经皮和局部给药系统——产品开发和质量考量工业指南翻译稿（下部分）

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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.

申请人必须提供足够详细的技术数据和信息，以使FDA能够对是否批准申请做出明智的判断，或者是否存在《FD&C法案》第505（d）或505（j）节规定的拒绝批准申请的理由。这包括关于药物物质的信息和关于TDS产品的信息。

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

以下各部分向申请人提供了关于药物开发和质量信息的建议，这些信息将包含在ICH M4Q中所述的应用章节中.

A.Pharmaceutical Development/药物研发

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节所述。申请应包含进行研究的信息，以确定申请中规定的剂型、配方、制造工艺、容器闭合系统、微生物属性和使用说明适用于TDS产品的预期用途。申请人应解决以下问题：

lA descr1ption of the QTPP/QTPP说明

lA list of the CQAs of the TDS product, along with the limit, range, or distribution associated with each CQA and appropriate justification. TDS产品的CQAs列表，以及与每个CQAs相关的限制、范围或分布以及适当的理由。

lIdentification of those aspects of the drug substance, excipients, container closure system, and manufacturing processes important to attaining product quality.  API、赋形剂、包装容器系统和制造工艺对实现产品质量至关重要的方面的识别。

●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. 特别应讨论影响TDS性能的赋形剂和成分的选择、其浓度（视情况而定）及其功能特性。例如，申请人应描述渗透促进剂对TDS的粘合性能、API在混合物中的溶解度和皮肤渗透的影响。

●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. 申请人应说明可能影响TDS产品CQA的工艺参数和材料属性的允许范围，并说明如何对其进行监控。

lA descr1ption of the quality risk assessments, potential failure modes, and product and process control strategies/质量风险评估、潜在故障模式以及产品和过程控制策略的描述。

1.Batch Formula/批次处方

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.

对于使用溶剂化原料的工艺，批次配方的设计应能承受原料溶剂的含量变化。过量的API和过量的辅料可添加到批次中，以解决干燥过程中的蒸发问题，但过量或过量的量应通过工艺开发研究加以控制和证明。申请人应描述任何一种交联反应，因为这些反应影响成品的化学成分和质量。

2.Expectations for Registration/Exhibit Batches.对注册/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

申请人应提交由三种不同层压材料制成的注册/展示批次的数据，其中每个层压材料使用不同批次的药物、粘合剂、背衬和/或TDS产品中的其他关键元素制成。释放和稳定性取样应代表层压板的整个长度和宽度，以证明制造过程稳健

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

任何临床批次（例如，在第3阶段、PK、BE、粘附或刺激和致敏研究中使用的批次）都应包含在正式的稳定性计划中。申请人应提供临床和BE研究中使用的所有批次（包括安慰剂批次）的执行批次记录和分析证书。安慰剂批次应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

申请人应报告制造、加工、包装和保存每个适当阶段结束时的实际产量、理论产量和理论产量百分比。应前瞻性地计算每批的理论产量。例如，如果由于制造问题而停止了涂覆过程，则理论产量应基于打算涂覆的质量，而不是实际涂覆的质量。TDS工艺的产率可能低于许多其他药物制造工艺的通常产率。但是，应在申请中说明 TDS 提交批次中异常低的产量。

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 产品对制造过程中的微小差异很敏感，应在申请书第3.2.P.2.3节中包含一份比较临床、BE、注册/展示和拟议商业批次的主表。对于每个批次，该表应详细说明所使用的制造工艺（包括设备、制造规模以及可能直接或间接影响CQA的参数），以及关键过程中测试的结果（规定测试程序和验收标准）、产量和调节数据。该表还应包括提交文件其他部分引用的任何信息的链接。还应澄清这些批次是否在模切和装袋阶段包装完成

3.Product Characterization Studies/产品特性研究

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剂型的独特性，建议进行专门的开发研究和评估，以证明在NDA和ANDA应用中对产品的全面理解。以下讨论了几项此类研究/评估。

a.Skin Permeability/皮肤渗透性

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.

皮肤渗透性是渗透热力学活性和TDS中药物饱和程度的函数。应评估药物在TDS中的溶解度和饱和度，并了解其对TDS性能的影响。

b.Crystallization/结晶

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，应避免 TDS 产品中API的结晶。如果发生结晶，应进行研究以评估其对TDS体内性能和粘附的影响。

c.Thermodynamic Stability of Drug Substance/原料药的热力学稳定性

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.

为了确认药物的热力学稳定性，应评估生产和储存过程中沉淀或盐形成的风险。如果不同盐形式之间存在平衡，则应彻底描述达到该平衡的动力学。应使用相关的体外药物释放、渗透和/或临床数据评估这种平衡对TDS性能的影响。

d.Strength/规格

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.

透皮系统的规格应表示为速率（例如，XXmg/天），而局部系统的强度则应表示为总药物负荷的百分比。对于透皮系统，强度可以由PK数据或对使用过的透皮系统进行的残留药物分析得出并得到支持。第一种方法涉及从药物的绝对生物利用度导出清除率（Cl）值，并将其乘以稳定状态下的浓度（Css）。第二种方法涉及在使用期结束时测量透皮系统中残留的药物量，并将“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.

尽管局部系统的强度以总药物负荷百分比表示，但仍应进行残留药物分析。

e.Residual Drug/残留药物

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:

根据FDA关于透皮和相关药物输送系统中残留药物的行业指南（2011年8月），申请的药物开发部分应包含足以支持TDS中残留药物量的科学依据。为了对残留药物进行可靠分析，我们建议如下：

1.Data should be based on analysis of the used TDS and not on a theoretical calculation. 数据应基于对所用TDS的分析，而非理论计算。

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. 应评估残留在皮肤表面的药物量。在储存或使用过程中可能转移到包装或 TDS 其他成分的任何药物都应考虑在内，以尝试进行质量平衡。

3.Tape or overlays should not be used in studies where the TDS is used to calculate residual drug在TDS用于计算残留药物的研究中，不应使用胶带或覆盖物

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. 应在整个使用期间进行TDS粘附评估，以确定TDS扩散表面积在整个研究期间是否与皮肤完全接触。

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. 应进行对照研究，以提供药物负荷的估计，而不是简单地使用表达的标签要求。这项研究应包括对研究中使用的相同产品的三种未使用产品的分析。

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. 应验证将TDS应用于皮肤之前和之后的样品存储条件。在选择合适的储存条件时，还应考虑TDS中活性成分的光稳定性和热稳定性。

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应使用适当敏感和有效的分析方法测定残留药物含量，以计算药物消耗和递送。当估计TDS中残留药物的量时，应使用目标提取效率接近100%的药物提取方法，将误差降至最低

f.In Vitro Permeation Testing/体外渗透测试

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:

使用离体人体皮肤的体外渗透试验（IVPT）可用于表征透皮或局部药物递送的速率和程度，并且在应用中应描述研究方案和结果。IVPT模型开发过程中应考虑以下因素：

相关阅读：《FDA IVPT 测试 工业指南翻译稿》

• 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）

选择扩散装置和操作条件，如搅拌速率或流速，以及温度控制，以保持正常条件下的皮肤表面温度（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)

皮肤来源、皮肤储存条件、皮肤类型的选择（即年龄范围、性别、种族和一致的解剖区域）和皮肤制备技术（例如全厚度、病理皮肤、分离表皮）

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方案应规定标称皮肤厚度及其范围、皮肤屏障完整性测试的细节以及IVPT期间产品的任何遮挡。仅凭视觉观察不足以表征皮肤的屏障完整性。可接受的屏障完整性测试可基于氚化水渗透、经表皮失水（TEWL）或通过皮肤测量的电阻抗/电导。用于皮肤屏障完整性测试的测试参数和验收标准应根据相关文献参考或其他信息进行证明

相关阅读：《IVPT测试中的皮肤研究》

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方案还应包括受体溶液、系统平衡、皮肤安装程序和TDS应用程序的详细信息，以及将TDS固定在皮肤表面以防止移动的任何措施。我们建议在受体溶液中加入抗菌剂（例如，约0.1%的*或约0.01%的硫酸庆大霉素）。

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研究报告应包括剂量持续时间、取样持续时间、取样时间点、样品浓度、抗菌成分浓度以及活性成分在受体溶液中的经验稳定性（在相关温度下）和溶解度。研究报告还应包括接受皮肤评估的个体数量（即，皮肤供体）以及每个治疗组每个供体的重复皮肤切片数量。

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研究中比较的所有治疗组应在同一组供体的皮肤样本上给药，每个治疗组每个供体的重复次数相同。这些治疗组还应使用来自所有供体的相同解剖部位的皮肤样本，除非改变这些参数对研究设计和TDS评估至关重要。研究报告应包括剂量应用前的平衡皮肤表面温度、实验室的环境温度和相对湿度，以及样品分析方法（如HPLC）的合格程度

g.Extractable and Leachable Testing/可提取且可浸出的测试

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

应评估所有TDS中可能从产品转移至患者的潜在化合物。该评估应包括与USP＜1663＞和＜1664＞一致的可提取物和可浸出物的评估

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《美国药典》（USP）第21章“与药物包装/输送系统相关的可提取物评估”中所定义的，“可提取物是在实验室条件下从药物包装/运输系统、包装组件或包装材料中释放并进入提取溶剂的有机和无机化学物质。提取条件应“加速或放大包装剂型的正常储存和使用条件”

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通用章节与药物包装/输送系统相关的药品浸出物评估中所定义，“可浸出物是指包装药品中存在的外来有机和无机物质，因为它们在正常储存和使用条件下或在加速药品稳定性研究期间从包装/输送系统、包装组件或包装材料中浸出到包装药品中。”

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，可提取杂质是可通过溶剂系统从背衬膜、释放衬垫、袋材料、印刷油墨、内膜和除药物和粘合剂基质以外的成分中抽出的化学物质。

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，提取研究可以检测从制造过程中引入TDS的化合物，这会影响TDS产品的最终杂质分布。在本指南中，可浸出物是包装TDS中存在的化学物质，因为它们在正常储存条件下或在加速稳定性研究期间浸出到粘合剂基质（或适用情况下的储层）中。在使用过程中，这些化合物可从粘合剂基质（或贮层）转移至患者。

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设计。如果可能的话，在不同的对照浸出研究条件下确定浸出物的分布。可提取和可浸出研究应具有足够的灵敏度，以检测当产品以最大日剂量使用时（例如，长期使用药物产品中的标准致突变化合物为1.5 mcg/天），可能释放的化合物，除非另有证明。对于某些产品，最大每日剂量可能需要应用一种以上的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.

粘合剂杂质，如残留单体、引发剂副产物和醛类，不被视为可提取或可浸出物，因为这些杂质在产品制造前以峰值浓度存在。本指南其他地方对粘合剂杂质的控制进行了讨论（见第四节C申请中提交的信息TDS产品的控制）。然而，以下讨论的可浸出性研究可用于证明粘合剂杂质限值，或作为粘合剂杂质毒理学风险评估的一部分，因为对拟议的商业产品进行了可浸出研究。

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.

为了帮助进行下文所述的可提取和可浸出分析，申请人应联系原材料供应商，以确定潜在的毒理学问题可提取物，例如背衬材料中的残留单体。

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

应在药物开发过程早期进行可提取性研究，以了解拟议商业TDS组分的潜在浸出物。这些研究应在背衬膜、释放衬垫、速率控制或其他内部膜、油墨和袋等组件上进行。测试组分应在各种极性不同的溶剂中，在剧烈的实验提取条件下提取，以最大限度地提高可提取物的水平，并尽可能多地确定潜在的可浸出物。可提取性研究中使用的提取溶剂之一应包括拟定商业粘合剂平台的溶剂或成品TDS的已知残留溶剂。所用溶剂的选择应合理

可浸出研究

可浸出研究的条件应尽可能接近皮肤的“最坏情况”临床条件（例如，剧烈运动期间出汗）。应为研究选择合理的溶剂/溶液（如盐浓度）、温度、搅拌水平、暴露于溶剂的时间等实验条件。在研究期间，应将隔离衬垫从系统中移除，以使粘合剂层充分暴露于生物相关溶剂。申请人应进行多时间点可浸出物分析（例如，0、6、12、24个月），以提供全面的可浸出物概况，并确定可浸出物的任何趋势，因为这些数据可能影响产品的保质期。提交申请时，应提交在加速和长期条件下储存至少6个月的多批次样品的可浸出研究数据。我们建议对三种不同的TDS层压板进行可浸出研究，并进行稳定性测试。

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.评估热效应的影响

来自外部来源（如加热毯）的热量，以及可能由于剧烈运动或发烧导致的体内温度升高，可能会影响TDS中药物释放的速率以及药物进入和通过皮肤的吸收。我们建议申请人研究相对于正常TDS/皮肤表面温度下的TDS释放曲线，升高TDS/皮肤表面温度对TDS释放曲线的影响。

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

对于在NDA中提交的TDS产品，我们建议将热效应研究作为临床研究的一部分，使用拟议的商业产品进行。在设计热效应研究时，应确定关键因素，如适当升高的试验温度、热暴露开始时间、持续时间和周期（如有），以及热暴露机制（如加热灯、加热垫等）

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.

对于将在ANDA中提交的TDS产品，申请人应评估在高温条件下使用的测试TDS是否比参考（R）TDS增加药物递送。ANDA申请人应提供一项IVPT研究的结果，该研究使用来自多个个体（供体）的皮肤，在正常和升高温度下比较（T）TDS和（R）TDS的药物递送特性，每个供体、每个治疗（T与R）和每个温度条件下评估多个复制扩散池。建议进行IVPT研究，以获得有意义的数据，该研究具有足够数量的供体，并在每个温度条件下对每个供体进行重复治疗。如果一项研究在每种温度下，每种处理的供体少于四个，每个供体有四个重复，这可能很难对结果进行解释。

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

我们建议在以下基础和高温条件下对试验和R TDS进行平行评估和比较：

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. 基础：在整个研究期间，T和R产品的TDS/皮肤表面温度应保持在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升高的温度：T和R产品应保持在32±1°C的TDS/皮肤表面温度，直到大约观察到峰值通量时的指定时间，然后在剩余持续研究时间段保持在42±2°C的TDS/皮肤表面温度

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.

不应假设循环水浴的设定温度可以提供TDS/皮肤表面的目标温度。应使用红外温度计或其他温度探头直接测量TDS/皮肤表面温度。7天使用TDS的研究持续时间不需要包括整个标示的使用持续时间。如果IVPT研究的持续时间足以达到基础条件下的峰值药物输送率，则进行48或72小时的IVPT研究可能就足够。或者，申请人可以评估证明暴露于高温的其他条件或情景是合理的，这些条件或情景代表给定TDS产品或指定患者人群的最坏情况。

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. 微观基质评价

由于许多TDS配方的复杂性，粘合剂基质通常不会形成真正的溶液，而是表现为分散体。如果分散样系统在基质中随着时间的推移发生重排，它们可能导致缺乏粘附或药物递送和释放的变化。因此，需要充分了解TDS配方、药物和赋形剂在粘合剂基质中的分散方式，以及有效期内，随着时间变化基质从产品中释放的趋势。因此，使用高性能显微镜、元素图谱或其他适当的工具评估TDS基质在整个开发批次保质期内的表面和横截面变化是有益的。这些工具可能不适用于所有TDS；申请人应为所使用的工具提供科学依据。这些评估将有助于全面了解产品和过程，降低质量相关风险，并确保TDS在其到期期间满足必要的质量属性

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.拟议的生产变更

原NDA或ANDA中可能会提出比例放大建议和其他流程变更，但支持这些变更所需的额外信息水平通常与变更对产品质量产生不利影响的风险相当。一般来说，在进行关键临床研究后，应尽可能避免TDS的变化，因为TDS对配方和制造过程中的微小变化很敏感。

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

可通过更新主批次记录和批次方案得到充分支持低风险变更。例如，使用相同设计和工作原理的设备，将溶剂基和水性混合物的规模扩大10倍，或建议对相同设计和工作原理的转换和装袋设备进行更改

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

中等风险变化可能需要对商业规模批次进行额外的开发研究和稳定性数据，以证明它们不会对产品质量产生不利影响。这种变化的例子可能包括将热熔混合物的比例提高到10倍以内，将螺杆混合工艺的比例提高，以及改变具有相同设计和操作原理的涂层/干燥/层压设备

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.

对质量构成高风险的变化可能需要额外的体内研究。一个例子是改变制造工艺，以采用不同设计和操作原理的设备。

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.生产

如ICH M4Q中所述，应用程序的第3.2.P.3节应包含关于TDS产品将在何处以及如何制造的信息。应提供批次配方以及制造工艺和工艺控制的说明。还应提供拟定生产工艺的详细示意图，包括设备、操作条件和工艺控制的说明。

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.

在工艺开发过程中，申请人应确定可能影响TDS产品CQA的工艺变量。这些工艺开发研究为商业工艺鉴定和产品生命周期后期的持续工艺验证提供了信息。

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制造步骤/装置操作（非详尽列表）。对于包含这些步骤的过程，申请人应说明每个操作和相关控制是如何制定的，并说明以下注意事项，特别是可能受操作影响的CQA，以及可能影响每个操作输出的相关工艺参数和材料属性：

●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：混合操作产生用于涂层步骤的散装混合物。混合可影响CQA，如含量测定、原料药和/或赋形剂的稳定性、含量均匀性、微观形态和粘合剂的物理性质。控制策略应解决设备设计、物料添加顺序和工艺参数（如混合速度、混合时间、温度、再分散或再循环条件以及脱气条件）对CQA的影响，并应根据开发研究在必要时予以证明。能够影响混合的cma包括原料药粒度、多态形态、原料流变特性和溶剂型混合物中供应的材料的固体百分比。。

●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、干燥和层压：涂布是将混合物涂覆到基材上。根据使用的设备，涂层可能会影响CQA，如含量均匀性和微观外观。尽管CPP依赖于设备，但企业应证明控制策略（例如，要控制的工艺参数）足以确保涂布操作整个过程中的含量均匀性和微观形态。可能影响涂层的CMA包括散装混合物的流变性和待涂层基材的辊内均匀性

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

干燥包括在涂布过程之后从混合物中除去溶剂。该工艺步骤可影响CQA，如测定、渗透促进剂含量、抗氧化剂含量、水含量（用于水凝胶）、含量均匀性、微观外观、药物释放、产品稳定性、残留溶剂、残留粘合剂杂质和粘合剂基质的物理性质。因此，在工艺开发过程中可能需要考虑用于干燥CPP的包括管线速度、泵或螺杆速度、区域温度、空气流速、干燥空气的温度和干燥空气的湿度。工艺开发还应考虑可能影响干燥的CMA，如散装混合物中的溶剂和粘合剂杂质含量。申请人还应提供数据，证明药物和辅料可能需要过量，以补偿干燥过程中的蒸发损失。

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

层压包括将给定透皮系统设计的多个层组合成单个普通层压。如果使用电晕处理工艺将胶粘剂粘合到背膜或速率控制膜上，则申请人应提供电晕处理的开发数据。

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：通常将散装产品纵向切成较窄的层压板卷，以便进一步加工。切片和印刷是典型的低风险步骤；然而，如果印刷过程的某些方面，例如过度的渗透深度或热量输入，会对产品质量产生不利影响，那么应对印刷工艺进行表征和控制。

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.

转换和封装：转换和封装通常涉及将连续层压材料切割成单个单元，并将该单元密封在热密封袋中。受这些过程影响的CQA包括产品的可用性（例如，移除释放衬垫的能力）和袋的完整性。这些步骤的常见CPP包括热封温度和停留时间。

●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在干燥或装袋后有加工步骤来完成固化反应。固化时间和固化条件是该步骤的常见CPPs。如果固化可能影响测试结果，则应在批放行测试前完成固化。

●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.

保持时间：必须定义和证明在单元操作之间保留的过程中材料的保留时间（21 CFR第211.111部分）。申请人应使用基于风险的方法来确定在保持时间研究期间要监控哪些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.

其他注意事项：管道和其他产品接触设备必须经过非反应性、非添加剂和非吸收性（21 CFR第211.65（a）部分）的认证。管道和某些产品接触设备的选择应基于风险，即取决于接触持续时间、工艺温度、溶剂系统、材料考虑因素、制造过程中可浸出物的清除以及临床使用考虑因素。

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的过程中控制（IPC）是控制策略的一个组成部分。拟议IPC方案的说明应包括以下内容：

●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.

在混合阶段，IPC可以保证水性混合物的含量、粘度、均匀性和pH值。如果从分散的混合物中提取多个样品，申请人应指定平均值、单个样品的范围和相对标准偏差百分比。

●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、干燥和层压的IPC可确保整个层压板和整个运行过程中的均匀性。例如，薄膜外观、涂层质量的测量和/或残留溶剂的测试可能适用于涂层和干燥的IPC。应在申请中描述允许检测和排除影响粘合剂层压板连续性的缺陷（例如条纹）的薄膜外观测量。此外，对于在微观尺度上为分散体的薄膜（例如，分散在硅酮中的丙烯酸粘合剂，分散在硅氧烷中的聚维酮，或分散在粘合剂中的固体药物），申请人应描述为在应用中监控整个涂层运行的均匀性而建立的IPC。用于测试涂层质量和均匀性的样品应代表层压板的整个长度和宽度。或者，可以连续监测这些属性（例如，通过使用在线涂层测量工具）。如果上游控制可用于确认某些成品TDS规范，如残留溶剂和残留粘合剂杂质，则可使用IPC测试代替这些属性的释放测试。

●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).

对于转换和装袋，IPC可以确保袋的完整性、袋内的产品放置以及产品外观（例如，印刷标签、模切和吻切的充分性）。如果证明自动化系统适用于预期任务，自动化系统可以代替人工操作员对产品外观进行过程中检查。

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产品控制

申请书第3.2.P.5节应包含以下关于TDS产品控制的信息：

●Specification规格

●Analytical procedures分析程序

●Validation of analytical procedures分析程序的验证

●ØCharacterization of impurities杂质的表征

●Batch analyses批次分析

●Justification for the proposed specification拟定规范的理由

Typical CQAs included in TDS specification:

TDS规范中包含的典型CQA

●Descr1ption说明

●Identification鉴别

●Assay含量测定

●Impurities and degradation products杂质和降解产物

●Uniformity of dosage units含量均匀度

●Permeation enhancer content, when applicable促渗剂含量（如适用）

●Adhesion粘合剂

●Release liner peel释放衬垫剥离

●Tack黏着力

●Shear剪切力

●Cold flow冷流

●In vitro drug release体外药物释放实验

●Drug substance crystal presence药物晶态

●Pouch integrity包装完整性

●Microbial limits, when applicable 微生物限度（如适用）

●Moisture content, when applicable水分测定（如适用）

●Residual solvents残留溶剂

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.

建议的分析程序应详细记录，以便在FDA实验室进行审查和复制。在某些情况下，如果上游控制可用于确认一批产品符合规范中列出的CQA，则该属性可能不需要在每批产品放行时进行测试，但应在规范中注明。申请人提出使用这种方法的控制策略时应提供理由。

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

一些与CQAs相关的TDS典型方法和标准如下所述。

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.粘合剂杂质

粘合剂可能含有残余单体、引发剂副产物、醛等。应评估这些化合物的安全性，因为其中一些化合物被分类为具有神经毒性（例如，四甲基丁二腈）或致突变性（例如巴豆醛）。鼓励制造商与原材料供应商联系，讨论所选粘合剂原材料和所有潜在杂质，因为供应商提供的分析证书中可能未报告某些杂质。申请人应在申请中讨论原材料可能产生的杂质。应制定并证明与毒理学相关的任何杂质的控制策略。控制策略可包括在原材料阶段进行测试，证明制造过程能够持续去除相关杂质，测试最终层压板，或以上各项的组合。

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.

为了支持基于制造工艺持续去除任何相关杂质的能力的拟议控制策略，申请人应提供数据，以证明最终层压板（或成品）中的杂质水平与同一批原材料中的水平相比有所降低。这些数据对于定量证明制造工艺去除杂质的有效性以及根据原材料中的含量而不是最终产品中的含量建立粘合剂杂质控制是必要的。

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.

申请人可考虑利用本指南药物开发部分中讨论的可浸出性研究，测试渗滤液中的粘合剂杂质。可浸出信息可用于为杂质限值提供毒理学依据，或将信息作为毒理学风险评估的一部分。

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.含量均匀度

TDS规范应包括剂量单位含量均匀性的测试和验收标准。如果最终TDS设计为由用户切割，则还应证明从单个单元切割的工件之间的一致性。

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.促渗剂含量

使用渗透促进剂建立或维持药物递送的产品应包括促渗剂在释放和整个稳定性试验时的测试和验收标准。在缺乏体外-体内相关性的情况下，比特定促渗剂的典型范围更宽的接受标准可能需要体内研究证明。

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.黏附试验(剥离粘附、释放衬垫剥离、粘性和剪切试验)

使用当前可用的方法，体外粘附测试与体内粘附无关，但体外黏附测试可用于质量控制（QC）目的。体外黏附测试应包括剥离黏附、剥离衬垫移除、粘性和剪切（动态或静态）。每个测试有多种方法和不同的实验参数。

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.

剥离附着力测试测量去除（剥离）已应用于标准测试面板（例如抛光不锈钢）的TDS所需的力。剥离附着力的测量受测试参数的影响，例如停留时间、基材（例如不锈钢、高密度聚乙烯（HDPE））、剥离角和剥离速度。

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.

释放衬垫剥离测试用于测量将TDS与释放衬套分离所需的力。释放衬垫剥离的测量受剥离角和剥离速度等实验参数的影响。

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.

探针粘性测试测量将测试探针与TDS粘合剂分离所需的力。粘性测量受测试参数的影响，如接触面积、接触压力、接触时间（或停留时间）和分离速度。

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

剪切试验有两类，即动态和静态。在动态测试中，TDS从标准测试面板（例如，抛光不锈钢）中拉出。停留时间、速度、试验板类型、失效模式和样本大小是动态剪切试验报告的典型试验参数。在静态剪切试验中，将TDS样品施加到与垂直方向成2°角的试验板上，并通过悬浮在TDS上的给定质量（例如1000 g）对样品施加剪切力；测量在标准负载下从不锈钢测试面板上分离TDS标准区域所需的时间。静态剪切试验报告的典型试验参数包括停留时间、所用质量、试验板类型、破坏模式和样品尺寸。也需报告TDS样品从测试面板上分离所需的时间

E.冷流

冷流是指粘合剂基质在背衬膜周边或通过剥离衬垫缝隙的流动或渗出。TDS、隔离衬垫、袋或一次性膜（有时称为滑动片或保护膜，例如背衬上的膜和隔离衬垫上的膜）上可能存在冷流。尽管评估冷流的定量方法可以提供有意义的测量，但它可能无法描述从袋中去除TDS或从TDS中去除保护膜的困难。TDS最准确的冷流评估可能来自特定产品的定量和定性方法的组合。

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

测试方法应具有鉴别性和科学合理性。制造商应提出产品特定的验收标准，并提供产品开发研究支持的理由。

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.体外药物释放

USP通则章节描述了用于体外释放测试的仪器以及每个仪器的验收标准；然而，方法开发和验证并未涉及。TDS体外释放试验的一般建议以及方法设计和验证的注意事项如下所述

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产品的体外药物释放测试通常使用特定合格的设备进行，例如：桨碟法（装置5）、转筒法（装置6）或往复支架法（装置7）。

（图片提供锐拓相应设备图片）

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产品的NDA或ANDA提交文件应包括方法开发和验证报告，其中包含支持拟定药物释放方法和验收标准的完整信息/数据。

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.

方法开发和验证报告中应包含足够的细节和数据，以便能够正确评估批放行和稳定性测试方法的充分性。方法开发过程中要评估的参数示例包括USP仪器/其他设备的选择、药物释放介质、旋转或搅拌速度、温度、pH值、沉降条件、表面活性剂的使用以及测试的其他技术方面。体外药物释放方法应简单、可靠、可重复、鉴别和耐用。申请人应努力开发一种释放尽可能多药物的方法。

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

报告的验证部分应包括以下方面的完整信息/数据：i）所选方法的区分力，ii）药物释放方法的验证，以及iii）测定药物释放样品所选分析方法的验证/验证。所选方法应能够区分有意制造的TDS的释放曲线，其关键工艺参数和配方组分存在有意义的变化。验证数据应证明该方法在TDS不同强度下的比例药物释放范围和灵敏度。此外，验证数据应证明药物释放方法在同一批次的不同运行中的再现性及其耐用性，即其不受受体介质温度、桨速率和其他方法参数变化影响的能力

相关阅读：《FDA IVRT测试 工业指南翻译稿》

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.

体外药物释放试验的验收标准应基于拟定的TDS产品批放行数据，包括生物批次（如BE、PK、临床）、注册/展示批次和商业批次（如可用）的数据。为了制定体外药物释放试验的验收标准，应通过收集数据建立完整的药物释放曲线，直到连续三个时间点（每2小时取样一次）药物释放量没有增加。TDS产品的药物释放概况通常包括初期、中期和末期；因此，为了设定验收标准，每个阶段至少应有一个采样时间点。药物释放数据应报告为药物随时间释放的累积百分比。每个特定时间点的验收标准范围应基于使用这些时间生成的药物释放数据的药物释放的平均百分比值±10%。百分比应根据TDS产品的标签声明确定。如果释放的药物少于100%，但在连续三个采样时间点内未观察到药物增加（即药物释放不完全），则应将达到稳定期的药物量视为100%，以估计药物随时间的释放百分比。

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.

如果有已批准的体外-体内相关模型支持，则药物释放试验的接受标准范围可能会更宽。

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.析晶现象

随着时间的推移，TDS中析出药物晶体或结晶会对产品性能产生负面影响。因此，建立一个测试和验收标准，以确认释放和稳定性时不存在待使用的晶体，这一点很重要。最好使用显微镜和光度法，而不是简单的目视计数。人们认识到，虽然有些产品设计为悬浮液，但这种设计并不排除对晶体规格的需求。悬浮产品仍应包括测试和验收标准，以防止晶体化，这可能会影响药物输送或产品的粘附性能。

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袋对产品的稳定性和完整性至关重要。袋完整性测试应作为成品放行的一部分进行，除非为确保符合成品规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 稳定性研究

除了ICH Q1A和ICH Q1B中讨论的原料药和药物产品的正式稳定性和光稳定性研究的标准组外，TDS申请人和制造商应在挑战条件下进行稳定性研究，包括温度漂移、冷冻/解冻和/或晶种。这些额外的研究旨在解决某些产品质量问题，如晶体形成和生长。此外，使用中的光稳定性测试可能适用于某些TDS制剂，这取决于背衬膜的不透明度、磨损持续时间以及使用时预期的光暴露。

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.产品附着力注意事项

体表粘附研究为拟定的商业产品提供了最大的粘附预测，即CQA。申请人应证明已作出合理努力以优化TDS的粘合特性。这种优化应平衡诸如粘附性、内聚性和稳定性等特性，以确保在整个使用期间其整个表面区域与皮肤的一致性和均匀粘附力。申请人应制定全面的策略来评估TDS的粘性属性。体内粘附研究是证明TDS充分粘附的必要条件。因此，在可能的情况下，例如在NDA的疗效研究中，应使用描述实际在用产品粘附性能的受试者日记。该信息支持从以下研究和其他指南中收集的粘附数据

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粘附特性的表征应证明标签用途得到证实。例如，如果TDS打算在沐浴和淋浴时使用，申请人应证明TDS在偶然接触水期间和之后将继续保持粘附。在体内粘附性评估期间，不允许使用产品加固，例如贴边或使用覆盖物，或在沐浴期间将产品与水隔绝

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:

我们建议，在评估TDS粘附性时，申请人使用5分制的数值量表，其中每个分数对应TDS粘附表面积的指定范围，如下所示：

0 = ≥ 90% adhered (essentially no lift off the skin) 粘附（基本上不会剥离皮肤）

1 = ≥ 75% to < 90% adhered (some edges only lifting off the skin) 粘附（某些边缘仅从皮肤上剥离）

2 = ≥ 50% to < 75% adhered (less than half of the TDS lifting off the skin) 粘附（少于TDS的一半剥离皮肤）

3 = > 0% to < 50% adhered (not detached, but more than half of the TDS lifting off the skin without falling off) 粘附（未脱落，但超过一半的TDS从皮肤上剥离而不脱落）

4 = 0% adhered (TDS detached; completely off) 粘附（TDS分离；完全脱落）

Additionally, the following information should be collected:

此外，还应收集以下信息：

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分制评估粘附力的每个时间点，记分员还应记录他们的实际粘附百分比估计值（例如，如果观察者在5分制上将产品评分为2分，并估计产品粘附率为60%，则应记录该时间点的2分和60%）。

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

应提供照片证据，显示在每个时间点TDS粘附到皮肤的程度。

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.产品储存和处理-标签注意事项

TDS储存条件应得到稳定性数据的支持，并在标签中说明。通常，我们建议在室温下储存TDS。如果允许，应在标签上注明。标签还应说明，如果为了保持TDS的安全性、有效性和质量，TDS不应存放在袋外。

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

经皮和局部递送系统使用后，通常会有残留的药物。考虑到药物的治疗性质和由于意外暴露引起的潜在不良事件，标签中应明确列出产品处理事项。处理过程必须防止残余药物暴露于环境和/或其他人。根据产品的性质，可能需要特殊说明，以防止儿童和护理人员接触，否则可能会导致严重的安全相关后果

实验仪器：锐拓 RT800 自动取样透皮扩散系统