FDA對藥物雜質(zhì)的控制要求優(yōu)選內(nèi)容

1、 國家食品藥品監(jiān)督管理局培訓(xùn)中心高級培訓(xùn)班 “美國仿制藥申報最新要求和案例分析”1嚴(yán)選內(nèi)容fda對藥物雜質(zhì)的控制要求：contents 目錄原料藥與成品藥中的有機雜質(zhì)有機雜質(zhì)來源和控制有機雜質(zhì)控制限度的論證案例分析：雜質(zhì)控制限度的設(shè)置和論證練習(xí)-雜質(zhì)控制限度的設(shè)置和論證原料藥與成品藥中的殘留溶劑殘留溶劑的指導(dǎo)原則和控制限額的建立案例分析：如何建立殘留溶劑控制限額具有基因毒性雜質(zhì)的控制練習(xí)-殘留溶劑控制限額的建立和論證2嚴(yán)選內(nèi)容drug production and quality control synthesis of api3嚴(yán)選內(nèi)容fda對藥物雜質(zhì)的控制要求 原料藥與成品藥中的有機雜質(zhì)p

2、 1999年11月，fda-“仿制藥申請的原料藥雜質(zhì)研究指導(dǎo)原則”，“仿制藥申請的制劑雜質(zhì)研究指導(dǎo)原則”。p 2003年，ich修訂的q3a(r)“新原料藥雜質(zhì)研究指導(dǎo)原則”，“新制劑的雜質(zhì)研究指導(dǎo)原則”（簡稱q3b(r)。p 雜質(zhì)分類有機雜質(zhì) 合成雜質(zhì)合成雜質(zhì)(synthetic impurity)或工藝雜質(zhì)或工藝雜質(zhì)(process impurity)：一般來自生產(chǎn)過程中殘留的原料、中間體、試劑、配體和催化劑以及反應(yīng)副產(chǎn)物。只與原料藥的生產(chǎn)過程有關(guān)，在原料藥和制劑的儲存中一般不可能增長。通過對合成路線的分析可以確定某一雜質(zhì)是否為合成雜質(zhì)。 降解產(chǎn)物降解產(chǎn)物(degradation prod

3、uct):來源于原料藥通過各種不同的化學(xué)反應(yīng)途徑的降解，一般需要結(jié)合對合成路線的分析和試驗研究的結(jié)果，以確定某一雜質(zhì)是否為降解產(chǎn)物。 有的有機雜質(zhì)既是合成雜質(zhì)，又是降解產(chǎn)物。有的有機雜質(zhì)既是合成雜質(zhì)，又是降解產(chǎn)物。無機雜質(zhì)：來自生產(chǎn)過程所用的試劑（如氯化物）、配體和催化劑（如鈀，鉑等），包括重金屬或其它金屬殘留，以及無機鹽（例如，助濾劑、活性炭等）。它們通常是已知和確定的。殘留溶劑：生產(chǎn)過程中使用后未完全除去的溶劑（如甲醇、甲苯、四氫呋喃等），殘留的可揮發(fā)性試劑（如三乙胺等）和反應(yīng)中生成的可揮發(fā)產(chǎn)物。4嚴(yán)選內(nèi)容有機雜質(zhì)來源5嚴(yán)選內(nèi)容常見的降解反應(yīng)6嚴(yán)選內(nèi)容常見的降解反應(yīng)7嚴(yán)選內(nèi)容確定降解產(chǎn)物-

4、強制降解研究（forced degradation study)stress type強制降解類型common stress 常用強制降解common forced degradation conditions 常見強制降解條件solution stress溶液降解acid 酸0.1n hcl , 室溫-100，4小時base 堿0.1n naoh，室溫-100，4小時h2o2 雙氧水1-3% h2o2， 室溫，4小時heat 加熱h2o， 100，4小時uv & visuable light 紫外光和可見光（300-800nm）15小時（相當(dāng)于波長范圍為300-800nm,約2.0百

5、萬勒克斯時stress固態(tài)降解thermal 加熱 60 ，14天heat/humidity 加熱/濕度40 /75%rh，14天uv & visuable light 紫外光和可見光（300-800nm）15小時（相當(dāng)于波長范圍為300-800nm,約2.0百萬勒克斯時p強制降解試驗：強制降解試驗：將原料藥或制劑置于比通常儲存條件劇烈得多的試驗條件下進行穩(wěn)定性考察的一系列試驗。p目的：目的：了解該藥品的穩(wěn)定性及其降解途徑與降解產(chǎn)物。在一定程度上對有關(guān)物質(zhì)分析方法的專屬性進行驗證。p實際操作：實際操作：試劑的濃度、反應(yīng)的溫度和時間等都應(yīng)根據(jù)具體情況作調(diào)整。p強制降解程度：強制降解程度：

6、根據(jù)經(jīng)驗一般認為，控制適當(dāng)?shù)膹娭平到鈼l件，從而達到大約10%的原料藥降解是比較合適的。p常見的強制降解具體試驗項目與試驗條件常見的強制降解具體試驗項目與試驗條件8嚴(yán)選內(nèi)容確定降解產(chǎn)物-原料藥和制劑的穩(wěn)定性試驗長期（25 2 、相對濕度60% 5%、至少12個月）穩(wěn)定性試驗加速（ 40 2 、相對濕度75% 5%、至少6個月）穩(wěn)定性試驗分析研究收集到的穩(wěn)定性測試數(shù)據(jù)（stability data）也是確定降解產(chǎn)物的重要依據(jù)之一。一般測定不同時間樣品的hplc圖譜并進行比較分析，并與長期保留制劑樣品的測定結(jié)果進行比較。在強制降解試驗研究過程中注意觀察樣品外觀性狀、原料藥含量等變化，并與雜質(zhì)檢查結(jié)果

7、相互印證。原料藥和雜質(zhì)的分離和檢測：將可能的中間體和副產(chǎn)物作為雜質(zhì)進行柱效、流動相及流動相比例、波長和分離度等方法學(xué)的研究。待方法建立成熟后，根據(jù)中間體和副產(chǎn)物的安全性和獲得雜質(zhì)標(biāo)樣的難易程度，決定是否定為已知雜質(zhì)。如果雜質(zhì)標(biāo)樣難以得到，且比較安全，可考慮采用雜質(zhì)校正因子加上相對保留時間的方法，或采用雜質(zhì)相對保留時間加上自身對照的方法，對該雜質(zhì)進行定量分析。如果得不到該雜質(zhì)樣品作為標(biāo)樣，對于有紫外吸收的樣品可以用二極管陣列檢測器，考察未精制的粗品，并對比已精制過的樣品，確定粗品種各成分的分離度和樣品中可能雜質(zhì)的檢測波長。方法確立后，可采用自身對照方法或面積歸一化法控制雜質(zhì)。9嚴(yán)選內(nèi)容原料藥與成

8、品藥中的有機雜質(zhì)p藥品中有機雜質(zhì)的分類有機雜質(zhì)特定雜質(zhì)（specified impurities)：特定雜質(zhì)是指在質(zhì)量標(biāo)準(zhǔn)中分別規(guī)定了明確的限度，并單獨進行控制的雜質(zhì)。特定雜質(zhì)包括化學(xué)結(jié)構(gòu)已知的雜質(zhì)（specified identified impurity) 和化學(xué)結(jié)構(gòu)未知（specified unidentified impurity）的雜質(zhì)。美國藥典通常采用代號來指認特定雜質(zhì)，如相關(guān)化合物a（related compound a）等。非特定雜質(zhì)（ unspecified impurities ）：在標(biāo)準(zhǔn)中未單獨列出，而僅采用一個通用的限度進行控制的一系列雜質(zhì)。其結(jié)構(gòu)未知，在藥品中出現(xiàn)的種

9、類與幾率并不固定。一般采用合適的定性分析指標(biāo)加以指認，如相對保留時間為3.5的雜質(zhì)。有機雜質(zhì)檢測確定原料藥和制劑中潛在的合成雜質(zhì)和降解產(chǎn)物，需要應(yīng)用專業(yè)的有機化學(xué)知識對有關(guān)合成化學(xué)反應(yīng)和條件、原料藥化學(xué)結(jié)構(gòu)、理化性質(zhì)、穩(wěn)定性等進行全面的科學(xué)分析和論證，并且比較實驗室對樣品的常規(guī)分析和強制降解（forced degradation study），以及穩(wěn)定性研究的結(jié)果。10嚴(yán)選內(nèi)容impurities: origination & identification classification of impuritiessynthetic impurities (residual substa

10、nces in the synthesis) starting material by-products intermediates degradation during synthesis reagents, ligands and catalystsdegradation productshydrolysisoxidationesterificationelimination of water, hcl, etc.dehydrogenationresidual solvents/ovis solvents/reagents used in the reactions, purificati

11、on process or formed during reactionmeoh, etoh, ipa, thf, dichloromethane, acetone, triethylamine, etc.impurity resources-api & drug product manufacturing processes11嚴(yán)選內(nèi)容impurities: origination & identification lists of impurities in ichorganic impuritieseach identified specified impurityeac

12、h unidentified specified impurityany unspecified impurity with an acceptance criterion of not more than () the figure in the identification threshold in attachment 1, ich q3a(r)total impuritiesresidual solventsinorganic impurities12嚴(yán)選內(nèi)容有機雜質(zhì)控制限度設(shè)置有機雜質(zhì)控制限度設(shè)置美國藥典雜質(zhì)：美國藥典雜質(zhì)：在美國藥典正文（monograph）中列為特定雜質(zhì)（spec

13、ified impurities）的雜質(zhì)，其控制限度應(yīng)設(shè)置不高于美國藥典的限度。非美國藥典雜質(zhì)：非美國藥典雜質(zhì)：如果美國藥典正文沒有對該雜質(zhì)設(shè)置控制限度，或者美國藥典沒有改藥物的正文，則根據(jù)ich的雜質(zhì)指導(dǎo)原則q3a(r)和q3b(r)，同時也參考其它藥典，如歐洲藥典（ep）和英國藥典（bp）來設(shè)置該雜質(zhì)的控制限度。就ich的雜質(zhì)指導(dǎo)原則來說，如果該雜質(zhì)在實驗測試中的實際觀測水平高于ich的鑒定限，則必須確定為特定雜質(zhì)，其控制限度必須設(shè)置為不高于ich的論證限（qualification threshold）。非特定雜質(zhì)：非特定雜質(zhì)：在藥品中出現(xiàn)的種類與幾率并不固定。因此，在藥品的臨床前與臨床

14、研究中，很難對這些雜質(zhì)的安全性進行評估。為將這些雜質(zhì)可能帶來的安全性隱患降至最小，ich的雜質(zhì)指導(dǎo)原則q3a(r)和q3b(r)對其限度用鑒定限（identification threshold）做了明確的規(guī)定，要求在原料藥標(biāo)準(zhǔn)中任何單個非特定雜質(zhì)的限度不得超過鑒定限。在仿制藥或改劑型藥品以及藥品上市后變更原料藥生產(chǎn)商等研究中，即使出現(xiàn)了新的雜質(zhì)，只要新雜質(zhì)的含量低于表中的鑒定限，就可以認定這些新雜質(zhì)的安全性。13嚴(yán)選內(nèi)容有機雜質(zhì)控制限度設(shè)置有機雜質(zhì)控制限度設(shè)置find out the maximum daily dose (mmd,每日最大劑量) from pdr, cps, etc.use

15、 mdd to calculate the ich thresholdsreporting threshold (rt)identification threshold (it)qualification threshold (qt)每日最大劑量1報告限(reporting threshold) 2,3鑒定限（identification threshold) 3論證限(qualification threshold) 3 2 g/day0.05%每日攝入量0.10%或1.0毫克（取低值）每日攝入量0.15%或1.0毫克（取低值） 2 g/day0.03%0.05%0.05%1 每日原料藥的服

16、用量。每日原料藥的服用量。2 更高的報告限必須提供充足的理由。更高的報告限必須提供充足的理由。3 如果雜質(zhì)的毒性特別高則適合于更低的報告限。如果雜質(zhì)的毒性特別高則適合于更低的報告限。14嚴(yán)選內(nèi)容control of impurities: compendia & ich establishing acceptance criteria for impuritiesacceptance criteria (limits) for impurities should be set no higher than the level that has been qualified.in est

17、ablishing impurity limits, the first critical consideration is whether an impurity is specified in the usp.if there is a monograph in the usp that includes a limit for an identified specified impurity, the limits should be set no higher than the official compendial limit.if qualified by an fda-appro

18、ved human drug product, the limits must be consistent with the level observed in the approved human drug product.in other circumstances (e.g. metabolites), the limits may need to be set tighter than the qualified level to assure drug substance quality. if the level of the impurity is above the level

19、 specified in the usp, qualification is necessary. then, if appropriate qualification has been achieved, an applicant may wish to petition the usp for revision of the impuritys limits.15嚴(yán)選內(nèi)容control of impurities: compendia & ich ich q3a(r) and q3b(r). scopedoes not apply to new drug substances (

20、q3a(r) ) or products (q3b(r) used during the clinical research stages of development. both do not cover: biological/ biotechniological products fermentation products peptides semi-synthetic products oligonucleotides herbal products radiopharmaceuticals crude products of animal plant originq3b (r) do

21、es not cover:lextraneous contaminants that should not occur in new drug products and are addressed as gmp issues.lpolymorphic formslenantiomeric impurities16嚴(yán)選內(nèi)容制劑的雜質(zhì)限度制劑的雜質(zhì)限度q3b(r2). ich threshold for degradation products in new drug products每日原料藥最大劑量 *報告限（reporting threshold)鑒定限（identification thr

22、eshold)論證限(qualification threshold) 1g0.1%n/an/a 1g0.05%n/an/a 10mg 2gn/a0.2% or 2mg tdin/a 100mg 2gn/an/a0.2% or 3mg tdi 2gn/a0.10%0.15%*取低值，按百分含量或每日總攝入量（tdi）計。17嚴(yán)選內(nèi)容有機雜質(zhì)控制限度論證有機雜質(zhì)控制限度論證雜質(zhì)控制限度論證：對一定限度的雜質(zhì)的生物安全性進行研究和評估，建立雜質(zhì)的可接受限度并提供包括安全性考慮在內(nèi)的依據(jù)。如果雜質(zhì)在樣品測試中的實際觀察值較高，而需要設(shè)置一個高于美國藥典或ich論證限（ qualification t

23、hreshold ）的控制限度時，則必須提供一個充分合理的論證來說明所設(shè)的控制限度是合理的。有時將雜質(zhì)水平降低至美國藥典或ich論證限以下是最為簡單的雜質(zhì)控制方法。對雜質(zhì)控制限度的論證如果被fda接受，申請人還可以向美國藥典提出修改該雜質(zhì)限度的申請（petition）。18嚴(yán)選內(nèi)容 制訂和論證雜質(zhì)合理限度的決策樹19嚴(yán)選內(nèi)容有機雜質(zhì)控制限度的論證方法有機雜質(zhì)控制限度的論證方法對比分析法：對比分析法：仿制藥申請中原料藥的雜質(zhì)可以采用相同的已驗證的分析方法（如hplc法），與fda已批準(zhǔn)的同品種人用制劑（reference listed drug, 簡稱rld，參照藥品）進行對比研究。如果無法獲得

24、參照藥品，也可對含有相同原料藥，以及相同給藥途徑和特征的不同藥物制劑（如片劑對膠囊）的雜質(zhì)含量進行研究。如果仿制藥申請原料藥中已鑒別雜質(zhì)的水平與相應(yīng)已獲準(zhǔn)上市人用藥物的雜質(zhì)水平相當(dāng)，則可以認為該雜質(zhì)得到了合理控制。科學(xué)文獻和主要代謝物法：科學(xué)文獻和主要代謝物法：如果科學(xué)文獻已經(jīng)證明某一水平的雜質(zhì)在安全性方面沒有問題，那么根據(jù)這一水平建立的該雜質(zhì)的限度就無需進一步論證。此外，如果科學(xué)文獻證明某雜質(zhì)本身也是原料藥在體內(nèi)代謝的主要代謝物，其安全性是顯而易見的，因而即使對該雜質(zhì)設(shè)置高于ich論證限的控制限度，通?？梢砸舱J為該雜質(zhì)已得到合理控制。遺傳毒性研究法：遺傳毒性研究法：由于遺傳毒性試驗費時間且成

25、本高昂，此法一般是在前兩種都無法對雜質(zhì)合理研究論證的情況下才采取的方法。這項研究可以采用含該雜質(zhì)的制劑或原料藥直接進行研究，但實際上采用已分離的雜質(zhì)進行研究可能更為恰當(dāng)。20嚴(yán)選內(nèi)容有機雜質(zhì)控制限度的論證方法有機雜質(zhì)控制限度的論證方法雜質(zhì)的合理控制應(yīng)基于多種因素，包括患者人群、日劑量、給藥途徑以及給藥周期。雜質(zhì)合理控制的最基本原則就是考慮其安全因素。根據(jù)ich的雜質(zhì)指導(dǎo)原則q3a(r)和q3b(r)。 當(dāng)滿足下述一個或多個條件時，可以認為該雜質(zhì)的控制限度是合理的：當(dāng)雜質(zhì)實際觀察水平以及控制限度未超出fda已經(jīng)批準(zhǔn)的人用制劑雜質(zhì)實際觀察水平； 當(dāng)雜質(zhì)本身是原料藥在動物和/或人體內(nèi)重要的代謝產(chǎn)物時

26、；當(dāng)雜質(zhì)實際觀察水平以及控制限度有充分合理的科學(xué)文獻支持時；當(dāng)雜質(zhì)實際觀察水平以及控制限度未超過通過體外遺傳毒性比較研究得出的正確評估限度時。21嚴(yán)選內(nèi)容有機雜質(zhì)控制限度的論證方法有機雜質(zhì)控制限度的論證方法當(dāng)雜質(zhì)本身是原料藥在動物和當(dāng)雜質(zhì)本身是原料藥在動物和/或人體內(nèi)重要的代謝產(chǎn)物時或人體內(nèi)重要的代謝產(chǎn)物時如果有可靠文獻報道該雜質(zhì)系人體代謝產(chǎn)物，其限度的確定并不需要從安全性方面進行論證。限度設(shè)定時主要考慮批分析數(shù)據(jù)、穩(wěn)定性研究數(shù)據(jù)。具體限度的確定因藥物而異，但應(yīng)能保證批間藥品質(zhì)量的一致性，且得到批分析數(shù)據(jù)、穩(wěn)定性數(shù)據(jù)的支持。example:simvastatin ep imp a, degra

27、dation product: proposed to increase the limit from 0.5% to 1.0%.rationale: the fda guideline for andas: significant metabolites do not need further qualification. the metabolic profiles of simvastatin in human and dog plasma showed that simvastatin ep imp a is one of the major metabolites.22嚴(yán)選內(nèi)容imp

28、urity limit establishment: examples simvastatin tablets usp. limits for sv rca and sv rcbsimvastatin (zocor): a lipid-lowering drug approved by fda in dec.1991. it reduces cholesterol by inhibiting an enzyme in the liver (hmg-coa reductase) required for the production of cholesterol. other statins i

29、nclude lovastatin (mevacor), atorvastatin (lipitor), fluvastatin (lescol), and rosuvastatin (crestor).sv rc a and sv rc b were controlled at nmt0.5% and 0.1%, respectively before. however, the results form the long term stability test exceeded the limits.sv rc b, degradation product: proposed to inc

30、rease the limit from 0.1% to 0.2%.rationale:the ich guideline q3b(r): qt for degradation products can be 0.5% or 200mg tdi, whichever is lower, for the drug with mdd of 10-100mg.mdd for simvastatin is 80mg. qt can be 0.25%. 23嚴(yán)選內(nèi)容impurity limit establishment: examplesbupropion er tablets: justificat

31、ion for increasing limitsthe limit for rc m-chlorobenzoic acid in bupropion hydrochloride er tablets is proposed to increase from 0.3% to 0.5%.rationale:bupropion is extensively metabolized in humans, rats and dogs. metabolism studies in human indicated that bupropion was metabolized to m-chlorohipp

32、uric acid, erythro-amino alcohol (eb), threo-amino alcohol (tb), hydroxy metabolite (hb) (references 1-3).it was obvious that m-chlorohippuric acid, which is excreted as the major urinary metabolite, was resulted from oxidation of the bupropion side chain to give m-chlorobenzoic acid followed by con

33、jugation with glycine. other aminoalcohol metabolites such as eb, tb and hb are formed from hydroxylation nof the tert-butyl group of bupropion and /or reduction of the intact parent aminoketone. this metabolism pathway has been confirmed by the fact that the metabolism in rats and dogs gave predomi

34、nantly m-chlorohippuric acid and m-chlorobenzoic acid as the metabolites, which are formed from side chain oxidative cleavage.the fda guideline for impurities for andas (see guidance for industry. andas: impurities in drug substances) indicates that the impurities that are significant metabolites do

35、 not need further qualification.it is considered reasonable to increase the test limit from 0.3% to 0.5% for bp rc2 (m-chlorobenzoic acid ).24嚴(yán)選內(nèi)容impurity limit establishment: examplessynthetic impurities: no need to monitor/report in dp specificationsresponse form fda on this type of question: synt

36、hetic impurities need not be reported or monitored for release and /or stability testing of the drug product. thus, no drug product limits for drug substance process impurities need be included in the drug testing protocol.rationale:synthetic impurities are generated during the manufacturing process

37、 of the drug substance.they are controlled in the drug substance specification.they are not expected to increase during the production and storage of the drug product.25嚴(yán)選內(nèi)容impurity limit establishment: examples semi-synthetic or synthetic chemical?“why is the fda asking us to qualify an impurity ob

38、served in this semi-synthetic drug substance? arent semi-synthetics excluded from the recommendations?”rationale: it depends on how far the drug substance is from the naturally derived source material. in general, drug substances separated from the source material by one or two chemical manipulation

39、s are still excluded from the recommendations. however, the agency believes that those drug substances separated from the source material by several synthetic steps resulting in multiple isolated and purified intermediates resemble traditional chemicals more than they resemble classical semi-synthet

40、ic moieties. hence, the new recommendations would apply to such drug substances. 26嚴(yán)選內(nèi)容impurity limit establishment: examples clyndamycin. semi-synthetic or synthetic chemical?27嚴(yán)選內(nèi)容案例分析：有機雜質(zhì)控制限度設(shè)置和論證案例分析：有機雜質(zhì)控制限度設(shè)置和論證 卡托普利（卡托普利（captopril) 原料藥的合成路線原料藥的合成路線28嚴(yán)選內(nèi)容卡托普利（卡托普利（captopril）有機雜質(zhì)控制限度的設(shè)置）有機雜質(zhì)控制

41、限度的設(shè)置29嚴(yán)選內(nèi)容卡托普利（卡托普利（captopril）有機雜質(zhì)控制限度的）有機雜質(zhì)控制限度的設(shè)置設(shè)置l美國藥典和歐洲藥典都發(fā)表了有關(guān)卡托普利原料藥的正文。根據(jù)美國藥典正文，captopril disulphide 雜質(zhì)控制限度不超過1.0%，而其它單一雜質(zhì)不超過0.2%，總雜質(zhì)不超過0.5%。歐洲藥典正文把雜質(zhì)a,b,c,d,e和f作為特定雜質(zhì)控制在不超過0.15%（其中例外的是雜質(zhì)a控制在1.0%，雜質(zhì)f控制在0.2%），非特定雜質(zhì)控制在不超過0.10%，總雜質(zhì)不超過1.2%。l如果原料藥生命符合美國或歐洲藥典標(biāo)準(zhǔn)，通常必須符合該藥典正文的每一項要求。然而，對于與合成路線毫無關(guān)系的藥

42、典雜質(zhì)，在實驗測試結(jié)果顯示“none detected未檢出”的基礎(chǔ)上，可以從合成路線和化學(xué)反應(yīng)機理的角度進行論證，提供足夠理由說明在原料藥標(biāo)準(zhǔn)中可以不設(shè)限度進行常規(guī)控制。l下面以聲明符合美國藥典標(biāo)準(zhǔn)的卡托普利為例來說明如何提供適當(dāng)?shù)睦碛蓪λ付ǖ臉?biāo)準(zhǔn)進行論證。從化學(xué)反應(yīng)機理的角度考慮，雜質(zhì)b和d產(chǎn)生于含溴的原料，與康樂化學(xué)公司的合成路線無關(guān)。標(biāo)準(zhǔn)規(guī)格中勿需設(shè)定限度來控制雜質(zhì)b和d。l卡托普利的最高劑量為450毫克/日。根據(jù)ich指導(dǎo)文件q3a(r)，原料藥的報告限（reporting threshold)為0.05%，鑒定限（identification threshold）為0.10%，論

43、證限(qualification threshold) 為0.15%。l原料藥中的控制限度設(shè)置如下：已知雜質(zhì)c和e中單一已知雜質(zhì)不超過0.1%，雜質(zhì)a不超過0.5%，雜質(zhì)f不超過0.2%，單一未知雜質(zhì)不超過0.10%，總雜質(zhì)不超過0.5%。此雜質(zhì)控制限度符合或緊于美國藥典要求，也與ich和原料藥廠家的要求一致。30嚴(yán)選內(nèi)容練習(xí)練習(xí)-雜質(zhì)控制限度的設(shè)置和論證雜質(zhì)控制限度的設(shè)置和論證michelle is working in a generic pharmaceutical company to develop a drug product called ome for ulcer diseas

44、e. she adopts the european pharmacopoeia hplc method to analyze the drug substance and observed known ep impurities a (0.25), b(0.46%) and c (0.20%), and an unknown impurity 1 (0.18%). the maximum daily dose for ome is 120mg. it is reported that impurity b is a degradation product and metabolite, im

45、purities a is also a degradation product, while impurity c is a synthetic impurity. table 1. ich thresholds for impurities in new drug substancesmaximum daily dose-1reporting threshold2,3identification threshold 3qualification threshold 32g/day0.05%0.10% or 1.0mg per day intake (whichever is lower)0

46、.15% or 1.0mg per day intake (whichever is lower)2g/day0.03%0.05%0.05%1 the amount of drug substance administered per day.2 higher reporting thresholds should be significantly justified.3 lower thresholds can be appropriate if the impurity is unusually toxic.31嚴(yán)選內(nèi)容練習(xí)練習(xí)-雜質(zhì)控制限度的設(shè)置和論證雜質(zhì)控制限度的設(shè)置和論證active

47、 ingredient maximum daily dosereporting thresholdsidentification threshold*qualification threshold* 1g0.1%n/an/a 1g0.05%n/an/a 10mg 2gn/a0.2% or 2mg tdin/a 100mg 2gn/an/a0.2% or 3mg tdi 2gn/a0.10%0.15%table 2. ich thresholds for degradation products in new drug products* take the lower figure, % or

48、total daily intake (tdi)32嚴(yán)選內(nèi)容練習(xí)練習(xí)-雜質(zhì)控制限度的設(shè)置和論證雜質(zhì)控制限度的設(shè)置和論證luse the above tables 1 and 2 as references and other knowledge you learned from this course to establish appropriate controlling limits and fill into table 3 for impurities a, b and c for both drug substance and drug product if necessary.li

49、t is not required to establish a limit to control impurity c for drug product. however, the hplc method for degradation products should be capable of detecting and separating impurity c from other impurities. why?lwhy can a limit for a degradation product be considered qualified even it exceeds the

50、ich limit?reporting threshold (%)impurity a (%)impurity b (%)impurity c (%)unknown impurity 1 (%)ich limits for drug substancerecommended limits for drug substanceich limits for drug productrecommended limits for drug product33嚴(yán)選內(nèi)容fda對藥物雜質(zhì)的控制要求對藥物雜質(zhì)的控制要求 原料藥與成品藥中的殘留溶劑原料藥與成品藥中的殘留溶劑1997年，ich制訂了“q3c雜質(zhì)：

51、殘留溶劑的指導(dǎo)原則”。美國藥典（usp）2008年修正了第節(jié)，重新命名為殘留溶劑（residual solvents）。ich將藥品生產(chǎn)及純化過程中常用的69種有機溶劑按照對人體和環(huán)境的危害程度分為4類。第1類溶劑：指已知或極可能對人體致癌和對環(huán)境有害的溶劑，在藥品制造過程中必須避免使用。其殘留量必須嚴(yán)格控制在規(guī)定的范圍內(nèi)。第2類溶劑：指無基因毒性但有動物致癌性的溶劑，可以選擇適當(dāng)?shù)姆椒ú⒔⒁欢ǖ南薅冗M行控制。第3類溶劑：指對人體低毒的溶劑，可用于生產(chǎn)過程中。其殘留溶劑的量如果不高于0.5%則無需論證。未分類溶劑：指目前沒有足夠毒性資料的溶劑，如異丙醚（isopropylether）。由于無

52、響應(yīng)的“允許日接觸量”（pde）資料，生產(chǎn)廠商在使用時必須提供這些溶劑在制劑中的殘留水平，以及對產(chǎn)品安全影響的論證報告，或者根據(jù)fda在2008年12月出版的控制基因毒性和致癌性以及任何可疑但未知具體毒理的雜質(zhì)的指導(dǎo)原則（草案），控制這類殘留溶劑日接觸量不超過1.5微克。34嚴(yán)選內(nèi)容ich q3c and usp general chapter “residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacturing

53、 of drug substance or excipient, or in the preparation of drug products.” note: “residual solvents” refers to the amount not removed during the purification of the product35嚴(yán)選內(nèi)容usp: residual solventsgeneral notices statement: all articles are subject to be tested for residual solvents (delayed imple

54、mentation)monograph changes residual solvents: meets the requirements added in all monograph (delayed implementation)revised retracted36嚴(yán)選內(nèi)容residual solvents :main pointsdriving force: safety of the patient; recommended use of less toxic solventstesting is to be performed only for solvents “l(fā)ikely t

55、o be present” used or produced in the final manufacturing step used in previous steps and not removed by a validated procedurethe limits for acceptable concentrations listed in the chapter are for drug products, not for its components37嚴(yán)選內(nèi)容residual solvents :main pointsthe concentration in the drug

56、product may be calculated from the concentrations of components determined experimentally; mandatory if solvents are used in its manufacture cumulative calculation exceeds limitsmanufactures of drug products may rely on data provided by the suppliers of componentsprovides unambiguous identification

57、and qualification methodincludes options to allow use of materials that exceed the limits established38嚴(yán)選內(nèi)容residual solvents :main points, continued “the procedures described in this general chapter are to be applied wherever possible. otherwise, manufactures may select the most appropriate validate

58、d analytical procedure for a particular application.” (ich and ep take similar approach, see validation of compendial procedures submission of alternative methods is not required.39嚴(yán)選內(nèi)容scope ich “the guide does not apply to existing marketed products.” usp (and ep) “this general chapter applies to e

59、xisting drug substances, excipients and medical products whether or not they are the subject of a monograph of the pharmacopeia”.40嚴(yán)選內(nèi)容risk-based classification of solvents class 1 -unacceptable toxicities; should be avoided, unless their use can be strongly justified in a risk-based assessment. cla

60、ss 2 -less severe toxicities; should be limited. class 3 -less toxic; should be used where practical. note: other solvents may be used but only after approval from a regulatory agency.41嚴(yán)選內(nèi)容supplier usp limits in excipients for each excipient limits are not specifications for each excipientsome excipients used as drug produc