ema問(wèn)答提高對(duì)norpardsp和工藝參數(shù)的正常波動(dòng)的理解

1、EMA問(wèn)答：提高對(duì)NOR、PAR、DSp和工藝參數(shù)的正常波動(dòng)的理解6 June 2017EMA/CHMP/CVMP/QWP/354895/2017 Questions and answers: Improving the understanding of NORs,PARs,DSp and normal variability of process parameters 問(wèn) 答：提高對(duì)NOR、PAR、DSp和工藝參數(shù)的正常波動(dòng)的理解 1 What is a Normal Operating Range (NOR) and how should NORs bepresented in the m

2、arketing authorisation dossier?什么 是NOR(正常運(yùn)行范圍)？ NOR在上市許可文件中應(yīng)如何呈 現(xiàn)？ Answer:答 NOR is not an establishedICH term. NOR 并不 是由ICH制 i丁白勺術(shù)i吾。The NOR describes a regionaround the target operating conditions that contain common operationalvariability (variabi lity that can t always becontrolled).NOR描述的是目標(biāo)操作條件

3、鄰近范圍，其中包括 正 常的操作波動(dòng)(波動(dòng)并不總能控制)。A NOR can be establishedfor several process parameters of the same process step, with the understandingthat the NOR does not represent deliberate adaptation of the process, and thatthe NOR does not cover a parameter range that affects the quality of theprocess output. Ot

4、herwise, a PAR or a multivariate Design space should beestablished.可以對(duì)同一個(gè)工藝步驟中的幾個(gè)工藝參數(shù)制訂一個(gè) NOR，要了解NOR并不代表在慎重考慮后采用該工藝，NOR并不覆蓋影 響工 藝輸出質(zhì)量的參數(shù)范圍。否則，就需要建立一個(gè)PAR或多變量設(shè) 計(jì)空間。The use of NORs alone isnot intended to introduce flexibility in the conditions for manufacturing butto better quantify the actual unc on

5、trollable operational variability of processparameters. NORs should therefore be presented in marketing authorisations aswhat is practically achievable單獨(dú)使 用NOR并不是要將條件波動(dòng)引入生產(chǎn)中，但NOR可能會(huì)更好 地量化工藝參數(shù)不受控制的實(shí)際操作波動(dòng)，因此需要在上市許可 中呈現(xiàn)實(shí)際能達(dá)到的 水平。2. What is a Proven Acceptable Range (PAR) and how should PARs bejustified

6、 and presented in the marketing authorisation dossier?什么是經(jīng)證明白勺可接受 范圍 (PAR ) ? PAR應(yīng)如何論證以及如何在上市許可文件中呈現(xiàn)？ Answer:The PAR is defined as acharacterized range of a process parameter for which operation within thisrange5 while keeping other parameters constant, will result in producing amaterial meeting rel

7、evant quality criteria (ICH Q8 R2).PAR 定義是“一個(gè) 經(jīng)過(guò)特征識(shí)別的工藝參數(shù)范圍，操作應(yīng)在此范圍內(nèi)進(jìn)行。當(dāng)保 持其它參數(shù)恒定時(shí)，此參數(shù)范圍內(nèi)操作將生成符合相矢質(zhì)量標(biāo)準(zhǔn) 的物料(ICH Q8 )。A PAR allows deliberatechange in one parameter without changing the others outside their NOR/ target.PARs could be presented in the description of the manufacturing process of thedrug

8、substance and/or the drug product (in S.2.2 or P.3.3 of the Module 3,respectively) as ranges PAR允許對(duì)一個(gè)參數(shù)進(jìn)行慎重修改，而不需要將其他參數(shù) 變更到超出其NOR/目標(biāo)。PAR可以放在原料藥(DS )和/或制劑(DP )生產(chǎn)工藝描述部分(分別在模塊3的S.2.2部分或P.3.3部分)作為工藝范圍。PARs for single parametersare proposed by the applicant and are subject to regulatory assessment andapp

9、roval.單個(gè)參數(shù)的 PAR 是由申報(bào)人擬定，經(jīng)過(guò)注冊(cè)評(píng)審和批準(zhǔn)的。The PAR should beadequately justified regardless of whether the process parameter is considereda critical process parameter (ICH Q8 R2) or not.不論工藝參數(shù)是否是矢鍵工藝參數(shù)(ICH Q8 R2)，PAR均 應(yīng)進(jìn)行充分論證 Where interaction e什ectsbetween different parameters exist and the acceptable rang

10、e for one processparameter depends on the setting of another parameter, the parameters should beineluded in a Design Space.Alternatively, a PAR can be defined for only one ofthe parameters in the process description, and other process parameters will belimited to target operating condition or NOR.如果

11、不同參數(shù)之間存在 著相互作用， 一個(gè)工藝參數(shù)的可接受范圍取決于另一個(gè)參數(shù) 的設(shè)置，則參數(shù)應(yīng) 放在一個(gè)設(shè)計(jì)空間里。在工藝描述中，一個(gè)PAR只能定義給一 個(gè)參數(shù)，其它工藝參數(shù)則要限制在目標(biāo)操作條件內(nèi)或NOR內(nèi)。PARs can initially beestablished at a smaller scale than the commercial scale .If so, the applica ntshould en sure that the PAR is scale independent and applicable acrossalternative manu facturi ng

12、 sites, if re leva nt. Verification of PAR at commercialscale could be in eluded in a post-approval verificatio n protocol ifappropriatePAR最初可以在較小的批量下建立，而不 需要在商業(yè)化規(guī)模建立。假設(shè)如此，則申報(bào)人應(yīng)確保PAR不受 批量大小的影響，適用于不同生產(chǎn)場(chǎng)所（如相矢）。在商業(yè)化規(guī) 模下對(duì)PAR的核查可以包括在批準(zhǔn)后的核查方案中（適當(dāng) 時(shí)） Working within the approvedPAR is not considered as a ch

13、ange to the marketing authorisation dossier.Changes to the target value within the registered PAR can be managed under thecompany sPharmaceutical Quality System without regulatory action.Consequently, there is no specific need to include a target set point within theregistered PAR, but if in eluded

14、no variation will be required when changed Anyunexpected result should be reported forthwith to the competent authorities.Movement out of the PAR is considered to be a change and will initiate aregulatory post approval change process.在批準(zhǔn)的PAR內(nèi)工作并不是一個(gè)變更。在注冊(cè)的PAR范圍內(nèi)對(duì)目標(biāo)值的變更可以依據(jù)公司的藥物 質(zhì)量體系(PQS )來(lái)管理，不需要注冊(cè)措施

15、。之后，也并沒(méi)有特定 要求將目標(biāo)設(shè)定點(diǎn)包括在已注冊(cè)的PAR中；但是如果包括了， 在變更時(shí)也不要求提交變更。所有非預(yù)期的結(jié)果均應(yīng)報(bào)告給藥監(jiān) 機(jī)構(gòu)。超出PAR范圍則是變更，需要遵守批準(zhǔn)后變更流程。 Considerations fordevelopment (S.2.6/ P.2.3 of Module 3): Several PARs can be presented andinvestigated as part of the process understanding and development.研發(fā)考量(模塊 3 的 S.2.6/P.2.3 ):幾個(gè)PAR可以放在工藝?yán)斫夂脱邪l(fā)部分進(jìn)行

16、呈現(xiàn) 和探討。3. What is a Design Space (DSp) and how should design spaces bejustified and presented in the marketing authorisation dossier?什么是設(shè)計(jì)空間(DSp ) ? DSp要如何進(jìn) 行論證并 呈現(xiàn)在上市許可文件中？ Answer:The design space is definedby the multidimensional combination and interaction of input variables (e.g.5material attrib

17、utes) and process parameters that have been dem on stratedtoprovide assuranee of quality. Working within the approved design space is notconsidered as a change Movement out of the design space is considered to be achange and would normally initiate a regulatory post approval change process.Design sp

18、ace is proposed by the applicant and is subject to regulatoryassessment and approval (ICH Q8 R2).設(shè)計(jì)空間定義 為輸入變更(例如，原料屬性)以及被證明能提供質(zhì)量保證的工藝 參數(shù)的相互作用和多維組合。在批準(zhǔn)的DSp內(nèi)工作不是變更，超 出DSp則是變更，一般需要遵守批準(zhǔn)后的注冊(cè)變更流程。DSp 是由申報(bào)人提議，經(jīng)由注冊(cè)審評(píng)和批準(zhǔn)的(ICH Q8 ) A design space (DSp) canpertain to an isolated process step, or it can cover p

19、arameters of severalprocess steps. 一個(gè)設(shè)計(jì)空 間可以屬 于一個(gè)獨(dú)立的工藝步驟，也可以覆蓋幾個(gè)工藝步驟的參數(shù)。A DSp can be supported bysuitable in-process controls, or output material quality can be assured byworking within the DSp ranges alone.可以用適當(dāng)?shù)闹锌貋?lái)支持設(shè)計(jì)空間，或者僅由在設(shè)計(jì)空間 范圍內(nèi)工作來(lái)確保輸 出物料質(zhì)量。A DSp can be restricted byranges of process paramet

20、ers only, input material attributes only，or acorn bin ation of process parameters and input material attributes. 一個(gè)DSp只可以由工藝參數(shù)范圍、輸入物料屬性、 或者是工藝參數(shù)和輸入物料屬性的組合來(lái)限制。Material attributes andprocess parameters that can affect quality, but are not described by ranges inthe DSp would need to be controlled by th

21、eir specification or target/NOR,respective!y. Critical processes should always be in eluded as part of theformal DSp, eve n if theyare con trolled. Process parameters (no n-criticalprocess parameters) that have been demonstrated to not be critical within theirstudied range can be defined by target o

22、r range outside the formal DSp.可能影響質(zhì)量，但未采用設(shè)計(jì)空間范 圍來(lái)描述的物 料屬性和工藝參數(shù)需要分別由其質(zhì)量標(biāo)準(zhǔn)或目標(biāo)/NOR來(lái)控制。 即使受到控制，尖鍵工藝應(yīng)總是包括在其中作為正式設(shè)計(jì)空間的 一部分。已在其研究范圍內(nèi)證明為非尖鍵的工藝參數(shù)(非矢鍵工藝 參數(shù))可以由目標(biāo)或超出正常設(shè)計(jì)空間的范圍來(lái)界定。The justification of a DSpshould be presented in the development of the manufacturing process of the drugsubstance and/or drug produ

23、ct (S.2.6 or P.2.3 of Module 3, respectively). Thenecessary level of details will depend on the significance, or the impact, ofthe DSp. The following should be considered:DSp 的論證應(yīng)放 在DS和/或DP的生產(chǎn)工藝研發(fā)部分(分別為模塊3的S.2.6 或P.2.3部分)。在所需的詳細(xì)程度方面應(yīng)考慮以下內(nèi)容:Does the DSp represent parameter ranges thatare much widerth

24、an what would normally be accepted as NORs? DSp呈現(xiàn)的參數(shù)范圍可否遠(yuǎn)遠(yuǎn)寬于常規(guī)可接受的 NOR ? Does any area of the DSp represe nt greater risk to quality thanthe rest of the DSp?是否有DSp的任何區(qū)域所呈現(xiàn)的風(fēng)險(xiǎn)是否比DSp的其余區(qū)域具有更大的質(zhì)量風(fēng) 險(xiǎn)？ To what extent do otherelements of the control strategycontribute to ensuring output material quality?

25、Examples in elude in-processcontrols, PAT analytics and dow nstream processes and controls. 控制策略的其它要素對(duì)確保 輸出物料質(zhì)量的影響到 何程度？例子包括中控、PAT技術(shù)和下游工藝和控制。Any multivariateinteractions between the DSp parameters n eed to be studied .In particular, whenthe acceptable range of one parameter within a DSp is dependent

26、 on any otherparameter, this should be thoroughly investigated, including consideration ofscale. If it is claimed that no interaction exists between parameters, thisshould be adequately justified.所有設(shè)i十空可參數(shù)之可 的多變量相互作用都需要進(jìn)行研究。尤其是，如果在一個(gè)設(shè)計(jì)空間內(nèi)有一個(gè)參 數(shù)的可接受范圍與所有其它參數(shù)都不相矣，則需要進(jìn)行徹底調(diào)查，包括考慮批 量。如果聲明參數(shù)之間不 存在相互作用、則應(yīng)進(jìn)

27、行充分論證。Depending on thesignificance of the DSp, its development should be guided by risk management asappropriate (ref. ICHQ8 and Q9)依據(jù)設(shè)計(jì)空間的重要性，其研發(fā)應(yīng)基于風(fēng)險(xiǎn)管理原 則(參見ICH Q8 和 Q9)。4. How to manage post-approval changes to approved design spaces?如何管理已批準(zhǔn) DSp 的批準(zhǔn)后變更？Answer:Extension of a design space(DSp) shou

28、ld be submitted as a Type II variation (B.l.e.1 or B.ll.g.1). By “ extension * 3 the following isunderstood: 1) introduction of new materialattributes or process parameters, 2) extension of the range of existingmaterial attributes or critical process parameters.放 寬設(shè)計(jì)空間應(yīng)作為II類變更(B.l.e.1或B.ll.g.1 )提交?！?/p>

29、放 寬”理解如下：1 )引入新物料屬性或工藝參數(shù)，2)放寬已有物料屬性或尖鍵 工藝參數(shù)的范圍。If the change has beenforeseen as described in an approved post-approval change management protocol(PACMP)3 depending upon what was agreed, the change can either be submitted asa Type lAin or IB notification (B丄e.5 or B.ll.g.5). In accordance with theva

30、riation classification guideline, changes foreseen in PACMP for abiological/immunological medicinal product are Type IB.如果這些變更已經(jīng)在一份批準(zhǔn)的上市后變更管理方案(PACMP )中進(jìn)行了描述，則根據(jù)已達(dá)成一致的內(nèi) 容，變更可以按IA或IB通知類提交(B丄e.5或B.ll.g.5 ) 根據(jù)變更分類指 南，在PACMP中可 預(yù)見生物/免疫藥品變更為IB類。Restrictions to an approveddesign space would typically only

31、be necessary if part of the DSp wasdiscovered to not produce satisfactory quality material. Such changes to themanufacturing process should be submitted as a Type II variation (B丄a.2b orBlb3.b): substantial changes to a process that may have a significantimpact on the quality, safety or efficacy of

32、the product.對(duì)已批準(zhǔn) DSp 的加嚴(yán)則一般只有在發(fā)現(xiàn)DSp不能生成令人滿意質(zhì)量的物料時(shí)才有必要。此 類生產(chǎn)工藝變更應(yīng)作為II類變更提交(B.l.a.2.b或B.ll.b.3.b ):可能會(huì)對(duì)質(zhì) 量、安全或有效性有重大影響的重大工藝變更。Some changes to inputmaterial attributes (specifications) or process parameter settings/ranges canbe relevant to the DSp, even if the DSp does not specifically cover theseparam

33、eters For example, the DSp can be established on the condition that othernon-critical process parameters, which are required in the manufacturingprocess description, but have been demonstrated not to be critical within therange studied, are kept constant or within their range. Changes to any of thes

34、eelements should be sought in accordance with the variations classificati on guideline, where, depe nding upon the n ature of the changes and type of productsome will be possible as Type IA, provided the relevant conditions anddocumentation requirements are fully met, whereas others will be possi bl

35、e asType IB notifications .In all cases the new process must lead to an equivalentproduct regarding all aspects of quality, safety and efficacy and the changeshould not adversely affect the reproducibility of the process and it should beshown that the criticality of the parameter in question is unch

36、anged 一些輸入物料屬性(質(zhì)量標(biāo)準(zhǔn))的變更或工藝參數(shù)設(shè)置/范圍可能會(huì)與設(shè)計(jì)空 間有矢，即使該設(shè)計(jì)空間DSp并不具體覆蓋哪些參數(shù)。例如，設(shè)計(jì)空間可以 建立在以下條件上，也就是其它生產(chǎn)工藝描述所需，但已證明在所研究范圍內(nèi) 并不尖鍵的非尖鍵工藝參數(shù)保持恒定或在其范圍內(nèi)。對(duì)這些要素的變更應(yīng)依據(jù) 變更分類指南執(zhí)行，這里，根據(jù)變更的屬性和藥品的類型，有些可能會(huì)分類為 IA類(如果滿足相矢條件和文件要求)，而另一些可能分類為IB類通知。 在所有情形下，新工藝都必須能生產(chǎn)出在質(zhì)量、安全和有效性方面等同的產(chǎn) 品，而變更則不能對(duì)工藝重復(fù)性產(chǎn)生不良影響，且所涉及的參數(shù)的矢鍵程度應(yīng) 證明沒(méi)有變化 The vari

37、ation categoriesrelated to changes to manufacturing sites apply regardless of DSp or not. However, the continued re leva nee of any registered DSp should be consideredwhenever there is a manufactoring site change.不論DSp變更與否，均適用與生 產(chǎn)場(chǎng)所變更相矣的變更類型。但 是，只要有生產(chǎn)場(chǎng)所變更，均應(yīng)考慮所有注冊(cè)的DSp的持續(xù)相矢性。It should be noted thatth

38、is Q&A has been developed considering the current variationclassification; Guidelines on the details of the various categories ofvariations, on the operation of the procedures laid down in Chapters II, Ila,III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008concerning the examin

39、ation of variations to the terms of marketingauthorisations for medicinal products for human use and veterinary medicinalproducts and on the documentation to be submitted pursuant to those procedures(2013/C 223/01).要注意的是，本問(wèn)題起草 時(shí)考慮了當(dāng)前的變更分 類“不同變更分類細(xì)則指南，2008年11月24日EC指令1234/2008第 II、Ila、III和IV章中設(shè) 定的程序，矢

40、于人藥和獸藥上市許可變更檢查，以及 依據(jù)這 些程序所需提交的文件檢查(2013/C223/01廣。5Whattype of process flexibility can be acceptable inthemarketing authorisation dossier, regardless of any mentioning of NOR, PARorDSp?在上市許可文件中，不管是否提到NOR、PAR或DSp，哪些類型的工藝靈活f生是可以接受的?Answer:答 The degree of processflexibility is dependent upon how the man

41、ufacturing process and its developmentis presented in the marketing authorisation dossier.工藝靈活性的程度取決于生產(chǎn)工藝及其開發(fā)在上 市許可文 件中是女I何呈現(xiàn)的 Irrespective of thedevelopment approach, the same requirements apply to the level of details inthe manufactoring process description.不論研發(fā)方法如何，相同的要求適用于生產(chǎn)工藝描述的詳細(xì)程 度 Steps in the process shouldhave the necessary details in terms of appropriate process parameters, alongwith their target values or ranges.工藝中 的步驟應(yīng)具備足夠的適當(dāng)工藝參數(shù)以及其目標(biāo)值或范圍的詳細(xì)信息。The establishment of a DSpis optional. A flexible manufactu