FDA指南：ANDA原料藥和制劑穩(wěn)定性試驗問答(201405)

1、 FDA指南：ANDA：原料藥和制劑穩(wěn)定性試驗問答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)定性試驗問答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)定性試驗問答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提問和回答A. G

4、eneral一般問題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ANDA申請的增補E. Stability Studies穩(wěn)定性試驗.Guidance for IndustryANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料藥和制劑穩(wěn)定性試驗問答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目前對這一專題的態(tài)度。它并未建立或賦予任何個人任何權利，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替代方法，請與FDA負責實施本指南的相關人員聯(lián)系。如果你無法識別要聯(lián)系的人，可以撥打本指南首頁所列的相應的電話號。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INTRODUCTION介紹This guidance provides answers to questions from the public comments we received on the draft guidance for industry on ANDAs: Stability Testing of Drug Substances and Products(stability gui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（穩(wěn)定性指南）起草中收到的公眾問題的答復匯總。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，討論了一般問題、DMF問題、藥品生產(chǎn)和包裝和穩(wěn)定性研究，意在澄清對ANDA穩(wěn)定性試驗數(shù)據(jù)的一些意見。在本文件中，“藥用物質”和“活性藥用物質成份”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，并未建立法定的強制責任。指南中只是描述了官方對一個議題的當前的考慮，除非引用了特定的法規(guī)或法定要求，則應只當作建議看待。在官方指南中， “應該（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)邦內食品、藥品和化妝品法規(guī)第505（j）下提交的新ANDA申請，和DMF申請（支持ANDA的二類藥用物質）。不適用于上市后變更。 實施日期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?本指南對緩解艾滋病總統(tǒng)緊急法案（PEPFAR）和正電子成像術（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對于化學、生產(chǎn)和控制（CMC）信息，PEPFAR ANDA應遵守指南中對已批準的治療艾滋病的抗逆轉錄病毒產(chǎn)品的固定劑量配方、組合包裝藥品、單化學體的規(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.對于PET的ANDA，當局建議至少三個最高或接近最高輻射強度

18、批次。如果采用了不同的合成方式（合成方法），建議每個合成方式三個最高或接近最高輻射強度批次。每批不需要在同一個廠房合成。對于增加的生產(chǎn)場所，即使采用正交方法提交申報資料，申請人應提供每個場所至少一批供穩(wěn)定性數(shù)據(jù)。對于增加的信息，當局已出版行業(yè)指南“FDA對PET產(chǎn)品的監(jiān)管：問答”。-Q3(i): Can an ANDA be submitted with 6 months of accelerated stability and 6 months of long-term stability data?ANDA提交時可否只包括6個月的加速試驗和6個月長期穩(wěn)定性試驗數(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個月加

20、速穩(wěn)定試驗和6個月長期穩(wěn)定性試驗數(shù)據(jù)。但如果6個月回事數(shù)據(jù)顯示有顯著的變化或任何失敗的跡象，建議提交時同時包括6個月的中間條件數(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，什么時候開始中間條件穩(wěn)定性試驗？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. 我們建議同時開展中間條件、加速和長期穩(wěn)定性研究，這樣在提交申報資料時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?如果三批加速試驗中有一批表現(xiàn)出顯著性變更，應該怎么辦？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屬性失敗，申請人應該提交每一批的中間

23、條件數(shù)據(jù)。另外，還應提交失敗的分析（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)如果沒有獲得官方通用藥（OGD）預批準，穩(wěn)定性試驗是否可以采用分類試驗和/或正交試驗來選擇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)定性試驗分類和正交設計”及其樣表的要求進行設計。-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?如果申報符合仿制藥付費法案（GDUFA）10個月審核要求，提交時包括了6個月的加速和長期穩(wěn)定性試驗數(shù)據(jù)，并且沒

26、有相關專利阻礙，也沒有行政保護，那么會被批準24個月的有效期嗎？Q5(ii): During the review cycle, will the application need to be updated with 12 months of long-term data?在審計過程中，是否需要提交12個月長期穩(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會給出一個保護期，根據(jù)ICH Q1E評價要求，如果提交的數(shù)據(jù)符合要求，對數(shù)據(jù)的評估符合ICH Q1E的要求，有效期長度為批準時長期穩(wěn)定性試驗數(shù)據(jù)的兩倍時長（最長為24個月）。參見ICH Q1E中決策樹（附件A）。ANDA應在更新12個月的長期穩(wěn)定性試驗數(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，申請人應提交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，申請人應提交正當理由。見C部分，第20條問題了解更多關于免責聲明。-

31、Q7: How is the proposed expiration date supposed to be calculated? Will 6 months of accelerated data equal 24 months at long-term?應如何計算建議效期？6個月的加速數(shù)據(jù)等同于24個月的長期試驗嗎？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原則可以幫助計算保護

33、期。三批ANDA申報批次（即6個月）穩(wěn)定性數(shù)據(jù)，加速數(shù)據(jù)符合所有標準（根據(jù)ICH Q1A (R2)無顯著變更），12個月長期穩(wěn)定性數(shù)據(jù)無變化則不需要進行統(tǒng)計學評估。如果預申請包含合適的穩(wěn)定性承諾，可以將保護期延長到24個月。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，提供了建議什么時候采用中間條件數(shù)據(jù)的詳細說明。-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個月加速數(shù)據(jù)與24個星期的數(shù)據(jù)可以對等嗎？因為12個星期的數(shù)據(jù)與3個月的數(shù)據(jù)是已經(jīng)對等了。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?如果一個專利即將過效期，而并沒有已批準的ANDA，我們可否提交3個月穩(wěn)定性試驗

36、數(shù)據(jù)，并承諾在獲得6個月數(shù)據(jù)時即進行補充？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對于采用中試批準進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間進行了討論。一般來說，ANDA申報批次樣品存貯時間應至少在ANDA批準后1年，用于生物等效性研究的制劑樣品應符合21 CFR 320.38 和21 CFR 320.

40、63.另外，行業(yè)指南中關于處理和保留BA和BE測試樣品的內容對處理BA和BE的保留樣品有幫助。更多有關樣品數(shù)量（供保存對照用）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.請說明穩(wěn)定性試驗指南對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? 進行DMF完整性評估時，需要提供幾個月的長期數(shù)據(jù)和加速數(shù)據(jù)？在DMF穩(wěn)定性部分應為完整性評估提供什么？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應包括穩(wěn)定性實驗方案、承諾和穩(wěn)定性研究數(shù)據(jù)，才可以通過完整性評估。初始的數(shù)據(jù)和新增加的一個時間點的數(shù)據(jù)和長期研究數(shù)據(jù)已經(jīng)足夠。如果在提交完整性評估的時候DMF仍不符合下述A1（ii）的要求，DMF持有人應增補DMF最新的穩(wěn)定性數(shù)據(jù)，準備接受全面的科學檢查。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？需要幾個月的中試放大批的長期數(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)定性試驗數(shù)據(jù)至少應在三個主要批次中提供，DMF中填寫的原料藥應生產(chǎn)最小中試批。這些批次也應符合CGMPs。FDA穩(wěn)定性指南建

47、議提交中試批次時提供6個月的加速數(shù)據(jù)和6個月長期數(shù)據(jù)，準備接受DMF全面的科學檢查。關于三批中新增的長期數(shù)據(jù)，若再測試試驗的數(shù)據(jù)有效，應作為增補提交。-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），申報文件中如果是在GMP條件下三個大生產(chǎn)批次，具有6個月加速和長期穩(wěn)定性試驗數(shù)據(jù)，覆蓋建議的復驗期，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作為不同批號嗎？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），散裝成品批應代表不同批次的散裝溶液。分裝一個批號散裝溶液至不同分裝體積不構成分批。-Q2: Can you clarify the packaging recommendations for the submission batches for blow-fill-seal containers?可否說明一下對吹瓶/灌裝/封口的包裝形式申報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，通常還會有外包裝或紙箱包裝。三個批次均應進行外包裝。ICH Q1A(R2

53、)里說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?所有三個批次均應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