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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:1068
 

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(he)(he)(he)局(ju)部給藥(yao)系統(TDS)的(de)(de)(de)(de)申請人和(he)(he)(he)制(zhi)造商提(ti)供(gong)了關于新(xin)藥(yao)應用(NDAs)和(he)(he)(he)仿制(zhi)藥(yao)應用(ANDAs)中(zhong)包含(han)的(de)(de)(de)(de)藥(yao)物開(kai)發和(he)(he)(he)質(zhi)量信息(xi)的(de)(de)(de)(de)建議。具體(ti)而言,該指南討(tao)論了FDA目前(qian)在(zai)產(chan)品設計(ji)和(he)(he)(he)藥(yao)物開(kai)發、制(zhi)造過程和(he)(he)(he)控制(zhi)以(yi)及成品控制(zhi)方面的(de)(de)(de)(de)思(si)考。它還針對(dui)質(zhi)量與產(chan)品性能密切相關的(de)(de)(de)(de)領域和(he)(he)(he)潛在(zai)的(de)(de)(de)(de)安(an)全問(wen)題(如粘附性和(he)(he)(he)受熱)提(ti)出(chu)了特(te)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(yi)般來(lai)說,FDA的(de)指(zhi)導文(wen)件沒(mei)有規定法律上可強(qiang)制執(zhi)行的(de)責任。相反,指(zhi)南描述了(le)機(ji)構(gou)(gou)當前對某一(yi)主題的(de)思考(kao),除非引用了(le)具體(ti)的(de)法規或(huo)法定要(yao)求,否則僅應視為(wei)建(jian)議。在機(ji)構(gou)(gou)指(zhi)南中使用“應該”一(yi)詞意味著建(jian)議或(huo)推薦,但不是必(bi)須(xu)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(pi)遞(di)送(song)(song)(song)(song)系統設計用(yong)于(yu)將(jiang)活性成(cheng)分(藥物)遞(di)送(song)(song)(song)(song)透過皮(pi)膚并進入(ru)全(quan)身循環,而局部(bu)(bu)遞(di)送(song)(song)(song)(song)系統設計為將(jiang)活性成(cheng)分遞(di)送(song)(song)(song)(song)至局部(bu)(bu)組織(zhi)。兩種輸送(song)(song)(song)(song)系統都存在(zai)類(lei)似的(de)制造和質(zhi)量控制問題,對患者也(ye)存在(zai)類(lei)似的(de)風險。TDS可大致分為基質(zhi)型(xing)和液體或凝膠(jiao)儲庫型(xing)輸送(song)(song)(song)(song)系統。

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(zhi)型(xing)TDS含有一種或多(duo)種活性成(cheng)分(fen),其溶解或部分(fen)懸浮在(zai)各(ge)種成(cheng)分(fen)的(de)(de)混合(he)物(wu)中,包括粘合(he)劑、滲透(tou)促進劑、柔(rou)軟劑和(he)防腐劑,通常使用溶劑、水(shui)凝(ning)膠(jiao)或基(ji)于熱熔的(de)(de)方(fang)法(fa)制(zhi)造。基(ji)質(zhi)型(xing)TDS的(de)(de)示(shi)例如圖1所(suo)示(shi),但基(ji)質(zhi)型(xing)TDS可能包括額外(wai)的(de)(de)層和(he)/或更復雜(za)的(de)(de)設計

圖1.基質型透皮(pi)或局(ju)部給(gei)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(xing)TDS同樣包含各種液(ye)體或半固體形(xing)式(shi)的組分;然而,儲(chu)庫型(xing)TDS利(li)用熱密封區域將活(huo)性凝膠截留在(zai)(zai)背襯膜(mo)和微孔膜(mo)之間。儲(chu)庫類型(xing)TDS的示例如(ru)圖(tu)2所示。由于(yu)儲(chu)庫TDS固有的故障模式(shi)和安全風險(xian),FDA建議TDS制(zhi)造商和申請人將開發工作重(zhong)點放在(zai)(zai)基質(zhi)類型(xing)TDS上。

圖2儲庫型(xing)經皮(pi)或局部遞送系統(tong)

 

B.Regulatory Status/監(jian)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)(bu)遞(di)送系(xi)(xi)統是21 CFR第3部(bu)(bu)(bu)分(fen)(fen)中定(ding)義的組合(he)產品,必須符合(he)21 CFR第4部(bu)(bu)(bu)分(fen)(fen)A子部(bu)(bu)(bu)分(fen)(fen)(組合(he)產品的現(xian)行良好生產規(gui)范要(yao)求)。在21 CFR第4部(bu)(bu)(bu)分(fen)(fen)中,描(miao)述了21 CFR第210和211部(bu)(bu)(bu)分(fen)(fen)(藥物CGMP)和21 CFR第820部(bu)(bu)(bu)分(fen)(fen)(器(qi)械質(zhi)量體系(xi)(xi)法規(gui))的要(yao)求如何適用于(yu)組合(he)產品。

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)(she)計(ji)(ji)控(kong)制(zhi)(21 CFR第(di)820.30部分)適用于包(bao)括TDS在內(nei)的(de)藥物器械組合(he)(he)產(chan)品(pin)。從本質上講,設(she)(she)(she)計(ji)(ji)控(kong)制(zhi)活動應確(que)認(ren)組成部分之間不存在消極作用,并(bing)確(que)保其組合(he)(he)使(shi)用產(chan)生安全有效,且(qie)性能符(fu)合(he)(he)預期。藥物開(kai)發行業指南還涉及(ji)產(chan)品(pin)設(she)(she)(she)計(ji)(ji)和(he)(he)開(kai)發程序,反映了設(she)(she)(she)計(ji)(ji)原則的(de)質量。雖然(ran)設(she)(she)(she)計(ji)(ji)質量和(he)(he)設(she)(she)(she)計(ji)(ji)控(kong)制(zhi)具(ju)有相(xiang)似的(de)特征和(he)(he)目標,但設(she)(she)(she)備質量體系法規(21 CFR第(di)820部分)包(bao)括制(zhi)造商必須(xu)滿足的(de)設(she)(she)(she)計(ji)(ji)開(kai)發的(de)具(ju)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(xie)調會(hui)議ICH Q8(R2)所述,可以利用藥物(wu)開發(fa)的(de)許多方(fang)面來實現(xian)設(she)計(ji)(ji)控制的(de)合規(gui)性。例(li)如,質(zhi)量目(mu)標(biao)產(chan)品(pin)概要(QTPP)(見下文第(di)III.A.節(jie))類似于(yu)“設(she)計(ji)(ji)輸入”(21 CFR第(di)820.30(c)部(bu)分),確(que)保(bao)設(she)計(ji)(ji)要求(qiu)適合于(yu)解決產(chan)品(pin)的(de)預期用途。此外,為驗證成品(pin)是(shi)否(fou)滿足關鍵質(zhi)量屬(shu)性(CQA)而進行的(de)研究(jiu)也可能涉及(ji)設(she)計(ji)(ji)“驗證”和“確(que)認”要求(qiu)(《美國聯邦法規(gui)》第(di)21篇第(di)820.30(f)、(g)部(bu)分),以確(que)保(bao)產(chan)品(pin)的(de)“設(she)計(ji)(ji)輸出(chu)”(《聯邦法規(gui)》21篇第(di)820.30(d)部(bu)分)產(chan)生安(an)全有效地達到預期效果的(de)產(chan)品(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)概述了從(cong)藥(yao)物開(kai)(kai)(kai)發角度描述了產(chan)品和(he)工藝的開(kai)(kai)(kai)發注意事項。如上(shang)所述,TDS產(chan)品的開(kai)(kai)(kai)發還(huan)必須符合設計控(kong)制(21 CFR第820.30部(bu)分(fen))。我們認識到,21 CFR第820.30部(bu)分(fen)中(zhong)(zhong)使用(yong)的術語(yu)可能與(yu)特定(ding)藥(yao)物開(kai)(kai)(kai)發計劃中(zhong)(zhong)使用(yong)的不同(tong)。申(shen)請(qing)人應該能夠與(yu)FDA溝通他們使用(yong)的術語(yu)如何與(yu)設計控(kong)制原則和(he)要求相關系。

A.Quality Target Product Profile/目(mu)標產品質量(liang)概(gai)況(kuang)

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(kai)發TDS之前,申請人應建立所需的質(zhi)量目標產品概要(QTPP)。QTPP是對TDS產品質(zhi)量特性(xing)(xing)(xing)的前瞻性(xing)(xing)(xing)總(zong)結,在考(kao)慮(lv)到產品的安全性(xing)(xing)(xing)和有效性(xing)(xing)(xing)的情況下,理想情況下可實現該特性(xing)(xing)(xing)以確保所需的質(zhi)量(ICH Q8(R2))。一般來說,TDS的QTPP元素(su)及其質(zhi)量考(kao)慮(lv)因素(su)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(ju)治(zhi)療(liao)需要、患者群體(ti)或(huo)其他功能特性要求,可能存在(zai)其他QTPP元件。例如(ru),成品的大(da)小(xiao)可以是QTPP元素,這取決于產品在(zai)身(shen)體(ti)上的應用位置,或(huo)者患者群體(ti)是否為兒童。

B.Critical Quality Attributes/關鍵質量屬(shu)性(xing)

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(kai)發過程的早(zao)期,申請人應(ying)生(sheng)成一(yi)份潛(qian)在CQAs列表。CQAs是一(yi)種物理、化學(xue)、生(sheng)物或(huo)(huo)微生(sheng)物性(xing)質或(huo)(huo)特性(xing),應(ying)在適當的限度、范圍或(huo)(huo)分布內,以(yi)確保(bao)所需的產品(pin)(pin)(pin)(pin)質量(ICH Q8(R2))。產品(pin)(pin)(pin)(pin)QTPP的知(zhi)識,結合先前的知(zhi)識、風(feng)險評估和/或(huo)(huo)實驗,可用于(yu)制(zhi)定(ding)(ding)產品(pin)(pin)(pin)(pin)CQAs列表。每(mei)個(ge)CQA(單獨或(huo)(huo)與(yu)一(yi)個(ge)或(huo)(huo)多(duo)個(ge)其他CQA聯合)應(ying)與(yu)TDS產品(pin)(pin)(pin)(pin)QTPP的一(yi)個(ge)或(huo)(huo)更多(duo)元(yuan)素相關。產品(pin)(pin)(pin)(pin)CQAs列表可以(yi)隨著產品(pin)(pin)(pin)(pin)開(kai)發的進展(zhan)和新(xin)知(zhi)識的獲得(de)而修改。申請中(zhong)還應(ying)確定(ding)(ding)原料(liao)藥、輔料(liao)、成分和包裝(zhuang)容器系統(tong)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(chang)包括外(wai)觀(例如無可見晶體(ti)(ti)(ti))、尺寸、劑量單位的均勻性(xing)、測定方(fang)法(fa)、滲透促(cu)進劑的含量、雜質和降解物(wu)、體(ti)(ti)(ti)外(wai)藥物(wu)釋放概況、防(fang)腐(fu)劑/抗氧化劑含量(如果有)、剝離強(qiang)度、粘(zhan)性(xing)、剝離襯墊(dian)剝離強(qiang)度、剪切強(qiang)度、冷流、殘留(liu)溶劑、殘留(liu)單體(ti)(ti)(ti)、微生物(wu)限度、以及包裝完整性(xing)。

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(ju)可(ke)影響TDS產品(pin)性(xing)(xing)能(neng)及其可(ke)制造性(xing)(xing)的(de)(de)藥(yao)(yao)物(wu)的(de)(de)物(wu)理化學和(he)(he)生物(wu)特(te)性(xing)(xing)來證(zheng)明原料藥(yao)(yao)的(de)(de)選擇是合理的(de)(de)。特(te)別是,應考慮(lv)影響遞送速率的(de)(de)性(xing)(xing)質(zhi),如分(fen)子量、熔點、分(fen)配系(xi)數log P、電(dian)離常(chang)數pKa、水(shui)溶性(xing)(xing)和(he)(he)pH。應根(gen)據(ju)產品(pin)性(xing)(xing)能(neng)評估和(he)(he)證(zheng)明藥(yao)(yao)物(wu)的(de)(de)其他特(te)性(xing)(xing),如顆粒(li)大小、晶(jing)體形式和(he)(he)多態(tai)性(xing)(xing)。

3.Excipients and Components/輔料(liao)及成(cheng)分(fen)

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(de)輔料(liao)和成分(fen)可以(yi)包括(kuo)各種粘合(he)劑(ji)、滲透促(cu)進(jin)劑(ji)、速率控制或非速率控制膜、增溶劑(ji)、增塑劑(ji)/軟(ruan)化劑(ji)或增稠劑(ji),所有(you)這些都會影(ying)響(xiang)TDS的(de)質(zhi)量和性(xing)能屬(shu)性(xing)

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(xing)劑和(he)成分的(de)嚴格(ge)確(que)認對于確(que)保透皮和(he)外用制劑的(de)最佳產品質量(liang)屬性非常重(zhong)要,并有助于原材(cai)料、制造工藝或(huo)供應商變更(geng)的(de)批準后變更(geng)流程(cheng)。

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

例如,在鑒定TDS產品中的粘(zhan)合劑(ji)時(shi),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(dui)于作為原料的粘合劑聚合物(wu):分(fen)子量(liang)、多分(fen)散性、光譜(pu)分(fen)析(xi)(例如,紅外光譜(pu)(IR)吸收)、熱(re)分(fen)析(xi)、固(gu)有或復合粘度,以及殘(can)余單體、二聚體、溶劑、重金屬、催化劑和引發劑的測量(liang)。

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(zuo)為層壓板(ban)的(de)粘合(he)劑(ji)(ji)(在沒有活性成(cheng)分(fen)和其他賦形(xing)劑(ji)(ji)的(de)情況下(xia)):殘余溶劑(ji)(ji)、剝離(li)、粘性、剪切(qie)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(zui)終產品中的粘(zhan)合劑(ji)(ji)(以及藥物(wu)和其他賦形(xing)劑(ji)(ji)和成分):鑒定、殘留單體(ti)、二聚體(ti)和溶劑(ji)(ji);雜質;干燥損失;以及均勻性(xing)(xing)。要考慮的其他性(xing)(xing)質包括粘(zhan)彈性(xing)(xing)性(xing)(xing)質(如彈性(xing)(xing)模量(liang)(G')、粘(zhan)性(xing)(xing)模量(liang)(G”)和蠕變順應(ying)性(xing)(xing)(J)),以及功能性(xing)(xing)質,包括但不限(xian)于剝離(li)、剪切、粘(zhan)附(fu)、粘(zhan)性(xing)(xing)、體(ti)外(wai)藥物(wu)釋放和體(ti)外(wai)藥物(wu)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(yuan)材料(liao)的(de)(de)(de)(de)粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)的(de)(de)(de)(de)性(xing)(xing)質(zhi)(例如,流變(bian)(bian)學(xue)(xue),包括(kuo)固有粘(zhan)(zhan)度和(he)復合(he)粘(zhan)(zhan)度)會影(ying)響最(zui)終產品的(de)(de)(de)(de)質(zhi)量屬性(xing)(xing)。粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)供應商的(de)(de)(de)(de)規(gui)格(ge)通常很(hen)寬;因(yin)(yin)此,在產品的(de)(de)(de)(de)整個生(sheng)命周期中接收(shou)的(de)(de)(de)(de)粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)原(yuan)料(liao)在粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)供應商的(de)(de)(de)(de)規(gui)格(ge)范圍(wei)內可能會有很(hen)大差(cha)異。例如,TDS關鍵體內試(shi)驗中使用(yong)的(de)(de)(de)(de)粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)批次(ci)的(de)(de)(de)(de)流變(bian)(bian)特性(xing)(xing)(例如生(sheng)物(wu)等效性(xing)(xing)(BE)、藥代動力(li)學(xue)(xue)(PK)、粘(zhan)(zhan)附研究)可能與(yu)供應商先前制造的(de)(de)(de)(de)粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)批次(ci)或其(qi)未來生(sheng)產的(de)(de)(de)(de)粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)批次(ci)不(bu)一致。因(yin)(yin)此,申請人應要(yao)求粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)制造商提供歷史(shi)流變(bian)(bian)學(xue)(xue)值,以(yi)便更好地了解其(qi)工藝能力(li)以(yi)及(ji)粘(zhan)(zhan)合(he)劑(ji)(ji)(ji)(ji)流變(bian)(bian)學(xue)(xue)變(bian)(bian)化對最(zui)終產品的(de)(de)(de)(de)潛在影(ying)響。這(zhe)可以(yi)進一步(bu)幫助(zhu)申請人評估是否需要(yao)建立或加強原(yuan)材料(liao)內部控制。

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(gu)和適當(dang)控制TDS產品其他關鍵(jian)部分的類(lei)似質(zhi)量屬性(xing),將(jiang)增強產品和過程(cheng)對(dui)TDS整個生(sheng)命周期的理(li)解(jie)。

4.Identifying Labeling/標簽確認

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

鼓勵申請人(ren)在開(kai)發初期加入具有代表性的(de)標簽,以確保用于印(yin)刷的(de)標簽工藝或油墨不會與TDS產(chan)品(pin)(pin)相互作用,并在可提取和(he)可浸出研究期間適當評(ping)估油墨。識(shi)別(bie)標簽通常放置在TDS的(de)背膜(mo)上,并且至少應該(gai)包括(kuo)產(chan)品(pin)(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)(ming)、半透明(ming)(ming)或(huo)顏色與人類膚色相(xiang)匹(pi)配的透皮系統和外(wai)用(yong)(yong)系統可(ke)(ke)能(neng)(neng)難(nan)以在患者身上找到TDS,并(bing)且當患者或(huo)護(hu)理(li)人員未能(neng)(neng)移除舊TDS并(bing)一次(ci)應用(yong)(yong)多(duo)個(ge)TDS時,會導致(zhi)用(yong)(yong)藥(yao)錯(cuo)誤。如(ru)果透明(ming)(ming)或(huo)半透明(ming)(ming)的 TDS 過早地(di)從患者身上脫落,也可(ke)(ke)能(neng)(neng)很(hen)難(nan)找到,從而增加了醫療保健提供者、護(hu)理(li)者或(huo)兒童二(er)次(ci)或(huo)意外(wai)接(jie)觸藥(yao)物(wu)的可(ke)(ke)能(neng)(neng)性(xing)。因此,我(wo)們建(jian)議使用(yong)(yong)具有足夠對比度的油墨印(yin)刷背(bei)襯膜,并(bing)在系統使用(yong)(yong)期間和處理(li)后保持(chi)可(ke)(ke)見。

C.Product and Process Development/產品與(yu)工藝開發

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中討論的設計質量原(yuan)則(QbD)和藥物開發要素(su)應在TDS的整(zheng)個生命周(zhou)期中應用,以(yi)確保TDS產品(pin)具有(you)特(te)性和強度,并滿足《聯邦食品(pin)、藥品(pin)和化妝品(pin)法案》(FD&C法案)第501(a)(2)(B)節(jie)要求(qiu)的質量和純度特(te)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(xiang)溶解在單(dan)一粘合(he)劑(ji)(ji)中(zhong)的(de)單(dan)一藥物(wu)一樣簡單(dan),也可(ke)以是(shi)高(gao)度復(fu)雜的(de)多組分、多粘合(he)劑(ji)(ji)、多層壓基質。TDS中(zhong)的(de)輔料和成分可(ke)包括各種粘合(he)劑(ji)(ji)系(xi)統、滲透促進劑(ji)(ji)、控(kong)釋或非控(kong)釋膜、增溶劑(ji)(ji)、增塑劑(ji)(ji)/柔軟劑(ji)(ji)或增稠劑(ji)(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(yi)項普(pu)遍原(yuan)則,產(chan)品(pin)開發策略(lve)應該尋求在實現QTPP的(de)同(tong)時(shi)最小(xiao)化產(chan)品(pin)復(fu)(fu)(fu)雜(za)性(xing)。較不(bu)復(fu)(fu)(fu)雜(za)的(de)產(chan)品(pin)可(ke)能(neng)比較復(fu)(fu)(fu)雜(za)的(de)產(chan)品(pin)具有更少的(de)潛在的(de)失效模式。隨著產(chan)品(pin)復(fu)(fu)(fu)雜(za)性(xing)的(de)降(jiang)低(di),可(ke)以簡化產(chan)品(pin)和過程控制(zhi),這可(ke)以降(jiang)低(di)在日常商業(ye)制(zhi)造過程中發生制(zhi)造問題的(de)風險(xian)。

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(de)質量(liang)風(feng)險評(ping)估和(he)(he)過程(cheng)特(te)征可(ke)以(yi)支(zhi)持(chi)識別(bie)制(zhi)造過程(cheng)變量(liang)進(jin)行(xing)適當(dang)的(de)控制(zhi),以(yi)生產具有(you)可(ke)接受的(de)CQAs的(de)TDS產品。風(feng)險評(ping)估還可(ke)以(yi)幫(bang)助(zhu)確定(ding)某(mou)些關(guan)鍵材料(liao)屬(shu)性(xing)(CMAs)和(he)(he)關(guan)鍵工藝參數(CPPs)的(de)穩健性(xing),如原材料(liao)特(te)性(xing)、保持(chi)時(shi)間和(he)(he)平衡期(qi)

 

在申請中需要提交的材料(liao)請看下(xia)期——下(xia)半(ban)部分

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