Q3A(R2)-新原料藥中的雜質(中英文)

1、Impurities In New Drug Substa nces新原料藥中的雜質 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH Harmonised Tripartite Guideline I MPURITIES I N NEW DRUG SUBSTANCES Q3A(R2) Current Step 4 version dated 25 October 2006 This Guideline

2、 has been developed by the appropriate ICH Expert Working Group and has bee n subject to con sultati on by the regulatory parties, in accorda nee with the ICH Process. At Step 4 of the Process the final draft is recommended for adopti on to the regulatory bodies of the Europea n Union, Japa n and US

3、A. Page 12 of 22 Q3A(R2) Docume nt History First Codificati on History Date New Codificati on November 2005 Q3 Approval by the Steering Committee underStep 2 and release for public con sultati on. 15 March 1994 Q3A Q3A Approval by the Steering Committee underStep 4 and recomme ndati onfor adopti on

4、to the three ICH regulatory bodies. Q3 was ren amed Q3A. 30 March 1995 Q3A Q3A(R) Approvalby the Steeri ngCommitteeof the first Revisi onun der Step 2 and release for public con sultati on. 7 October 1999 Q3A(R1) Q3A(R) Approval by the Steeri ng Committeeof the first Revisio n un der Step 4 and reco

5、mme ndati onfor adopti on to the three ICH regulatory bodies. 6 February 2002 Q3A(R1) Curre nt Step 4 vers ion Approval by the Steering Committee of the revision of 25 Q3A(R2) the Attachme nt 2 directly un der Step 4 without further October Q3A(R2) public con sultati on. 2006 Impurities In New Drug

6、Substances ICH Harmoni sed Tripartite Guideli ne Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 7 February 2002, this guideli ne is recomme nded for adopti on to the three regulatory parties to ICH. Attachme nt 2 has bee n revised on 25 October 2006. TABLE OF CONTE

7、NTS 1. PREAMBLE 4 2. CLASSIFICATION OF IMPURITIES 4 3. rationale for the reporting and control OF IMPURITIES 6 3.1 Organic Impurities6 3.2 Inorganic Impurities 7 3.3 Solvents7 4. ANALYTICAL PROCEDURES 8 5. REPORTING IMPURITY content OF BATCHES 9 6. LISTING OF IMPURITIES in SPECIFICATIONS10 7. qualif

8、ication OF IMPURITIES12 8. GLOSSARY 14 ATTACHMENT 1 17 ATTACHMENT 2 18 ATTACHMENT 3 20 Impurities In New Drug Substances 新原料藥中的雜質 1. PREAMBLE 序言 This docume nt is inten ded to provide guida nee for registrati on applicati ons on the content and qualification of impurities in new drug substancesprodu

9、ced by chemical syntheses and not previously registered in a region or member state. It is not intended to apply to new drug substa nces used duri ng the cli ni cal research stage of developme nt. The follow ing types of drug substa nces are not covered in this guideli ne: biological/biotech no logi

10、cal, peptide, olig onu cleotide, radiopharmaceutical, ferme ntatio n product and semi-s yn thetic products derived therefrom, herbal products, and crude products of ani mal or pla nt orig in. 本文件旨在為化學合成的新原料藥（這些新原料藥尚未在任何地區(qū)或成員國注冊）在注 冊申請時，對其雜質的含量和界定的申報提供指導。本報導原則不適用于臨床研究期間 所用的新原料藥。本文件不涵蓋生物/生物制品、肽、寡聚核苷酸。

11、放射性藥物、發(fā)酵 和半合成產品、草藥以及來源于動、植物的粗制品。 Impurities in new drug substa nces are addressed from two perspectives: 新原料藥中的雜質分兩個方面闡述： Chemistry Aspectsinclude classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedu

12、res; and 化學方面：包括對雜質的分類和鑒定、雜質生成、規(guī)范中雜質的檢查項目以及對分 析方法的簡要討論。 Safety Aspects include specific guidance for qualifying those impurities that were not prese nt, or were prese nt at substa ntially lower levels, in batches of a new drug substa nce used in safety and cli ni cal studies. 安全性方面：對用于安全性研究和臨床研究的新原料

13、藥批次中不存在或含量很低的 那些雜質的界定的指南。 2. classification of impurities 雜質的分類 Impurities can be classified into the following categories:雜質可分為下列類型 : ?Orga nic impurities （process- and drug-related）有機雜質（與工藝和藥物有關的） ?Inorganic impurities 無機雜質 ?Residual solve nts 殘留溶劑 Organic impurities can arise during the manufactu

14、ring process and/or storage of the new drug substanee. They can be identified or unidentified, volatile or non-volatile, and include: 有機雜質可能會在新原料藥的生產過程和（或）儲存期間有所增加。這些雜質可能是已確定的或 者是未確定的、揮發(fā)性的或者非揮發(fā)性的。它包括： ?Starti ng materials 起始物 ?By-products 副產物 ?In termediates 中間體 ?Degradation products 降解產物 ?Reage nts

15、, liga nds and catalyst試劑、配位體、催化劑 Inorganic impurities can result from the manu facturi ng process. They are no rmally known and identified and include: 無機雜質可能來源于生產過程，它們一般是已知的和確定的。包括： ?Reage nts, liga nds and catalysts試劑、配位體、催化劑 ? Heavy metals or other residual metals 重金屬或其他殘留金屬 ? Inorganic salts 無機

16、鹽 ? Other materials （e.g., filter aids, charcoal）其他物質（例如：過濾介質、活性炭等） Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspe nsions in the syn thesis of a new drug substa nee. Si nce these are gen erally of known toxicity, the selecti on of appropriate con

17、 trols is easily accomplished （see ICH Guideli ne Q3C on Residual Solve nts）. 溶劑是在新原料藥合成過程中用于制備溶液或混懸液的有機或無機液體，由于它們一般 具有已知毒性，故容易選擇控制方法（見 ICH指導原則Q3C殘留溶劑項下）。 Excluded from this docume nt are: （1） extra neous con tam inants that should not occur in new drug substa nces and are more appropriately address

18、ed as Good Manu facturi ng Practice （GMP） issues, （2） polymorphic forms, and （3） enantiomeric impurities. 不包括在本文件中的雜質為：（1 ）外源性污染物（不應該存在于新原料藥中，可以用 GMP來控制）；（2 ）多晶型；（3）對映體雜質。 3. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES 雜質報告和控制的說明 3.1 Orga nic Impurities有機雜質 The applicant should summarise t

19、he actual and potential impurities most likely to arise during the synthesis, purification, and storage of the new drug substanee. This summary should be based on sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could con t

20、ribute to the impurity profile of the new drug substanee, and possible degradation products. This discussion can be limited to those impurities that might reas on ably be expected based on kno wledge of the chemical reacti ons and con diti ons invo lved. 申報者應對新原料藥在合成、精制和儲存過程中最可能產生的那些實際存在的和潛在的 雜質進行概述

21、。該描述應建立在對合成所涉及的化學反應、由原材料引入的雜質及可能 的降解產物進行合理地、科學地評估的基礎上?？梢跃窒抻诟鶕?jù)化學反應以及相關條件 下可能會產生的雜質進行討論。 In additi on, the applica nt should summarise the laboratory studies con ducted to detect impurities in the new drug substance.This summary should include test results of batches manufactured duri ng the developme

22、 nt process and batches from the proposed commercial process, as well as the results of stress testing (see ICH Guideline Q1A on Stability) used to identify potential impurities aris ing duri ng storage. The impurity profile of the drug substa nce batches in ten ded for market ing should be compared

23、 with those used in developme nt, and any differe nces discussed. 此外，申報者還應對新原料藥中雜質檢測的實驗室研究工作進行概述，其內容包括對研 制期間和模擬上市的所有批次產品的試驗結果、以及為鑒定在儲存期間可能產生的潛在 雜質而進行強力破壞試驗的結果(見 ICH指導原則Q1A穩(wěn)定性項下)。同時應對那些模 擬上市的原料批次中的雜質概況和用于研制開發(fā)過程的原料批次中的雜質概況進行比 較，任何不同之處均應加以討論。 The studies con ducted to characterise the structure of actu

24、al impurities prese nt in the new drug substanceat a level greater than () the identification threshold given in Attachment 1 (e.g., calculated using the resp onse factor of the drug substa nce) should be described. Note that any impurity at a level greater than () the identification threshold in an

25、y batch manufactured by the proposed commercial process should be identified. In addition, any degradation product observed in stability studies at recommended storage conditions at a level greater than () the identification threshold should be identified. When identification of an impurity is not f

26、easible, a summary of the laboratory studies dem on strati ng the un successful effort should be in cluded in the application. Where attempts have been made to identify impurities present at levels of not more than ( ) the identification thresholds, it is useful also to report the results of these s

27、tudies. 申報資料中還應對那些在新原料藥中實際存在的、含量大于（）附錄1中鑒定閾值的雜 質（例如：以原料藥的響應因子計算）的結構特征進行描述。應該注意，在模擬上市生 產的批次中，所有出現(xiàn)的大于（）鑒定閾值的雜質應予鑒定；也應同樣鑒定在推薦的 放置條件下的穩(wěn)定性研究中發(fā)現(xiàn)大于（）鑒定閾值的降解產物；當某個雜質無法鑒定 時。申報資料中應包括對該雜質所進行的不成功的試驗研究的概述。如果已嘗試過鑒定 含量不大于（弓鑒定閾值的雜質。那么把這些研究結果也報告進去是很有用的。 Identification of impurities present at an apparentlevel of not

28、 more than ( ) the identification threshold is gen erally not con sidered n ecessary. However, an alytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than () the identification

29、 threshold. All impurities should be qualified as described later in this guideli ne. 通常沒有必要對含量在閾值以下( 弓 的雜質進行鑒定。然而，對那些含量不大于( 勻 閾值但可能產生不尋常功效或毒性藥理作用的潛在雜質，則應力求鑒定他們。所有雜質 均應按照本指導原則后續(xù)章節(jié)中的要求來鑒定。 3.2 Inorganic Impurities 無機雜質 Inorganic impurities are normally detected and quantified using pharmacopoeial or

30、other appropriate procedures. Carry-over of catalysts to the new drug substa nee should be evaluated duri ng developme nt. The n eed for in clusi on or exclusi on of inorganic impurities in the new drug substanee specification should be discussed. Acceptanee criteria should be based on pharmacopoeia

31、l sta ndards or known safety data. 無機雜質通常按藥典或其他適當?shù)姆椒▉頇z測和定量。在新藥的研制過程中應對遺留在 新原料藥中的催化劑進行評估。在新原料藥規(guī)范中是否收載無機雜質檢查項目，應進行 討論。其認可限度應根據(jù)藥典標準或已知的安全性數(shù)據(jù)來制定。 3.3 Solve nts 溶劑 The control of residues of the solvents used in the manufacturing process for the new drug substa nee should be discussed and prese nted acco

32、rd ing to the ICH Q3C Guideli ne for Residual Solve nts. 應按ICH Q3C “殘留溶劑”指導原則的要求，對新原料藥生產過程中所用的溶劑的殘留量的 控制進行討論和申報。 4. ANALYTICAL PROCEDURES分析方法 The registrati on applicati on should in clude docume nted evide nee that the an alytical procedures are validated and suitable for the detect ion and qua nti

33、ficati on of impurities (see ICH Q2A and Q2B Guideli nes for An alytical Validatio n). Tech ni cal factors (e.g., manu facturi ng capability and con trol methodology) can be con sidered as part of the justificati on for select ion of alter native thresholds based on manu facturi ng experie nee with

34、the proposed commercial process. The use of two decimal places for thresholds (See Attachment 1) does not necessarily reflect the precision of the analytical procedure used for routine quality control purposes. Thus, the use of lower precision techniques (e.g., thin-layer chromatography) can be acce

35、ptable where justified and appropriately validated. Differe nces in the an alytical procedures used duri ng developme nt and those proposed for the commercial product should be discussed in the registrati on applicati on. 注冊申請中應提供書面文件，證明分析方法是經過論證并適用于雜質的檢測和定量(見 ICH Q2A及Q2B分析方法論證指導原則項下)，技術因素(如生產能力與質控方

36、法)可 用于說明為什么在準備上市產品中采用其他的閾值。閾值采用兩位小數(shù)(見附錄 1)并不 代表常規(guī)質量控制中分析方法的精度。因此，只需經過驗證和論證，可以使用較低精度 的技術(如薄層色譜法)。如果研發(fā)中所采用的分析方法和準備上市產品的分析方法不 同，在申報資料中應予以討論。 The quantitation limit for the analytical procedure should be not more than ( ) the reporting threshold. 分析方法的定量限度應不大于(菊報告閾值。 Organic impurity leve ls can be meas

37、ured by a variety of techniques, including those that compare an an alytical resp onse for an impurity to that of an appropriate refere nee sta ndard or to the response of the new drug substance itself. Reference standards used in the analytical procedures for control of impurities should be evaluat

38、ed and characterised according to their intended uses. The drug substance can be used as a standard to estimate the levels of impurities. In cases where the resp onse factors of the drug substa nce and the releva nt impurity are not close, this practice can still be appropriate, provided a correct i

39、on factor is applied or the impurities are, in fact, being overestimated. Acceptance criteria and analytical procedures used to estimate iden tified or uniden tified impurities can be based on an alytical assumptio ns (e.g., equivale nt detector resp on se). These assumpti ons should be discussed in

40、 the registrati on applicati on. 可用各種技術測定有機雜質的含量，這些技術包括把雜質的響應值與適當?shù)膮⒈葮藴势?的響應值比較或與藥物本身的響應值比較。應根據(jù)使用目的，對分析過程中用于控制雜 質的參比標準品進行定性和定量?？捎迷纤幾鳛闃藴饰镔|來估計雜質的量，如果原料 要和雜質的響應因子不接近，只要應用了校正因子或測得的雜質量膏腴實際的雜質量， 該方法仍是可行的。用于評估已鑒定或未鑒定雜質的認可標準和分析方法可基于分析的 假設(例如：相同的檢測響應等)。為此，這些假設也應在注冊申請中加以討論。 5. REPORTING IMPURITY CONTENT OF BA

41、TCHES 各批次產品雜質含量的報告 An alytical results should be provided in the applicati on for all batches of the new drug substa nee used for clinical, safety, and stability testing, as well as for batches representative of the proposed commercial process. Quantitative results should be presentednumerically, an

42、d not in general terms such as “ complies ” ,“ meets limit ” etc. Any impurity at a level greater than （） the rep（ 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 1.0%, the result

43、s should be reported to two decimal places （e.g., 0.06%, 0.13%）; at and above 1.0%, the results should be reported to one decimal place （e.g., 1.3%）. Results should be rounded using conventional rules （see Attachment 2）. A tabulation （e.g., spreadsheet） of the data is recomme nded. Impurities should

44、 be desig nated by code nu mber or by an appropriate descriptor, e.g., retention time. If a higher reporting threshold is proposed, it should be fully justified. All impurities at a level greater tha n （） the report ing threshold should be summed and reported as total impurities. 注冊申請應提供用于臨床、安全性研究、穩(wěn)

45、定性試驗的所有新原料藥批次產品的分析結 果以及用于準備上市產品的分析結果。定量測定結果應數(shù)字化，不應用符合規(guī)定”，符 合限度”等一般性術語。在新原料藥的所有批次中，應報告檢測到的大于（）報告閾值 （見附錄1）的任何雜質和總雜質，并附所用的分析方法。若低于1.0%，結果應報告至 小數(shù)點后兩位（如0.06%，0.13%），若大于或等于1.0%，結果報告至小數(shù)點后1位（如 1.3%）。結果應按傳統(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 雜質均應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，應進行 充分論證。所有大于（）報告閾值的雜質應進行累加，報告為總雜質”。 W

46、he n an alytical procedures cha nge duri ng developme nt, reported results should be lin ked to the procedure used, with appropriate validati onin formatio n provided. Represe ntative chromatograms should be provided. Chromatograms of representative batchesfrom analytical validation studies showing

47、separation and detectability of impurities （e.g., on spiked samples）, along with any other impurity tests rout in ely performed, can serve as the represe ntative impurity profiles. The applicant should ensure that complete impurity profiles （e.g., chromatograms） of in dividual batches are available,

48、 if requested. 若在研制期間，分析方法發(fā)生了變化，報告測試結果時，應附上所用的分析方法。并提 供相應的方法學論證資料。應提供有代表性的色譜圖。方法學論證中，顯示雜質分離度 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)雜質檢測得到的 色譜圖，可以反映出有代表性的雜質概況。申報者應保證：如需要，可提供各個批次產 品的完整的雜質概況（例如；色譜圖）。 A tabulatio n should be provided that li nks the specific new drug substa nee batch to each safety study and e

49、ach cli nical study in which the new drug substa nee has bee n used. 另外，申報者還應提供應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 對應的名單。 For each batch of the new drug substa nee, the report should in clude: 對每批新原料藥、報告內容應包括： ? Batch ide ntity and size 批號與批量 ?Date of manu facture生 產日期 ? Site of manu facture 生產地點 ? Manu fa

50、cturi ng process 生產工藝 ?Impurity conten t, i ndividual a nd total單個雜質含量和總雜質含量 ? Use of batches批 次的用途 ? Refere nee to an alytical procedure use所 采用分析方法的闡釋 6. LISTING OF IMPURITIES IN SPECIFICATIONS規(guī)范中所列的雜質檢查項目 The specification for a new drug substance should include a list of impurities. Stability st

51、udies, chemical development studies, and routine batch analyses can be used to predict those impurities likely to occur in the commercial product. The select ion of impurities in the new drug substa nce specificati on should be based on the impurities found in batches manu factured by the proposed c

52、ommercial process. Those in dividual impurities with specific accepta nce criteria in cluded 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)范中應包括雜質檢查項目。穩(wěn)定性研究、化學方面的開發(fā)研究以及日常 批次分析檢

53、驗的結果有助于預測在市售產品中可能出現(xiàn)的雜質。在新原料藥規(guī)范中收載 的雜質應根據(jù)在準備上市生產的批次中所發(fā)現(xiàn)的雜質來選擇。在本指導原則中。列入新 原料藥規(guī)范中、具有特定的認可標準的各個雜質稱為特定雜質。特定雜質可以是已鑒定 的，也可以是未鑒定的。 A rati on ale for the in clusi on or exclusi on of impurities in the specificati on should be prese nted. This rati on ale should in clude a discussi on of the impurity profile

54、s observed in the safety and clinical development batches, together with a consideration of the impurity profile of batches manufactured by the proposed commercial process. Specified identified impurities should be included along with specified unidentified impurities estimated to be present at a le

55、vel greater than () the identification threshold given in Attachment 1. For impurities known to be unusually pote nt or to produce toxic or un expected pharmacological effects, the qua ntitati on/detecti on limit of the analytical procedures should be commensuratewith the level at which the impuriti

56、es should be con trolled. For uniden tified impurities, the procedure used and assumpti ons made in establishing the level of the impurity should be clearly stated. Specified, unidentified impurities should be referred to by an appropriate qualitative an alytical descriptive label （e.g.,“ A,“ uniden

57、tified with relative retention of 0.9” ）. A general acceptanee criterion of not m （）the identification threshold （Attachment 1） for any unspecified impurity and an acceptanee criterion for total impurities should be included. 應對用于安全性和臨床研究中的批次中所發(fā)現(xiàn)雜質情況，以及對擬上市生產的原料中雜 質概況綜合進行考慮后，再對規(guī)范中列入或不列入哪些雜質的理由進行說明。特

58、定的已 鑒定雜質應與特定的其喊兩估計大于（）鑒定閾值（附錄 1）的未鑒定雜質一起考慮。 對于那些具有特殊功效或產生毒性或為預料到的藥理作用的雜質，其分析方法的定量限 或檢測限度必須與該雜質應被控制的量相當。對于未鑒定的雜質，所使用的檢測方法和 確定雜質量時所采用的假設應予明確說明。特定的未鑒定的雜質應采用適當?shù)姆椒枋?標記（例如：朱鑒定雜質A”相對保留時間為0.9的雜質”）。對于任何一個非特定雜質 應有一個不大于（弓鑒定閾值（附錄 1）的認可標準，對總雜質也應建立一個認可標 準。 Acceptance criteria should be set no higher than the lev

59、el that can be justified by safety data, and should be con siste nt with the level achievable by the manu facturi ng process and the an alytical capability. Where there is no safety concernmpurity accepta nce criteria should be based on data gen erated on batches of the new drug substa nce manu fact

60、ured by the proposed commercial 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 batch-to-batch impurity levels