USP<3>外用和透皮制剂：产品质量测试
Topical and transdermal drug products — Product Quality tests
外用和透皮制剂——产品质量测试
INTRODUCTION 引言
Topically applied drug products fall into two general categories: those applied to achieve local action and those applied to achieve systemic effects after absorption through the skin into the blood circulation. Local action can occur at or on the surface of the application site (e.g., stratum corneum); in the underlying tissues (e.g., epidermis and/or dermis); and in subcutaneous tissues (e.g., muscle or joint). Topically applied drug products include, but are not limited to, creams, gels, ointments, pastes, suspensions, lotions, foams, sprays, aerosols, solutions, and transdermal delivery systems (TDS). The definitions and descriptions of these dosage forms, as well as brief information on their composition and/or manufacturing processes, can be found in Pharmaceutical Dosage Forms <1151>.
局部应用的药品分为两大类：用于实现局部作用的产品和用于通过皮肤吸收进入血液循环后实现全身作用的产品。局部作用可发生在应用部位的表面（例如角质层）、下层组织（例如表皮和/或真皮）和皮下组织（例如肌肉或关节）上。局部应用的药物产品包括但不限于乳膏剂、凝胶剂、软膏剂、糊剂、混悬剂、洗剂、泡沫剂、喷雾剂、气雾剂、溶液和透皮给药系统（TDS）。这些剂型的定义和描述，以及它们的组成和/或制造工艺的简要信息，参见通则<1151>药物剂型。
Procedures and acceptable criteria for testing topically applied drug products can be divided into those that assess general product quality attributes and those that assess product performance. The product quality attributes include the following: description, identification, assay (strength), impurities, physicochemical properties, uniformity of dosage units, water content, pH, apparent viscosity, microbial limits, antimicrobial preservative content, antioxidant content, sterility (if applicable), and other tests that may be product specific. Product performance testing assesses drug release and other attributes that affect drug release from the finished dosage form.
测试局部应用药品的程序和可接受的标准可分为：评估一般产品质量属性的程序，和评估产品性能的程序和可接受的标准。产品质量属性包括以下内容：性状、鉴别、含量测定（规格）、杂质、理化特性、含量均匀度、水分、pH、表观粘度、微生物限度、抗菌防腐剂含量、抗氧化剂含量、无菌（如适用），以及产品相关的特定检测。产品性能测试评估药物释放和其他影响药物从成品制剂释放的属性。
This chapter provides lists of consolidated common product quality test requirements in a concise and coherent fashion. This chapter applies, in whole or in part, when referenced in a drug product monograph (see General Notices, 3.10 Applicability of Standards ) and includes the quality tests for the specific route of administration. The quality tests listed can be used as appropriate by manufacturers toward the development of new drug product monographs for submission to USP–NF.
本章以简洁和连贯的方式提供了常见的产品质量测试要求列表。在药品各论中引用时（见通则 3.10 标准适用性），本章全部或部分适用，并包括特定给药途径的质量属性。如适用，制造商可以根据列出的产品质量属性来起草新的药品各论，提交申报资料至USP-NF 。
TDS release their active ingredients by different mechanisms. They can be passive or active. This chapter covers only the tests related to passive TDS.
TDS 通过不同的机制释放其活性成分。它们可以是被动的或主动的。本章仅涵盖与被动释放的TDS 相关测试。
Change to read: 变更内容
PRODUCT QUALITY TESTS FOR TOPICAL AND TRANSDERMAL DRUG PRODUCTS
Additional Procedure for Products Packaged in Containers with a Non-Metered Pump
外用和透皮药物产品的产品质量测试
配备非计量泵包装产品的附加程序
For some tests (e.g., viscosity, assay, etc.), with the exception of the uniformity in containers test, samples need to be collected from the pumped-out product. In these instances, the samples should be collected as follows:
1.Remove cap from container.
2.Fully depress and release the actuator, disposing of any material dispensed, and allowing the pump actuator to return to the initial position after each actuation. Repeat the sequence, as indicated in the patient instructions, until a full amount of material is dispensed.
3.Collect the next material dispensed as the sample. Generally, collect NMT the amount needed to perform a single analysis (for the assay test, typically NMT 2 actuations).
对于某些测试（例如，粘度、含量等），不仅要对容器中的样品进行均匀性测试，也需要对泵出的样品进行收集后测试。在这些情况下，应按如下方式收集样本：
1、从容器上取下盖子；
2、完全按下并释放触动器，对样品进行分配，并让泵触动器在每次启动后返回到初始位置。按照患者说明书中的相关要求，重复该顺序，直到分配出全部样品；
3、按照上述方法收集另一份样品。通常，收集执行单次分析所需的量（对于含量测定，通常为不超过两倍量）。
UNIVERSAL TESTS 通用测试
Universal tests [see International Council for Harmonisation (ICH) guidance Q6A—Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, available at www.ich.org] are listed as follows and are applicable to all topically applied drug products.
通用测试[参见ICH Q6A指南，质量标准：新原料药和新药制剂的检测方法和可接受标准：化学药物，网址链接 www.ich.org ]如下所列，适用于所有局部应用的药物产品。
Description 描述
A qualitative description of the drug product should be provided. The acceptance criteria should include the final acceptable appearance of the finished dosage form and packaging. A visual examination should identify changes in color, adhesive migration (i.e., cold flow; see Cold Flow Test) for TDS, separations, crystallization, and others that are specific to the drug product. The description should specify the content or the label claim of the article. For TDS, a visual examination should also be done to assess potential use issues with the product. The examination should include an assessment of the difficulty of removing the TDS from the pouch (e.g., due to adhesive migration adhering the system to the pouch); inability to remove the TDS from the pouch without damage to the system; and adhesive residue remaining on the pouch after removal of the TDS. This is not a compendial test but is part of the manufacturer’s specification for the drug product.
应提供药品的定性描述。验收标准应包括成品剂型和包装的最终可接受外观。目视检查应识别TDS的颜色、粘合剂迁移（即冷流；参见冷流测试）、分离、结晶和产品的其他特定变化。描述应指明物品的内容或标签声明。对于TDS，还应进行目视检查以评估产品的潜在使用问题。检查应包括评估从袋中取出TDS的难度（例如，由于粘合剂迁移将系统粘附到袋上）；无法在不损坏系统的情况下从袋中取出TDS；和取出TDS后，袋子上有粘合剂残留物残留。这些虽不是药典要求测试的内容，却也是药品生产商质量控制的一部分。
Identification 鉴别
Identification tests are discussed in General Notices, 5.40 Identification. Identification tests should establish the identity of the drug or drugs present in the article and should discriminate between compounds of closely related structures that are likely to be present. Identification tests should be specific for the drug substance(s) (e.g., infrared spectroscopy). Near-infrared (NIR) or Raman spectrophotometric methods also could be acceptable for the identification of the drug product (for additional information, see Near-Infrared Spectroscopy—Theory and Practice <1856>and Raman Spectroscopy—Theory and Practice <1858>.Identification solely by a single chromatographic retention time is not specific.
鉴别测试在通则<5.40>鉴别中讨论。鉴定试验应确定物品中存在的一种或多种药物的成份，并应区分可能存在的结构密切相关的化合物。鉴别试验依赖于原料药的特定性质（例如，红外光谱）。近红外（NIR） 或拉曼分光光度法也可以用于鉴别药品（更多信息，请参见近红外光谱—理论与实践 <1856>和拉曼光谱—理论与实践 <1858>）。仅通过单个色谱保留时间进行鉴定并不具有特异性。
Assay 含量测定
A specific and stability-indicating test should be used to determine the strength (content) of the drug product. This assay requirement can be satisfied for topical products containing antibiotics by a standard microbiological method (see Antibiotics —Microbial Assays <81>). In cases when the use of a nonspecific assay (e.g., Titrimetry<541>) is justified, other supporting analytical procedures should be used to achieve overall specificity.
应使用特定的具有稳定性指针的方法来确定药品的规格（含量）。对于含有抗生素的外用产品，可以通过标准微生物学方法满足该检测要求（参见抗生素-微生物检测<81>）。如果使用非特异性测定法（例如滴定法<541>），应使用其他支持性分析方法来实现整体特异性。
Impurities 杂质
Process impurities, synthetic byproducts, impurities associated with the adhesive (e.g., residual monomers), residual solvents (see Residual Solvents <467>), and other inorganic and organic impurities may be present in the drug substance and in the excipients used in the manufacture of the drug product and should be assessed and controlled. Impurities arising from the degradation of the drug substance and those arising during the manufacturing process of the drug product also should be assessed and controlled.
工艺杂质、合成副产物、与粘合剂相关的杂质（例如，残留单体）、残留溶剂（参见残留溶剂 <467>）、原料药和用于生产药品的辅料中可能存在其他无机和有机杂质，应进行评估和控制。原料药降解产生的杂质和制剂生产过程中产生的杂质也应进行评估和控制。
SPECIFIC TESTS 特定测试
In addition to the Universal Tests listed previously, the following Specific Tests should be considered on a case-by-case basis.
除了前面列出的通用测试之外，还应根据具体情况考虑以下特定测试。
Uniformity of Dosage units 剂量单位均一性
This test is applicable for TDS and for topical dosage forms intended for systemic delivery, or where tight control of the dose is necessary to limit local irritation or undesired systemic exposure, packaged in single-unit containers, such as packets (see Uniformity of Dosage Units <905>). The uniformity of dosage units specification is not intended to apply to solutions, suspensions, emulsions, ointments, or gels in single-unit containers intended for local action following external, cutaneous administration.
该测试适用于TDS和用于全身给药的局部剂型，或需要严格控制剂量以限制局部刺激或不希望的全身暴露的情况，包装在单个容器中，例如小包（见剂量单位的均一性 <905>）。剂量单位均一性不适用于，在单个单位容器中包装的，皮肤外用起局部作用的溶液、混悬液、乳液、软膏或凝胶剂。
Water Content 水分
A test for water content should be included when appropriate (see Water Determination <921>). This test is generally formulation dependent. Therefore, it is not included in the compendial drug product monograph but is part of the manufacturer＇s specification for the drug product.
如适用，应包括水分测定（见水分测定 <921>）。该测试通常与配方有关。因此，虽是药品生产商质量标准的一部分，却未包含在药典药品专论中。
Microbial Limits 微生物限度
Microbial examination of nonsterile drug products is performed according to the methods given in Microbial Enumeration Tests<61>and Tests for Specified Microorganisms<62>, unless the formulation itself is demonstrated to have antimicrobial properties. Acceptance criteria for nonsterile pharmaceutical products based on total aerobic microbial count and total combined yeasts and molds count are given in Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use<1111>.
非无菌药品的微生物检查根据微生物计数法 <61>和控制菌检查法 <62>中给出的方法进行，除非证明配方本身具有抗菌特性。基于需氧菌总数、酵母菌和霉菌总数的非无菌药品的接受标准，在非无菌产品的微生物学检查：药物制剂和药用物质的接受标准 <1111>中给出。
Antimicrobial preservative content 抗菌防腐剂含量
Acceptance criteria for antimicrobial preservative content in multi-unit products should be established. They should be based on the levels of antimicrobial preservative necessary to maintain the product’s microbiological quality at all stages throughout its proposed usage and shelf life (see Antimicrobial Effectiveness Testing<51>).
应建立多剂量包装产品中抗菌防腐剂含量的接受标准。它们应基于在产品建议使用和货架期的所有阶段保持产品微生物质量所需的抗菌防腐剂水平设定（参见抗菌效力测试 <51>）。
Antioxidant content 抗氧剂含量
If antioxidants are present in the drug product, tests of their content should be established unless oxidative degradation can be detected by another test method such as impurity testing. Acceptance criteria for antioxidant content should be established. They should be based on the levels of antioxidant necessary to maintain the product’s stability at all stages throughout the product＇s proposed usage and shelf life.
如果药品中存在抗氧剂，则应对其含量进行测试，除非可以通过其他测试方法（如杂质测试）检测到氧化降解产物。应建立抗氧剂含量的接受标准。它们应该基于在产品的建议使用和货架期的所有阶段保持产品稳定性所需的抗氧化剂水平设定。
Sterility 无菌
Depending on the use of the dosage form (e.g., products that will be applied to open wounds or burned areas), sterility of the product should be demonstrated as appropriate (see Sterility Tests<71>).
根据剂型的用途（例如，用于开放性创伤或烧伤部位的产品），应适当证明产品的无菌性（参见无菌检查法<71>）。
PH
When applicable, topically applied drug products should be tested for pH. Because some topically applied drug products contain very limited quantities of water or aqueous phase, pH measurements may not always be warranted. This test is generally formulation dependent. Therefore, it is not included in the compendial drug product monograph but is part of the manufacturer＇s specification for the drug product.
适用时，应测试局部应用的药物产品的 pH 值。由于一些局部应用的药物产品含有非常有限的水或水相，因此可能并不总是需要测定 pH 值。该测试通常取决于配方。因此，它不包含在药典药品专论中，而是制造商药品质量标准的一部分。
Particle size 粒径
When the finished product contains a suspended solid drug substance, the product should be examined for particle size. The particle size of the active drug substance(s) in topically applied drug products is usually established and controlled at the formulation development stage. However, topically applied drug products should be examined for evidence of particle alteration (i.e., drug polymorphic form, appearance of particles, size, shape, morphology, agglomeration, or aggregation) of the drug substance that may occur during the course of product processing and storage. These types of tests are generally formulation dependent. Therefore, such tests are not included in compendial drug product monographs but are part of the manufacturer＇s specification for the drug product.
当产品含有悬浮固体药物时，应检查产品的粒径。外用药物产品中活性药物的粒径通常在制剂开发阶段确定和控制。然而，对于局部应用的药品，在产品加工以及贮存过程中，应检查原料药颗粒（即，药物多晶型、颗粒外观、大小、形状、形态、团聚或聚集）是否改变。这些类型的测试通常取决于配方。因此，此类测试不包括在药典药品专论中，而是制造商药品标准的一部分。
Crystal formation 结晶
When the drug substance is dissolved in the finished product, the product should be microscopically examined for evidence of crystal formation of the active drug substance. This test is generally formulation dependent. Therefore, it is not included in the compendial drug product monograph but is part of the manufacturer’s specification for the drug product. It is recommended that the potential for the drug product to form crystals of drug substance be examined during product development.
当原料药溶解在成品中时，应在显微镜下检查产品中是否有API结晶形成。该测试通常取决于配方。因此，它不包含在药典药品专论中，而是制造商药品标准的一部分。建议在产品开发过程中，检查药品中原料药形成结晶的可能性。
IN VITRO DRUG RELEASE TEST 体外药物释放试验
For TDS, the in vitro drug release test is required as a batch-to-batch quality control. See Drug Release<724>for apparatus and test conditions. The development and validation report of the in vitro drug release test needs to include sufficient detail and data to facilitate the assessment of whether the method is adequate as a quality control test for batch release and stability testing.
对于TDS，需进行体外药物释放测试，以对产品质量进行控制。有关仪器和测试条件，请参阅释放度测定法 <724>。体外药物释放测试的开发和验证报告需要包括足够的细节和数据，以方便评估该方法是否足以作为批次放行和稳定性测试的质量控制测试。
For semisolid dosage forms, in vitro drug release testing is currently not required for batch release. See Semisolid Drug Products—Performance Tests<1724>for apparatus, test conditions, and test applicability.
对于半固体剂型，批次放行中，目前不需要进行体外药物释放测试。有关仪器、测试条件和测试适用性的信息，请参阅半固体药物产品-性能测试 <1724>。
SPECIFIC TESTS FOR OPHTHALMIN DRUG PRODUCTS 眼用制剂的特定测试
See Ophthalmic Products—Quality Tests<771>. 参见眼用制剂-质量测试 <771>
SPECIFIC TESTS FOR TOPICAL AEROSOLS 局部气溶胶的特定测试
SeeTopical Aerosols<603>. 参见局部气溶胶 <603>
SPECIFIC TESTS FOR TOPICALLY APPLIED SEMISOLID DRUG PRODUCTS 局部应用的半固体药物产品的特定测试
Minimum Fill 最低装量
Single- and multiple-unit containers must meet minimum fill requirements as established by testing described in Minimum Fill<775>. For single-unit containers where the test for <905>is applied, the test for <755>is not required.
单剂量和多剂量包装产品，必须按照最低装量 <755>的规定进行最低装量检查，以确定其满足最低装量要求。对于单剂量包装产品，如果按照通则剂量单位均匀度 <905>进行了检查，就不需要再进行 <755>中规定的相关测试。
Apparent Viscosity 表观粘度
Viscosity is a measure of a formulation’s resistance to flow and is an assessment of a rheological property of a semisolid dosage form. The term “apparent viscosity” applies to non-Newtonian fluids, which comprise the majority of semisolid pharmaceutical dosage forms.
粘度是制剂流动阻力的量度，是对半固体剂型流变特性的评估。术语“表观粘度”适用于非牛顿流体，包括大部分半固体药物剂型。
Measurement procedures should be developed as outlined in Viscosity—Capillary Methods<911>, Viscosity—Rotational Methods<912> and Viscosity—Rolling Ball Method<913>. For semisolids that show thixotropy and/or irreversible changes in viscosity after shearing, specific attention should be given to sample preparation procedures to minimize variability in the measurement of apparent viscosity caused by variable shear histories (e.g., mixing speed and temperature, filling operation, and sample handling). Furthermore, for some products it may be warranted to have apparent viscosity specifications at more than one stage of the manufacturing process or with more than one set of test conditions (e.g., bulk in-process stage, final packaged product, high and low shear rates, and different temperatures).
应按照粘度—毛细管方法 <911>、粘度—旋转方法 <912>和粘度—滚球方法 <913>中的概述进行方法开发。对于具有触变性和/或剪切后出现不可逆变化的半固体，在样品制备过程中应特别注意，减小由剪切过程变化（如，混合速度和温度、填充操作和样品处理）引起的表观粘度测定的变异性。此外，对于某些产品，可能需要在生产工艺的多个阶段或多组测试条件下，拟定表观粘度的接受标准（例如，批量加工阶段、最终包装产品、高和低剪切速率以及不同的温度）。
Apart from single-point viscosity measurements, more advanced rheological techniques (flow, oscillatory, creep, and stress relaxation testing) can be applied to develop a mechanistic understanding of a formulation and its structure. These techniques may be useful for product development using the principles of quality by design or for comparative physicochemical characterization of the test and reference formulations in the case of a biowaiver argument in a generic drug application. However, these techniques are not generally suitable for routine quality testing. Common parameters derived from rheological testing of semisolid pharmaceutical dosage forms that may be useful for characterization and comparison are the storage modulus, loss modulus, relaxation modulus, compliance, thixotropic index, and yield stress.
除了单点粘度测定外，还可以应用更先进的流变技术（流动、振荡、蠕变和应力松弛测试）来开发对配方及其组成的机理理解。这些技术可用于使用质量源于设计原则的产品开发，或在仿制药申请中的生物豁免论证中，用于自研制剂和参比制剂的物理化学性质的比较。然而，这些技术通常不适合常规质量测试。从半固体药物剂型的流变测试得出的可用于表征和比较的常见参数是储能模量、损耗模量、松弛模量、顺应性、触变指数和屈服应力。
Acceptance criteria are product specific and defined to ensure that the apparent viscosity of each batch of semisolid drug product is within the range defined by the product design and is consistent between batches based on the product development specifications and statistical assessment of multiple product batches over the product’s shelf life.
接受标准具有产品特异性，需根据产品开发规范和产品货架期内多个产品批次的统计评估，以确保每批半固体药品的表观粘度在产品设计定义的范围内，并在批次之间保持一致。
Uniformity in Containers 容器内容物的均匀性
Topically applied semisolid drug products may show physical separation during manufacturing processes and during their shelf life. To ensure the integrity of the drug product, it is essential to evaluate the uniformity of the finished product. This test applies only to multiple-unit containers, such as tubes and jars. This test does not apply to more fluid topical drug products in multiple-unit containers, such as emulsions, lotions, two-phase gels, or topical suspensions, in which the labeling directs the user to mix the product (e.g., shake well) before use.
局部应用的半固体药物产品可能会在生产过程和货架期内出现物理分离。为了确保药品的完整性，必须评估成品的均匀性。此测试仅适用于多剂量包装产品，例如管和罐。该测试不适用于多剂量包装容器中更多流体的局部药品，例如乳液、洗剂、两相凝胶或局部悬浮液、说明书要求在使用前需混合的产品（例如，摇匀）。
Products packaged in tubes 管状产品
Visual uniformity: Carefully remove or cut off the bottom tube seal and make a vertical cut from the bottom to the top of the tube. Carefully cut the tube around the upper rim, open the two flaps, and lay the flaps open to expose the product.
视觉均匀性：小心地去除或切断底部管密封，并从管底部到顶部进行垂直切割。小心地切割上缘周围的管，向两侧打开以露出产品。
Inspect the product visually for the presence of phase separation, change in physical appearance and texture (e.g., color change, crystallization, lumping), and other properties described in the product specification for Description. If there is no significant phase separation or change in physical appearance and texture, and if the product meets the Description criteria, the product passes the test. If the product exhibits significant phase separation or change in physical appearance or texture, the product fails the test.
目视检查产品是否存在相分离、物理外观和织构的变化（例如，颜色变化、结晶、结块）以及产品规范中描述的其他特性。如果没有明显的相分离或物理外观和织构的变化，并且产品符合描述标准，则产品通过测试。如果产品表现出显着的相分离或物理外观或织构的变化，则产品未通过测试。
Uniformity of active ingredient(s): The following procedures can be modified depending on the sensitivity of the quantitative procedure used to determine the amount of the drug substance(s) present in the formulation.
活性成分的均匀性：可以根据测定处方中原料药含量的定量分析方法的灵敏度，修改下面的检测方法。
For multiple-unit tubes that contain 5 g or more of product 对于含有5g或更多量的多剂量管
STAGE 1: 第一阶段
1.Using a single tube, after performing the test for Visual uniformity, remove an appropriate amount of the product from the top (i.e., cap end), middle, and bottom (i.e., seal end) portions of the tube. The sample size should be sufficient for at least one quantitative determination of the active ingredient(s) and should not exceed the maximum dose recommended by the product labeling for a single application.
使用单个管，在进行视觉均匀性测试后，从管的顶部（即盖端）、中间和底部（即密封端）分别取出适量的产品。样品量应足以对活性成分进行至少一次定量测定，并且不应超过产品说明书推荐的单次使用的最大剂量。
2.Determine the amount of the active ingredient(s) in each portion of the product using any appropriate validated quantitative procedure, and evaluate the test results from the single tube using the Stage 1 acceptance criteria outlined in number 3.
使用适当的经过验证的定量分析方法测定产品每个部分中活性成分的量，并使用第3段中概述的第1阶段可接受标准评估单管的测试结果。
3.Stage 1 acceptance criteria are met if:
None of the three results are outside of the product assay range, and
The maximum difference in the amount of active ingredient(s) determined within the tube is NMT 10.0%. For example, if the three measurements within the tube are 97.0%, 95.2%, and 99.7%, the maximum difference would be 4.5% (i.e., 99.7% − 95.2% = 4.5%).
如果满足以下条件，则符合第 1 阶段的接受标准：
3个结果均未超出产品含量规定的范围，并且
测定的三个部分活性成分含量的最大差异不超过10.0%。例如，如果管内的三个测定值分别为 97.0%、95.2%和 99.7%，则最大差异为4.5%（即，99.7% - 95.2% = 4.5%）
4.Proceed to Stage 2 testing if Stage 1 acceptance criteria are not met and none of the test results are outside the product assay range by more than 5.0% (e.g., if the product assay range is 90.0%−120%, the range will be 85.0%−125.0%), and the maximum difference in the amount of active ingredient(s) measured within the tube is NMT 10.0%. An example of a product that fails to meet Stage 1 criteria: if the highest and lowest assay values were 106.0% and 94.7% of label claim, then the difference would be 106.0% − 94.7% = 11.3%.
如果不符合第 1 阶段的接受标准，但测试结果均未超出产品含量规定范围的5.0%（例如，如果产品含量的规定范围为90.0%-120%，则该范围为85.0%-125.0%），且测定的管内活性成分含量的最大差异不超过10.0%，则继续第2 阶段测试。不符合第1阶段标准的产品示例：如果最高和最低检测值分别为标示量的106.0%和94.7%，则差异为106.0% - 94.7% = 11.3%。
5.Proceed to Stage 3 testing if Stage 1 acceptance criteria are not met, Stage 2 acceptance criteria cannot be met, NMT one of the three test results is outside of the product assay range by more than ±5.0%, and the maximum difference of the amount of active ingredient(s) measured within the tube is NMT 15.0%.
如果不符合第 1 阶段和第 2 阶段接受标准，但测试结果均不超过产品含量规定范围的±5.0%，且测定的管内活性成分含量的最大差异不超过15.0%，则继续第 3 阶段测试。
STAGE 2: 第二阶段
1.Test an additional 2 tubes for Visual uniformity and Uniformity of active ingredient(s) for a total of 3 samples each from 3 tubes.
测试另外2管，对总共3管、每管3个样品的视觉均匀性和活性成分均匀度进行评价。
2.Determine the amount of the active ingredient(s) in each portion of the product using any appropriate validated quantitative procedure, and evaluate the test results from the 3 tubes using the Stage 2 acceptance criteria.
使用适当的经过验证的定量分析方法测定产品每个部分中活性成分的量，并根据第2阶段可接受标准评估3个管的测试结果。
3.Stage 2 acceptance criteria are met if:
The Visual uniformity test is met for all tubes;
None of the 9 results (i.e., 3 each from 3 tubes) are outside of the product assay range by NMT 5.0%; and
The maximum difference of the amount of active ingredient(s) measured within each tube, for each of the samples tested, is NMT 10.0%.
如果满足以下条件，则符合第2阶段的接受标准：
所有管的视觉均匀性均符合规定；
9个测试结果（即，3个管、每个管3个样品）均不超过产品含量规定范围的±5.0%；和
每个管中的三个部分（即，管与管之间不做比较）活性成分含量的最大差异不超过10.0%。
4.Proceed to Stage 3 testing if NMT one of the 9 test results is outside of the product assay range by ±5.0% and the maximum difference of the amount of active ingredient(s) measured within each tube is NMT 15.0%.
如果9个测试结果中，有不多于1个结果超过±5.0%，且每个管中的三个部分活性成分含量的最大差异不超过15.0%，则继续第 3 阶段测试。
STAGE 3: 第三阶段
1.If Stage 2 has been completed, test an additional 7 tubes for Visual uniformity and Uniformity of active ingredient(s) for a total of 3 samples each from 10 tubes. If Stage 2 was skipped, test an additional 9 tubes for Visual uniformity and Uniformity of active ingredient(s) for a total of 3 samples each from 10 tubes.
如果进行了第二阶段测试，另取7管（每管3个样品）进行视觉均匀性和活性成分均匀度测试。如果跳过第二阶段测试，则取9管（每管3个样品）进行视觉均匀性和活性成分均匀度测试。
2.Determine the amount of active ingredient(s) in each portion of the product using any appropriate validated quantitative procedure, and evaluate the test results from the 10 tubes using the Stage 3 acceptance criteria as outlined in number 3.
使用适当的经过验证的定量分析方法测定产品每个部分中活性成分的量，采用第三阶段的接受标准，对10管（每管3个部分，共30个样品）的测定结果，进行评价。
3.Stage 3 acceptance criteria are met if:
The Visual uniformity test is met for all tubes;
NMT 1 of the 30 test results is outside of the product assay range by ±5.0%; and
The maximum difference of the amount of active ingredient(s) measured within each tube, for each of the 10 tubes tested, is NMT 15.0%.
如果满足以下条件，则符合第3阶段的接受标准：
所有管的视觉均匀性均符合规定；
30个样品中，含量测定结果超过规定范围±5.0%的样品，不超过1个；和
10个管中，每个管中的三个部分活性成分含量的最大差异不超过15.0%。
For multiple-unit tubes that contain less than 5 g of product 对于剂量低于5g的多剂量管
STAGE 1: 第一阶段
1.Using a single tube, after performing the test for Visual uniformity, remove an appropriate amount of product from the top (i.e., cap end) and bottom (i.e., seal end) portions of the tube. The sample size should be sufficient for at least one quantitative determination of the active ingredient(s) and should not exceed the maximum dose recommended by the product labeling for a single application.
使用单个管，在进行视觉均匀性测试后，从管的顶部（即盖端）和底部（即密封端）分别取出适量的产品。样品量应足以对活性成分进行至少一次定量测定，并且不应超过产品说明书推荐的单次使用的最大剂量。
2.Determine the amount of the active ingredient(s) in each portion of the product using any appropriate validated quantitative procedure, and evaluate the test results from the tube using the Stage 1 acceptance criteria outlined in number 3.
使用适当的经过验证的定量分析方法测定产品每个部分中活性成分的量，并使用第3段中概述的第1阶段可接受标准评估单管的测试结果。
3.Stage 1 acceptance criteria are met if:
Neither result is outside of the product assay range; and
The difference between the amount of active ingredient(s) determined for the 2 samples within the tube tested is NMT 10.0%. For example, if the two measurements within a tube were 95.2% and 89.7%, the difference would be 5.5%.
如果满足以下条件，则符合第 1 阶段的接受标准：
2个结果均未超出产品含量规定的范围，并且
测定的两个部分活性成分含量的最大差异不超过10.0%。例如，如果管内的两个测定值分别为 95.2%和 89.7%，则最大差异为5.5%。
4.Proceed to Stage 2 testing if Stage 1 acceptance criteria are not met and neither of the test results are outside the product assay range by more than ±5.0% (e.g., if the product assay range is 90.0%−120.0%, the range will be 85.0%−125.0%), and the difference between the amounts of active ingredient(s) measured within the tube is NMT 10.0%.
如果不符合第 1 阶段的接受标准，但测试结果均未超出产品含量规定范围的5.0%（例如，如果产品含量的规定范围为90.0%-120%，则该范围为85.0%-125.0%），且测定的管内活性成分含量的差异不超过10.0%，则继续第2 阶段测试。
5.Proceed to Stage 3 testing if Stage 1 acceptance criteria are not met, Stage 2 acceptance criteria cannot be met, NMT one of the test results is outside of the product assay range by more than ±5.0%, and the difference between the amounts of active ingredient(s) measured within the tube is NMT 15.0%.
如果不符合第 1 阶段和第 2 阶段接受标准，但测试结果均不超过产品含量规定范围的±5.0%，且测定的管内活性成分含量的差异不超过15.0%，则继续第 3 阶段测试。
STAGE 2: 第二阶段
1.Test an additional 2 tubes for Visual uniformity and Uniformity of active ingredient(s) for a total of 2 samples each from 3 tubes.
测试另外2管，对总共3管、每管2个样品的视觉均匀性和活性成分均匀度进行评价。
2.Determine the amount of the active ingredient(s) in each portion of the product using any appropriate validated quantitative procedure, and evaluate the test results from the 3 tubes using the Stage 2 acceptance criteria as outlined in number 3.
使用适当的经过验证的定量分析方法测定产品每个部分中活性成分的量，并根据第2阶段可接受标准评估3个管的测试结果。
3.Stage 2 acceptance criteria are met if:
The Visual uniformity test is met for all tubes;
None of the 6 test results (i.e., 2 each from 3 tubes) are outside of the product assay range by ±5.0%; and
The difference between the amount of active ingredient(s) determined for the 2 samples within each tube, for each of the 3 tubes tested is NMT 10.0%.
如果满足以下条件，则符合第2阶段的接受标准：
所有管的视觉均匀性均符合规定；
6个测试结果（即，3个管、每个管2个样品）均不超过产品含量规定范围的±5.0%；和
每个管（即，管与管之间不做比较）中的活性成分含量的差异不超过10.0%。
4.Proceed to Stage 3 testing if NMT one of the 6 test results is outside of the product assay range by ±5.0%, and the difference between the amounts of active ingredient(s) measured within each tube is NMT 15.0%.
如果6个测试结果中，有不多于1个结果超过±5.0%，且每个管中的活性成分含量的最大差异不超过15.0%，则继续第 3 阶段测试。
STAGE 3: 第三阶段
1.If Stage 2 has been completed, test an additional 7 tubes for Visual uniformity and Uniformity of active ingredient(s) for a total of 2 samples each from 10 tubes. If Stage 2 was skipped, test an additional 9 tubes for Visual uniformity and Uniformity of active ingredient(s) for a total of 2 samples each from 10 tubes.
如果进行了第二阶段测试，另取7管（每管2个样品）进行视觉均匀性和活性成分均匀度测试。如果跳过第二阶段测试，则取9管（每管2个样品）进行视觉均匀性和活性成分均匀度测试。
2.Determine the amount of active ingredient(s) in each portion of the product using any appropriate validated quantitative procedure, and evaluate the test results from the 10 tubes using the Stage 3 acceptance criteria as outlined in number 3.
使用适当的经过验证的定量分析方法测定产品每个部分中活性成分的量，采用第三阶段的接受标准，对10管（每管2个部分，共20个样品）的测定结果，进行评价。
3.Stage 3 acceptance criteria are met if:
The Visual uniformity test is met for all tubes;
19 of 20 test results are within ±5.0% of the product assay range; and
The difference between the amount of active ingredient(s) determined for the 2 samples within each tube, for each of the 10 tubes tested, is NMT 15.0%.
如果满足以下条件，则符合第3阶段的接受标准：
所有管的视觉均匀性均符合规定；
20个样品中，含量测定结果超过规定范围±5.0%的样品，不超过1个；和
10个管中，每个管中的两个部分活性成分含量的差异不超过15.0%。
Products packaged in containers other than tubes 非管状包装产品
For semisolid products packaged in a container other than a tube when the sampling method presented previously cannot be used, other sampling methods are acceptable, such as this method described for a jar:
对于非管状包装的半固体产品，当不能使用前面介绍的取样方法时，其他采样方法是可以接受的，例如针对罐子描述的这种方法：
1.Select a suitable syringe of sufficient length to extend to the bottom of the container.
选择一个足够长的合适注射液以延伸到容器底部。
2.Remove and set aside the syringe plunger, and cut off the bottom of the syringe barrel. Sampling should take place from a location to the left or right of the mid-line of the jar surface to preserve an undisturbed region on the other side for any additional investigation (see Figure 1).
取下注射器柱塞放在一边，切掉注射器针筒的底部。采样应从罐表面中线左侧或右侧的位置进行，以在另一侧保留未受干扰的区域，以便进行任何其他调查（见图 1）
Figure 1. Sampling from a jar container 图1：从罐式容器中取样
3.Slowly push the syringe barrel into the container until it reaches the bottom. Then twist the syringe barrel containing the sample core, and remove the syringe from the container.
缓慢地将注射器筒推入容器，直至到达底部。然后扭转装有样品芯的注射器筒，并从容器中取出注射器。
4.Insert the syringe plunger into the barrel, and carefully extrude the sample core onto a clean surface in three equal portions to represent the top, middle, and bottom portions of the container.
将注射器柱塞插入针筒中，小心地将样品芯分三等份挤压到干净的表面上，分别代表容器的顶部、中部和底部。
5.Remove an appropriate sample representative of the top, middle, and bottom portions of the container samples, and test according to the instructions outlined in Products Packaged in Tubes.
取出代表容器样品顶部、中部和底部的适当样品，并根据管装产品中概述的说明进行测试。
Delivered-Dose Uniformity in Metered Dose Containers 定量容器的递送剂量均匀性
The test for delivered-dose uniformity is required for drug products contained either in metered-dose containers or in premetered unit presentations. The test for delivered-dose uniformity includes dose uniformity over the entire unit shelf life. Select 1 container. Using separate collection vessels, quantitatively collect delivered doses representing the initial, middle, and the final dose from the container. Appropriately discard doses not collected for testing. Determine the drug substance content of each of the 3 collected samples using an appropriate and validated quantitative procedure or the procedure indicated in the individual monograph. A dose in this test is defined as the minimum recommended number of actuations specified in the product labeling or in the instructions for use but NMT 2 actuations. The target-delivered dose is specified by the product label claim, unless otherwise specified in the individual monograph.
对于包含在定量容器或预先计量单位展示中的药品，需要进行给药剂量均匀性测试。递送剂量均匀性测试包括整个货架期内的剂量均匀性。选择1个容器。使用单独的收集容器，从容器中定量收集代表初始、中间和最终剂量的递送剂量。适当丢弃未收集用于测试的剂量。使用适当且经过验证的定量方法或各论中指定的方法确定3个收集样品中每一个的原料药含量。该测试中的剂量定义为产品标签或使用说明书中指定的最小推荐驱动次数，但应不少于2次驱动。除非在各论中另有规定，否则目标递送剂量由产品标签声明指定。
In-Process Testing 在线测试
Pump functionality test for metered and non-metered dose container closures 定量和非定量容器封闭的泵功能测试
This test is conducted during product development to establish that the airless pumps are performing as intended. This test is product dependent. Therefore, it is part of the manufacturer’s controls for the drug product and it is not included in compendial drug product monographs.
该测试在产品开发期间进行，以确定无气泵按预期运行。该测试取决于产品。因此，它是制造商对药品控制的一部分，不包括在药典药品专论中。
During the filling process for semisolid or liquid products packaged in a non-metered dose container closure requiring an actuator to dispense the product (for example, an airless pump container), in-process testing to verify pump functionality should be examined. Example tests include pumps to prime and total amount dispensed.
对于需要采用促动器分配产品（如，无气泵容器），包装在非定量包装容器中半固体或液体产品，在填充过程中，应进行在线测试，以验证泵的性能。示例测试包括泵启动和分配总量。
SPECIFIC TESTS FOR TDS TDS的特定测试
TDS are formulated with an adhesive layer to ensure intimate contact with the skin and allow the delivery of the desired dose of the drug. Adhesives in TDS must permit easy removal of the release liner before use, adhere properly to human skin upon application, maintain adhesion to the skin during the prescribed period of use, and permit easy removal of the TDS at the end of use without leaving a residue or causing damage to the skin or other undesirable effect(s). Additionally, adhesives must be able to maintain the performance of the TDS throughout the shelf life of the drug product.
TDS配制有粘合剂层，以确保与皮肤紧密接触并允许递送所需剂量的药物。TDS中的粘合剂必须允许在使用前轻松去除隔离衬垫，必须在使用时正确粘附在人体皮肤上，必须在规定的使用期内保持对皮肤的粘附，并且必须允许在使用结束时轻松去除TDS，不会留下残留物或对皮肤造成损害或其他不良影响。此外，粘合剂必须能够在药品的整个货架期内保持TDS的性能。
Testing of the physical properties of the TDS generally include peel adhesion, release liner peel, tack, cold flow, shear, and crystal formation (see Crystal Formation). The peel adhesion, release liner peel, and tack tests measure the adhesion properties of the TDS. Each of these tests measures the force required to separate the TDS from another surface. The cold flow and shear tests measure the cohesive properties of the TDS. These latter tests measure the resistance to flow of the adhesive matrix.
TDS物理特性的测试通常包括剥离粘合力、隔离衬垫剥离、粘性、冷流、剪切和晶体形成（参见晶体形成）。剥离粘合力、隔离衬垫剥离和粘性测试测量TDS的粘合特性。这些测试用于测定将TDS与另一个表面分离所需的力。冷流和剪切试验测量TDS的内聚特性。这些后面的测试测量粘合剂基质的流动阻力。
Acceptance criteria are product specific and defined to ensure that adhesion of each batch of TDS is within the range defined by the product design and is consistent between batches based on the product development specifications and statistical assessment of multiple product batches over the product’s shelf life.
In addition to physical testing, this section also discusses the Leak Test applicable to form-fill-seal-type (reservoir or pouched) TDS.
接受标准具有产品特异性，是基于产品开发规范和货架期内多批次产品的统计学评估确定，以确保每批TDS的粘合力在产品规定的范围内，并保持批次之间的一致性。
除了物理测试外，本节还讨论了适用于成型-填充-密封型（储罐或袋装）TDS 的泄漏测试。
Peel Adhesion Test 剥离强度测试
This test measures the force required to remove (peel away) a TDS attached to a standard substrate surface (e.g., polished stainless steel). The TDS is applied to the substrate using specified techniques for application and is conditioned at a specified temperature and time. Then the TDS is peeled away from the substrate with an instrument that allows for control of the peel angle (e.g., 90° or 180°) and peel rate (e.g., 300 mm/min), and the force profile is recorded. This procedure is repeated using a minimum of 5 independent samples yielding results from a suitable method (see Development of Peel Adhesion and Static Shear Test Methods). The in vitro adhesive properties of the drug product should thus be characterized with the specifications limits for the specified tests in accordance with the results obtained on clinical batches for which satisfactory in vivo adhesive properties under product use have been demonstrated and used to support their justification of the drug product specification. Release and shelf life limits should be the same, unless justified by reference to clinical batches.
该测试测量移除（剥离）附着在标准基底表面（例如，抛光不锈钢）上的TDS所需的力。使用指定的应用技术将TDS粘附在基底上，并在指定的温度和时间进行调节。然后使用可以控制剥离角度（例如，90° 或180°）和剥离速率（例如，300 毫米/分钟）的仪器将TDS从基底上剥离，并同时记录力分布。采用合适的方法，使用至少5个独立样品重复测定（参见剥离强度和静态剪切测试方法的发展）。可以根据在临床试验中使用的获得令人满意的体内粘附特性的批次结果，论述产品规范制定依据，对产品的体外粘附特性进行表征，为特定测试拟定合理的接受限度。放行和货架期限度应保持一致，除非参考临床批次证明是合理的。
The geometry of a TDS (e.g., round or rectangular shaped) and its design (e.g., TDS with different surfaces such as an inner part and with a peripheral adhesive ring) should be considered in the method.
The substrate surface should be cleaned regularly and checked for scratches, as this may influence test results.
方法中应考虑TDS的几何形状（例如，圆形或矩形）及其设计（例如，具有不同表面的TDS，例如内部部件和外围粘合剂环）。
应定期清洁基底表面并检查是否有划痕，因为这可能会影响测试结果。
Development of Peel Adhesion and Static Shear Test Methods 剥离强度和静态剪切试验方法的开发
During method development, suitable methods (including test panel surface) need to be identified. For peel adhesion testing, the method should allow the TDS to be removed entirely and cleanly, leaving no visually noticeable matrix residue on the substrate surface (i.e., cohesive failure).
在方法开发过程中，需要确定合适的方法（包括测试面板表面）。对于剥离强度测试，该方法应使TDS被完全和干净地去除，在基底表面上不留下视觉上明显的基质残留物（即内聚力破坏）。
In contrast, for static shear testing, cohesive failure (i.e., adhesive is left on the TDS and on the substrate plate) should occur.
Suitable peel adhesion and static shear test methods do not result in undesired adhesive failures. Undesired adhesive failure occurs when the TDS delaminates at an interface (e.g., between a membrane and an adhesive layer, or between two different adhesive layers of a bilayer product). During peel adhesion testing, transfer of adhesive to the test panel (i.e., cohesive failure) is an additional undesired adhesive failure mode.
相比之下，对于静态剪切测试，会发生内聚破坏（即粘合剂留在TDS和基底上）。
合适的剥离强度和静态剪切测试方法不会导致不希望的粘合失效。当TDS在界面（例如，膜和粘合剂层之间，或双层产品的两个不同粘合剂层之间）分层时，会发生不希望的粘合失效。在剥离强度测试期间，粘合剂转移到测试板上（即内聚破坏）是另一种不希望的粘合剂破坏模式。
Release Liner Peel Test 释放衬垫剥离测试
This test measures the force required to separate the release liner from the adhesive layer of the TDS. The test is performed with a finished product sample. The test sample is conditioned using specific procedures (temperature and time). Then, the release liner is pulled away from the TDS with an instrument that allows for control of the peel angle (e.g., 90° or 180°) and peel rate (300 mm/min), and the force profile is recorded. This procedure is repeated using a minimum of 5 independent samples. The product fails the test if the mean peel force is outside the acceptable range determined during product development and based on statistical assessment of multiple product batches over the product’s shelf life.
该测试测量将释放衬垫与TDS的粘合剂层分离所需的力。使用成品样品进行测试。使用特定程序（温度和时间）调节测试样品。然后，使用可以控制剥离角度（例如，90°或180°）和剥离速率（300 mm/min）的仪器将释放衬垫从TDS上拉开，并记录力分布。使用最少5个独立样本重复此过程。如果平均剥离力超出产品开发过程中基于产品货架期内多个产品批次的统计评估确定的可接受范围，则产品未通过测试。
Tack Test 粘性测试
A few tack test methods have been developed and the current predominantly used method is the Probe Tack Method. It is up to the TDS manufacturer to decide which tack test is most appropriate for each drug product.
已经开发了一些粘性测试方法，目前主要使用的方法是探针粘性测试方法。TSD生产商可以决定哪种粘性测试法适用。
Probe tack method 探针粘性方法
This test measures the force required to separate the tip of the test probe from the adhesive layer of the TDS. This test uses an instrument designed to create a bond between the tip of the stainless steel test probe (of defined geometry) and the TDS using a controlled force (light pressure) and specified test conditions (i.e., rate, contact time, contact pressure, and temperature). Then while controlling the rate of probe removal, the test measures the force required to separate the probe tip from the TDS and the maximum force required to break the bond (tack). This procedure is repeated using a minimum of 5 individual samples. The product fails the test if the mean test result is outside the acceptable range determined during product development and based on statistical assessment of multiple product batches over the product’s shelf life.
The probe head surface should be cleaned regularly and checked for scratches, as this may influence the test results.
该测试测量将测试探针的尖端与 TDS 的粘合剂层分离所需的力。该测试采用仪器进行，旨在使用受控的力（轻压）和指定的测试条件（即速率、接触时间、接触压力、温度）。然后，在控制探针移除速率的同时，该测试测量将探针尖端与 TDS 分离所需的力以及破坏键合（粘性）所需的最大力。使用最少 5 个单独的样品重复该过程。如果平均测试结果超出产品开发过程中基于产品货架期期内多个产品批次的统计评估确定的可接受范围，则产品未通过测试。
应定期清洁探头表面并检查是否有划痕，因为这可能会影响测试结果。
Cold Flow Test 冷流测试
Cold flow is the migration of the adhesive matrix beyond the edge of the TDS backing, and through the slit in the release liner, which may occur during the course of product processing and storage. Cold flow is an inherent property of TDS due to the use of pressure-sensitive adhesives that flow when force is applied (i.e., if the adhesive matrix did not flow, the TDS would not stick). The magnitude of the cold flow is generally dependent on the product formulation, packaging design, storage conditions, and storage time. Cold flow should be assessed using a combination of quantitative and qualitative methods. No single quantitative method has been identified to work universally for all TDS. The TDS manufacturer should determine the most suitable cold flow test, or tests, as cold flow may manifest differently for different products. Several different cold flow tests have been developed. Examples include:
冷流是粘合剂基质的迁移超出 TDS 背衬的边缘，并通过隔离衬垫中的狭缝，这种情况可能发生在产品加工和存储过程中。冷流是 TDS的固有特性，因为使用了在施加力时会流动的压敏粘合剂（即，如果粘合剂基质不流动，则 TDS 不会粘住）。冷流的大小通常取决于产品配方、包装设计、储存条件和储存时间。应使用定量和定性方法的组合来评估冷流。没有一种单一的定量方法适用于所有TDS的冷流测试。因为不同产品的冷流表现可能不同，TDS制造商应确定最合适的冷流测试方法。已经开发了几种不同的冷流测试。例子包括：
・Linear measurement of the radial cold flow using microscopy
・Measuring the distance of migrated adhesive matrix at predefined and evenly spaced positions of a TDS
・Measuring cold flow by applying a reference plate in the size of the TDS plus the acceptable cold flow
・Swabbing and stripping the migrated part of the matrix and determining it gravimetrically or by assay of the drug substance
・Die cutting and punching out the original size of the TDS and determining the amount of migrated matrix on the outside
・Overall area determining methods of cold flow using image analysis tools
・使用显微镜对径向冷流进行线性测量
・在TDS的预定义和均匀分布位置，测量迁移的粘合剂基质的距离
・通过应用TDS尺寸加上可接受的冷流量的参考板来测量冷流量
・擦拭和剥离基质的迁移部分，并通过重量分析或通过原料药测定进行测定
・模切和冲出TDS的原始尺寸并确定外部迁移基质的数量
・使用图像分析工具确定冷流总面积的方法。
Acceptance criteria are product specific and defined to ensure that the cold flow of each batch of TDS is within the range defined by the product design and is consistent between batches based on the product development specifications and statistical assessment of multiple batches over the product’s shelf life.
接受标准具有产品特异性，需根据产品开发规范和产品货架期内多个产品批次的统计评估，以确保每批TDS的冷流在产品设计定义的范围内，并在批次之间保持一致。
Shear Test 剪切试验
The shear test measures the cohesive strength of a TDS. It can be measured under static (see Static Shear Test) or dynamic conditions. Shear testing may not be feasible for all TDS because the presence of multiple layers of adhesive in the system, the presence of a membrane or scrim, or the use of an emulsion adhesive system may result in the inability to achieve cohesive failure. TDS that are constructed with a peripheral adhesive ring or form-fill-seal TDS may not be suitable for this test. The TDS manufacturer should decide if a shear test is appropriate, and if so, which shear test is most appropriate for each drug product. Acceptance criteria are product specific and defined to ensure that the shear of each batch of TDS is within the range defined by the product design and is consistent between batches based on the product development specifications and statistical assessment of multiple product batches over the product’s shelf life.
剪切试验测量TDS的内聚强度。它可以在静态（参见静态剪切测试）或动态条件下进行测量。因为系统中存在多层粘合剂、存在膜或稀松布、或使用乳液粘合剂系统可能导致无法实现内聚破坏，因此，并不是所有TDS都需要进行剪切测试。由外围粘合环或成型-填充-密封TDS构成的TDS可能不适合该测试。TDS制造商应决定剪切试验是否合适，如果合适，药品最适合采用哪种剪切试验。接受标准具有产品特异性，需根据产品开发规范和产品货架期内多个产品批次的统计评估，以确保每批TDS的剪切测试结果在产品设计定义的范围内，并在批次之间保持一致。
Static Shear Test 静态剪切试验
For the static shear test, the time required to remove a standard area of the TDS from the substrate (i.e., stainless steel test panel) under a standard load (e.g., 250 g) is measured. The TDS is applied to a test panel, and the sample is subjected to a shearing force by means of a given weight suspended from the TDS. The test apparatus holds the test panels at 0°− 2° from vertical to ensure that the TDS will not experience peeling action when the weight is attached. Dwell time, weight used, test panel type, mode of failure, and sample size should be noted; the time taken for the TDS sample to detach from the test panel is reported. This procedure is repeated using a minimum of 5 independent samples yielding results from a suitable method (see Development of Peel Adhesion and Static Shear Test Methods). The product fails the test if the mean shear force (i.e., arithmetic mean or geometric mean as determined by the manufacturer) is outside the acceptable range determined during product development and based on statistical assessment of multiple product batches over the product’s shelf life.
对于静态剪切测试，测量在标准负载（例如，250 g）下从基材（即不锈钢测试板）上去除标准区域的TDS 所需的时间。将TDS施加到测试板上，样品通过悬挂在TDS上的给定重量承受剪切力。测试设备将测试面板保持在与垂直方向成0°- 2°的位置，以确保在连接重物时TDS不会发生剥离作用。应注意停留时间、使用的重量、测试板类型、失效模式和样本大小；报告TDS样品从测试面板上分离所需的时间。使用至少5个独立样品重复此过程，从合适的方法中得出结果（参见剥离附着力和静态剪切测试方法的发展）。如果平均剪切力（即，制造商确定的算术平均值或几何平均值）超出“在产品开发期间和依据产品货架期内多个产品批次的统计评估确定的”可接受范围，则产品未通过测试。
Leak Test 泄漏测试
This test is applicable only for form-fill-seal-type (reservoir or pouched) TDS. Form-fill-seal TDS must be manufactured with zero tolerance for leaks because of their potential for dose dumping if leaking occurs.
In-process control methods to examine TDS for leaks or potential leaks are needed and require considerable development on the part of TDS manufacturers.
该测试仅适用于成型-填充-密封型（储罐或袋装）TDS。成型-填充-密封TDS的生产，不允许泄露的发生，因为如果发生泄漏，它们可能会剂量倾泻。
需要使用在线测试方法来检查TDS是否存在泄漏或潜在泄漏，并且需要TDS制造商进行大量开发研究。
In-process testing 在线测试
During the manufacturing process, the presence of leakage (or potential for leakage) due to TDS perforation, cuts, and faulty seals resulting from failures such as air bubbles, gel splash, or misalignment of a TDS backing and release liner layers must be examined. Unless automated process analytical technology is implemented, in-process testing to identify these defects should be performed using the following test procedures.
在生产过程中，必须检查泄漏（或泄漏的可能性），这些泄露可能是由，如气泡、凝胶飞溅或TDS的背衬和隔离衬层错位等，致使TDS穿孔、切割和密封不良产生。除非采用自动化过程分析技术，否则应使用以下测试程序进行在线测试以识别这些缺陷。
Visual inspection: 目视检查
・A specified number of TDS, defined on the basis of batch size, should be examined randomly
・Each sampled TDS should be thoroughly visually inspected for leakage
・The product fails if any of the TDS examined are detected with a leak
・应随机检查基于批量大小定义的指定数量的TDS
・应彻底目视检查每个采样的TDS是否有泄漏
・如果检测到任何TDS有泄漏，则产品不合格
Seal integrity: TDS seals should be stress tested to ensure that the application of pressure does not force seals to open, thereby leading to leakage.
・A specified number of TDS, defined on the basis of batch size, should be randomly examined.
・Each sampled TDS should be thoroughly visually inspected for leakage.
・Each sampled TDS is placed on a hard, flat surface and overlaid with a weight so that it is subjected to 13.6 kg. The weight should be left in place for 2 min. Upon removal of the weight, the TDS should be visually inspected for leakage.
・The product fails if the number of TDS detected with a leak is greater than the acceptable limit established by the manufacturer.
密封完整性：TDS 密封件应进行应力测试，以确保施加的压力不会迫使密封件打开，从而导致泄漏。
・应随机检查根据批量大小定义的特定数量的TDS
・应彻底目视检查每个采样的TDS是否有泄漏
・每个采样的TDS都放在坚硬、平坦的表面上，并用重物覆盖，使其承受13.6公斤的重量，并保持2分钟。卸下重物后，应目测查TDS是否有泄漏
・如果检测到泄漏的TDS数量大于制造商规定的可接受限度，则产品不合格
Packaged product testing: TDS may leak after they have been individually placed in the primary packaging material as a result of the packaging operation itself or by a user opening the packaging. Therefore, TDS should be tested for leakage after they have been manufactured and packaged in their primary packaging material.
・A specified number of TDS, defined on the basis of batch size, should be randomly examined after they have been placed in their primary packaging material.
・The sampled TDS should be removed from their packaging and thoroughly visually inspected for leakage.
・Each sampled TDS should then be uniformly wiped with a solvent-moistened swab. Both the backing side and the release liner side of the TDS should be wiped. The inside surface of the pouch should also be wiped. The swab(s) is then extracted and assayed for the drug.
・The product fails if the total amount of drug from the TDS, and the corresponding pouch, exceed the acceptable limit established by the manufacturer.
包装产品测试：由于包装操作本身或用户打开包装，将TDS单独放入初级包装材料后，TDS 可能会泄漏。因此，应在生产和包装在初级包装材料后，对TDS进行泄露测试。
・根据批次大小定义的特定数量的 TDS，应在将它们放入其初级包装材料后进行随机检查。
・取样的TDS应从包装中取出并彻底目视检查是否有泄漏。
・然后应使用浸有溶剂的棉签均匀地擦拭每个采样的TDS。应擦拭TDS 的背衬侧和隔离衬垫侧。袋子的内表面也应擦拭。然后提取擦拭物并进行测定。
・如果来自TDS和相应袋子的药物总量超过制造商规定的可接受限度，则产品不合格。
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