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（上部分）

 

This guidance provides recommendations to applicants and manufacturers of transdermal and topical delivery systems (TDS) regarding the pharmaceutical development and quality information to include in new drug applications (NDAs) and abbreviated new drug applications (ANDAs). Specifically, the guidance discusses FDA’s current thinking on product design and pharmaceutical development, manufacturing process and control, and finished product control. It also addresses special considerations for areas where quality is closely tied to product performance and potential safety issues, such as adhesion failure and the impact of applied heat on drug delivery.

本指南为透皮和局部给药系统（TDS）的申请人和制造商提供了关于新药应用（NDAs）和仿制药应用（ANDAs）中包含的药物开发和质量信息的建议。具体而言，该指南讨论了FDA目前在产品设计和药物开发、制造过程和控制以及成品控制方面的思考。它还针对质量与产品性能密切相关的领域和潜在的安全问题(如粘附性和受热)提出了特殊考虑。

In general, FDA’s guidance d0cuments do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of he word should in Agency guidances means that something is suggested or recommended, but not required.

一般来说，FDA的指导文件没有规定法律上可强制执行的责任。相反，指南描述了机构当前对某一主题的思考，除非引用了具体的法规或法定要求，否则仅应视为建议。在机构指南中使用“应该”一词意味着建议或推荐，但不是必须的。

A.General/通则

Transdermal delivery systems are designed to deliver an active ingredient (drug substance) across the skin and into systemic circulation, while topical delivery systems are designed to deliver the active ingredient to local tissue. Both delivery systems present similar manufacturing and quality control concerns and similar risks to patients. TDS can be broadly divided into matrix type and liquid or gel reservoir type delivery systems.

经皮递送系统设计用于将活性成分（药物）递送透过皮肤并进入全身循环，而局部递送系统设计为将活性成分递送至局部组织。两种输送系统都存在类似的制造和质量控制问题，对患者也存在类似的风险。TDS可大致分为基质型和液体或凝胶储库型输送系统。

Matrix type TDS contain one or more active ingredients dissolved or partially suspended in a mixture of various components, including adhesives, penetration enhancers, softeners, and preservatives, and are typically manufactured using solvent, hydrogel, or hot melt-based practices. An example of a matrix type TDS is shown in Figure 1, but matrix TDS may include additional layers and/or more complex designs

基质型TDS含有一种或多种活性成分，其溶解或部分悬浮在各种成分的混合物中，包括粘合剂、渗透促进剂、柔软剂和防腐剂，通常使用溶剂、水凝胶或基于热熔的方法制造。基质型TDS的示例如图1所示，但基质型TDS可能包括额外的层和/或更复杂的设计

图1.基质型透皮或局部给药系统

Reservoir type TDS similarly contain a variety of components in liquid or semi-solid form; however, reservoir type TDS utilize a heat-sealed area to entrap the active gel between the backing membrane and a microporous membrane. An example of a reservoir type TDS is shown in Figure 2. Because of the inherent failure modes and safety risks associated with the reservoir TDS, FDA recommends TDS manufacturers and applicants focus development efforts on matrix type TDS.

储库型TDS同样包含各种液体或半固体形式的组分；然而，储库型TDS利用热密封区域将活性凝胶截留在背衬膜和微孔膜之间。储库类型TDS的示例如图2所示。由于储库TDS固有的故障模式和安全风险，FDA建议TDS制造商和申请人将开发工作重点放在基质类型TDS上。

图2储库型经皮或局部递送系统

B.Regulatory Status/监管状况

Transdermal and topical delivery systems are combination products as defined by 21 CFR part 3, and must comply with 21 CFR part 4 subpart A (Current Good Manufacturing Practice Requirements for Combination Products). Within 21 CFR part 4, there is descr1ption of how requirements from 21 CFR parts 210 and 211 (drug CGMPs) and 21 CFR part 820 (device Quality System regulation) apply to combination products.

经皮和局部递送系统是21 CFR第3部分中定义的组合产品，必须符合21 CFR第4部分A子部分（组合产品的现行良好生产规范要求）。在21 CFR第4部分中，描述了21 CFR第210和211部分（药物CGMP）和21 CFR第820部分（器械质量体系法规）的要求如何适用于组合产品。

In particular, design controls (21 CFR part 820.30) apply to drug-device combination products including TDS. Essentially, design control activities should confirm that there are no negative interactions between constituent parts and assure that their combined use results in a combination product that is safe and effective and performs as expected. Guidance for industry on pharmaceutical development also addresses product design and development procedures, reflecting quality by design principles. While quality by design and design controls share similar characteristics and goals, the device Quality System regulation (21 CFR part 820) includes specific requirements for design development that manufacturers must satisfy.

特别是，设计控制（21 CFR第820.30部分）适用于包括TDS在内的药物器械组合产品。从本质上讲，设计控制活动应确认组成部分之间不存在消极作用，并确保其组合使用产生安全有效，且性能符合预期。药物开发行业指南还涉及产品设计和开发程序，反映了设计原则的质量。虽然设计质量和设计控制具有相似的特征和目标，但设备质量体系法规（21 CFR第820部分）包括制造商必须满足的设计开发的具体要求。

It may be possible to leverage many aspects of pharmaceutical development as described in International Conference for Harmonisation ICH Q8(R2) to achieve compliance with design controls. For example, the Quality Target Product Profile (QTPP) (see section III.A. below) is similar to “design inputs” (21 CFR part 820.30(c)), which ensure that design requirements are appropriate to address the intended use of the product. Further, studies conducted to verify that the critical quality attributes (CQAs) are met in the finished product may also address requirements for design “verification” and “validation” (21 CFR part 820.30(f), (g)), which ensure that the product’s “design outputs” (21 CFR part 820.30(d)) result in a product that safely and effectively achieves its intended effects).

如国际协调会议ICH Q8（R2）所述，可以利用药物开发的许多方面来实现设计控制的合规性。例如，质量目标产品概要（QTPP）（见下文第III.A.节）类似于“设计输入”（21 CFR第820.30（c）部分），确保设计要求适合于解决产品的预期用途。此外，为验证成品是否满足关键质量属性（CQA）而进行的研究也可能涉及设计“验证”和“确认”要求（《美国联邦法规》第21篇第820.30（f）、（g）部分），以确保产品的“设计输出”（《联邦法规》21篇第820.30（d）部分）产生安全有效地达到预期效果的产品。

The following section provides an overview of considerations for product and process development, described from a pharmaceutical development perspective. As described above, development of a TDS product must also be compliant with design controls (21 CFR part 820.30). We recognize that the terminology used in 21 CFR part 820.30 can differ from that used in a particular pharmaceutical development program. Where pharmaceutical development practices are leveraged and built upon to demonstrate compliance with design controls for a TDS product, applicants should be able to communicate to FDA how the terminology they use relates to design control principles and requirements

以下部分概述了从药物开发角度描述了产品和工艺的开发注意事项。如上所述，TDS产品的开发还必须符合设计控制（21 CFR第820.30部分）。我们认识到，21 CFR第820.30部分中使用的术语可能与特定药物开发计划中使用的不同。申请人应该能够与FDA沟通他们使用的术语如何与设计控制原则和要求相关系。

A.Quality Target Product Profile/目标产品质量概况

Prior to TDS development, the applicant should establish the desired quality target product profile (QTPP). The QTPP is a prospective summary of the quality characteristics of the TDS product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the product (ICH Q8(R2)). In general, QTPP elements and their quality considerations for TDS may include

在开发TDS之前，申请人应建立所需的质量目标产品概要（QTPP）。QTPP是对TDS产品质量特性的前瞻性总结，在考虑到产品的安全性和有效性的情况下，理想情况下可实现该特性以确保所需的质量（ICH Q8（R2））。一般来说，TDS的QTPP元素及其质量考虑因素可能包括

Other QTPP elements may exist depending on therapeutic need, patient population, or other functional property requirements. For example, the size of the finished product may be a QTPP element depending on the location on the body where the product is to be applied or if the patient population is pediatric.

根据治疗需要、患者群体或其他功能特性要求，可能存在其他QTPP元件。例如，成品的大小可以是QTPP元素，这取决于产品在身体上的应用位置，或者患者群体是否为儿童。

B.Critical Quality Attributes/关键质量属性

1.TDS Product/TDS产品

Early in the TDS development process, the applicant should generate a list of potential CQAs. A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8(R2)). Knowledge of the QTPP for the product, in combination with prior knowledge, risk assessments, and/or experimentation, can be used to develop the list of product CQAs. Each CQA, either alone or in concert with one or more other CQAs, should relate to one or more elements of the TDS product QTPP. The list of product CQAs can be modified as product development progresses and new knowledge is gained. The CQAs of the drug substance(s), excipients, components and container closure system should also be identified in the application.

在TDS开发过程的早期，申请人应生成一份潜在CQAs列表。CQAs是一种物理、化学、生物或微生物性质或特性，应在适当的限度、范围或分布内，以确保所需的产品质量（ICH Q8（R2））。产品QTPP的知识，结合先前的知识、风险评估和/或实验，可用于制定产品CQAs列表。每个CQA（单独或与一个或多个其他CQA联合）应与TDS产品QTPP的一个或更多元素相关。产品CQAs列表可以随着产品开发的进展和新知识的获得而修改。申请中还应确定原料药、辅料、成分和包装容器系统的CQAs。

For TDS, CQAs typically include appearance (such as lack of visible crystals), dimensions, uniformity of dosage units, assay, permeation enhancer content, impurities and degradants, in vitro drug release profile, preservative/antioxidant content (if present), peel adhesion, tack, release liner peel strength, shear strength, cold flow, residual solvents, residual monomers, microbial limits, and package integrity.

对于TDS，CQAs通常包括外观（例如无可见晶体）、尺寸、剂量单位的均匀性、测定方法、渗透促进剂的含量、杂质和降解物、体外药物释放概况、防腐剂/抗氧化剂含量（如果有）、剥离强度、粘性、剥离衬垫剥离强度、剪切强度、冷流、残留溶剂、残留单体、微生物限度、以及包装完整性。

2.Drug Substance/原料药

Selection of a drug substance should be justified based on the physicochemical and biological properties of the drug substance that can influence the performance of the TDS product and its manufacturability. In particular, properties that influence the rate of delivery, such as molecular weight, melting point, partition coefficient, pKa, aqueous solubility, and pH, should be considered. Other characteristics of the drug substance such as particle size, crystal form, and polymorphism should be eva1uated and justified in terms of product performance.

应根据可影响TDS产品性能及其可制造性的药物的物理化学和生物特性来证明原料药的选择是合理的。特别是，应考虑影响递送速率的性质，如分子量、熔点、分配系数log P、电离常数pKa、水溶性和pH。应根据产品性能评估和证明药物的其他特性，如颗粒大小、晶体形式和多态性。

3.Excipients and Components/辅料及成分

Excipients and components used in TDS can include various adhesives, permeation enhancers, rate controlling or non-rate controlling membranes, solubilizers, plasticizers/softeners, or tackifiers, all of which can influence the quality and performance attributes of TDS

TDS中使用的辅料和成分可以包括各种粘合剂、渗透促进剂、速率控制或非速率控制膜、增溶剂、增塑剂/软化剂或增稠剂，所有这些都会影响TDS的质量和性能属性

Rigorous qualification of key excipients and components is important to ensure optimum product quality attributes in transdermal and topical formulations, and facilitates the postapproval change process for changes in the raw materials, manufacturing process, or suppliers.

关键赋形剂和成分的严格确认对于确保透皮和外用制剂的最佳产品质量属性非常重要，并有助于原材料、制造工艺或供应商变更的批准后变更流程。

For example, when qualifying the adhesives in a TDS product, an applicant should consider the following attributes:

例如，在鉴定TDS产品中的粘合剂时，申请人应考虑以下属性：

●For adhesive polymer(s) as raw material(s): molecular weight, polydispersity, spectroscopic analysis (e.g., infrared radiation (IR) absorption), thermal analysis, intrinsic or complex viscosity, and measurement of residual monomers, dimers, solvents, heavy metals, catalysts, and initiators.

对于作为原料的粘合剂聚合物：分子量、多分散性、光谱分析（例如，红外光谱（IR）吸收）、热分析、固有或复合粘度，以及残余单体、二聚体、溶剂、重金属、催化剂和引发剂的测量。

●For adhesive as a laminate (in the absence of the active ingredient and other excipients): residual solvents, peel, tack, shear, and adhesion.

对于作为层压板的粘合剂（在没有活性成分和其他赋形剂的情况下）：残余溶剂、剥离、粘性、剪切和粘附。

●For adhesive in the final product (along with drug substance and other excipients and components): identification, residual monomers, dimers, and solvents; impurities; loss on drying; and uniformity. Other properties to be considered include the viscoelastic properties (such as elastic modulus (G’), viscous modulus (G”), and creep compliance (J)), and functional properties including, but not limited to, peel, shear, adhesion, tack, in vitro drug release, and in vitro drug permeation.

对于最终产品中的粘合剂（以及药物和其他赋形剂和成分）：鉴定、残留单体、二聚体和溶剂；杂质；干燥损失；以及均匀性。要考虑的其他性质包括粘弹性性质（如弹性模量（G'）、粘性模量（G”）和蠕变顺应性（J）），以及功能性质，包括但不限于剥离、剪切、粘附、粘性、体外药物释放和体外药物渗透。

The properties of an adhesive as raw material (e.g., rheology, including intrinsic viscosity and complex viscosity) can impact the final product quality attributes. Adhesive suppliers’ specifications are often wide; thus, adhesive raw material received throughout the life cycle of the product may vary greatly within the adhesive suppliers’ specifications. For example, the rheological properties of the adhesive lots used in the pivotal in vivo trial for TDS (e.g., bioequivalence (BE), Pharmacokinetic (PK), adhesion studies) may not be consistent with the supplier’s previously manufactured adhesive lots or their future adhesive lots. Therefore, applicants should request historical rheology values from the adhesive manufacturer to better understand their process capabilities and the potential influence of variability in the adhesive rheology on the final product. This can further assist applicants in assessing the need to establish or tighten internal controls for the raw material.

作为原材料的粘合剂的性质（例如，流变学，包括固有粘度和复合粘度）会影响最终产品的质量属性。粘合剂供应商的规格通常很宽；因此，在产品的整个生命周期中接收的粘合剂原料在粘合剂供应商的规格范围内可能会有很大差异。例如，TDS关键体内试验中使用的粘合剂批次的流变特性（例如生物等效性（BE）、药代动力学（PK）、粘附研究）可能与供应商先前制造的粘合剂批次或其未来生产的粘合剂批次不一致。因此，申请人应要求粘合剂制造商提供历史流变学值，以便更好地了解其工艺能力以及粘合剂流变学变化对最终产品的潜在影响。这可以进一步帮助申请人评估是否需要建立或加强原材料内部控制。

Identifying, eva1uating, and properly controlling similar quality attributes of other key components of TDS products will enhance product and process understanding of the TDS throughout its life cycle.

识别、评估和适当控制TDS产品其他关键部分的类似质量属性，将增强产品和过程对TDS整个生命周期的理解。

4.Identifying Labeling/标签确认

Applicants are encouraged to incorporate a representative label early in development to assure the labeling process or inks utilized for printing do not interact with the TDS product, and to properly assess inks during extractable and leachable studies. The identifying label is typically placed on the backing membrane of TDS and should, at minimum, include the product name and strength

鼓励申请人在开发初期加入具有代表性的标签，以确保用于印刷的标签工艺或油墨不会与TDS产品相互作用，并在可提取和可浸出研究期间适当评估油墨。识别标签通常放置在TDS的背膜上，并且至少应该包括产品名称和规格

Transdermal and topical systems that are clear, translucent, or colored to match human skin tones can make it difficult to find the TDS on the patient, and have led to medication administration errors when patients or caregivers fail to remove old systems and apply more than one system at a time. Clear or translucent TDS may also be difficult to find if they detach prematurely from a patient, thereby increasing the potential for secondary or accidental exposure of the drug to a health care provider, caregiver, or child. Therefore, we recommend the backing membrane be printed with ink that has adequate contrast and remains visible for the duration of system wear and after disposal.

透明、半透明或颜色与人类肤色相匹配的透皮系统和外用系统可能难以在患者身上找到TDS，并且当患者或护理人员未能移除旧TDS并一次应用多个TDS时，会导致用药错误。如果透明或半透明的 TDS 过早地从患者身上脱落，也可能很难找到，从而增加了医疗保健提供者、护理者或儿童二次或意外接触药物的可能性。因此，我们建议使用具有足够对比度的油墨印刷背衬膜，并在系统使用期间和处理后保持可见。

C.Product and Process Development/产品与工艺开发

The principles of quality by design (QbD) and elements of pharmaceutical development discussed in ICH Q8(R2), Q9, and Q10should be applied throughout the TDS life cycle to ensure TDS products have the identity and strength, and meet the quality and purity characteristics required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)

ICH Q8（R2）、Q9和Q10中讨论的设计质量原则（QbD）和药物开发要素应在TDS的整个生命周期中应用，以确保TDS产品具有特性和强度，并满足《联邦食品、药品和化妆品法案》（FD&C法案）第501（a）（2）（B）节要求的质量和纯度特征

TDS can be as simple as a single drug substance dissolved in a single adhesive, or highly complex, multi-component, multi-adhesive, multi-laminate matrices. Excipients and components in TDS can include various adhesive systems, permeation enhancers, rate controlling or non-rate controlling membranes, solubilizers, plasticizers/softeners, or tackifiers

TDS可以像溶解在单一粘合剂中的单一药物一样简单，也可以是高度复杂的多组分、多粘合剂、多层压基质。TDS中的辅料和成分可包括各种粘合剂系统、渗透促进剂、控释或非控释膜、增溶剂、增塑剂/柔软剂或增稠剂。

As a general principle, product development strategies should seek to minimize product complexity while still achieving the QTPP. Less complex products are likely to have fewer potential failure modes than more complex products. Product and process controls can be simplified as product complexity decreases, which can reduce the risk of manufacturing problems occurring during routine commercial manufacture.

作为一项普遍原则，产品开发策略应该寻求在实现QTPP的同时最小化产品复杂性。较不复杂的产品可能比较复杂的产品具有更少的潜在的失效模式。随着产品复杂性的降低，可以简化产品和过程控制，这可以降低在日常商业制造过程中发生制造问题的风险。

Systematic quality risk assessments and process characterizations can support the identification of appropriate controls for manufacturing process variables, in order to produce TDS products with acceptable CQAs. Risk assessments can also help define the robustness of certain critical material attributes (CMAs) and critical process parameters (CPPs), such as raw material characteristics, hold times and equilibration periods

系统的质量风险评估和过程特征可以支持识别制造过程变量进行适当的控制，以生产具有可接受的CQAs的TDS产品。风险评估还可以帮助确定某些关键材料属性（CMAs）和关键工艺参数（CPPs）的稳健性，如原材料特性、保持时间和平衡期

在申请中需要提交的材料请看下期——下半部分

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