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.

本指南為透皮和局部給藥系統(tǒng)（TDS）的申請人和制造商提供了關(guān)于新藥應(yīng)用（NDAs）和仿制藥應(yīng)用（ANDAs）中包含的藥物開發(fā)和質(zhì)量信息的建議。具體而言，該指南討論了FDA目前在產(chǎn)品設(shè)計和藥物開發(fā)、制造過程和控制以及成品控制方面的思考。它還針對質(zhì)量與產(chǎn)品性能密切相關(guān)的領(lǐng)域和潛在的安全問題(如粘附性和受熱)提出了特殊考慮。

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.

一般來說，F(xiàn)DA的指導(dǎo)文件沒有規(guī)定法律上可強制執(zhí)行的責(zé)任。相反，指南描述了機構(gòu)當(dāng)前對某一主題的思考，除非引用了具體的法規(guī)或法定要求，否則僅應(yīng)視為建議。在機構(gòu)指南中使用“應(yīng)該”一詞意味著建議或推薦，但不是必須的。

A.General/通則

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.

經(jīng)皮遞送系統(tǒng)設(shè)計用于將活性成分（藥物）遞送透過皮膚并進入全身循環(huán)，而局部遞送系統(tǒng)設(shè)計為將活性成分遞送至局部組織。兩種輸送系統(tǒng)都存在類似的制造和質(zhì)量控制問題，對患者也存在類似的風(fēng)險。TDS可大致分為基質(zhì)型和液體或凝膠儲庫型輸送系統(tǒng)。

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

基質(zhì)型TDS含有一種或多種活性成分，其溶解或部分懸浮在各種成分的混合物中，包括粘合劑、滲透促進劑、柔軟劑和防腐劑，通常使用溶劑、水凝膠或基于熱熔的方法制造。基質(zhì)型TDS的示例如圖1所示，但基質(zhì)型TDS可能包括額外的層和/或更復(fù)雜的設(shè)計

圖1.基質(zhì)型透皮或局部給藥系統(tǒng)

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.

儲庫型TDS同樣包含各種液體或半固體形式的組分；然而，儲庫型TDS利用熱密封區(qū)域?qū)⒒钚阅z截留在背襯膜和微孔膜之間。儲庫類型TDS的示例如圖2所示。由于儲庫TDS固有的故障模式和安全風(fēng)險，F(xiàn)DA建議TDS制造商和申請人將開發(fā)工作重點放在基質(zhì)類型TDS上。

圖2儲庫型經(jīng)皮或局部遞送系統(tǒng)

B.Regulatory Status/監(jiān)管狀況

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.

經(jīng)皮和局部遞送系統(tǒng)是21 CFR第3部分中定義的組合產(chǎn)品，必須符合21 CFR第4部分A子部分（組合產(chǎn)品的現(xiàn)行良好生產(chǎn)規(guī)范要求）。在21 CFR第4部分中，描述了21 CFR第210和211部分（藥物CGMP）和21 CFR第820部分（器械質(zhì)量體系法規(guī)）的要求如何適用于組合產(chǎn)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.

特別是，設(shè)計控制（21 CFR第820.30部分）適用于包括TDS在內(nèi)的藥物器械組合產(chǎn)品。從本質(zhì)上講，設(shè)計控制活動應(yīng)確認(rèn)組成部分之間不存在消極作用，并確保其組合使用產(chǎn)生安全有效，且性能符合預(yù)期。藥物開發(fā)行業(yè)指南還涉及產(chǎn)品設(shè)計和開發(fā)程序，反映了設(shè)計原則的質(zhì)量。雖然設(shè)計質(zhì)量和設(shè)計控制具有相似的特征和目標(biāo)，但設(shè)備質(zhì)量體系法規(guī)（21 CFR第820部分）包括制造商必須滿足的設(shè)計開發(fā)的具體要求。

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).

如國際協(xié)調(diào)會議ICH Q8（R2）所述，可以利用藥物開發(fā)的許多方面來實現(xiàn)設(shè)計控制的合規(guī)性。例如，質(zhì)量目標(biāo)產(chǎn)品概要（QTPP）（見下文第III.A.節(jié)）類似于“設(shè)計輸入”（21 CFR第820.30（c）部分），確保設(shè)計要求適合于解決產(chǎn)品的預(yù)期用途。此外，為驗證成品是否滿足關(guān)鍵質(zhì)量屬性（CQA）而進行的研究也可能涉及設(shè)計“驗證”和“確認(rèn)”要求（《美國聯(lián)邦法規(guī)》第21篇第820.30（f）、（g）部分），以確保產(chǎn)品的“設(shè)計輸出”（《聯(lián)邦法規(guī)》21篇第820.30（d）部分）產(chǎn)生安全有效地達到預(yù)期效果的產(chǎn)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

以下部分概述了從藥物開發(fā)角度描述了產(chǎn)品和工藝的開發(fā)注意事項。如上所述，TDS產(chǎn)品的開發(fā)還必須符合設(shè)計控制（21 CFR第820.30部分）。我們認(rèn)識到，21 CFR第820.30部分中使用的術(shù)語可能與特定藥物開發(fā)計劃中使用的不同。申請人應(yīng)該能夠與FDA溝通他們使用的術(shù)語如何與設(shè)計控制原則和要求相關(guān)系。

A.Quality Target Product Profile/目標(biāo)產(chǎn)品質(zhì)量概況

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

在開發(fā)TDS之前，申請人應(yīng)建立所需的質(zhì)量目標(biāo)產(chǎn)品概要（QTPP）。QTPP是對TDS產(chǎn)品質(zhì)量特性的前瞻性總結(jié)，在考慮到產(chǎn)品的安全性和有效性的情況下，理想情況下可實現(xiàn)該特性以確保所需的質(zhì)量（ICH Q8（R2））。一般來說，TDS的QTPP元素及其質(zhì)量考慮因素可能包括

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.

根據(jù)治療需要、患者群體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，這取決于產(chǎn)品在身體上的應(yīng)用位置，或者患者群體是否為兒童。

B.Critical Quality Attributes/關(guān)鍵質(zhì)量屬性

1.TDS Product/TDS產(chǎn)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開發(fā)過程的早期，申請人應(yīng)生成一份潛在CQAs列表。CQAs是一種物理、化學(xué)、生物或微生物性質(zhì)或特性，應(yīng)在適當(dāng)?shù)南薅?、范圍或分布?nèi)，以確保所需的產(chǎn)品質(zhì)量（ICH Q8（R2））。產(chǎn)品QTPP的知識，結(jié)合先前的知識、風(fēng)險評估和/或?qū)嶒?，可用于制定產(chǎn)品CQAs列表。每個CQA（單獨或與一個或多個其他CQA聯(lián)合）應(yīng)與TDS產(chǎn)品QTPP的一個或更多元素相關(guān)。產(chǎn)品CQAs列表可以隨著產(chǎn)品開發(fā)的進展和新知識的獲得而修改。申請中還應(yīng)確定原料藥、輔料、成分和包裝容器系統(tǒng)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.

對于TDS，CQAs通常包括外觀（例如無可見晶體）、尺寸、劑量單位的均勻性、測定方法、滲透促進劑的含量、雜質(zhì)和降解物、體外藥物釋放概況、防腐劑/抗氧化劑含量（如果有）、剝離強度、粘性、剝離襯墊剝離強度、剪切強度、冷流、殘留溶劑、殘留單體、微生物限度、以及包裝完整性。

2.Drug Substance/原料藥

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.

應(yīng)根據(jù)可影響TDS產(chǎn)品性能及其可制造性的藥物的物理化學(xué)和生物特性來證明原料藥的選擇是合理的。特別是，應(yīng)考慮影響遞送速率的性質(zhì)，如分子量、熔點、分配系數(shù)log P、電離常數(shù)pKa、水溶性和pH。應(yīng)根據(jù)產(chǎn)品性能評估和證明藥物的其他特性，如顆粒大小、晶體形式和多態(tài)性。

3.Excipients and Components/輔料及成分

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中使用的輔料和成分可以包括各種粘合劑、滲透促進劑、速率控制或非速率控制膜、增溶劑、增塑劑/軟化劑或增稠劑，所有這些都會影響TDS的質(zhì)量和性能屬性

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.

關(guān)鍵賦形劑和成分的嚴(yán)格確認(rèn)對于確保透皮和外用制劑的最佳產(chǎn)品質(zhì)量屬性非常重要，并有助于原材料、制造工藝或供應(yīng)商變更的批準(zhǔn)后變更流程。

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

例如，在鑒定TDS產(chǎn)品中的粘合劑時，申請人應(yīng)考慮以下屬性：

●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.

對于作為原料的粘合劑聚合物：分子量、多分散性、光譜分析（例如，紅外光譜（IR）吸收）、熱分析、固有或復(fù)合粘度，以及殘余單體、二聚體、溶劑、重金屬、催化劑和引發(fā)劑的測量。

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

對于作為層壓板的粘合劑（在沒有活性成分和其他賦形劑的情況下）：殘余溶劑、剝離、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.

對于最終產(chǎn)品中的粘合劑（以及藥物和其他賦形劑和成分）：鑒定、殘留單體、二聚體和溶劑；雜質(zhì)；干燥損失；以及均勻性。要考慮的其他性質(zhì)包括粘彈性性質(zhì)（如彈性模量（G'）、粘性模量（G”）和蠕變順應(yīng)性（J）），以及功能性質(zhì)，包括但不限于剝離、剪切、粘附、粘性、體外藥物釋放和體外藥物滲透。

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.

作為原材料的粘合劑的性質(zhì)（例如，流變學(xué)，包括固有粘度和復(fù)合粘度）會影響最終產(chǎn)品的質(zhì)量屬性。粘合劑供應(yīng)商的規(guī)格通常很寬；因此，在產(chǎn)品的整個生命周期中接收的粘合劑原料在粘合劑供應(yīng)商的規(guī)格范圍內(nèi)可能會有很大差異。例如，TDS關(guān)鍵體內(nèi)試驗中使用的粘合劑批次的流變特性（例如生物等效性（BE）、藥代動力學(xué)（PK）、粘附研究）可能與供應(yīng)商先前制造的粘合劑批次或其未來生產(chǎn)的粘合劑批次不一致。因此，申請人應(yīng)要求粘合劑制造商提供歷史流變學(xué)值，以便更好地了解其工藝能力以及粘合劑流變學(xué)變化對最終產(chǎn)品的潛在影響。這可以進一步幫助申請人評估是否需要建立或加強原材料內(nèi)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.

識別、評估和適當(dāng)控制TDS產(chǎn)品其他關(guān)鍵部分的類似質(zhì)量屬性，將增強產(chǎn)品和過程對TDS整個生命周期的理解。

4.Identifying Labeling/標(biāo)簽確認(rèn)

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

鼓勵申請人在開發(fā)初期加入具有代表性的標(biāo)簽，以確保用于印刷的標(biāo)簽工藝或油墨不會與TDS產(chǎn)品相互作用，并在可提取和可浸出研究期間適當(dāng)評估油墨。識別標(biāo)簽通常放置在TDS的背膜上，并且至少應(yīng)該包括產(chǎn)品名稱和規(guī)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、半透明或顏色與人類膚色相匹配的透皮系統(tǒng)和外用系統(tǒng)可能難以在患者身上找到TDS，并且當(dāng)患者或護理人員未能移除舊TDS并一次應(yīng)用多個TDS時，會導(dǎo)致用藥錯誤。如果透明或半透明的 TDS 過早地從患者身上脫落，也可能很難找到，從而增加了醫(yī)療保健提供者、護理者或兒童二次或意外接觸藥物的可能性。因此，我們建議使用具有足夠?qū)Ρ榷鹊挠湍∷⒈骋r膜，并在系統(tǒng)使用期間和處理后保持可見。

C.Product and Process Development/產(chǎn)品與工藝開發(fā)

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中討論的設(shè)計質(zhì)量原則（QbD）和藥物開發(fā)要素應(yīng)在TDS的整個生命周期中應(yīng)用，以確保TDS產(chǎn)品具有特性和強度，并滿足《聯(lián)邦食品、藥品和化妝品法案》（FD&C法案）第501（a）（2）（B）節(jié)要求的質(zhì)量和純度特征

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可以像溶解在單一粘合劑中的單一藥物一樣簡單，也可以是高度復(fù)雜的多組分、多粘合劑、多層壓基質(zhì)。TDS中的輔料和成分可包括各種粘合劑系統(tǒng)、滲透促進劑、控釋或非控釋膜、增溶劑、增塑劑/柔軟劑或增稠劑。

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.

作為一項普遍原則，產(chǎn)品開發(fā)策略應(yīng)該尋求在實現(xiàn)QTPP的同時最小化產(chǎn)品復(fù)雜性。較不復(fù)雜的產(chǎn)品可能比較復(fù)雜的產(chǎn)品具有更少的潛在的失效模式。隨著產(chǎn)品復(fù)雜性的降低，可以簡化產(chǎn)品和過程控制，這可以降低在日常商業(yè)制造過程中發(fā)生制造問題的風(fēng)險。

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

系統(tǒng)的質(zhì)量風(fēng)險評估和過程特征可以支持識別制造過程變量進行適當(dāng)?shù)目刂?，以生產(chǎn)具有可接受的CQAs的TDS產(chǎn)品。風(fēng)險評估還可以幫助確定某些關(guān)鍵材料屬性（CMAs）和關(guān)鍵工藝參數(shù)（CPPs）的穩(wěn)健性，如原材料特性、保持時間和平衡期

在申請中需要提交的材料請看下期——下半部分

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