?    

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.

申請人必須提供足夠詳細的技術數(shù)據(jù)和信息，以使FDA能夠對是否批準申請做出明智的判斷，或者是否存在《FD&C法案》第505（d）或505（j）節(jié)規(guī)定的拒絕批準申請的理由。這包括關于藥物物質的信息和關于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.

以下各部分向申請人提供了關于藥物開發(fā)和質量信息的建議，這些信息將包含在ICH M4Q中所述的應用章節(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。申請應包含進行研究的信息，以確定申請中規(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明適用于TDS產(chǎn)品的預期用途。申請人應解決以下問題：

lA descr1ption of the QTPP/QTPP說明

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CQAs相關的限制、范圍或分布以及適當?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)和制造工藝對實現(xiàn)產(chǎn)品質量至關重要的方面的識別。

●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，申請人應描述滲透促進劑對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. 申請人應說明可能影響TDS產(chǎn)品CQA的工藝參數(shù)和材料屬性的允許范圍，并說明如何對其進行監(jiān)控。

lA descr1ption of the quality risk assessments, potential failure modes, and product and process control strategies/質量風險評估、潛在故障模式以及產(chǎn)品和過程控制策略的描述。

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.

對于使用溶劑化原料的工藝，批次配方的設計應能承受原料溶劑的含量變化。過量的API和過量的輔料可添加到批次中，以解決干燥過程中的蒸發(fā)問題，但過量或過量的量應通過工藝開發(fā)研究加以控制和證明。申請人應描述任何一種交聯(lián)反應，因為這些反應影響成品的化學成分和質量。

2.Expectations for Registration/Exhibit Batches.對注冊/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

申請人應提交由三種不同層壓材料制成的注冊/展示批次的數(shù)據(jù)，其中每個層壓材料使用不同批次的藥物、粘合劑、背襯和/或TDS產(chǎn)品中的其他關鍵元素制成。釋放和穩(wěn)定性取樣應代表層壓板的整個長度和寬度，以證明制造過程穩(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）都應包含在正式的穩(wěn)定性計劃中。申請人應提供臨床和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。安慰劑批次應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

申請人應報告制造、加工、包裝和保存每個適當階段結束時的實際產(chǎn)量、理論產(chǎn)量和理論產(chǎn)量百分比。應前瞻性地計算每批的理論產(chǎn)量。例如，如果由于制造問題而停止了涂覆過程，則理論產(chǎn)量應基于打算涂覆的質量，而不是實際涂覆的質量。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，應在申請中說明 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)品對制造過程中的微小差異很敏感，應在申請書第3.2.P.2.3節(jié)中包含一份比較臨床、BE、注冊/展示和擬議商業(yè)批次的主表。對于每個批次，該表應詳細說明所使用的制造工藝（包括設備、制造規(guī)模以及可能直接或間接影響CQA的參數(shù)），以及關鍵過程中測試的結果（規(guī)定測試程序和驗收標準）、產(chǎn)量和調節(jié)數(shù)據(jù)。該表還應包括提交文件其他部分引用的任何信息的鏈接。還應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劑型的獨特性，建議進行專門的開發(fā)研究和評估，以證明在NDA和ANDA應用中對產(chǎn)品的全面理解。以下討論了幾項此類研究/評估。

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活性和TDS中藥物飽和程度的函數(shù)。應評估藥物在TDS中的溶解度和飽和度，并了解其對TDS性能的影響。

b.Crystallization/結晶

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，應避免 TDS 產(chǎn)品中API的結晶。如果發(fā)生結晶，應進行研究以評估其對TDS體內性能和粘附的影響。

c.Thermodynamic Stability of Drug Substance/原料藥的熱力學穩(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.

為了確認藥物的熱力學穩(wěn)定性，應評估生產(chǎn)和儲存過程中沉淀或鹽形成的風險。如果不同鹽形式之間存在平衡，則應徹底描述達到該平衡的動力學。應使用相關的體外藥物釋放、滲透和/或臨床數(shù)據(jù)評估這種平衡對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)格應表示為速率（例如，XXmg/天），而局部系統(tǒng)的強度則應表示為總藥物負荷的百分比。對于透皮系統(tǒng)，強度可以由PK數(shù)據(jù)或對使用過的透皮系統(tǒng)進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生物利用度導出清除率（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束時測量透皮系統(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)的強度以總藥物負荷百分比表示，但仍應進行殘留藥物分析。

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關于透皮和相關藥物輸送系統(tǒng)中殘留藥物的行業(yè)指南（2011年8月），申請的藥物開發(fā)部分應包含足以支持TDS中殘留藥物量的科學依據(jù)。為了對殘留藥物進行可靠分析，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)應基于對所用TDS的分析，而非理論計算。

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. 應評估殘留在皮膚表面的藥物量。在儲存或使用過程中可能轉移到包裝或 TDS 其他成分的任何藥物都應考慮在內，以嘗試進行質量平衡。

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

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. 應在整個使用期間進行TDS粘附評估，以確定TDS擴散表面積在整個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. 應進行對照研究，以提供藥物負荷的估計，而不是簡單地使用表達的標簽要求。這項研究應包括對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. 應驗證將TDS應用于皮膚之前和之后的樣品存儲條件。在選擇合適的儲存條件時，還應考慮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應使用適當敏感和有效的分析方法測定殘留藥物含量，以計算藥物消耗和遞送。當估計TDS中殘留藥物的量時，應使用目標提取效率接近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（IVPT）可用于表征透皮或局部藥物遞送的速率和程度，并且在應用中應描述研究方案和結果。IVPT模型開發(fā)過程中應考慮以下因素：

相關閱讀：《FDA IVPT 測試 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)

皮膚來源、皮膚儲存條件、皮膚類型的選擇（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（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方案應規(guī)定標稱皮膚厚度及其范圍、皮膚屏障完整性測試的細節(jié)以及IVPT期間產(chǎn)品的任何遮擋。僅憑視覺觀察不足以表征皮膚的屏障完整性?？山邮艿钠琳贤暾詼y試可基于氚化水滲透、經(jīng)表皮失水（TEWL）或通過皮膚測量的電阻抗/電導。用于皮膚屏障完整性測試的測試參數(shù)和驗收標準應根據(jù)相關文獻參考或其他信息進行證明

相關閱讀：《IVPT測試中的皮膚研究》

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方案還應包括受體溶液、系統(tǒng)平衡、皮膚安裝程序和TDS應用程序的詳細信息，以及將TDS固定在皮膚表面以防止移動的任何措施。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研究報告應包括劑量持續(xù)時間、取樣持續(xù)時間、取樣時間點、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)驗穩(wěn)定性（在相關溫度下）和溶解度。研究報告還應包括接受皮膚評估的個體數(shù)量（即，皮膚供體）以及每個治療組每個供體的重復皮膚切片數(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在同一組供體的皮膚樣本上給藥，每個治療組每個供體的重復次數(shù)相同。這些治療組還應使用來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)對研究設計和TDS評估至關重要。研究報告應包括劑量應用前的平衡皮膚表面溫度、實驗室的環(huán)境溫度和相對濕度，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

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

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《美國藥典》（USP）第21章“與藥物包裝/輸送系統(tǒng)相關的可提取物評估”中所定義的，“可提取物是在實驗室條件下從藥物包裝/運輸系統(tǒng)、包裝組件或包裝材料中釋放并進入提取溶劑的有機和無機化學物質。提取條件應“加速或放大包裝劑型的正常儲存和使用條件”

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)相關的藥品浸出物評估中所定義，“可浸出物是指包裝藥品中存在的外來有機和無機物質，因為它們在正常儲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，可提取雜質是可通過溶劑系統(tǒng)從背襯膜、釋放襯墊、袋材料、印刷油墨、內膜和除藥物和粘合劑基質以外的成分中抽出的化學物質。

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，提取研究可以檢測從制造過程中引入TDS的化合物，這會影響TDS產(chǎn)品的最終雜質分布。在本指南中，可浸出物是包裝TDS中存在的化學物質，因為它們在正常儲存條件下或在加速穩(wěn)定性研究期間浸出到粘合劑基質（或適用情況下的儲層）中。在使用過程中，這些化合物可從粘合劑基質（或貯層）轉移至患者。

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計。如果可能的話，在不同的對照浸出研究條件下確定浸出物的分布?？商崛『涂山鲅芯繎哂凶銐虻撵`敏度，以檢測當產(chǎn)品以最大日劑量使用時（例如，長期使用藥物產(chǎn)品中的標準致突變化合物為1.5 mcg/天），可能釋放的化合物，除非另有證明。對于某些產(chǎn)品，最大每日劑量可能需要應用一種以上的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，如殘留單體、引發(fā)劑副產(chǎn)物和醛類，不被視為可提取或可浸出物，因為這些雜質在產(chǎn)品制造前以峰值濃度存在。本指南其他地方對粘合劑雜質的控制進行了討論（見第四節(jié)C申請中提交的信息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限值，或作為粘合劑雜質毒理學風險評估的一部分，因為對擬議的商業(yè)產(chǎn)品進行了可浸出研究。

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.

為了幫助進行下文所述的可提取和可浸出分析，申請人應聯(lián)系原材料供應商，以確定潛在的毒理學問題可提取物，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

應在藥物開發(fā)過程早期進行可提取性研究，以了解擬議商業(yè)TDS組分的潛在浸出物。這些研究應在背襯膜、釋放襯墊、速率控制或其他內部膜、油墨和袋等組件上進行。測試組分應在各種極性不同的溶劑中，在劇烈的實驗提取條件下提取，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?？商崛⌒匝芯恐惺褂玫奶崛∪軇┲粦〝M定商業(yè)粘合劑平臺的溶劑或成品TDS的已知殘留溶劑。所用溶劑的選擇應合理

可浸出研究

可浸出研究的條件應盡可能接近皮膚的“最壞情況”臨床條件（例如，劇烈運動期間出汗）。應為研究選擇合理的溶劑/溶液（如鹽濃度）、溫度、攪拌水平、暴露于溶劑的時間等實驗條件。在研究期間，應將隔離襯墊從系統(tǒng)中移除，以使粘合劑層充分暴露于生物相關溶劑。申請人應進行多時間點可浸出物分析（例如，0、6、12、24個月），以提供全面的可浸出物概況，并確定可浸出物的任何趨勢，因為這些數(shù)據(jù)可能影響產(chǎn)品的保質期。提交申請時，應提交在加速和長期條件下儲存至少6個月的多批次樣品的可浸出研究數(shù)據(jù)。我們建議對三種不同的TDS層壓板進行可浸出研究，并進行穩(wěn)定性測試。

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.評估熱效應的影響

來自外部來源（如加熱毯）的熱量，以及可能由于劇烈運動或發(fā)燒導致的體內溫度升高，可能會影響TDS中藥物釋放的速率以及藥物進入和通過皮膚的吸收。我們建議申請人研究相對于正常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

對于在NDA中提交的TDS產(chǎn)品，我們建議將熱效應研究作為臨床研究的一部分，使用擬議的商業(yè)產(chǎn)品進行。在設計熱效應研究時，應確定關鍵因素，如適當升高的試驗溫度、熱暴露開始時間、持續(xù)時間和周期（如有），以及熱暴露機制（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.

對于將在ANDA中提交的TDS產(chǎn)品，申請人應評估在高溫條件下使用的測試TDS是否比參考（R）TDS增加藥物遞送。ANDA申請人應提供一項IVPT研究的結果，該研究使用來自多個個體（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，每個供體、每個治療（T與R）和每個溫度條件下評估多個復制擴散池。建議進行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，并在每個溫度條件下對每個供體進行重復治療。如果一項研究在每種溫度下，每種處理的供體少于四個，每個供體有四個重復，這可能很難對結果進行解釋。

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和高溫條件下對試驗和R TDS進行平行評估和比較：

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：在整個研究期間，T和R產(chǎn)品的TDS/皮膚表面溫度應保持在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的指定時間，然后在剩余持續(xù)研究時間段保持在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.

不應假設循環(huán)水浴的設定溫度可以提供TDS/皮膚表面的目標溫度。應使用紅外溫度計或其他溫度探頭直接測量TDS/皮膚表面溫度。7天使用TDS的研究持續(xù)時間不需要包括整個標示的使用持續(xù)時間。如果IVPT研究的持續(xù)時間足以達到基礎條件下的峰值藥物輸送率，則進行48或72小時的IVPT研究可能就足夠。或者，申請人可以評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. 微觀基質評價

由于許多TDS配方的復雜性，粘合劑基質通常不會形成真正的溶液，而是表現(xiàn)為分散體。如果分散樣系統(tǒng)在基質中隨著時間的推移發(fā)生重排，它們可能導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中的分散方式，以及有效期內，隨著時間變化基質從產(chǎn)品中釋放的趨勢。因此，使用高性能顯微鏡、元素圖譜或其他適當?shù)墓ぞ咴u估TDS基質在整個開發(fā)批次保質期內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；申請人應為所使用的工具提供科學依據(jù)。這些評估將有助于全面了解產(chǎn)品和過程，降低質量相關風險，并確保TDS在其到期期間滿足必要的質量屬性

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產(chǎn)品質量產(chǎn)生不利影響的風險相當。一般來說，在進行關鍵臨床研究后，應盡可能避免TDS的變化，因為TDS對配方和制造過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

可通過更新主批次記錄和批次方案得到充分支持低風險變更。例如，使用相同設計和工作原理的設備，將溶劑基和水性混合物的規(guī)模擴大10倍，或建議對相同設計和工作原理的轉換和裝袋設備進行更改

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

中等風險變化可能需要對商業(yè)規(guī)模批次進行額外的開發(fā)研究和穩(wěn)定性數(shù)據(jù)，以證明它們不會對產(chǎn)品質量產(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倍以內，將螺桿混合工藝的比例提高，以及改變具有相同設計和操作原理的涂層/干燥/層壓設備

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.

對質量構成高風險的變化可能需要額外的體內研究。一個例子是改變制造工藝，以采用不同設計和操作原理的設備。

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，應用程序的第3.2.P.3節(jié)應包含關于TDS產(chǎn)品將在何處以及如何制造的信息。應提供批次配方以及制造工藝和工藝控制的說明。還應提供擬定生產(chǎn)工藝的詳細示意圖，包括設備、操作條件和工藝控制的說明。

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.

在工藝開發(fā)過程中，申請人應確定可能影響TDS產(chǎn)品CQA的工藝變量。這些工藝開發(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）。對于包含這些步驟的過程，申請人應說明每個操作和相關控制是如何制定的，并說明以下注意事項，特別是可能受操作影響的CQA，以及可能影響每個操作輸出的相關工藝參數(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?；旌峡捎绊慍QA，如含量測定、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?？刂撇呗詰鉀Q設備設計、物料添加順序和工藝參數(shù)（如混合速度、混合時間、溫度、再分散或再循環(huán)條件以及脫氣條件）對CQA的影響，并應根據(jù)開發(fā)研究在必要時予以證明。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)使用的設備，涂層可能會影響CQA，如含量均勻性和微觀外觀。盡管CPP依賴于設備，但企業(yè)應證明控制策略（例如，要控制的工藝參數(shù)）足以確保涂布操作整個過程中的含量均勻性和微觀形態(tài)?？赡苡绊懲繉拥腃MA包括散裝混合物的流變性和待涂層基材的輥內均勻性

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

干燥包括在涂布過程之后從混合物中除去溶劑。該工藝步驟可影響CQA，如測定、滲透促進劑含量、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、殘留粘合劑雜質和粘合劑基質的物理性質。因此，在工藝開發(fā)過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。工藝開發(fā)還應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含量。申請人還應提供數(shù)據(jù)，證明藥物和輔料可能需要過量，以補償干燥過程中的蒸發(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)設計的多個層組合成單個普通層壓。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，則申請人應提供電暈處理的開發(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，以便進一步加工。切片和印刷是典型的低風險步驟；然而，如果印刷過程的某些方面，例如過度的滲透深度或熱量輸入，會對產(chǎn)品質量產(chǎn)生不利影響，那么應對印刷工藝進行表征和控制。

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.

轉換和封裝：轉換和封裝通常涉及將連續(xù)層壓材料切割成單個單元，并將該單元密封在熱密封袋中。受這些過程影響的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CPP包括熱封溫度和停留時間。

●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完成固化反應。固化時間和固化條件是該步驟的常見CPPs。如果固化可能影響測試結果，則應在批放行測試前完成固化。

●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.

保持時間：必須定義和證明在單元操作之間保留的過程中材料的保留時間（21 CFR第211.111部分）。申請人應使用基于風險的方法來確定在保持時間研究期間要監(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：管道和其他產(chǎn)品接觸設備必須經(jīng)過非反應性、非添加劑和非吸收性（21 CFR第211.65（a）部分）的認證。管道和某些產(chǎn)品接觸設備的選擇應基于風險，即取決于接觸持續(xù)時間、工藝溫度、溶劑系統(tǒng)、材料考慮因素、制造過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的過程中控制（IPC）是控制策略的一個組成部分。擬議IPC方案的說明應包括以下內容：

●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樣品，申請人應指定平均值、單個樣品的范圍和相對標準偏差百分比。

●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可確保整個層壓板和整個運行過程中的均勻性。例如，薄膜外觀、涂層質量的測量和/或殘留溶劑的測試可能適用于涂層和干燥的IPC。應在申請中描述允許檢測和排除影響粘合劑層壓板連續(xù)性的缺陷（例如條紋）的薄膜外觀測量。此外，對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），申請人應描述為在應用中監(jiān)控整個涂層運行的均勻性而建立的IPC。用于測試涂層質量和均勻性的樣品應代表層壓板的整個長度和寬度。或者，可以連續(xù)監(jiān)測這些屬性（例如，通過使用在線涂層測量工具）。如果上游控制可用于確認某些成品TDS規(guī)范，如殘留溶劑和殘留粘合劑雜質，則可使用IPC測試代替這些屬性的釋放測試。

●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).

對于轉換和裝袋，IPC可以確保袋的完整性、袋內的產(chǎn)品放置以及產(chǎn)品外觀（例如，印刷標簽、模切和吻切的充分性）。如果證明自動化系統(tǒng)適用于預期任務，自動化系統(tǒng)可以代替人工操作員對產(chǎn)品外觀進行過程中檢查。

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

申請書第3.2.P.5節(jié)應包含以下關于TDS產(chǎn)品控制的信息：

●Specification規(guī)格

●Analytical procedures分析程序

●Validation of analytical procedures分析程序的驗證

●ØCharacterization of impurities雜質的表征

●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說明

●Identification鑒別

●Assay含量測定

●Impurities and degradation products雜質和降解產(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體外藥物釋放實驗

●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.

建議的分析程序應詳細記錄，以便在FDA實驗室進行審查和復制。在某些情況下，如果上游控制可用于確認一批產(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)品放行時進行測試，但應在規(guī)范中注明。申請人提出使用這種方法的控制策略時應提供理由。

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

一些與CQAs相關的TDS典型方法和標準如下所述。

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

粘合劑可能含有殘余單體、引發(fā)劑副產(chǎn)物、醛等。應評估這些化合物的安全性，因為其中一些化合物被分類為具有神經(jīng)毒性（例如，四甲基丁二腈）或致突變性（例如巴豆醛）。鼓勵制造商與原材料供應商聯(lián)系，討論所選粘合劑原材料和所有潛在雜質，因為供應商提供的分析證書中可能未報告某些雜質。申請人應在申請中討論原材料可能產(chǎn)生的雜質。應制定并證明與毒理學相關的任何雜質的控制策略?？刂撇呗钥砂ㄔ谠牧想A段進行測試，證明制造過程能夠持續(xù)去除相關雜質，測試最終層壓板，或以上各項的組合。

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)去除任何相關雜質的能力的擬議控制策略，申請人應提供數(shù)據(jù)，以證明最終層壓板（或成品）中的雜質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)對于定量證明制造工藝去除雜質的有效性以及根據(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.

申請人可考慮利用本指南藥物開發(fā)部分中討論的可浸出性研究，測試滲濾液中的粘合劑雜質?？山鲂畔⒖捎糜跒殡s質限值提供毒理學依據(jù)，或將信息作為毒理學風險評估的一部分。

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)范應包括劑量單位含量均勻性的測試和驗收標準。如果最終TDS設計為由用戶切割，則還應證明從單個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

使用滲透促進劑建立或維持藥物遞送的產(chǎn)品應包括促滲劑在釋放和整個穩(wěn)定性試驗時的測試和驗收標準。在缺乏體外-體內相關性的情況下，比特定促滲劑的典型范圍更寬的接受標準可能需要體內研究證明。

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(剝離粘附、釋放襯墊剝離、粘性和剪切試驗)

使用當前可用的方法，體外粘附測試與體內粘附無關，但體外黏附測試可用于質量控制（QC）目的。體外黏附測試應包括剝離黏附、剝離襯墊移除、粘性和剪切（動態(tài)或靜態(tài)）。每個測試有多種方法和不同的實驗參數(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.

剝離附著力測試測量去除（剝離）已應用于標準測試面板（例如拋光不銹鋼）的TDS所需的力。剝離附著力的測量受測試參數(shù)的影響，例如停留時間、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.

釋放襯墊剝離測試用于測量將TDS與釋放襯套分離所需的力。釋放襯墊剝離的測量受剝離角和剝離速度等實驗參數(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.

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

剪切試驗有兩類，即動態(tài)和靜態(tài)。在動態(tài)測試中，TDS從標準測試面板（例如，拋光不銹鋼）中拉出。停留時間、速度、試驗板類型、失效模式和樣本大小是動態(tài)剪切試驗報告的典型試驗參數(shù)。在靜態(tài)剪切試驗中，將TDS樣品施加到與垂直方向成2°角的試驗板上，并通過懸浮在TDS上的給定質量（例如1000 g）對樣品施加剪切力；測量在標準負載下從不銹鋼測試面板上分離TDS標準區(qū)域所需的時間。靜態(tài)剪切試驗報告的典型試驗參數(shù)包括停留時間、所用質量、試驗板類型、破壞模式和樣品尺寸。也需報告TDS樣品從測試面板上分離所需的時間

E.冷流

冷流是指粘合劑基質在背襯膜周邊或通過剝離襯墊縫隙的流動或滲出。TDS、隔離襯墊、袋或一次性膜（有時稱為滑動片或保護膜，例如背襯上的膜和隔離襯墊上的膜）上可能存在冷流。盡管評估冷流的定量方法可以提供有意義的測量，但它可能無法描述從袋中去除TDS或從TDS中去除保護膜的困難。TDS最準確的冷流評估可能來自特定產(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.

測試方法應具有鑒別性和科學合理性。制造商應提出產(chǎn)品特定的驗收標準，并提供產(chǎn)品開發(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試的儀器以及每個儀器的驗收標準；然而，方法開發(fā)和驗證并未涉及。TDS體外釋放試驗的一般建議以及方法設計和驗證的注意事項如下所述

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試通常使用特定合格的設備進行，例如：槳碟法（裝置5）、轉筒法（裝置6）或往復支架法（裝置7）。

（圖片提供銳拓相應設備圖片）

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提交文件應包括方法開發(fā)和驗證報告，其中包含支持擬定藥物釋放方法和驗收標準的完整信息/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.

方法開發(fā)和驗證報告中應包含足夠的細節(jié)和數(shù)據(jù)，以便能夠正確評估批放行和穩(wěn)定性測試方法的充分性。方法開發(fā)過程中要評估的參數(shù)示例包括USP儀器/其他設備的選擇、藥物釋放介質、旋轉或攪拌速度、溫度、pH值、沉降條件、表面活性劑的使用以及測試的其他技術方面。體外藥物釋放方法應簡單、可靠、可重復、鑒別和耐用。申請人應努力開發(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

報告的驗證部分應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）藥物釋放方法的驗證，以及iii）測定藥物釋放樣品所選分析方法的驗證/驗證。所選方法應能夠區(qū)分有意制造的TDS的釋放曲線，其關鍵工藝參數(shù)和配方組分存在有意義的變化。驗證數(shù)據(jù)應證明該方法在TDS不同強度下的比例藥物釋放范圍和靈敏度。此外，驗證數(shù)據(jù)應證明藥物釋放方法在同一批次的不同運行中的再現(xiàn)性及其耐用性，即其不受受體介質溫度、槳速率和其他方法參數(shù)變化影響的能力

相關閱讀：《FDA IVRT測試 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.

體外藥物釋放試驗的驗收標準應基于擬定的TDS產(chǎn)品批放行數(shù)據(jù)，包括生物批次（如BE、PK、臨床）、注冊/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的驗收標準，應通過收集數(shù)據(jù)建立完整的藥物釋放曲線，直到連續(xù)三個時間點（每2小時取樣一次）藥物釋放量沒有增加。TDS產(chǎn)品的藥物釋放概況通常包括初期、中期和末期；因此，為了設定驗收標準，每個階段至少應有一個采樣時間點。藥物釋放數(shù)據(jù)應報告為藥物隨時間釋放的累積百分比。每個特定時間點的驗收標準范圍應基于使用這些時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%。百分比應根據(jù)TDS產(chǎn)品的標簽聲明確定。如果釋放的藥物少于100%，但在連續(xù)三個采樣時間點內未觀察到藥物增加（即藥物釋放不完全），則應將達到穩(wěn)定期的藥物量視為100%，以估計藥物隨時間的釋放百分比。

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.

如果有已批準的體外-體內相關模型支持，則藥物釋放試驗的接受標準范圍可能會更寬。

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

隨著時間的推移，TDS中析出藥物晶體或結晶會對產(chǎn)品性能產(chǎn)生負面影響。因此，建立一個測試和驗收標準，以確認釋放和穩(wěn)定性時不存在待使用的晶體，這一點很重要。最好使用顯微鏡和光度法，而不是簡單的目視計數(shù)。人們認識到，雖然有些產(chǎn)品設計為懸浮液，但這種設計并不排除對晶體規(guī)格的需求。懸浮產(chǎn)品仍應包括測試和驗收標準，以防止晶體化，這可能會影響藥物輸送或產(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袋對產(chǎn)品的穩(wěn)定性和完整性至關重要。袋完整性測試應作為成品放行的一部分進行，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)定性研究的標準組外，TDS申請人和制造商應在挑戰(zhàn)條件下進行穩(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)品質量問題，如晶體形成和生長。此外，使用中的光穩(wěn)定性測試可能適用于某些TDS制劑，這取決于背襯膜的不透明度、磨損持續(xù)時間以及使用時預期的光暴露。

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

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測，即CQA。申請人應證明已作出合理努力以優(yōu)化TDS的粘合特性。這種優(yōu)化應平衡諸如粘附性、內聚性和穩(wěn)定性等特性，以確保在整個使用期間其整個表面區(qū)域與皮膚的一致性和均勻粘附力。申請人應制定全面的策略來評估TDS的粘性屬性。體內粘附研究是證明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，應使用描述實際在用產(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粘附特性的表征應證明標簽用途得到證實。例如，如果TDS打算在沐浴和淋浴時使用，申請人應證明TDS在偶然接觸水期間和之后將繼續(xù)保持粘附。在體內粘附性評估期間，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，在評估TDS粘附性時，申請人使用5分制的數(shù)值量表，其中每個分數(shù)對應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分制評估粘附力的每個時間點，記分員還應記錄他們的實際粘附百分比估計值（例如，如果觀察者在5分制上將產(chǎn)品評分為2分，并估計產(chǎn)品粘附率為60%，則應記錄該時間點的2分和60%）。

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

應提供照片證據(jù)，顯示在每個時間點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)品儲存和處理-標簽注意事項

TDS儲存條件應得到穩(wěn)定性數(shù)據(jù)的支持，并在標簽中說明。通常，我們建議在室溫下儲存TDS。如果允許，應在標簽上注明。標簽還應說明，如果為了保持TDS的安全性、有效性和質量，TDS不應存放在袋外。

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，通常會有殘留的藥物。考慮到藥物的治療性質和由于意外暴露引起的潛在不良事件，標簽中應明確列出產(chǎn)品處理事項。處理過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，可能需要特殊說明，以防止兒童和護理人員接觸，否則可能會導致嚴重的安全相關后果

實驗儀器：銳拓 RT800 自動取樣透皮擴散系統(tǒng)