緩控釋口服固體制劑放大和批準(zhǔn)后的輔料變更指南

1、III. COMPONENTS AND COMPOSITION NONRELEASE CONTROLLING EXCIPIENT組分和成分-非釋放控制輔料This section of the guidance focuses on changes in nonrelease controlling excipients in the drug product. For modified release solid oral dosage forms, consideration should be given as to whether the excipient is critical o

2、r not critical to drug release. The sponsor should provide appropriate justifications for claiming any excipient(s) as a nonrelease controlling excipient in the formulation of the modified release solid oral dosage form. The functionality of each excipient should be identified. Changes in the amount

3、 of the drug substance are not addressed by this guidance. Changes in components or composition that have the effect of adding a new excipient or deleting an excipient are defined at level 3 (defined below), except as described below in Section III.A.1.a. Waiver of bioequivalence testing for a chang

4、e in composition which involves only a different color, flavor or preservative may be permissible as described in 21 CFR 320.22(d)(4). 本指南這部分主要針對藥品非釋放控制輔料的變更。對于緩控釋固體口服制劑，應(yīng)該對輔料是否為藥物釋放的關(guān)鍵輔料或非關(guān)鍵輔料進行考慮。發(fā)起人如果判定任何輔料為緩控釋固體口服制劑中的非釋放控制輔料，應(yīng)該提供相應(yīng)的理由。應(yīng)該對每種輔料的功能進行識別。本指南未對藥品中原料藥量的變更進行規(guī)定。對組分或成分的變更中涉及到新增或刪除輔料時，歸類為3

5、級變更，第III.A.1.a中的情況除外。成分的變更如果只涉及到變更顏色、口味或防腐劑，按照21 CFR 320.22(d)(4)的規(guī)定可能允許豁免生物等效性測試。A. Level 1 Change一級變更1. Definition of Level級別定義Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance. 一級變更指那些不太可能對劑型的質(zhì)量和功效有可檢測的影響的變更。Examples:例如a. Deletion or

6、partial deletion of an ingredient intended to affect the color or flavor of the drug product; or change in the ingredient of the printing ink to another approved ingredient. 刪除或部分刪除組分，這個組分會影響藥品的顏色或口味；或者將印刷用油墨成分變更為另一種已批準(zhǔn)成分。b. Changes in nonrelease controlling excipients, expressed as percentage (w/w)

7、 of total formulation, less than or equal to the following percent ranges:非釋放控制輔料的變更，以總配方的百分比表示，小于等于以下百分比范圍：Nonrelease Controlling Excipient非釋放控制輔料Percent Excipient (w/w)Out Of Total Target Dosage Form Weight輔料占總劑型重量的百分比Filler填充劑±5Disintegrant崩解劑Starch淀粉Other其他±3±1Binder粘合劑±0.5Lu

8、bricant潤滑劑Ca or Mg stearate鈣或鎂硬脂酸鹽Other其他±0.25±1Glidant 助流劑Talc滑石粉Other其他Film Coat包衣±1±0.1±1These percentages are based on the assumption that the drug substance in the product is formulated to 100% of label/potency. The total additive effect of all nonrelease controlling ex

9、cipient changes should not be more than 5%.2 The total weight of the dosage form should still be within the original approved application range. 以上的百分比是假設(shè)產(chǎn)品是100%按標(biāo)簽/效價配方制造的。所有非釋放控制輔料變更的累加效應(yīng)應(yīng)該不超過5%。劑型總重量應(yīng)該在原始批準(zhǔn)申請的范圍內(nèi)。The components (active and excipients) in the formulation should have numerical targ

10、ets that represent the nominal composition of the drug product on which any future changes in the composition of the product are to be based. Allowable changes in the composition should be based on the original approved target composition and not on previous level 1 changes in the composition. For p

11、roducts approved with only a range for excipients, the target value may be assumed to be the midpoint of the original approved application range.劑型中的成分（活性成分和輔料）應(yīng)該有數(shù)量化的投放范圍，這個范圍代表的是藥品的公稱成分，藥品以后任何的變更都是基于這個范圍的。成分中可允許的變更應(yīng)該是基于原始批準(zhǔn)的目標(biāo)成分，并且不是基于成分中之前的一級變更。對于輔料的批準(zhǔn)是在一個范圍內(nèi)的產(chǎn)品，目標(biāo)值假設(shè)為原始批準(zhǔn)范圍的中值。2. Test Documentat

12、ion檢測文件a. Chemistry Documentation化學(xué)文件Application/compendial product release requirements and stability testing. 申請/注冊產(chǎn)品放行要求和穩(wěn)定性測試。Stability: First production batch on long-term stability data reported in annual report.穩(wěn)定性測試：第一批生產(chǎn)的產(chǎn)品做長期穩(wěn)定性測試，并在年報中進行報告。b. Dissolution documentation溶解文件None beyond appli

13、cation/compendial requirements. 除申請、注冊要求外無其他要求。c. Bioequivalence documentation生物等效性文件None.無3. Filing Documentation檔案文件Annual report (all information including long-term stability data).年報（所有信息包括長期穩(wěn)定性測試數(shù)據(jù)）B. Level 2 Change二級變更1. Definition of Level級別定義Level 2 changes are those that could have a signi

14、ficant impact on formulation quality and performance.二級變更指的是那些可能會對劑型質(zhì)量和功效有嚴(yán)重影響的變更。Examples:例如a. A change in the technical grade and/or specifications of a nonrelease controlling excipient.對技術(shù)等級和/或非釋放控制輔料的變更。b. Changes in nonrelease controlling excipients, expressed as percentage (w/w) of total formu

15、lation, greater than those listed above for a level 1 change, but less than or equal to the following percent ranges (which represent a two-fold increase over level 1 changes):非釋放控制輔料的變更，以總配方的百分比表示，大于前面一級變更的百分比，但是小于等于以下百分比范圍（以一級變更兩倍的增長表示）：Nonrelease Controlling Excipient非釋放控制輔料Percent Excipient (w/w

16、)Out Of Total Target Dosage Form Weight輔料占總劑型重量的百分比Filler填充劑±10Disintegrant崩解劑Starch淀粉Other其他±6±2Binder粘合劑±1Lubricant潤滑劑Ca or Mg stearate鈣或鎂硬脂酸鹽Other其他±0.5±2Glidant 助流劑Talc滑石粉Other其他Film Coat包衣±2±0.2±2These percentages are based on the assumption that the

17、 drug substance in the drug product is formulated to 100% of label/potency. The total additive effect of all nonrelease controlling excipient changes should not change by more than 10%. The total weight of the dosage form could still be within or outside the original approved application range.以上的百分

18、比是假設(shè)產(chǎn)品是100%按標(biāo)簽/效價配方制造的。所有非釋放控制輔料變更的累加效應(yīng)應(yīng)該不超過10%。劑型的總重量應(yīng)該在原始批準(zhǔn)申請的范圍內(nèi)。The components (active and excipients) in the formulation should have numerical targets that represent the nominal composition of the product on which any future changes in the composition of the product are to be based. Allowable c

19、hanges in the composition are based on the original approved target composition and not on the composition based on previous level 1 or level 2 changes. For products approved with only a range for excipients, the target value may be assumed to be the midpoint of the original approved application ran

20、ge. 劑型中的成分（活性成分和輔料）應(yīng)該有數(shù)量化的投放范圍，這個范圍代表的是藥品的公稱成分，藥品以后任何的變更都是基于這個范圍的。成分中可允許的變更應(yīng)該是基于原始批準(zhǔn)的目標(biāo)成分，并且不是基于成分中之前的一級、二級變更。對于輔料的批準(zhǔn)是在一個范圍內(nèi)的產(chǎn)品，目標(biāo)值假設(shè)為原始批準(zhǔn)范圍的中值。2. Test Documentation檢測文件a. Chemistry Documentation化學(xué)文件Application/compendial product release requirements and updated executed batch records. 申請/注冊產(chǎn)品的放行要求和

21、已更新并生效的批記錄。Stability: One batch with three months accelerated stability data reported in prior approval supplement and long-term stability data of first production batch reported in annual report. 穩(wěn)定性測試：一批產(chǎn)品做三個月的加速穩(wěn)定性測試，并在預(yù)批準(zhǔn)補充申請里進行報告；生產(chǎn)的第一批產(chǎn)品做長期穩(wěn)定性測試，并在年報里進行報告。b. Dissolution documentation溶解文件Extend

22、ed release: In addition to application/compendial release requirements, multipoint dissolution profiles should be obtained in three other media, for example, in water, 0.1N HCl, and USP buffer media at pH 4.5, and 6.8 for the changed drug product and the biobatch or marketed batch (unchanged drug pr

23、oduct). Adequate sampling should be performed, for example, at 1, 2, and 4 hours and every two hours thereafter until either 80% of the drug from the drug product is released or an asymptote is reached. A surfactant may be used with appropriate justification. 緩釋：除了申請/注冊產(chǎn)品的放行要求之外，應(yīng)使用另外三種介質(zhì)獲取多點溶解分析數(shù)據(jù)，

24、例如將變更后的產(chǎn)品和生物批次或市售批次（變更前產(chǎn)品）分別在水、0.1 HCl、和pH4.5和6.8的USP緩沖介質(zhì)中試驗。應(yīng)該進行充分的取樣，例如在第1、2、4小時分別取樣，之后每兩小時取一次，直到產(chǎn)品釋放了80%，或者釋放達到了漸近線。必要時可使用表面活性劑，但是要有適當(dāng)?shù)睦碛山忉?。Delayed release: In addition to application/compendial release requirements, dissolution tests should be performed in 0.1 N HCl for 2 hours (acid stage) foll

25、owed by testing in USP buffer media, in the range of pH 4.5-7.5 (buffer stage) under standard (application/compendial) test conditions and two additional agitation speeds using the application/ compendial test apparatus (three additional test conditions). If the application/compendial test apparatus

26、 is the rotating basket method (Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and if the application/compendial test apparatus is the rotating paddle method (Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used. Multipoint dissolution profiles should be obtained du

27、ring the buffer stage of testing. Adequate sampling should be performed, for example, at 15, 30, 45, 60, and 120 minutes (following the time from which the dosage form is placed in the buffer) until either 80% of the drug from the drug product is released or an asymptote is reached. The above dissol

28、ution testing should be performed using the changed drug product and the biobatch or marketed batch (unchanged drug product). 延時釋放：除了申請/注冊產(chǎn)品的放行要求之外，還要進行溶出度檢查，先在0.1 N HCl 中進行2小時（酸性階段），然后在USP的緩沖介質(zhì)中檢測，緩沖液的范圍為pH 4.5-7.5（緩沖階段），檢測條件均為標(biāo)準(zhǔn)（申請/注冊）條件，使用申請/注冊中的檢測儀器（三個額外的檢測條件），額外加兩種攪拌速度。如果申請/注冊中的檢測儀器為旋轉(zhuǎn)籃法（儀器1），可

29、選用50、100和150的旋轉(zhuǎn)速度，如果申請/注冊中的檢測儀器為旋轉(zhuǎn)槳法（儀器2），可選用50、75和100的旋轉(zhuǎn)速度。在檢測的緩沖階段應(yīng)該獲得多點溶解度分析數(shù)據(jù)。并應(yīng)進行充分的取樣，例如，在第15、30、45、60和120分鐘（從劑型放入緩沖液中開始計時）分別取樣，直到產(chǎn)品釋放了80%，或者釋放達到了漸近線。上述溶解度檢測應(yīng)該分別對變更后的產(chǎn)品和生物批次或市售批次（變更前產(chǎn)品）進行檢測。All modified release solid oral dosage forms: In the presence of an established in vitro/in vivo correla

30、tion (6), only application/compendial dissolution testing need be performed (i.e., only in vitro release data by the correlating method need to be submitted). The dissolution profiles of the changed drug product and the biobatch or marketed batch (unchanged drug product) should be similar. The spons

31、or should apply appropriate statistical testing with justifications (e.g., the f equation) for comparing 2 dissolution profiles (5). Similarity testing for the two dissolution profiles (i.e., for the unchanged drug product and the changed drug product) obtained in each individual medium is appropria

32、te. 所有的緩控釋固體口服制劑：在已有體外/體內(nèi)釋放相關(guān)性的情況下，只需要做申請/注冊的溶解度檢測（只需要提供用相關(guān)性方法做的體外釋放的數(shù)據(jù)）。變更后產(chǎn)品的溶解度分析數(shù)據(jù)和生物批次或市售批次（變更前產(chǎn)品）的溶解度分析數(shù)據(jù)應(yīng)該是相類似的。發(fā)起人應(yīng)該應(yīng)用適當(dāng)?shù)慕y(tǒng)計檢驗方法去比較溶解度分析數(shù)據(jù)，并有理由支持（例如F方程式）。在不同介質(zhì)中獲取的兩種溶解度分析數(shù)據(jù)（變更前和變更后）應(yīng)該是相似的。c. Bioequivalence documentation 生物等效性文件None.無3. Filing Documentation檔案文件Prior approval supplement (all in

33、formation including accelerated stability data); annual report (long-term stability data).預(yù)批準(zhǔn)補充申請（所有信息，包括加速穩(wěn)定性實驗數(shù)據(jù)）；年報（長期穩(wěn)定性實驗數(shù)據(jù)）。C. Level 3 Change三級變更1. Definition of Level級別定義Level 3 changes are those that are likely to have a significant impact on formulation quality and performance.三級變更指的是很有可能對劑

34、型質(zhì)量和功效有嚴(yán)重影響的變更。Example:例如a. Changes in the nonrelease controlling excipient range beyond those listed in Section III.B.1.b. The total weight of the dosage form may be within or outside the approved original application range. 除了III.B.1.b中列出的變更之外的非釋放控制輔料的變更?？傊亓靠赡芊匣虺隽嗽寂鷾?zhǔn)的范圍。2. Test Documentation檢測文

35、件a. Chemistry Documentation化學(xué)文件Application/compendial product release requirements and updated executed batch records. 申請/注冊產(chǎn)品的放行要求和已更新并生效的批記錄。Stability: 穩(wěn)定性：Significant body of information available: One batch with three months' accelerated stability data reported in prior approval supplement a

36、nd longterm stability data of first three production batches reported in annual report.必須要包含的重要信息部分：一個產(chǎn)品批次的三個月加速穩(wěn)定性測試，并在預(yù)批準(zhǔn)補充申請里進行報告，生產(chǎn)的前三批產(chǎn)品做長期穩(wěn)定性測試，并在年報里進行報告。Significant body of information not available: Three batches with three months' accelerated stability data reported in prior approval su

37、pplement and long-term stability data of first three production batches reported in annual report. 遞交時還未準(zhǔn)備好，但是也很重要的信息：三個產(chǎn)品批次的三個月加速穩(wěn)定性測試，并在預(yù)批準(zhǔn)補充申請里進行報告，生產(chǎn)的前三批產(chǎn)品做長期穩(wěn)定性測試，并在年報里進行報告。b. Dissolution documentation溶解文件Extended release: In addition to application/compendial release requirements, a multipoint

38、 dissolution profile should be obtained using the application/compendial test conditions for the changed drug product and the biobatch or marketed batch (unchanged drug product). Adequate sampling should be performed, for example, at 1, 2, and 4 hours and every two hours thereafter, until either 80%

39、 of the drug from the drug product is released or an asymptote is reached. 緩釋：除了申請/注冊產(chǎn)品的放行要求之外，應(yīng)將變更后的產(chǎn)品和生物批次或市售批次（變更前產(chǎn)品）使用申請/注冊的檢測方法進行檢測，并獲取多點溶解分析數(shù)據(jù)。應(yīng)該進行充分的取樣，例如在第1、2、4小時分別取樣，之后每兩小時取一次，直到產(chǎn)品釋放了80%，或者釋放達到了漸近線。Delayed release: In addition to application/compendial release requirements, a multipoint dis

40、solution profile should be obtained during the buffer stage of testing using the application/compendial test conditions for the changed drug product and the biobatch or marketed batch (unchanged drug product). Adequate sampling should be performed, for example at 15, 30, 45, 60, and 120 minutes (fol

41、lowing the time from which the dosage form is placed in the buffer) until either 80% of the drug from the drug product is released or an asymptote is reached. 延時釋放：除了申請/注冊產(chǎn)品的放行要求之外，應(yīng)將變更后的產(chǎn)品和生物批次或市售批次（變更前產(chǎn)品）使用申請/注冊的檢測方法中緩沖階段的檢測方法進行檢測，并獲取多點溶解分析數(shù)據(jù)。并應(yīng)進行充分的取樣，例如，在第15、30、45、60和120分鐘（從劑型放入緩沖液中開始計時）分別取樣，直到產(chǎn)

42、品釋放了80%，或者釋放達到了漸近線。c. Bioequivalence documentation生物等效性文件A single-dose bioequivalence study (3). The bioequivalence study may be waived in the presence of an established in vitro/in vivo correlation (6).單次劑量的生物等效性研究。在已有體外/體內(nèi)釋放相關(guān)性的情況下，生物等效性研究可能會得到豁免。3. Filing Documentation檔案文件Prior approval supplemen

43、t (all information including accelerated stability data); annual report (long-term stability data). 預(yù)批準(zhǔn)補充申請（所有信息，包括加速穩(wěn)定性實驗數(shù)據(jù)）；年報（長期穩(wěn)定性實驗數(shù)據(jù)）。IV. COMPONENTS AND COMPOSITION RELEASE CONTROLLINGEXCIPIENT組分和成分-釋放控制輔料This section of the guidance focuses on changes in release controlling excipients in the

44、drug product. For modified release solid oral dosage forms, consideration should be given as to whether or not the excipient is critical to drug release. The sponsor should provide appropriate justifications (i.e., mechanism of drug release and manufacturing process) for claiming any excipient(s) as

45、 a release controlling excipient in the formulation of the modified release solid oral dosage form. The functionality of each excipient should be identified. Changes in the amount of the drug substance are not addressed by this guidance. Changes exceeding the ranges defined in each of the levels bel

46、ow may be allowed if considered to be within normal batch-to-batch variation and contained within an approved original application. In such situations, sponsors should contact the appropriate CDER review division for further guidance. 本指南這部分主要針對藥品釋放控制輔料的變更。對于緩控釋固體口服制劑，應(yīng)該對輔料是否為藥物釋放的關(guān)鍵輔料進行考慮。發(fā)起人如果判定任何

47、輔料為緩控釋固體口服制劑中的釋放控制輔料，應(yīng)該提供相應(yīng)的理由。應(yīng)該對每種輔料的功能進行識別。本指南未對藥品中原料藥量的變更進行規(guī)定。如果變更超出了以下幾級變更規(guī)定的范圍，但是任然是在批與批之間變化范圍內(nèi)并且包含在原始批準(zhǔn)申請中，這類變更也是可能被批準(zhǔn)的。這種情況下，發(fā)起人需要聯(lián)系相關(guān)的CDER審核部門以獲得進一步的指示。A. Level 1 Change一級變更1. Definition of Level級別定義Level 1 changes are those that are unlikely to have any detectable impact on formulation qua

48、lity and performance. 一級變更指不太可能對劑型的質(zhì)量和功效有可檢測的影響的變更。Example:例如a. Changes in the release controlling excipient(s), expressed as percentage (w/w) of total release controlling excipient(s) in the formulation less than or equal to 5% w/w of total release controlling excipient content in the modified rele

49、ase solid oral dosage form. 釋放控制輔料的變更，以總配方的百分比表示，小于或等于緩控釋固體口服制劑中總釋放控制輔料含量的5%。The drug substance in the product is formulated to 100% of label/potency. The total additive effect of all release controlling excipient changes should not be more than 5% w/w of the total release controlling excipients in

50、the original approved formulation.4 The total weight of the dosage form should still be within the approved original application range.藥品是100%按標(biāo)簽/效價配方制造的。所有釋放控制輔料變更的總累加作用應(yīng)該不超過原始批準(zhǔn)劑型中總釋放控制輔料的5%。The components (active and excipients) in the formulation should have numerical targets that represent the

51、nominal composition of the product on which any future changes in the composition of the product are to be based. Allowable changes in the composition should be based on the original approved target composition and not on previous level 1 changes in the composition. For products approved with only a

52、 range for excipients, the target value may be assumed to be the midpoint of the original approved application range. 劑型中的成分（活性成分和輔料）應(yīng)該有數(shù)量化的投放范圍，這個范圍代表的是藥品的公稱成分，藥品以后任何的變更都是基于這個范圍的。成分中可允許的變更應(yīng)該是基于原始批準(zhǔn)的目標(biāo)成分，并且不是基于成分中之前的一級變更。對于輔料的批準(zhǔn)是在一個范圍內(nèi)的產(chǎn)品，目標(biāo)值假設(shè)為原始批準(zhǔn)范圍的中值。2. Test Documentation檢測文件a. Chemistry Documen

53、tation化學(xué)文件Application/compendial product release requirements and stability testing. 申請、注冊產(chǎn)品放行要求和穩(wěn)定性測試。Stability: First production batch on long-term stability data reported in annual report.穩(wěn)定性測試：生產(chǎn)的第一批產(chǎn)品做長期穩(wěn)定性測試，并在年報中進行報告。b. Dissolution documentation溶解文件None beyond application/compendial requireme

54、nts. 除申請、注冊要求外無其他要求。c. Bioequivalence documentation生物等效性文件None.無3. Filing Documentation檔案文件Annual report (all information including long-term stability data). 年報（所有信息包括長期穩(wěn)定性測試數(shù)據(jù)）B. Level 2 Change二級變更1. Definition of Level級別定義Level 2 changes are those that could have a significant impact on formulati

55、on quality and performance. Test documentation for a level 2 change would vary depending on whether the product could be considered to have a narrow therapeutic range. 二級變更指的是那些可能會對劑型質(zhì)量和功效有嚴(yán)重影響的變更。二級變更所需的檢測文件根據(jù)是否產(chǎn)品是狹窄治療范圍而不同。Examples:例如a. Change in the technical grade and/or specifications of the re

56、lease controlling excipient(s).對技術(shù)等級和/或釋放控制輔料的變更。b. Changes in the release controlling excipient(s), expressed as percentage (w/w) of total release controlling excipient(s) in the formulation, greater than those listed above for a level 1 change, but less than or equal to 10% w/w of total release co

57、ntrolling excipient content in the modified release solid oral dosage form. The drug substance in the drug product is formulated to 100% of label/potency. The total additive effect of all release controlling excipient changes should not be more than 10% w/w of the total release controlling excipient

58、(s) in the original approved formulation. The total weight of the dosage form could still be within or outside the approved original application range. 釋放控制輔料的變更，以總配方的百分比表示，大于前面一級變更的百分比，但是小于等于緩控釋固體口服制劑中總釋放控制輔料含量的10%。.藥品是100%按標(biāo)簽/效價制造的。所有釋放控制輔料變更的總累加作用應(yīng)該不超過原始批準(zhǔn)劑型中總釋放控制輔料的10%。劑型的總重量可能仍然符合或者超出了原始批準(zhǔn)的范圍。T

59、he components (active and excipients) in the formulation should have numerical targets that represent the nominal composition of the product on which any future changes in the composition of the product are to be based. Allowable changes in the composition are based on the original approved target composition and not on the composition base