【正文】 Drug Substances) indicates that the impurities that are significant metabolites do not need further qualification. ? It is considered reasonable to increase the test limit from % to % for BP RC2 (mchlorobenzoic acid ). Impurity Limit Establishment: Examples Synthetic Impurities: No Need to Monitor/Report in DP Specifications ? Response form FDA on this type of question: Synthetic 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 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。然而，對于與合成路線毫無關(guān)系的藥典雜質(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(jī)理的角度進(jìn)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(jìn)行常規(guī)控制。 ? 卡托普利的最高劑量為 450毫克 /日。 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 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”。其殘留量必須嚴(yán)格控制在規(guī)定的范圍內(nèi)。 ? 未分類溶劑：指目前沒有足夠毒性資料的溶劑，如異丙醚（ Isopropylether）。 mandatory if ? Solvents are used in its manufacture ? Cumulative calculation exceeds limits ? Manufactures of drug products may rely on data provided by the suppliers of ponents ? Provides unambiguous identification and qualification method ? Includes options to allow use of materials that exceed the limits established Residual Solvents 467:Main Points, Continued… ? “ The procedures described in this general chapter are to be applied wherever possible. Otherwise, manufactures may select the most appropriate validated analytical procedure for a particular application.” (ICH and EP take similar approach, see 1225Validation of Compendial Procedures ? Submission of alternative methods is not required. Scope ? ICH “ …The guide does not apply to existing marketed products.” ? USP (and EP) “ This general chapter applies to existing drug substances, excipients and medical products whether or not they are the subject of a monograph of the Pharmacopeia” . Riskbased classification of solvents ? Class 1 Unacceptable toxicities。 no need for unnecessary testing. Supplier ? Generally, Class 1 Solvents such as benzene are no longer being used in producing excipients. ? Many produced with Class 2 or 3. ? Eliminating or lowering solvent levels may change quality and performance for certain functions. ? Take advantage of calculation