【正文】 norganic impurities are normally detected and quantified using pharmacopoeial or other appropriate procedures. Carryover of catalysts to the new drug substance should be evaluated during development. The need for inclusion or exclusion of inorganic impurities in the new drug substance specification should be discussed. Acceptance criteria should be based on pharmacopoeial standards or known safety data. 無機(jī)雜質(zhì)通常按藥典或其他適當(dāng)?shù)姆椒▉頇z測和定量。 Solvents溶劑The control of residues of the solvents used in the manufacturing process for the new drug substance should be discussed and presented according to the ICH Q3C Guideline for Residual Solvents.應(yīng)按ICH Q3C“殘留溶劑”指導(dǎo)原則的要求，對(duì)新原料藥生產(chǎn)過程中所用的溶劑的殘留量的控制進(jìn)行討論和申報(bào)。如果研發(fā)中所采用的分析方法和準(zhǔn)備上市產(chǎn)品的分析方法不同，在申報(bào)資料中應(yīng)予以討論。應(yīng)根據(jù)使用目的，對(duì)分析過程中用于控制雜質(zhì)的參比標(biāo)準(zhǔn)品進(jìn)行定性和定量。5. REPORTING IMPURITY CONTENT OF BATCHES 各批次產(chǎn)品雜質(zhì)含量的報(bào)告Analytical results should be provided in the application for all batches of the new drug substance used for clinical, safety, and stability testing, as well as for batches representative of the proposed mercial process. Quantitative results should be presented numerically, and not in general terms such as “plies”, “meets limit” etc. Any impurity at a level greater than () the reporting threshold (see Attachment 1) and total impurities observed in these batches of the new drug substance should be reported with the analytical procedures indicated. Below %, the results should be reported to two decimal places (., %, %)。%，結(jié)果應(yīng)報(bào)告至小數(shù)點(diǎn)后兩位（%，%），%，結(jié)果報(bào)告至小數(shù)點(diǎn)后1位（%）。所有大于（＞）報(bào)告閾值的雜質(zhì)應(yīng)進(jìn)行累加，報(bào)告為“總雜質(zhì)”。方法學(xué)論證中，顯示雜質(zhì)分離度和檢測靈敏度的、具有代表性批次（例如：加樣試驗(yàn)）的色譜圖和常規(guī)雜質(zhì)檢測得到的色譜圖，可以反映出有代表性的雜質(zhì)概況。 Batch identity and size 批號(hào)與批量 Impurity content, individual and total單個(gè)雜質(zhì)含量和總雜質(zhì)含量在新原料藥規(guī)范中收載的雜質(zhì)應(yīng)根據(jù)在準(zhǔn)備上市生產(chǎn)的批次中所發(fā)現(xiàn)的雜質(zhì)來選擇。A rationale for the inclusion or exclusion of impurities in the specification should be presented. This rationale should include a discussion of the impurity profiles observed in the safety and clinical development batches, together with a consideration of the impurity profile of batches manufactured by the proposed mercial process. Specified identified impurities should be included along with specified unidentified impurities estimated to be present at a level greater than () the identification threshold given in Attachment 1. For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be mensurate with the level at which the impurities should be controlled. For unidentified impurities, the procedure used and assumptions made in establishing the level of the impurity should be clearly stated. Specified, unidentified impurities should be referred to by an appropriate qualitative analytical descriptive label (., “unidentified A, “unidentified with relative retention of ”). A general acceptance criterion of not more than (163。對(duì)于未鑒定的雜質(zhì)，所使用的檢測方法和確定雜質(zhì)量時(shí)所采用的假設(shè)應(yīng)予明確說明。如果沒有安全性方面的問題，雜質(zhì)認(rèn)可標(biāo)準(zhǔn)應(yīng)根據(jù)擬上市生產(chǎn)的新原料藥批次測定的數(shù)據(jù)來建立，并應(yīng)為常規(guī)生產(chǎn)和分析上的正常變異及藥物的穩(wěn)定性特性留有足夠的余地。 Each specified identified impurity每種特定的已鑒定雜質(zhì)對(duì)于一個(gè)通過充分的安全性研究和臨床研究的新原料藥，其中任何一個(gè)雜質(zhì)的水平即被認(rèn)為是已經(jīng)通過界定了的。Higher or lower thresholds for qualification of impurities can be appropriate for some individual drugs based on scientific rationale and level of concern, including drug class effects and clinical experience. For example, qualification can be especially important when there is evidence that such impurities in certain drugs or therapeutic classes have previously been associated with adverse reactions in patients. In these instances, a lower qualification threshold can be appropriate. Conversely, a higher qualification threshold can be appropriate for individual drugs when the level of concern for safety is less than usual based on similar considerations (., patient population, drug class effects, clinical considerations). Proposals for alternative thresholds would be considered on a casebycase basis.對(duì)于某些藥物，可以根據(jù)科學(xué)原理并考慮藥物的類別和臨床經(jīng)驗(yàn)，對(duì)其雜質(zhì)界定閾值進(jìn)行適當(dāng)調(diào)整。對(duì)限度的改變應(yīng)具體情況具體對(duì)待。如果兩者均不可行，則應(yīng)考慮進(jìn)行附加的安全性試驗(yàn)。在研究后期，任何含量大于（＞）附件1中鑒定閾值（見附件3鑒定和界定流程圖）的新的雜質(zhì)均許鑒定。8. GLOSSARY 術(shù)語Chemical Development Studies: Studies conducted to scaleup, optimise, and validate the manufacturing process for a new drug substance.化學(xué)方面的開發(fā)研究:對(duì)新原料藥合成工藝進(jìn)行放大、優(yōu)化以及確證的研究。在一些傳統(tǒng)藥中，可能也含有無機(jī)物或動(dòng)物組織。Impurity Profile: A description of the identified and unidentified impurities present in a new drug substance.雜質(zhì)概況：對(duì)存在于某一新原料藥中的已知或未知雜質(zhì)情況的描述。它可以是某種已獲批準(zhǔn)的藥物的一種復(fù)合物、簡單的酯或鹽。其在新原料藥中可能存在，也可能是不存在的。Solvent: An inorganic or an organic liquid used as a vehicle for the preparation of solutions or suspensions in the synthesis of a new drug substance.溶劑：在新原料藥合成中用于制備溶液或混懸液的無機(jī)或有機(jī)液體。起始物通常市場上有供應(yīng)，并具有確定的化學(xué)和物理性質(zhì)及結(jié)構(gòu)。ATTACHMENT 1 Thresholds 附件1 閾值Maximum Daily Dose The amount of drug substance administered per day日常使用的藥物劑量 Reporting Threshold Higher reporting thresholds should be scientifically justified應(yīng)當(dāng)對(duì)較高的報(bào)告閾值進(jìn)行科學(xué)論證,Identification Threshold3Qualification Threshold Lower thresholds can be appropriate if the impurity is unusually toxic 如果雜質(zhì)具有特殊毒性，可以采用較低的閾值163。Example 1: g Maximum Daily Dose Reporting threshold = % Identification threshold = % Qualification threshold = %Raw Result(%)Reported Result(%)Reporting threshold =%Calculated Total Daily Intake (TDI) (mg) of the impurity(rounded result in mg)ActionIdentification(Threshold % exceeded?)Qualification(Threshold % exceeded?)Not reportedNoneNoneNoneNone)YesNone1))YesYes1)例1： 最大日劑量報(bào)告閾值＝%鑒定閾值＝% 界定閾值＝%“原始”結(jié)果（%）報(bào)告結(jié)果（%）報(bào)告閾值=%計(jì)算的雜質(zhì)每日總攝入量（TDI）（mg）（修約至mg)反應(yīng)鑒定（%%？）界定（%？）未報(bào)告否否否否)是否1))是是1)Example 2: g Maximum Daily Dose Reporting threshold = % Identification threshold = % Qualification threshold = mg TDI“Raw” Result(%)Reported Result(%)Reporting threshold =%Calculated Total Daily Intake (TDI) (mg)of the impurity(rounded result in mg)ActionIdentification(Threshold % exc