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An applicant must provide technical data and information in sufficient detail to permit the Agency to make a knowledgeable judgment about whether to approve the application or whether grounds exist under section 505(d) or 505(j) of the FD&C Act to refuse to approve the application. This includes information about the drug substance and information about the TDS product.

申請(qǐng)人必須提供足夠詳細(xì)的技術(shù)數(shù)據(jù)和信息，以使FDA能夠?qū)κ欠衽鷾?zhǔn)申請(qǐng)做出明智的判斷，或者是否存在《FD&C法案》第505（d）或505（j）節(jié)規(guī)定的拒絕批準(zhǔn)申請(qǐng)的理由。這包括關(guān)于藥物物質(zhì)的信息和關(guān)于TDS產(chǎn)品的信息。

The following sections provide recommendations to applicants about pharmaceutical development and quality information to be included in the application sections described in ICH M4Q.

以下各部分向申請(qǐng)人提供了關(guān)于藥物開(kāi)發(fā)和質(zhì)量信息的建議，這些信息將包含在ICH M4Q中所述的應(yīng)用章節(jié)中.

A.Pharmaceutical Development/藥物研發(fā)

As described in ICH M4Q, section 3.2.P.2 of the application should contain information on studies conducted to establish that the dosage form, formulation, manufacturing process, container closure system, microbiological attributes, and usage instructions specified in the application are appropriate for the intended use of the TDS product. The applicant should address the following:

如ICH M4Q第3.2.P.2節(jié)所述。申請(qǐng)應(yīng)包含進(jìn)行研究的信息，以確定申請(qǐng)中規(guī)定的劑型、配方、制造工藝、容器閉合系統(tǒng)、微生物屬性和使用說(shuō)明適用于TDS產(chǎn)品的預(yù)期用途。申請(qǐng)人應(yīng)解決以下問(wèn)題：

lA descr1ption of the QTPP/QTPP說(shuō)明

lA list of the CQAs of the TDS product, along with the limit, range, or distribution associated with each CQA and appropriate justification. TDS產(chǎn)品的CQAs列表，以及與每個(gè)CQAs相關(guān)的限制、范圍或分布以及適當(dāng)?shù)睦碛伞?/span>

lIdentification of those aspects of the drug substance, excipients, container closure system, and manufacturing processes important to attaining product quality.  API、賦形劑、包裝容器系統(tǒng)和制造工藝對(duì)實(shí)現(xiàn)產(chǎn)品質(zhì)量至關(guān)重要的方面的識(shí)別。

●In particular, the selection of excipients and components, their concentrations (as appropriate), and their functional characteristics affecting TDS performance should be discussed. For example, the applicant should describe the impact of penetration enhancers on the adhesive properties of the TDS, solubility of the drug substance in the blend, and skin permeation. 特別應(yīng)討論影響TDS性能的賦形劑和成分的選擇、其濃度（視情況而定）及其功能特性。例如，申請(qǐng)人應(yīng)描述滲透促進(jìn)劑對(duì)TDS的粘合性能、API在混合物中的溶解度和皮膚滲透的影響。

●Applicants should specify the allowable ranges around the process parameters and material attributes that have a potential to impact TDS product CQAs with justification and describe how they will be monitored. 申請(qǐng)人應(yīng)說(shuō)明可能影響TDS產(chǎn)品CQA的工藝參數(shù)和材料屬性的允許范圍，并說(shuō)明如何對(duì)其進(jìn)行監(jiān)控。

lA descr1ption of the quality risk assessments, potential failure modes, and product and process control strategies/質(zhì)量風(fēng)險(xiǎn)評(píng)估、潛在故障模式以及產(chǎn)品和過(guò)程控制策略的描述。

1.Batch Formula/批次處方

For processes that use solvated raw materials, batch formulas should be designed to tolerate variation in the solvent content of raw materials. Drug substance overages and excipient excesses can be added to a batch to account for evaporation during drying, but the amount of overage or excess should be controlled and justified by process development studies. Applicants should describe any cross-linking reactions since these reactions impact the chemical composition and quality of the finished product.

對(duì)于使用溶劑化原料的工藝，批次配方的設(shè)計(jì)應(yīng)能承受原料溶劑的含量變化。過(guò)量的API和過(guò)量的輔料可添加到批次中，以解決干燥過(guò)程中的蒸發(fā)問(wèn)題，但過(guò)量或過(guò)量的量應(yīng)通過(guò)工藝開(kāi)發(fā)研究加以控制和證明。申請(qǐng)人應(yīng)描述任何一種交聯(lián)反應(yīng)，因?yàn)檫@些反應(yīng)影響成品的化學(xué)成分和質(zhì)量。

2.Expectations for Registration/Exhibit Batches.對(duì)注冊(cè)/展示批次的期望

Applicants should submit data for registration/exhibit batches manufactured from three distinct laminates, where each laminate is made using different lots of drug substance, adhesives, backing, and/or other critical elements in the TDS product. Release and stability sampling should be representative of the full length and width of the laminates to demonstrate that the manufacturing process is robust

申請(qǐng)人應(yīng)提交由三種不同層壓材料制成的注冊(cè)/展示批次的數(shù)據(jù)，其中每個(gè)層壓材料使用不同批次的藥物、粘合劑、背襯和/或TDS產(chǎn)品中的其他關(guān)鍵元素制成。釋放和穩(wěn)定性取樣應(yīng)代表層壓板的整個(gè)長(zhǎng)度和寬度，以證明制造過(guò)程穩(wěn)健

Any clinical batch (e.g., those used in phase 3, PK, BE, adhesion, or irritation and sensitization studies) should be included in the formal stability program. Applicants should provide the executed batch records and certificates of analysis for all batches used in clinical and BE studies, including placebo batches. Placebo batches should include all inactive ingredients and components and representative printing

任何臨床批次（例如，在第3階段、PK、BE、粘附或刺激和致敏研究中使用的批次）都應(yīng)包含在正式的穩(wěn)定性計(jì)劃中。申請(qǐng)人應(yīng)提供臨床和BE研究中使用的所有批次（包括安慰劑批次）的執(zhí)行批次記錄和分析證書(shū)。安慰劑批次應(yīng)包括所有非活性成分和成分以及代表性印刷。

Applicants should report the actual yields, theoretical yield, and percentages of theoretical yield from the conclusion of each appropriate phase of manufacturing, processing, packaging, and holding. The theoretical yield should be calculated for each batch prospectively. For example, if a coating process is stopped due to a manufacturing issue, the theoretical yield should be based on the mass that was intended to be coated rather than the mass that was actually coated. The yield for TDS processes may be lower than the usual yield for many other drug manufacturing processes. However, abnormally low yields in the TDS submission batches should be explained in the application

申請(qǐng)人應(yīng)報(bào)告制造、加工、包裝和保存每個(gè)適當(dāng)階段結(jié)束時(shí)的實(shí)際產(chǎn)量、理論產(chǎn)量和理論產(chǎn)量百分比。應(yīng)前瞻性地計(jì)算每批的理論產(chǎn)量。例如，如果由于制造問(wèn)題而停止了涂覆過(guò)程，則理論產(chǎn)量應(yīng)基于打算涂覆的質(zhì)量，而不是實(shí)際涂覆的質(zhì)量。TDS工藝的產(chǎn)率可能低于許多其他藥物制造工藝的通常產(chǎn)率。但是，應(yīng)在申請(qǐng)中說(shuō)明 TDS 提交批次中異常低的產(chǎn)量。

Because of the sensitivity of TDS products to small differences in manufacturing process, a master table comparing the clinical, BE, registration/exhibit, and proposed commercial batches should be included in section 3.2.P.2.3 of the application. For each batch, this table should specify the manufacturing process used (including equipment, and manufacturing scale, and those parameters that could directly or indirectly impact a CQA), and the results of critical in process tests (specifying the test procedure and acceptance criteria), yield, and reconciliation data. The table should also include links to any information referenced from other parts of the submission. It should also clarify whether these batches were packaged to completion at the die cutting and pouching stage

由于 TDS 產(chǎn)品對(duì)制造過(guò)程中的微小差異很敏感，應(yīng)在申請(qǐng)書(shū)第3.2.P.2.3節(jié)中包含一份比較臨床、BE、注冊(cè)/展示和擬議商業(yè)批次的主表。對(duì)于每個(gè)批次，該表應(yīng)詳細(xì)說(shuō)明所使用的制造工藝（包括設(shè)備、制造規(guī)模以及可能直接或間接影響CQA的參數(shù)），以及關(guān)鍵過(guò)程中測(cè)試的結(jié)果（規(guī)定測(cè)試程序和驗(yàn)收標(biāo)準(zhǔn)）、產(chǎn)量和調(diào)節(jié)數(shù)據(jù)。該表還應(yīng)包括提交文件其他部分引用的任何信息的鏈接。還應(yīng)澄清這些批次是否在模切和裝袋階段包裝完成

3.Product Characterization Studies/產(chǎn)品特性研究

Because of the uniqueness of the TDS dosage form, specialized developmental studies and eva1uations are recommended to demonstrate full product understanding in both new and abbreviated new drug applications. Several such studies/eva1uations are discussed below.

由于TDS劑型的獨(dú)特性，建議進(jìn)行專(zhuān)門(mén)的開(kāi)發(fā)研究和評(píng)估，以證明在NDA和ANDA應(yīng)用中對(duì)產(chǎn)品的全面理解。以下討論了幾項(xiàng)此類(lèi)研究/評(píng)估。

a.Skin Permeability/皮膚滲透性

Skin permeability is a function of permeant thermodynamic activity and degree of saturation of the drug substance in the TDS. The solubility and degree of saturation of the drug substance in the TDS should be eva1uated, and their impact on the performance of the TDS understood.

皮膚滲透性是滲透熱力學(xué)活性和TDS中藥物飽和程度的函數(shù)。應(yīng)評(píng)估藥物在TDS中的溶解度和飽和度，并了解其對(duì)TDS性能的影響。

b.Crystallization/結(jié)晶

Generally, crystallization of the drug substance in the TDS product should be avoided. If crystallization occurs, studies should be conducted to assess its impact on the in vivo performance and adhesion of TDS.

通常，應(yīng)避免 TDS 產(chǎn)品中API的結(jié)晶。如果發(fā)生結(jié)晶，應(yīng)進(jìn)行研究以評(píng)估其對(duì)TDS體內(nèi)性能和粘附的影響。

c.Thermodynamic Stability of Drug Substance/原料藥的熱力學(xué)穩(wěn)定性

To confirm thermodynamic stability of the drug substance, the risk of precipitation or salt formation during manufacturing and storage should be eva1uated. If there is an equilibrium between different salt forms, the kinetics to reach this equilibrium should be thoroughly haracterized. The impact of this equilibrium on TDS performance should be eva1uated with relevant in vitro drug release, permeation, and/or clinical data.

為了確認(rèn)藥物的熱力學(xué)穩(wěn)定性，應(yīng)評(píng)估生產(chǎn)和儲(chǔ)存過(guò)程中沉淀或鹽形成的風(fēng)險(xiǎn)。如果不同鹽形式之間存在平衡，則應(yīng)徹底描述達(dá)到該平衡的動(dòng)力學(xué)。應(yīng)使用相關(guān)的體外藥物釋放、滲透和/或臨床數(shù)據(jù)評(píng)估這種平衡對(duì)TDS性能的影響。

d.Strength/規(guī)格

The strength of a transdermal system should be expressed as a rate (e.g., XX mg/day), whereas the strength of a topical system should be expressed as a percent total drug load. For transdermal systems, the strength can be derived from and supported by either PK data or by residual drug analysis performed on used transdermal systems. The first approach involves the derivation of a clearance (Cl) value from absolute bioavailability of the drug and multiplying that by the concentration (Css) at the steady state. The second approach involves the measurement of the amount of drug left in the transdermal systems at the end of the wear period and dividing the “consumed amount” by the wear period.

透皮系統(tǒng)的規(guī)格應(yīng)表示為速率（例如，XXmg/天），而局部系統(tǒng)的強(qiáng)度則應(yīng)表示為總藥物負(fù)荷的百分比。對(duì)于透皮系統(tǒng)，強(qiáng)度可以由PK數(shù)據(jù)或?qū)κ褂眠^(guò)的透皮系統(tǒng)進(jìn)行的殘留藥物分析得出并得到支持。第一種方法涉及從藥物的絕對(duì)生物利用度導(dǎo)出清除率（Cl）值，并將其乘以穩(wěn)定狀態(tài)下的濃度（Css）。第二種方法涉及在使用期結(jié)束時(shí)測(cè)量透皮系統(tǒng)中殘留的藥物量，并將“消耗量”除以使用期。

Although the strength of a topical system is expressed as percent total drug load, a residual drug analysis should still be conducted.

盡管局部系統(tǒng)的強(qiáng)度以總藥物負(fù)荷百分比表示，但仍應(yīng)進(jìn)行殘留藥物分析。

e.Residual Drug/殘留藥物

Consistent with FDA guidance for industry Residual Drug in Transdermal and Related Drug Delivery Systems (August 2011), scientific justification sufficient to support the amount of residual drug in a TDS should be included in the pharmaceutical development section of the application. To provide a robust analysis of the residual drug, we recommend the following:

根據(jù)FDA關(guān)于透皮和相關(guān)藥物輸送系統(tǒng)中殘留藥物的行業(yè)指南（2011年8月），申請(qǐng)的藥物開(kāi)發(fā)部分應(yīng)包含足以支持TDS中殘留藥物量的科學(xué)依據(jù)。為了對(duì)殘留藥物進(jìn)行可靠分析，我們建議如下：

1.Data should be based on analysis of the used TDS and not on a theoretical calculation. 數(shù)據(jù)應(yīng)基于對(duì)所用TDS的分析，而非理論計(jì)算。

2.The amount of drug left on the skin surface should be assessed. Any drug that may have been transferred to packaging or other components of the TDS during storage or use should be accounted for in an attempt to perform a mass balance. 應(yīng)評(píng)估殘留在皮膚表面的藥物量。在儲(chǔ)存或使用過(guò)程中可能轉(zhuǎn)移到包裝或 TDS 其他成分的任何藥物都應(yīng)考慮在內(nèi)，以嘗試進(jìn)行質(zhì)量平衡。

3.Tape or overlays should not be used in studies where the TDS is used to calculate residual drug在TDS用于計(jì)算殘留藥物的研究中，不應(yīng)使用膠帶或覆蓋物

4.TDS adhesion assessments should be conducted over the entire period of wear to determine whether the TDS diffusional surface area remains in full contact with the skin during the entire period of the study. 應(yīng)在整個(gè)使用期間進(jìn)行TDS粘附評(píng)估，以確定TDS擴(kuò)散表面積在整個(gè)研究期間是否與皮膚完全接觸。

5.A control study should be performed to provide an estimate of drug load, rather than simply using the expressed label claim. This study should include analysis of a minimum of three unused products from the same lot of product used in the study. 應(yīng)進(jìn)行對(duì)照研究，以提供藥物負(fù)荷的估計(jì)，而不是簡(jiǎn)單地使用表達(dá)的標(biāo)簽要求。這項(xiàng)研究應(yīng)包括對(duì)研究中使用的相同產(chǎn)品的三種未使用產(chǎn)品的分析。

6.Sample storage conditions before and after application of the TDS on the skin should be validated. Photostability and thermal stability of the active ingredient(s) in the TDS should also be considered when selecting the appropriate storage conditions. 應(yīng)驗(yàn)證將TDS應(yīng)用于皮膚之前和之后的樣品存儲(chǔ)條件。在選擇合適的儲(chǔ)存條件時(shí)，還應(yīng)考慮TDS中活性成分的光穩(wěn)定性和熱穩(wěn)定性。

7.Appropriately sensitive and valid analytical methods should be used to assay the residual drug content for the purpose of calculating drug depletion and delivery. When estimating the amount of residual drug in the TDS, a drug extraction method with a target extraction efficiency close to 100 percent should be utilized to minimize error應(yīng)使用適當(dāng)敏感和有效的分析方法測(cè)定殘留藥物含量，以計(jì)算藥物消耗和遞送。當(dāng)估計(jì)TDS中殘留藥物的量時(shí)，應(yīng)使用目標(biāo)提取效率接近100%的藥物提取方法，將誤差降至最低

f.In Vitro Permeation Testing/體外滲透測(cè)試

In vitro permeation testing (IVPT) with the use of excised human skin may be utilized to characterize the rate and extent of transdermal or topical drug delivery, and the study protocols and results should be described in the application. The following factors should be considered during IVPT model development:

使用離體人體皮膚的體外滲透試驗(yàn)（IVPT）可用于表征透皮或局部藥物遞送的速率和程度，并且在應(yīng)用中應(yīng)描述研究方案和結(jié)果。IVPT模型開(kāi)發(fā)過(guò)程中應(yīng)考慮以下因素：

相關(guān)閱讀：《FDA IVPT 測(cè)試 工業(yè)指南翻譯稿》

• Selection of the diffusion apparatus and the operating conditions like stirring rate or flow rate, as well as temperature control to maintain the under-normal-conditions skin surface temperature (32°C ±1°C）

選擇擴(kuò)散裝置和操作條件，如攪拌速率或流速，以及溫度控制，以保持正常條件下的皮膚表面溫度（32°C±1°C）

●Source of the skin, skin storage conditions, choice of skin type (i.e., age range, sex , race, and consistent anatomical region) and the skin preparation technique (e.g., full-thickness, dermatomed, isolated epidermis)

皮膚來(lái)源、皮膚儲(chǔ)存條件、皮膚類(lèi)型的選擇（即年齡范圍、性別、種族和一致的解剖區(qū)域）和皮膚制備技術(shù)（例如全厚度、病理皮膚、分離表皮）

The IVPT protocol should specify the nominal skin thickness and its range, details of the skin barrier integrity test, and any occlusion of the product during the IVPT. Visual observations alone are not sufficient to characterize the barrier integrity of the skin. Acceptable barrier integrity tests may be based on tritiated water permeation, trans-epidermal water loss (TEWL), or electrical impedance/conductance measured across the skin. The test parameters and acceptance criteria used for the skin barrier integrity test should be justified based on relevant literature references or other information

IVPT方案應(yīng)規(guī)定標(biāo)稱(chēng)皮膚厚度及其范圍、皮膚屏障完整性測(cè)試的細(xì)節(jié)以及IVPT期間產(chǎn)品的任何遮擋。僅憑視覺(jué)觀察不足以表征皮膚的屏障完整性。可接受的屏障完整性測(cè)試可基于氚化水滲透、經(jīng)表皮失水（TEWL）或通過(guò)皮膚測(cè)量的電阻抗/電導(dǎo)。用于皮膚屏障完整性測(cè)試的測(cè)試參數(shù)和驗(yàn)收標(biāo)準(zhǔn)應(yīng)根據(jù)相關(guān)文獻(xiàn)參考或其他信息進(jìn)行證明

相關(guān)閱讀：《IVPT測(cè)試中的皮膚研究》

The IVPT protocol should also include details about the receptor solution, system equilibration, procedures for skin mounting and application of the TDS, as well as any measures to secure the TDS on the skin surface to prevent lifting. We recommend that an antimicrobial agent be included in the receptor solution (e.g., ~0.1 percent sodium azide or ~0.01 percent gentamicin sulfate).

IVPT方案還應(yīng)包括受體溶液、系統(tǒng)平衡、皮膚安裝程序和TDS應(yīng)用程序的詳細(xì)信息，以及將TDS固定在皮膚表面以防止移動(dòng)的任何措施。我們建議在受體溶液中加入抗菌劑（例如，約0.1%的*或約0.01%的硫酸慶大霉素）。

The IVPT study report should include dose duration, sampling duration, sampling time points, concentration of samples, concentration of the antimicrobial component, and the empirical stability (at relevant temperatures) and solubility of the active ingredient in the receptor solution. The study report should also include the number of individuals whose skin was eva1uated (i.e., skin donors) and the number of replicate skin sections per donor per treatment group

IVPT研究報(bào)告應(yīng)包括劑量持續(xù)時(shí)間、取樣持續(xù)時(shí)間、取樣時(shí)間點(diǎn)、樣品濃度、抗菌成分濃度以及活性成分在受體溶液中的經(jīng)驗(yàn)穩(wěn)定性（在相關(guān)溫度下）和溶解度。研究報(bào)告還應(yīng)包括接受皮膚評(píng)估的個(gè)體數(shù)量（即，皮膚供體）以及每個(gè)治療組每個(gè)供體的重復(fù)皮膚切片數(shù)量。

All treatment groups compared in an IVPT study should be dosed on the skin samples from the same set of donors, with the same number of replicates per donor per treatment group. These treatment groups should also use the skin samples from the same anatomical site from all donors, unless varying these parameters is essential to the design of the study and the eva1uation of the TDS. The study report should include the equilibrated skin surface temperature prior to dose application, and the ambient temperature and relative humidity in the laboratory, as well as the extent of qualification of the sample analytical methods (e.g., HPLC)

IVPT研究中比較的所有治療組應(yīng)在同一組供體的皮膚樣本上給藥，每個(gè)治療組每個(gè)供體的重復(fù)次數(shù)相同。這些治療組還應(yīng)使用來(lái)自所有供體的相同解剖部位的皮膚樣本，除非改變這些參數(shù)對(duì)研究設(shè)計(jì)和TDS評(píng)估至關(guān)重要。研究報(bào)告應(yīng)包括劑量應(yīng)用前的平衡皮膚表面溫度、實(shí)驗(yàn)室的環(huán)境溫度和相對(duì)濕度，以及樣品分析方法（如HPLC）的合格程度

g.Extractable and Leachable Testing/可提取且可浸出的測(cè)試

All TDS should be eva1uated for potential compounds that could be transferred from the product to the patient. This eva1uation should include assessments of extractables and leachables, consistent with USP and

應(yīng)評(píng)估所有TDS中可能從產(chǎn)品轉(zhuǎn)移至患者的潛在化合物。該評(píng)估應(yīng)包括與USP＜1663＞和＜1664＞一致的可提取物和可浸出物的評(píng)估

As defined in United States Pharmacopeia (USP)21 General Chapter Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, “extractables are organic and inorganic chemical entities that are released from a pharmaceutical packaging/ delivery system, packaging component, or packaging material of construction and into an extraction solvent under laboratory conditions.” The extraction conditions should “accelerate or exaggerate the normal conditions of storage and use for a packaged dosage form.”

如《美國(guó)藥典》（USP）第21章“與藥物包裝/輸送系統(tǒng)相關(guān)的可提取物評(píng)估”中所定義的，“可提取物是在實(shí)驗(yàn)室條件下從藥物包裝/運(yùn)輸系統(tǒng)、包裝組件或包裝材料中釋放并進(jìn)入提取溶劑的有機(jī)和無(wú)機(jī)化學(xué)物質(zhì)。提取條件應(yīng)“加速或放大包裝劑型的正常儲(chǔ)存和使用條件”

As defined in USP General Chapter  Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems, “leachables are foreign organic and inorganic entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies.”

如USP通用章節(jié)與藥物包裝/輸送系統(tǒng)相關(guān)的藥品浸出物評(píng)估中所定義，“可浸出物是指包裝藥品中存在的外來(lái)有機(jī)和無(wú)機(jī)物質(zhì)，因?yàn)樗鼈冊(cè)谡?chǔ)存和使用條件下或在加速藥品穩(wěn)定性研究期間從包裝/輸送系統(tǒng)、包裝組件或包裝材料中浸出到包裝藥品中。”

In the context of this guidance, extractable impurities are chemical entities that can be drawn out of the backing membrane, release liner, pouching material, printed ink, internal membranes, and components other than the drug substance and adhesive matrix by a solvent system.

在本指南的上下文中，可提取雜質(zhì)是可通過(guò)溶劑系統(tǒng)從背襯膜、釋放襯墊、袋材料、印刷油墨、內(nèi)膜和除藥物和粘合劑基質(zhì)以外的成分中抽出的化學(xué)物質(zhì)。

Additionally, an extraction study can detect compounds introduced into the TDS from the manufacturing process, which can impact the final impurity profile of the TDS product. In the context of this guidance, leachables are chemical entities present in a packaged TDS because they leached into the adhesive matrix (or where applicable, reservoir) under normal conditions of storage or during accelerated stability studies. These compounds may transfer from the adhesive matrix (or reservoir) to the patient during use.

此外，提取研究可以檢測(cè)從制造過(guò)程中引入TDS的化合物，這會(huì)影響TDS產(chǎn)品的最終雜質(zhì)分布。在本指南中，可浸出物是包裝TDS中存在的化學(xué)物質(zhì)，因?yàn)樗鼈冊(cè)谡?chǔ)存條件下或在加速穩(wěn)定性研究期間浸出到粘合劑基質(zhì)（或適用情況下的儲(chǔ)層）中。在使用過(guò)程中，這些化合物可從粘合劑基質(zhì)（或貯層）轉(zhuǎn)移至患者。

Extractable studies are used to inform the leachable study design. The leachable data should be correlated, if possible, with the extractables profile(s) determined under the various control extraction study conditions. Both extractable and leachable studies should have adequate sensitivity to detect compounds potentially released at a level associated with patient exposure when a product is used at the maximum daily dose (e.g., 1.5 mcg/day for standard mutagenic compounds in a chronic-use drug product22 ), unless otherwise justified. For some products, the maximum daily dose may require applying more than one TDS.

可提取研究用于告知可浸出研究設(shè)計(jì)。如果可能的話，在不同的對(duì)照浸出研究條件下確定浸出物的分布。可提取和可浸出研究應(yīng)具有足夠的靈敏度，以檢測(cè)當(dāng)產(chǎn)品以最大日劑量使用時(shí)（例如，長(zhǎng)期使用藥物產(chǎn)品中的標(biāo)準(zhǔn)致突變化合物為1.5 mcg/天），可能釋放的化合物，除非另有證明。對(duì)于某些產(chǎn)品，最大每日劑量可能需要應(yīng)用一種以上的TDS。

Adhesive impurities such as residual monomers, initiator byproducts, and aldehydes are not considered extractables or leachables because these impurities are present at peak concentrations before product manufacture. Control of adhesive impurities is discussed elsewhere in this guidance (see section IV. INFORMATION TO BE SUBMITTED IN AN APPLICATION, C. Control of TDS Product). However, the leachable studies discussed below may be leveraged to justify adhesive impurity limits or as part of the toxicological risk assessment for adhesive impurities because a leachable study is performed on the proposed commercial product.

粘合劑雜質(zhì)，如殘留單體、引發(fā)劑副產(chǎn)物和醛類(lèi)，不被視為可提取或可浸出物，因?yàn)檫@些雜質(zhì)在產(chǎn)品制造前以峰值濃度存在。本指南其他地方對(duì)粘合劑雜質(zhì)的控制進(jìn)行了討論（見(jiàn)第四節(jié)C申請(qǐng)中提交的信息TDS產(chǎn)品的控制）。然而，以下討論的可浸出性研究可用于證明粘合劑雜質(zhì)限值，或作為粘合劑雜質(zhì)毒理學(xué)風(fēng)險(xiǎn)評(píng)估的一部分，因?yàn)閷?duì)擬議的商業(yè)產(chǎn)品進(jìn)行了可浸出研究。

To aid in the extractable and leachable analyses described below, applicants should contact raw material suppliers to identify potential extractables of toxicological concern, such as residual monomers from backing materials.

為了幫助進(jìn)行下文所述的可提取和可浸出分析，申請(qǐng)人應(yīng)聯(lián)系原材料供應(yīng)商，以確定潛在的毒理學(xué)問(wèn)題可提取物，例如背襯材料中的殘留單體。

lExtractable Studies

Extractable studies should be conducted early in the pharmaceutical development process to understand the potential leachables from components of the proposed commercial TDS. These studies should be conducted on components such as backing membrane, release liner, rate controlling or other internal membranes, ink and pouching. The testing components should be extracted in a variety of solvents with a range of polarities under vigorous laboratory extraction conditions to maximize the levels of extractables and identify as many potential leachables as possible. One of the extraction solvents used in the extractable studies should include the solvent of the proposed commercial adhesive(s) platform or the known residual solvents for the finished TDS. The choices of solvents used should be justified

可提取性研究

應(yīng)在藥物開(kāi)發(fā)過(guò)程早期進(jìn)行可提取性研究，以了解擬議商業(yè)TDS組分的潛在浸出物。這些研究應(yīng)在背襯膜、釋放襯墊、速率控制或其他內(nèi)部膜、油墨和袋等組件上進(jìn)行。測(cè)試組分應(yīng)在各種極性不同的溶劑中，在劇烈的實(shí)驗(yàn)提取條件下提取，以最大限度地提高可提取物的水平，并盡可能多地確定潛在的可浸出物。可提取性研究中使用的提取溶劑之一應(yīng)包括擬定商業(yè)粘合劑平臺(tái)的溶劑或成品TDS的已知?dú)埩羧軇Ｋ萌軇┑倪x擇應(yīng)合理

可浸出研究

可浸出研究的條件應(yīng)盡可能接近皮膚的“最壞情況”臨床條件（例如，劇烈運(yùn)動(dòng)期間出汗）。應(yīng)為研究選擇合理的溶劑/溶液（如鹽濃度）、溫度、攪拌水平、暴露于溶劑的時(shí)間等實(shí)驗(yàn)條件。在研究期間，應(yīng)將隔離襯墊從系統(tǒng)中移除，以使粘合劑層充分暴露于生物相關(guān)溶劑。申請(qǐng)人應(yīng)進(jìn)行多時(shí)間點(diǎn)可浸出物分析（例如，0、6、12、24個(gè)月），以提供全面的可浸出物概況，并確定可浸出物的任何趨勢(shì)，因?yàn)檫@些數(shù)據(jù)可能影響產(chǎn)品的保質(zhì)期。提交申請(qǐng)時(shí)，應(yīng)提交在加速和長(zhǎng)期條件下儲(chǔ)存至少6個(gè)月的多批次樣品的可浸出研究數(shù)據(jù)。我們建議對(duì)三種不同的TDS層壓板進(jìn)行可浸出研究，并進(jìn)行穩(wěn)定性測(cè)試。

h.Assessing the Effects of Heat

Heat from external sources such as a heating blanket, and potentially from a rise in internal body temperature due to strenuous exercise or fever, may affect the rate of drug release from the TDS and the absorption of drug into and through the skin. We recommend that applicants study the impact of an elevated TDS/skin surface temperature on the delivery profile of TDS relative to its delivery profile at a normal TDS/skin surface temperature.

h.評(píng)估熱效應(yīng)的影響

來(lái)自外部來(lái)源（如加熱毯）的熱量，以及可能由于劇烈運(yùn)動(dòng)或發(fā)燒導(dǎo)致的體內(nèi)溫度升高，可能會(huì)影響TDS中藥物釋放的速率以及藥物進(jìn)入和通過(guò)皮膚的吸收。我們建議申請(qǐng)人研究相對(duì)于正常TDS/皮膚表面溫度下的TDS釋放曲線，升高TDS/皮膚表面溫度對(duì)TDS釋放曲線的影響。

For a TDS product to be submitted in an NDA, we recommend that the heat effect studies be conducted as part of a clinical study using the proposed commercial product. In designing the heat effect studies, critical factors such as appropriate elevated test temperature(s), heat exposure onset time(s), duration(s), and cycles (if any), as well as mechanisms of heat exposure (e.g., heating lamp, heating pad, etc.) should be identified

對(duì)于在NDA中提交的TDS產(chǎn)品，我們建議將熱效應(yīng)研究作為臨床研究的一部分，使用擬議的商業(yè)產(chǎn)品進(jìn)行。在設(shè)計(jì)熱效應(yīng)研究時(shí)，應(yīng)確定關(guān)鍵因素，如適當(dāng)升高的試驗(yàn)溫度、熱暴露開(kāi)始時(shí)間、持續(xù)時(shí)間和周期（如有），以及熱暴露機(jī)制（如加熱燈、加熱墊等）

For a TDS product to be submitted in an ANDA, the applicant should eva1uate whether the test TDS, used under elevated temperature conditions, increases drug delivery compared to the reference (R) TDS. The ANDA applicant should provide the results of an IVPT study comparing the drug delivery characteristics for the test TDS and the R TDS at normal and elevated temperatures using skin from multiple individuals (donors), with multiple replicate diffusion cells eva1uated per donor, per treatment (test versus R), and per temperature condition. An IVPT study with a sufficient number of donors and replicates per donor per treatment per temperature condition is recommended to obtain meaningful data. A study with fewer than four donors and four replicates per donor per treatment per temperature may be difficult to interpret.

對(duì)于將在ANDA中提交的TDS產(chǎn)品，申請(qǐng)人應(yīng)評(píng)估在高溫條件下使用的測(cè)試TDS是否比參考（R）TDS增加藥物遞送。ANDA申請(qǐng)人應(yīng)提供一項(xiàng)IVPT研究的結(jié)果，該研究使用來(lái)自多個(gè)個(gè)體（供體）的皮膚，在正常和升高溫度下比較（T）TDS和（R）TDS的藥物遞送特性，每個(gè)供體、每個(gè)治療（T與R）和每個(gè)溫度條件下評(píng)估多個(gè)復(fù)制擴(kuò)散池。建議進(jìn)行IVPT研究，以獲得有意義的數(shù)據(jù)，該研究具有足夠數(shù)量的供體，并在每個(gè)溫度條件下對(duì)每個(gè)供體進(jìn)行重復(fù)治療。如果一項(xiàng)研究在每種溫度下，每種處理的供體少于四個(gè)，每個(gè)供體有四個(gè)重復(fù)，這可能很難對(duì)結(jié)果進(jìn)行解釋。

We recommend a parallel eva1uation and comparison of the test and R TDS under the following baseline and elevated temperature conditions:

我們建議在以下基礎(chǔ)和高溫條件下對(duì)試驗(yàn)和R TDS進(jìn)行平行評(píng)估和比較：

1.BASELINE: Both the test and R products should be maintained at a TDS/skin surface temperature of 32 ±1°C for the entire study duration. 基礎(chǔ)：在整個(gè)研究期間，T和R產(chǎn)品的TDS/皮膚表面溫度應(yīng)保持在32±1°C。

2.ELEVATED TEMPERATURE: Both the test and R products should be maintained at a TDS/skin surface temperature of 32 ±1°C until a specified time, approximately when the peak flux is observed, and then maintained at a TDS/skin surface  temperature of 42 ±2°C for a period thereafter, which may be the remainder of the study duration升高的溫度：T和R產(chǎn)品應(yīng)保持在32±1°C的TDS/皮膚表面溫度，直到大約觀察到峰值通量時(shí)的指定時(shí)間，然后在剩余持續(xù)研究時(shí)間段保持在42±2°C的TDS/皮膚表面溫度

It should not be assumed that a set temperature for a circulating water bath will provide the target temperature at the TDS/skin surface. The TDS/skin surface temperature should be directly measured using an infrared thermometer or other temperature probe. The study duration for a 7-day wear TDS need not encompass the entire labeled duration of wear. It may be adequate to perform an IVPT study for a 48 or 72 hour duration, if that duration is sufficient to reach the peak drug delivery rate under baseline conditions. Alternatively, an applicant may justify eva1uating other conditions or scenarios of exposure to elevated temperatures that represent the worst-case scenario for a given TDS product or indicated patient population.

不應(yīng)假設(shè)循環(huán)水浴的設(shè)定溫度可以提供TDS/皮膚表面的目標(biāo)溫度。應(yīng)使用紅外溫度計(jì)或其他溫度探頭直接測(cè)量TDS/皮膚表面溫度。7天使用TDS的研究持續(xù)時(shí)間不需要包括整個(gè)標(biāo)示的使用持續(xù)時(shí)間。如果IVPT研究的持續(xù)時(shí)間足以達(dá)到基礎(chǔ)條件下的峰值藥物輸送率，則進(jìn)行48或72小時(shí)的IVPT研究可能就足夠。或者，申請(qǐng)人可以評(píng)估證明暴露于高溫的其他條件或情景是合理的，這些條件或情景代表給定TDS產(chǎn)品或指定患者人群的最壞情況。

i.Microscopic Matrix eva1uation

Due to complexities of many TDS formulations, adhesive matrices often do not form true solutions, rather they manifest as dispersions. If rearrangements of the dispersed-like system occur over time within the matrix, they can possibly lead to lack of adhesion or changes in drug delivery and release. As such, it is important to have a good understanding of the TDS formulation, the way the drug substance and excipients are dispersed within the adhesive matrix, and the tendency of the matrix to change over time from product release through its expiry period. Therefore, it is informative to assess surface and cross-sectional changes in the TDS matrix throughout the shelf life of the developmental batches using high-powered microscopy, elemental mapping, or other appropriate tools. These tools may not be appropriate for every TDS; applicants should provide a scientific justification for the tools used. These assessments  will help achieve comprehensive understanding of product and process, mitigate quality-related risks, and assure that the TDS meets the requisite quality attributes through its expiry period

i. 微觀基質(zhì)評(píng)價(jià)

由于許多TDS配方的復(fù)雜性，粘合劑基質(zhì)通常不會(huì)形成真正的溶液，而是表現(xiàn)為分散體。如果分散樣系統(tǒng)在基質(zhì)中隨著時(shí)間的推移發(fā)生重排，它們可能導(dǎo)致缺乏粘附或藥物遞送和釋放的變化。因此，需要充分了解TDS配方、藥物和賦形劑在粘合劑基質(zhì)中的分散方式，以及有效期內(nèi)，隨著時(shí)間變化基質(zhì)從產(chǎn)品中釋放的趨勢(shì)。因此，使用高性能顯微鏡、元素圖譜或其他適當(dāng)?shù)墓ぞ咴u(píng)估TDS基質(zhì)在整個(gè)開(kāi)發(fā)批次保質(zhì)期內(nèi)的表面和橫截面變化是有益的。這些工具可能不適用于所有TDS；申請(qǐng)人應(yīng)為所使用的工具提供科學(xué)依據(jù)。這些評(píng)估將有助于全面了解產(chǎn)品和過(guò)程，降低質(zhì)量相關(guān)風(fēng)險(xiǎn)，并確保TDS在其到期期間滿足必要的質(zhì)量屬性

4.Proposed Manufacturing Changes

Scale-up proposals and other process changes may be proposed in an original NDA or ANDA, but the level of additional information needed to support these changes will generally be commensurate with the risk of the change to adversely impact product quality. In general, changes to TDS after the conduct of pivotal clinical studies should be avoided when possible because of the sensitivity of TDS to small changes in formulation and manufacturing process.

4.擬議的生產(chǎn)變更

原NDA或ANDA中可能會(huì)提出比例放大建議和其他流程變更，但支持這些變更所需的額外信息水平通常與變更對(duì)產(chǎn)品質(zhì)量產(chǎn)生不利影響的風(fēng)險(xiǎn)相當(dāng)。一般來(lái)說(shuō)，在進(jìn)行關(guān)鍵臨床研究后，應(yīng)盡可能避免TDS的變化，因?yàn)門(mén)DS對(duì)配方和制造過(guò)程中的微小變化很敏感。

Low-risk changes may be adequately supported with updated master batch records and batch formulas. Examples include scale-up of solvent-based and aqueous mixtures within a factor of 10 using equipment of the same design and operating principles, or proposing a change to converting and pouching equipment of the same design and operating principle

可通過(guò)更新主批次記錄和批次方案得到充分支持低風(fēng)險(xiǎn)變更。例如，使用相同設(shè)計(jì)和工作原理的設(shè)備，將溶劑基和水性混合物的規(guī)模擴(kuò)大10倍，或建議對(duì)相同設(shè)計(jì)和工作原理的轉(zhuǎn)換和裝袋設(shè)備進(jìn)行更改

Moderate-risk changes may warrant additional developmental studies and stability data on commercial scale batches to demonstrate that they will not result in an adverse impact on the quality of the product. Examples of such changes may include scale-up of hot-melt mixtures within a factor of 10, scale-up of screw-based mixing processes, and changes to coating/drying/laminating equipment of the same design and operating principle

中等風(fēng)險(xiǎn)變化可能需要對(duì)商業(yè)規(guī)模批次進(jìn)行額外的開(kāi)發(fā)研究和穩(wěn)定性數(shù)據(jù)，以證明它們不會(huì)對(duì)產(chǎn)品質(zhì)量產(chǎn)生不利影響。這種變化的例子可能包括將熱熔混合物的比例提高到10倍以?xún)?nèi)，將螺桿混合工藝的比例提高，以及改變具有相同設(shè)計(jì)和操作原理的涂層/干燥/層壓設(shè)備

Changes that pose a high risk to quality may warrant additional in vivo studies. An example is changing the manufacturing process to incorporate equipment of a different design and operating principle.

對(duì)質(zhì)量構(gòu)成高風(fēng)險(xiǎn)的變化可能需要額外的體內(nèi)研究。一個(gè)例子是改變制造工藝，以采用不同設(shè)計(jì)和操作原理的設(shè)備。

B.Manufacture

As described in ICH M4Q, section 3.2.P.3 of the application should contain information about where and how the TDS product will be manufactured. The batch formula and a descr1ption of the manufacturing process and process controls should be provided. A detailed schematic diagram of the proposed production process, including descr1ptions of the equipment, operating conditions, and process controls, should also be provided.

B.生產(chǎn)

如ICH M4Q中所述，應(yīng)用程序的第3.2.P.3節(jié)應(yīng)包含關(guān)于TDS產(chǎn)品將在何處以及如何制造的信息。應(yīng)提供批次配方以及制造工藝和工藝控制的說(shuō)明。還應(yīng)提供擬定生產(chǎn)工藝的詳細(xì)示意圖，包括設(shè)備、操作條件和工藝控制的說(shuō)明。

During process development, the applicant should identify process variables that have a potential to impact TDS product CQAs. These process development studies inform commercial process qualification and continued process verification later in the product life cycle.

在工藝開(kāi)發(fā)過(guò)程中，申請(qǐng)人應(yīng)確定可能影響TDS產(chǎn)品CQA的工藝變量。這些工藝開(kāi)發(fā)研究為商業(yè)工藝鑒定和產(chǎn)品生命周期后期的持續(xù)工藝驗(yàn)證提供了信息。

Typical TDS manufacturing steps/unit operations are listed below (a non-exhaustive list). For processes that incorporate these steps, the applicant should describe how each operation and associated controls were developed, addressing the considerations below, specifically, the CQAs that may be impacted by the operation, and the relevant process parameters and material attributes that may impact the output of each operation:

下面列出了典型的TDS制造步驟/裝置操作（非詳盡列表）。對(duì)于包含這些步驟的過(guò)程，申請(qǐng)人應(yīng)說(shuō)明每個(gè)操作和相關(guān)控制是如何制定的，并說(shuō)明以下注意事項(xiàng)，特別是可能受操作影響的CQA，以及可能影響每個(gè)操作輸出的相關(guān)工藝參數(shù)和材料屬性：

●Mixing: Mixing operations produce bulk mixtures for the coating step. Mixing can impact CQAs such as assay, stability of drug substance and/or excipients, content uniformity, microscopic appearance, and physical properties of the adhesive. The control strategy should address the impact of equipment design, order of material addition, and process parameters (such as mixing speeds, mixing times, temperatures, redispersion or recirculation conditions, and deaeration conditions) on CQAs, and should be justified, as necessary, based on development studies. CMAs that can impact mixing include drug substance particle size, polymorphic form, raw material rheological attributes, and percent solids for materials supplied in solvent-based mixtures.

混合：混合操作產(chǎn)生用于涂層步驟的散裝混合物。混合可影響CQA，如含量測(cè)定、原料藥和/或賦形劑的穩(wěn)定性、含量均勻性、微觀形態(tài)和粘合劑的物理性質(zhì)。控制策略應(yīng)解決設(shè)備設(shè)計(jì)、物料添加順序和工藝參數(shù)（如混合速度、混合時(shí)間、溫度、再分散或再循環(huán)條件以及脫氣條件）對(duì)CQA的影響，并應(yīng)根據(jù)開(kāi)發(fā)研究在必要時(shí)予以證明。能夠影響混合的cma包括原料藥粒度、多態(tài)形態(tài)、原料流變特性和溶劑型混合物中供應(yīng)的材料的固體百分比。。

●Coating, drying, and lamination: Coating is the application of a mixture to a substrate.  Depending on the equipment used, coating can impact CQAs such as content uniformity and microscopic appearance. Though CPPs are equipment dependent,  firms should demonstrate that the control strategy (e.g., process parameters to be controlled) is adequate to ensure content uniformity and microscopic appearance for the full duration of the coating operation. CMAs that can impact coating include the rheology of the bulk mixture and within-roll uniformity of the substrate to be coated

涂布、干燥和層壓：涂布是將混合物涂覆到基材上。根據(jù)使用的設(shè)備，涂層可能會(huì)影響CQA，如含量均勻性和微觀外觀。盡管CPP依賴(lài)于設(shè)備，但企業(yè)應(yīng)證明控制策略（例如，要控制的工藝參數(shù)）足以確保涂布操作整個(gè)過(guò)程中的含量均勻性和微觀形態(tài)。可能影響涂層的CMA包括散裝混合物的流變性和待涂層基材的輥內(nèi)均勻性

Drying involves the removal of solvent from the mixture following the coating process. This process step can impact CQAs such as assay, permeation enhancer content, antioxidant content, water content (for hydrogels), content uniformity, microscopic appearance, drug release, product stability, residual solvents, residual adhesive impurities, and physical properties of the adhesive matrix. Therefore, CPPs for drying that may need to be considered during process development include line speed, the pump or screw speed, zone temperatures, air flow rates, temperature of the drying air, and humidity of the drying air. Process development should also consider the CMAs that can impact drying such as solvent and adhesive impurity content in the bulk mixture. Applicants should also provide data to justify any drug substance overage or excipient excess that may be needed to compensate for any evaporation during drying

干燥包括在涂布過(guò)程之后從混合物中除去溶劑。該工藝步驟可影響CQA，如測(cè)定、滲透促進(jìn)劑含量、抗氧化劑含量、水含量（用于水凝膠）、含量均勻性、微觀外觀、藥物釋放、產(chǎn)品穩(wěn)定性、殘留溶劑、殘留粘合劑雜質(zhì)和粘合劑基質(zhì)的物理性質(zhì)。因此，在工藝開(kāi)發(fā)過(guò)程中可能需要考慮用于干燥CPP的包括管線速度、泵或螺桿速度、區(qū)域溫度、空氣流速、干燥空氣的溫度和干燥空氣的濕度。工藝開(kāi)發(fā)還應(yīng)考慮可能影響干燥的CMA，如散裝混合物中的溶劑和粘合劑雜質(zhì)含量。申請(qǐng)人還應(yīng)提供數(shù)據(jù)，證明藥物和輔料可能需要過(guò)量，以補(bǔ)償干燥過(guò)程中的蒸發(fā)損失。

Lamination involves the combining of multiple layers of a given transdermal system design into a single common laminate. Applicants should provide development data for corona treatments if such a process is used to bond the adhesive to a backing film or rate-controlling membrane

層壓包括將給定透皮系統(tǒng)設(shè)計(jì)的多個(gè)層組合成單個(gè)普通層壓。如果使用電暈處理工藝將膠粘劑粘合到背膜或速率控制膜上，則申請(qǐng)人應(yīng)提供電暈處理的開(kāi)發(fā)數(shù)據(jù)。

ØSlitting and Printing: The bulk product is typically slit longitudinally into narrower rolls of laminate for further processing. Slitting and printing are typically low risk steps; however, if certain aspects of the printing processes, e.g., excessive penetration depth or heat input, can adversely affect product quality, then printing processes should be characterized and controlled.

分切和印刷：通常將散裝產(chǎn)品縱向切成較窄的層壓板卷，以便進(jìn)一步加工。切片和印刷是典型的低風(fēng)險(xiǎn)步驟；然而，如果印刷過(guò)程的某些方面，例如過(guò)度的滲透深度或熱量輸入，會(huì)對(duì)產(chǎn)品質(zhì)量產(chǎn)生不利影響，那么應(yīng)對(duì)印刷工藝進(jìn)行表征和控制。

ØConverting and pouching: Converting and pouching typically involve cutting a  continuous laminate into individual units and sealing the unit in a heat-sealed pouch.  CQAs affected by these processes include usability of the product (e.g., the ability to remove a release liner) and pouch integrity. Common CPPs for these steps include heat sealing temperatures and dwell times.

轉(zhuǎn)換和封裝：轉(zhuǎn)換和封裝通常涉及將連續(xù)層壓材料切割成單個(gè)單元，并將該單元密封在熱密封袋中。受這些過(guò)程影響的CQA包括產(chǎn)品的可用性（例如，移除釋放襯墊的能力）和袋的完整性。這些步驟的常見(jiàn)CPP包括熱封溫度和停留時(shí)間。

●Curing: Some TDS have processing steps to complete a curing reaction after drying or pouching. Curing time and curing conditions are common CPPs for this step. Curing should be completed before batch release testing if curing could impact test results.

固化：有些TDS在干燥或裝袋后有加工步驟來(lái)完成固化反應(yīng)。固化時(shí)間和固化條件是該步驟的常見(jiàn)CPPs。如果固化可能影響測(cè)試結(jié)果，則應(yīng)在批放行測(cè)試前完成固化。

●Hold times: Hold times must be defined and justified for in-process materials held between unit operations (21 CFR part 211.111). Applicants should use a risk-based approach to determine which CQAs to monitor during hold time studies.

保持時(shí)間：必須定義和證明在單元操作之間保留的過(guò)程中材料的保留時(shí)間（21 CFR第211.111部分）。申請(qǐng)人應(yīng)使用基于風(fēng)險(xiǎn)的方法來(lái)確定在保持時(shí)間研究期間要監(jiān)控哪些CQA。

●Other considerations: Tubing and other product-contact equipment must be qualified as non-reactive, non-additive, and non-absorptive (21 CFR part 211.65(a)). The selection of the tubing and certain product-contacting equipment should be risk based, i.e., dependent on the duration of contact, process temperature, solvent system,  material considerations, clearance of leachables during manufacturing, and clinical use considerations.

其他注意事項(xiàng)：管道和其他產(chǎn)品接觸設(shè)備必須經(jīng)過(guò)非反應(yīng)性、非添加劑和非吸收性（21 CFR第211.65（a）部分）的認(rèn)證。管道和某些產(chǎn)品接觸設(shè)備的選擇應(yīng)基于風(fēng)險(xiǎn)，即取決于接觸持續(xù)時(shí)間、工藝溫度、溶劑系統(tǒng)、材料考慮因素、制造過(guò)程中可浸出物的清除以及臨床使用考慮因素。

In-process controls (IPCs) for TDS are an integral part of the control strategy. The descr1ption of the proposed IPCs should address the following:

TDS的過(guò)程中控制（IPC）是控制策略的一個(gè)組成部分。擬議IPC方案的說(shuō)明應(yīng)包括以下內(nèi)容：

●At the mixing stage, IPCs can provide assurance of assay, viscosity, uniformity, and pH for aqueous mixtures. If multiple samples are taken from a dispersed mixture, applicants should specify the mean, range for individual samples, and percent relative standard deviation.

在混合階段，IPC可以保證水性混合物的含量、粘度、均勻性和pH值。如果從分散的混合物中提取多個(gè)樣品，申請(qǐng)人應(yīng)指定平均值、單個(gè)樣品的范圍和相對(duì)標(biāo)準(zhǔn)偏差百分比。

●IPCs for coating, drying, and lamination can provide assurance of uniformity across the laminate and throughout the run. For example, measurements for film appearance, coat weight, and/or a test for residual solvents may be applicable IPCs for coating and drying. Film appearance measurements that allow detection and rejection of defects affecting continuity of an adhesive laminate (e.g., streaks) should be described in the application. Additionally, for films that are dispersions at the microscopic scale (e.g.,  acrylic adhesive dispersed in silicone, povidone dispersed in silicone, or solid drug  substance dispersed in adhesive), applicants should describe the IPCs established to monitor uniformity throughout a coating run in the application. Samples for testing coat weight and uniformity should be representative of the full length and width of a laminate. Alternatively, these attributes can be monitored continuously (e.g., by the use of in-line coating measurement tools). In cases where the upstream controls can be used to confirm certain finished TDS specifications, such as residual solvents and  residual adhesive impurities, IPC testing can be used in lieu of release testing for these attributes.

用于涂布、干燥和層壓的IPC可確保整個(gè)層壓板和整個(gè)運(yùn)行過(guò)程中的均勻性。例如，薄膜外觀、涂層質(zhì)量的測(cè)量和/或殘留溶劑的測(cè)試可能適用于涂層和干燥的IPC。應(yīng)在申請(qǐng)中描述允許檢測(cè)和排除影響粘合劑層壓板連續(xù)性的缺陷（例如條紋）的薄膜外觀測(cè)量。此外，對(duì)于在微觀尺度上為分散體的薄膜（例如，分散在硅酮中的丙烯酸粘合劑，分散在硅氧烷中的聚維酮，或分散在粘合劑中的固體藥物），申請(qǐng)人應(yīng)描述為在應(yīng)用中監(jiān)控整個(gè)涂層運(yùn)行的均勻性而建立的IPC。用于測(cè)試涂層質(zhì)量和均勻性的樣品應(yīng)代表層壓板的整個(gè)長(zhǎng)度和寬度。或者，可以連續(xù)監(jiān)測(cè)這些屬性（例如，通過(guò)使用在線涂層測(cè)量工具）。如果上游控制可用于確認(rèn)某些成品TDS規(guī)范，如殘留溶劑和殘留粘合劑雜質(zhì)，則可使用IPC測(cè)試代替這些屬性的釋放測(cè)試。

●For converting and pouching, IPCs can provide assurance of pouch integrity, product placement within the pouch, and product appearance (e.g., adequacy of the printed label, die-cuts, and kiss-cuts). An automated system can perform in-process checks for product appearance in lieu of human operators if the automated system is demonstrated to be suitable for the intended task(s).

對(duì)于轉(zhuǎn)換和裝袋，IPC可以確保袋的完整性、袋內(nèi)的產(chǎn)品放置以及產(chǎn)品外觀（例如，印刷標(biāo)簽、模切和吻切的充分性）。如果證明自動(dòng)化系統(tǒng)適用于預(yù)期任務(wù)，自動(dòng)化系統(tǒng)可以代替人工操作員對(duì)產(chǎn)品外觀進(jìn)行過(guò)程中檢查。

C.Control of TDS Product

Section 3.2.P.5 of the application should contain the following information on control of the TDS product:

C.TDS產(chǎn)品控制

申請(qǐng)書(shū)第3.2.P.5節(jié)應(yīng)包含以下關(guān)于TDS產(chǎn)品控制的信息：

●Specification規(guī)格

●Analytical procedures分析程序

●Validation of analytical procedures分析程序的驗(yàn)證

●ØCharacterization of impurities雜質(zhì)的表征

●Batch analyses批次分析

●Justification for the proposed specification擬定規(guī)范的理由

Typical CQAs included in TDS specification:

TDS規(guī)范中包含的典型CQA

●Descr1ption說(shuō)明

●Identification鑒別

●Assay含量測(cè)定

●Impurities and degradation products雜質(zhì)和降解產(chǎn)物

●Uniformity of dosage units含量均勻度

●Permeation enhancer content, when applicable促滲劑含量（如適用）

●Adhesion粘合劑

●Release liner peel釋放襯墊剝離

●Tack黏著力

●Shear剪切力

●Cold flow冷流

●In vitro drug release體外藥物釋放實(shí)驗(yàn)

●Drug substance crystal presence藥物晶態(tài)

●Pouch integrity包裝完整性

●Microbial limits, when applicable 微生物限度（如適用）

●Moisture content, when applicable水分測(cè)定（如適用）

●Residual solvents殘留溶劑

The proposed analytical procedures should be d0cumented in sufficient detail that they can be reviewed and reproduced in FDA laboratories. In some cases, if upstream controls can be used to confirm that a batch of product meets a CQA listed on the specification, that attribute may not need to be tested at release for every batch, but should be indicated as such on the specification. Applicants proposing a control strategy using such an approach should provide justification.

建議的分析程序應(yīng)詳細(xì)記錄，以便在FDA實(shí)驗(yàn)室進(jìn)行審查和復(fù)制。在某些情況下，如果上游控制可用于確認(rèn)一批產(chǎn)品符合規(guī)范中列出的CQA，則該屬性可能不需要在每批產(chǎn)品放行時(shí)進(jìn)行測(cè)試，但應(yīng)在規(guī)范中注明。申請(qǐng)人提出使用這種方法的控制策略時(shí)應(yīng)提供理由。

Some of the methods and criteria associated with CQAs typical for TDS are described below.

一些與CQAs相關(guān)的TDS典型方法和標(biāo)準(zhǔn)如下所述。

a.Adhesive Impurities

Adhesives may contain residual monomers, initiator byproducts, aldehydes, etc. The safety of these compounds should be assessed, as some of these compounds are classified as neurotoxic (e.g., tetramethylsuccinonitrile) or mutagenic (e.g., crotonoaldehyde). Manufacturers are encouraged to contact the raw material suppliers to discuss the selected adhesive raw material  and all potential impurities, as some impurities may not be reported on the certificates of analysis provided by the supplier. Applicants should discuss the potential impurities arising from the raw material in the application. A control strategy for any impurity of toxicological relevance should be established and justified. The control strategy may include testing at the raw material stage,  demonstrating that the manufacturing process is capable of consistently removing the impurities of concern, testing of the final laminate, or a combination of the above.

a.粘合劑雜質(zhì)

粘合劑可能含有殘余單體、引發(fā)劑副產(chǎn)物、醛等。應(yīng)評(píng)估這些化合物的安全性，因?yàn)槠渲幸恍┗衔锉环诸?lèi)為具有神經(jīng)毒性（例如，四甲基丁二腈）或致突變性（例如巴豆醛）。鼓勵(lì)制造商與原材料供應(yīng)商聯(lián)系，討論所選粘合劑原材料和所有潛在雜質(zhì)，因?yàn)楣?yīng)商提供的分析證書(shū)中可能未報(bào)告某些雜質(zhì)。申請(qǐng)人應(yīng)在申請(qǐng)中討論原材料可能產(chǎn)生的雜質(zhì)。應(yīng)制定并證明與毒理學(xué)相關(guān)的任何雜質(zhì)的控制策略。控制策略可包括在原材料階段進(jìn)行測(cè)試，證明制造過(guò)程能夠持續(xù)去除相關(guān)雜質(zhì)，測(cè)試最終層壓板，或以上各項(xiàng)的組合。

To support a proposed control strategy based on the capability of the manufacturing process to consistently remove any impurities of concern, applicants should provide data to demonstrate a reduction in the level of the impurity in the final laminate (or finished product) compared to the level in the same batch of raw material.These data are necessary to quantitatively demonstrate effectiveness of the manufacturing process in removing the impurity and to establish controls for adhesive impurities based on levels in the raw material rather than on the final product.

為了支持基于制造工藝持續(xù)去除任何相關(guān)雜質(zhì)的能力的擬議控制策略，申請(qǐng)人應(yīng)提供數(shù)據(jù)，以證明最終層壓板（或成品）中的雜質(zhì)水平與同一批原材料中的水平相比有所降低。這些數(shù)據(jù)對(duì)于定量證明制造工藝去除雜質(zhì)的有效性以及根據(jù)原材料中的含量而不是最終產(chǎn)品中的含量建立粘合劑雜質(zhì)控制是必要的。

Applicants may consider leveraging the leachable study discussed in the pharmaceutical development section of this guidance by testing adhesive impurities in the leachate. The leachable information can be used to provide toxicological justification for impurity limits or the information can be included as part of the toxicological risk assessment.

申請(qǐng)人可考慮利用本指南藥物開(kāi)發(fā)部分中討論的可浸出性研究，測(cè)試滲濾液中的粘合劑雜質(zhì)。可浸出信息可用于為雜質(zhì)限值提供毒理學(xué)依據(jù)，或?qū)⑿畔⒆鳛槎纠韺W(xué)風(fēng)險(xiǎn)評(píng)估的一部分。

b.Uniformity of Dosage Units

TDS specifications should include a test and acceptance criterion for content uniformity for the dosage units. If the finished TDS is designed to be cut by the user, uniformity should also be demonstrated among pieces cut from a single unit.

b.含量均勻度

TDS規(guī)范應(yīng)包括劑量單位含量均勻性的測(cè)試和驗(yàn)收標(biāo)準(zhǔn)。如果最終TDS設(shè)計(jì)為由用戶切割，則還應(yīng)證明從單個(gè)單元切割的工件之間的一致性。

c.Permeation Enhancer Content

Products that utilize permeation enhancers to establish or maintain drug delivery should include a test and acceptance criterion for permeation enhancers at release and throughout stability. An acceptance criterion that is wider than the typical range for a particular permeation enhancer may require in vivo justification in the absence of an in vitro in vivo correlation.

C.促滲劑含量

使用滲透促進(jìn)劑建立或維持藥物遞送的產(chǎn)品應(yīng)包括促滲劑在釋放和整個(gè)穩(wěn)定性試驗(yàn)時(shí)的測(cè)試和驗(yàn)收標(biāo)準(zhǔn)。在缺乏體外-體內(nèi)相關(guān)性的情況下，比特定促滲劑的典型范圍更寬的接受標(biāo)準(zhǔn)可能需要體內(nèi)研究證明。

d.Adhesion Testing (Peel Adhesion, Release Liner Peel, Tack, and Shear Tests)

Using currently available methods, in vitro adhesion testing does not correlate to in vivo adhesion, but in vitro adhesion testing can be useful for quality control (QC) purposes. In vitro adhesion testing should include peel adhesion, release liner removal, tack, and shear (dynamic or static). There are multiple methods and different experimental parameters for each of the tests.

D.黏附試驗(yàn)(剝離粘附、釋放襯墊剝離、粘性和剪切試驗(yàn))

使用當(dāng)前可用的方法，體外粘附測(cè)試與體內(nèi)粘附無(wú)關(guān)，但體外黏附測(cè)試可用于質(zhì)量控制（QC）目的。體外黏附測(cè)試應(yīng)包括剝離黏附、剝離襯墊移除、粘性和剪切（動(dòng)態(tài)或靜態(tài)）。每個(gè)測(cè)試有多種方法和不同的實(shí)驗(yàn)參數(shù)。

The peel adhesion test measures the force required to remove (peel away) a TDS that has been applied to a standard test panel (e.g., polished stainless steel). The measurement of peel adhesion is influenced by the test parameters such as dwell time, substrate (e.g., stainless steel, high density polyethylene (HDPE)), peel angle, and peel speed.

剝離附著力測(cè)試測(cè)量去除（剝離）已應(yīng)用于標(biāo)準(zhǔn)測(cè)試面板（例如拋光不銹鋼）的TDS所需的力。剝離附著力的測(cè)量受測(cè)試參數(shù)的影響，例如停留時(shí)間、基材（例如不銹鋼、高密度聚乙烯（HDPE））、剝離角和剝離速度。

A release liner peel test measures the force required to separate a TDS from its release liner. The measurement of release liner peel is influenced by experimental parameters such as peel angle and peel speed.

釋放襯墊剝離測(cè)試用于測(cè)量將TDS與釋放襯套分離所需的力。釋放襯墊剝離的測(cè)量受剝離角和剝離速度等實(shí)驗(yàn)參數(shù)的影響。

The probe tack test measures the force required to separate the test probe from the adhesive of the TDS. Tack measurement is influenced by the test parameters such as the contact area, the contact pressure, the time of contact (or dwell time), and rate of separation.

探針粘性測(cè)試測(cè)量將測(cè)試探針與TDS粘合劑分離所需的力。粘性測(cè)量受測(cè)試參數(shù)的影響，如接觸面積、接觸壓力、接觸時(shí)間（或停留時(shí)間）和分離速度。

There are two categories of shear testing, namely dynamic and static. In the dynamic test, the TDS is pulled from a standard test panel (e.g., polished stainless steel). Dwell time, speed, type of test panel, mode of failure, and sample size are the typical test parameters reported for the dynamic shear test. In the static shear test, the TDS sample is applied to a test panel that is at an angle 2° from the vertical, and the sample is subjected to a shearing force by a means of a givenweight (e.g., 1000 g) suspended from the TDS; the time required to detach a standard area of the TDS from a stainless steel test panel under a standard load is measured. Dwell time, weight used, type of test panel, mode of failure, and sample size are the typical test parameters reported for the static shear test. The time taken for the TDS sample to detach from the test panel is also reported

剪切試驗(yàn)有兩類(lèi)，即動(dòng)態(tài)和靜態(tài)。在動(dòng)態(tài)測(cè)試中，TDS從標(biāo)準(zhǔn)測(cè)試面板（例如，拋光不銹鋼）中拉出。停留時(shí)間、速度、試驗(yàn)板類(lèi)型、失效模式和樣本大小是動(dòng)態(tài)剪切試驗(yàn)報(bào)告的典型試驗(yàn)參數(shù)。在靜態(tài)剪切試驗(yàn)中，將TDS樣品施加到與垂直方向成2°角的試驗(yàn)板上，并通過(guò)懸浮在TDS上的給定質(zhì)量（例如1000 g）對(duì)樣品施加剪切力；測(cè)量在標(biāo)準(zhǔn)負(fù)載下從不銹鋼測(cè)試面板上分離TDS標(biāo)準(zhǔn)區(qū)域所需的時(shí)間。靜態(tài)剪切試驗(yàn)報(bào)告的典型試驗(yàn)參數(shù)包括停留時(shí)間、所用質(zhì)量、試驗(yàn)板類(lèi)型、破壞模式和樣品尺寸。也需報(bào)告TDS樣品從測(cè)試面板上分離所需的時(shí)間

E.冷流

冷流是指粘合劑基質(zhì)在背襯膜周邊或通過(guò)剝離襯墊縫隙的流動(dòng)或滲出。TDS、隔離襯墊、袋或一次性膜（有時(shí)稱(chēng)為滑動(dòng)片或保護(hù)膜，例如背襯上的膜和隔離襯墊上的膜）上可能存在冷流。盡管評(píng)估冷流的定量方法可以提供有意義的測(cè)量，但它可能無(wú)法描述從袋中去除TDS或從TDS中去除保護(hù)膜的困難。TDS最準(zhǔn)確的冷流評(píng)估可能來(lái)自特定產(chǎn)品的定量和定性方法的組合。

The test methods should be discriminating and scientifically justified. Manufacturers should propose product-specific acceptance criteria with justification supported by product development research.

測(cè)試方法應(yīng)具有鑒別性和科學(xué)合理性。制造商應(yīng)提出產(chǎn)品特定的驗(yàn)收標(biāo)準(zhǔn)，并提供產(chǎn)品開(kāi)發(fā)研究支持的理由。

f.In vitro Drug Release

USP General Chapter describes the apparatuses to use for in vitro release testing and the acceptance criteria for each apparatus; however, method development and validation is not addressed. General recommendations for in vitro release testing of TDS are described below along with considerations for method design and validation

F.體外藥物釋放

USP通則章節(jié)描述了用于體外釋放測(cè)試的儀器以及每個(gè)儀器的驗(yàn)收標(biāo)準(zhǔn)；然而，方法開(kāi)發(fā)和驗(yàn)證并未涉及。TDS體外釋放試驗(yàn)的一般建議以及方法設(shè)計(jì)和驗(yàn)證的注意事項(xiàng)如下所述

In vitro drug release testing of TDS products is typically performed using specific, qualified apparatus such as: Paddle over Disk (Apparatus 5), Cylinder (Apparatus 6), or Reciprocating Holder (Apparatus 7).

TDS產(chǎn)品的體外藥物釋放測(cè)試通常使用特定合格的設(shè)備進(jìn)行，例如：槳碟法（裝置5）、轉(zhuǎn)筒法（裝置6）或往復(fù)支架法（裝置7）。

（圖片提供銳拓相應(yīng)設(shè)備圖片）

The NDA or ANDA submission for the TDS product should include a method development and validation report with complete information/data supporting the proposed drug release method and acceptance criteria.

TDS產(chǎn)品的NDA或ANDA提交文件應(yīng)包括方法開(kāi)發(fā)和驗(yàn)證報(bào)告，其中包含支持?jǐn)M定藥物釋放方法和驗(yàn)收標(biāo)準(zhǔn)的完整信息/數(shù)據(jù)。

Sufficient detail and data should be included in the method development and validation report so the adequacy of the method for batch release and stability testing can be properly assessed. Examples of parameters to eva1uate during method development include selection of USP apparatus/other equipment, drug release medium, rotation or agitation speed, temperature, pH,  sink conditions, use of a surfactant, and other technical aspects of the test. An in vitro drug release method should be simple, reliable, reproducible, discriminating, and robust. Applicants should strive to develop a method that releases as much drug as possible.

方法開(kāi)發(fā)和驗(yàn)證報(bào)告中應(yīng)包含足夠的細(xì)節(jié)和數(shù)據(jù)，以便能夠正確評(píng)估批放行和穩(wěn)定性測(cè)試方法的充分性。方法開(kāi)發(fā)過(guò)程中要評(píng)估的參數(shù)示例包括USP儀器/其他設(shè)備的選擇、藥物釋放介質(zhì)、旋轉(zhuǎn)或攪拌速度、溫度、pH值、沉降條件、表面活性劑的使用以及測(cè)試的其他技術(shù)方面。體外藥物釋放方法應(yīng)簡(jiǎn)單、可靠、可重復(fù)、鑒別和耐用。申請(qǐng)人應(yīng)努力開(kāi)發(fā)一種釋放盡可能多藥物的方法。

The validation section of the report should include complete information/data regarding: i) the discriminating ability of the selected method, ii) the validation of the drug release methodology, and iii) the validation/verification of the analytical method selected to assay the drug release samples. The selected method should be able to differentiate the release profiles of TDS that are intentionally manufactured with meaningful variations in critical process parameters and formulation components. Validation data should demonstrate the range and sensitivity of the  method for proportional drug release across different strengths of the TDS. In addition,  validation data should demonstrate reproducibility of the method for drug release across different runs of the same batch and its robustness, i.e., its capacity to remain unaffected by changes in receptor medium temperature, paddle rate, and other method parameters

報(bào)告的驗(yàn)證部分應(yīng)包括以下方面的完整信息/數(shù)據(jù)：i）所選方法的區(qū)分力，ii）藥物釋放方法的驗(yàn)證，以及iii）測(cè)定藥物釋放樣品所選分析方法的驗(yàn)證/驗(yàn)證。所選方法應(yīng)能夠區(qū)分有意制造的TDS的釋放曲線，其關(guān)鍵工藝參數(shù)和配方組分存在有意義的變化。驗(yàn)證數(shù)據(jù)應(yīng)證明該方法在TDS不同強(qiáng)度下的比例藥物釋放范圍和靈敏度。此外，驗(yàn)證數(shù)據(jù)應(yīng)證明藥物釋放方法在同一批次的不同運(yùn)行中的再現(xiàn)性及其耐用性，即其不受受體介質(zhì)溫度、槳速率和其他方法參數(shù)變化影響的能力

相關(guān)閱讀：《FDA IVRT測(cè)試 工業(yè)指南翻譯稿》

The acceptance criteria for the in vitro drug release test should be based on the proposed TDS product batch release data, including data from bio-batches (e.g., BE, PK, Clinical), registration/exhibit batches, and commercial batches (if available). To set the acceptance criteria for the in vitro drug release test, a complete drug release profile should be established by collecting data until there is no increase in drug release over three consecutive time points (sampling every 2 hours). The drug release profile of TDS products typically encompasses  initial, middle, and terminal phases; thus, for setting the acceptance criteria, there should be at least one sampling time point covering each phase. The drug release data should be reported as  the cumulative percent of drug being released with time. The acceptance criteria range for each specific timepoint should be based on the mean percentage value of drug released ± 10 percent using the drug release data generated at these times. The percentage should be determined based  on the TDS product’s label claim. If less than 100 percent drug is released, but no drug increase is observed over three consecutive sampling timepoints (i.e., incomplete drug release), the amount of drug reached at the plateau should be considered 100 percent for the purposes of estimating the percent of drug release over time.

體外藥物釋放試驗(yàn)的驗(yàn)收標(biāo)準(zhǔn)應(yīng)基于擬定的TDS產(chǎn)品批放行數(shù)據(jù)，包括生物批次（如BE、PK、臨床）、注冊(cè)/展示批次和商業(yè)批次（如可用）的數(shù)據(jù)。為了制定體外藥物釋放試驗(yàn)的驗(yàn)收標(biāo)準(zhǔn)，應(yīng)通過(guò)收集數(shù)據(jù)建立完整的藥物釋放曲線，直到連續(xù)三個(gè)時(shí)間點(diǎn)（每2小時(shí)取樣一次）藥物釋放量沒(méi)有增加。TDS產(chǎn)品的藥物釋放概況通常包括初期、中期和末期；因此，為了設(shè)定驗(yàn)收標(biāo)準(zhǔn)，每個(gè)階段至少應(yīng)有一個(gè)采樣時(shí)間點(diǎn)。藥物釋放數(shù)據(jù)應(yīng)報(bào)告為藥物隨時(shí)間釋放的累積百分比。每個(gè)特定時(shí)間點(diǎn)的驗(yàn)收標(biāo)準(zhǔn)范圍應(yīng)基于使用這些時(shí)間生成的藥物釋放數(shù)據(jù)的藥物釋放的平均百分比值±10%。百分比應(yīng)根據(jù)TDS產(chǎn)品的標(biāo)簽聲明確定。如果釋放的藥物少于100%，但在連續(xù)三個(gè)采樣時(shí)間點(diǎn)內(nèi)未觀察到藥物增加（即藥物釋放不完全），則應(yīng)將達(dá)到穩(wěn)定期的藥物量視為100%，以估計(jì)藥物隨時(shí)間的釋放百分比。

Wider acceptance criteria range for the drug release test may be acceptable if they are supported by an approved in-vitro in-vivo correlation model.

如果有已批準(zhǔn)的體外-體內(nèi)相關(guān)模型支持，則藥物釋放試驗(yàn)的接受標(biāo)準(zhǔn)范圍可能會(huì)更寬。

g.Crystal Presence

The presence of crystals or crystallization of the drug in the TDS over time can negatively impact the product performance. Therefore, it is important to establish a test and acceptance criteria to confirm the absence of crystals to be used at release and on stability. Microscopic and photometric methods are preferred rather than a simple visual count. It is recognized that some products are designed to be suspensions, however, this design does not preclude the need for a crystal specification. Suspension products should still include tests and acceptance criterion to ensure against crystal propagation, which may impact drug delivery or adhesion properties of the product.

g.析晶現(xiàn)象

隨著時(shí)間的推移，TDS中析出藥物晶體或結(jié)晶會(huì)對(duì)產(chǎn)品性能產(chǎn)生負(fù)面影響。因此，建立一個(gè)測(cè)試和驗(yàn)收標(biāo)準(zhǔn)，以確認(rèn)釋放和穩(wěn)定性時(shí)不存在待使用的晶體，這一點(diǎn)很重要。最好使用顯微鏡和光度法，而不是簡(jiǎn)單的目視計(jì)數(shù)。人們認(rèn)識(shí)到，雖然有些產(chǎn)品設(shè)計(jì)為懸浮液，但這種設(shè)計(jì)并不排除對(duì)晶體規(guī)格的需求。懸浮產(chǎn)品仍應(yīng)包括測(cè)試和驗(yàn)收標(biāo)準(zhǔn)，以防止晶體化，這可能會(huì)影響藥物輸送或產(chǎn)品的粘附性能。

h.Pouch Integrity

The pouch for a TDS is critical to the stability and integrity of the product. Pouch integrity testing should be conducted as part of finished product release unless justification is provided for an alternative approach that assures the finished product specification is met.

h.袋的完整性

TDS袋對(duì)產(chǎn)品的穩(wěn)定性和完整性至關(guān)重要。袋完整性測(cè)試應(yīng)作為成品放行的一部分進(jìn)行，除非為確保符合成品規(guī)范的替代方法提供了理由。

D.Additional Stability Studies

In addition to the standard battery of formal stability and photostability studies for drug substance and drug products discussed in ICH Q1A and ICH Q1B, TDS applicants and manufacturers should conduct stability studies under challenge conditions that include temperature excursions, freeze/thaw, and/or crystal seeding. These additional studies are intended to address certain product quality issues such as crystal formation and growth. Moreover, in-use photostability testing may be appropriate to conduct for certain TDS formulations, depending on backing membrane opacity, duration of wear, and its expected exposure to light when in use.

D.其他 穩(wěn)定性研究

除了ICH Q1A和ICH Q1B中討論的原料藥和藥物產(chǎn)品的正式穩(wěn)定性和光穩(wěn)定性研究的標(biāo)準(zhǔn)組外，TDS申請(qǐng)人和制造商應(yīng)在挑戰(zhàn)條件下進(jìn)行穩(wěn)定性研究，包括溫度漂移、冷凍/解凍和/或晶種。這些額外的研究旨在解決某些產(chǎn)品質(zhì)量問(wèn)題，如晶體形成和生長(zhǎng)。此外，使用中的光穩(wěn)定性測(cè)試可能適用于某些TDS制劑，這取決于背襯膜的不透明度、磨損持續(xù)時(shí)間以及使用時(shí)預(yù)期的光暴露。

A.Product Adhesion Considerations

In vivo adhesion studies provide the greatest prediction of adhesion, a CQA, for a proposed commercial product. Applicants should demonstrate that reasonable efforts were made to optimize adhesive characteristics of the TDS. This optimization should balance properties such as adhesiveness, cohesiveness, and stability to ensure a consistent and uniform adhesion of its entire surface area to the skin for the entire duration of wear. Applicants should develop a comprehensive strategy for assessing the adhesive attributes of the TDS. In vivo adhesion studies are necessary to demonstrate adequate adhesion of the TDS. Therefore, when possible, such as in efficacy studies for an NDA, subject diaries describing the actual in-use product adhesion performance should be used. This information bolsters adhesion data collected from the studies described below and in other guidances

A.產(chǎn)品附著力注意事項(xiàng)

體表粘附研究為擬定的商業(yè)產(chǎn)品提供了最大的粘附預(yù)測(cè)，即CQA。申請(qǐng)人應(yīng)證明已作出合理努力以?xún)?yōu)化TDS的粘合特性。這種優(yōu)化應(yīng)平衡諸如粘附性、內(nèi)聚性和穩(wěn)定性等特性，以確保在整個(gè)使用期間其整個(gè)表面區(qū)域與皮膚的一致性和均勻粘附力。申請(qǐng)人應(yīng)制定全面的策略來(lái)評(píng)估TDS的粘性屬性。體內(nèi)粘附研究是證明TDS充分粘附的必要條件。因此，在可能的情況下，例如在NDA的療效研究中，應(yīng)使用描述實(shí)際在用產(chǎn)品粘附性能的受試者日記。該信息支持從以下研究和其他指南中收集的粘附數(shù)據(jù)

Characterization of the adhesive properties of a TDS should demonstrate that the labelled uses are substantiated. For example, if the TDS is intended to be worn during bathing and showering, applicants should demonstrate that the TDS will continue to adhere during and after such incidental exposure to water. Product reinforcement, such as taping the edges or use of overlays, or occluding the product from water during bathing should not be permitted during the in vivo adhesion eva1uation

TDS粘附特性的表征應(yīng)證明標(biāo)簽用途得到證實(shí)。例如，如果TDS打算在沐浴和淋浴時(shí)使用，申請(qǐng)人應(yīng)證明TDS在偶然接觸水期間和之后將繼續(xù)保持粘附。在體內(nèi)粘附性評(píng)估期間，不允許使用產(chǎn)品加固，例如貼邊或使用覆蓋物，或在沐浴期間將產(chǎn)品與水隔絕

We recommend that when assessing the adhesion of a TDS, applicants use a 5-point numerical scale in which each score corresponds to a specified range of adhered surface area of the TDS, as follows:

我們建議，在評(píng)估TDS粘附性時(shí)，申請(qǐng)人使用5分制的數(shù)值量表，其中每個(gè)分?jǐn)?shù)對(duì)應(yīng)TDS粘附表面積的指定范圍，如下所示：

0 = ≥ 90% adhered (essentially no lift off the skin) 粘附（基本上不會(huì)剝離皮膚）

1 = ≥ 75% to < 90% adhered (some edges only lifting off the skin) 粘附（某些邊緣僅從皮膚上剝離）

2 = ≥ 50% to < 75% adhered (less than half of the TDS lifting off the skin) 粘附（少于TDS的一半剝離皮膚）

3 = > 0% to < 50% adhered (not detached, but more than half of the TDS lifting off the skin without falling off) 粘附（未脫落，但超過(guò)一半的TDS從皮膚上剝離而不脫落）

4 = 0% adhered (TDS detached; completely off) 粘附（TDS分離；完全脫落）

Additionally, the following information should be collected:

此外，還應(yīng)收集以下信息：

At each time point when adhesion is assessed on the above described 5-point scale, the scorer should also record their actual percent adherence estimate (e.g., if the observer scores the product as a two on the five point scale and estimates that the product appears to be 60 percent adhered, a score of two and a 60 percent should be recorded for that time point).

在以上述5分制評(píng)估粘附力的每個(gè)時(shí)間點(diǎn)，記分員還應(yīng)記錄他們的實(shí)際粘附百分比估計(jì)值（例如，如果觀察者在5分制上將產(chǎn)品評(píng)分為2分，并估計(jì)產(chǎn)品粘附率為60%，則應(yīng)記錄該時(shí)間點(diǎn)的2分和60%）。

Photographic evidence showing the extent of TDS adherence to the skin at each time point should be provided.

應(yīng)提供照片證據(jù)，顯示在每個(gè)時(shí)間點(diǎn)TDS粘附到皮膚的程度。

B.Product Storage and Disposal – Labeling Considerations

TDS storage conditions should be supported by stability data and stated in the label. Generally, we recommend controlled room temperature for the storage of TDS. Excursions, if permitted, should be indicated on the label. The label should also state that TDS should not be stored outside of the pouch if that is necessary to preserve the safety, efficacy, and quality of the TDS.

B.產(chǎn)品儲(chǔ)存和處理-標(biāo)簽注意事項(xiàng)

TDS儲(chǔ)存條件應(yīng)得到穩(wěn)定性數(shù)據(jù)的支持，并在標(biāo)簽中說(shuō)明。通常，我們建議在室溫下儲(chǔ)存TDS。如果允許，應(yīng)在標(biāo)簽上注明。標(biāo)簽還應(yīng)說(shuō)明，如果為了保持TDS的安全性、有效性和質(zhì)量，TDS不應(yīng)存放在袋外。

Transdermal and topical delivery systems often contain post-use residual drug in the delivery system. Considering the therapeutic nature of the drug compound and potential adverse events resulting from unintended exposure, the instruction for product disposal should be clearly outlined in the labeling. It is important that the disposal process prevents exposure of the residual drug to the environment and/or other people. Depending on the nature of the product, special instructions may be required to prevent exposure to children and caregivers, which could result in significant safety-related consequences

經(jīng)皮和局部遞送系統(tǒng)使用后，通常會(huì)有殘留的藥物。考慮到藥物的治療性質(zhì)和由于意外暴露引起的潛在不良事件，標(biāo)簽中應(yīng)明確列出產(chǎn)品處理事項(xiàng)。處理過(guò)程必須防止殘余藥物暴露于環(huán)境和/或其他人。根據(jù)產(chǎn)品的性質(zhì)，可能需要特殊說(shuō)明，以防止兒童和護(hù)理人員接觸，否則可能會(huì)導(dǎo)致嚴(yán)重的安全相關(guān)后果

實(shí)驗(yàn)儀器：銳拓 RT800 自動(dòng)取樣透皮擴(kuò)散系統(tǒng)