【文章內(nèi)容簡(jiǎn)介】 onitored 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 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. 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 remendations?” ? 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 remendations. 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 remendations would apply to such drug substances. Impurity Limit Establishment: Examples Clyndamycin. Semisynthetic or Synthetic Chemical? 案例分析：有機(jī)雜質(zhì)控制限度設(shè)置和論證 卡托普利（ Captopril) 原料藥的合成路線 卡托普利（ Captopril）有機(jī)雜質(zhì)控制限度的設(shè)置 卡托普利（ Captopril）有機(jī)雜質(zhì)控制限度的設(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 %，而其它單一雜質(zhì)不超過 %，總雜質(zhì)不超過 %。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 %（其中例外的是雜質(zhì) A控制在 ≤%，雜質(zhì) F控制在 ≤%），非特定雜質(zhì)控制在不超過%，總雜質(zhì)不超過 %。 ? 如果原料藥生命符合美國(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，與康樂化學(xué)公司的合成路線無(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 %，鑒定限（ Identification Threshold）為 %，論證限 (Qualification Threshold) 為 %。 ? 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 %，雜質(zhì) A不超過 %，雜質(zhì) F不超過 %，單一未知雜質(zhì)不超過 %，總雜質(zhì)不超過 %。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。 練習(xí) 雜質(zhì)控制限度的設(shè)置和論證 ? Michelle is working in a generic pharmaceutical pany 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 (), B(%) and C (%), and an unknown impurity 1 (%). 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 Maximum Daily Dose1 Reporting Threshold 2,3 Identification Threshold 3 Qualification Threshold 3 ≤2g/day % % or per day intake (whichever is lower) % or per day intake (whichever is lower) ＞ 2g/day % % % 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. 練習(xí) 雜質(zhì)控制限度的設(shè)置和論證 Active ingredient maximum daily dose Reporting Thresholds Identification Threshold* Qualification Threshold* ≤ 1g % N/A N/A 1g % N/A N/A 1mg N/A % or 5181。g TDI N/A 1mg ~ 10mg N/A % or 20181。g TDI N/A 10mg ~ 2g N/A % or 2mg TDI N/A 10mg N/A N/A % or 50181。g TDI 10mg ~100mg N/A N/A % or 200181。g TDI 100mg ~2g N/A N/A % or 3mg TDI 2g N/A % % Table 2. ICH Thresholds for Degradation Products in New Drug Products * Take the lower figure, % or total daily intake (TDI) 練習(xí) 雜質(zhì)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? Reporting Threshold (%) Impurity A (%) Impurity B (%) Impurity C (%) Unknown Impurity 1 (%) ICH limits for Drug substance Remended Limits for Drug Substance ICH limits for Drug Product Remended Limits for Drug Product FDA對(duì)藥物雜質(zhì)的控制要求 原料藥與成品藥中的殘留溶劑 ? 1997年， ICH制訂了“ Q3C雜質(zhì)：殘留溶劑的指導(dǎo)原則”。 ? 美國(guó)藥典（ USP） 2023年修正了第 467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(jī)溶劑按照對(duì)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(duì)人體致癌和對(duì)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(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類溶劑：指對(duì)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 %則無(wú)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(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 2023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 。 ICH Q3C and USP General Chapter 467 “ …residual solvents in pharmaceuticals are defined as anic 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] USP: Residual Solvents ? General Notices Statement: All articles are subject to be tested for residual solvents (Delayed implementation) ? Monograph Changes ? 467 Residual solvents: meets the requirements added in all monograph (Delayed Implementation) ? Revised retracted Residual Solvents 467:Main Points ? Driving force: Safe