【文章內(nèi)容簡(jiǎn)介】 hetic impurities are generated during the manufacturing process 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.,第二十五頁(yè)，共七十一頁(yè)。,Impurity Limit Establishment: Examples SemiSynthetic or Synthetic Chemical?,“Why is the FDA asking us to qualify an impurity observed in this semisynthetic drug substance? Aren’t semisynthetics 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 manipulations 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 semisynthetic moieties. Hence, the new recommendations would apply to such drug substances.,第二十六頁(yè)，共七十一頁(yè)。,Impurity Limit Establishment: Examples Clyndamycin. Semisynthetic or Synthetic Chemical?,第二十七頁(yè)，共七十一頁(yè)。,案例分析：有機(jī)雜質(zhì)控制(k242。ngzh236。)限度設(shè)置和論證 卡托普利（Captopril) 原料藥的合成路線(xiàn),第二十八頁(yè)，共七十一頁(yè)。,卡托普利（Captopril）有機(jī)雜質(zhì)控制限度(xi224。nd249。)的設(shè)置,第二十九頁(yè)，共七十一頁(yè)。,卡托普利（Captopril）有機(jī)雜質(zhì)控制(k242。ngzh236。)限度的設(shè)置,美國(guó)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(guó)藥典正文，Captopril disulphide 雜質(zhì)控制限度不超過(guò)1.0%，而其它單一雜質(zhì)不超過(guò)0.2%，總雜質(zhì)不超過(guò)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(guò)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(guò)0.10%，總雜質(zhì)不超過(guò)1.2%。 如果原料藥生命(shēngm236。ng)符合美國(guó)或歐洲藥典標(biāo)準(zhǔn)，通常必須符合該藥典正文的每一項(xiàng)要求。然而，對(duì)于與合成路線(xiàn)毫無(wú)關(guān)系的藥典雜質(zhì)，在實(shí)驗(yàn)測(cè)試結(jié)果顯示“None Detected未檢出”的基礎(chǔ)上，可以從合成路線(xiàn)和化學(xué)反應(yīng)機(jī)理的角度進(jìn)行論證，提供足夠理由說(shuō)明在原料藥標(biāo)準(zhǔn)中可以不設(shè)限度進(jìn)行常規(guī)控制。 下面以聲明符合美國(guó)藥典標(biāo)準(zhǔn)的卡托普利為例來(lái)說(shuō)明如何提供適當(dāng)?shù)睦碛蓪?duì)所指定的標(biāo)準(zhǔn)進(jìn)行論證。從化學(xué)反應(yīng)機(jī)理的角度考慮，雜質(zhì)B和D產(chǎn)生于含溴的原料，與康樂(lè)化學(xué)公司的合成路線(xiàn)無(wú)關(guān)。標(biāo)準(zhǔn)規(guī)格中勿需設(shè)定限度來(lái)控制雜質(zhì)B和D。 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(bào)告限（Reporting Threshold)為0.05%，鑒定限（Identification Threshold）為0.10%，論證限(Qualification Threshold) 為0.15%。 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(guò)0.1%，雜質(zhì)A不超過(guò)0.5%，雜質(zhì)F不超過(guò)0.2%，單一未知雜質(zhì)不超過(guò)0.10%，總雜質(zhì)不超過(guò)0.5%。此雜質(zhì)控制限度符合或緊于美國(guó)藥典要求，也與ICH和原料藥廠家的要求一致。,第三十頁(yè)，共七十一頁(yè)。,練習(xí)雜質(zhì)控制限度(xi224。nd249。)的設(shè)置和論證,Michelle is working in a generic pharmaceutical company to develop a drug product called OME for ulcer disease. 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, impurities A is also a degradation product, while impurity C is a synthetic impurity. Table 1. ICH Thresholds for Impurities in New Drug Substances,第三十一頁(yè)，共七十一頁(yè)。,練習(xí)雜質(zhì)(z225。zh236。)控制限度的設(shè)置和論證,Table 2. ICH Thresholds for Degradation Products in New Drug Products,* Take the lower figure, % or total daily intake (TDI),第三十二頁(yè)，共七十一頁(yè)。,練習(xí)雜質(zhì)(z225。zh236。)控制限度的設(shè)置和論證,Use 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. It 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? Why can a limit for a degradation product be considered qualified even it exceeds the ICH limit?,第三十三頁(yè)，共七十一頁(yè)。,FDA對(duì)藥物雜質(zhì)的控制要求(yāoqi) 原料藥與成品藥中的殘留溶劑,1997年，ICH制訂了“Q3C雜質(zhì)：殘留溶劑(r243。ngj236。)的指導(dǎo)原則”。 美國(guó)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(guò)程中常用的69種有機(jī)溶劑按照對(duì)人體和環(huán)境的危害程度分為4類(lèi)。 第1類(lèi)溶劑：指已知或極可能對(duì)人體致癌和對(duì)環(huán)境有害的溶劑，在藥品制造過(guò)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(lèi)溶劑：指無(wú)基因毒性但有動(dòng)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(jìn)行控制。 第3類(lèi)溶劑：指對(duì)人體低毒的溶劑，可用于生產(chǎn)過(guò)程中。其殘留溶劑的量如果不高于0.5%則無(wú)需論證。 未分類(lèi)溶劑：指目前沒(méi)有足夠毒性資料的溶劑，如異丙醚（Isopropylether）。由于無(wú)響應(yīng)的“允許日接觸量”（PDE）資料，生產(chǎn)廠商在使用時(shí)必須提供這些溶劑在制劑中的殘留水平，以及對(duì)產(chǎn)品安全影響的論證報(bào)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(lèi)殘留溶劑日接觸量不超過(guò)1.5微克。,第三十四頁(yè)，共七十一頁(yè)。,ICH Q3C and USP General Chapter ,“…residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacturing 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 product],第三十五頁(yè)，共七十一頁(yè)。,USP: Residual Solvents,General Notices Statement: All articles are subject to be tested for residual solvents (Delayed implementation) Monograph Changes Residual solvents: meets the requirements added in all monograph (Delayed Implementation) Revised retracted,第三十六頁(yè)，共七十一頁(yè)。,Residual Solvents :Main Points,Driving force: Safety of the patient。 recommended use of less toxic solvents Testing is to be performed only for solvents “l(fā)ikely to be present” Used or produced in the final manufacturing step Used in previous steps and not removed by a validated procedure The limits for acceptable concentrations listed in the Chapter are for drug products, not for its components,第三十七頁(yè)，共七十一頁(yè)。,Residual Solvents :Main Points,The concentration in the drug product may be Calculated from the concentrations of components Determined experimentally。 mandatory if Solvents are used in its manufacture Cumulative calculation exceeds limits Manufactures of drug products ma