1、 FDA指南：ANDA：原料藥和制劑穩(wěn)定性試驗(yàn)問(wèn)答Guidance for Industry 行業(yè)指南ANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料藥和制劑穩(wěn)定性試驗(yàn)問(wèn)答Final GUIDANCE最終稿指南U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)May 2014GenericsG

2、uidance for IndustryANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料藥和制劑穩(wěn)定性試驗(yàn)問(wèn)答Additional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 2201Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Ha

3、mpshire Ave., Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)May 2014Generics TABLE OF CONTENTS 目錄I. INTRODUCTION介紹II. QUESTIONS AND ANSWERS提問(wèn)和回答A. G

4、eneral一般問(wèn)題B. Drug Master File藥物主文件.C. Drug Product Manufacturing and Packaging藥品生產(chǎn)和包裝D. Amendments to Pending ANDA Application未批準(zhǔn)ANDA申請(qǐng)的增補(bǔ)E. Stability Studies穩(wěn)定性試驗(yàn).Guidance for IndustryANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料藥和制劑穩(wěn)定性試驗(yàn)問(wèn)答This guidance repres

5、ents the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and reg

6、ulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.本指南代表的是FDA目前對(duì)這一專題的態(tài)度。它并未建立或賦予任何個(gè)人任何權(quán)利，并不與FDA或公眾有任何綁定。你可以

7、使用任何一種替代方法，只要所用的方法滿足成文的法規(guī)要求。如果你想要討論一個(gè)替代方法，請(qǐng)與FDA負(fù)責(zé)實(shí)施本指南的相關(guān)人員聯(lián)系。如果你無(wú)法識(shí)別要聯(lián)系的人，可以撥打本指南首頁(yè)所列的相應(yīng)的電話號(hào)。I. INTRODUCTION介紹This guidance provides answers to questions from the public comments we received on the draft guidance for industry on ANDAs: Stability Testing of Drug Substances and Products(stability gui

8、dance) that published on September 25, 2012. The final guidance for industry of the same title published on June 20, 2013.Comments received on the draft of this guidance published in the Federal Register of August 27, 2013 have also been incorporated. General issues; drug master files (DMFs); drug p

9、roduct manufacturing and packaging; and stability studies are discussed in this guidance and are intended to clarify the stability testing data recommendations for abbreviated new drug applications (ANDAs). In this document, the terms drug substance and active pharmaceutical ingredient (API) are use

10、d interchangeably.本指南是2012年9月25日公布的行業(yè)指南草案（ANDA：原料藥和制劑穩(wěn)定性試驗(yàn)（穩(wěn)定性指南）起草中收到的公眾問(wèn)題的答復(fù)匯總。該指南終稿在2013年6月20日出版。本指南也吸收了2013年8月27日的草案意見。在本指南中，討論了一般問(wèn)題、DMF問(wèn)題、藥品生產(chǎn)和包裝和穩(wěn)定性研究，意在澄清對(duì)ANDA穩(wěn)定性試驗(yàn)數(shù)據(jù)的一些意見。在本文件中，“藥用物質(zhì)”和“活性藥用物質(zhì)成份”交互使用。FDAs guidance documents, including this guidance, do not establish legally enforceable respon

11、sibilities. Instead, guidances describe the Agencys current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not requi

12、red.FDA的指南文件，包括本指南，并未建立法定的強(qiáng)制責(zé)任。指南中只是描述了官方對(duì)一個(gè)議題的當(dāng)前的考慮，除非引用了特定的法規(guī)或法定要求，則應(yīng)只當(dāng)作建議看待。在官方指南中， “應(yīng)該（should）”一詞表示這是建議或推薦，而非必須。A. General一般Q1: What is the scope of and implementation date for the stability guidance?穩(wěn)定性指南的范圍和實(shí)施日期？A1: The stability guidance covers all new ANDAs under the Federal Food, Drug, and

13、Cosmetic Act, section 505 (j), and DMFs (Type II for drug substances that support the ANDAs). It does not apply to postapproval changes.The implementation date is June 20, 2014.穩(wěn)定性指南適用于所有聯(lián)邦內(nèi)食品、藥品和化妝品法規(guī)第505（j）下提交的新ANDA申請(qǐng)，和DMF申請(qǐng)（支持ANDA的二類藥用物質(zhì)）。不適用于上市后變更。 實(shí)施日期2013年6月20日。-Q2: How will this guidance affe

14、ct the Presidents Emergency Plan for AIDS Relief (PEPFAR)and positron emission tomography (PET) ANDAs?本指南對(duì)緩解艾滋病總統(tǒng)緊急法案（PEPFAR）和正電子成像術(shù)（PET）ANDA有何影響？A2: For chemistry, manufacturing, and controls (CMC) information, PEPFAR ANDAs should follow the guidance for industry on Fixed Dose Combinations, Co-Pack

15、aged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV對(duì)于化學(xué)、生產(chǎn)和控制（CMC）信息，PEPFAR ANDA應(yīng)遵守指南中對(duì)已批準(zhǔn)的治療艾滋病的抗逆轉(zhuǎn)錄病毒產(chǎn)品的固定劑量配方、組合包裝藥品、單化學(xué)體的規(guī)定。For PET ANDAs, the Agency recommends a minimum of three batches at or near the upper end of the proposed radio-co

16、ncentration. If different synthesizers (methods of synthesis) are used, three batches from each method of synthesis at or near the upper end of the proposed radio-concentration are recommended. Batches do not have to be made in the same facility. For the additional manufacturing facilities, applican

17、ts should provide stability data on at least one batch from each facility, although bracketing approaches could be submitted for review. For additional information, the Agency has published a guidance for industry on FDA Oversight of PET Products, Questions and Answers.對(duì)于PET的ANDA，當(dāng)局建議至少三個(gè)最高或接近最高輻射強(qiáng)度

18、批次。如果采用了不同的合成方式（合成方法），建議每個(gè)合成方式三個(gè)最高或接近最高輻射強(qiáng)度批次。每批不需要在同一個(gè)廠房合成。對(duì)于增加的生產(chǎn)場(chǎng)所，即使采用正交方法提交申報(bào)資料，申請(qǐng)人應(yīng)提供每個(gè)場(chǎng)所至少一批供穩(wěn)定性數(shù)據(jù)。對(duì)于增加的信息，當(dāng)局已出版行業(yè)指南“FDA對(duì)PET產(chǎn)品的監(jiān)管：?jiǎn)柎稹薄?Q3(i): Can an ANDA be submitted with 6 months of accelerated stability and 6 months of long-term stability data?ANDA提交時(shí)可否只包括6個(gè)月的加速試驗(yàn)和6個(gè)月長(zhǎng)期穩(wěn)定性試驗(yàn)數(shù)據(jù)？A3(i): Yes.

19、Stability data expectation at the time of ANDA submission is 6 months of accelerated and 6 months of long-term data. However, if 6 months accelerated data show significant change2 or failure of any attribute, 6 months of intermediate data are also recommended at the time of submission. 可以。要求提交的是6個(gè)月加

20、速穩(wěn)定試驗(yàn)和6個(gè)月長(zhǎng)期穩(wěn)定性試驗(yàn)數(shù)據(jù)。但如果6個(gè)月回事數(shù)據(jù)顯示有顯著的變化或任何失敗的跡象，建議提交時(shí)同時(shí)包括6個(gè)月的中間條件數(shù)據(jù)。Q3(ii): When do intermediate stability studies need to be initiated in the event of failure at accelerated condition?如果加速條件失敗，什么時(shí)候開始中間條件穩(wěn)定性試驗(yàn)？A3(ii): We recommend starting intermediate stability, accelerated, and long-term studies at

21、the same time so the data are available at the time of submission, if needed. 我們建議同時(shí)開展中間條件、加速和長(zhǎng)期穩(wěn)定性研究，這樣在提交申報(bào)資料時(shí)就能獲得所有需要的數(shù)據(jù)。Q3(iii): If one among the three batches in accelerated conditions show a significant change, what should be done?如果三批加速試驗(yàn)中有一批表現(xiàn)出顯著性變更，應(yīng)該怎么辦？A3(iii): If accelerated data show a

22、significant change or failure of any attribute in one or more batches, an applicant should submit intermediate data for all three batches. In addition, the submission should contain a failure analysis (i.e., discussion concerning the observed failure(s). 如果加速數(shù)據(jù)有一批或更多批次表現(xiàn)出顯著性變更或任何一個(gè)屬性失敗，申請(qǐng)人應(yīng)該提交每一批的中間

23、條件數(shù)據(jù)。另外，還應(yīng)提交失敗的分析（比如討論觀察到的失敗現(xiàn)象）則建議提交所有3批的中間條件的數(shù)據(jù)。-Q4: Can stability bracketing and/or matrixing be used to determine the configurations to be placed on stability for an original ANDA without prior approval from the Office of Generic Drugs (OGD)如果沒(méi)有獲得官方通用藥（OGD）預(yù)批準(zhǔn)，穩(wěn)定性試驗(yàn)是否可以采用分類試驗(yàn)和/或正交試驗(yàn)來(lái)選擇ANDA初始提交中的參

24、數(shù)？A4: Yes. You should follow the International Conference on Harmonisation (ICH) guidance for industry on Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products and its example tables. 可以。你可以根據(jù)ICH行業(yè)指南Q1D“新原料藥和新制劑穩(wěn)定性試驗(yàn)分類和正交設(shè)計(jì)”及其樣表的要求進(jìn)行設(shè)計(jì)。-Q5(i): If an applicati

25、on that qualifies for the Generic Drug User Fee Act (GDUFA) 10-month review is filed with 6 months of accelerated and 6 months of long-term data, and there are no blocking patents or exclusivities, will 24 months of expiration dating be granted?如果申報(bào)符合仿制藥付費(fèi)法案（GDUFA）10個(gè)月審核要求，提交時(shí)包括了6個(gè)月的加速和長(zhǎng)期穩(wěn)定性試驗(yàn)數(shù)據(jù)，并且沒(méi)

26、有相關(guān)專利阻礙，也沒(méi)有行政保護(hù)，那么會(huì)被批準(zhǔn)24個(gè)月的有效期嗎？Q5(ii): During the review cycle, will the application need to be updated with 12 months of long-term data?在審計(jì)過(guò)程中，是否需要提交12個(gè)月長(zhǎng)期穩(wěn)定性更新數(shù)據(jù)？A5(i,ii): FDA will grant a shelf life period of two times the available long-term data at the time of approval (up to 24 months) follow

27、ing the recommendation of the ICH Q1E Evaluation of Stability Data (ICH Q1E) guidance, provided the submitted data are satisfactory, and data evaluation and appropriate commitments are provided in accordance with ICH Q1E. Please refer to the decision tree (Appendix A) in ICH Q1E. The ANDA should be

28、updated with 12 months of long-term data during the review cycle. FDA會(huì)給出一個(gè)保護(hù)期，根據(jù)ICH Q1E評(píng)價(jià)要求，如果提交的數(shù)據(jù)符合要求，對(duì)數(shù)據(jù)的評(píng)估符合ICH Q1E的要求，有效期長(zhǎng)度為批準(zhǔn)時(shí)長(zhǎng)期穩(wěn)定性試驗(yàn)數(shù)據(jù)的兩倍時(shí)長(zhǎng)（最長(zhǎng)為24個(gè)月）。參見ICH Q1E中決策樹（附件A）。ANDA應(yīng)在更新12個(gè)月的長(zhǎng)期穩(wěn)定性試驗(yàn)數(shù)據(jù)。-Q6: Can only two lots of finished product at pilot scale batch size ever be sufficient to support the

29、 stability of an ANDA for simple dosage forms?如果僅有兩批成品中試批量，是否足以支持ANDA單劑型穩(wěn)定性試驗(yàn)要求？A6: According to the FDA stability guidance, the applicant should submit data from three pilot scale batches or should submit data from two pilot scale batches and one small scale batch. This applies to all dosage forms.

30、 If the size of the pilot scale batch does not follow ICH recommendations, the applicant should provide a justification. See also section C, question 20 for additional information regarding exceptions. 根據(jù)FDA穩(wěn)定性指南，申請(qǐng)人應(yīng)提交3批中試批量或2批中試批量加一批中試放大批量。該要求適用于所有劑型。如果批量大小不符合ICH，申請(qǐng)人應(yīng)提交正當(dāng)理由。見C部分，第20條問(wèn)題了解更多關(guān)于免責(zé)聲明。-

31、Q7: How is the proposed expiration date supposed to be calculated? Will 6 months of accelerated data equal 24 months at long-term?應(yīng)如何計(jì)算建議效期？6個(gè)月的加速數(shù)據(jù)等同于24個(gè)月的長(zhǎng)期試驗(yàn)嗎？A7: ICH Q1E principles will help in the calculation of shield life. Data from the three ANDA submission batches (i.e., 6 months), accelera

32、ted data meeting all criteria (without significant change per ICH Q1A(R2), and 12 months long-term data without variability will not need statistical evaluation.and with appropriate post approval stability commitments, can be used to support extrapolation to a 24 months shelf life. ICH Q1E原則可以幫助計(jì)算保護(hù)

33、期。三批ANDA申報(bào)批次（即6個(gè)月）穩(wěn)定性數(shù)據(jù)，加速數(shù)據(jù)符合所有標(biāo)準(zhǔn)（根據(jù)ICH Q1A (R2)無(wú)顯著變更），12個(gè)月長(zhǎng)期穩(wěn)定性數(shù)據(jù)無(wú)變化則不需要進(jìn)行統(tǒng)計(jì)學(xué)評(píng)估。如果預(yù)申請(qǐng)包含合適的穩(wěn)定性承諾，可以將保護(hù)期延長(zhǎng)到24個(gè)月。If there is a significant change in the accelerated data, ICH Q1E, Appendix A, provides more detail regarding when intermediate condition stability data are recommended.如果加速數(shù)據(jù)有顯著性變更，ICH Q1

34、E 附件A，提供了建議什么時(shí)候采用中間條件數(shù)據(jù)的詳細(xì)說(shuō)明。-Q8: Will the recommendation for 6 months accelerated data be met by providing 24 weeks of data as 12 weeks is typically accepted as equivalent to 3 months?6個(gè)月加速數(shù)據(jù)與24個(gè)星期的數(shù)據(jù)可以對(duì)等嗎？因?yàn)?2個(gè)星期的數(shù)據(jù)與3個(gè)月的數(shù)據(jù)是已經(jīng)對(duì)等了。A8：No. FDA, following the recommendations of ICH stability guidances

35、refers to timeframes in terms of months and not weeks. 不可以，F(xiàn)DA根據(jù)ICH穩(wěn)定性指南中的月時(shí)間為主，而不是星期。-Q9: When a patent is due to shortly expire and there are no approved ANDAs, can we file with 3 months stability data with a commitment to supply 6 months data when available?如果一個(gè)專利即將過(guò)效期，而并沒(méi)有已批準(zhǔn)的ANDA，我們可否提交3個(gè)月穩(wěn)定性試驗(yàn)

36、數(shù)據(jù)，并承諾在獲得6個(gè)月數(shù)據(jù)時(shí)即進(jìn)行補(bǔ)充？A9: No. ICH stability guidances should be followed irrespective of patent status; 不可以。不論專利狀態(tài)如何，必須遵守ICH穩(wěn)定性指南。-Q10: How long do the three pilot scale batches, submitted as a part of an ANDA, need to be stored before destruction?如果ANDA申報(bào)批次是三批中試放大批，是否需要存貯直至銷毀？A10: Sample storage tim

37、es are discussed in 21 CFR 320.38 and 21 CFR 320.63 for bioequivalence-study-samples when the pilot scale batch is used in the bioequivalence study or studies.In general, ANDA submission batch samples should be stored for 1 year after approval of the ANDA, and samples of the drug product used for bi

38、oequivalence studies must be stored following the requirements listed in 21 CFR 320.38 and 21 CFR 320.63. In addition, the guidance for industry on Handling and Retention of BA and BE Testing Samples may be helpful regarding the procedure for handling reserve samples from relevant bioavailability an

39、d bioequivalence studies. Additional information on sample quantities (for retention purposes) is discussed in 21 CFR 211.170 (a) and (b), Reserve Samples. 在21CFR 320.38和21CFR 320.63對(duì)于采用中試批準(zhǔn)進(jìn)行生物等效性研究的情況下，生物等效性研究樣品的存貯時(shí)間進(jìn)行了討論。一般來(lái)說(shuō)，ANDA申報(bào)批次樣品存貯時(shí)間應(yīng)至少在ANDA批準(zhǔn)后1年，用于生物等效性研究的制劑樣品應(yīng)符合21 CFR 320.38 和21 CFR 320.

40、63.另外，行業(yè)指南中關(guān)于處理和保留BA和BE測(cè)試樣品的內(nèi)容對(duì)處理BA和BE的保留樣品有幫助。更多有關(guān)樣品數(shù)量（供保存對(duì)照用）的討論見21 CFR 211.170（a）和（b），保留樣品。B. Drug Master File藥物主文件Q1: Please clarify the effect of the stability guidance on Drug Master File (DMF) holders.請(qǐng)說(shuō)明穩(wěn)定性試驗(yàn)指南對(duì)DMF持有人的影響Q1(i): How many months of long-term and accelerated data are required wh

41、en a “Completeness Assessment” is performed on the DMF? Also, what should the DMF stability section contain for a Completeness Assessment? 進(jìn)行DMF完整性評(píng)估時(shí)，需要提供幾個(gè)月的長(zhǎng)期數(shù)據(jù)和加速數(shù)據(jù)？在DMF穩(wěn)定性部分應(yīng)為完整性評(píng)估提供什么？A1(i): To pass the Completeness Assessment, DMFs should include the stability protocol, commitments, and data

42、demonstrating that stability studies have started. The initial and one additional time point for the accelerated studies and long-term studies are sufficient. If the DMF does not meet the recommendations under A1(ii) below at the time of the Completeness Assessment the DMF holder should amend the DM

43、F with updated stability data to prepare for full scientific review. DMFs應(yīng)包括穩(wěn)定性實(shí)驗(yàn)方案、承諾和穩(wěn)定性研究數(shù)據(jù)，才可以通過(guò)完整性評(píng)估。初始的數(shù)據(jù)和新增加的一個(gè)時(shí)間點(diǎn)的數(shù)據(jù)和長(zhǎng)期研究數(shù)據(jù)已經(jīng)足夠。如果在提交完整性評(píng)估的時(shí)候DMF仍不符合下述A1（ii）的要求，DMF持有人應(yīng)增補(bǔ)DMF最新的穩(wěn)定性數(shù)據(jù)，準(zhǔn)備接受全面的科學(xué)檢查。Q1(ii): Are stability data from three current good manufacturing practice (CGMP) batches required t

44、o be filed in the DMF to support the API retest date? Also, how many months of long-term and accelerated data are required for pilot scale batches? 用于支持API再測(cè)試的穩(wěn)定性數(shù)據(jù)是根據(jù)cGMP要求取的三批（填在DMF）嗎？需要幾個(gè)月的中試放大批的長(zhǎng)期數(shù)據(jù)和加速數(shù)據(jù)？A1(ii): Yes. Per ICH Q1A(R2) data from formal stability studies should be provided on at lea

45、st three primary batches and the batches should be manufactured to a minimum of pilot scale for the drug substance to be filed in the DMF. These batches should be made under CGMPs. The FDA stability guidance recommends 6 months of accelerated data and 6 months of long-term data for the pilot scale b

46、atches to be submitted for a full scientific review of the DMF. Additional long-term data for all three batches, as the data becomes available through the proposed retest period, should be submitted as an amendment. 是的，符合ICH Q1A（R2）要求的正式穩(wěn)定性試驗(yàn)數(shù)據(jù)至少應(yīng)在三個(gè)主要批次中提供，DMF中填寫的原料藥應(yīng)生產(chǎn)最小中試批。這些批次也應(yīng)符合CGMPs。FDA穩(wěn)定性指南建

47、議提交中試批次時(shí)提供6個(gè)月的加速數(shù)據(jù)和6個(gè)月長(zhǎng)期數(shù)據(jù)，準(zhǔn)備接受DMF全面的科學(xué)檢查。關(guān)于三批中新增的長(zhǎng)期數(shù)據(jù)，若再測(cè)試試驗(yàn)的數(shù)據(jù)有效，應(yīng)作為增補(bǔ)提交。-Q2: Will submissions to DMFs be accepted based on stability data from production scale batches?基于生產(chǎn)批量的批次的穩(wěn)定性數(shù)據(jù)的DMF申報(bào)能被接受嗎？A2: Yes. Per ICH Q1A(R2), section II, A, 8, Stability Commitment (2.1.8), the submission is appropriat

48、e if satisfactory stability data from three production batches made under CGMP are filed in the DMF with 6 months of accelerated data and long-term data covering the proposed retest period.是的。根據(jù)ICH Q1A(R2)，第II部分，A，8，穩(wěn)定性承諾（2.1.8），申報(bào)文件中如果是在GMP條件下三個(gè)大生產(chǎn)批次，具有6個(gè)月加速和長(zhǎng)期穩(wěn)定性試驗(yàn)數(shù)據(jù)，覆蓋建議的復(fù)驗(yàn)期，是可以接受的。-Q3: Should ex

49、ecuted batch records for the three batches be included in the DMF submission? 三批的批生產(chǎn)記錄應(yīng)含在提交的DMF中嗎？A3: One representative executed batch record will be sufficient. 1份具有代表性的批生產(chǎn)記錄就足夠C. Drug Product Manufacturing and Packaging 藥品生產(chǎn)和包裝Q1: Can the split bulk solution filled into different fill volumes be

50、considered different batches?將散裝溶液裝入不同分裝體積應(yīng)作為不同批號(hào)嗎？A1: To be consistent with ICH Q1A(R2), we recommend that discrete finished product batches be produced that represent different batches of bulk solution.Split filling one batch of bulk solution into different fill volume sizes would not constitute d

51、iscrete batches.根據(jù)ICH Q1A（R2），散裝成品批應(yīng)代表不同批次的散裝溶液。分裝一個(gè)批號(hào)散裝溶液至不同分裝體積不構(gòu)成分批。-Q2: Can you clarify the packaging recommendations for the submission batches for blow-fill-seal containers?可否說(shuō)明一下對(duì)吹瓶/灌裝/封口的包裝形式申報(bào)批有什么包裝方面的建議？A2: Blow-fill-seal containers are not an exception from regular packaging and are usual

52、ly packaged inside a secondary container or a carton. The secondary packaging should be included in all three batches. ICH Q1A(R2) addresses secondary packaging usefulness (see section II, B, 4, Drug Product Container Closure System (2.2.4).吹瓶/灌裝/封口的包裝形式仍是常規(guī)包裝的一種，通常還會(huì)有外包裝或紙箱包裝。三個(gè)批次均應(yīng)進(jìn)行外包裝。ICH Q1A(R2

53、)里說(shuō)明了外包裝是有用的。（參見第II部分，B，4，藥品包裝（2.2.4）-Q3: Should all three batches be stored in final proposed packaging?所有三個(gè)批次均應(yīng)以完整的包裝形式存貯嗎？A3: Yes. You should package all three batches in the container closure system proposed for marketing. Q1A(R2) addresses this question (see section II, B, 4, Drug Product Container