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FDA IVRT測試 工業指南翻譯稿

更新時間:2023-01-11      點擊次數:2349

In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs Guidance for Industry
工業指南中ANDAs申請遞交的(de)外用提交的外(wai)用制劑的體(ti)外(wai)釋(shi)放(fang)試驗研究

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),以下稱為局部產品。由于與這些產品相關的復雜遞送途徑(通常是局部作用的)以及某些制劑的潛在復雜性,局部產品(非局部溶液)被歸類為復雜產品。本指南為體外釋放試驗(IVRT)研究提供了建議,該研究可用于比較擬用非**(試驗)局部產品及其參考標準品(RS),以支持證明與參考上市藥物(RLD)的生物等效性(BE)。參考標準通常為RLD。

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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(bu)適(shi)用于通過眼、耳、鼻、吸入、口(kou)服(fu)或(huo)(huo)注射途徑給(gei)藥(yao)的藥(yao)物產品,也不(bu)適(shi)用于經皮或(huo)(huo)局(ju)部(bu)給(gei)藥(yao)系統(包括貼片、局(ju)部(bu)貼片或(huo)(huo)緩釋(shi)膜產品)。

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(zhi)南適(shi)用(yong)的(de)特定主題產品(pin)超出了本指(zhi)南的(de)范圍(wei)。FDA建議申請(qing)人(ren)在考(kao)慮IVRT研究的(de)設計(ji)和(he)實(shi)施時,參考(kao)本指(zhi)南和(he)任(ren)何相關的(de)產品(pin)特定指(zhi)南(PSG)以(yi)及(ji)任(ren)何其(qi)(qi)他相關的(de)行業指(zhi)南,這些研究與其(qi)(qi)他研究(如有(you)必(bi)要)可(ke)能(neng)適(shi)用(yong)于(yu)(yu)證明擬用(yong)仿制藥及(ji)其(qi)(qi)RLD具有(you)生物等效性。FDA還(huan)建議申請(qing)人(ren)定期(qi)參考(kao)FDA的(de)指(zhi)導網頁,因為可(ke)能(neng)會有(you)其(qi)(qi)他指(zhi)導信息(xi),有(you)助(zhu)于(yu)(yu)開發通用(yong)的(de)外用(yong)產品(pin)。

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(yi)般而言,FDA指南(nan)(nan)性文件并非(fei)(fei)具有強制執(zhi)行的(de)法律職能。實際上(shang),指南(nan)(nan)描述了管里部門對某一(yi)問題當前的(de)思考,并且僅作為建(jian)議,除非(fei)(fei)引用了具體的(de)法規或(huo)法定要求,。在指南(nan)(nan)中使用“應該(gai)"一(yi)詞,意(yi)味著(zhu)建(jian)議或(huo)推(tui)薦,并非(fei)(fei)要求的(de)意(yi)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(zhi)南(nan)是作(zuo)為FDA“藥品競爭行(xing)動(dong)計(ji)劃(hua)"的一部分,該計(ji)劃(hua)配合通(tong)用(yong)藥品用(yong)戶費(fei)用(yong)修正案(an)(GDUFA)計(ji)劃(hua)和(he)其他(ta)FDA舉措(cuo),旨在(zai)促(cu)進(jin)處方(fang)藥市場的競爭,促(cu)進(jin)高質量和(he)實惠的藥品的進(jin)入(ru)市場,并改善公眾醫療。

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、規格和標簽方面(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。

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(yan)究(jiu)(jiu)(jiu)可用(yong)于評估局部產品的(de)藥物(wu)釋(shi)放速率(即(ji)活性(xing)成分的(de)釋(shi)放)。一旦驗證,IVRT研(yan)究(jiu)(jiu)(jiu)也可用(yong)于控制(zhi)(zhi)產品質量和/或確定批準(zhun)后制(zhi)(zhi)造變更的(de)可接受性(xing)。本指南側重于方法(fa)開發、方法(fa)驗證和IVRT研(yan)究(jiu)(jiu)(jiu)的(de)一般考慮(lv)和建(jian)議,這些研(yan)究(jiu)(jiu)(jiu)在ANDA申請中提交(jiao),旨在支持(chi)BE的(de)論證。

IVRT METHOD DEVELOPMENT IVRT 方法開發

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(de)(de)(de)(de)論證,則應(ying)在ANDA中(zhong)提交IVRT方(fang)(fang)法(fa)(fa)(fa)(fa)開(kai)發報(bao)告(gao),以顯示(shi)IVRT方(fang)(fang)法(fa)(fa)(fa)(fa)是如何優化(hua)(hua)的(de)(de)(de)(de),并支持為(wei)IVRT選(xuan)擇(ze)的(de)(de)(de)(de)方(fang)(fang)法(fa)(fa)(fa)(fa)參(can)(can)數(shu)(shu)(shu)是合(he)適(shi)或必(bi)要(yao)的(de)(de)(de)(de)演(yan)示(shi),特別是在方(fang)(fang)法(fa)(fa)(fa)(fa)參(can)(can)數(shu)(shu)(shu)不同于本指南(nan)中(zhong)推薦的(de)(de)(de)(de)方(fang)(fang)法(fa)(fa)(fa)(fa)和美國藥(yao)典(USP)一般章節中(zhong)描述的(de)(de)(de)(de)方(fang)(fang)法(fa)(fa)(fa)(fa)的(de)(de)(de)(de)情況下。監管機構在審(shen)查方(fang)(fang)法(fa)(fa)(fa)(fa)開(kai)發報(bao)告(gao)時,比較關(guan)注IVRT方(fang)(fang)法(fa)(fa)(fa)(fa)參(can)(can)數(shu)(shu)(shu)選(xuan)擇(ze)的(de)(de)(de)(de)合(he)理性,以及這些參(can)(can)數(shu)(shu)(shu)是否具有合(he)適(shi)的(de)(de)(de)(de)敏(min)感度(du)和重現性。該方(fang)(fang)法(fa)(fa)(fa)(fa)開(kai)發報(bao)告(gao)應(ying)明確指出/區分每(mei)組數(shu)(shu)(shu)據所(suo)用的(de)(de)(de)(de)方(fang)(fang)法(fa)(fa)(fa)(fa)參(can)(can)數(shu)(shu)(shu),說明為(wei)優化(hua)(hua)IVRT方(fang)(fang)法(fa)(fa)(fa)(fa)所(suo)做的(de)(de)(de)(de)努力,并證明為(wei)IVRT選(xuan)擇(ze)的(de)(de)(de)(de)方(fang)(fang)法(fa)(fa)(fa)(fa)參(can)(can)數(shu)(shu)(shu)是合(he)適(shi)的(de)(de)(de)(de)。

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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(ren)使(shi)用(yong)本指(zhi)(zhi)南中(zhong)的(de)(de)建(jian)議(yi),如果申請人(ren)選(xuan)擇使(shi)用(yong)與本指(zhi)(zhi)南中(zhong)建(jian)議(yi)的(de)(de)方(fang)法(fa)不同(tong)的(de)(de)方(fang)法(fa),IVRT方(fang)法(fa)開發報告應(ying)(ying)說明選(xuan)擇替(ti)(ti)代(dai)(dai)方(fang)法(fa),進行(xing)IVRT方(fang)法(fa)優化的(de)(de)科學合理性(xing)。后續章節中(zhong)描述了具體示例,以幫助申請人(ren)確定應(ying)(ying)在(zai)ANDA中(zhong)提交信息的(de)(de)情況,以解釋為什么使(shi)用(yong)替(ti)(ti)代(dai)(dai)的(de)(de)方(fang)法(fa)。

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方法開發研究本質上是探索性的,通常使用未經驗證的樣品分析方法(例如,高效液相色譜(HPLC)或超高效液相色譜儀(UPLC)方法)進行;此外,IVRT方法開發研究通常以與質量管理體系不兼容的方式進行,所生成的證據不足以支持結論的可靠性。此類方法開發研究不適于證明IVRT方法或相關結果的有效性。因此,盡管這可能顯得多余,但在IVRT方法驗證期間,可能需要使用適當的控制措施(如與適當的質量管理體系兼容的經驗證的分析方法和程序)重復IVRT方法開發期間進行的某些實驗。

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(fa)開(kai)發過程(cheng)中(zhong)的(de)(de)實驗(yan)和結(jie)(jie)果(guo)(guo)與(yu)IVRT方法(fa)驗(yan)證(zheng)過程(cheng)中(zhong)的(de)(de)試驗(yan)和結(jie)(jie)果(guo)(guo)分開(kai)進(jin)行(xing)明(ming)確區分和一致識(shi)別是非常重要(yao)的(de)(de)。對(dui)于每組(zu)IVRT結(jie)(jie)果(guo)(guo),一致地確定(ding)所有相(xiang)關的(de)(de)方法(fa)參數和實驗(yan)條件/對(dui)照也很重要(yao)。方法(fa)開(kai)發報(bao)告中(zhong)的(de)(de)信(xin)息應(ying)明(ming)確識(shi)別/區分使用不同(tong)方法(fa)參數可(ke)能獲得的(de)(de)明(ming)顯相(xiang)似實驗(yan)組(zu)的(de)(de)結(jie)(jie)果(guo)(guo)。方法(fa)的(de)(de)開(kai)發報(bao)告應(ying)澄清平(ping)行(xing)或單獨運行(xing)的(de)(de)擴散池組(zu)(例如,在不同(tong)的(de)(de)日期)。此外,應(ying)確定(ding)用于分(fen)析(xi)每組IVRT實(shi)驗樣本的樣品分(fen)析(xi)方法(例(li)如(ru)HPLC或(huo)(huo)UPLC方法),報告應說明樣品分(fen)析(xi)方法是否(fou)有經過驗證(在樣品分(fen)析(xi)時或(huo)(huo)隨后(hou))。

A. IVRT Method Parameters IVRT 方法(fa)參數

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(ying)提供理論或經驗信息,以解(jie)釋(shi)IVRT方法參數的(de)選擇,如(ru)設備、上(shang)(shang)樣(yang)量、取樣(yang)時間(jian)、攪拌/攪拌速率(lv)等。當(dang)選擇的(de)設備是USP<1724>半固體藥(yao)物制劑—性能測試中(zhong)所(suo)述設備時,且(qie)上(shang)(shang)樣(yang)量或攪拌速率(lv)與所(suo)選的(de)設備匹配(未調節),可充分解(jie)釋(shi)選擇的(de)合理性。

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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(shi)長不應少于(yu)4小(xiao)(xiao)時(shi)。但是,對于(yu)某些特定類型的(de)(de)(de)制劑(ji),這可(ke)能(neng)發生在(zai)固定產品劑(ji)量(liang)在(zai)4小(xiao)(xiao)時(shi)內耗盡到如此大(da)的(de)(de)(de)程度(du),以(yi)至于(yu)釋(shi)放動力(li)(li)學(xue)此后不再是線性的(de)(de)(de)情況下(當以(yi)釋(shi)放量(liang)對時(shi)間(jian)(jian)的(de)(de)(de)平(ping)方(fang)根作圖)。在(zai)這種情況下,應解釋(shi)為優化IVRT方(fang)法所做的(de)(de)(de)努力(li)(li)(例如,使用允許(xu)使用更(geng)大(da)產品上樣量(liang)的(de)(de)(de)不同擴(kuo)散池設備),以(yi)便在(zai)4至6小(xiao)(xiao)時(shi)的(de)(de)(de)常規IVRT持(chi)續時(shi)間(jian)(jian)內可(ke)能(neng)表征(zheng)持(chi)續的(de)(de)(de)穩態釋(shi)放動力(li)(li)學(xue)。

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B. IVRT Receptor Solution  IVRT接收介質

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(chang),需(xu)要在(zai)IVRT方(fang)法開發過程中(zhong)對不同接(jie)(jie)(jie)受(shou)介(jie)(jie)質(zhi)進行評(ping)估都使用(yong)與待評(ping)估的(de)接(jie)(jie)(jie)受(shou)介(jie)(jie)質(zhi)具(ju)有廣泛化學相容性的(de)同一(yi)類(lei)型膜);這些接(jie)(jie)(jie)受(shou)液通常(chang)是基(ji)于受(shou)體(ti)溶液中(zhong)(通常(chang)是疏(shu)水性的(de))藥物的(de)溶解度和穩定性而(er)選擇(ze)的(de)二元水醇混合物。接(jie)(jie)(jie)受(shou)液通常(chang)在(zai)6小(xiao)時(shi)持續(xu)時(shi)間內(nei)至少每小(xiao)時(shi)取樣一(yi)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.

應提供藥(yao)(yao)物(wu)在(zai)接(jie)受(shou)液(ye)中(zhong)(zhong)的(de)(de)(de)(de)(de)(de)(de)經驗溶解(jie)度和穩(wen)定性(xing)的(de)(de)(de)(de)(de)(de)(de)信息(xi),以(yi)及IVRT中(zhong)(zhong)產(chan)生的(de)(de)(de)(de)(de)(de)(de)藥(yao)(yao)物(wu)釋(shi)放(fang)(fang)率(lv)(lv)(lv)的(de)(de)(de)(de)(de)(de)(de)線性(xing)和精密度的(de)(de)(de)(de)(de)(de)(de)信息(xi),用于解(jie)釋(shi)試(shi)驗方法中(zhong)(zhong)接(jie)受(shou)液(ye)選擇(ze)的(de)(de)(de)(de)(de)(de)(de)合理(li)性(xing)。理(li)想情況(kuang)下(xia)(xia),所有時(shi)(shi)(shi)間(jian)點(dian)的(de)(de)(de)(de)(de)(de)(de)藥(yao)(yao)物(wu)釋(shi)放(fang)(fang)速(su)率(lv)(lv)(lv)(斜率(lv)(lv)(lv))應成線性(xing)關系(r2值≥ 0.97).如(ru)何(he)在(zai)藥(yao)(yao)物(wu)在(zai)接(jie)受(shou)液(ye)中(zhong)(zhong)的(de)(de)(de)(de)(de)(de)(de)溶解(jie)度限(xian)制釋(shi)放(fang)(fang)動(dong)力學,導(dao)致最后(hou)一個時(shi)(shi)(shi)間(jian)點(dian)釋(shi)放(fang)(fang)速(su)率(lv)(lv)(lv)降低的(de)(de)(de)(de)(de)(de)(de)情況(kuang)下(xia)(xia),評(ping)估不(bu)同的(de)(de)(de)(de)(de)(de)(de)接(jie)受(shou)液(ye)可(ke)能(neng)是(shi)更有必要的(de)(de)(de)(de)(de)(de)(de)。如(ru)果縮(suo)短(duan)的(de)(de)(de)(de)(de)(de)(de)時(shi)(shi)(shi)間(jian)段內釋(shi)放(fang)(fang)速(su)率(lv)(lv)(lv)的(de)(de)(de)(de)(de)(de)(de)線性(xing)得到改善(表(biao)現出較(jiao)高的(de)(de)(de)(de)(de)(de)(de)r2值),并且與(yu)評(ping)估的(de)(de)(de)(de)(de)(de)(de)其他(ta)受(shou)體溶液(ye)相(xiang)比,該受(shou)體溶液(ye)中(zhong)(zhong)釋(shi)放(fang)(fang)動(dong)力學的(de)(de)(de)(de)(de)(de)(de)其他(ta)方面(例如(ru),精度)得到優化(hua),則將(jiang)IVRT方法縮(suo)短(duan)為(wei)4小時(shi)(shi)(shi)或5小時(shi)(shi)(shi)的(de)(de)(de)(de)(de)(de)(de)采樣(yang)時(shi)(shi)(shi)間(jian)段可(ke)能(neng)是(shi)合適的(de)(de)(de)(de)(de)(de)(de)。

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(shou)體溶液作(zuo)為IVRT方法開發的初(chu)始步驟的一(yi)個優點是,在(zai)使用(yong)接受(shou)液對不同膜(mo)進行評估之前,可(ke)先選定的接受(shou)液對樣品分析方法進行優化。

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(fang)(fang)(fang)法(fa)(fa)開(kai)發過程中(zhong)(zhong),通常評(ping)估不同的(de)膜(mo)(均(jun)使用相(xiang)同的(de)接(jie)受液(ye)(ye));這(zhe)些膜(mo)通常是(shi)(shi)用于(yu)(yu)過濾溶液(ye)(ye)中(zhong)(zhong)的(de)顆粒物(wu)質的(de)合(he)成膜(mo)。IVRT膜(mo)的(de)選(xuan)擇(ze)基于(yu)(yu)其有效孔徑(例如0.45微米(µm))以(yi)及(ji)其與藥物(wu)結合(he)的(de)預期惰性(xing)(xing)。IVRT方(fang)(fang)(fang)法(fa)(fa)開(kai)發報告中(zhong)(zhong)應提供每種膜(mo)與藥物(wu)的(de)結合(he)及(ji)其與為(wei)IVRT方(fang)(fang)(fang)法(fa)(fa)選(xuan)擇(ze)的(de)相(xiang)關(guan)受體溶液(ye)(ye)的(de)化學相(xiang)容(rong)性(xing)(xing)的(de)信息(xi)(基于(yu)(yu)IVRT方(fang)(fang)(fang)法(fa)(fa)發展的(de)前一階段),以(yi)及(ji)在IVRT中(zhong)(zhong)使用每種膜(mo)時所產生的(de)釋(shi)(shi)放速率的(de)線性(xing)(xing)和精度的(de)信息(xi),因(yin)為(wei)該(gai)信息(xi)可以(yi)幫(bang)助(zhu)解釋(shi)(shi)為(wei)什么特定膜(mo)對(dui)于(yu)(yu)IVRT方(fang)(fang)(fang)法(fa)(fa)是(shi)(shi)最佳(jia)的(de)。

IV. IVRT METHOD VALIDATION IVRT  方法驗證

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關鍵研(yan)(yan)究(jiu)(jiu)中使用(yong)的(de)(de)(de)(de)(de)設備(bei)、方(fang)(fang)(fang)(fang)(fang)法(fa)和研(yan)(yan)究(jiu)(jiu)條(tiao)件(jian)應經(jing)過合理的(de)(de)(de)(de)(de)驗(yan)(yan)(yan)證(zheng)或確(que)認(ren)。在啟動IVRT方(fang)(fang)(fang)(fang)(fang)法(fa)驗(yan)(yan)(yan)證(zheng)之前(qian),啟動IVRT的(de)(de)(de)(de)(de)樣品分析(xi)方(fang)(fang)(fang)(fang)(fang)法(fa)(例如,HPLC或UPLC方(fang)(fang)(fang)(fang)(fang)法(fa))的(de)(de)(de)(de)(de)驗(yan)(yan)(yan)證(zheng)是(shi)(shi)常(chang)規的(de)(de)(de)(de)(de),盡管(guan)樣品分析(xi)方(fang)(fang)(fang)(fang)(fang)法(fa)驗(yan)(yan)(yan)證(zheng)的(de)(de)(de)(de)(de)某(mou)些(xie)試驗(yan)(yan)(yan)(例如,穩定(ding)性)通常(chang)與(yu)IVRT方(fang)(fang)(fang)(fang)(fang)法(fa)的(de)(de)(de)(de)(de)驗(yan)(yan)(yan)證(zheng)平(ping)(ping)行(xing)進(jin)行(xing)。如果(guo)申(shen)(shen)請(qing)人選擇使用(yong)的(de)(de)(de)(de)(de)設備(bei)、方(fang)(fang)(fang)(fang)(fang)法(fa)或研(yan)(yan)究(jiu)(jiu)條(tiao)件(jian)與(yu)本(ben)指南或USP中推(tui)薦的(de)(de)(de)(de)(de)不同,申(shen)(shen)請(qing)人應證(zheng)明這些(xie)差異在科學上是(shi)(shi)合理的(de)(de)(de)(de)(de)。重要的(de)(de)(de)(de)(de)是(shi)(shi)要一致地確(que)定(ding)每組IVRT結(jie)果(guo)的(de)(de)(de)(de)(de)所有相關方(fang)(fang)(fang)(fang)(fang)法(fa)參數(shu),明確(que)結(jie)果(guo)是(shi)(shi)使用(yong)相同的(de)(de)(de)(de)(de)IVRT方(fang)(fang)(fang)(fang)(fang)法(fa)參數(shu)獲(huo)得的(de)(de)(de)(de)(de),并闡明哪些(xie)組擴散(san)池是(shi)(shi)平(ping)(ping)行(xing)或單獨運行(xing)的(de)(de)(de)(de)(de)。建議建立詳細的(de)(de)(de)(de)(de)方(fang)(fang)(fang)(fang)(fang)案和嚴格控(kong)制(zhi)的(de)(de)(de)(de)(de)測試程(cheng)序,以確(que)保(bao)精確(que)控(kong)制(zhi)上樣、取樣和其他IVRT研(yan)(yan)究(jiu)(jiu)參數(shu),以及實驗(yan)(yan)(yan)偏(pian)差的(de)(de)(de)(de)(de)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方法參數的限定指的是定(ding)義哪些屬性適合在IVRT方法中執行其功能的過程。例如,當每小時測量膜表面溫度(當安裝在擴散池中時)表明IVRT設備可以在6小時內將膜表面溫度保持在32°C±1°C的范圍內時,結果可以證明該設備在IVRT方法中執行其功能,其中方法參數是在6小時內將膜表面溫度控制在32°C±1°C的范圍內。盡管IVRT膜表面溫度在32°C±1°C范圍內適用于涂抹在皮膚上的局部產品,但對于粘膜外用制劑(如陰道凝膠),相關IVRT膜的表面溫度應為37°C±1°C。如適用,使用經驗證的樣品分析方法,在IVRT方法的驗證進行以下確認和控制。


A. Equipment Qualification設備確認

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(yong)(yong)章(zhang)節中有適用(yong)(yong)于IVRT方法(fa)的設備描述。(淺析(xi)FDA指導(dao)原則中(zhong)對申(shen)報用Franz測試裝(zhuang)置的(de)要求)這些包(bao)括不(bu)同模(mo)型(xing)的(de)(de)垂直(zhi)擴散池和浸(jin)沒(mei)池的(de)(de)。在(zai)設計和/或操作原(yuan)理(li)上與(yu)USP<1724>通用(yong)章節(jie)中(zhong)描述(shu)的(de)(de)那些基(ji)本(ben)相同的(de)(de)垂直(zhi)擴散池和浸(jin)沒(mei)池的(de)(de)其(qi)他模(mo)型(xing)也可(ke)能使(shi)用(yong)。

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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(mei)種設備的(de)工(gong)作原理和(he)特定測試方法(fa)不同;制造商的(de)相關程(cheng)序(xu)可(ke)用于安(an)裝、操作和(he)性(xing)能(neng)鑒(jian)定。每(mei)個(ge)擴散(san)池的(de)實驗室(shi)確定,至少應包括:(1)測量(liang)供給室(shi)和(he)接(jie)(jie)受(shou)室(shi)之間(jian)膜(mo)(mo)安(an)裝位置的(de)孔口的(de)擴散(san)面積,;(2) 每(mei)個(ge)擴散(san)池的(de)接(jie)(jie)受(shou)室(shi)的(de)容積;(3)在相關研究持續時間(jian)(例如,6小時)內(nei)測量(liang)膜(mo)(mo)表(biao)面(例如,32°C&plusmn;1°C)或(huo)膜(mo)(mo)正下方的(de)溫度,的(de)穩定性(xing);以及(4)如適用,測定攪(jiao)拌或(huo)攪(jiao)拌的(de)速(su)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(ru)(ru)(ru)(ru)果制(zhi)造商提供(gong)了與每個擴散(san)(san)池(chi)的(de)孔擴散(san)(san)面(mian)積(ji)(ji)和接受室容積(ji)(ji)相關的(de)信息,則除了實驗(yan)室進行(xing)的(de)經驗(yan)測量外,還應提供(gong)每個相關擴散(san)(san)池(chi)的(de)信息。設(she)備應控制(zhi)擴散(san)(san)池(chi)溫度(du)(du)調節,以便在(zai)(zai)給藥前(qian)驗(yan)證(zheng)每個擴散(san)(san)池(chi)的(de)膜(mo)表面(mian)溫度(du)(du)是否(fou)穩(wen)定(ding)(例如(ru)(ru)(ru)(ru),32°C±1°C)(例如(ru)(ru)(ru)(ru),通過校(xiao)準的(de)紅外溫度(du)(du)計測量)。如(ru)(ru)(ru)(ru)果由(you)于(yu)(yu)特定(ding)設(she)備的(de)設(she)計和操作原(yuan)理,在(zai)(zai)給藥前(qian)無法驗(yan)證(zheng)擴散(san)(san)池(chi)的(de)膜(mo)表面(mian)溫度(du)(du)是否(fou)已達到平衡(heng)和穩(wen)定(ding)(例如(ru)(ru)(ru)(ru),在(zai)(zai)32°C±1°C),對(dui)于(yu)(yu)該類(lei)型的(de)設(she)備確認應證(zheng)明,在(zai)(zai)IVRT方法使用的(de)特定(ding)條件下(xia),在(zai)(zai)整個測試過程中,每個擴散(san)(san)池(chi)的(de)膜(mo)表面(mian)溫度(du)(du)可(ke)以預期保持穩(wen)定(ding)的(de)(例如(ru)(ru)(ru)(ru),在(zai)(zai)32°C±1°C)。(如(ru)(ru)(ru)(ru)下(xia)圖,膜(mo)溫度(du)(du)平衡(heng)預實驗(yan))

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B. Membrane Qualification  膜確(que)認

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(zai)試驗期間,應在(zai)與接受液(ye)中藥(yao)物濃度范(fan)圍下(xia),根(gen)據藥(yao)物在(zai)接受液(ye)中與膜(mo)(mo)吸附(fu)來評估(gu)膜(mo)(mo)惰性。測(ce)定(ding)應基于(yu)在(zai)相關溫度下(xia)(例如,32°C±1°C下(xia)6小時)IVRT持續時間內(nei)(nei)至少重(zhong)復三次膜(mo)(mo)孵育。應在(zai)沒有膜(mo)(mo)的情況(kuang)下(xia)平行進(jin)行三次重(zhong)復對(dui)照孵育,以監測(ce)與膜(mo)(mo)結合無關的藥(yao)物損(sun)失。應在(zai)孵育前后收集(ji)這(zhe)些溶液(ye)的等分試樣,以評估(gu)溶液(ye)中藥(yao)物量(liang)的減(jian)少。建(jian)議在(zai)試驗結束(shu)時,溶液(ye)中藥(yao)物的回收率(lv)在(zai)100%±5%的范(fan)圍內(nei)(nei),可以確認(ren)膜(mo)(mo)的惰性。

C. Receptor Solution Qualification  接收介質確認

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)

應解釋選擇(ze)IVRT研究(jiu)(jiu)所(suo)用接(jie)受液(ye)成分(fen)的(de)原(yuan)因。藥物在(zai)(zai)IVRT接(jie)受液(ye)中的(de)溶解度,應根據經驗測定(ding)一式三份,以(yi)說明藥物在(zai)(zai)接(jie)受液(ye)中溶解度超過(guo)IVRT正式研究(jiu)(jiu)中的(de)最大藥物濃度,理想情況下是一個(ge)數量級或者(zhe)是足以(yi)促成研究(jiu)(jiu)期(qi)間釋放速率的(de)線性關系(xi)(穩態)(即使在(zai)(zai)IVRT方法驗證期(qi)間評估配方的(de)相對較(jiao)高釋放率時,即RS標(biao)稱規格的(de)150%)

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D. Receptor Solution Sampling Qualification  接收液取(qu)樣確(que)認

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(mei)個時間點的接(jie)(jie)受(shou)液取(qu)(qu)樣的準(zhun)確(que)(que)度(du)和精密度(du)應進行確(que)(que)認。確(que)(que)認取(qu)(qu)樣程序的過程應証明(ming),取(qu)(qu)樣技術可(ke)在每(mei)次取(qu)(qu)樣時從的混合良(liang)好的接(jie)(jie)受(shou)室(shi)中(zhong)(zhong)可(ke)靠地(di)收(shou)集相同(tong)體積的樣品,并且不會(hui)因(yin)取(qu)(qu)樣技術的原因(yin)引(yin)起誤(wu)差(例如,由于自動取(qu)(qu)樣系(xi)統(tong)中(zhong)(zhong)的樣本(ben)之間的干擾或殘留,或由于從垂直擴散池(chi)的未混合均一取(qu)(qu)樣臂(bei)中(zhong)(zhong)取(qu)(qu)樣)。應描述設備制造商關(guan)于接(jie)(jie)受(shou)液取(qu)(qu)樣準(zhun)確(que)(que)度(du)和精密度(du)的規(gui)范(fan)信息(如有)。

E. Environmental Control  環境控(kong)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.

應監測和報告研究期間的實(shi)驗室環(huan)(huan)境溫(wen)度(du)(du)(du)和濕度(du)(du)(du)。建(jian)(jian)議環(huan)(huan)境控制(zhi)溫(wen)度(du)(du)(du)范圍(wei)為(wei)(wei)21°C±2°C,如果可行,建(jian)(jian)議濕度(du)(du)(du)范圍(wei)為(wei)(wei)50%±20%相(xiang)對濕度(du)(du)(du)。

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的整個研究期間,根據所有采樣時間點的釋放速率繪制標準曲線,應呈線性關系(r2值)。應計算并報告每個擴散池的藥物釋放線性方程,并與所有IVRT研究結果進行比較。為了使釋放速率為線性的前提是,建議IVRT研究持續時間為4–6小時,其應具有r2值≥0.97。通常小于4小時的IVRT研究持續時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態藥物釋放動力學,但是,如果方法開發報告中有令人信服的實驗數據支持,說明已做出合理和科學上的努力來優化IVRT方法,則IVRT研究持續時間小于4小時(不推薦)也是可以接受的。IVRT方法的線性和范圍應根據精密度和重復性試驗的結果確定,詳見如下所述。

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G. Precision and Reproducibility   精密度和(he)重現性

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(ke)以針對每個擴散(san)池的(de)釋放速率(斜率)計(ji)算批(pi)(pi)內(nei)和批(pi)(pi)間精密度和重(zhong)(zhong)現(xian)性(xing)(xing)。應計(ji)算批(pi)(pi)內(nei)和批(pi)(pi)間斜率的(de)平均值、標準偏(pian)差和變異系(xi)數百分(fen)比(%CV),批(pi)(pi)內(nei)和批(pi)(pi)間%CV,均應≤ 15%。可(ke)以組(zu)織(zhi)運行響應面實驗(yan)(yan),以便于同(tong)時(shi)評(ping)估儀(yi)器內(nei)部/內(nei)部和/或(huo)操作員內(nei)部/內(nei)部的(de)精密度和重(zhong)(zhong)復性(xing)(xing)。建議至(zhi)少進(jin)行三次獨立(li)的(de)精密度和重(zhong)(zhong)現(xian)性(xing)(xing)試驗(yan)(yan)。

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(ying)計算(suan)接受(shou)液(ye)中(zhong)(zhong)釋(shi)放(fang)藥物(wu)的(de)(de)(de)(de)(de)回收率,用(yong)(yong)以(yi)(yi)表(biao)征IVRT研(yan)究期間,釋(shi)放(fang)到接受(shou)液(ye)中(zhong)(zhong)的(de)(de)(de)(de)(de)累積藥物(wu)量(liang)(liang)(liang)(liang)。這可(ke)(ke)以(yi)(yi)表(biao)示為上(shang)樣(yang)(yang)(yang)劑(ji)(ji)量(liang)(liang)(liang)(liang)中(zhong)(zhong)藥物(wu)量(liang)(liang)(liang)(liang)的(de)(de)(de)(de)(de)百(bai)分(fen)比(其(qi)可(ke)(ke)以(yi)(yi)根(gen)據外用(yong)(yong)制(zhi)(zhi)劑(ji)(ji)中(zhong)(zhong)藥物(wu)的(de)(de)(de)(de)(de)標示規(gui)格和膜上(shang)大(da)致上(shang)樣(yang)(yang)(yang)量(liang)(liang)(liang)(liang)來評(ping)估(gu)(gu)(gu))。例如,如果在(zai)每(mei)(mei)個(ge)擴(kuo)散(san)(san)池的(de)(de)(de)(de)(de)膜上(shang)的(de)(de)(de)(de)(de)上(shang)樣(yang)(yang)(yang)量(liang)(liang)(liang)(liang)為1克(g),制(zhi)(zhi)劑(ji)(ji)標示規(gui)格含(han)有5%藥物(wu),則(ze)上(shang)樣(yang)(yang)(yang)劑(ji)(ji)量(liang)(liang)(liang)(liang)中(zhong)(zhong)的(de)(de)(de)(de)(de)藥物(wu)量(liang)(liang)(liang)(liang)可(ke)(ke)估(gu)(gu)(gu)計為50mg。如果在(zai)IVRT的(de)(de)(de)(de)(de)6小時(shi)(shi)(shi)持續(xu)時(shi)(shi)(shi)間內(nei),共有10mg的(de)(de)(de)(de)(de)藥物(wu)擴(kuo)散(san)(san)到每(mei)(mei)個(ge)擴(kuo)散(san)(san)測試池的(de)(de)(de)(de)(de)接受(shou)液(ye)中(zhong)(zhong),則(ze)可(ke)(ke)以(yi)(yi)估(gu)(gu)(gu)計50mg劑(ji)(ji)量(liang)(liang)(liang)(liang)已(yi)經消耗(hao)(hao)(hao)10mg,相當(dang)于20%的(de)(de)(de)(de)(de)劑(ji)(ji)量(liang)(liang)(liang)(liang)消耗(hao)(hao)(hao)。因此(ci),可(ke)(ke)以(yi)(yi)估(gu)(gu)(gu)計并(bing)報告平(ping)均劑(ji)(ji)量(liang)(liang)(liang)(liang)消耗(hao)(hao)(hao)百(bai)分(fen)比。雖然在(zai)劑(ji)(ji)量(liang)(liang)(liang)(liang)消耗(hao)(hao)(hao)小于30%的(de)(de)(de)(de)(de)條件下通常(chang)可(ke)(ke)以(yi)(yi)假設穩態(tai)釋(shi)放(fang)動力學,但對于一些外用(yong)(yong)制(zhi)(zhi)劑(ji)(ji),在(zai)較(jiao)高百(bai)分(fen)比的(de)(de)(de)(de)(de)劑(ji)(ji)量(liang)(liang)(liang)(liang)消耗(hao)(hao)(hao)下可(ke)(ke)以(yi)(yi)繼續(xu)觀(guan)察到穩態(tai)釋(shi)放(fang)動力學。當(dang)實驗(yan)證(zheng)據表(biao)明每(mei)(mei)個(ge)擴(kuo)散(san)(san)池的(de)(de)(de)(de)(de)釋(shi)放(fang)速(su)率(斜率)與時(shi)(shi)(shi)間的(de)(de)(de)(de)(de)平(ping)方根(gen)作圖時(shi)(shi)(shi),每(mei)(mei)個(ge)擴(kuo)散(san)(san)池的(de)(de)(de)(de)(de)釋(shi)放(fang)速(su)率也能保持線性關(guan)系,盡(jin)管劑(ji)(ji)量(liang)(liang)(liang)(liang)消耗(hao)(hao)(hao)大(da)于30%,IVRT方法也被認為是考慮充分(fen)的(de)(de)(de)(de)(de)

I.Discrimination Sensitivity, Specificity, and Selectivity   區(qu)分力—靈敏度(du)、專屬性(xing)和選擇(ze)性(xing)

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(ying)能(neng)(neng)夠區分相(xiang)似制(zhi)(zhi)劑(ji)的(de)(de)(de)(de)藥(yao)(yao)物釋放(fang)率。應(ying)通(tong)(tong)過將試驗制(zhi)(zhi)劑(ji)的(de)(de)(de)(de)釋放(fang)速率與藥(yao)(yao)物濃度(du)發(fa)生變化的(de)(de)(de)(de)兩(liang)種改變規(gui)(gui)(gui)格的(de)(de)(de)(de)制(zhi)(zhi)劑(ji)的(de)(de)(de)(de)釋放(fang)率進行比較(jiao)來評估這一點——一個較(jiao)高規(gui)(gui)(gui)格(RS標稱濃度(du)的(de)(de)(de)(de)150%),另(ling)一個較(jiao)低(di)(di)規(gui)(gui)(gui)格(RS額定濃度(du)的(de)(de)(de)(de)50%)。如果在配制(zhi)(zhi)與標示規(gui)(gui)(gui)格相(xiang)比為(wei)150%的(de)(de)(de)(de)局部產品時觀察到(dao)活性成分析出(chu),則可能(neng)(neng)需要使(shi)用不(bu)同的(de)(de)(de)(de)策略(lve),這可以(yi)在ANDA前產品開(kai)發(fa)會議期間(jian)或通(tong)(tong)過受(shou)控通(tong)(tong)信在提(ti)交ANDA之(zhi)前與機構(gou)討論。應(ying)報告(gao)較(jiao)高和(he)較(jiao)低(di)(di)規(gui)(gui)(gui)格配方的(de)(de)(de)(de)組成和(he)制(zhi)(zhi)備(bei)程序(xu),盡管這些(xie)配方制(zhi)(zhi)劑(ji)不(bu)是(shi)在符(fu)合GMP條(tiao)件下制(zhi)(zhi)備(bei)。IVRT方法的(de)(de)(de)(de)區分力(li)應(ying)從以(yi)下三個概念來描述:靈敏度(du)、特異性和(he)選(xuan)擇(ze)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(du)是檢測釋(shi)放(fang)速率變(bian)化的(de)能力(li),釋(shi)放(fang)速率作為(wei)制(zhi)劑(ji)中藥物(wu)濃度(du)的(de)函數。如(ru)果同一(yi)天,對RS、較高規(gui)格和較低(di)規(gui)格平行實(shi)驗,IVRT方法一(yi)致地識別制(zhi)劑(ji)的(de)釋(shi)放(fang)速率更高或(huo)更低(di),則通(tong)常認為(wei)IVRT方法是靈敏的(de)。

IVRT Specificity IVRT  特異性(xing)

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(yi)(yi)性是準確(que)監測釋(shi)放(fang)(fang)速(su)率隨制劑(ji)中(zhong)藥物濃(nong)度變化的(de)(de)(de)(de)(de)比例(li)的(de)(de)(de)(de)(de)能力(li)。該比例(li)可以用制劑(ji)濃(nong)度和(he)平(ping)均IVRT釋(shi)放(fang)(fang)速(su)率(斜(xie)(xie)率)之間的(de)(de)(de)(de)(de)關系圖來(lai)說明(ming)。應通(tong)過繪制線性趨勢線,將線性量化并(bing)報告為r2值,評估IVRT方法的(de)(de)(de)(de)(de)特異(yi)(yi)性,。IVRT方法在其對釋(shi)放(fang)(fang)速(su)率差異(yi)(yi)的(de)(de)(de)(de)(de)響應中(zhong)應該是成比例(li)的(de)(de)(de)(de)(de)線性的(de)(de)(de)(de)(de),制劑(ji)濃(nong)度與平(ping)均IVRT釋(shi)放(fang)(fang)速(su)率(斜(xie)(xie)率)最小的(de)(de)(de)(de)(de)r2值≥ 0.95,表示改方法具有(you)合適的(de)(de)(de)(de)(de)特異(yi)(yi)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(chan)品不(bu)同(tong)(tong)規(gui)格(ge)(ge)的(de)釋放速率(lv)比例(li)的(de)函數,其中一(yi)些或全部可(ke)作為小規(gui)模實驗室批次(ci)配(pei)制,每個規(gui)格(ge)(ge)的(de)制劑組成略有不(bu)同(tong)(tong),以適(shi)應該產(chan)品規(gui)格(ge)(ge)中活性成分的(de)不(bu)同(tong)(tong)量(liang)。產(chan)品不(bu)同(tong)(tong)規(gui)格(ge)(ge)的(de)這些輕(qing)微配(pei)方差異可(ke)能會影響(xiang)產(chan)品不(bu)同(tong)(tong)規(gui)格(ge)(ge)釋放速率(lv)的(de)理想比例(li)。

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,產品不同規格的釋放速率的比例線性可能受到不同規格的配方差異的影響,這些差異與IVRT方法的比例響應性無關。由于制劑差異與IVRT方法無關,考慮到IVRT方法對釋放速率差異的響應可能不全部成比例,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(chan)品不同(tong)規格的(de)(de)(de)(de)釋(shi)放速率的(de)(de)(de)(de)線性(xing)(評(ping)(ping)估(gu)IVRT方法(fa)(fa)的(de)(de)(de)(de)特異性(xing),最小r2值≥ 0.95)與在取樣時間范(fan)圍內的(de)(de)(de)(de)產(chan)品單一濃度的(de)(de)(de)(de)釋(shi)放速率的(de)(de)(de)(de)線性(xing)(這(zhe)評(ping)(ping)估(gu)了IVRT方法(fa)(fa)監(jian)測活性(xing)成分(fen)穩態釋(shi)放動力學(xue)的(de)(de)(de)(de)能(neng)力,具(ju)有最小r2值≥0.97)。盡(jin)管(guan)在每種情況(kuang)下(xia),不同(tong)的(de)(de)(de)(de)科學(xue)考(kao)慮因素可(ke)能(neng)會(hui)影響IVRT結果的(de)(de)(de)(de)線性(xing),但(dan)對于良好開發和適(shi)當(dang)控(kong)制(zhi)的(de)(de)(de)(de)IVRT方法(fa)(fa),在兩種情況(kuang)下(xia),r2值≥ 0.99通(tong)常都(dou)是(shi)滿足的(de)(de)(de)(de)。(如(ru)下(xia)圖r2=0.9915)

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IVRT Selectivity IVRT   選擇(ze)性(xing)

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(xuan)擇性是IVRT方法(fa)區分(fen)參考(kao)外(wai)用(yong)制(zhi)劑和改變的(de)(de)(50%和150%標(biao)示規格)濃度測試制(zhi)劑之(zhi)間(jian)的(de)(de)藥物釋放(fang)速(su)(su)率(lv)的(de)(de)能力,從而確定它們的(de)(de)釋放(fang)速(su)(su)率(lv)與標(biao)示參考(kao)規格制(zhi)劑的(de)(de)釋放(fang)速(su)(su)率(lv)在統計(ji)上(shang)不(bu)相等。應(ying)使用(yong)USP通(tong)用(yong)章(zhang)節<1724>中描(miao)述(shu)的(de)(de)統計(ji)方法(fa)評估釋放(fang)速(su)(su)率(lv)之(zhi)間(jian)的(de)(de)不(bu)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(yan),應使(shi)用(yong)USP通用(yong)<1724>章節中所述(shu)的(de)統計方法,將六(liu)(liu)杯(bei)(bei)標(biao)示(shi)規(gui)格(ge)制(zhi)劑(ji)的(de)測試(shi)池的(de)釋(shi)放(fang)率(lv)(lv)與六(liu)(liu)杯(bei)(bei)150%標(biao)示(shi)制(zhi)劑(ji)的(de)測試(shi)池釋(shi)放(fang)率(lv)(lv)進(jin)行比較,根據(ju)<1724>章節要求(qiu),這12杯(bei)(bei)應在(zai)同一天(tian)平行實驗,在(zai)標(biao)示(shi)規(gui)格(ge)的(de)150%時,制(zhi)劑(ji)的(de)釋(shi)放(fang)速率(lv)(lv)不能顯示(shi)出(chu)與標(biao)示(shi)規(gui)格(ge)制(zhi)劑(ji)的(de)釋(shi)放(fang)率(lv)(lv)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(ying)使用USP通用章(zhang)節<1724>中描述的統計方(fang)法,將6個測試(shi)池的標示規(gui)格(ge)(ge)濃度(du)制(zhi)劑(即100%規(gui)格(ge)(ge))的釋放(fang)(fang)(fang)率與6個測試(shi)池50%規(gui)格(ge)(ge)時的釋放(fang)(fang)(fang)率進行(xing)比(bi)較,這(zhe)12杯(bei)應(ying)在(zai)同一天(tian)平行(xing)實驗,50%規(gui)格(ge)(ge)制(zhi)劑配方(fang)的釋放(fang)(fang)(fang)速(su)率應(ying)與對照制(zhi)劑的釋放(fang)(fang)(fang)率不等效(xiao)。

IVRT Supplemental Selectivity IVRT  補充(chong)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補充選擇(ze)性是IVRT方法區分參考(kao)外用制劑(ji)和(he)具有相同標示規格的(de)改變制劑(ji)之間的(de)藥物釋放速率的(de)能力,從(cong)而(er)確定它(ta)們的(de)釋放速率在統(tong)計上不等效。

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(xuan)擇性的(de)(de)證明(不(bu)同(tong)于補充選(xuan)擇性)驗證了IVRT方(fang)(fang)法在預(yu)計(ji)釋(shi)放速(su)(su)率(lv)可以(yi)預(yu)測的(de)(de)方(fang)(fang)式(shi)不(bu)同(tong)的(de)(de)條件下(即(ji),當制劑中存在不(bu)同(tong)濃度的(de)(de)藥(yao)物時(shi))區(qu)分釋(shi)放速(su)(su)率(lv)差異(yi)的(de)(de)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(zai)可(ke)行(xing)的(de)(de)(de)情況下,IVRT方(fang)(fang)法(fa)(fa)選擇性(xing)的(de)(de)(de)單獨(du)和補充證(zheng)明獨(du)立驗證(zheng)了IVRT方(fang)(fang)法(fa)(fa)在(zai)關鍵IVRT研究條件下區(qu)分釋(shi)放(fang)率差異的(de)(de)(de)能(neng)力(li),其(qi)中自制(zhi)和對照(zhao)外用制(zhi)劑以相同的(de)(de)(de)規(gui)格進行(xing)比較。因此(ci),在(zai)可(ke)行(xing)情況下,理想情況下的(de)(de)(de)IVRT方(fang)(fang)法(fa)(fa)選擇性(xing)的(de)(de)(de)補充論(lun)證(zheng)證(zheng)明了它可(ke)以檢測與制(zhi)劑的(de)(de)(de)規(gui)格以外的(de)(de)(de)方(fang)(fang)面相關的(de)(de)(de)釋(shi)放(fang)速率的(de)(de)(de)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(ying)使用(yong)(yong)USP通用(yong)(yong)章(zhang)節(jie)<1724>中所述的(de)統計(ji)方法評(ping)估釋(shi)放(fang)速率(lv)之間的(de)不等(deng)效(xiao)。具體而(er)言(yan),應(ying)使用(yong)(yong)USP通用(yong)(yong)章(zhang)節(jie)<1724>中描述的(de)統計(ji)方法,將對照標(biao)(biao)示(shi)配方給(gei)(gei)藥(yao)的(de)6個測(ce)試池(chi)(chi)的(de)釋(shi)放(fang)速率(lv)與相同(tong)規格(ge)下(xia)的(de)改變配方給(gei)(gei)藥(yao)6個測(ce)試池(chi)(chi)的(de)釋(shi)放(fang)率(lv)進(jin)行比較,并且在(zai)相同(tong)的(de)標(biao)(biao)示(shi)規格(ge)下(xia),來自(zi)改變的(de)制劑的(de)釋(shi)放(fang)速率(lv)應(ying)當顯(xian)示(shi)出與對照標(biao)(biao)示(shi)制劑的(de)釋(shi)放(fang)率(lv)等(deng)效(xiao)。

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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(yong)(yong)(yong)(yong)于(yu)(yu)評估補(bu)充(chong)選擇(ze)性(xing)(xing)的(de)(de)(de)(de)(de)改(gai)變配(pei)方應(ying)具(ju)有與對(dui)照外(wai)用(yong)(yong)(yong)(yong)制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji)具(ju)有相(xiang)同(tong)規格(ge)、不同(tong)配(pei)方的(de)(de)(de)(de)(de)制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji),并且可改(gai)變的(de)(de)(de)(de)(de)特性(xing)(xing)包括:非(fei)(fei)活(huo)(huo)性(xing)(xing)成(cheng)分(fen)的(de)(de)(de)(de)(de)變化(hua)(hua)、非(fei)(fei)活(huo)(huo)性(xing)(xing)成(cheng)分(fen)濃(nong)度的(de)(de)(de)(de)(de)變化(hua)(hua)、制(zhi)(zhi)(zhi)造(zao)工藝(yi)的(de)(de)(de)(de)(de)變化(hua)(hua)或(huo)其(qi)組合。然而,與對(dui)照配(pei)方制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji)相(xiang)比,并非(fei)(fei)所有制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji)的(de)(de)(de)(de)(de)變化(hua)(hua)都(dou)必然會(hui)產(chan)生釋(shi)放速(su)率(lv)的(de)(de)(de)(de)(de)差異,如果(guo)發(fa)現兩種(zhong)類(lei)似的(de)(de)(de)(de)(de)制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji)具(ju)有相(xiang)同(tong)的(de)(de)(de)(de)(de)釋(shi)放速(su)率(lv),則不適(shi)用(yong)(yong)(yong)(yong)于(yu)(yu)論證補(bu)充(chong)選擇(ze)性(xing)(xing)。因此,鼓(gu)勵申(shen)請(qing)人根(gen)據制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji)(相(xiang)對(dui)于(yu)(yu)對(dui)照配(pei)方)的(de)(de)(de)(de)(de)物理化(hua)(hua)學和結(jie)構性(xing)(xing)質的(de)(de)(de)(de)(de)差異,開發(fa)或(huo)選擇(ze)一(yi)種(zhong)可能會(hui)改(gai)變活(huo)(huo)性(xing)(xing)成(cheng)分(fen)釋(shi)放速(su)率(lv)的(de)(de)(de)(de)(de)制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji),以論證補(bu)充(chong)選擇(ze)性(xing)(xing)。變更的(de)(de)(de)(de)(de)制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji)可以是上市(shi)的(de)(de)(de)(de)(de)外(wai)用(yong)(yong)(yong)(yong)制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji),例如相(xiang)同(tong)規格(ge)的(de)(de)(de)(de)(de)相(xiang)同(tong)藥物的(de)(de)(de)(de)(de)不同(tong)劑(ji)(ji)(ji)(ji)型(例如,5%凝膠與5%軟膏)。如適(shi)用(yong)(yong)(yong)(yong),應(ying)在(zai)研(yan)究報告中提交,IVRT方法開發(fa)和驗(yan)證研(yan)究中使用(yong)(yong)(yong)(yong)的(de)(de)(de)(de)(de)所有外(wai)用(yong)(yong)(yong)(yong)制(zhi)(zhi)(zhi)劑(ji)(ji)(ji)(ji)相(xiang)關批次信(xin)息。包括但不限于(yu)(yu):有關批次配(pei)方、生產(chan)日期(qi)、批次大小、變更的(de)(de)(de)(de)(de)生產(chan)工藝(yi)(如適(shi)用(yong)(yong)(yong)(yong))以及效價(jia)和含(han)量均勻度(如可用(yong)(yong)(yong)(yong))的(de)(de)(de)(de)(de)信(xin)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(guo)在改(gai)變的(de)(de)(de)IVRT方(fang)法(fa)參數(shu)下,IVRT運行(xing)的(de)(de)(de)平均(jun)斜率在精密度和重現(xian)性研究中獲得IVRT運行(xing)平均(jun)斜率的(de)(de)(de)±15%以內,則(ze)IVRT方(fang)法(fa)可被認(ren)為(wei)對該(gai)參數(shu)的(de)(de)(de)的(de)(de)(de)改(gai)變具有耐用性。耐用性測試可能包括(kuo)IVRT方(fang)法(fa)中相關(guan)的(de)(de)(de)設備和測試方(fang)法(fa)的(de)(de)(de)改(gai)變,例(li)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(shang)樣(yang)體積變化(例如(ru),上(shang)樣(yang)體積的+10%和(he)-10%)

lReceptor solution variations (e.g., slight change in composition and/or pH) 接受液(ye)變(bian)化(hua)(例(li)如,輕微改變(bian)組(zu)成(cheng)和/或pH值)

lMixing rate variation (e.g., slight change in stirring speed, as applicable) 混合速率變(bian)(bian)化(例(li)如,輕微改變(bian)(bian)攪拌速率,如適用)

V. SAMPLE  ANALYTICAL  METHOD  VALIDATION  樣品分析方法驗證

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(jin)管IVRT方(fang)(fang)(fang)(fang)(fang)法(fa)(fa)開發(fa)期間進(jin)(jin)行的(de)(de)(de)探(tan)索性研(yan)究(jiu),可以使用未經驗(yan)證(zheng)(zheng)的(de)(de)(de)樣(yang)品(pin)(pin)分析方(fang)(fang)(fang)(fang)(fang)法(fa)(fa),但作為(wei)IVRT方(fang)(fang)(fang)(fang)(fang)法(fa)(fa)驗(yan)證(zheng)(zheng)的(de)(de)(de)一部(bu)分,在(zai)進(jin)(jin)行IVRT的(de)(de)(de)所(suo)有研(yan)究(jiu)都(dou)必(bi)須使用經驗(yan)證(zheng)(zheng)的(de)(de)(de)樣(yang)品(pin)(pin)分析方(fang)(fang)(fang)(fang)(fang)法(fa)(fa)。已驗(yan)證(zheng)(zheng)的(de)(de)(de)IVRT方(fang)(fang)(fang)(fang)(fang)法(fa)(fa)應使用已驗(yan)證(zheng)(zheng)的(de)(de)(de)接受液樣(yang)品(pin)(pin)分析方(fang)(fang)(fang)(fang)(fang)法(fa)(fa)。因此,本部(bu)分討論的(de)(de)(de)IVRT方(fang)(fang)(fang)(fang)(fang)法(fa)(fa)樣(yang)品(pin)(pin)分析方(fang)(fang)(fang)(fang)(fang)法(fa)(fa)。

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(de)注意的是,與IVRT方(fang)法(fa)相關的研究方(fang)案(an)和(he)報(bao)告(gao)(gao)與用于(yu)定量IVRT接受液(ye)樣品中藥物濃度的樣品分析(xi)(xi)方(fang)法(fa)不同(tong)。樣品分析(xi)(xi)方(fang)法(fa)的驗證本身并不能證明(ming)IVRT方(fang)法(fa)的有(you)效性(xing)。因此,應提(ti)交單獨和(he)具體(ti)的報(bao)告(gao)(gao),已驗證樣品分析(xi)(xi)(如HPLC或UPLC)方(fang)法(fa)和(he)IVRT方(fang)法(fa)的驗證報(bao)告(gao)(gao)。

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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(fang)(fang)(fang)法(fa)(fa)(fa)開發期間(jian)使用(yong)的(de)(de)(de)(de)樣(yang)(yang)(yang)品(pin)(pin)(pin)分(fen)析方(fang)(fang)(fang)法(fa)(fa)(fa)與(yu)最終驗(yan)證(zheng)(zheng)(zheng)的(de)(de)(de)(de)樣(yang)(yang)(yang)品(pin)(pin)(pin)分(fen)析方(fang)(fang)(fang)法(fa)(fa)(fa)不同,與(yu)其相關(guan)的(de)(de)(de)(de)IVRT方(fang)(fang)(fang)法(fa)(fa)(fa)研究結(jie)(jie)果無法(fa)(fa)(fa)支持IVRT方(fang)(fang)(fang)法(fa)(fa)(fa)的(de)(de)(de)(de)有效性。IVRT方(fang)(fang)(fang)法(fa)(fa)(fa)驗(yan)證(zheng)(zheng)(zheng)報(bao)告(gao)(gao)中應提供參考(單獨)樣(yang)(yang)(yang)品(pin)(pin)(pin)分(fen)析方(fang)(fang)(fang)法(fa)(fa)(fa)驗(yan)證(zheng)(zheng)(zheng)的(de)(de)(de)(de)信(xin)息,并明確指出IVRT方(fang)(fang)(fang)法(fa)(fa)(fa)確認報(bao)告(gao)(gao)中的(de)(de)(de)(de)所有相關(guan)結(jie)(jie)果均是使用(yong)經(jing)驗(yan)證(zheng)(zheng)(zheng)的(de)(de)(de)(de)樣(yang)(yang)(yang)品(pin)(pin)(pin)分(fen)析方(fang)(fang)(fang)法(fa)(fa)(fa)獲得的(de)(de)(de)(de)(而不是使用(yong)與(yu)經(jing)驗(yan)證(zheng)(zheng)(zheng)的(de)(de)(de)(de)分(fen)析方(fang)(fang)(fang)法(fa)(fa)(fa)具有不同參數(shu)的(de)(de)(de)(de)樣(yang)(yang)(yang)品(pin)(pin)(pin)分(fen)析方(fang)(fang)(fang)法(fa)(fa)(fa))。

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(fa),通(tong)常涉及HPLC或(huo)UPLC,應(ying)(ying)使用帶有審計跟(gen)蹤的色譜(pu)軟件(例如色譜(pu)數(shu)據(ju)系統(tong))進行(xing),,并應(ying)(ying)包括多點(6-8濃度)校準曲(qu)線,以及適(shi)當的質(zhi)量(liang)控制樣品,并且應(ying)(ying)以符(fu)合FDA工業(ye)生物分析方法(fa)驗證指(zhi)南(nan)(2018年5月)的方式進行(xing)驗證。

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(ru)適用,接受(shou)(shou)液(ye)中(zhong)樣品分析方法(fa)的(de)(de)(de)驗證應包括稀釋完(wan)整性(xing)的(de)(de)(de)相關(guan)(guan)確(que)認,以(yi)及在最長相關(guan)(guan)時間內接受(shou)(shou)液(ye)中(zhong)最高(gao)(gao)(gao)相關(guan)(guan)溫(wen)度(du)的(de)(de)(de)穩定性(xing)評估(gu);最高(gao)(gao)(gao)相關(guan)(guan)溫(wen)度(du)可(ke)(ke)以(yi)略高(gao)(gao)(gao)于IVRT膜表面(mian)(mian)溫(wen)度(du),因(yin)為(wei)接受(shou)(shou)液(ye)的(de)(de)(de)溫(wen)度(du)通(tong)常(chang)高(gao)(gao)(gao)于膜表面(mian)(mian)的(de)(de)(de)溫(wen)度(du)(例如(ru),當(dang)膜表面(mian)(mian)的(de)(de)(de)溫(wen)度(du)為(wei)32°C時,接受(shou)(shou)液(ye)的(de)(de)(de)溫(wen)度(du)可(ke)(ke)能(neng)為(wei)34°C,因(yin)此IVRT接受(shou)(shou)液(ye)的(de)(de)(de)穩定性(xing)評估(gu)可(ke)(ke)在34°C下進行(xing)6小時;而(er)在陰道凝膠制劑的(de)(de)(de)IVRT研究中(zhong)的(de)(de)(de)溫(wen)度(du)會(hui)更高(gao)(gao)(gao))。

VI. IVRT PIVOTAL STUDY IVRT  正式研(yan)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正式研究中應對自制制劑和對照外用制劑之間的藥物釋放率進行比較,應符合USP一般章節<1724>中規定的一般程序和統計分析方法進行。應報告每個擴散池在每個取樣時間點釋放的藥物累積量。還應報告IVRT研究的相關匯總統計數據。

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

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(can)考21 CFR 320.38、320.63以(yi)及FDA行(xing)業指南(nan)《生(sheng)物(wu)利(li)用度(BA)和(he)(he)生(sheng)物(wu)等效性(BE)研究中(zhong)測(ce)試(shi)樣(yang)品(pin)(pin)的(de)處(chu)理和(he)(he)保(bao)存(cun)》(2004年5月)和(he)(he)《21 CFR 320.38(c) BE樣(yang)品(pin)(pin)留存(cun)的(de)數量及生(sheng)物(wu)利(li)用度》(2020年8月),如適用,關于保(bao)留研究藥(yao)物(wu)樣(yang)品(pin)(pin)的(de)考慮以(yi)及21 CFR 320.36關于保(bao)存(cun)BE檢(jian)測(ce)記錄的(de)要求。在IVRT中(zhong)比(bi)較自研外(wai)用制(zhi)(zhi)劑和(he)(he)RS前應從收到(dao)的(de)藥(yao)品(pin)(pin)中(zhong)隨(sui)機選擇樣(yang)品(pin)(pin)進(jin)行(xing)留樣(yang)。應報告可能(neng)影響(xiang)研究結果解釋的(de)實驗觀察(cha)結果以(yi)及任何方案偏差。Control of Study Procedures 研究程序的(de)控制(zhi)(zhi)

Procedures   研(yan)究(jiu)程序的(de)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(ying)適當控(kong)制可能(neng)影(ying)響研(yan)究結果的研(yan)究程序。此外,應(ying)報告可能(neng)影(ying)響研(yan)究結果解釋的實驗(yan)觀察結果,以及(ji)任何方案或標準操作程序(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(ci)外,研究人員(yuan)應在質量(liang)管理體系(xi)內進(jin)行IVRT驗證和正式研究,該體系(xi)包括但不限于:

lStudy personnel identification, training, qualification, and responsibilities研究人(ren)員識別、培訓、資質和職責

lStudy management and study management personnel responsibilities研(yan)究管理和研(yan)究管理人(ren)員職責

lQuality control (QC) and QC personnel responsibilities質量控(kong)制(zhi)(QC)和(he)QC人員職責

lQuality assurance (QA) and QA personnel responsibilities質量保證(zheng)(QA)和QA人員職責

lUse of SOPs SOP的使(shi)用

lUse of study protocols研究方案的(de)使用

lUse of study reports研究報告的(de)使用

lMaintenance and control of the study facility environment and systems研(yan)究設(she)施環境(jing)和(he)系統的維護和(he)控制

lQualification and calibration of instruments and computerized systems儀(yi)器和計算機系統(tong)的驗證和校準

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(de)(de)文件記(ji)錄規(gui)范,包(bao)括但(dan)不限于:研(yan)究程(cheng)序的(de)(de)同期記(ji)錄和實驗觀(guan)察結果的(de)(de)記(ji)錄,或與研(yan)究方(fang)案或相關SOP中規(gui)定的(de)(de)程(cheng)序的(de)(de)偏(pian)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(jin)行適當維護(hu),有助于(yu)重現(xian)研(yan)究過程(cheng)(cheng),包括:研(yan)究樣品(pin)處(chu)理和保存記錄(例(li)如,樣品(pin)跟蹤(zong)日志)、樣品(pin)分析(xi)過程(cheng)(cheng)的(de)(de)審計跟蹤(zong)、研(yan)究物料和試劑的(de)(de)控制(zhi)以及電子(zi)數據控制(zhi)

lArchival of study records研究記錄(lu)歸檔

C.Blinding Procedure   盲法(fa)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(shi)研究的(de)(de)研究方案和最終(zhong)報告中應(ying)詳細說明盲法(fa)(fa)程序。自制(zhi)(zhi)外用制(zhi)(zhi)劑(ji)和RS的(de)(de)包(bao)裝外觀應(ying)相似,以(yi)保持(chi)研究者和任何(he)實(shi)驗操作人(ren)員(yuan)的(de)(de)充分隨機(ji)。一(yi)旦采用盲法(fa)(fa)程序,應(ying)通過(guo)隨機(ji)名稱(例如“A"或“B")來區別自制(zhi)(zhi)外用制(zhi)(zhi)劑(ji)和RS

D.Dosing   上樣(yang)

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(yan)究中,自制外用制劑和RS應在連續(xu)擴散池上交替(ti)給(gei)藥(yao)。交替(ti)模式有兩種(zhong)(zhong)可(ke)能的(de)序列(ABABAB或BABABA)。可(ke)以隨機選(xuan)擇這(zhe)兩種(zhong)(zhong)給(gei)藥(yao)順序中的(de)一(yi)種(zhong)(zhong)。


VII. SUBMITTING INFORMATION ON IVRT STUDIES IN AN ANDA  ANDA中遞交的IVRT研(yan)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(zai)ANDA中提(ti)交的外用制劑用于支持BE論證的IVRT研究,應(ying)為IVRT方(fang)法(fa)驗證和IVRT正式研究提(ti)交詳細(xi)的研究方(fang)案、相關SOPs和詳細(xi)報(bao)告。此外,還(huan)應(ying)提(ti)交一(yi)份(fen)詳細(xi)報(bao)告,關于IVRT方(fang)法(fa)的開發。這些方(fang)案、SOPs和報(bao)告應(ying)在(zai)電子通用技術文件(eCTD)的模塊5.3.1.2中提(ti)交,并應(ying)描述實驗程序、研究控制、質量管(guan)理程序和數據分析。

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(yu)IVRT方法(fa)(fa)相關的(de)(de)(de)研究方案、SOPs和(he)(he)報告(gao)與(yu)用于定量IVRT接受液中樣(yang)(yang)品(pin)藥物濃度的(de)(de)(de)樣(yang)(yang)品(pin)分析方法(fa)(fa)(例(li)如HPLC或UPLC方法(fa)(fa))不(bu)同(tong)。樣(yang)(yang)品(pin)分析方法(fa)(fa)驗(yan)證應提交單(dan)獨的(de)(de)(de)方案和(he)(he)SOPs。樣(yang)(yang)品(pin)分析方法(fa)(fa)開(kai)發和(he)(he)驗(yan)證報告(gao)、正式IVRT研究樣(yang)(yang)品(pin)分析報告(gao)以及與(yu)IVRT研究的(de)(de)(de)樣(yang)(yang)品(pin)分析相關的(de)(de)(de)相關SOPs和(he)(he)協議,應在(zai)eCTD的(de)(de)(de)模塊(kuai)5.3.1.4中提交。


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