In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs Guidance for Industry
工业指南中ANDAs申请递交的外用提交的外用制剂的体外释放试验研究

INTRODUCTION 绪论

This guidance is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called topical products. Because of the complex route of delivery associated with these products, which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products. This guidance provides recommendations for in vitro release test (IVRT) studies that can be used to compare a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD). The reference standard ordinarily is the RLD.4

本指南旨在帮助申请人提交适用于皮肤的液体和/或其他半固体产品的仿制药申请（ANDA），包括皮肤和粘膜（如阴道），以下称为局部产品。由于与这些产品相关的复杂递送途径（通常是局部作用的）以及某些制剂的潜在复杂性，局部产品（非局部溶液）被归类为复杂产品。本指南为体外释放试验（IVRT）研究提供了建议，该研究可用于比较拟用非**（试验）局部产品及其参考标准品（RS），以支持证明与参考上市药物（RLD）的生物等效性（BE）。参考标准通常为RLD。

This guidance does not address drug products that are administered via ophthalmic, otic, nasal, inhalation, oral, or injection-based routes, or that are transdermal or topical delivery systems (including products known as patches, topical patches, or extended-release films).

本指南不适用于通过眼、耳、鼻、吸入、口服或注射途径给药的药物产品，也不适用于经皮或局部给药系统（包括贴片、局部贴片或缓释膜产品）。

It is beyond the scope of this guidance to discuss specific topical products to which this guidance applies. FDA recommends that applicants consult this guidance and any relevant productspecific guidances (PSGs) and any other relevant guidances for industry, when considering the design and conduct of IVRT studies that, in conjunction with other studies, as deemed necessary, may be appropriate to support a demonstration that a proposed generic topical product and its RLD are bioequivalent. FDA also recommends that applicants routinely refer to FDA’s guidance web pages, because additional guidances may become available that could assist in the development of a generic topical product.

讨论本指南适用的特定主题产品超出了本指南的范围。FDA建议申请人在考虑IVRT研究的设计和实施时，参考本指南和任何相关的产品特定指南（PSG）以及任何其他相关的行业指南，这些研究与其他研究（如有必要）可能适用于证明拟用仿制药及其RLD具有生物等效性。FDA还建议申请人定期参考FDA的指导网页，因为可能会有其他指导信息，有助于开发通用的外用产品。

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s 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 guidance means that something is suggested or recommended, but not required.

一般而言，FDA指南性文件并非具有强制执行的法律职能。实际上，指南描述了管里部门对某一问题当前的思考，并且仅作为建议，除非引用了具体的法规或法定要求，。在指南中使用“应该”一词，意味着建议或推荐，并非要求的意思。

BACKGROUND 背景

This guidance has been developed as part of FDA’s “Drug Competition Action Plan,” which, in coordination with the Generic Drug User Fee Amendments (GDUFA) program and other FDA activities, is intended to increase competition in the marketplace for prescription drugs, facilitate the entry of high-quality and affordable generic drugs, and improve public health.

本指南是作为FDA“药品竞争行动计划”的一部分，该计划配合通用药品用户费用修正案（GDUFA）计划和其他FDA举措，旨在促进处方药市场的竞争，促进高质量和实惠的药品的进入市场，并改善公众医疗。

The Federal Food, Drug, and Cosmetic Act (FD&C Act) generally requires an ANDA to contain, among other things, information to show that the proposed generic drug product (1) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences); and (2) is bioequivalent to the RLD. Thus, an ANDA will not be approved if the information submitted in the ANDA is insufficient to show that the test product is bioequivalent to the RLD.

《联邦食品、药品和化妆品法案》（FD&C法案）通常要求ANDA包含合适的信息，说明：仿制药与RLD相比（1）具有相同的活性成分、使用条件、给药途径、剂型、规格和标签方面（允许存在某些的差异）；和（2）与RLD生物等效。因此，如果ANDA中提交的信息不足以证明自制制剂与RLD具有生物等效性，ANDA将不予批准。

An IVRT study may be used to assess the rate of drug release (i.e., release of an active ingredient) from a topical product. Once validated, an IVRT study may also be useful in controlling product quality and/or establishing the acceptability of post-approval manufacturing changes. This guidance focuses on general considerations and recommendations for the method 66 development, method validation, and conduct of IVRT studies that are submitted in ANDAs and intended to support a demonstration of BE.

IVRT研究可用于评估局部产品的药物释放速率（即活性成分的释放）。一旦验证，IVRT研究也可用于控制产品质量和/或确定批准后制造变更的可接受性。本指南侧重于方法开发、方法验证和IVRT研究的一般考虑和建议，这些研究在ANDA申请中提交，旨在支持BE的论证。

IVRT METHOD DEVELOPMENT IVRT 方法开发

If an IVRT study is intended to support a demonstration of BE, the IVRT method development report should be submitted in the ANDA to show how the IVRT method was optimized, and to support a demonstration that the method parameters selected for the IVRT are appropriate or necessary, particularly in situations where the method parameters are different from the methods recommended in this guidance and described in the United States Pharmacopeia (USP) General Chapter . The Agency’s interest in reviewing the method development report is to understand why specific IVRT method parameters were selected and whether they are suitably sensitive and reproducible. This method development report should clearly indicate/distinguish the method parameters used for each set of data, illustrate the efforts made to optimize the IVRT method, and demonstrate that the method parameters selected for the IVRT are appropriate.

如果IVRT研究旨在支持BE的论证，则应在ANDA中提交IVRT方法开发报告，以显示IVRT方法是如何优化的，并支持为IVRT选择的方法参数是合适或必要的演示，特别是在方法参数不同于本指南中推荐的方法和美国药典（USP）一般章节中描述的方法的情况下。监管机构在审查方法开发报告时，比较关注IVRT方法参数选择的合理性，以及这些参数是否具有合适的敏感度和重现性。该方法开发报告应明确指出/区分每组数据所用的方法参数，说明为优化IVRT方法所做的努力，并证明为IVRT选择的方法参数是合适的。

Applicants are encouraged to use the recommendations in this guidance, and if an applicant elects to use methods that are different from those recommended in this guidance, the IVRT method development report should demonstrate why it is scientifically justified to use an alternative approach than what is recommended in this guidance or USP to optimize the IVRT method. Specific examples of procedures are described in subsequent sections, to help applicants identify circumstances when information should be submitted in the ANDA to explain why an alternative procedure was utilized.

鼓励申请人使用本指南中的建议，如果申请人选择使用与本指南中建议的方法不同的方法，IVRT方法开发报告应说明选择替代方法，进行IVRT方法优化的科学合理性。后续章节中描述了具体示例，以帮助申请人确定应在ANDA中提交信息的情况，以解释为什么使用替代的方法。

The IVRT method development studies, being exploratory in nature, are often performed using a sample analytical method that is not validated (e.g., a high-performance liquid chromatography (HPLC) or ultrahigh performance liquid chromatography (UPLC) method); also, IVRT method development studies are often conducted in a manner that is not compatible with a quality management system which would otherwise make the evidence generated suitable to support valid conclusions. Such method development studies would not be suitable to demonstrate the validity of an IVRT method, or the associated results. Therefore, although it may appear to be redundant, certain experiments performed during IVRT method development may need to be repeated during IVRT method validation, using appropriate controls, like a validated analytical method and procedures that are compatible with a suitable quality management system.

IVRT方法开发研究本质上是探索性的，通常使用未经验证的样品分析方法（例如，高效液相色谱（HPLC）或超高效液相色谱仪（UPLC）方法）进行；此外，IVRT方法开发研究通常以与质量管理体系不兼容的方式进行，所生成的证据不足以支持结论的可靠性。此类方法开发研究不适于证明IVRT方法或相关结果的有效性。因此，尽管这可能显得多余，但在IVRT方法验证期间，可能需要使用适当的控制措施（如与适当的质量管理体系兼容的经验证的分析方法和程序）重复IVRT方法开发期间进行的某些实验。

It is important to clearly segregate and consistently identify those experiments and results that were part of IVRT method development separately from those that were part of IVRT method validation. It is also important to consistently identify all relevant method parameters and experimental conditions/controls for each set of IVRT results. Information in the method development report should clearly identify/distinguish when the results for apparently similar sets of experiments may have been obtained using different method parameters. Method development reports should clarify which sets of diffusion cells were run in parallel or separately (e.g., on separate days). In addition, the sample analytical method (e.g., a HPLC or UPLC method) used to analyze the samples from each set of IVRT experiments should be specified, and the reports should indicate whether or not the sample analytical method was validated (either at the time of sample analysis or subsequently).

将IVRT方法开发过程中的实验和结果与IVRT方法验证过程中的试验和结果分开进行明确区分和一致识别是非常重要的。对于每组IVRT结果，一致地确定所有相关的方法参数和实验条件/对照也很重要。方法开发报告中的信息应明确识别/区分使用不同方法参数可能获得的明显相似实验组的结果。方法的开发报告应澄清平行或单独运行的扩散池组（例如，在不同的日期）。此外，应确定用于分析每组IVRT实验样本的样品分析方法（例如HPLC或UPLC方法），报告应说明样品分析方法是否有经过验证（在样品分析时或随后）。

A. IVRT Method Parameters IVRT 方法参数

Theoretical or empirical information should be provided to explain the selection of IVRT method parameters such as the equipment, product dose amount, sampling times, stirring/agitation rate, etc. When the equipment selected is among the models of equipment in the USP<1724>, Semisolid Drug Products – Performance Tests, and when the product dose amount or stirring rate is a parameter that is fixed (not adjustable) with the selected equipment, it may be sufficient to explain these facts.

应提供理论或经验信息，以解释IVRT方法参数的选择，如设备、上样量、取样时间、搅拌/搅拌速率等。当选择的设备是USP<1724>半固体药物制剂—性能测试中所述设备时，且上样量或搅拌速率与所选的设备匹配（未调节），可充分解释选择的合理性。

It is unconventional for IVRT sampling times to be selected within a study duration of less than 4 hours. This may occur in situations where the fixed product dose was depleted to such a great extent by 4 hours that the release kinetics were no longer linear thereafter (when plotted vs. the square root of time). In such instances, it would be appropriate to explain the efforts that were made to optimize the IVRT method (e.g., using a different diffusion cell equipment that allowed for a larger product dose to be used) so that the sustained steady state release kinetics could potentially be characterized over a conventional IVRT duration of 4 to 6 hours.

通常情况下，IVRT取样时长不应少于4小时。但是，对于某些特定类型的制剂，这可能发生在固定产品剂量在4小时内耗尽到如此大的程度，以至于释放动力学此后不再是线性的情况下（当以释放量对时间的平方根作图）。在这种情况下，应解释为优化IVRT方法所做的努力（例如，使用允许使用更大产品上样量的不同扩散池设备），以便在4至6小时的常规IVRT持续时间内可能表征持续的稳态释放动力学。

B. IVRT Receptor Solution  IVRT接收介质

It is conventional to evaluate different receptor solutions during IVRT method development (all using the same membrane that has broad chemical compatibility with the receptor solutions evaluated); these receptor solutions are frequently binary hydro-alcoholic mixtures selected based upon the solubility and stability of the (frequently hydrophobic) drug in the receptor solution. The receptor solutions are conventionally sampled at least hourly across a 6-hour duration.

通常，需要在IVRT方法开发过程中对不同接受介质进行评估都使用与待评估的接受介质具有广泛化学相容性的同一类型膜）；这些接受液通常是基于受体溶液中（通常是疏水性的）药物的溶解度和稳定性而选择的二元水醇混合物。接受液通常在6小时持续时间内至少每小时取样一次。

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Information on the empirical solubility and stability of the drug in the receptor solution, as well as information on the linearity and precision of the resulting drug release rate in an IVRT should be provided to help explain the selection of a receptor solution for the test method. The linearity of the drug release rate (slope) across all time points should ideally have an r2 value of ≥ 0.97. In situations where the solubility of the drug in the receptor solution limits the release kinetics, causing a reduction in the release rate at the last time point(s), it may be appropriate to evaluate different receptor solutions. It may be appropriate to truncate the IVRT method to a 4- or 5-hour sampling duration if the linearity of the release rate in that truncated duration is improved (exhibiting a higher r2 value), and if other aspects of the release kinetics (e.g., precision) in that receptor solution are optimized compared to other receptor solutions evaluated.

应提供药物在接受液中的经验溶解度和稳定性的信息，以及IVRT中产生的药物释放率的线性和精密度的信息，用于解释试验方法中接受液选择的合理性。理想情况下，所有时间点的药物释放速率（斜率）应成线性关系（r2值≥ 0.97）.如何在药物在接受液中的溶解度限制释放动力学，导致最后一个时间点释放速率降低的情况下，评估不同的接受液可能是更有必要的。如果缩短的时间段内释放速率的线性得到改善（表现出较高的r2值），并且与评估的其他受体溶液相比，该受体溶液中释放动力学的其他方面（例如，精度）得到优化，则将IVRT方法缩短为4小时或5小时的采样时间段可能是合适的。

One advantage of selecting an optimal receptor solution as an initial step in IVRT method development is that it allows for the sample analysis method to be optimized for the selected receptor solution sample matrix before proceeding to an evaluation of different membranes using that receptor solution.

选择最佳受体溶液作为IVRT方法开发的初始步骤的一个优点是，在使用接受液对不同膜进行评估之前，可先选定的接受液对样品分析方法进行优化。

C. IVRT Membrane IVRT膜

It is conventional to evaluate different membranes during IVRT method development (all using the same receptor solution); these membranes are frequently synthetic membranes used for the filtration of particulate matter in solutions. IVRT membranes are selected based upon their effective pore size (e.g., 0.45 micrometers (µm)), as well as their expected inertness to binding the drug. Information should be provided in the IVRT method development report on each membrane’s binding to the drug and its chemical compatibility with relevant receptor solution(s) selected for the IVRT method (based on the preceding phase of IVRT method development), as well as information on the linearity and precision of the resulting release rate when each membrane is used in an IVRT, as this information can help to explain why a specific membrane is optimal for the IVRT method.

在IVRT方法开发过程中，通常评估不同的膜（均使用相同的接受液）；这些膜通常是用于过滤溶液中的颗粒物质的合成膜。IVRT膜的选择基于其有效孔径（例如0.45微米（µm））以及其与药物结合的预期惰性。IVRT方法开发报告中应提供每种膜与药物的结合及其与为IVRT方法选择的相关受体溶液的化学相容性的信息（基于IVRT方法发展的前一阶段），以及在IVRT中使用每种膜时所产生的释放速率的线性和精度的信息，因为该信息可以帮助解释为什么特定膜对于IVRT方法是最佳的。

IV. IVRT METHOD VALIDATION IVRT  方法验证

The equipment, methodologies, and study conditions used in the IVRT pivotal study should be appropriately validated or qualified. It is conventional to initiate the validation of the sample analytical method (e.g., a HPLC or UPLC method) for the IVRT before initiating the IVRT method validation itself, although certain components of the sample analysis method validation (e.g., stability) often proceed in parallel with the IVRT method validation. If an applicant elects to use equipment, methodologies, or study conditions that are different from those recommended in this guidance or in USP , the applicant should demonstrate why the differences are scientifically justified. It is important to consistently identify all relevant method parameters for each set of IVRT results, making it clear that the results were obtained using the same IVRT method parameters, and clarifying which sets of diffusion cells were run in parallel or separately. Detailed protocols and well-controlled test procedures are recommended to ensure the precise control of dosing, sampling, and other IVRT study parameters, and of potential sources of experimental bias.

IVRT关键研究中使用的设备、方法和研究条件应经过合理的验证或确认。在启动IVRT方法验证之前，启动IVRT的样品分析方法（例如，HPLC或UPLC方法）的验证是常规的，尽管样品分析方法验证的某些试验（例如，稳定性）通常与IVRT方法的验证平行进行。如果申请人选择使用的设备、方法或研究条件与本指南或USP中推荐的不同，申请人应证明这些差异在科学上是合理的。重要的是要一致地确定每组IVRT结果的所有相关方法参数，明确结果是使用相同的IVRT方法参数获得的，并阐明哪些组扩散池是平行或单独运行的。建议建立详细的方案和严格控制的测试程序，以确保精确控制上样、取样和其他IVRT研究参数，以及实验偏差的潜在来源。

The qualification of an IVRT method parameter refers to the process of defining what attributes make it suitable to perform its function in the IVRT method. For example, when hourly measurements of the temperature at the membrane surface (when mounted in a diffusion cell) demonstrate that an IVRT equipment can maintain a membrane surface temperature in the range of 32°C ± 1°C across 6 hours, the results can support a demonstration that the equipment is qualified to perform its function in an IVRT method for which a method parameter is the control of membrane surface temperature in the range of 32°C ± 1°C across 6 hours. While an IVRT membrane surface temperature in the range of range of 32°C ± 1°C is appropriate for topical products applied on the skin, for topical products applied on mucosal membranes (e.g., a vaginal gel) the relevant IVRT membrane surface temperature would be 37°C ± 1°C. The validation of the IVRT method should incorporate the following qualifications and controls, performed using validated sample analytical procedures, as applicable.

IVRT方法参数的限定指的是定义哪些属性适合在IVRT方法中执行其功能的过程。例如，当每小时测量膜表面温度（当安装在扩散池中时）表明IVRT设备可以在6小时内将膜表面温度保持在32°C±1°C的范围内时，结果可以证明该设备在IVRT方法中执行其功能，其中方法参数是在6小时内将膜表面温度控制在32°C±1°C的范围内。尽管IVRT膜表面温度在32°C±1°C范围内适用于涂抹在皮肤上的局部产品，但对于粘膜外用制剂（如阴道凝胶），相关IVRT膜的表面温度应为37°C±1°C。如适用，使用经验证的样品分析方法，在IVRT方法的验证进行以下确认和控制。

A. Equipment Qualification设备确认

Suitable equipment for the IVRT method are described in USP General Chapter . These include different models of a vertical diffusion cell and an immersion cell. Other models of vertical diffusion cells and immersion cells that are essentially the same in design and/or operational principles as those described in USP General Chapter may also be suitable.

在USP<1724>通用章节中有适用于IVRT方法的设备描述。（浅析FDA指导原则中对申报用Franz测试装置的要求）这些包括不同模型的垂直扩散池和浸没池的。在设计和/或操作原理上与USP<1724>通用章节中描述的那些基本相同的垂直扩散池和浸没池的其他模型也可能使用。

The operating principles and specific test procedures differ among the various equipment; relevant procedures from the manufacturer may be used for installation, operation, and performance qualifications. The laboratory qualification of each diffusion cell should, at minimum, include: (1) measurements of the diffusional area of the orifices of the donor and receptor compartments between which the membrane is mounte; (2) the empirically measured volume of the receptor solution compartment/vessel for each diffusion cell; (3) the stability of the temperature measured at the membrane surface (e.g., at 32°C ± 1°C), or just below the membrane, across a relevant duration (e.g., 6 hours); and (4) the rate of stirring or agitation, as applicable.

每种设备的工作原理和特定测试方法不同；制造商的相关程序可用于安装、操作和性能鉴定。每个扩散池的实验室确定，至少应包括：（1）测量供给室和接受室之间膜安装位置的孔口的扩散面积，；（2） 每个扩散池的接受室的容积；（3）在相关研究持续时间（例如，6小时）内测量膜表面（例如，32°C±1°C）或膜正下方的温度，的稳定性；以及（4）如适用，测定搅拌或搅拌的速率。

If information related to the diffusional area of the orifice and the volume of the receptor solution compartment for each diffusion cell is available from the manufacturer, that information should be provided for each relevant diffusion cell, in addition to the empirical measurements made by the laboratory. The equipment should control the diffusion cell thermoregulation so that the membrane surface temperature is verified to be stable (e.g., at 32°C ± 1°C) for each diffusion cell (e.g., measured by a calibrated infrared thermometer) before dosing. If it is not feasible to verify that the membrane surface temperature of a diffusion cell has equilibrated and stabilized (e.g., at 32°C ± 1°C) before dosing because of design and operating principles of a specific equipment, the qualification of that equipment should demonstrate that, under the specific conditions used for the IVRT method, the membrane surface temperature can be expected to be stable (e.g., at 32°C ± 1°C) for each diffusion cell throughout the test.

如果制造商提供了与每个扩散池的孔扩散面积和接受室容积相关的信息，则除了实验室进行的经验测量外，还应提供每个相关扩散池的信息。设备应控制扩散池温度调节，以便在给药前验证每个扩散池的膜表面温度是否稳定（例如，32°C±1°C）（例如，通过校准的红外温度计测量）。如果由于特定设备的设计和操作原理，在给药前无法验证扩散池的膜表面温度是否已达到平衡和稳定（例如，在32°C±1°C），对于该类型的设备确认应证明，在IVRT方法使用的特定条件下，在整个测试过程中，每个扩散池的膜表面温度可以预期保持稳定的（例如，在32°C±1°C）。（如下图，膜温度平衡预实验）

B. Membrane Qualification  膜确认

Membrane inertness should be evaluated in relation to membrane binding of the drug in the receptor solution at a concentration relevant to the range of drug concentrations in the receptor solution during the test. Determinations should be based upon a minimum of three replicate membrane incubations for the IVRT duration at the relevant temperature (e.g., 6 hours at 32°C ± 1°C). Three replicate control incubations should be performed in parallel, without membranes, to monitor for drug loss that is not associated with membrane binding. Aliquots of these solutions should be collected before and after the duration of incubation, to assess any decrease in the amount of drug in solution. The recovery of drug in solution is recommended to be within the range of 100% ± 5% at the end of the test duration to qualify the inertness of the membrane.

在试验期间，应在与接受液中药物浓度范围下，根据药物在接受液中与膜吸附来评估膜惰性。测定应基于在相关温度下（例如，32°C±1°C下6小时）IVRT持续时间内至少重复三次膜孵育。应在没有膜的情况下平行进行三次重复对照孵育，以监测与膜结合无关的药物损失。应在孵育前后收集这些溶液的等分试样，以评估溶液中药物量的减少。建议在试验结束时，溶液中药物的回收率在100%±5%的范围内，可以确认膜的惰性。

C. Receptor Solution Qualification  接收介质确认

The reason for selecting the composition of the receptor solution used for the IVRT study should be explained. The solubility of the drug in the IVRT receptor solution should be empirically determined in triplicate, to illustrate that the solubility of the drug in the receptor solution exceeds the highest sample concentration in the IVRT pivotal study, ideally by an order of magnitude, but demonstrably sufficient to facilitate a linear (steady state) release rate for the duration of the study (even when evaluating the relatively higher release rate of a formulation that is 150% of the nominal strength of the RS during the IVRT method validation)

应解释选择IVRT研究所用接受液成分的原因。药物在IVRT接受液中的溶解度，应根据经验测定一式三份，以说明药物在接受液中溶解度超过IVRT正式研究中的最大药物浓度，理想情况下是一个数量级或者是足以促成研究期间释放速率的线性关系（稳态）（即使在IVRT方法验证期间评估配方的相对较高释放率时，即RS标称规格的150%）

D. Receptor Solution Sampling Qualification  接收液取样确认

The accuracy and precision of receptor solution sample collection at each time point should be appropriately qualified. Evidence to qualify a sampling procedure should illustrate that the sampling technique can reliably collect a consistent volume of the sample from the well-mixed volume of the receptor compartment at each sampling event, and that no artifacts are likely to be created by the sampling technique (e.g., because of carryover between samples in automated sampling systems or because of sampling from an unmixed volume in the sampling arm of a vertical diffusion cell). Information should be included describing the equipment manufacturer’s specification for the accuracy and precision of receptor solution sampling, when available.

每个时间点的接受液取样的准确度和精密度应进行确认。确认取样程序的过程应証明，取样技术可在每次取样时从的混合良好的接受室中可靠地收集相同体积的样品，并且不会因取样技术的原因引起误差（例如，由于自动取样系统中的样本之间的干扰或残留，或由于从垂直扩散池的未混合均一取样臂中取样）。应描述设备制造商关于接受液取样准确度和精密度的规范信息（如有）。

E. Environmental Control  环境控制

Ambient laboratory temperature and humidity during the study should be monitored and reported. An environmentally controlled temperature range of 21°C ± 2°C is recommended, and, if feasible, a humidity range of 50% ± 20% relative humidity is recommended.

应监测和报告研究期间的实验室环境温度和湿度。建议环境控制温度范围为21°C±2°C，如果可行，建议湿度范围为50%±20%相对湿度。

F. Linearity and Range  线性和范围

The linearity (r2 value) of the release rate (slope) should be plotted across the range of the sampling times, which corresponds to the IVRT study duration. The linearity of drug release should be calculated and reported for each diffusion cell and compared within and across all IVRT runs. For the release rate to be considered suitably linear, it should have an r2 value ≥ 0.97 across the recommended IVRT study duration of 4–6 hours. An IVRT study duration of less than 4 hours may be insufficient to assess whether the release rates being compared for the test topical product and RS represent their steady state drug release kinetics, but an IVRT study duration of less than 4 hours (which is not recommended) may be justified if supported by compelling experimental data within the method development report to illustrate that reasonable and scientifically appropriate efforts were made to optimize the IVRT method. The IVRT method linearity and range should be established based upon the results of the precision and reproducibility runs, described further below.

在IVRT的整个研究期间，根据所有采样时间点的释放速率绘制标准曲线，应呈线性关系（r2值）。应计算并报告每个扩散池的药物释放线性方程，并与所有IVRT研究结果进行比较。为了使释放速率为线性的前提是，建议IVRT研究持续时间为4–6小时，其应具有r2值≥0.97。通常小于4小时的IVRT研究持续时间可能不足以评估自制制剂和RS的释放速率是否代表其稳态药物释放动力学，但是，如果方法开发报告中有令人信服的实验数据支持，说明已做出合理和科学上的努力来优化IVRT方法，则IVRT研究持续时间小于4小时（不推荐）也是可以接受的。IVRT方法的线性和范围应根据精密度和重复性试验的结果确定，详见如下所述。

G. Precision and Reproducibility   精密度和重现性

The intra-run and inter-run precision and reproducibility may be compared for the release rate (slopes) calculated for each diffusion cell. The mean, standard deviation, and percent coefficient of variation (%CV) among slopes may be calculated within and across all runs, and a minimum intra-run and inter-run %CV ≤ 15% is recommended. Runs may be organized to facilitate a simultaneousevaluation of intra/inter-instrumentation and/or intra/inter-operator precision and reproducibility. A minimum of three independent precision and reproducibility runs is recommended.

可以针对每个扩散池的释放速率（斜率）计算批内和批间精密度和重现性。应计算批内和批间斜率的平均值、标准偏差和变异系数百分比（%CV），批内和批间%CV，均应≤ 15%。可以组织运行响应面实验，以便于同时评估仪器内部/内部和/或操作员内部/内部的精密度和重复性。建议至少进行三次独立的精密度和重现性试验。

H. Dose Depletion   剂量消耗

The recovery of released drug in the receptor solution should be characterized in each diffusion cell as the cumulative amount of drug released into the receptor solution over the IVRT study duration. This may be expressed as a percentage of the amount of drug in the applied dose (which may be estimated based upon the nominal strength of the drug in the topical product and the approximate mass of topical product dosed on the membrane). For example, if 1 gram (g) of a topical product containing 5% drug was dosed on the membrane of each diffusion cell, the amount of drug in the applied dose may be estimated to be 50 mg. If a total of 10 mg of drug diffused into the receptor solution of each diffusion cell across the 6-hour duration of the IVRT, it would be possible to estimate that the 50 mg dose would have been depleted by 10 mg, amounting to a 20% dose depletion. The average percentage dose depletion may thereby be estimated and should be reported. While steady state release kinetics can typically be assumed under conditions when the dose depletion is less than 30%, for some topical products, steady state release kinetics may continue to be observed at higher percentage dose depletions. The IVRT method may be considered adequate despite a dose depletion of greater than 30% when experimental evidence illustrates that the release rate (slope) remains suitably linear for each diffusion cell when plotted versus the square root of time

应计算接受液中释放药物的回收率，用以表征IVRT研究期间，释放到接受液中的累积药物量。这可以表示为上样剂量中药物量的百分比（其可以根据外用制剂中药物的标示规格和膜上大致上样量来评估）。例如，如果在每个扩散池的膜上的上样量为1克（g），制剂标示规格含有5%药物，则上样剂量中的药物量可估计为50mg。如果在IVRT的6小时持续时间内，共有10mg的药物扩散到每个扩散测试池的接受液中，则可以估计50mg剂量已经消耗10mg，相当于20%的剂量消耗。因此，可以估计并报告平均剂量消耗百分比。虽然在剂量消耗小于30%的条件下通常可以假设稳态释放动力学，但对于一些外用制剂，在较高百分比的剂量消耗下可以继续观察到稳态释放动力学。当实验证据表明每个扩散池的释放速率（斜率）与时间的平方根作图时，每个扩散池的释放速率也能保持线性关系，尽管剂量消耗大于30%，IVRT方法也被认为是考虑充分的

I.Discrimination Sensitivity, Specificity, and Selectivity   区分力—灵敏度、专属性和选择性

The IVRT method should be able to discriminate drug release rates from similar formulations. This should be evaluated by comparing the release rate from the test formulation with that from two comparable formulations in which the concentration of drug has been altered – one with a higher strength (150% of the nominal concentration of the RS) and one with a lower strength (50% of the nominal concentration of the RS). If precipitation of the active ingredient is observed when formulating a topical product at 150% compared to the nominal strength, it may be necessary to use different strategies, which may be discussed with the Agency before the submission of an ANDA during a pre-ANDA product development meeting or via a controlled correspondence. The composition and procedures for preparation of these higher and lower strength formulations should be reported, although these formulations need not be prepared in a manner compatible with current Good Manufacturing Practices. The discrimination ability of the IVRT method should be described using three concepts of discrimination ability: sensitivity, specificity, and selectivity.

IVRT方法应能够区分相似制剂的药物释放率。应通过将试验制剂的释放速率与药物浓度发生变化的两种改变规格的制剂的释放率进行比较来评估这一点——一个较高规格（RS标称浓度的150%），另一个较低规格（RS额定浓度的50%）。如果在配制与标示规格相比为150%的局部产品时观察到活性成分析出，则可能需要使用不同的策略，这可以在ANDA前产品开发会议期间或通过受控通信在提交ANDA之前与机构讨论。应报告较高和较低规格配方的组成和制备程序，尽管这些配方制剂不是在符合GMP条件下制备。IVRT方法的区分力应从以下三个概念来描述：灵敏度、特异性和选择性。

IVRT Sensitivity IVRT   灵敏度

IVRT sensitivity is the ability to detect changes in the release rate, as a function of drug concentration in the formulation. If the IVRT method consistently identifies higher or lower rates of release for test formulations with increased or decreased drug concentrations, respectively, relative to the formulation at the nominal strength of the RS run in parallel on the same day, the IVRT method would generally be considered sensitive.

IVRT灵敏度是检测释放速率变化的能力，释放速率作为制剂中药物浓度的函数。如果同一天，对RS、较高规格和较低规格平行实验，IVRT方法一致地识别制剂的释放速率更高或更低，则通常认为IVRT方法是灵敏的。

IVRT Specificity IVRT  特异性

IVRT specificity is the ability to accurately monitor the proportionality of changes in the release rate as a function of drug concentration in the formulation. This proportionality may be illustrated in a plot of the relationship between the formulation concentration and the average IVRT release rate (slope). The specificity of the IVRT method should be calculated, plotted with a linear trendline, and the linearity quantified and reported as an r2 value. To be considered suitably specific, an IVRT method should be proportionally linear in its response to differences in release rates, with a minimum r2 value ≥ 0.95 for the correlation of the formulation concentration to the average IVRT release rate (slope).

IVRT特异性是准确监测释放速率随制剂中药物浓度变化的比例的能力。该比例可以用制剂浓度和平均IVRT释放速率（斜率）之间的关系图来说明。应通过绘制线性趋势线，将线性量化并报告为r2值，评估IVRT方法的特异性，。IVRT方法在其对释放速率差异的响应中应该是成比例的线性的，制剂浓度与平均IVRT释放速率（斜率）最小的r2值≥ 0.95，表示改方法具有合适的特异性。

IVRT specificity is a function of the proportionality of release rates across different strengths of the product, some, or all of which may be formulated as small-scale laboratory batches, with each strength having a slightly different formulation composition to accommodate for the different amount of the active ingredient in that strength of the product. These slight formulation differences across the different strengths of the product may impact the ideal proportionality of release rates across the different strengths of the product.

IVRT特异性是产品不同规格的释放速率比例的函数，其中一些或全部可作为小规模实验室批次配制，每个规格的制剂组成略有不同，以适应该产品规格中活性成分的不同量。产品不同规格的这些轻微配方差异可能会影响产品不同规格释放速率的理想比例。

Thus, the proportional linearity of release rates across different strengths of the product may be impacted by formulation differences across the strengths that are independent of the proportional responsiveness of the IVRT method. The minimum r2 value ≥ 0.95 for the correlation of the formulation concentration to the average IVRT release rate (slope) takes into account that the IVRT method’s response to differences in release rates may not appear to be perfectly proportional because of formulation differences that are independent of the IVRT method.

因此，产品不同规格的释放速率的比例线性可能受到不同规格的配方差异的影响，这些差异与IVRT方法的比例响应性无关。由于制剂差异与IVRT方法无关，考虑到IVRT方法对释放速率差异的响应可能不全部成比例，因此，制剂浓度与平均IVRT释放速率（斜率）的相关性最小r2值≥ 0.95的。

Note that the linearity of release rates across different strengths of the product (which assesses the specificity of the IVRT method, with a minimum r2 value ≥ 0.95) is fundamentally different and has different scientific considerations than the linearity of the release rate for a single strength of the product across the range of the sampling times (which assesses the IVRT method’s ability to monitor the steady state release kinetics of the active ingredient, with a minimum r2 value ≥ 0.97). Despite the potential for different scientific considerations to impact the linearity of the IVRT results in each context, for well-developed and suitably controlled IVRT methods, the r2 value ≥ 0.99 is routinely observed in both contexts.

注意，产品不同规格的释放速率的线性（评估IVRT方法的特异性，最小r2值≥ 0.95）与在取样时间范围内的产品单一浓度的释放速率的线性（这评估了IVRT方法监测活性成分稳态释放动力学的能力，具有最小r2值≥0.97）。尽管在每种情况下，不同的科学考虑因素可能会影响IVRT结果的线性，但对于良好开发和适当控制的IVRT方法，在两种情况下，r2值≥ 0.99通常都是满足的。（如下图r2=0.9915）

IVRT Selectivity IVRT   选择性

IVRT selectivity is the ability of the IVRT method to discriminate the drug release rates between the reference topical product and the altered (50% and 150% nominal strength) concentration test formulations such that their release rates are determined to be statistically inequivalent compared to that from the nominal reference strength formulation. Determination of inequivalence between release rates should be evaluated using the statistical approach described in USP General Chapter<1724>.

IVRT选择性是IVRT方法区分参考外用制剂和改变的（50%和150%标示规格）浓度测试制剂之间的药物释放速率的能力，从而确定它们的释放速率与标示参考规格制剂的释放速率在统计上不相等。应使用USP通用章节<1724>中描述的统计方法评估释放速率之间的不等效性。

Specifically, the release rates from six cells dosed with the nominal reference strength formulation should be compared with the release rates from 6 cells dosed with the formulation at 150% the nominal reference strength, using the statistical approach described in USP General Chapter<1724>. All 12 cells being compared should have been run in parallel on the same day, and the release rate from the formulation at 150% the nominal reference strength should fail to show equivalence to the release rate from the nominal reference strength formulation.

具体而言，应使用USP通用<1724>章节中所述的统计方法，将六杯标示规格制剂的测试池的释放率与六杯150%标示制剂的测试池释放率进行比较，根据<1724>章节要求，这12杯应在同一天平行实验，在标示规格的150%时，制剂的释放速率不能显示出与标示规格制剂的释放率相等。

The release rates from 6 cells dosed with the nominal reference strength formulation should also be compared with the release rates from 6 cells dosed with the formulation at 50% the nominal reference strength, using the statistical approach described in USP General Chapter<1724>. All 12 cells being compared should have been run in parallel on the same day, and the release rate from the formulation at 50% the nominal reference strength should fail to show equivalence to the release rate from the nominal reference strength formulation.

还应使用USP通用章节<1724>中描述的统计方法，将6个测试池的标示规格浓度制剂（即100%规格）的释放率与6个测试池50%规格时的释放率进行比较，这12杯应在同一天平行实验，50%规格制剂配方的释放速率应与对照制剂的释放率不等效。

IVRT Supplemental Selectivity IVRT  补充选择性

IVRT supplemental selectivity is the ability of the IVRT method to discriminate the drug release rates between the reference topical product and an altered formulation with the same nominal reference strength, such that their release rates are determined to be statistically inequivalent.

IVRT补充选择性是IVRT方法区分参考外用制剂和具有相同标示规格的改变制剂之间的药物释放速率的能力，从而确定它们的释放速率在统计上不等效。

The demonstration of IVRT selectivity (distinct from supplemental selectivity) validates the ability of the IVRT method to discriminate differences in release rates under conditions when the release rate is expected to differ in a predictable manner (i.e., when there are different concentrations of drug in the formulation).

IVRT选择性的证明（不同于补充选择性）验证了IVRT方法在预计释放速率可以预测的方式不同的条件下（即，当制剂中存在不同浓度的药物时）区分释放速率差异的能力。

A separate and supplemental demonstration of the selectivity of an IVRT method, when feasible, independently validates the ability of the IVRT method to discriminate differences in release rates under the conditions of the pivotal IVRT study, in which the test and reference topical products are compared at the same strength. Thus, the supplemental demonstration of the selectivity of the IVRT method validates that it can detect differences in the release rate that are associated with aspects of the formulation other than the strength, and this is ideal, when feasible.

在可行的情况下，IVRT方法选择性的单独和补充证明独立验证了IVRT方法在关键IVRT研究条件下区分释放率差异的能力，其中自制和对照外用制剂以相同的规格进行比较。因此，在可行情况下，理想情况下的IVRT方法选择性的补充论证证明了它可以检测与制剂的规格以外的方面相关的释放速率的差异。

Determination of inequivalence between release rates should be evaluated using the statistical approach described in USP General Chapter<1724>. Specifically, the release rates from 6 cells dosed with the nominal reference strength formulation should be compared with the release rates from 6 cells dosed with an altered formulation, also at the nominal reference strength, using the statistical approach described in USP General Chapter<1724>. All 12 cells being compared should have been run in parallel on the same day, and the release rate from the altered formulation at the same nominal reference strength should fail to show equivalence to the release rate from the nominal reference strength formulation.

应使用USP通用章节<1724>中所述的统计方法评估释放速率之间的不等效。具体而言，应使用USP通用章节<1724>中描述的统计方法，将对照标示配方给药的6个测试池的释放速率与相同规格下的改变配方给药6个测试池的释放率进行比较，并且在相同的标示规格下，来自改变的制剂的释放速率应当显示出与对照标示制剂的释放率等效。

The altered formulation used in the assessment of supplemental selectivity should have the same nominal strength as the reference topical product, and may include changes in inactive ingredients, changes in inactive ingredient concentration(s), changes in the manufacturing processes, or combinations thereof. However, not all variations in a formulation will necessarily produce a difference in the release rate compared to the reference formulation, and if two similar formulations are found to have equivalent release rates, the demonstration of supplemental selectivity may be inconclusive.Therefore, applicants are encouraged to develop or select an altered formulation for the demonstration of supplemental selectivity based on differences in physicochemical and structural properties of the formulation (relative to the reference formulation) that are likely to alter the release rate of the active ingredient from the formulation. The altered formulation may be a marketed topical product, such as a different dosage form at the same strength of the same drug (e.g., a 5% gel versus a 5% ointment). Product batch information for all topical product lots used in IVRT method development, and validation studies, as applicable, should be submitted in the study reports. The topical product information should include, but not be limited to, information about the batch formula, manufacturing date, batch size, altered manufacturing processes (if applicable) and, if available, potency and content uniformity.

用于评估补充选择性的改变配方应具有与对照外用制剂具有相同规格、不同配方的制剂，并且可改变的特性包括：非活性成分的变化、非活性成分浓度的变化、制造工艺的变化或其组合。然而，与对照配方制剂相比，并非所有制剂的变化都必然会产生释放速率的差异，如果发现两种类似的制剂具有相同的释放速率，则不适用于论证补充选择性。因此，鼓励申请人根据制剂（相对于对照配方）的物理化学和结构性质的差异，开发或选择一种可能会改变活性成分释放速率的制剂，以论证补充选择性。变更的制剂可以是上市的外用制剂，例如相同规格的相同药物的不同剂型（例如，5%凝胶与5%软膏）。如适用，应在研究报告中提交，IVRT方法开发和验证研究中使用的所有外用制剂相关批次信息。包括但不限于:有关批次配方、生产日期、批次大小、变更的生产工艺（如适用）以及效价和含量均匀度（如可用）的信息。

J. Robustness   耐用性

The IVRT method may be considered robust to a variation in the test method if the average slope of an IVRT run under the altered IVRT method parametersis within ± 15% of the average slope of the precision and reproducibility IVRT runs. Robustness testing may encompass variations in the IVRT method that are relevant to the equipment and test method, for example:

如果在改变的IVRT方法参数下，IVRT运行的平均斜率在精密度和重现性研究中获得IVRT运行平均斜率的±15%以内，则IVRT方法可被认为对该参数的的改变具有耐用性。耐用性测试可能包括IVRT方法中相关的设备和测试方法的改变，例如：

lTemperature variations (e.g., - 1°C and +1°C relative to 32°C ± 1°C) 温度变化（例如，相对于32°C±1°C，-1°C和+1°C）

lDose volume variations (e.g., +10% and -10% in the dose volume) 上样体积变化（例如，上样体积的+10%和-10%）

lReceptor solution variations (e.g., slight change in composition and/or pH) 接受液变化（例如，轻微改变组成和/或pH值）

lMixing rate variation (e.g., slight change in stirring speed, as applicable) 混合速率变化（例如，轻微改变搅拌速率，如适用）

V. SAMPLE  ANALYTICAL  METHOD  VALIDATION  样品分析方法验证

While exploratory studies performed during IVRT method development may use an unvalidated sample analytical method, it is essential that all studies conducted as part of the IVRT method validation use a validated sample analytical method. A validated IVRT method should use a validated receptor solution sample analytical method. Therefore, a discussion of the sample analytical method for the IVRT method is included in this guidance under this section.

尽管IVRT方法开发期间进行的探索性研究,可以使用未经验证的样品分析方法，但作为IVRT方法验证的一部分，在进行IVRT的所有研究都必须使用经验证的样品分析方法。已验证的IVRT方法应使用已验证的接受液样品分析方法。因此，本部分讨论的IVRT方法样品分析方法。

It is important to note that the study protocols and reports related to the IVRT method are distinct from those for the sample analytical method that is used to quantify drug concentrations in IVRT receptor solution samples. The validation of a sample analytical method, in and of itself, does not demonstrate the validity of an IVRT method. Separate and specific reports should be submitted for the validation of the sample analysis (e.g., HPLC or UPLC) method and for the validation of the IVRT method.

值得注意的是，与IVRT方法相关的研究方案和报告与用于定量IVRT接受液样品中药物浓度的样品分析方法不同。样品分析方法的验证本身并不能证明IVRT方法的有效性。因此，应提交单独和具体的报告，已验证样品分析（如HPLC或UPLC）方法和IVRT方法的验证报告。

Any results from studies of the IVRT method that are performed (during method development) using a different sample analytical method than that which is ultimately validated, cannot support a demonstration of the validity of the IVRT method. Information should be provided in the IVRT method validation report referencing the (separate) sample analytical method validation, and clearly indicate that all relevant results in the IVRT method validation report were obtained using a validated sample analytical method (as opposed to an analytical method with different parameters than those which were validated).

在方法开发期间使用的样品分析方法与最终验证的样品分析方法不同，与其相关的IVRT方法研究结果无法支持IVRT方法的有效性。IVRT方法验证报告中应提供参考（单独）样品分析方法验证的信息，并明确指出IVRT方法确认报告中的所有相关结果均是使用经验证的样品分析方法获得的（而不是使用与经验证的分析方法具有不同参数的样品分析方法）。

The receptor sample analysis procedures, typically involving HPLC or UPLC, should be performed using chromatography software (e.g., a chromatography data system) with audit trails, and should include a multi-point (6–8 concentration) calibration curve with suitable quality control samples, and should be validated in a manner compatible with the FDA guidance for industry Bioanalytical Method Validation (May 2018).

接受液中样品分析方法，通常涉及HPLC或UPLC，应使用带有审计跟踪的色谱软件（例如色谱数据系统）进行，，并应包括多点（6-8浓度）校准曲线，以及适当的质量控制样品，并且应以符合FDA工业生物分析方法验证指南（2018年5月）的方式进行验证。

The validation of the receptor sample analytical method should include relevant qualifications of dilution integrity, if applicable, as well as stability assessments with the highest relevant temperature in the receptor solution for the longest relevant duration; the highest relevant temperature may be warmer than the IVRT membrane surface temperature because the temperature of the receptor solution is often higher than the temperature at the surface of the membrane (e.g., the temperature of the receptor solution may be 34°C when the temperature of membrane surface is 32°C, so stability assessments with the IVRT receptor solution may be performed at 34°C for 6 hours; the temperature would be higher for an IVRT with a vaginal gel, for example).

如适用，接受液中样品分析方法的验证应包括稀释完整性的相关确认，以及在最长相关时间内接受液中最高相关温度的稳定性评估；最高相关温度可以略高于IVRT膜表面温度，因为接受液的温度通常高于膜表面的温度（例如，当膜表面的温度为32°C时，接受液的温度可能为34°C，因此IVRT接受液的稳定性评估可在34°C下进行6小时；而在阴道凝胶制剂的IVRT研究中的温度会更高）。

VI. IVRT PIVOTAL STUDY IVRT  正式研究

The IVRT pivotal study comparing the drug release rates between the test and reference topical products should be performed in a manner compatible with the general procedures and statistical analysis method specified in USP General Chapter<1724>. The cumulative amount of drug released at each sampling time point should be reported for each diffusion cell. Relevant summary statistics for the IVRT study should also be reported.

IVRT正式研究中应对自制制剂和对照外用制剂之间的药物释放率进行比较，应符合USP一般章节<1724>中规定的一般程序和统计分析方法进行。应报告每个扩散池在每个取样时间点释放的药物累积量。还应报告IVRT研究的相关汇总统计数据。

A. Handling and Retention of Samples   样品的处理和保存

Refer to 21 CFR 320.38, 320.63 and the guidances for industry Handling and Retention of BA and BE Testing Samples (May 2004) and Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c) (August 2020), as applicable, regarding considerations for retention of study drug samples and to 21 CFR 320.36 for requirements for maintenance of records of BE testing. Retention samples should be randomly selected from the drug supplies received before dispensing during the IVRT study in which the test topical product and RS are compared. Experimental observations that may have the potential to influence the interpretation of the study results, as well as any protocol deviations, should be reported

B.参考21 CFR 320.38、320.63以及FDA行业指南《生物利用度（BA）和生物等效性（BE）研究中测试样品的处理和保存》（2004年5月）和《21 CFR 320.38(c) BE样品留存的数量及生物利用度》（2020年8月），如适用，关于保留研究药物样品的考虑以及21 CFR 320.36关于保存BE检测记录的要求。在IVRT中比较自研外用制剂和RS前应从收到的药品中随机选择样品进行留样。应报告可能影响研究结果解释的实验观察结果以及任何方案偏差。Control of Study Procedures 研究程序的控制

Procedures   研究程序的控制

Study procedures that have the potential to influence the results of the study should be appropriately controlled. Also, experimental observations that may have the potential to influence the interpretation of the study results, as well as any protocol or standard operating procedure (SOP) deviations, should be reported.

应适当控制可能影响研究结果的研究程序。此外，应报告可能影响研究结果解释的实验观察结果，以及任何方案或标准操作程序（SOP）偏差。

In addition, investigators should perform the IVRT validation and pivotal studies within a quality management system that includes, but is not limited to, documented procedures for:

此外，研究人员应在质量管理体系内进行IVRT验证和正式研究，该体系包括但不限于：

lStudy personnel identification, training, qualification, and responsibilities研究人员识别、培训、资质和职责

lStudy management and study management personnel responsibilities研究管理和研究管理人员职责

lQuality control (QC) and QC personnel responsibilities质量控制（QC）和QC人员职责

lQuality assurance (QA) and QA personnel responsibilities质量保证（QA）和QA人员职责

lUse of SOPs SOP的使用

lUse of study protocols研究方案的使用

lUse of study reports研究报告的使用

lMaintenance and control of the study facility environment and systems研究设施环境和系统的维护和控制

lQualification and calibration of instruments and computerized systems仪器和计算机系统的验证和校准

lGood documentation practices including, but not limited to, contemporaneous documentation of study procedures and recording of experimental observations or deviations from procedures specified in the study protocol or in relevant SOPs良好的文件记录规范，包括但不限于：研究程序的同期记录和实验观察结果的记录，或与研究方案或相关SOP中规定的程序的偏差

lMaintenance of suitable records that facilitate the reconstruction of study events and procedures, including study sample handling and storage records (e.g., sample tracking logs), audit trails for sample analysis procedures, control of study materials and reagents, and electronic data control对记录进行适当维护，有助于重现研究过程，包括：研究样品处理和保存记录（例如，样品跟踪日志）、样品分析过程的审计跟踪、研究物料和试剂的控制以及电子数据控制

lArchival of study records研究记录归档

C.Blinding Procedure   盲法程序

A detailed description of the blinding procedure should be provided in the study protocol and final report for the IVRT pivotal study. The packaging of the test topical product and RS should be similar in appearance to maintain adequate blinding of the investigator and any experimental operators. Once blinded, the test topical product and RS should be identified by a random designation, e.g., “A” or “B.”

IVRT正式研究的研究方案和最终报告中应详细说明盲法程序。自制外用制剂和RS的包装外观应相似，以保持研究者和任何实验操作人员的充分随机。一旦采用盲法程序，应通过随机名称（例如“A”或“B”）来区别自制外用制剂和RS

D.Dosing   上样

In the IVRT pivotal study, the test topical product and RS should be dosed in an alternating pattern on successive diffusion cells. There are two possible sequences for the alternating pattern (either ABABAB or BABABA). One of these two dosing sequences should be randomly selected.

在IVRT正式研究中，自制外用制剂和RS应在连续扩散池上交替给药。交替模式有两种可能的序列（ABABAB或BABABA）。可以随机选择这两种给药顺序中的一种。

VII. SUBMITTING INFORMATION ON IVRT STUDIES IN AN ANDA  ANDA中递交的IVRT研究信息

For IVRT studies with topical products submitted in ANDAs that are intended to support a demonstration of BE, detailed study protocols, relevant SOPs, and detailed reports should be submitted for the IVRT method validation and the IVRT pivotal study. In addition, a detailed report describing the IVRT method development should be submitted. These protocols, SOPs, and reports should be submitted in module 5.3.1.2 of the electronic Common Technical Document (eCTD) and should describe experimental procedures, study controls, quality management procedures, and data analyses.

对于在ANDA中提交的外用制剂用于支持BE论证的IVRT研究，应为IVRT方法验证和IVRT正式研究提交详细的研究方案、相关SOPs和详细报告。此外，还应提交一份详细报告，关于IVRT方法的开发。这些方案、SOPs和报告应在电子通用技术文件（eCTD）的模块5.3.1.2中提交，并应描述实验程序、研究控制、质量管理程序和数据分析。

Note that the study protocols, SOPs, and reports related to the IVRT method are distinct from those for the sample analytical method that is used to quantify drug concentrations in IVRT receptor solution samples (e.g., a HPLC or UPLC method). Separate protocols and SOPs should be submitted for the sample analytical method validation. Sample analytical method development and validation reports, pivotal IVRT study sample analysis reports, as well as associated SOPs and protocols relevant to the sample analysis for an IVRT study should be submitted in Module 5.3.1.4 of the eCTD.

注意:与IVRT方法相关的研究方案、SOPs和报告与用于定量IVRT接受液中样品药物浓度的样品分析方法（例如HPLC或UPLC方法）不同。样品分析方法验证应提交单独的方案和SOPs。样品分析方法开发和验证报告、正式IVRT研究样品分析报告以及与IVRT研究的样品分析相关的相关SOPs和协议,应在eCTD的模块5.3.1.4中提交。