【文章內(nèi)容簡介】 ll 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 (., %, %)。 at and above %, the results should be reported to one decimal place (., %). Results should be rounded using conventional rules (see Attachment 2). A tabulation (., spreadsheet) of the data is remended. Impurities should be designated by code number or by an appropriate descriptor, ., retention time. If a higher reporting threshold is proposed, it should be fully justified. All impurities at a level greater than () the reporting threshold should be summed and reported as total impurities. 注冊申請應(yīng)提供用于臨床、安全性研究、穩(wěn)定性試驗的所有新原料藥批次產(chǎn)品的分析結(jié)果以及用于準(zhǔn)備上市產(chǎn)品的分析結(jié)果。定量測定結(jié)果應(yīng)數(shù)字化，不應(yīng)用“符合規(guī)定”，“符合限度”等一般性術(shù)語。在新原料藥的所有批次中，應(yīng)報告檢測到的大于（＞）報告閾值（見附錄1）的任何雜質(zhì)和總雜質(zhì)，并附所用的分析方法。%，結(jié)果應(yīng)報告至小數(shù)點后兩位（%，%），%，結(jié)果報告至小數(shù)點后1位（%）。結(jié)果應(yīng)按傳統(tǒng)規(guī)則修約（見附錄2）。建議使用數(shù)據(jù)表格（如電子數(shù)據(jù)表），各雜質(zhì)均應(yīng)以編號或合適的描述表示（如保留時間）。如果采用較高的報告閾值，應(yīng)進(jìn)行充分論證。所有大于（＞）報告閾值的雜質(zhì)應(yīng)進(jìn)行累加，報告為“總雜質(zhì)”。When analytical procedures change during development, reported results should be linked to the procedure used, with appropriate validation information provided. Representative chromatograms should be provided. Chromatograms of representative batches from analytical validation studies showing separation and detectability of impurities (., on spiked samples), along with any other impurity tests routinely performed, can serve as the representative impurity profiles. The applicant should ensure that plete impurity profiles (., chromatograms) of individual batches are available, if requested. 若在研制期間，分析方法發(fā)生了變化，報告測試結(jié)果時，應(yīng)附上所用的分析方法。并提供相應(yīng)的方法學(xué)論證資料。應(yīng)提供有代表性的色譜圖。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）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。申報者應(yīng)保證：如需要，可提供各個批次產(chǎn)品的完整的雜質(zhì)概況（例如；色譜圖）。A tabulation should be provided that links the specific new drug substance batch to each safety study and each clinical study in which the new drug substance has been used.另外，申報者還應(yīng)提供應(yīng)用在每個安全性研究和臨床研究中的新原料藥的每個批次一一對應(yīng)的名單。For each batch of the new drug substance, the report should include:對每批新原料藥、報告內(nèi)容應(yīng)包括： Batch identity and size 批號與批量 Date of manufacture生產(chǎn)日期 Site of manufacture 生產(chǎn)地點 Manufacturing process 生產(chǎn)工藝 Impurity content, individual and total單個雜質(zhì)含量和總雜質(zhì)含量 Use of batches批次的用途 Reference to analytical procedure used所采用分析方法的闡釋6. LISTING OF IMPURITIES IN SPECIFICATIONS 規(guī)范中所列的雜質(zhì)檢查項目The specification for a new drug substance should include a list of impurities. Stability studies, chemical development studies, and routine batch analyses can be used to predict those impurities likely to occur in the mercial product. The selection of impurities in the new drug substance specification should be based on the impurities found in batches manufactured by the proposed mercial process. Those individual impurities with specific acceptance criteria included in the specification for the new drug substance are referred to as specified impurities in this guideline. Specified impurities can be identified or unidentified.在新原料藥的規(guī)范中應(yīng)包括雜質(zhì)檢查項目。穩(wěn)定性研究、化學(xué)方面的開發(fā)研究以及日常批次分析檢驗的結(jié)果有助于預(yù)測在市售產(chǎn)品中可能出現(xiàn)的雜質(zhì)。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。在本指導(dǎo)原則中。列入新原料藥規(guī)范中、具有特定的認(rèn)可標(biāo)準(zhǔn)的各個雜質(zhì)稱為特定雜質(zhì)。特定雜質(zhì)可以是已鑒定的，也可以是未鑒定的。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。) the identification threshold (Attachment 1) for any unspecified impurity and an acceptance criterion for total impurities should be included.應(yīng)對用于安全性和臨床研究中的批次中所發(fā)現(xiàn)雜質(zhì)情況，以及對擬上市生產(chǎn)的原料中雜質(zhì)概況綜合進(jìn)行考慮后，再對規(guī)范中列入或不列入哪些雜質(zhì)的理由進(jìn)行說明。特定的已鑒定雜質(zhì)應(yīng)與特定的其喊兩估計大于（＞）鑒定閾值（附錄1）的未鑒定雜質(zhì)一起考慮。對于那些具有特殊功效或產(chǎn)生毒性或為預(yù)料到的藥理作用的雜質(zhì)，其分析方法的定量限或檢測限度必須與該雜質(zhì)應(yīng)被控制的量相當(dāng)。對于未鑒定的雜質(zhì)，所使用的檢測方法和確定雜質(zhì)量時所采用的假設(shè)應(yīng)予明確說明。特定的未鑒定的雜質(zhì)應(yīng)采用適當(dāng)?shù)姆椒枋鰳?biāo)記（例如：“未鑒定雜質(zhì)A”“”）。對于任何一個非特定雜質(zhì)應(yīng)有一個不大于（≤）鑒定閾值（附錄1）的認(rèn)可標(biāo)準(zhǔn)，對總雜質(zhì)也應(yīng)建立一個認(rèn)可標(biāo)準(zhǔn)。Acceptance criteria should be set no higher than the level that can be justified by safety data, and should be consistent with the level achievable by the manufacturing process and the analytical capability. Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the new drug substance manufactured by the proposed mercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substance. Although normal manufacturing variations are expected, significant variation in batchtobatch impurity levels can indicate that the manufacturing process of the new drug substance is not adequately controlled and validated (see ICH Q6A Guideline on Specifications, Decision Tree 1, for establishing an accept