或要求在原料藥中進(jìn)行控制（例如，發(fā)現(xiàn)超出報(bào)告的閾值）的雜質(zhì)，應(yīng)當(dāng)闡述EP各論對(duì)該雜質(zhì)控制的適用性的問(wèn)題。

In the context of the related substances discussion it is expected that statements such as “not detected” or “l(fā)ess than limit of quantification” be supported by the provision of the LOD / LOQ for the associated method.

在討論有關(guān)物質(zhì)的描述中，應(yīng)通過(guò)提供相關(guān)方法的LOD/LOQ來(lái)支持諸如“未檢出”或者“低于定量限”的描述。

 

TOP 9: 3.2.S.3.2

第九大缺陷：在3.2.S.3.2中

Deficient discussion on residual solvents. (4% of all questions)

對(duì)殘留溶劑的討論不充分。（占總問(wèn)題的4%）

Specific points:

具體要點(diǎn):

In the context of the discussion on residual solvents, it is expected that statements such as “not detected” or “l(fā)ess than limit of quantification” be supported by provision of the LOD / LOQ for the associated method.

在討論殘留溶劑的描述中，應(yīng)通過(guò)提供相關(guān)方法的LOD/LOQ來(lái)支持諸如“未檢出”或者“低于定量限”的描述。

The origin of impurities that are formed as by-products of the manufacturing process, but which are also common solvents (e.g. acetic acid, ethanol), should be clarified.

源于生產(chǎn)工藝中產(chǎn)生的副產(chǎn)物，同時(shí)也是常用溶劑（如乙酸、乙醇）的雜質(zhì)，應(yīng)進(jìn)行澄清說(shuō)明。

Where relevant, CEP applicants are expected to discuss the potential presence of Class 1 solvents (e.g. Benzene / Carbon tetrachloride /1,2-Dichloroethane / 1,1-Dichloroethene / 1,1,1-Trichloroethane) as contaminants of other solvents and to demonstrate compliance with the requirements of ICH Q3c Annex 1.

如適用， CEP申請(qǐng)人應(yīng)對(duì)作為其他溶劑污染物的1類溶劑（例如，苯、四氯化碳、1,2-二氯乙烷、1,1-二氯乙烯、1,1,1-三氯乙烷）進(jìn)行討論，并且證明符合ICHQ3c附件1的要求。

 

TOP 10: 3.2.S.2.3

第十大缺陷：在3.2.S.2.3中

Failure to suitably identify starting materials. (3.5% of all questions)

沒(méi)有恰當(dāng)?shù)亩x起始物料。（占總問(wèn)題的3.5%）

Specific points:

具體要點(diǎn)：

Starting materials should be identified and selected according to the requirements outlined in ICH Q11 and the associated Q&A document. The reasons why the proposed starting materials are considered acceptable and in line with applicable guidelines should be explained in detail in the dossier, in Section S.2.3.

應(yīng)該根據(jù)ICHQ11及其Q&A文件的要求定義和選擇起始物料。應(yīng)在提交的S.2.3章節(jié)中，詳細(xì)地解釋提議的起始物料被認(rèn)為可接受的原因以及與相應(yīng)的指南的符合性。

Identification of a substance that contributes a significant structural component to the final substance as a reagent is not acceptable. In accordance with ICH Q11 such substances should be identified as starting materials.

將構(gòu)成原料藥重要結(jié)構(gòu)片段的物質(zhì)作為試劑是不可接受的。根據(jù)ICHQ11，這些物質(zhì)應(yīng)被定義為起始物料。

 

In addition to the information provided above, applicants are encouraged to ensure they stay up to date on news about the CEP procedure, relevant trainings, and on the work of EDQM in general (including the elaboration and revision of Ph.Eur monographs) by consulting the EDQM website www.edqm.eu.

除了上面提到的信息之外，鼓勵(lì)申請(qǐng)人通過(guò)EDQM網(wǎng)站www.edqm.eu確保持續(xù)關(guān)注CEP程序的新信息、相關(guān)的培訓(xùn)和EDQM日常工作（包括歐洲藥典各論的詳細(xì)描述和修訂）。

Applicants are also reminded that from the EDQM website they may also access tools to assist them in the preparation of their application for a CEP, including policies and guidelines, FAQ, the EDQM Helpdesk, and the possibility to request a technical advice meeting with the Certification department of the EDQM.

也提醒申請(qǐng)人在CEP申請(qǐng)的準(zhǔn)備過(guò)程中可通過(guò)EDQM網(wǎng)站獲得工具來(lái)得到幫助，包括政策和指南、常見(jiàn)的問(wèn)題解答、EDQM的幫助平臺(tái)以及請(qǐng)求EDQM認(rèn)證部門(mén)舉行技術(shù)咨詢會(huì)議的可能性。