TOP TEN DEFICIENCIES

New Applications for Certificates of Suitability (2015-2016)

for chemical purity

純化學(xué)類新CEP申請(qǐng)十大常見(jiàn)缺陷（2015-2016）

This document is a summary of the ten most frequent questions raised after the initial evaluation of new applications for Certificates of suitability (CEP) for chemical purity. It is based on the content of a sample of 20 deficiency letters sent selected randomly during the second half of 2015 and beginning of 2016.

本文件總結(jié)了純化學(xué)類CEP證書(shū)新申請(qǐng)首次審評(píng)所產(chǎn)生的十個(gè)最常見(jiàn)的問(wèn)題。根據(jù)2015年下半年和2016年初期間隨機(jī)抽取的20封缺陷信的內(nèi)容編制的。

The top ten most frequent questions are listed below together with expectations and recommendations on how to address the specific deficiencies, with reference to applicable guidelines.

下面列出了最常見(jiàn)的十個(gè)問(wèn)題，以及如何參考適用的指南解決具體缺陷的期望和建議。

This document is intended to help applicants to improve the quality of their dossiers, in order to facilitate and speed up the granting of their CEPs. It should be taken into account while building up a dossier, in combination with the EDQM Guideline “Content of the Dossier for Chemical Purity and Microbiological Quality (PA/PH/CEP 04 1)” available on the EDQM website.

本文件旨在協(xié)助申請(qǐng)人提高其注冊(cè)文件的質(zhì)量，以促進(jìn)和加快CEP的授予。在建立注冊(cè)文件時(shí)，應(yīng)結(jié)合EDQM網(wǎng)站上提供的EDQM指南“化學(xué)純度和微生物質(zhì)量注冊(cè)文件內(nèi)容(PA/PH/CEP 04 1)”的要求。

TOP 1 (S.3.2) Absence or deficient discussion on the risk of having potential mutagenic impurities in the final substance.

TOP 1 (S.3.2)對(duì)最終產(chǎn)品中含有潛在致突變雜質(zhì)風(fēng)險(xiǎn)的討論缺失或存在缺陷。

This is applicable to sources of substances which have not yet been introduced in medicinal products available on the European market.

適用于尚未在歐洲市場(chǎng)上銷售的藥品中產(chǎn)生的物質(zhì)來(lái)源。

Applicants are expected to provide a complete discussion on mutagenic impurities in their application for a CEP. It is necessary to refer to ICH M7 (in force since January 2016). Any addendum, available on the ICH website, may also be useful reading for product-specific recommended safety values (refer also to Note 5 of ICH M7).

申請(qǐng)人應(yīng)在其CEP申請(qǐng)中提供關(guān)于致突變雜質(zhì)的完整討論。應(yīng)參考ICH M7（自2016年1月起生效）。ICH網(wǎng)站上的任何附錄也可能會(huì)對(duì)特定產(chǎn)品所推薦的安全值是有用的（也請(qǐng)參閱ICH M7的注釋5）。

It is expected that potential mutagenic impurities arising from the synthesis of the substance and its starting materials (if relevant and if not otherwise justified) or from degradation processes are listed and classified in the CEP dossier as per ICH M7. Impurities can be classified with respect to their mutagenic and carcinogenic potential in 5 different classes (refer to table 1 of ICH M7) and actions for control are proposed accordingly. Sometimes no mutagenicity data are available for impurities showing alerting structures and arising from synthetic processes (class 3 impurities as per ICH M7); these impurities should be controlled at or below an acceptable limit or mutagenicity assays should be conducted (refer to Note 2 of ICH M7) in order to understand if the impurity is non-mutagenic (hence class 5) or mutagenic (hence class 2). The outcome of bacterial mutagenicity assays can also be predicted by (Q)SAR methodologies (in-silico studies). According to ICH M7 two (Q)SAR methodologies that complement each other should be applied, one which is expert rule-based and a second one which is statistical-based. The principles set by the OECD should be followed.

應(yīng)根據(jù)ICH M7將成品和起始物料（如相關(guān)且未另作論證）合成中或降解過(guò)程中形成的潛在致突變雜質(zhì)在CEP注冊(cè)文件中列出并進(jìn)行分類?？梢愿鶕?jù)其潛在的致突變性和致癌性將雜質(zhì)分為5類（參見(jiàn)ICH M7表1），并制定相應(yīng)的控制措施。有時(shí)，對(duì)于一些具有警戒結(jié)構(gòu)的雜質(zhì)和合成過(guò)程中產(chǎn)生的雜質(zhì)（ICH M7規(guī)定的3類雜質(zhì)），沒(méi)有可用的致突變性數(shù)據(jù)，則應(yīng)將這些雜質(zhì)控制在可接受的限度或以下，或應(yīng)進(jìn)行致突變性測(cè)定(參見(jiàn)ICH M7注2)，以確認(rèn)該雜質(zhì)不具有致突變性（屬于5類）還是具有致突變性（屬于2類）?？梢酝ㄟ^(guò)(Q)SAR方法（模擬研究）預(yù)測(cè)細(xì)菌致突變性測(cè)定的結(jié)果。根據(jù)ICH M7，應(yīng)該應(yīng)用兩種相互補(bǔ)充的(Q)SAR方法，一種基于專家規(guī)則，另一種基于統(tǒng)計(jì)。應(yīng)該遵循OECD制定的原則。

In order to set an acceptable limit for (potential) mutagenic impurities in the substance it is necessary to divide the “acceptable intake” of the (potential) mutagenic impurity by the maximum daily dose of the substance. In order to identify the acceptable intake for a mutagenic impurity, the “l(fā)ess-than-lifetime” (LTL) concept may be used. Note 7 of ICH M7 is very helpful to identify this acceptable intake, and ICH M7 also gives guidance on how to identify acceptable total intakes for multiple impurities.

為了確定物質(zhì)中（潛在的）致突變雜質(zhì)的可接受限度，有必要將（潛在的）致突變雜質(zhì)的“可接受攝入量”除以該物質(zhì)的最大日劑量。為了確定致突變雜質(zhì)的可接受攝入量，可以使用“少于壽命”（LTL）概念。ICH M7的注釋7對(duì)識(shí)別這種可接受攝入量非常有幫助，ICH M7也對(duì)如何識(shí)別多種雜質(zhì)的可接受總攝入量提供了指導(dǎo)。

Once an acceptable limit is adequately identified, it is expected that a control strategy is developed according to the four proposals given by ICH M7 (from option 1 to option 4), according to the nature of those impurities and their probability to be present in the final substance. Batch data should be given in support (if deemed necessary) and the analytical methods used should be described. Purge studies may be developed in support to approaches based on option 3 and option 4. Purge studies should be well-developed and justified and all the physico-chemical parameters used (reactivity, solubility, volatility, ionisability, physical processes, etc) should be given with the studies and discussed.

一旦充分確定了可接受的限度，根據(jù)這些雜質(zhì)的性質(zhì)及其在最終物質(zhì)中出現(xiàn)的概率，預(yù)計(jì)將根據(jù)ICH M7給出的四個(gè)建議（從選項(xiàng)1到選項(xiàng)4）制定控制策略。應(yīng)提供批數(shù)據(jù)作為支持（如果認(rèn)為必要），并應(yīng)描述所使用的分析方法?？梢蚤_(kāi)展清除研究，以支持基于選項(xiàng)3和選項(xiàng)4的方法。吹掃研究應(yīng)充分發(fā)展和合理，所使用的所有物理化學(xué)參數(shù)（反應(yīng)性、溶解度、揮發(fā)性、電離性、物理過(guò)程等）應(yīng)與研究一起給出和討論。

TOP 2 (S.2.3): Absence or insufficient discussion on fate and carryover of related substances of starting materials (included) to the final substance.

TOP 2 (S.2.3):缺少對(duì)起始物料（包括）到最終產(chǎn)品的有關(guān)物質(zhì)的殘留和去向的討論或討論不充分。

The impurity profile of molecules identified as starting materials should be well characterised. This means that applicants need to know what kind of impurities can be found in starting materials, in particular with regard to related substances since usually these are molecules that can react according to the chemistry foreseen by the process, leading to impurities in intermediates and potentially in the final substance. Once the impurity profile of starting materials is sufficiently characterised a detailed discussion is expected not only with regard to carryover of impurities from starting materials to the final substance but also with regard to their fate: what happens to them once introduced in the process along with the starting material. Carryover of unreacted starting materials themselves should also be discussed. If deemed necessary, adequate evidence (e.g., analytical data, literature, information from process development or process validation, etc.) should be given in support.

起始物料的雜質(zhì)概況應(yīng)進(jìn)行完整的確證。這意味著申請(qǐng)人需要知道在起始物料中可能發(fā)現(xiàn)哪些雜質(zhì)，特別是關(guān)于有關(guān)物質(zhì)，因?yàn)橥ǔ＿@些雜質(zhì)可以根據(jù)工藝所預(yù)見(jiàn)的化學(xué)反應(yīng)產(chǎn)生的分子，形成中間體的雜質(zhì)并可能形成最終產(chǎn)品中的潛在雜質(zhì)。在充分確證起始物料的雜質(zhì)概況后，不僅需要詳細(xì)討論雜質(zhì)從起始物料轉(zhuǎn)移到最終產(chǎn)品的問(wèn)題，還需要詳細(xì)討論它們的去向:它們與起始物料一起引入工藝中會(huì)發(fā)生什么。未反應(yīng)完全的起始物料在最終產(chǎn)品中的殘留也應(yīng)進(jìn)行討論。如果認(rèn)為必要，應(yīng)提供充分的證據(jù)（如分析數(shù)據(jù)、文獻(xiàn)、工藝開(kāi)發(fā)或工藝驗(yàn)證的信息等）作為支持。

TOP 3 (S.2.2, S.2.4): Lack of details and/or poor description of the manufacturing process of the substance from the introduction of starting materials (synthesis, narrative description, flow charts, recovery and reprocessing procedures). Incongruences noted between information given in section S.2.2 and section S.2.4.

TOP 3 (S.2.2, S.2.4):缺乏對(duì)起始物料到成品的生產(chǎn)工藝的詳細(xì)和/或簡(jiǎn)單描述(合成、敘述性描述、流程圖、回收和返工工序)。S.2.2和S.2.4所提供的信息不一致。

The manufacturing process should be described in details including all used chemicals along with their quantities, all the operations conducted and all the corresponding operational conditions adopted (in terms of temperatures, pressures, times, etc.). The process needs to be well-described since this is the main source of information that allows assessors to take position on potential formation of impurities and on the potential ability of the process to remove impurities. In-process controls should be mentioned in section S.2.2 (as part of the description of the manufacturing process) and details should be given in section S.2.4 (in terms of acceptance criteria and analytical methods), including controls implemented on isolated intermediates. It is expected that no incongruences are noted while comparing information given in these two sections of the dossier.

應(yīng)詳細(xì)描述工藝過(guò)程，包括所有使用的化學(xué)品及其用量，進(jìn)行的所有操作及所有相應(yīng)的操作條件（如溫度、壓力、時(shí)間等）。工藝應(yīng)詳細(xì)描述，因?yàn)檫@是審評(píng)員獲得信息的主要來(lái)源，依據(jù)這些信息，審評(píng)員可以對(duì)潛在雜質(zhì)形成和工藝去除雜質(zhì)的潛在能力進(jìn)行評(píng)估。S.2.2應(yīng)描述中控信息（作為生產(chǎn)工藝描述的一部分），S.2.4應(yīng)對(duì)中控進(jìn)行詳細(xì)說(shuō)明（可接受標(biāo)準(zhǔn)和分析方法），包括對(duì)分離中間體進(jìn)行的控制。在注冊(cè)文件的這兩個(gè)部分中給出的信息不應(yīng)該有不一致的情況。

The maximum batch size or the batch size range the process described in the dossier refers to should be given in section S.2.2. This information should be congruent with the size of batches described in section S.4.4.

在注冊(cè)文件S.2.2中應(yīng)描述工藝的最大批量或批量范圍。應(yīng)與S.4.4所述批量一致。

These requirements apply equally to the manufacturing steps for outsourced intermediates, which should be fully described in the CEP applications.

這些要求同樣適用于外購(gòu)中間體的生產(chǎn)步驟，應(yīng)在CEP申請(qǐng)中充分說(shuō)明。

TOP 4 (S.2.3): Non-acceptable starting materials, necessity to redefine them earlier in the process.

TOP 4 (S.2.3): 擬定的起始物料不被接受，需要重新定義工藝中更早的物料為起始物料。

Starting materials are the starting points for GMP and variations/revisions and they should be representative of the overall synthetic process. Starting materials should be identified and selected according to the requirements set by ICH Q11 and any additional related available guidance. These are considered as mandatory readings before initiating the exercise of defining starting materials. The reasons why the proposed starting materials are considered as adequate and in line with applicable guidelines should be explained in details in the dossier, in section S.2.3.

起始物料是GMP和變更/修訂的起點(diǎn)，應(yīng)該代表整個(gè)合成工藝。起始物料的界定和選擇應(yīng)根據(jù)ICH Q11和其他所有相關(guān)可獲得的指南規(guī)定的要求。在開(kāi)始定義起始物料之前應(yīng)閱讀上述指南。在S.2.3節(jié)中應(yīng)詳細(xì)說(shuō)明擬議的起始物料的選擇是充分的，并符合所有適用的指南。

If found not acceptable by the assessors, starting materials should be redefined back in the process and this may have major consequences on the manufacture and on the content of the dossier. Manufacturers initially proposed for those non-acceptable starting materials become manufacturers of intermediates (subject to EU GMP Part II and willingness to be inspected) and the dossier should be completely restructured accordingly, since the process from new starting materials to intermediates should be described in section S.2.2. Therefore applicants are expected to select carefully their starting materials.

如果審評(píng)人員認(rèn)為擬定的起始物料不可接受，則需要重新定義起始物料，需要順著工藝往前推，這可能會(huì)對(duì)生產(chǎn)和注冊(cè)文件的內(nèi)容產(chǎn)生重大影響。最初擬定的未被接受的起始物料的生產(chǎn)商變?yōu)橹虚g體的生產(chǎn)商(符合EU GMP Part II，并愿意接受檢查)，由于需要在S.2.2中重新描述自起始物料到中間體的工藝過(guò)程，注冊(cè)文件整體應(yīng)完全重組。因此，申請(qǐng)人應(yīng)該慎重選擇起始物料。

TOP 5 (S.2.3): Non-adequate or poorly justified specifications in place to control the quality of starting materials.

TOP 5 (S.2.3):起始物料的質(zhì)量控制不充分或論證不足。

The quality of molecules identified as starting materials should be sufficiently characterised and kept under control by adequately justified specifications. It is expected that specifications in place to control the quality of starting materials mirror their manufacturing processes. The specification of a starting material should include tests for identity and purity (e.g., controls on impurities), and acceptance criteria for assay, specified, unspecified and total impurities, residual solvents, reagents, mutagenic impurities etc as needed. Tests and acceptance criteria should be based on process knowledge and control strategy. The analytical methods used should be suitably validated and described in section S.2.3. The justification of the specification should include evaluation of the risks and the ability of the subsequent steps to purge impurities. Assurance should be given in the dossier that there are no risks of having uncontrolled impurities in the final substance potentially above acceptable limits. These are risks always kept in mind by assessors while evaluating applications in the context of the Certification Procedure.

被確定為起始物料的分子的質(zhì)量應(yīng)充分確證，并由充分論證的質(zhì)量標(biāo)準(zhǔn)加以控制。預(yù)期控制起始物料質(zhì)量的質(zhì)量標(biāo)準(zhǔn)應(yīng)反映其生產(chǎn)過(guò)程。起始物料的質(zhì)量標(biāo)準(zhǔn)應(yīng)包括鑒別和純度的測(cè)試（例如，雜質(zhì)控制），以及所需的含量、特定雜質(zhì)、非特定雜質(zhì)和總雜、殘留溶劑、試劑、致突變雜質(zhì)等的可接受標(biāo)準(zhǔn)。測(cè)試和可接受標(biāo)準(zhǔn)應(yīng)基于工藝知識(shí)和控制策略確定。所使用的分析方法應(yīng)經(jīng)過(guò)適當(dāng)?shù)尿?yàn)證，并在S.2.3中說(shuō)明。質(zhì)量標(biāo)準(zhǔn)的論述應(yīng)包括對(duì)風(fēng)險(xiǎn)和后續(xù)步驟清除雜質(zhì)的能力的評(píng)估。在注冊(cè)文件中應(yīng)保證最終產(chǎn)品中不存在未受控雜質(zhì)可能超過(guò)可接受限度的風(fēng)險(xiǎn)。審評(píng)員在認(rèn)證程序的背景下評(píng)估申請(qǐng)始終會(huì)牢記對(duì)這些風(fēng)險(xiǎn)予以關(guān)注。

TOP 6 (S.2.3): Non-adequate or missing specifications (and analytical methods) for reagents and solvents (recovered and recycled included) used to manufacture the substance from the introduction of starting materials.

TOP 6 (S.2.3):從引入起始物料開(kāi)始，用于生產(chǎn)最終產(chǎn)品的試劑和溶劑（包括回收）的質(zhì)量標(biāo)準(zhǔn)(和分析方法）不充分或缺失。

It is expected that specifications, including analytical methods in place are described in section S.2.3 for all chemicals and reagents used to manufacture the substance from the introduction of starting materials. It is also expected that a purity test is included in the specification and that a reasonable mass balance is shown by the specification, unless otherwise justified. Specifications in place to test recycled materials before being reused should be given. Any relevant difference comparing to the corresponding specification for the fresh material should be highlighted and the potential impact these differences might have on the quality of the final substance should be discussed.

應(yīng)在S.2.3節(jié)中描述從引入起始物料開(kāi)始用于生產(chǎn)成品的所有化學(xué)物質(zhì)和試劑的質(zhì)量標(biāo)準(zhǔn)和分析方法。除非另有論述，還應(yīng)在質(zhì)量標(biāo)準(zhǔn)中包含純度測(cè)試，并在質(zhì)量標(biāo)準(zhǔn)中顯示出合理的物料平衡。應(yīng)提供回收物料在再次使用前檢測(cè)的質(zhì)量標(biāo)準(zhǔn)。應(yīng)與新鮮物料的相應(yīng)質(zhì)量標(biāo)準(zhǔn)進(jìn)行對(duì)比，標(biāo)出相關(guān)差異情況，并應(yīng)討論這些差異可能對(duì)最終產(chǎn)品質(zhì)量產(chǎn)生的潛在影響。

TOP 7 (S.3.2): Non-adequate or missing discussion on carryover of reagents and elemental impurities to the final substance.

TOP 7 (S.3.2):缺少對(duì)最終產(chǎn)品中試劑和元素雜質(zhì)殘留的討論或討論不充分。

A discussion (as part of the general discussion on the impurity profile of the substance in section S.3.2) on fate and carryover to the final substance of reagents is expected, as applicable. If elemental impurities are used or likely to be present, a discussion on their carryover is expected. For elemental impurities, the guidelines of reference are ICH Q3D and the related EDQM document PA/PH/CEP (16) 23 available on the EDQM website.

如果適用，應(yīng)對(duì)最終產(chǎn)品中試劑和元素雜質(zhì)殘留和去向進(jìn)行討論(作為S.3.2節(jié)中關(guān)于產(chǎn)品雜質(zhì)概況的一般性討論的一部分)。如果使用了元素雜質(zhì)或可能存在元素雜質(zhì)，則應(yīng)討論其殘留問(wèn)題。對(duì)于元素雜質(zhì)，參考指南為ICH Q3D和EDQM網(wǎng)站上的EDQM文件PA/PH/CEP(16)23。

TOP 8 (S.2.4): Non-adequate or poorly justified specifications in place to control the quality of isolated intermediate.

TOP 8 (S.2.4):分離中間體的質(zhì)量控制不充分或質(zhì)量標(biāo)準(zhǔn)論證不足。

Sometimes poorly justified specifications are proposed for isolated intermediates. It is expected that the impurity profile of isolated intermediates is sufficiently characterised and kept under control by adequate specifications. This piece of information (as part of the control strategy of the substance) is particularly important for intermediates which are isolated late in the process, for intermediates that show low purity, or when an impurity is tested in an intermediate instead of the final substance. Also in these cases acceptance criteria should be justified in relation to the fate and carryover of impurities (see top 9).

有時(shí)對(duì)分離中間體的質(zhì)量標(biāo)準(zhǔn)論述不夠合理。分離中間體的雜質(zhì)概況應(yīng)得到充分的確證，并通過(guò)適當(dāng)?shù)馁|(zhì)量標(biāo)準(zhǔn)加以控制。對(duì)于在工藝后期分離的中間體、顯示出低純度的中間體，或者在中間體中檢測(cè)代替在最終產(chǎn)品中檢測(cè)的雜質(zhì)來(lái)說(shuō)，這部分信息（作為最終產(chǎn)品控制策略的一部分）尤為重要。在這些情況下，可接受標(biāo)準(zhǔn)應(yīng)結(jié)合雜質(zhì)的殘留和去向進(jìn)行論證（見(jiàn)TOP 9）。

TOP 9 (S.3.2): Absence or insufficient discussion on fate and carryover of impurities from synthetic intermediates (included) to the final substance.

TOP 9 (S.3.2):缺乏對(duì)雜質(zhì)從合成中間體(包括在內(nèi))到最終產(chǎn)品的殘留和去向的討論或討論不充分。

Isolated intermediates are most of the times contaminated by related substances that can react the same way as the intermediate to give intermediate-like and eventually final substance-like impurities. Hence a discussion based on evidence (e.g., analytical data, literature, information from process development or process validation, etc.) on fate and carryover of impurities present in intermediates is expected in the dossier. It is necessary to take into account impurities controlled in isolated intermediates in the section on impurities (S.3.2) and in the discussion on the suitability of the Ph.Eur monograph to control the quality of the substance. The risks of having uncontrolled impurities in the final substance potentially above acceptable limits should be addressed. Demonstration of absence in the final substance of the last synthetic intermediates is also expected.

分離的中間體大多數(shù)時(shí)候會(huì)受到有關(guān)物質(zhì)的污染，這些物質(zhì)以與中間體相同的方式反應(yīng)，產(chǎn)生類似中間體的雜質(zhì)和類似最終產(chǎn)品的雜質(zhì)。因此，注冊(cè)文件中應(yīng)基于證據(jù)（如分析數(shù)據(jù)、文獻(xiàn)、工藝開(kāi)發(fā)或工藝驗(yàn)證的信息等）討論中間體中存在的雜質(zhì)的殘留和去向。在雜質(zhì)部分（S.3.2）和討論P(yáng)h.Eur各論對(duì)最終產(chǎn)品質(zhì)量控制的適用性時(shí)，有必要考慮到分離中間體的雜質(zhì)控制。應(yīng)說(shuō)明最終產(chǎn)品中不受控制的雜質(zhì)可能超過(guò)可接受限度的風(fēng)險(xiǎn)。另外還應(yīng)證明最終產(chǎn)品中不存在最后一步反應(yīng)的中間體。

TOP 10 (S.2.3): Non-adequate or missing information on the synthesis of starting materials and their manufacturers.

TOP 10 (S.2.3):起始物料的合成信息及其生產(chǎn)商的信息缺失或不充分。

A brief description of the preparation of the starting materials (flow diagram of the process, including solvents and reagents used), along with name(s) and address(es) of their manufacturers (not their suppliers) is expected to be found in section S.2.3 of the dossier. This is to evaluate the suitability of the proposed starting material and its specification. In case more than one source of the same starting material is used, quality equivalence should be demonstrated by means of batch data collected on the final substance manufactured using all the possible sources of the same starting material.

在注冊(cè)文件的S.2.3節(jié)中提供起始物料制備的簡(jiǎn)要描述（工藝流程圖，包括所用的溶劑和試劑）以及制造商（不是供應(yīng)商）的名稱和地址。這是為了評(píng)估擬定的起始物料及其質(zhì)量標(biāo)準(zhǔn)是否合適。如果使用多個(gè)來(lái)源的起始物料，應(yīng)通過(guò)收集使用所有可能來(lái)源的起始物料的最終產(chǎn)品的批數(shù)據(jù)來(lái)證明質(zhì)量等同。

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