Pre-ANDA Product Development Meeting
ANDA 产品开发前会议

FINAL WRITTEN RESPONSE 最终书面回复

Seacross Pharma USA, Inc.
Seacross Pharma 美国公司
245 First Street, Suite 1400
第一街 245 号，套房 1400
Cambridge, MA 02142 剑桥， MA 02142
Attention: Jack Zhai 收件人：Jack Zhai
Vice President 副总统
Dear Jack Zhai: 尊敬的 Jack Zhai：
This is in reference to your pre-abbreviated new drug application (pre-ANDA) file for ferric oxyhydroxide ${}^1$${}^1$^(1){ }^{1} intravenous injectable, referencing Venofer (ferric oxyhydroxide) intravenous injectable, approved under new drug application (NDA) 021135, as the reference listed drug (RLD).
这是指您关于氢氧化 ${}^1$${}^1$^(1){ }^{1} 铁静脉注射剂的简化新药申请 （ANDA 前） 文件，其中引用了根据新药申请 （NDA） 021135批准的 Venofer（羟氢氧化铁）静脉注射剂作为参考上市药物 （RLD）。

Silver Spring, MD 20993 马里兰州银泉 20993
www.fda.gov

Reference is also made to your request for a pre-ANDA product development meeting, received on March 25, 2024, and granted on April 5, 2024.
此外，还提到了您对 ANDA 前产品开发会议的请求，该会议于 2024 年 3 月 25 日收到，并于 2024 年 4 月 5 日获得批准。

The Agency’s final written 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 Agency 对您的会议问题的最终书面答复。提供的回答基于您提交的会议文件包中的信息，在对您的 ANDA 进行全面评估后，可能会进行修改。我们提醒您，仿制药办公室 （OGD） 是否会收到您的 ANDA 进行实质性评估，将在对您的 ANDA 进行申请审查时确定，而您拟议产品的可批准性将在对您的 ANDA 进行科学评估时确定。

This closes out your meeting request.
这将关闭您的会议请求。
If you have any questions regarding this meeting request, you may send them via email to PreANDAHelp@fda.hhs.gov.
如果您对此会议请求有任何疑问，可以通过电子邮件将其发送给 PreANDAHelp@fda.hhs.gov。

Sincerely, 真诚地
{See Appended electronic signature page}
{见附加的电子签名页}
Yan Wang, PhD Yan Wang 博士
Acting Deputy Director 署理副主任
Division of Therapeutic Performance I
治疗性能 I 科
Office of Research and Standards
研究与标准办公室
Office of Generic Drugs 仿制药办公室
Center for Drug Evaluation and Research
药物评价与研究中心
U.S. Food and Drug Administration
美国食品药品监督管理局

Prospective Applicant Name:
潜在申请人姓名：
Meeting Request Tracking Number:
会议请求跟踪号：
Meeting Request Type: 会议请求类型：
Meeting Format: 会议形式：
Reference Listed Drug: 参考上市药物：
Active Ingredient: 活性成分：
Route; Dosage Form; Strength:
路线;剂型;强度：

Meeting Granted Date: 会议授权日期：

Seacross Pharma USA, Inc.
Seacross Pharma 美国公司
ANDA-219563-PDEV-Meeting-00211192
ANDA-219563-PDEV-会议-00211192
Pre-ANDA Product Development
ANDA 前产品开发
Written Response Only 仅限书面回复
NDA 021135, Venofer NDA 021135，维诺法
Ferric oxyhydroxide 羟基氧化铁
Intravenous injectable; 静脉注射剂;
EQ 50 mg iron $/2.5\mathrm{mL}$$/2.5\mathrm{mL}$//2.5mL/ 2.5 \mathrm{~mL} (EQ 20 mg iron $/\mathrm{mL}$$/\mathrm{mL}$//mL/ \mathrm{mL} );
EQ 50 毫克铁 $/2.5\mathrm{mL}$$/2.5\mathrm{mL}$//2.5mL/ 2.5 \mathrm{~mL} （EQ 20 毫克铁 $/\mathrm{mL}$$/\mathrm{mL}$//mL/ \mathrm{mL} ）;
EQ 100 mg iron/5 mL (EQ 20 mg iron $/\mathrm{mL}$$/\mathrm{mL}$//mL/ \mathrm{mL} );
EQ 100 毫克铁/5 mL（EQ 20 毫克铁 $/\mathrm{mL}$$/\mathrm{mL}$//mL/ \mathrm{mL} ）;
EQ 200 mg iron $/10\mathrm{mL}$$/10\mathrm{mL}$//10mL/ 10 \mathrm{~mL} (EQ 20 mg iron $/\mathrm{mL}$$/\mathrm{mL}$//mL/ \mathrm{mL} )
EQ 200 毫克铁 $/10\mathrm{mL}$$/10\mathrm{mL}$//10mL/ 10 \mathrm{~mL} （EQ 20 毫克铁 $/\mathrm{mL}$$/\mathrm{mL}$//mL/ \mathrm{mL} ）
April 5, 2024 4月 5， 2024

On March 25, 2024, Seacross Pharma USA, Inc., submitted a pre-ANDA product development meeting request to obtain FDA’s feedback and guidance on their development program, to increase the efficiency of the sponsor’s ANDA filing and agency review process.
2024 年 3 月 25 日，Seacross Pharma USA， Inc. 提交了 ANDA 产品开发前会议请求，以获得 FDA 对其开发计划的反馈和指导，以提高申办方的 ANDA 申报和机构审查流程的效率。

The following includes questions from the pre-ANDA product development meeting package (shown in bold) followed by the Agency’s final written response (shown in normal font).
以下内容包括 ANDA 会前产品开发会议文件包中的问题（以粗体显示），然后是 Agency 的最终书面回复（以普通字体显示）。

Regarding comparative characterization studies of the drug substance as provided in Section 8.2, does the Agency agree that these studies are adequate to demonstrate the sameness between Huiyu Iron Sucrose drug substance and the drug substance of the RLD? Some of these studies were conducted in contract laboratories which are research institute laboratories and non-GMP/GLP laboratories. Does the Agency agree that these studies can be conducted in these research institute laboratories?
关于第 8.2 节中规定的原料药的比较表征研究，原子能机构是否同意这些研究足以证明汇玉蔗糖铁原料药与 RLD 原料药之间的相同性？其中一些研究是在合同实验室进行的，这些实验室是研究机构实验室和非 GMP/GLP 实验室。原子能机构是否同意这些研究可以在这些研究机构的实验室中进行？

The adequacy of the comparative characterization studies between the Huiyu iron sucrose drug substance and the drug substance of the RLD is an assessment issue and can only be determined in the full scientific assessment. We have the following additional comments regarding the sameness/characterization study based on your preliminary data:
惠玉蔗糖铁原料药与 RLD 原料药之间的比较表征研究的充分性是一个评估问题，只能在完整的科学评估中确定。根据您的初步数据，我们对相同性/特征研究有以下补充意见：
a) Please be aware that if the characterization/sameness tests are part of the drug substance release/stability specification tests, they should be conducted in good manufacturing practice (GMP)/good laboratory practice (GLP) facilities.
a） 请注意，如果表征/相同性测试是原料药放行/稳定性规范测试的一部分，则应在良好生产规范 （GMP）/良好实验室规范 （GLP） 设施中进行。

Otherwise, if the studies are for one-time comparative characterization, they are not required to be conducted at GMP/GLP facilities. However, it is still expected that all laboratories performing comparative characterization studies should follow the applicable good laboratory practices, so that all data submitted to the Agency are accurate, complete, and reliable, and that applicants and testing sites achieve and maintain data integrity throughout the data lifecycle of the product. It is each applicant’s responsibility to achieve and maintain data integrity for their studies, which includes identifying and implementing the most effective and efficient risk-based controls. As such, you should implement meaningful and effective strategies to manage the data integrity risks based on the process understanding and knowledge management of technologies and business models.
否则，如果研究用于一次性比较表征，则不需要在 GMP/GLP 设施中进行。但是，仍然希望所有进行比较特性研究的实验室都应遵循适用的良好实验室规范，以便提交给原子能机构的所有数据都是准确、完整和可靠的，并且申请人和测试站点在产品的整个数据生命周期内实现并保持数据完整性。每个申请人都有责任实现和维护其研究的数据完整性，其中包括确定和实施最有效和最高效的基于风险的控制措施。因此，您应该根据对技术和业务模型的流程理解和知识管理，实施有意义且有效的策略来管理数据完整性风险。
b) Regarding the analytical methods, according to FDA guidance for industry Process Validation: General Principles and Practices (January 2011), drug product manufacturing process knowledge depends on accurate and precise measuring techniques used to test and examine the quality of drug components, in-process materials, and finished products. Analytical methods should be scientifically sound (e.g., specific, sensitive, and accurate) and provide results that are reliable. There should be assurance of proper equipment function for laboratory experiments. Procedures for analytical method and equipment maintenance, documentation practices, and calibration practices supporting process-development efforts should be documented or described. Provide method validation for your comparative characterization whenever applicable.
b） 关于分析方法，根据 FDA 行业工艺验证指南：一般原则和实践（2011 年 1 月），药品生产工艺知识取决于用于测试和检查药品成分、过程材料和成品质量的准确和精密的测量技术。分析方法应具有科学依据（例如，特异性、灵敏度和准确性）并提供可靠的结果。应保证实验室实验的设备功能正常。应记录或描述支持工艺开发工作的分析方法和设备维护程序、文档记录实践和校准实践。在适用时为您的比较表征提供方法验证。
c) For the Dynamic Light Scattering (DLS) particle size distribution study, provide intensity-weighted average particle diameter, polydispersity index (PDI), and a histogram for the measured particle size distribution of your drug substance characterization batches in comparison with RLD batches. Provide information on the DLS method such as cuvette type, scattering angle, laser wavelength, and refractive index for the particles. To assess the dilution effects on the hydrodynamic particle size, measure a series of test drug substance/drug product batches and RLD batches diluted with $0.9\mathrm{\%}\mathrm{NaCl}$$0.9\mathrm{\%}\mathrm{NaCl}$0.9%NaCl0.9 \% \mathrm{NaCl} solution, ranging from $0.01\mathrm{mg}/\mathrm{mL}$$0.01\mathrm{mg}/\mathrm{mL}$0.01mg//mL0.01 \mathrm{mg} / \mathrm{mL} to $20\mathrm{mg}/\mathrm{mL}$$20\mathrm{mg}/\mathrm{mL}$20mg//mL20 \mathrm{mg} / \mathrm{mL}, including $1\mathrm{mg}/\mathrm{mL}$$1\mathrm{mg}/\mathrm{mL}$1mg//mL1 \mathrm{mg} / \mathrm{mL}, which is the in-use concentration.
c） 对于动态光散射 （DLS） 粒度分布研究，提供强度加权平均粒径、多分散指数 （PDI） 和直方图，用于将原料药表征批次的测量粒度分布与 RLD 批次进行比较。提供有关 DLS 方法的信息，例如比色皿类型、散射角、激光波长和颗粒的折射率。为了评估稀释对流体动力学粒径的影响，测量一系列用 $0.9\mathrm{\%}\mathrm{NaCl}$$0.9\mathrm{\%}\mathrm{NaCl}$0.9%NaCl0.9 \% \mathrm{NaCl} 溶液稀释的测试原料药/药品批次和 RLD 批次，范围从 $0.01\mathrm{mg}/\mathrm{mL}$$0.01\mathrm{mg}/\mathrm{mL}$0.01mg//mL0.01 \mathrm{mg} / \mathrm{mL} 到 $20\mathrm{mg}/\mathrm{mL}$$20\mathrm{mg}/\mathrm{mL}$20mg//mL20 \mathrm{mg} / \mathrm{mL} ，包括 $1\mathrm{mg}/\mathrm{mL}$$1\mathrm{mg}/\mathrm{mL}$1mg//mL1 \mathrm{mg} / \mathrm{mL} ，这是使用浓度。
d) It appears the X-ray diffraction (XRD) diffractograms have low signal-to-noise ratios. Please refer to “Physicochemical Characterization of Iron Carbohydrate Colloid Drug Products. Zou, P., Tyner, K., Raw, A., Lee, S., The AAPS Journal. 2017, 19(5), 1559 - 1376” for discussions and methods on determining iron core crystallinity. We recommend that you provide additional X-ray absorption spectroscopy study using X-ray absorption near edge structure (XANES), extended $X$$X$XX-ray absorption fine structure (EXAFS), or small angle X-ray scattering (SAXS) for the iron core crystalline form and particle size sameness studies. Assign the major peaks in the diffractograms and provide a tabular comparison of the major $2\theta$$2\theta$2theta2 \theta peaks observed in each batch.
d） X 射线衍射 （XRD） 衍射图似乎具有低信噪比。请参阅“碳水化合物铁胶体药物产品的物理化学表征”。Zou， P.， Tyner， K.， Raw， A.， Lee， S.， AAPS 杂志。2017， 19（5）， 1559 - 1376“，用于确定铁芯结晶度的讨论和方法。我们建议您使用 X 射线吸收近边缘结构 （XANES）、扩展 $X$$X$XX 射线吸收精细结构 （EXAFS） 或小角 X 射线散射 （SAXS） 进行铁芯晶体形式和粒度相同性研究，提供额外的 X 射线吸收光谱研究。在衍射图中分配主峰，并提供每个批次中观察到的主 $2\theta$$2\theta$2theta2 \theta 峰的表格比较。
e) For the Mössbauer spectra comparison, record Mössbauer spectra at various temperatures and compare the temperature dependence of quadrupole splitting for characterization batches and RLD. Determine the average blocking
e） 对于穆斯堡尔光谱比较，记录不同温度下的穆斯堡尔光谱，并比较表征批次和 RLD 的四极杆分裂的温度依赖性。确定平均阻塞
temperature and relative core size of iron sucrose complex in your characterization batches and RLD.
温度和相对核心大小 蔗糖铁复合物 在表征批次和 RLD 中的测量。
f) To demonstrate the same environment of iron cores between your characterization batches and RLD batches, we recommend you provide an electron spin resonance (ESR) comparison. Provide ESR experimental conditions such as the reference standard for g-value, the external magnetic field, spectrometer, temperature and the concentration of iron sucrose samples.
f） 为了证明您的表征批次和 RLD 批次之间的铁芯环境相同，我们建议您提供电子自旋共振 （ESR） 比较。提供 ESR 实验条件，如 g 值的参考标准、外部磁场、光谱仪、温度和蔗糖铁样品的浓度。
g) Surface charge/zeta potential describe the nature of electrostatic charge near the surface of a particle and are crucial for determination of colloidal stability. Provide a zeta potential comparison between your characterization batches and RLD batches over a range of pH values. Consider removing free sucrose to eliminate its interference before fourier transfer infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), and zeta-potential experiments.
g） 表面电荷/zeta 电位描述了颗粒表面附近静电荷的性质，对于确定胶体稳定性至关重要。在一系列 pH 值下，提供表征批次和 RLD 批次之间的 zeta 电位比较。考虑在傅里叶转移红外光谱 （FT-IR）、核磁共振 （NMR） 和 zeta 电位实验之前去除游离蔗糖以消除其干扰。
h) You have performed testing for labile iron using an inductively coupled plasma mass spectrometry (ICP-MS) method. In your test procedure the sample is diluted using buffer which contained EDTA. Evaluate the effect of time and pH when using EDTA as your chelation agent. Be advised that the labile iron determination is to be conducted under physiologically relevant conditions. We refer to you the recommendations on labile iron characterization in the productspecific guidance on Ferric Oxyhydroxide (September 2021). Because the labile iron determination in your proposed study is affected by factors such as the nature of chelating agents, incubation time, and pH , etc., please ensure that adequate consideration and justification are given to the development of the analytical procedure. We refer you to “A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer ${}^{\circledR }$${}^{\circledR }$^(®){ }^{\circledR} ), a new intravenous iron preparation of its clinical implications, Jahn, M. R., Eur. J. Pharm. Biopharm., 78 (2011), 480 - 491.” In the article, the labile iron testing samples were incubated for multiple time periods, and the labile iron content was calculated “by linear regression analysis of the obtained intercepts from curves at the different incubation time periods.” We recommend that you incorporate the above approach in your sample preparations, if applicable. In addition, EDTA is a strong chelating agent, which could actively extract iron from the iron sucrose complex and result in overestimation of labile iron content. We recommend you evaluate the suitability of the chelating agent in your study. Adequate justification with data should be provided for the selected study design.
h） 您已使用电感耦合等离子体质谱 （ICP-MS） 方法进行不稳定铁检测。在您的测试程序中，使用含有 EDTA 的缓冲液稀释样品。评估使用 EDTA 作为螯合剂时时间和 pH 值的影响。请注意，不稳定铁测定应在生理相关条件下进行。我们参考了氢氧化铁产品特定指南（2021 年 9 月）中关于不稳定铁特性的建议。由于您拟议研究中的不稳定铁测定受螯合剂性质、孵育时间和 pH 值等因素的影响，请确保对分析程序的开发给予充分的考虑和理由。我们建议您参阅“异麦芽糖苷 1000 （Monofer） 物理化学性质的比较研究 ${}^{\circledR }$${}^{\circledR }$^(®){ }^{\circledR} ，一种新型静脉注射铁制剂的临床意义，Jahn， MR， Eur. J. Pharm. Biopharm.， 78 （2011）， 480 - 491。在文章中，不稳定铁测试样品被孵育多个时间段，并且“通过对不同孵育时间段的曲线截距进行线性回归分析”计算不稳定铁含量。如果适用，我们建议您在样品制备中采用上述方法。此外，EDTA 是一种强螯合剂，可以主动从蔗糖铁复合物中提取铁，并导致高估不稳定的铁含量。我们建议您评估螯合剂在研究中的适用性。应为选定的研究设计提供充分的数据证明。

Regarding comparative characterization studies of the finished product, the same studies (i.e., characterization of iron core, carbohydrate shell and whole particles) as mentioned in Section 8.2 will be conducted between multiple batches of the generic iron sucrose injection manufactured at proposed commercial scale and multiple batches of the RLD sourced from the US market. Does the Agency agree that these studies are adequate to demonstrate the equivalence between the proposed generic product and the RLD? Does the Agency recommend any additional studies? Some of these studies will be conducted in contract
关于成品的比较特性研究，第 8.2 节中提到的相同研究（即铁核、碳水化合物壳和整个颗粒的表征）将在以拟议商业规模生产的多批次仿制药蔗糖铁注射液和来自美国市场的多批次 RLD 之间进行。原子能机构是否同意这些研究足以证明拟议的仿制药和 RLD 之间的等效性？该机构是否建议进行任何其他研究？其中一些研究将以合同形式进行
laboratories which are research institute laboratories and non-GMP/GLP laboratories. Does the Agency agree that these studies can be conducted in these research institute laboratories?
实验室，即研究机构实验室和非 GMP/GLP 实验室。原子能机构是否同意这些研究可以在这些研究机构的实验室中进行？

The adequacy of the comparative characterization studies is an assessment issue and will be determined during the ANDA assessment. We have the following recommendations regarding the comparative characterization studies provided in Section 8.2 of your meeting package, as well as the studies you intend to conduct between multiple batches of your proposed product manufactured at the proposed commercial scale and multiple batches of the RLD sourced from the U.S. market:
比较特征研究的充分性是一个评估问题，将在 ANDA 评估期间确定。对于您的会议套餐第 8.2 节中提供的比较特性研究，以及您打算在以拟议商业规模生产的多个批次的拟议产品与来自美国市场的多个批次的 RLD 之间进行的研究，我们提出了以下建议：
a) Comparative characterization studies should be conducted on at least three batches of the test and reference products. At least one test batch should be produced by the commercial scale process and used in the in vitro and in vivo bioequivalence study.
a） 应对至少三个批次的供试品和参比品进行比较特性研究。至少应通过商业规模的工艺生产一个测试批次，并用于体外和体内生物等效性研究。
b) Refer to our response to Question #1, point a) and b) regarding recommendations for laboratories, which would perform comparative characterization studies, and validation of the methods used in these studies.
b） 请参阅我们对问题 #1 的 a） 点和 b） 关于实验室的建议的回答，这些实验室将进行比较表征研究，并验证这些研究中使用的方法。
c) Provide test results for the individual batches of the test and reference products. Provide the date of testing and sample age for all batches.
c） 提供测试商品和参考商品的单个批次的测试结果。提供所有批次的检测日期和样本年龄。
d) The drug product contains unbound carbohydrates, low molecular weight iron and free iron species, and other impurities which may mask the real composition of the iron colloid whole particles. It is important that the unbound species and impurities are removed if they interfere with the intended characterization studies on the colloid particles. Therefore, we recommend you perform characterization studies using dialyzed samples as applicable.
d） 药品含有未结合的碳水化合物、低分子量铁和游离铁物种，以及其他可能掩盖铁胶体全颗粒真实成分的杂质。如果未结合的物质和杂质干扰了对胶体颗粒的预期表征研究，则去除它们非常重要。因此，我们建议您使用透析样品进行表征研究（如适用）。
e) In addition to the characterization of crystallinity of the iron core by X-ray powder diffraction, we recommend you use an orthogonal method, such as Mössbauer spectroscopy. Because Mössbauer spectra can be obtained on the as-is drug product formulation and are sensitive to temperature, conduct the study at various temperatures for comparison of chemical and magnetic environment of the nanoparticles. We recommend the temperature range covers the transition range where the blocking temperature (Tb) is determined.
e） 除了通过 X 射线粉末衍射表征铁芯的结晶度外，我们还建议您使用正交方法，例如穆斯堡尔光谱法。由于穆斯堡尔光谱可以在原样药品配方中获得并且对温度敏感，因此请在各种温度下进行研究，以比较纳米颗粒的化学和磁性环境。我们建议温度范围涵盖确定封闭温度 （Tb） 的转变范围。
f) The sample preparation for transmission electron microscopy (TEM) at room temperature involves dilution and drying, which could impact the property of the iron colloid. Therefore, we recommend you characterize iron core size and iron core morphology using methods that require minimal sample manipulation such as cryo-TEM and SAXS technology.
f） 室温下透射电子显微镜 （TEM） 的样品制备涉及稀释和干燥，这可能会影响铁胶体的性能。因此，我们建议您使用需要最少样品操作的方法（如冷冻 TEM 和 SAXS 技术）来表征铁芯尺寸和铁芯形态。
g) You are planning to conduct characterization of the iron core morphology and size by atomic force microscopy (AFM). Please note that AFM is generally considered as characterization of the colloid particle (whole particle) instead of the iron core.
g） 您计划通过原子力显微镜 （AFM） 对铁芯的形态和尺寸进行表征。请注意，AFM 通常被认为是胶体颗粒（整个颗粒）而不是铁芯的表征。
h) You characterized the iron environment by UV-Visible spectroscopy using diluted samples of the drug product. We recommend you perform this characterization study using dialyzed samples. Include sample preparation details in your characterization report.
h） 您使用稀释的药品样品通过紫外-可见光谱法表征了铁环境。我们建议您使用透析样品进行此表征研究。在表征报告中包括样品制备详细信息。
i) In addition to other studies proposed, we recommend you characterize the iron environment using ESR. Because ESR can be obtained using the as-is drug product formulation and ESR data at different temperatures can provide information regarding the iron core environment and paramagnetic iron structure, conduct the study at different temperatures using the as-is drug product formulation. Include analysis of minor peaks in addition to the main peak.
i） 除了建议的其他研究外，我们还建议您使用 ESR 来表征铁环境。由于 ESR 可以使用原样药品配方获得，并且不同温度下的 ESR 数据可以提供有关铁芯环境和顺磁性铁结构的信息，因此请使用原样药品配方在不同温度下进行研究。除了主峰之外，还包括对小峰的分析。
j) You characterized ferrous (Iron (II) content), low molecular weight complexes, and reduction potential using a compendial polarography method. We recommend you use a more sensitive method to conduct these characterization studies. We refer you to publication “Physicochemical Characterization of Iron Carbohydrate Colloid Drug Products. Zou, P., Tyner, K., Raw, A., Lee, S., The AAPS Journal. 2017, 19(5), 1559 - 1376” for more information.
j） 您使用药典极谱法表征了亚铁（铁 （II） 含量）、低分子量复合物和还原电位。我们建议您使用更灵敏的方法来进行这些表征研究。我们建议您参考出版物“碳水化合物铁胶体药物产品的物理化学表征”。Zou， P.， Tyner， K.， Raw， A.， Lee， S.， AAPS 杂志。2017， 19（5）， 1559 - 1376“了解更多信息。
k) For the characterization of the carbohydrate composition and carbohydrate-iron core interaction, in addition to NMR, thermal gravimetric analysis (TGA) and FTIR methods, we recommend you include characterization by differential scanning calorimetry (DSC). We recommend you isolate the colloid particles from the small molecular weight species by dialysis. Include sample preparation details in your characterization report.
k） 为了表征碳水化合物组成和碳水化合物-铁核相互作用，除了 NMR、热重分析 （TGA） 和 FTIR 方法外，我们建议您包括通过差示扫描量热法 （DSC） 进行表征。我们建议您通过透析将胶体颗粒与小分子量物质分离。在表征报告中包括样品制备详细信息。
I) Zeta potential is pH dependent. Therefore, we recommend you determine zeta potential at a range that spans acidic, neutral, and basic pH .
I） Zeta 电位与 pH 值有关。因此，我们建议您在酸性、中性和碱性 pH 值范围内确定 zeta 电位。
m) For the particle size distribution study by DLS, we recommend you perform the study on serially diluted samples. Provide representative histograms, including overlapping histograms for the test product and RLD.
m） 对于 DLS 的粒度分布研究，我们建议您对连续稀释的样品进行研究。提供具有代表性的直方图，包括测试产品和 RLD 的重叠直方图。
n) You have provided the results for the iron content and sucrose content. In addition, for comparative characterization of stoichiometry, we recommend you determine the content of sodium and chloride. Because sodium carbonate is used in the manufacture of your drug substance, include carbonate content in your stoichiometry study. Perform the stoichiometry study using dialyzed and undialyzed samples of your drug product and the RLD. Also provide comparative characterization of the free iron, bound and unbound sucrose for your drug product and the RLD.
n） 您已提供铁含量和蔗糖含量的结果。此外，为了比较化学计量的表征，我们建议您测定钠和氯化物的含量。由于碳酸钠用于生产原料药，因此在化学计量研究中包括碳酸盐含量。使用药品和 RLD 的透析和未透析样品进行化学计量研究。此外，还提供药品和 RLD 的游离铁、结合和未结合蔗糖的比较表征。
o) Include a test for in vitro reductive iron release (reduction kinetic) in your comparative physicochemical characterization studies.
o） 在比较物理化学表征研究中包括体外还原铁释放（还原动力学）测试。
p) You have performed testing for labile iron using an inductively coupled plasma mass spectrometry (ICP-MS) method. Please refer to our recommendations for this testing, provided in the response to Question #1, point h).
p） 您已使用电感耦合等离子体质谱法 （ICP-MS） 方法进行不稳定铁检测。请参阅我们对此测试的建议，该建议在对问题 #1 的回答中提供。

Does the Agency agree that the proposed formulations for the generic Iron Sucrose Injection USP as shown in Table 5, 6 and 7 (page 37) is qualitatively and quantitatively (Q1/Q2) the same as the formulations of the reference listed drug Venofer (N021135)?
原子能机构是否同意表 5、6 和 7（第 37 页）所示的仿制药蔗糖铁注射液 USP 的拟议配方在定性和定量上 （Q1/Q2） 与参比上市药物 Venofer （N021135） 的配方相同？

As detailed below, the Q1 and Q2 assessment of the ferric oxyhydroxide formulations referencing Venofer (ferric oxyhydroxide) intravenous injectable, approved under NDA 021135, as the RLD currently raises complex issues that may affect the Agency’s current thinking on the matter. We recommend you submit a controlled correspondence or pre-submission meeting request just prior to submitting an ANDA to confirm the Agency’s thinking at that time on the acceptability of your proposed formulation for submission as an ANDA.
如下所述，根据 NDA 021135 批准的 Venofer（羟氢氧化铁）静脉注射剂的氢氧化铁制剂的第 1 季度和第 2 季度评估，因为 RLD 目前提出了可能影响该机构当前对此事的看法的复杂问题。我们建议您在提交 ANDA 之前提交受控通信或提交前会议请求，以确认 AGENCY 当时对作为 ANDA 提交的拟议公式的可接受性的看法。

However, per the Agency’s thinking at the time of this product development meeting, OGD has made a preliminary determination that OGD would not likely refuse to receive an ANDA submitted pursuant to section 505(j) of the FD&C Act and its implementing regulations based on the proposed formulation in your meeting request, pursuant to the requirements pertaining to inactive ingredients described in 21 CFR 314.101(d)(3) and 21 CFR 314.94(a)(9).
但是，根据原子能机构在本次产品开发会议时的想法，OGD 已初步确定，OGD 不太可能拒绝接收根据 FD&C 法案第 505（j） 节及其实施条例提交的 ANDA，该提案基于您会议请求中的拟议配方，根据 21 CFR 314.101（d）（3） 和 21 CFR 314.94（a）（9） 中描述的与非活性成分相关的要求。

Reference is made to the definition of quantitative sameness to the RLD as stated in the guidance for industry ANDA Submissions - Refuse-to-Receive Standards Rev. 2 (December 2016).
参考了行业 ANDA 提交指南 - 拒绝接收标准 Rev. 2（2016 年 12 月）中所述的 RLD 定量相同性定义。

It should be noted that ultimately, whether OGD will receive an ANDA for substantive review will be determined during the filing review of the submitted ANDA. The approvability of your product and requests for waivers of in vivo bioequivalence studies will be determined during the scientific review of your ANDA. FDA may request additional information at the time of filing or during the scientific review to support the assessment of your proposed generic ferric oxyhydroxide formulation to the RLD. This may include, but is not limited to, the identity and associated concentration ranges of all components in the final drug product considering FDA’s response to Foley Hoag LLP submitted Citizen Petition [Docket ID: FDA- 2016-P-1163]. You may also consider including comparative characterization composition data for your proposed product and the RLD as supportive information.
需要注意的是，最终，OGD 是否会收到 ANDA 进行实质性审查，将在对提交的 ANDA 进行备案审查时确定。您的产品的可批准性和体内生物等效性研究的豁免请求将在对您的 ANDA 进行科学审查时确定。FDA 可能会在提交申请时或科学审查期间要求提供其他信息，以支持向 RLD 评估您提议的仿制药羟基氢氧化铁制剂。这可能包括但不限于，考虑到 FDA 对 Foley Hoag LLP 提交的公民请愿书 [案卷编号：FDA-2016-P-1163] 的回应，最终药品中所有成分的特性和相关浓度范围。您还可以考虑将拟议产品和 RLD 的比较表征组成数据作为支持信息。

The manufacture process will include the following process steps, i.e., compounding, sterile filtration, aseptic filling, stoppering & capping, and heat treatment ( ${100}^{\circ }\mathrm{C},35$${100}^{\circ }\mathrm{C},35$100^(@)C,35100^{\circ} \mathrm{C}, 35 minutes). Does the Agency agree that the post-aseptic processing heat treatment step ( ${100}^{\circ }\mathrm{C},35$${100}^{\circ }\mathrm{C},35$100^(@)C,35100^{\circ} \mathrm{C}, 35 minutes) can be included in the manufacture process?
制造过程将包括以下工艺步骤，即混合、无菌过滤、无菌灌装、塞和封口以及热处理（ ${100}^{\circ }\mathrm{C},35$${100}^{\circ }\mathrm{C},35$100^(@)C,35100^{\circ} \mathrm{C}, 35 分钟）。该机构是否同意无菌加工后热处理步骤（ ${100}^{\circ }\mathrm{C},35$${100}^{\circ }\mathrm{C},35$100^(@)C,35100^{\circ} \mathrm{C}, 35 分钟）可以包含在制造过程中？

Yes, we agree with your proposal of including a post-aseptic processing heat treatment step $({100}^{\circ }\mathrm{C},35$$\left({100}^{\circ }\mathrm{C},35\right.$(100^(@)C,35:}\left(100^{\circ} \mathrm{C}, 35\right. minutes) after aseptic filling, stoppering & capping in the manufacturing process. Adequacy of the drug product manufacturing process including the postaseptic processing step will be assessed during scientific assessment of your ANDA, when all data are available.
是的，我们同意您的建议，即在无菌灌装、塞子和封盖之后的制造过程中包括一个无菌处理后的热处理步骤 $({100}^{\circ }\mathrm{C},35$$\left({100}^{\circ }\mathrm{C},35\right.$(100^(@)C,35:}\left(100^{\circ} \mathrm{C}, 35\right. 分钟）。当所有数据可用时，将在对您的 ANDA 进行科学评估时评估药品制造过程（包括无菌后加工步骤）的充分性。

From the microbiology perspective, at the time of ANDA submission, it is expected that results are provided for container closure integrity test (CCIT) performed using a container closure system (CCS) that is representative to the CCS proposed for commercial batches and has been exposed to the worst-case manufacturing conditions including the heat treatment step.
从微生物学的角度来看，在提交 ANDA 时，预计会提供使用容器密封系统 （CCS） 进行的容器密封完整性测试 （CCIT） 的结果，该系统具有代表性，适用于商业批次的 CCS，并且已暴露于最坏情况下的制造条件，包括热处理步骤。

Does the agency agree that the proposed quality specification for the API as shown in Table 1 in Section 8 (page 10) is adequate?
该机构是否同意第 8 节（第 10 页）中表 1 所示的拟议 API 质量规范是足够的？

The adequacy of the drug substance specifications can only be determined in the full scientific assessment. Based on your preliminary proposal, we have the following comments regarding the drug substance specification:
原料药规格的充分性只能在全面的科学评估中确定。根据您的初步提案，我们对原料药规格有以下意见：
a) To demonstrate manufacturing consistency, add a particle size test and acceptance criteria to the drug substance specification.
a） 为了证明生产一致性，在原料药规格中增加粒度测试和验收标准。
b) Add degradation kinetics and acceptance criterion to the drug substance specification.
b） 在原料药规格中增加降解动力学和验收标准。
c) We recommend you include test for organic impurities (degradants of sucrose).
c） 我们建议您包括有机杂质（蔗糖降解物）的检测。
d) We recommend you include test for free iron or dialyzable iron with justified acceptance criteria, or clear justification for the absence of these routine tests.
d） 我们建议您包括游离铁或可透析铁的检测，并附上合理的验收标准，或明确理由证明没有这些常规检测。

Does the Agency agree that the proposed quality specification for the finished product as shown in Table 8 in Section 9 (page 41) is adequate?
原子能机构是否同意第 9 节（第 41 页）表 8 所示的成品拟议质量规格是足够的？

The adequacy of the specifications and limits for your drug product is an assessment issue and will be determined during ANDA assessment. We have the following recommendations regarding the proposed drug product specifications:
您的药品的规格和限制是否充分是一个评估问题，将在 ANDA 评估期间确定。对于拟议的药品规格，我们提出了以下建议：
a) We recommend you include “free of sediments” in the specification for appearance.
a） 我们建议您在外观规范中包括“无沉淀物”。
b) You proposed to control Iron [Fe (II)] using the United States Pharmacopeia (USP) Monograph method. We recommend you use a more sensitive method for routine control of Iron (II) in your drug product.
b） 您提议使用美国药典 （USP） 专论方法控制铁 [Fe （II）]。我们建议您使用更灵敏的方法对药品中的铁 （II） 进行常规控制。
c) In addition to the tests listed in Table 8 of your meeting package, we recommend you include tests for uniformity of dosage unit (for product packaged in single-unit container), organic impurities (degradants of sucrose), in vitro reductive iron release, test for free iron or dialyzable iron, three-tier particle size distribution with justified acceptance criteria for each test.
c） 除了会议套餐表 8 中列出的测试外，我们建议您包括剂量单位均匀性测试（对于包装在单单元容器中的产品）、有机杂质（蔗糖降解物）、体外还原铁释放、游离铁或可透析铁测试、三层粒度分布以及每项测试的合理验收标准。
d) Because the visibility of particulate matter depends on the detection method, we recommend you adopt a microscopic method for the control of visible particles. We recommend using a stereomicroscope equipped with coaxial illumination, coupled with a polarizer for the visualization.
d） 由于颗粒物的可见度取决于检测方法，因此我们建议您采用显微方法控制可见颗粒。我们建议使用配备同轴照明的立体显微镜，并结合偏光镜进行可视化。
e) Because the product is a colloid product and has very dark color, the light obscuration test (USP <788>, method 1) for particulate matter (subvisible particles) is not recommended for your product. We recommend you adopt a suitable method such as USP <788> method 2 for the analysis of particulate matter.
e） 由于商品是胶体商品，颜色非常深，因此不建议对贵商品进行颗粒物（不可见颗粒）的遮光测试（USP <788>，方法 1）。我们建议您采用合适的方法，例如 USP <788> 方法 2 来分析颗粒物。
f) Include compliance with USP Chapter <1> in your specifications.
f） 在您的规格中包括对 USP 第 <1> 章的合规性。
g) Include the Gross Content test with upper and lower limits. Please refer to FDA guidance for industry Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products (June 2015) and the accompanying MAPP 5019.1 Rev. 1 Allowable Excess Volume/Content in Injectable Drug and Biological Products (Effective Date: January28, 2022) describing its implementation.
g） 包括毛含量测试的上限和下限。请参阅 FDA 关于注射药物和生物制品中允许的超量体积和标示样品瓶填充尺寸的行业指南（2015 年 6 月）和随附的 MAPP 5019.1 Rev. 1 注射药物和生物制品中允许的超量体积/含量指南（生效日期：2022 年 1 月 28 日），了解其实施情况。
h) The bacterial endotoxins and sterility specifications appear to be reasonable for the proposed finished drug product.
h） 细菌内毒素和无菌规格对于拟议的成品药来说似乎是合理的。