In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs Guidance for Industry
工業(yè)指南中ANDAs申請遞交的外用提交的外用制劑的體外釋放試驗(yàn)研究

INTRODUCTION 緒論

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

本指南旨在幫助申請人提交適用于皮膚的液體和/或其他半固體產(chǎn)品的仿制藥申請（ANDA），包括皮膚和粘膜（如陰道），以下稱為局部產(chǎn)品。由于與這些產(chǎn)品相關(guān)的復(fù)雜遞送途徑（通常是局部作用的）以及某些制劑的潛在復(fù)雜性，局部產(chǎn)品（非局部溶液）被歸類為復(fù)雜產(chǎn)品。本指南為體外釋放試驗(yàn)（IVRT）研究提供了建議，該研究可用于比較擬用非**（試驗(yàn)）局部產(chǎn)品及其參考標(biāo)準(zhǔn)品（RS），以支持證明與參考上市藥物（RLD）的生物等效性（BE）。參考標(biāo)準(zhǔn)通常為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).

本指南不適用于通過眼、耳、鼻、吸入、口服或注射途徑給藥的藥物產(chǎn)品，也不適用于經(jīng)皮或局部給藥系統(tǒng)（包括貼片、局部貼片或緩釋膜產(chǎn)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.

討論本指南適用的特定主題產(chǎn)品超出了本指南的范圍。FDA建議申請人在考慮IVRT研究的設(shè)計(jì)和實(shí)施時(shí)，參考本指南和任何相關(guān)的產(chǎn)品特定指南（PSG）以及任何其他相關(guān)的行業(yè)指南，這些研究與其他研究（如有必要）可能適用于證明擬用仿制藥及其RLD具有生物等效性。FDA還建議申請人定期參考FDA的指導(dǎo)網(wǎng)頁，因?yàn)榭赡軙衅渌笇?dǎo)信息，有助于開發(fā)通用的外用產(chǎn)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，F(xiàn)DA指南性文件并非具有強(qiáng)制執(zhí)行的法律職能。實(shí)際上，指南描述了管里部門對某一問題當(dāng)前的思考，并且僅作為建議，除非引用了具體的法規(guī)或法定要求，。在指南中使用“應(yīng)該"一詞，意味著建議或推薦，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.

本指南是作為FDA“藥品競爭行動計(jì)劃"的一部分，該計(jì)劃配合通用藥品用戶費(fèi)用修正案（GDUFA）計(jì)劃和其他FDA舉措，旨在促進(jìn)處方藥市場的競爭，促進(jìn)高質(zhì)量和實(shí)惠的藥品的進(jìn)入市場，并改善公眾醫(yī)療。

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.

《聯(lián)邦食品、藥品和化妝品法案》（FD&C法案）通常要求ANDA包含合適的信息，說明：仿制藥與RLD相比（1）具有相同的活性成分、使用條件、給藥途徑、劑型、規(guī)格和標(biāo)簽方面（允許存在某些的差異）；和（2）與RLD生物等效。因此，如果ANDA中提交的信息不足以證明自制制劑與RLD具有生物等效性，ANDA將不予批準(zhǔn)。

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研究可用于評估局部產(chǎn)品的藥物釋放速率（即活性成分的釋放）。一旦驗(yàn)證，IVRT研究也可用于控制產(chǎn)品質(zhì)量和/或確定批準(zhǔn)后制造變更的可接受性。本指南側(cè)重于方法開發(fā)、方法驗(yàn)證和IVRT研究的一般考慮和建議，這些研究在ANDA申請中提交，旨在支持BE的論證。

IVRT METHOD DEVELOPMENT IVRT 方法開發(fā)

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的論證，則應(yīng)在ANDA中提交IVRT方法開發(fā)報(bào)告，以顯示IVRT方法是如何優(yōu)化的，并支持為IVRT選擇的方法參數(shù)是合適或必要的演示，特別是在方法參數(shù)不同于本指南中推薦的方法和美國藥典（USP）一般章節(jié)中描述的方法的情況下。監(jiān)管機(jī)構(gòu)在審查方法開發(fā)報(bào)告時(shí)，比較關(guān)注IVRT方法參數(shù)選擇的合理性，以及這些參數(shù)是否具有合適的敏感度和重現(xiàn)性。該方法開發(fā)報(bào)告應(yīng)明確指出/區(qū)分每組數(shù)據(jù)所用的方法參數(shù)，說明為優(yōu)化IVRT方法所做的努力，并證明為IVRT選擇的方法參數(shù)是合適的。

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.

鼓勵申請人使用本指南中的建議，如果申請人選擇使用與本指南中建議的方法不同的方法，IVRT方法開發(fā)報(bào)告應(yīng)說明選擇替代方法，進(jìn)行IVRT方法優(yōu)化的科學(xué)合理性。后續(xù)章節(jié)中描述了具體示例，以幫助申請人確定應(yīng)在ANDA中提交信息的情況，以解釋為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方法開發(fā)研究本質(zhì)上是探索性的，通常使用未經(jīng)驗(yàn)證的樣品分析方法（例如，高效液相色譜（HPLC）或超高效液相色譜儀（UPLC）方法）進(jìn)行；此外，IVRT方法開發(fā)研究通常以與質(zhì)量管理體系不兼容的方式進(jìn)行，所生成的證據(jù)不足以支持結(jié)論的可靠性。此類方法開發(fā)研究不適于證明IVRT方法或相關(guān)結(jié)果的有效性。因此，盡管這可能顯得多余，但在IVRT方法驗(yàn)證期間，可能需要使用適當(dāng)?shù)目刂拼胧ㄈ缗c適當(dāng)?shù)馁|(zhì)量管理體系兼容的經(jīng)驗(yàn)證的分析方法和程序）重復(fù)IVRT方法開發(fā)期間進(jìn)行的某些實(shí)驗(yàn)。

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).

將IVRT方法開發(fā)過程中的實(shí)驗(yàn)和結(jié)果與IVRT方法驗(yàn)證過程中的試驗(yàn)和結(jié)果分開進(jìn)行明確區(qū)分和一致識別是非常重要的。對于每組IVRT結(jié)果，一致地確定所有相關(guān)的方法參數(shù)和實(shí)驗(yàn)條件/對照也很重要。方法開發(fā)報(bào)告中的信息應(yīng)明確識別/區(qū)分使用不同方法參數(shù)可能獲得的明顯相似實(shí)驗(yàn)組的結(jié)果。方法的開發(fā)報(bào)告應(yīng)澄清平行或單獨(dú)運(yùn)行的擴(kuò)散池組（例如，在不同的日期）。此外，應(yīng)確定用于分析每組IVRT實(shí)驗(yàn)樣本的樣品分析方法（例如HPLC或UPLC方法），報(bào)告應(yīng)說明樣品分析方法是否有經(jīng)過驗(yàn)證（在樣品分析時(shí)或隨后）。

A. IVRT Method Parameters IVRT 方法參數(shù)

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.

應(yīng)提供理論或經(jīng)驗(yàn)信息，以解釋IVRT方法參數(shù)的選擇，如設(shè)備、上樣量、取樣時(shí)間、攪拌/攪拌速率等。當(dāng)選擇的設(shè)備是USP<1724>半固體藥物制劑—性能測試中所述設(shè)備時(shí)，且上樣量或攪拌速率與所選的設(shè)備匹配（未調(diào)節(jié)），可充分解釋選擇的合理性。

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.

通常情況下，IVRT取樣時(shí)長不應(yīng)少于4小時(shí)。但是，對于某些特定類型的制劑，這可能發(fā)生在固定產(chǎn)品劑量在4小時(shí)內(nèi)耗盡到如此大的程度，以至于釋放動力學(xué)此后不再是線性的情況下（當(dāng)以釋放量對時(shí)間的平方根作圖）。在這種情況下，應(yīng)解釋為優(yōu)化IVRT方法所做的努力（例如，使用允許使用更大產(chǎn)品上樣量的不同擴(kuò)散池設(shè)備），以便在4至6小時(shí)的常規(guī)IVRT持續(xù)時(shí)間內(nèi)可能表征持續(xù)的穩(wěn)態(tài)釋放動力學(xué)。

B. IVRT Receptor Solution  IVRT接收介質(zhì)

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方法開發(fā)過程中對不同接受介質(zhì)進(jìn)行評估都使用與待評估的接受介質(zhì)具有廣泛化學(xué)相容性的同一類型膜）；這些接受液通常是基于受體溶液中（通常是疏水性的）藥物的溶解度和穩(wěn)定性而選擇的二元水醇混合物。接受液通常在6小時(shí)持續(xù)時(shí)間內(nèi)至少每小時(shí)取樣一次。

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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.

應(yīng)提供藥物在接受液中的經(jīng)驗(yàn)溶解度和穩(wěn)定性的信息，以及IVRT中產(chǎn)生的藥物釋放率的線性和精密度的信息，用于解釋試驗(yàn)方法中接受液選擇的合理性。理想情況下，所有時(shí)間點(diǎn)的藥物釋放速率（斜率）應(yīng)成線性關(guān)系（r2值≥ 0.97）.如何在藥物在接受液中的溶解度限制釋放動力學(xué)，導(dǎo)致最后一個(gè)時(shí)間點(diǎn)釋放速率降低的情況下，評估不同的接受液可能是更有必要的。如果縮短的時(shí)間段內(nèi)釋放速率的線性得到改善（表現(xiàn)出較高的r2值），并且與評估的其他受體溶液相比，該受體溶液中釋放動力學(xué)的其他方面（例如，精度）得到優(yōu)化，則將IVRT方法縮短為4小時(shí)或5小時(shí)的采樣時(shí)間段可能是合適的。

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.

選擇最佳受體溶液作為IVRT方法開發(fā)的初始步驟的一個(gè)優(yōu)點(diǎn)是，在使用接受液對不同膜進(jìn)行評估之前，可先選定的接受液對樣品分析方法進(jìn)行優(yōu)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方法開發(fā)過程中，通常評估不同的膜（均使用相同的接受液）；這些膜通常是用于過濾溶液中的顆粒物質(zhì)的合成膜。IVRT膜的選擇基于其有效孔徑（例如0.45微米（µm））以及其與藥物結(jié)合的預(yù)期惰性。IVRT方法開發(fā)報(bào)告中應(yīng)提供每種膜與藥物的結(jié)合及其與為IVRT方法選擇的相關(guān)受體溶液的化學(xué)相容性的信息（基于IVRT方法發(fā)展的前一階段），以及在IVRT中使用每種膜時(shí)所產(chǎn)生的釋放速率的線性和精度的信息，因?yàn)樵撔畔⒖梢詭椭忉尀槭裁刺囟τ贗VRT方法是最佳的。

IV. IVRT METHOD VALIDATION IVRT  方法驗(yàn)證

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關(guān)鍵研究中使用的設(shè)備、方法和研究條件應(yīng)經(jīng)過合理的驗(yàn)證或確認(rèn)。在啟動IVRT方法驗(yàn)證之前，啟動IVRT的樣品分析方法（例如，HPLC或UPLC方法）的驗(yàn)證是常規(guī)的，盡管樣品分析方法驗(yàn)證的某些試驗(yàn)（例如，穩(wěn)定性）通常與IVRT方法的驗(yàn)證平行進(jìn)行。如果申請人選擇使用的設(shè)備、方法或研究條件與本指南或USP中推薦的不同，申請人應(yīng)證明這些差異在科學(xué)上是合理的。重要的是要一致地確定每組IVRT結(jié)果的所有相關(guān)方法參數(shù)，明確結(jié)果是使用相同的IVRT方法參數(shù)獲得的，并闡明哪些組擴(kuò)散池是平行或單獨(dú)運(yùn)行的。建議建立詳細(xì)的方案和嚴(yán)格控制的測試程序，以確保精確控制上樣、取樣和其他IVRT研究參數(shù)，以及實(shí)驗(yàn)偏差的潛在來源。

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方法參數(shù)的限定指的是定義哪些屬性適合在IVRT方法中執(zhí)行其功能的過程。例如，當(dāng)每小時(shí)測量膜表面溫度（當(dāng)安裝在擴(kuò)散池中時(shí)）表明IVRT設(shè)備可以在6小時(shí)內(nèi)將膜表面溫度保持在32°C±1°C的范圍內(nèi)時(shí)，結(jié)果可以證明該設(shè)備在IVRT方法中執(zhí)行其功能，其中方法參數(shù)是在6小時(shí)內(nèi)將膜表面溫度控制在32°C±1°C的范圍內(nèi)。盡管IVRT膜表面溫度在32°C±1°C范圍內(nèi)適用于涂抹在皮膚上的局部產(chǎn)品，但對于粘膜外用制劑（如陰道凝膠），相關(guān)IVRT膜的表面溫度應(yīng)為37°C±1°C。如適用，使用經(jīng)驗(yàn)證的樣品分析方法，在IVRT方法的驗(yàn)證進(jìn)行以下確認(rèn)和控制。

A. Equipment Qualification設(shè)備確認(rèn)

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>通用章節(jié)中有適用于IVRT方法的設(shè)備描述。（淺析FDA指導(dǎo)原則中對申報(bào)用Franz測試裝置的要求）這些包括不同模型的垂直擴(kuò)散池和浸沒池的。在設(shè)計(jì)和/或操作原理上與USP<1724>通用章節(jié)中描述的那些基本相同的垂直擴(kuò)散池和浸沒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.

每種設(shè)備的工作原理和特定測試方法不同；制造商的相關(guān)程序可用于安裝、操作和性能鑒定。每個(gè)擴(kuò)散池的實(shí)驗(yàn)室確定，至少應(yīng)包括：（1）測量供給室和接受室之間膜安裝位置的孔口的擴(kuò)散面積，；（2） 每個(gè)擴(kuò)散池的接受室的容積；（3）在相關(guān)研究持續(xù)時(shí)間（例如，6小時(shí)）內(nèi)測量膜表面（例如，32°C±1°C）或膜正下方的溫度，的穩(wěn)定性；以及（4）如適用，測定攪拌或攪拌的速率。

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.

如果制造商提供了與每個(gè)擴(kuò)散池的孔擴(kuò)散面積和接受室容積相關(guān)的信息，則除了實(shí)驗(yàn)室進(jìn)行的經(jīng)驗(yàn)測量外，還應(yīng)提供每個(gè)相關(guān)擴(kuò)散池的信息。設(shè)備應(yīng)控制擴(kuò)散池溫度調(diào)節(jié)，以便在給藥前驗(yàn)證每個(gè)擴(kuò)散池的膜表面溫度是否穩(wěn)定（例如，32°C±1°C）（例如，通過校準(zhǔn)的紅外溫度計(jì)測量）。如果由于特定設(shè)備的設(shè)計(jì)和操作原理，在給藥前無法驗(yàn)證擴(kuò)散池的膜表面溫度是否已達(dá)到平衡和穩(wěn)定（例如，在32°C±1°C），對于該類型的設(shè)備確認(rèn)應(yīng)證明，在IVRT方法使用的特定條件下，在整個(gè)測試過程中，每個(gè)擴(kuò)散池的膜表面溫度可以預(yù)期保持穩(wěn)定的（例如，在32°C±1°C）。（如下圖，膜溫度平衡預(yù)實(shí)驗(yàn)）

B. Membrane Qualification  膜確認(rèn)

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.

在試驗(yàn)期間，應(yīng)在與接受液中藥物濃度范圍下，根據(jù)藥物在接受液中與膜吸附來評估膜惰性。測定應(yīng)基于在相關(guān)溫度下（例如，32°C±1°C下6小時(shí)）IVRT持續(xù)時(shí)間內(nèi)至少重復(fù)三次膜孵育。應(yīng)在沒有膜的情況下平行進(jìn)行三次重復(fù)對照孵育，以監(jiān)測與膜結(jié)合無關(guān)的藥物損失。應(yīng)在孵育前后收集這些溶液的等分試樣，以評估溶液中藥物量的減少。建議在試驗(yàn)結(jié)束時(shí)，溶液中藥物的回收率在100%±5%的范圍內(nèi)，可以確認(rèn)膜的惰性。

C. Receptor Solution Qualification  接收介質(zhì)確認(rèn)

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)

應(yīng)解釋選擇IVRT研究所用接受液成分的原因。藥物在IVRT接受液中的溶解度，應(yīng)根據(jù)經(jīng)驗(yàn)測定一式三份，以說明藥物在接受液中溶解度超過IVRT正式研究中的最大藥物濃度，理想情況下是一個(gè)數(shù)量級或者是足以促成研究期間釋放速率的線性關(guān)系（穩(wěn)態(tài)）（即使在IVRT方法驗(yàn)證期間評估配方的相對較高釋放率時(shí)，即RS標(biāo)稱規(guī)格的150%）

D. Receptor Solution Sampling Qualification  接收液取樣確認(rèn)

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.

每個(gè)時(shí)間點(diǎn)的接受液取樣的準(zhǔn)確度和精密度應(yīng)進(jìn)行確認(rèn)。確認(rèn)取樣程序的過程應(yīng)証明，取樣技術(shù)可在每次取樣時(shí)從的混合良好的接受室中可靠地收集相同體積的樣品，并且不會因取樣技術(shù)的原因引起誤差（例如，由于自動取樣系統(tǒng)中的樣本之間的干擾或殘留，或由于從垂直擴(kuò)散池的未混合均一取樣臂中取樣）。應(yīng)描述設(shè)備制造商關(guān)于接受液取樣準(zhǔn)確度和精密度的規(guī)范信息（如有）。

E. Environmental Control  環(huán)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.

應(yīng)監(jiān)測和報(bào)告研究期間的實(shí)驗(yàn)室環(huán)境溫度和濕度。建議環(huán)境控制溫度范圍為21°C±2°C，如果可行，建議濕度范圍為50%±20%相對濕度。

F. Linearity and Range  線性和范圍

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的整個(gè)研究期間，根據(jù)所有采樣時(shí)間點(diǎn)的釋放速率繪制標(biāo)準(zhǔn)曲線，應(yīng)呈線性關(guān)系（r2值）。應(yīng)計(jì)算并報(bào)告每個(gè)擴(kuò)散池的藥物釋放線性方程，并與所有IVRT研究結(jié)果進(jìn)行比較。為了使釋放速率為線性的前提是，建議IVRT研究持續(xù)時(shí)間為4–6小時(shí)，其應(yīng)具有r2值≥0.97。通常小于4小時(shí)的IVRT研究持續(xù)時(shí)間可能不足以評估自制制劑和RS的釋放速率是否代表其穩(wěn)態(tài)藥物釋放動力學(xué)，但是，如果方法開發(fā)報(bào)告中有令人信服的實(shí)驗(yàn)數(shù)據(jù)支持，說明已做出合理和科學(xué)上的努力來優(yōu)化IVRT方法，則IVRT研究持續(xù)時(shí)間小于4小時(shí)（不推薦）也是可以接受的。IVRT方法的線性和范圍應(yīng)根據(jù)精密度和重復(fù)性試驗(yàn)的結(jié)果確定，詳見如下所述。

G. Precision and Reproducibility   精密度和重現(xiàn)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.

可以針對每個(gè)擴(kuò)散池的釋放速率（斜率）計(jì)算批內(nèi)和批間精密度和重現(xiàn)性。應(yīng)計(jì)算批內(nèi)和批間斜率的平均值、標(biāo)準(zhǔn)偏差和變異系數(shù)百分比（%CV），批內(nèi)和批間%CV，均應(yīng)≤ 15%?？梢越M織運(yùn)行響應(yīng)面實(shí)驗(yàn)，以便于同時(shí)評估儀器內(nèi)部/內(nèi)部和/或操作員內(nèi)部/內(nèi)部的精密度和重復(fù)性。建議至少進(jìn)行三次獨(dú)立的精密度和重現(xiàn)性試驗(yàn)。

H. Dose Depletion   劑量消耗

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

應(yīng)計(jì)算接受液中釋放藥物的回收率，用以表征IVRT研究期間，釋放到接受液中的累積藥物量。這可以表示為上樣劑量中藥物量的百分比（其可以根據(jù)外用制劑中藥物的標(biāo)示規(guī)格和膜上大致上樣量來評估）。例如，如果在每個(gè)擴(kuò)散池的膜上的上樣量為1克（g），制劑標(biāo)示規(guī)格含有5%藥物，則上樣劑量中的藥物量可估計(jì)為50mg。如果在IVRT的6小時(shí)持續(xù)時(shí)間內(nèi)，共有10mg的藥物擴(kuò)散到每個(gè)擴(kuò)散測試池的接受液中，則可以估計(jì)50mg劑量已經(jīng)消耗10mg，相當(dāng)于20%的劑量消耗。因此，可以估計(jì)并報(bào)告平均劑量消耗百分比。雖然在劑量消耗小于30%的條件下通?？梢约僭O(shè)穩(wěn)態(tài)釋放動力學(xué)，但對于一些外用制劑，在較高百分比的劑量消耗下可以繼續(xù)觀察到穩(wěn)態(tài)釋放動力學(xué)。當(dāng)實(shí)驗(yàn)證據(jù)表明每個(gè)擴(kuò)散池的釋放速率（斜率）與時(shí)間的平方根作圖時(shí)，每個(gè)擴(kuò)散池的釋放速率也能保持線性關(guān)系，盡管劑量消耗大于30%，IVRT方法也被認(rèn)為是考慮充分的

I.Discrimination Sensitivity, Specificity, and Selectivity   區(qū)分力—靈敏度、專屬性和選擇性

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方法應(yīng)能夠區(qū)分相似制劑的藥物釋放率。應(yīng)通過將試驗(yàn)制劑的釋放速率與藥物濃度發(fā)生變化的兩種改變規(guī)格的制劑的釋放率進(jìn)行比較來評估這一點(diǎn)——一個(gè)較高規(guī)格（RS標(biāo)稱濃度的150%），另一個(gè)較低規(guī)格（RS額定濃度的50%）。如果在配制與標(biāo)示規(guī)格相比為150%的局部產(chǎn)品時(shí)觀察到活性成分析出，則可能需要使用不同的策略，這可以在ANDA前產(chǎn)品開發(fā)會議期間或通過受控通信在提交ANDA之前與機(jī)構(gòu)討論。應(yīng)報(bào)告較高和較低規(guī)格配方的組成和制備程序，盡管這些配方制劑不是在符合GMP條件下制備。IVRT方法的區(qū)分力應(yīng)從以下三個(gè)概念來描述：靈敏度、特異性和選擇性。

IVRT Sensitivity IVRT   靈敏度

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靈敏度是檢測釋放速率變化的能力，釋放速率作為制劑中藥物濃度的函數(shù)。如果同一天，對RS、較高規(guī)格和較低規(guī)格平行實(shí)驗(yàn)，IVRT方法一致地識別制劑的釋放速率更高或更低，則通常認(rèn)為IVRT方法是靈敏的。

IVRT Specificity IVRT  特異性

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特異性是準(zhǔn)確監(jiān)測釋放速率隨制劑中藥物濃度變化的比例的能力。該比例可以用制劑濃度和平均IVRT釋放速率（斜率）之間的關(guān)系圖來說明。應(yīng)通過繪制線性趨勢線，將線性量化并報(bào)告為r2值，評估IVRT方法的特異性，。IVRT方法在其對釋放速率差異的響應(yīng)中應(yīng)該是成比例的線性的，制劑濃度與平均IVRT釋放速率（斜率）最小的r2值≥ 0.95，表示改方法具有合適的特異性。

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特異性是產(chǎn)品不同規(guī)格的釋放速率比例的函數(shù)，其中一些或全部可作為小規(guī)模實(shí)驗(yàn)室批次配制，每個(gè)規(guī)格的制劑組成略有不同，以適應(yīng)該產(chǎn)品規(guī)格中活性成分的不同量。產(chǎn)品不同規(guī)格的這些輕微配方差異可能會影響產(chǎn)品不同規(guī)格釋放速率的理想比例。

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，產(chǎn)品不同規(guī)格的釋放速率的比例線性可能受到不同規(guī)格的配方差異的影響，這些差異與IVRT方法的比例響應(yīng)性無關(guān)。由于制劑差異與IVRT方法無關(guān)，考慮到IVRT方法對釋放速率差異的響應(yīng)可能不全部成比例，因此，制劑濃度與平均IVRT釋放速率（斜率）的相關(guān)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，產(chǎn)品不同規(guī)格的釋放速率的線性（評估IVRT方法的特異性，最小r2值≥ 0.95）與在取樣時(shí)間范圍內(nèi)的產(chǎn)品單一濃度的釋放速率的線性（這評估了IVRT方法監(jiān)測活性成分穩(wěn)態(tài)釋放動力學(xué)的能力，具有最小r2值≥0.97）。盡管在每種情況下，不同的科學(xué)考慮因素可能會影響IVRT結(jié)果的線性，但對于良好開發(fā)和適當(dāng)控制的IVRT方法，在兩種情況下，r2值≥ 0.99通常都是滿足的。（如下圖r2=0.9915）

IVRT Selectivity IVRT   選擇性

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選擇性是IVRT方法區(qū)分參考外用制劑和改變的（50%和150%標(biāo)示規(guī)格）濃度測試制劑之間的藥物釋放速率的能力，從而確定它們的釋放速率與標(biāo)示參考規(guī)格制劑的釋放速率在統(tǒng)計(jì)上不相等。應(yīng)使用USP通用章節(jié)<1724>中描述的統(tǒng)計(jì)方法評估釋放速率之間的不等效性。

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.

具體而言，應(yīng)使用USP通用<1724>章節(jié)中所述的統(tǒng)計(jì)方法，將六杯標(biāo)示規(guī)格制劑的測試池的釋放率與六杯150%標(biāo)示制劑的測試池釋放率進(jìn)行比較，根據(jù)<1724>章節(jié)要求，這12杯應(yīng)在同一天平行實(shí)驗(yàn)，在標(biāo)示規(guī)格的150%時(shí)，制劑的釋放速率不能顯示出與標(biāo)示規(guī)格制劑的釋放率相等。

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.

還應(yīng)使用USP通用章節(jié)<1724>中描述的統(tǒng)計(jì)方法，將6個(gè)測試池的標(biāo)示規(guī)格濃度制劑（即100%規(guī)格）的釋放率與6個(gè)測試池50%規(guī)格時(shí)的釋放率進(jìn)行比較，這12杯應(yīng)在同一天平行實(shí)驗(yàn)，50%規(guī)格制劑配方的釋放速率應(yīng)與對照制劑的釋放率不等效。

IVRT Supplemental Selectivity IVRT  補(bǔ)充選擇性

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補(bǔ)充選擇性是IVRT方法區(qū)分參考外用制劑和具有相同標(biāo)示規(guī)格的改變制劑之間的藥物釋放速率的能力，從而確定它們的釋放速率在統(tǒng)計(jì)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選擇性的證明（不同于補(bǔ)充選擇性）驗(yàn)證了IVRT方法在預(yù)計(jì)釋放速率可以預(yù)測的方式不同的條件下（即，當(dāng)制劑中存在不同濃度的藥物時(shí)）區(qū)分釋放速率差異的能力。

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.

在可行的情況下，IVRT方法選擇性的單獨(dú)和補(bǔ)充證明獨(dú)立驗(yàn)證了IVRT方法在關(guān)鍵IVRT研究條件下區(qū)分釋放率差異的能力，其中自制和對照外用制劑以相同的規(guī)格進(jìn)行比較。因此，在可行情況下，理想情況下的IVRT方法選擇性的補(bǔ)充論證證明了它可以檢測與制劑的規(guī)格以外的方面相關(guān)的釋放速率的差異。

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.

應(yīng)使用USP通用章節(jié)<1724>中所述的統(tǒng)計(jì)方法評估釋放速率之間的不等效。具體而言，應(yīng)使用USP通用章節(jié)<1724>中描述的統(tǒng)計(jì)方法，將對照標(biāo)示配方給藥的6個(gè)測試池的釋放速率與相同規(guī)格下的改變配方給藥6個(gè)測試池的釋放率進(jìn)行比較，并且在相同的標(biāo)示規(guī)格下，來自改變的制劑的釋放速率應(yīng)當(dāng)顯示出與對照標(biāo)示制劑的釋放率等效。

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.

用于評估補(bǔ)充選擇性的改變配方應(yīng)具有與對照外用制劑具有相同規(guī)格、不同配方的制劑，并且可改變的特性包括：非活性成分的變化、非活性成分濃度的變化、制造工藝的變化或其組合。然而，與對照配方制劑相比，并非所有制劑的變化都必然會產(chǎn)生釋放速率的差異，如果發(fā)現(xiàn)兩種類似的制劑具有相同的釋放速率，則不適用于論證補(bǔ)充選擇性。因此，鼓勵申請人根據(jù)制劑（相對于對照配方）的物理化學(xué)和結(jié)構(gòu)性質(zhì)的差異，開發(fā)或選擇一種可能會改變活性成分釋放速率的制劑，以論證補(bǔ)充選擇性。變更的制劑可以是上市的外用制劑，例如相同規(guī)格的相同藥物的不同劑型（例如，5%凝膠與5%軟膏）。如適用，應(yīng)在研究報(bào)告中提交，IVRT方法開發(fā)和驗(yàn)證研究中使用的所有外用制劑相關(guān)批次信息。包括但不限于:有關(guān)批次配方、生產(chǎn)日期、批次大小、變更的生產(chǎn)工藝（如適用）以及效價(jià)和含量均勻度（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:

如果在改變的IVRT方法參數(shù)下，IVRT運(yùn)行的平均斜率在精密度和重現(xiàn)性研究中獲得IVRT運(yùn)行平均斜率的±15%以內(nèi)，則IVRT方法可被認(rèn)為對該參數(shù)的的改變具有耐用性。耐用性測試可能包括IVRT方法中相關(guān)的設(shè)備和測試方法的改變，例如：

lTemperature variations (e.g., - 1°C and +1°C relative to 32°C ± 1°C) 溫度變化（例如，相對于32°C±1°C，-1°C和+1°C）

lDose volume variations (e.g., +10% and -10% in the dose volume) 上樣體積變化（例如，上樣體積的+10%和-10%）

lReceptor solution variations (e.g., slight change in composition and/or pH) 接受液變化（例如，輕微改變組成和/或pH值）

lMixing rate variation (e.g., slight change in stirring speed, as applicable) 混合速率變化（例如，輕微改變攪拌速率，如適用）

V. SAMPLE  ANALYTICAL  METHOD  VALIDATION  樣品分析方法驗(yàn)證

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.

盡管IVRT方法開發(fā)期間進(jìn)行的探索性研究,可以使用未經(jīng)驗(yàn)證的樣品分析方法，但作為IVRT方法驗(yàn)證的一部分，在進(jìn)行IVRT的所有研究都必須使用經(jīng)驗(yàn)證的樣品分析方法。已驗(yàn)證的IVRT方法應(yīng)使用已驗(yàn)證的接受液樣品分析方法。因此，本部分討論的IVRT方法樣品分析方法。

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，與IVRT方法相關(guān)的研究方案和報(bào)告與用于定量IVRT接受液樣品中藥物濃度的樣品分析方法不同。樣品分析方法的驗(yàn)證本身并不能證明IVRT方法的有效性。因此，應(yīng)提交單獨(dú)和具體的報(bào)告，已驗(yàn)證樣品分析（如HPLC或UPLC）方法和IVRT方法的驗(yàn)證報(bào)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).

在方法開發(fā)期間使用的樣品分析方法與最終驗(yàn)證的樣品分析方法不同，與其相關(guān)的IVRT方法研究結(jié)果無法支持IVRT方法的有效性。IVRT方法驗(yàn)證報(bào)告中應(yīng)提供參考（單獨(dú)）樣品分析方法驗(yàn)證的信息，并明確指出IVRT方法確認(rèn)報(bào)告中的所有相關(guān)結(jié)果均是使用經(jīng)驗(yàn)證的樣品分析方法獲得的（而不是使用與經(jīng)驗(yàn)證的分析方法具有不同參數(shù)的樣品分析方法）。

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).

接受液中樣品分析方法，通常涉及HPLC或UPLC，應(yīng)使用帶有審計(jì)跟蹤的色譜軟件（例如色譜數(shù)據(jù)系統(tǒng)）進(jìn)行，，并應(yīng)包括多點(diǎn)（6-8濃度）校準(zhǔn)曲線，以及適當(dāng)?shù)馁|(zhì)量控制樣品，并且應(yīng)以符合FDA工業(yè)生物分析方法驗(yàn)證指南（2018年5月）的方式進(jìn)行驗(yàn)證。

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).

如適用，接受液中樣品分析方法的驗(yàn)證應(yīng)包括稀釋完整性的相關(guān)確認(rèn)，以及在最長相關(guān)時(shí)間內(nèi)接受液中最高相關(guān)溫度的穩(wěn)定性評估；最高相關(guān)溫度可以略高于IVRT膜表面溫度，因?yàn)榻邮芤旱臏囟韧ǔ８哂谀け砻娴臏囟龋ɡ?，?dāng)膜表面的溫度為32°C時(shí)，接受液的溫度可能為34°C，因此IVRT接受液的穩(wěn)定性評估可在34°C下進(jìn)行6小時(shí)；而在陰道凝膠制劑的IVRT研究中的溫度會更高）。

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正式研究中應(yīng)對自制制劑和對照外用制劑之間的藥物釋放率進(jìn)行比較，應(yīng)符合USP一般章節(jié)<1724>中規(guī)定的一般程序和統(tǒng)計(jì)分析方法進(jìn)行。應(yīng)報(bào)告每個(gè)擴(kuò)散池在每個(gè)取樣時(shí)間點(diǎn)釋放的藥物累積量。還應(yīng)報(bào)告IVRT研究的相關(guān)匯總統(tǒng)計(jì)數(shù)據(jù)。

A. Handling and Retention of Samples   樣品的處理和保存

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.參考21 CFR 320.38、320.63以及FDA行業(yè)指南《生物利用度（BA）和生物等效性（BE）研究中測試樣品的處理和保存》（2004年5月）和《21 CFR 320.38(c) BE樣品留存的數(shù)量及生物利用度》（2020年8月），如適用，關(guān)于保留研究藥物樣品的考慮以及21 CFR 320.36關(guān)于保存BE檢測記錄的要求。在IVRT中比較自研外用制劑和RS前應(yīng)從收到的藥品中隨機(jī)選擇樣品進(jìn)行留樣。應(yīng)報(bào)告可能影響研究結(jié)果解釋的實(shí)驗(yàn)觀察結(jié)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.

應(yīng)適當(dāng)控制可能影響研究結(jié)果的研究程序。此外，應(yīng)報(bào)告可能影響研究結(jié)果解釋的實(shí)驗(yàn)觀察結(jié)果，以及任何方案或標(biāo)準(zhǔn)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，研究人員應(yīng)在質(zhì)量管理體系內(nèi)進(jìn)行IVRT驗(yàn)證和正式研究，該體系包括但不限于：

lStudy personnel identification, training, qualification, and responsibilities研究人員識別、培訓(xùn)、資質(zhì)和職責(zé)

lStudy management and study management personnel responsibilities研究管理和研究管理人員職責(zé)

lQuality control (QC) and QC personnel responsibilities質(zhì)量控制（QC）和QC人員職責(zé)

lQuality assurance (QA) and QA personnel responsibilities質(zhì)量保證（QA）和QA人員職責(zé)

lUse of SOPs SOP的使用

lUse of study protocols研究方案的使用

lUse of study reports研究報(bào)告的使用

lMaintenance and control of the study facility environment and systems研究設(shè)施環(huán)境和系統(tǒng)的維護(hù)和控制

lQualification and calibration of instruments and computerized systems儀器和計(jì)算機(jī)系統(tǒng)的驗(yàn)證和校準(zhǔn)

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良好的文件記錄規(guī)范，包括但不限于：研究程序的同期記錄和實(shí)驗(yàn)觀察結(jié)果的記錄，或與研究方案或相關(guān)SOP中規(guī)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對記錄進(jìn)行適當(dāng)維護(hù)，有助于重現(xiàn)研究過程，包括：研究樣品處理和保存記錄（例如，樣品跟蹤日志）、樣品分析過程的審計(jì)跟蹤、研究物料和試劑的控制以及電子數(shù)據(jù)控制

lArchival of study records研究記錄歸檔

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終報(bào)告中應(yīng)詳細(xì)說明盲法程序。自制外用制劑和RS的包裝外觀應(yīng)相似，以保持研究者和任何實(shí)驗(yàn)操作人員的充分隨機(jī)。一旦采用盲法程序，應(yīng)通過隨機(jī)名稱（例如“A"或“B"）來區(qū)別自制外用制劑和RS

D.Dosing   上樣

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，自制外用制劑和RS應(yīng)在連續(xù)擴(kuò)散池上交替給藥。交替模式有兩種可能的序列（ABABAB或BABABA）。可以隨機(jī)選擇這兩種給藥順序中的一種。

VII. SUBMITTING INFORMATION ON IVRT STUDIES IN AN ANDA  ANDA中遞交的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.

對于在ANDA中提交的外用制劑用于支持BE論證的IVRT研究，應(yīng)為IVRT方法驗(yàn)證和IVRT正式研究提交詳細(xì)的研究方案、相關(guān)SOPs和詳細(xì)報(bào)告。此外，還應(yīng)提交一份詳細(xì)報(bào)告，關(guān)于IVRT方法的開發(fā)。這些方案、SOPs和報(bào)告應(yīng)在電子通用技術(shù)文件（eCTD）的模塊5.3.1.2中提交，并應(yīng)描述實(shí)驗(yàn)程序、研究控制、質(zhì)量管理程序和數(shù)據(jù)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:與IVRT方法相關(guān)的研究方案、SOPs和報(bào)告與用于定量IVRT接受液中樣品藥物濃度的樣品分析方法（例如HPLC或UPLC方法）不同。樣品分析方法驗(yàn)證應(yīng)提交單獨(dú)的方案和SOPs。樣品分析方法開發(fā)和驗(yàn)證報(bào)告、正式IVRT研究樣品分析報(bào)告以及與IVRT研究的樣品分析相關(guān)的相關(guān)SOPs和協(xié)議,應(yīng)在eCTD的模塊5.3.1.4中提交。