Meeting Request Tracking Number: ANDA-219900-PDEV-Meeting-00259762
会议请求追踪编号：ANDA-219900-PDEV-会议-00259762

Pre-ANDA Product Development Meeting
ANDA 申报前产品开发会议

PRELIMINARY RESPONSE
初步回复

Meitheal Pharmaceuticals, Inc.
美泰尔制药有限公司

8700 West Bryn Mawr Avenue, Suite 600S Chicago, IL 60631
伊利诺伊州芝加哥市布林茂尔西路 8700 号 600S 室，邮编 60631

Attention: Roopang Shah
收件人：Roopang Shah

Director, Regulatory Affairs Dear Roopang Shah:
监管事务部主任 尊敬的 Roopang Shah：

This is in reference to your pre-abbreviated new drug application (pre-ANDA) file for leuprolide acetate subcutaneous solution, 14 mg/2.8 mL (1 mg/0.2 mL), referencing Lupron (leuprolide acetate) subcutaneous solution, 14 mg/2.8 mL (1 mg/0.2 mL), approved under new drug application (NDA) 019010, as the reference listed drug (RLD).
本函针对贵方关于醋酸亮丙瑞林皮下注射液（14 mg/2.8 mL，即 1 mg/0.2 mL）的简化新药申请预备案（pre-ANDA），该申请以 NDA 019010 批准的 Lupron（醋酸亮丙瑞林）皮下注射液（14 mg/2.8 mL，即 1 mg/0.2 mL）作为参照列明药品（RLD）。

Reference is also made to your request for a pre-ANDA product development meeting, received on December 27, 2024, and granted on January 7, 2025.
关于贵方于 2024 年 12 月 27 日提交并于 2025 年 1 月 7 日获批的仿制药申请前产品开发会议请求，特此回复。

The Agency’s preliminary responses to your meeting questions are enclosed. The responses provided are based on the information in your submitted meeting package and are subject to revision after comprehensive assessment of your ANDA. We remind you that whether the Office of Generic Drugs (OGD) will receive your ANDA for substantive assessment will be determined during the filing review of your ANDA and that the approvability of your proposed product will be determined during the scientific assessment of your ANDA.
随函附上药监局对贵方会议问题的初步答复。这些答复基于贵方提交的会议资料包所含信息，并将在全面评估贵方仿制药申请（ANDA）后可能进行修订。我们提醒贵方，仿制药办公室（OGD）是否会对贵方 ANDA 进行实质性评估，将在贵方 ANDA 的受理审查阶段确定；而贵方所申报产品的可批准性，将在 ANDA 的科学评估阶段作出判定。

If applicable, provide an electronic version (maximum allowable size is 45 MB) of your updated agenda and any presentation materials (i.e., slides) via the CDER Direct NextGen Collaboration Portal (the portal) (https://edm.fda.gov/) at least 48 hours prior to the scheduled meeting. Do not submit any new data or additional questions not presented in the original meeting package, as this information will not be addressed or discussed at the meeting.
如适用，请至少在预定会议召开前 48 小时，通过 CDER Direct NextGen 协作门户（https://edm.fda.gov/）提交更新后的会议议程电子版（最大允许容量 45MB）及任何演示材料（即幻灯片）。请勿提交原始会议资料包中未包含的新数据或补充问题，因该等信息将不会在会议中予以讨论或处理。

If you have any questions or would like to cancel the meeting, contact Irfan Memon via email at Irfan.Memon@fda.hhs.gov
如有任何疑问或需取消会议，请通过电子邮件联系 Irfan Memon，邮箱地址：Irfan.Memon@fda.hhs.gov.

U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov
美国食品药品监督管理局 马里兰州银泉市 20993 www.fda.gov

Sincerely,
此致

{See Appended electronic signature page}
{参见所附电子签名页}

Markham C. Luke, MD, PhD Director
马克·卢克医学博士、哲学博士 主任

Division of Therapeutic Performance I Office of Research and Standards Office of Generic Drugs
仿制药办公室研究与标准一处 治疗性能部门

Center for Drug Evaluation and Research
药品评价与研究中心

U.S. Food and Drug Administration
美国食品药品监督管理局

Enclosure: Meeting Preliminary Response
附件：会议初步回复

MEETING PRELIMINARY RESPONSE
会议初步回复

Prospective Applicant Name: Meeting Request Tracking Number: Meeting Request Type:
申请方名称：会议请求追踪编号：会议请求类型：

Meeting Format:
会议形式：

Meitheal Pharmaceuticals, Inc.
迈塞尔制药公司

ANDA-219900-PDEV-Meeting-00259762
ANDA-219900-PDEV-会议-00259762

Pre-ANDA Product Development Videoconference
ANDA 申报前产品开发视频会议

Meeting Date and Time: April 30, 2025/9:30 a.m. ET
会议日期与时间：2025 年 4 月 30 日/美国东部时间上午 9:30

Reference Listed Drug: NDA 019010; Lupron
参比制剂：NDA019010；亮丙瑞林

Active Ingredient: Leuprolide acetate Route; Dosage Form; Strength: Subcutaneous solution,
活性成分：醋酸亮丙瑞林；给药途径；剂型；规格：皮下注射溶液，

14 mg/2.8 mL (1 mg/0.2 mL)
14 毫克/2.8 毫升（1 毫克/0.2 毫升）

Meeting Granted Date: January 7, 2025
会议批准日期：2025 年 1 月 7 日

The Agency provides the following preliminary responses and any additional comments in preparation for the discussion at the meeting as scheduled above for your proposed leuprolide acetate subcutaneous solution, 14 mg/2.8 mL (1 mg/0.2 mL). The responses do not reflect agreements, key issues, or action items. This information is shared to promote a collaborative and successful discussion at the meeting.
本机构针对贵方提出的醋酸亮丙瑞林皮下注射液（14 mg/2.8 mL，即 1 mg/0.2 mL）产品，提供以下初步答复及补充意见，以供上述预定会议讨论。这些答复不代表达成协议、关键问题或行动事项，旨在促进会议期间开展建设性对话并取得预期成果。

If the following preliminary responses and comments are clear to you and you determine further discussion is not needed, you have the option of notifying the project manager via email that the preliminary written responses provide a meaningful written response and a meeting is not needed. FDA will close the meeting request and consider the preliminary written responses as the final meeting response. If you determine discussion is needed for only some of the original questions, you have the option of updating the agenda. Your updated agenda should list the questions for discussion and the order of priority.
若贵方认为以下初步答复和意见表述清晰且无需进一步讨论，可选择通过电子邮件通知项目经理，表明初步书面答复已构成实质性回应且无需召开会议。FDA 将据此关闭会议请求，并将初步书面答复视为最终会议回复。若贵方认为仅需对部分原始问题进行讨论，可选择更新会议议程。更新后的议程应列明拟讨论问题及其优先顺序。

If there are any major changes to your development plan, the purpose of the meeting, or questions based on our preliminary responses, we may not be prepared to discuss or reach agreement on such changes at the meeting.
如果您的开发计划、会议目的或基于我们初步答复的问题有任何重大变更，我们可能无法在会议上准备讨论或就此达成一致。

BACKGROUND
背景

On December 27, 2024, Meitheal Pharmaceuticals, Inc. (Meitheal) submitted a request for a pre-ANDA product development meeting to discuss the feasibility of the proposed drug product leuprolide acetate subcutaneous solution, 14 mg/2.8 mL (1 mg/0.2 mL) multi-dose pre-filled pen to be developed as a generic to the RLD Lupron subcutaneous solution, 14 mg/2.8 mL (1 mg/0.2 mL) multi-dose vial by AbbVie Endocrine Inc., and approved through the ANDA pathway and consult with the FDA about the strategies for the chemistry, manufacturing and controls (CMC) and Human Factors components of the leuprolide acetate subcutaneous solution, 14 mg/2.8 mL (1 mg/0.2 mL) multi-dose pre-filled pen development program.
2024 年 12 月 27 日，Meitheal Pharmaceuticals 公司（Meitheal）提交了一份 ANDA 前产品开发会议申请，旨在讨论将醋酸亮丙瑞林皮下注射液（14 mg/2.8 mL，1 mg/0.2 mL）多剂量预充笔开发为 AbbVie Endocrine 公司 RLD 药物 Lupron 皮下注射液（14 mg/2.8 mL，1 mg/0.2 mL）多剂量瓶仿制药的可行性。该产品拟通过 ANDA 途径获批，并就醋酸亮丙瑞林皮下注射液（14 mg/2.8 mL，1 mg/0.2 mL）多剂量预充笔开发计划中的化学、生产和控制（CMC）策略及人因工程要素与 FDA 进行磋商。

Industry Submitted Questions and FDA Response
企业提交问题及 FDA 答复

The following includes questions from the pre-ANDA meeting package (shown in bold) followed by the Agency’s preliminary responses and comments (shown in normal font).
以下内容包含预 ANDA 会议材料中的问题（以粗体显示）及药监局的初步回复与意见（以常规字体显示）。

Question 1
问题 1

Does the FDA agree that the proposed product, Leuprolide Acetate Injection, 14 mg/2.8 mL (1 mg/0.2 mL) multi-dose prefilled pen (Pre-Filled Pen) will be submitted as ANDA generic to Reference Listed Drug (RLD) product, LUPRON® INJECTION, 14 mg/2.8 mL (1 mg/0.2 mL) multi-dose vial (NDA# 019010) for approval?
FDA 是否同意将拟议产品——醋酸亮丙瑞林注射液，14 mg/2.8 mL（1 mg/0.2 mL）多剂量预充式笔（预充笔）作为参照列名药物（RLD）产品 LUPRON®注射液，14 mg/2.8 mL（1 mg/0.2 mL）多剂量瓶装（NDA# 019010）的 ANDA 仿制药提交审批？

Agency’s Response
药监局回复

After assessing your comparative analyses, the sample test devices, and the RLD devices submitted in your meeting package, with respect to the external critical design attributes and external operating principles only, our preliminary view is that there are multiple “other design differences” between the device user interfaces of your proposed generic product and the RLD. These differences may or may not be appropriate for submission as part of an ANDA referencing Lupron, NDA 019010, and would be subject to ANDA assessment. The change from the RLD presentation of a multiple dose vial with 14 disposable syringes and 28 alcohol swabs to an integrated, prefilled multi-dose injection pen presentation creates differences in multiple critical tasks compared to the RLD. The key inquiry is whether your proposed product could be substituted with the full expectation that it will produce the same clinical effect and safety profile as the RLD under the conditions specified in labeling and without additional training prior to use.
在评估了贵方提交的会议资料包中的对比分析、样品测试装置以及参比制剂（RLD）装置后，仅就外部关键设计属性和外部操作原理而言，我们的初步观点是：贵方提议的仿制产品与参比制剂在装置用户界面上存在多项"其他设计差异"。这些差异是否适合作为参照 Lupron（NDA 019010）的简化新药申请（ANDA）提交内容尚待商榷，需接受 ANDA 评估。从参比制剂的多剂量小瓶（配 14 支一次性注射器及 28 个酒精棉片）包装形式改为集成式预充多剂量注射笔，导致多项关键操作环节与参比制剂存在差异。核心问题在于：在标签规定使用条件下且无需额外培训时，贵方提议的产品能否实现与参比制剂完全相同的临床疗效和安全性特征的可替代性。

【需要澄清，等一下DS的反馈】

Question 2
问题 2

Does the FDA agree that the finished product release and stability specifications approved for Meitheal’s ANDA 075471, Leuprolide Acetate Injection, 14 mg/2.8 mL (1 mg/0.2 mL) multi-dose vial are applicable to the proposed Pre-Filled Pen product, with the addition of pen functionality tests?
美国 FDA 是否同意，在增加笔式注射器功能测试的前提下，将已批准的 Meitheal 公司 ANDA 075471（醋酸亮丙瑞林注射液，14 mg/2.8 mL（1 mg/0.2 mL）多剂量小瓶）的成品放行和稳定性标准适用于拟议的预充式笔产品？

Agency’s Response
机构回复

The adequacy of your proposed drug product release and stability specifications described in your product development meeting package (Table 5) will be determined during ANDA assessment. The Agency provides the following recommendations for your ANDA submission:
贵方在产品开发会议资料包（表 5）中描述的药品放行和稳定性标准的适当性将在 ANDA 评估期间确定。针对贵方的 ANDA 申报，本机构提供以下建议：

Regarding physicochemical testing at release and stability:
关于放行时和稳定性期间的理化测试：

The specified impurities of the proposed drug product appear to be identified and controlled through Relative Retention Times (RRTs). Structural characterization of all RRT impurities is recommended. A detailed impurity method information consisting of sample preparation, reference standards used, and validation/verification should be provided in ANDA submission. 除特定杂质外的其他所有RRT非特定杂质FDA均要求做结构表征并且提出样品的配制、标准品和方法验证/确认的要求。我们是否要参照多肽法规以及门冬的类似回复拟定0.10%为鉴定限。
该拟议药品的特定杂质似乎已通过相对保留时间（RRT）进行识别和控制。建议对所有 RRT 杂质进行结构表征。ANDA 申报材料中应提供详细的杂质方法信息，包括样品制备、所用对照品以及验证/确认数据。除特定杂质外，FDA 要求对所有 RRT 非特定杂质进行结构表征，并提出样品配制、标准品及方法验证/确认的要求。我们是否应参照多肽法规及门冬类似回复，将 0.10%定为鉴定限。

【需要和FDA澄清，把我们的做法写给FDA，澄清以0.10%鉴定限，可以参照甘精BPD2b给FA回复的写法】-焦2025.04.27

【内部后续行动项：除了B/F两个杂质外，还有3个特定杂质需要鉴定，已经做了2个，还有一个RRT还没有做表征，需要补做；此外，需要把3个特定杂质增加到标准里作为特定杂质。最终杂质方法验证应能体现这5个特定杂质的方法学。】-焦

Visible particulates testing in drug product release and stability specifications includes “Meet the requirement of USP<790>, three batches of drug product are essentially free of visible particulates.” It is recommended to remove the reference to “three batches of drug product” and propose the specification in line with United States Pharmacopeia (USP)<790> Visible Particulates in Injections. The requirement of USP<790> at batch release should be made according to the acceptance quality limit (AQL) sampling after 100% inspection. Additionally, the details of standard operating procedure for the monitoring of visible foreign particulate matter, sampling and testing plan and acceptance criterion as per USP<790> should be provided in Section 3.2.P.5.1 of your ANDA submission.
药品放行和稳定性标准中的可见异物检测包括"符合 USP<790>要求，三批药品基本无可见异物"。建议删除"三批药品"的表述，并按照美国药典(USP)<790>注射剂可见异物标准制定规范。USP<790>对批次放行的要求应基于 100%检查后的验收质量限(AQL)抽样进行判定。此外，应在 ANDA 申报资料 3.2.P.5.1 章节提供可见异物监测的标准操作规程、取样检测方案及 USP<790>验收标准的详细内容。

拿掉3批的描述，编写错误。

【不需要和FDA澄清，但是承认一下错误，给FDA回复一下】

For additional product development related issues and routine control strategy, refer to ICH Q6A: Specifications: Test procedures and acceptance criteria for new drug substances and new drug products: chemical substances Q6A (October 1999), ICH Q8: Pharmaceutical Development Q8(R2) (August 2009), and USP<1> Injections and Implanted Drug Products (Parenterals) - Product Quality Tests. 就是提了一下法规，没有实质性内容。
关于其他产品开发相关问题和常规控制策略，请参考 ICH Q6A：新原料药和新制剂的标准：测试程序和验收标准：化学物质 Q6A(1999 年 10 月)、ICH Q8：药物开发 Q8(R2)(2009 年 8 月)以及 USP<1>注射剂和植入药物(肠外制剂)-产品质量测试。

【不需要和FDA澄清】

Regarding essential performance requirements of pen injector device at release and stability:
关于笔式注射器设备在放行和稳定性方面的基本性能要求：

You propose to test pen injector functionality at baseline and stability by assessing dose accuracy and injection force. However, your dose accuracy testing is not in accordance with ISO 11608-1:2022 Needle-based injection systems for medical use — Requirements and test methods Part 1: Needle- based injection systems. For needle injection systems with multiple dose containers, ISO 11608-1:2022 outlines verifying dose accuracy for three regions of the cartridge along with last dose. Validating the dose accuracy of your combination product is important to ensure that the patient does not receive an under- or over-dose of the drug which could result in patient harm due to the return or worsening of symptoms or increased side-effects from the drug. Therefore, please ensure that you perform your dose accuracy studies in accordance with ISO 11608-1:2022 for needle injection systems with multi-dose containers. 【同赖脯，按照ISO修订，可能不需要讨论】 Additionally, ensure that you perform the testing with the final finished combination product as device performance may change compared to the manufacturer's reported performance due to the assembly process and with different drug products. 强调了一下要用自制最终成品进行测试，区别于供应商的笔系统评估。
贵方提议通过评估剂量准确性和注射力来测试笔式注射器在基线和稳定性阶段的功能。然而，贵方的剂量准确性测试不符合 ISO 11608-1:2022《医用针式注射系统 要求和试验方法 第 1 部分：针式注射系统》标准。对于多剂量容器的针式注射系统，ISO 11608-1:2022 规定需验证药筒三个区域及末次给药的剂量准确性。验证组合产品的剂量准确性至关重要，可确保患者不会因剂量不足或过量而导致症状复发/加重或药物副作用增加等医疗风险。因此，请确保按照 ISO 11608-1:2022 标准对多剂量容器针式注射系统进行剂量准确性研究。此外，必须使用最终成品组合产品进行测试，因为装配工艺及不同药物产品可能导致设备性能与制造商报告数据存在差异。 强调了应使用自制最终成品进行测试，而非供应商的笔系统评估。

【不需要和FDA澄清】

【内部后续行动项：剂量准确度方法和限度需要参照ISO进行修订】-焦

You provided the acceptance criteria of your break loose force and gliding force as <40N in “Table 5: Release and Stability Specification Comparison between Leuprolide Acetate Injection, 14 mg/2.8 mL (1 mg/0.2 mL) Pre-filled Pen and the approved ANDA 075471.” The specification should be based on the weakest 5th percentile user population per “ANSI/AAMI HE75:2009/(R)2018 Human factors engineering - Design of medical devices.” 40N appears high for 5th percentile female to operate the pen injector resulting in patient missing a dose or receiving a delayed dose. We recommend you tighten the acceptance criterion for injection force in your future marketing application. 现有数据均在15N以下，且没有明显增长趋势。加速0→3M结果分别为11、12、15、13N；长期0→3M结果分别为11、12N。
贵方在《表 5：醋酸亮丙瑞林注射液 14 mg/2.8 mL（1 mg/0.2 mL）预充式笔与已获批 ANDA 075471 的释放及稳定性参数对比》中提供的松脱力和滑动力的验收标准为<40N。根据《ANSI/AAMI HE75:2009/(R)2018 人因工程学-医疗器械设计》要求，该标准应基于最弱势的 5%百分位用户群体。40N 对于 5%百分位女性用户操作笔式注射器而言数值偏高，可能导致患者漏注射或延迟给药。建议在未来的上市申请中收紧注射力的验收标准。现有数据均低于 15N 且无显著上升趋势：加速试验 0→3 月结果分别为 11、12、15、13N；长期试验 0→3 月结果分别为 11、12N。

【不需要和FDA澄清】

【内部后续行动项：研发申报前需要根据稳定性结果收紧标准限度】-焦

You propose to assess device performance under the following conditions: cool atmosphere, warm atmosphere, standard atmosphere, free-fall, vibration, dry- heat, and cold storage. However, you do not propose to test pen injector performance following transport and functional stability pre-conditioning as described in Clause 10 in ISO 11808-1:2022. This information is important to ensure proper device functionality after pre-conditioning representative of intended use. Device malfunction could result in under-dose, over-dose, or a delayed therapy. Therefore, we recommend that you ensure the testing is performed after pre-conditioning representative of intended use (e.g., shipping, drop) and to a reliability commensurate with the risk of the device. Please refer to ISO 11608-1:2022 Needle-based injection systems for medical use — Requirements and test methods Part 1: Needle-based injection systems. 当时运输预处理和老化预处理没有列到表格里，被FDA提出来了。但是需要研发安排模拟运输验证和功能性测试。
贵方提议在以下条件下评估设备性能：低温环境、高温环境、标准环境、自由落体、振动、干热及冷藏条件。但未按照 ISO 11808-1:2022 标准第 10 条款要求，对笔式注射器进行运输预处理和功能稳定性预处理后的性能测试。该数据对确保设备在模拟实际使用场景的预处理后仍能正常运作至关重要，设备故障可能导致给药不足、过量或治疗延迟。因此，建议贵方补充开展模拟实际使用场景（如运输、跌落）的预处理测试，并根据设备风险等级确定相应的可靠性验证标准。具体请参照 ISO 11608-1:2022《医用针式注射系统 要求与试验方法 第 1 部分：针式注射系统》。此前运输预处理和老化预处理未列入测试表格，已被 FDA 提出质疑，现需研发部门安排模拟运输验证和功能性测试。

【不需要和FDA澄清】

【内部后续行动项：需要开展模拟运输验证和运输后功能性测试】-夏

Regarding microbiological related testing at release and stability:
关于放行检测和稳定性研究中的微生物相关检测：

We acknowledge the specification contains the microbiological tests of bacterial endotoxins, sterility, and container closure integrity testing (CCIT). The inclusion of the microbiological tests and the proposed acceptance criteria appears reasonable; however, the final decision regarding the microbiological component of the specification will be determined once the ANDA has been received and assessed by the Agency. FDA对微生物方面的标准按时没有意见。Please note that for the ANDA submission, the actual CCIT method should be specified, as USP<1> should not be identified as the “method.” 标准里边CCIT需要明确具体到USP中的哪个方法，不能笼统写USP<1>. Be advised that guidance for industry ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers (May 2014) recommends that “one of the primary batches of drug product should be tested for antimicrobial effectiveness testing (AET) (in addition to preservative content) at the end of the proposed shelf life.” Therefore, a commitment to perform AET on one primary batch of the drug product at the end of the proposed shelf life should also be included in the ANDA submission. 要承诺至少1批在效期末评价AET。
我们确认该质量标准包含细菌内毒素、无菌及容器密封完整性测试（CCIT）等微生物检测项目。所包含的微生物检测项目及拟定的可接受标准总体合理；但关于质量标准中微生物部分的最终决定，将在收到并评估该简略新药申请（ANDA）后由药监局作出。FDA 对微生物方面的标准暂无异议。请注意，在 ANDA 申报资料中应明确具体的 CCIT 检测方法，不应笼统标注 USP<1>作为检测方法。标准中的 CCIT 需具体说明采用 USP 中的何种方法，不可仅标注 USP<1>。另提请知悉，根据行业指南《ANDA：原料药与制剂稳定性研究问答》（2014 年 5 月版）建议："在拟定的有效期结束时，应对至少一批主要批次药品进行抗菌效力测试（AET）（除防腐剂含量外）"。因此，ANDA 申报资料中应包含对至少一批主要批次药品在拟定效期末进行 AET 检测的承诺。需承诺至少 1 批产品在效期末进行 AET 评价。

【不需要和FDA澄清】

The following is suggested for reference during the ongoing development of the ANDA submission to support the sterility assurance package: The Agency’s guidance for industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products (November 1994). https://www.fda.gov/regulatory-information/search-fda-guidance- documents/submission-documentation-sterilization-process-validation- applications-human-and-veterinary-drug
在 ANDA 申报的持续开发过程中，建议参考以下文件以支持无菌保证方案：美国 FDA 行业指南《人用和兽用药品申请中灭菌工艺验证的提交文件》（1994 年 11 月）。https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submission-documentation-sterilization-process-validation-applications-human-and-veterinary-drug

提了一下无菌验证的法规

【不需要和FDA澄清】。

Additional comments:
补充说明：

We recognize that the draft Prescribing Information and Instructions for Use document indicates that the pen can be stored for 28 days below 35°C (95°F) after first use. In-use stability data, including microbial quality and device performance data, in support of labeling statements should be provided. 强调要做亮丙的in-use研究，并且要考虑微生物和功能性。目前试验做完了，但是没有做功能性，需要补做。
我们注意到处方信息和使用说明草案中指出，该笔式注射器首次使用后可在 35°C（95°F）以下保存 28 天。需提供支持标签声明的使用中稳定性数据，包括微生物质量和器械性能数据。强调必须完成亮丙瑞林的使用中研究，并需考虑微生物和功能性指标。目前试验已完成但未包含功能性测试，需进行补充。

【不需要和FDA澄清】

【内部后续行动：in-use缺少功能性测试，需要补做】-夏

Extractable study on the container-closure system following USP<1663> and leachable study on the drug product following USP<1664> should be performed to evaluate quality and safety of the proposed drug product. Analysis of stability
应按照 USP<1663>对容器密封系统进行可提取物研究，并按照 USP<1664>对药品进行可浸出物研究，以评估拟申报药品的质量和安全性。稳定性分析

samples (6 months accelerated and 6 months or longer long-term samples) from the worst-case orientation storage condition is recommended at the time of ANDA submission. Please also ensure that the methods are suitable for leachable compound analysis. If leachables are detected above the AET, a justification for why such leachables in the product do not affect the safety and efficacy of the product should be provided. 描述了包材相容性的做法要求。【不需要讨论】Proposed high temperature storage at 35°C for 28 days after the first use should be justified in your study design. 需要把这个最差条件的in-use时间和条件考虑到包材相容性中
建议在提交 ANDA 申请时提供来自最差储存条件下的样品（6 个月加速和 6 个月或更长期长期样品）。同时请确保所采用方法适用于可浸出物化合物分析。若检测到可浸出物超过 AET 阈值，需提供论证说明产品中此类可浸出物不会影响产品的安全性和有效性。描述了包材相容性的做法要求。【不需要讨论】首次使用后 35°C 高温储存 28 天的方案应在研究设计中予以论证。需将这种最差使用条件下的时间和条件纳入包材相容性研究考量。

【不需要和FDA澄清】

【内部后续行动：需要增加提取和迁移试验在测试前样品需要增加35℃放28天的前处理（提取是考虑这个时间的换算）】-夏

Question 3
问题 3

Does the FDA agree with using the same finished product pH range approved for Meitheal’s ANDA 075471, Leuprolide Acetate Injection, 14 mg/2.8 mL
美国 FDA 是否同意采用与 Meitheal 公司 ANDA 075471（醋酸亮丙瑞林注射液，14 mg/2.8 mL）获批相同的成品 pH 值范围

(1 mg/0.2 mL) multi-dose vial for the proposed Pre-Filled Pen product?
(1 毫克/0.2 毫升) 多剂量小瓶用于拟议预充式笔产品？

Agency’s Response
机构回复

The inclusion of pH range of 5.5-6.5 for proposed drug product’s release and stability specifications appears reasonable; however, the final decision regarding the pH specification will be determined during ANDA assessment. The stability data supporting low and high extremities of proposed pH specification should be provided in the ANDA submission. FDA暂时同意，ANDA后续再审核。
对于所提议药品产品的放行和稳定性规范中 pH 值范围 5.5-6.5 的设定，目前看来是合理的；但关于 pH 值规范的最终决定将在 ANDA 评估过程中确定。申请人应在 ANDA 申报材料中提供支持所提议 pH 值规范下限和上限的稳定性数据。

【不需要和FDA澄清】

【研发需要补一个不同ph的实验室批次稳定性研究】。-夏

Question 4
问题 4

Does FDA agree that no immunogenicity study is needed for this proposed pre- filled pen product?
FDA 是否同意该预充式笔型制剂无需进行免疫原性研究？

Agency’s Response
监管机构的回复

The need for immunogenicity study for a proposed generic peptide product depends on its similarity to the RLD. When the API is demonstrated to be the same, the differences in product’s impurity profile (including peptide-related impurities and non-peptide process-related impurities) could impact the risk of immunogenicity. 做不做免疫取决于和RLD的杂质谱差异。
对于拟议的仿制肽类产品是否需要开展免疫原性研究，取决于其与参比上市药品（RLD）的相似性。当原料药（API）被证实相同时，产品杂质谱（包括肽类相关杂质和非肽类工艺相关杂质）的差异可能会影响免疫原性风险。是否需要进行免疫原性研究取决于与 RLD 的杂质谱差异。

With respect to peptide-related impurities, we recommend that you compare the impurity profile of multiple batches of your proposed product with that of the RLD’s. If there are significant differences in peptide-related impurity profiles, then immunogenicity assessment and justifications may be requested to qualify these differences. 关于肽类相关杂质，建议将多批次拟议产品的杂质谱与参比上市药品（RLD）的杂质谱进行对比。如果肽类相关杂质谱存在显著差异，可能会要求进行免疫原性评估并给出合理解释，以说明这些差异的合理性。
关于肽类相关杂质，我们建议将贵方拟议产品的多批次杂质谱与参比上市药品（RLD）的杂质谱进行比对。若肽类相关杂质谱存在显著差异，则可能需要提供免疫原性评估数据及合理性说明，以论证这些差异的可接受性。

In general, non-peptide process-related impurities and aggregates can alter the product’s innate immunogenicity profile. Differences found in comparability studies assessing aggregates should be mitigated. Levels of non-peptide process-related impurities (including particulate matter, microbial contaminants, residual organic solvents, elemental impurities, and leachables) should meet compendial acceptance criteria and toxicological limits. If non-peptide process-related impurities comply with these requirements, and aggregation profiles are similar to the RLD’s, no innate immune testing is necessary. 一般来说，非肽类工艺相关杂质和聚集体会改变产品的固有免疫原性特征。在评估聚集体的可比性研究中，若发现差异，应设法减小。非肽类工艺相关杂质（包括颗粒物、微生物污染物、残留有机溶剂、元素杂质和可提取物）的含量应符合药典验收标准和毒理学限值。如果非肽类工艺相关杂质符合这些要求，且聚集体特征与参比上市药品（RLD）相似，则无需进行固有免疫测试。
一般来说，非肽类工艺相关杂质和聚集体会改变产品的固有免疫原性特征。在评估聚集体的可比性研究中发现的差异应当予以消除。非肽类工艺相关杂质（包括颗粒物、微生物污染物、残留有机溶剂、元素杂质及浸出物）的水平应符合药典验收标准及毒理学限值要求。若非肽类工艺相关杂质符合上述要求且聚集体特征与参照上市药品（RLD）相似，则无需进行固有免疫检测。

【需要和FDA澄清】-田博！

Question 5
问题 5

Does the FDA agree with conducting a Human Factors Validation Study instead of a Comparative Use Human Factor Study for the proposed Pre-Filled Pen product?
对于所申报的预充式注射笔产品，FDA 是否同意以人因工程验证研究替代对比使用人因研究？

Agency’s Response
监管机构回复

We acknowledge your plan to conduct a Human Factors Validation Study (HFVS) instead of a Comparative Use Human Factor Study (CUHF) to demonstrate your proposed prefilled pen presentation can be substituted with the full expectation that the generic product will produce the same clinical effect and safety profile as the RLD. As a general matter, we agree it may be feasible to develop alternative study methodologies to assess the acceptability of user interface design differences. However, the acceptability of your proposed study methodology is under review. FDA will provide comprehensive recommendations for your proposed approach with the meeting minutes. To further inform our review, please provide responses to the following:
我们注意到贵方计划进行人因验证研究(HFVS)而非比较使用人因研究(CUHF)，以证明所提议的预充式笔呈现方式可被替代，并完全预期仿制产品将产生与原研药(RLD)相同的临床效果和安全性特征。原则上，我们认同开发替代性研究方法来评估用户界面设计差异的可接受性可能是可行的。然而，贵方提议的研究方法是否可接受尚在审查中。FDA 将在会议纪要中就贵方提出的方案提供全面建议。为进一步协助我们的审查，请就以下问题作出回应：

You state the RLD has been withdrawn from market, thus rendering a CUHF study using the RLD impossible. Clarify why you have not proposed use of the reference standard (RS) product for the purposes of evaluating the differences in a conventional CUHF study.
贵方声明原研药已退出市场，因此无法使用原研药进行 CUHF 研究。请说明为何未提议使用参考标准(RS)产品来进行传统 CUHF 研究以评估差异。

Provide your justification for how your proposed study methodology can assess the acceptability of differences identified in the user interface for the proposed generic product and support substitution with the full expectation that the proposed generic product will produce the same clinical effect and safety profile as the RLD (see response to Question 1).
请说明您提出的研究方法如何评估所发现的拟议仿制产品用户界面差异的可接受性，并支持替代使用，同时完全预期该仿制产品将产生与参照药品（RLD）相同的临床效果和安全性特征（参见对问题 1 的回复）。

Question 6
问题 6

Does FDA agree that the user groups for the human factors validation study for the proposed Leuprolide Acetate Injection, 14 mg/2.8 mL (1 mg/0.2 mL) Pre-Filled Pen have been appropriately defined?
FDA 是否同意用于醋酸亮丙瑞林注射液（14 毫克/2.8 毫升（1 毫克/0.2 毫升）预充式笔）人因工程验证研究的用户群体定义恰当？

Agency’s Response
监管机构回复

FDA will provide comprehensive recommendations within the meeting minutes.
FDA 将在会议纪要中提供全面建议。

Question 7
问题 7

Does FDA agree to the use of surrogates if needed to recruit the required number of participants as specified in the study protocol?
若需招募研究方案规定数量的受试者，FDA 是否同意使用替代指标？

Agency’s Response
机构回复

See response to Question 6.
见问题 6 的回复。

Question 8
问题 8

Does FDA agree that appropriate simulated use and knowledge assessment tasks have been selected for evaluation based on the URRA?
FDA 是否同意基于 URRA 选择了适当的模拟使用和知识评估任务进行评估？

Agency’s Response
机构回复

See response to Question 6.
见问题 6 的回复。

Question 9
问题 9

Does the FDA have any further comments or suggestions regarding the proposed human factors validation study or the use-related risk analysis?
FDA 对于拟议的人因工程验证研究或使用相关风险分析是否有其他意见或建议？

Agency’s Response
机构回复

See response to Question 6.
见问题 6 的回复。

Question 10
问题 10

Does the FDA have any comments or suggestions on the proposed Package Insert or Instructions for Use for the proposed Leuprolide Acetate Injection Pen?
FDA 对拟议的醋酸亮丙瑞林注射笔的包装说明书或使用说明是否有任何意见或建议？

Agency’s Response
机构回复

See response to Question 6.
参见问题 6 的回复。

Digitally signed by Markham Luke Date: 4/24/2025 02:56:50PM
数字签名：马克汉姆·卢克 日期：2025 年 4 月 24 日 下午 02:56:50