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首頁 > 技術文章 > 經皮和局部給藥系統——產品開發和質量考量工業指南翻譯稿(上部分)

經皮和局部給藥系統——產品開發和質量考量工業指南翻譯稿(上部分)

更新時間:2023-03-08      點擊次數:778
 

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(ben)指(zhi)南為透皮和(he)(he)局(ju)部給藥系統(TDS)的申(shen)請人和(he)(he)制(zhi)造商提(ti)供了關于新藥應用(NDAs)和(he)(he)仿制(zhi)藥應用(ANDAs)中包(bao)含的藥物開(kai)發和(he)(he)質(zhi)量信(xin)息(xi)的建議(yi)。具體而言,該指(zhi)南討論了FDA目(mu)前在產品設計和(he)(he)藥物開(kai)發、制(zhi)造過(guo)程(cheng)和(he)(he)控制(zhi)以及成品控制(zhi)方面的思(si)考。它還(huan)針對質(zhi)量與(yu)產品性能密切相關的領域(yu)和(he)(he)潛在的安(an)全問題(ti)(如粘附性和(he)(he)受熱)提(ti)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,FDA的(de)指(zhi)(zhi)導文件沒有規定法(fa)律上(shang)可(ke)強制執(zhi)行的(de)責任。相反,指(zhi)(zhi)南描述了(le)機構當前對某(mou)一主題的(de)思考(kao),除非引用(yong)了(le)具體(ti)的(de)法(fa)規或法(fa)定要求,否(fou)則僅應(ying)視為建(jian)議。在(zai)機構指(zhi)(zhi)南中使用(yong)“應(ying)該(gai)”一詞意味著建(jian)議或推薦(jian),但(dan)不(bu)是必須的(de)。

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.

經皮遞(di)送(song)系統(tong)設(she)計(ji)用于將(jiang)活性(xing)成(cheng)分(fen)(藥物)遞(di)送(song)透過皮膚并進入全身(shen)循環,而局部遞(di)送(song)系統(tong)設(she)計(ji)為將(jiang)活性(xing)成(cheng)分(fen)遞(di)送(song)至(zhi)局部組(zu)織。兩種(zhong)輸送(song)系統(tong)都存在(zai)類(lei)似的(de)制造和質量(liang)控制問題,對患者(zhe)也存在(zai)類(lei)似的(de)風(feng)險。TDS可大致分(fen)為基質型和液體或(huo)凝膠(jiao)儲庫型輸送(song)系統(tong)。

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(ji)質型TDS含有一(yi)種(zhong)或多(duo)種(zhong)活(huo)性(xing)成分,其溶(rong)解或部(bu)分懸浮在(zai)各種(zhong)成分的混合物中(zhong),包(bao)(bao)括粘(zhan)合劑、滲(shen)透促(cu)進(jin)劑、柔軟劑和(he)防腐劑,通常使用溶(rong)劑、水(shui)凝膠或基(ji)于(yu)熱熔的方(fang)法制造(zao)。基(ji)質型TDS的示例如(ru)圖1所示,但基(ji)質型TDS可能(neng)包(bao)(bao)括額外(wai)的層和(he)/或更復(fu)雜的設計

圖1.基質(zhi)型透皮或(huo)局部給藥系統

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(chu)庫型TDS同樣包含(han)各種液體或半固(gu)體形式(shi)的組分;然而,儲(chu)庫型TDS利用熱密封區域(yu)將活性凝膠截(jie)留在背襯膜(mo)和微孔(kong)膜(mo)之間(jian)。儲(chu)庫類(lei)型TDS的示例如(ru)圖(tu)2所(suo)示。由于儲(chu)庫TDS固(gu)有(you)的故障(zhang)模式(shi)和安全風險,FDA建議TDS制造(zao)商和申(shen)請人將開發工作(zuo)重點放在基質(zhi)類(lei)型TDS上。

圖2儲庫型(xing)經皮(pi)或局部遞送系(xi)統

 

B.Regulatory Status/監管狀況

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.

經皮和局部(bu)(bu)遞送系統是21 CFR第3部(bu)(bu)分(fen)(fen)中定義(yi)的(de)組合(he)產(chan)品,必須符合(he)21 CFR第4部(bu)(bu)分(fen)(fen)A子部(bu)(bu)分(fen)(fen)(組合(he)產(chan)品的(de)現(xian)行(xing)良好生(sheng)產(chan)規范要(yao)求)。在21 CFR第4部(bu)(bu)分(fen)(fen)中,描述了21 CFR第210和211部(bu)(bu)分(fen)(fen)(藥物CGMP)和21 CFR第820部(bu)(bu)分(fen)(fen)(器械質量體系法規)的(de)要(yao)求如何適用于組合(he)產(chan)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(she)(she)計(ji)(ji)控(kong)制(zhi)(21 CFR第820.30部分)適用于包(bao)括(kuo)TDS在內的(de)(de)藥物器械(xie)組合產(chan)品。從本質(zhi)上講,設(she)(she)計(ji)(ji)控(kong)制(zhi)活動應確認(ren)組成部分之間不存(cun)在消(xiao)極作用,并確保其組合使(shi)用產(chan)生安全有效,且性能符(fu)合預期。藥物開發行業指南還涉及產(chan)品設(she)(she)計(ji)(ji)和開發程(cheng)序,反映了(le)設(she)(she)計(ji)(ji)原則的(de)(de)質(zhi)量。雖然設(she)(she)計(ji)(ji)質(zhi)量和設(she)(she)計(ji)(ji)控(kong)制(zhi)具有相(xiang)似的(de)(de)特征和目標(biao),但設(she)(she)備質(zhi)量體系法規(21 CFR第820部分)包(bao)括(kuo)制(zhi)造(zao)商(shang)必須滿足的(de)(de)設(she)(she)計(ji)(ji)開發的(de)(de)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(ru)國際協調會議ICH Q8(R2)所述,可(ke)(ke)以(yi)利用藥物開發的(de)(de)(de)許多方(fang)面來實現設計(ji)(ji)控制(zhi)的(de)(de)(de)合規性。例如(ru),質量(liang)目(mu)標產品(pin)(pin)(pin)概要(yao)(QTPP)(見下(xia)文第III.A.節)類似于“設計(ji)(ji)輸(shu)入”(21 CFR第820.30(c)部(bu)分),確(que)(que)保設計(ji)(ji)要(yao)求適合于解決產品(pin)(pin)(pin)的(de)(de)(de)預(yu)期用途。此外,為驗(yan)證成品(pin)(pin)(pin)是否(fou)滿足關(guan)鍵(jian)質量(liang)屬性(CQA)而進(jin)行的(de)(de)(de)研究也可(ke)(ke)能涉及設計(ji)(ji)“驗(yan)證”和“確(que)(que)認”要(yao)求(《美國聯邦(bang)(bang)法規》第21篇第820.30(f)、(g)部(bu)分),以(yi)確(que)(que)保產品(pin)(pin)(pin)的(de)(de)(de)“設計(ji)(ji)輸(shu)出”(《聯邦(bang)(bang)法規》21篇第820.30(d)部(bu)分)產生安全有效地達到(dao)預(yu)期效果的(de)(de)(de)產品(pin)(pin)(pin)。

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(bu)分(fen)概述(shu)(shu)了從藥物(wu)開(kai)(kai)發角度描(miao)述(shu)(shu)了產(chan)(chan)品和工藝的開(kai)(kai)發注(zhu)意(yi)事項。如(ru)(ru)上所述(shu)(shu),TDS產(chan)(chan)品的開(kai)(kai)發還必須(xu)符(fu)合(he)設計(ji)控制(zhi)(21 CFR第820.30部(bu)分(fen))。我們認識到,21 CFR第820.30部(bu)分(fen)中使(shi)用的術(shu)語可能與特定藥物(wu)開(kai)(kai)發計(ji)劃中使(shi)用的不同(tong)。申請人應該(gai)能夠與FDA溝通他們使(shi)用的術(shu)語如(ru)(ru)何(he)與設計(ji)控制(zhi)原則和要求(qiu)相關系。

A.Quality Target Product Profile/目(mu)標產品質量概況

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(zai)開發(fa)TDS之前,申請人應建立所需的(de)(de)質(zhi)量目(mu)標產品概要(yao)(QTPP)。QTPP是對TDS產品質(zhi)量特性(xing)的(de)(de)前瞻性(xing)總(zong)結,在(zai)考(kao)(kao)慮(lv)到產品的(de)(de)安(an)全性(xing)和(he)有效性(xing)的(de)(de)情況(kuang)下(xia),理想情況(kuang)下(xia)可(ke)實現該特性(xing)以確保所需的(de)(de)質(zhi)量(ICH Q8(R2))。一般來說,TDS的(de)(de)QTPP元素(su)(su)及其質(zhi)量考(kao)(kao)慮(lv)因(yin)素(su)(su)可(ke)能包(bao)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.

根據治療需(xu)要、患(huan)者群體(ti)(ti)或(huo)其他功能特性要求,可(ke)能存在其他QTPP元件。例(li)如,成品(pin)的(de)大小可(ke)以是QTPP元素,這(zhe)取決于產品(pin)在身(shen)體(ti)(ti)上的(de)應用(yong)位(wei)置,或(huo)者患(huan)者群體(ti)(ti)是否為兒(er)童。

B.Critical Quality Attributes/關鍵質量屬性

1.TDS Product/TDS產品

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開發過程的(de)(de)(de)(de)早期(qi),申請人應生(sheng)成一(yi)(yi)份潛在CQAs列(lie)表。CQAs是(shi)一(yi)(yi)種物(wu)理、化(hua)學(xue)、生(sheng)物(wu)或(huo)(huo)(huo)(huo)微生(sheng)物(wu)性質(zhi)或(huo)(huo)(huo)(huo)特性,應在適當的(de)(de)(de)(de)限度(du)、范圍或(huo)(huo)(huo)(huo)分(fen)布內(nei),以確保所需的(de)(de)(de)(de)產(chan)(chan)品(pin)質(zhi)量(liang)(ICH Q8(R2))。產(chan)(chan)品(pin)QTPP的(de)(de)(de)(de)知(zhi)識,結合(he)先前的(de)(de)(de)(de)知(zhi)識、風險評估和(he)/或(huo)(huo)(huo)(huo)實驗(yan),可用于制定產(chan)(chan)品(pin)CQAs列(lie)表。每個CQA(單(dan)獨或(huo)(huo)(huo)(huo)與一(yi)(yi)個或(huo)(huo)(huo)(huo)多個其他CQA聯合(he))應與TDS產(chan)(chan)品(pin)QTPP的(de)(de)(de)(de)一(yi)(yi)個或(huo)(huo)(huo)(huo)更多元素相(xiang)關。產(chan)(chan)品(pin)CQAs列(lie)表可以隨(sui)著產(chan)(chan)品(pin)開發的(de)(de)(de)(de)進展和(he)新知(zhi)識的(de)(de)(de)(de)獲(huo)得而(er)修(xiu)改(gai)。申請中還應確定原料藥、輔料、成分(fen)和(he)包(bao)裝容器系(xi)統的(de)(de)(de)(de)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(dui)于TDS,CQAs通常包括(kuo)外觀(guan)(例如(ru)無可見晶(jing)體)、尺(chi)寸(cun)、劑(ji)(ji)(ji)量單(dan)位(wei)的均勻性、測(ce)定方法、滲透促進劑(ji)(ji)(ji)的含(han)量、雜(za)質和(he)降解物(wu)(wu)、體外藥物(wu)(wu)釋放概況、防(fang)腐劑(ji)(ji)(ji)/抗(kang)氧化劑(ji)(ji)(ji)含(han)量(如(ru)果有(you))、剝離強(qiang)度、粘性、剝離襯(chen)墊剝離強(qiang)度、剪切強(qiang)度、冷流、殘(can)留溶劑(ji)(ji)(ji)、殘(can)留單(dan)體、微(wei)生物(wu)(wu)限度、以(yi)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.

應根(gen)據可影響(xiang)TDS產品(pin)性(xing)(xing)能(neng)及其可制造性(xing)(xing)的(de)(de)藥(yao)物(wu)的(de)(de)物(wu)理化學和(he)生物(wu)特(te)性(xing)(xing)來證明(ming)原(yuan)料藥(yao)的(de)(de)選擇是合理的(de)(de)。特(te)別是,應考(kao)慮影響(xiang)遞送速率的(de)(de)性(xing)(xing)質,如分子量(liang)、熔點、分配系數log P、電離(li)常數pKa、水溶(rong)性(xing)(xing)和(he)pH。應根(gen)據產品(pin)性(xing)(xing)能(neng)評(ping)估和(he)證明(ming)藥(yao)物(wu)的(de)(de)其他特(te)性(xing)(xing),如顆粒大小(xiao)、晶體形式和(he)多(duo)態性(xing)(xing)。

3.Excipients and Components/輔(fu)料及(ji)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(fu)料和成分可以包(bao)括各(ge)種粘(zhan)合(he)劑(ji)、滲透促進劑(ji)、速率控(kong)制或非(fei)速率控(kong)制膜、增(zeng)(zeng)溶劑(ji)、增(zeng)(zeng)塑劑(ji)/軟化劑(ji)或增(zeng)(zeng)稠劑(ji),所(suo)有這些(xie)都會(hui)影響TDS的質量和性能屬性

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.

關鍵賦形劑(ji)(ji)和成分的(de)嚴格確(que)認對于確(que)保透皮和外用(yong)制劑(ji)(ji)的(de)最(zui)佳產品質量(liang)屬性(xing)非常(chang)重要,并有(you)助于原材料、制造工藝(yi)或供應商變更(geng)的(de)批準后變更(geng)流(liu)程(cheng)。

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

例(li)如,在鑒定(ding)TDS產品(pin)中的粘合劑時,申請人應考慮以下屬性(xing):

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(yuan)料的粘(zhan)合劑(ji)聚合物:分子量、多分散性、光譜分析(例如(ru),紅外光譜(IR)吸收(shou))、熱分析、固有或(huo)復合粘(zhan)度(du),以及殘余單體(ti)、二聚體(ti)、溶劑(ji)、重金屬、催化(hua)劑(ji)和引(yin)發劑(ji)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(dui)于作為層壓板的粘合劑(ji)(ji)(ji)(在沒(mei)有活性成分(fen)和其他賦形(xing)劑(ji)(ji)(ji)的情況下):殘余溶劑(ji)(ji)(ji)、剝離、粘性、剪(jian)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.

對于最終產品中的粘(zhan)合劑(以(yi)及(ji)藥(yao)(yao)物和(he)其他(ta)賦形劑和(he)成分):鑒定、殘留單(dan)體(ti)、二聚體(ti)和(he)溶劑;雜質;干燥損失(shi);以(yi)及(ji)均(jun)勻性(xing)。要(yao)考慮(lv)的其他(ta)性(xing)質包括粘(zhan)彈(dan)性(xing)性(xing)質(如彈(dan)性(xing)模(mo)量(G')、粘(zhan)性(xing)模(mo)量(G”)和(he)蠕(ru)變(bian)順應性(xing)(J)),以(yi)及(ji)功(gong)能性(xing)質,包括但不(bu)限于剝離、剪切、粘(zhan)附、粘(zhan)性(xing)、體(ti)外藥(yao)(yao)物釋放和(he)體(ti)外藥(yao)(yao)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(cai)料的(de)(de)(de)粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)的(de)(de)(de)性質(例(li)如(ru),流(liu)(liu)變學,包括固有(you)粘(zhan)(zhan)(zhan)(zhan)度(du)和復合(he)(he)粘(zhan)(zhan)(zhan)(zhan)度(du))會(hui)影響最終(zhong)產品的(de)(de)(de)質量屬性。粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)供應(ying)(ying)商(shang)(shang)的(de)(de)(de)規格通常很寬;因此,在(zai)產品的(de)(de)(de)整個(ge)生命周(zhou)期中接收的(de)(de)(de)粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)原料在(zai)粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)供應(ying)(ying)商(shang)(shang)的(de)(de)(de)規格范圍內可(ke)能會(hui)有(you)很大差(cha)異(yi)。例(li)如(ru),TDS關鍵體內試驗(yan)中使用的(de)(de)(de)粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)批(pi)次的(de)(de)(de)流(liu)(liu)變特性(例(li)如(ru)生物等效性(BE)、藥(yao)代動力學(PK)、粘(zhan)(zhan)(zhan)(zhan)附研究)可(ke)能與供應(ying)(ying)商(shang)(shang)先前制(zhi)造的(de)(de)(de)粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)批(pi)次或其未(wei)來(lai)生產的(de)(de)(de)粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)批(pi)次不一(yi)致。因此,申請人(ren)應(ying)(ying)要求粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)制(zhi)造商(shang)(shang)提供歷(li)史流(liu)(liu)變學值(zhi),以便更(geng)好地了解其工藝能力以及粘(zhan)(zhan)(zhan)(zhan)合(he)(he)劑(ji)(ji)(ji)流(liu)(liu)變學變化對最終(zhong)產品的(de)(de)(de)潛在(zai)影響。這可(ke)以進一(yi)步幫助申請人(ren)評估是否需要建立(li)或加強原材(cai)料內部控制(zhi)。

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(ping)估和(he)(he)適當控制TDS產品其(qi)他(ta)關鍵部分的類似質量屬性,將(jiang)增(zeng)強產品和(he)(he)過程(cheng)對TDS整個生命周期的理解。

4.Identifying Labeling/標(biao)簽(qian)確認

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(qing)人(ren)在開發初期加(jia)入具(ju)有代表性的標簽(qian)(qian),以確保用(yong)于印刷的標簽(qian)(qian)工藝或油(you)墨不會(hui)與(yu)TDS產品(pin)相互作用(yong),并在可提取和(he)可浸出研究期間適當評(ping)估(gu)油(you)墨。識別標簽(qian)(qian)通常放置(zhi)在TDS的背膜上,并且至少應該包括產品(pin)名(ming)稱和(he)規格

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(ming)、半透明(ming)或顏色(se)(se)與人(ren)類膚色(se)(se)相匹配的(de)(de)透皮系(xi)統和外用(yong)系(xi)統可(ke)能(neng)難(nan)以(yi)在患(huan)者(zhe)身(shen)(shen)上找(zhao)到TDS,并(bing)且當(dang)患(huan)者(zhe)或護理人(ren)員未能(neng)移除舊TDS并(bing)一次應用(yong)多(duo)個TDS時,會(hui)導(dao)致用(yong)藥(yao)錯誤(wu)。如果透明(ming)或半透明(ming)的(de)(de) TDS 過早地從(cong)患(huan)者(zhe)身(shen)(shen)上脫落,也可(ke)能(neng)很難(nan)找(zhao)到,從(cong)而增加了醫療保健提供者(zhe)、護理者(zhe)或兒童(tong)二次或意外接(jie)觸藥(yao)物的(de)(de)可(ke)能(neng)性。因此,我們建議使用(yong)具(ju)有足夠對比度的(de)(de)油墨印刷(shua)背襯膜,并(bing)在系(xi)統使用(yong)期間和處(chu)理后保持可(ke)見。

C.Product and Process Development/產品(pin)與工藝(yi)開(kai)發

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(de)設計質(zhi)量(liang)原則(QbD)和藥物(wu)開發(fa)要素應在(zai)TDS的(de)整個生命周期中應用,以確保(bao)TDS產品具有(you)特性和強度,并滿(man)足《聯邦食品、藥品和化(hua)妝品法案》(FD&C法案)第501(a)(2)(B)節要求(qiu)的(de)質(zhi)量(liang)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(ke)以像溶解在單一粘合劑(ji)中的單一藥物一樣簡單,也可(ke)以是高(gao)度復雜(za)的多組分(fen)、多粘合劑(ji)、多層(ceng)壓基(ji)質。TDS中的輔(fu)料和(he)成分(fen)可(ke)包括(kuo)各(ge)種粘合劑(ji)系統、滲透促進(jin)劑(ji)、控釋(shi)或非控釋(shi)膜、增溶劑(ji)、增塑(su)劑(ji)/柔軟(ruan)劑(ji)或增稠劑(ji)。

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(wei)一項普遍原則,產(chan)品(pin)開發(fa)策略應該尋(xun)求在(zai)實現QTPP的(de)(de)同時最(zui)小(xiao)化產(chan)品(pin)復雜(za)性。較(jiao)(jiao)不復雜(za)的(de)(de)產(chan)品(pin)可(ke)能比較(jiao)(jiao)復雜(za)的(de)(de)產(chan)品(pin)具有更(geng)少的(de)(de)潛在(zai)的(de)(de)失效模式。隨著(zhu)產(chan)品(pin)復雜(za)性的(de)(de)降低,可(ke)以(yi)簡化產(chan)品(pin)和過程控制,這可(ke)以(yi)降低在(zai)日常(chang)商(shang)業制造過程中發(fa)生制造問題的(de)(de)風險。

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

系統的質量風險評估和(he)過程特征可(ke)以支(zhi)持識別制(zhi)造過程變量進行適(shi)當的控制(zhi),以生產具有可(ke)接受的CQAs的TDS產品。風險評估還可(ke)以幫助確定某些關鍵材料屬性(xing)(CMAs)和(he)關鍵工藝參(can)數(CPPs)的穩健性(xing),如原(yuan)材料特性(xing)、保持時間(jian)和(he)平衡期

 

在申請中需要提交的(de)材料請看下期——下半部分(fen)

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