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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(下部分)

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(下部分)

更新時間:2023-03-24      點擊次數:707

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An applicant must provide technical data and information in sufficient detail to permit the Agency to make a knowledgeable judgment about whether to approve the application or whether grounds exist under section 505(d) or 505(j) of the FD&C Act to refuse to approve the application. This includes information about the drug substance and information about the TDS product.

申(shen)請人必須提供足夠詳細(xi)的技術數據和信息,以(yi)使FDA能夠對是否(fou)批(pi)準申(shen)請做出明智(zhi)的判斷,或(huo)者是否(fou)存(cun)在《FD&C法案》第505(d)或(huo)505(j)節規定的拒絕批(pi)準申(shen)請的理由(you)。這包括關(guan)于藥物物質的信息和關(guan)于TDS產品的信息。

The following sections provide recommendations to applicants about pharmaceutical development and quality information to be included in the application sections described in ICH M4Q.

以(yi)下各部(bu)分向(xiang)申請(qing)人提(ti)供了關于藥物開發和質量信(xin)息的建(jian)議,這些信(xin)息將包含在ICH M4Q中所述的應用章節(jie)中.


A.Pharmaceutical Development/藥物(wu)研發(fa)

As described in ICH M4Q, section 3.2.P.2 of the application should contain information on studies conducted to establish that the dosage form, formulation, manufacturing process, container closure system, microbiological attributes, and usage instructions specified in the application are appropriate for the intended use of the TDS product. The applicant should address the following:

如(ru)ICH M4Q第3.2.P.2節所述。申請(qing)應(ying)包含進行研究的信(xin)息,以確定申請(qing)中規定的劑型、配方、制造工藝、容器閉合系統、微(wei)生物屬性和使用說明適用于TDS產品的預(yu)期(qi)用途。申請(qing)人應(ying)解決以下問題:

lA descr1ption of the QTPP/QTPP說明

lA list of the CQAs of the TDS product, along with the limit, range, or distribution associated with each CQA and appropriate justification. TDS產品的(de)CQAs列表,以及與每(mei)個(ge)CQAs相關的(de)限制、范圍或分(fen)布(bu)以及適當的(de)理由。

lIdentification of those aspects of the drug substance, excipients, container closure system, and manufacturing processes important to attaining product quality.  API、賦形(xing)劑、包(bao)裝容器系(xi)統(tong)和制造工(gong)藝對實現產品質量至關重要的方面的識別。

In particular, the selection of excipients and components, their concentrations (as appropriate), and their functional characteristics affecting TDS performance should be discussed. For example, the applicant should describe the impact of penetration enhancers on the adhesive properties of the TDS, solubility of the drug substance in the blend, and skin permeation. 特別應討論影響TDS性能的賦形劑和成分的選擇、其濃度(視情況而定)及其功能特性。例如,申請人應描述滲透促進劑對TDS的粘合性能、API在混合物中的溶解度和皮膚滲透的影響。

Applicants should specify the allowable ranges around the process parameters and material attributes that have a potential to impact TDS product CQAs with justification and describe how they will be monitored. 申請人應說明可能影響TDS產品CQA的工藝參數和材料屬性的允許范圍,并說明如何對其進行監控。

lA descr1ption of the quality risk assessments, potential failure modes, and product and process control strategies/質量(liang)風險評(ping)估、潛在故障模式(shi)以及產(chan)品和過(guo)程控制策(ce)略(lve)的描述。

1.Batch Formula/批次處方

For processes that use solvated raw materials, batch formulas should be designed to tolerate variation in the solvent content of raw materials. Drug substance overages and excipient excesses can be added to a batch to account for evaporation during drying, but the amount of overage or excess should be controlled and justified by process development studies. Applicants should describe any cross-linking reactions since these reactions impact the chemical composition and quality of the finished product.

對于使用溶劑(ji)(ji)化(hua)原料(liao)(liao)的(de)(de)工藝,批(pi)次配方的(de)(de)設計應能承(cheng)受原料(liao)(liao)溶劑(ji)(ji)的(de)(de)含量(liang)(liang)變化(hua)。過量(liang)(liang)的(de)(de)API和(he)過量(liang)(liang)的(de)(de)輔料(liao)(liao)可添加到批(pi)次中,以(yi)解(jie)決(jue)干燥過程中的(de)(de)蒸(zheng)發問題,但(dan)過量(liang)(liang)或過量(liang)(liang)的(de)(de)量(liang)(liang)應通過工藝開發研究加以(yi)控制(zhi)和(he)證明。申請(qing)人應描述(shu)任何一種交聯反應,因為這些反應影響成品的(de)(de)化(hua)學成分(fen)和(he)質量(liang)(liang)。

2.Expectations for Registration/Exhibit Batches.對注冊/展(zhan)示批次的期望

Applicants should submit data for registration/exhibit batches manufactured from three distinct laminates, where each laminate is made using different lots of drug substance, adhesives, backing, and/or other critical elements in the TDS product. Release and stability sampling should be representative of the full length and width of the laminates to demonstrate that the manufacturing process is robust

申請人應提交由三種不(bu)(bu)同(tong)層(ceng)壓(ya)材料(liao)制(zhi)成(cheng)的(de)注冊/展示(shi)批次(ci)的(de)數據,其中每個層(ceng)壓(ya)材料(liao)使用不(bu)(bu)同(tong)批次(ci)的(de)藥(yao)物、粘合劑、背(bei)襯和/或TDS產(chan)品中的(de)其他關鍵元素制(zhi)成(cheng)。釋放和穩定性取樣應代表層(ceng)壓(ya)板的(de)整個長(chang)度(du)和寬度(du),以證明制(zhi)造過程穩健

Any clinical batch (e.g., those used in phase 3, PK, BE, adhesion, or irritation and sensitization studies) should be included in the formal stability program. Applicants should provide the executed batch records and certificates of analysis for all batches used in clinical and BE studies, including placebo batches. Placebo batches should include all inactive ingredients and components and representative printing

任何臨床批(pi)(pi)次(ci)(例如,在第3階段、PK、BE、粘附(fu)或刺激(ji)和(he)(he)(he)致敏研(yan)(yan)究中(zhong)使用(yong)的批(pi)(pi)次(ci))都應包(bao)含在正式的穩定性計劃中(zhong)。申請人應提供臨床和(he)(he)(he)BE研(yan)(yan)究中(zhong)使用(yong)的所(suo)有(you)批(pi)(pi)次(ci)(包(bao)括安慰劑批(pi)(pi)次(ci))的執行批(pi)(pi)次(ci)記錄和(he)(he)(he)分析(xi)證書。安慰劑批(pi)(pi)次(ci)應包(bao)括所(suo)有(you)非活性成分和(he)(he)(he)成分以及代表性印刷。

Applicants should report the actual yields, theoretical yield, and percentages of theoretical yield from the conclusion of each appropriate phase of manufacturing, processing, packaging, and holding. The theoretical yield should be calculated for each batch prospectively. For example, if a coating process is stopped due to a manufacturing issue, the theoretical yield should be based on the mass that was intended to be coated rather than the mass that was actually coated. The yield for TDS processes may be lower than the usual yield for many other drug manufacturing processes. However, abnormally low yields in the TDS submission batches should be explained in the application

申(shen)(shen)請(qing)人應(ying)(ying)報告制造(zao)(zao)、加工(gong)、包裝和(he)(he)保存每(mei)個適當階段(duan)結束時的實際(ji)產(chan)量(liang)、理論(lun)產(chan)量(liang)和(he)(he)理論(lun)產(chan)量(liang)百分比。應(ying)(ying)前(qian)瞻性地計算每(mei)批(pi)的理論(lun)產(chan)量(liang)。例如,如果由(you)于(yu)制造(zao)(zao)問(wen)題而停(ting)止了涂(tu)覆(fu)過程,則(ze)理論(lun)產(chan)量(liang)應(ying)(ying)基于(yu)打(da)算涂(tu)覆(fu)的質量(liang),而不是實際(ji)涂(tu)覆(fu)的質量(liang)。TDS工(gong)藝的產(chan)率可能(neng)低(di)于(yu)許多其他藥物制造(zao)(zao)工(gong)藝的通常產(chan)率。但是,應(ying)(ying)在申(shen)(shen)請(qing)中(zhong)說明(ming) TDS 提交批(pi)次中(zhong)異常低(di)的產(chan)量(liang)。

Because of the sensitivity of TDS products to small differences in manufacturing process, a master table comparing the clinical, BE, registration/exhibit, and proposed commercial batches should be included in section 3.2.P.2.3 of the application. For each batch, this table should specify the manufacturing process used (including equipment, and manufacturing scale, and those parameters that could directly or indirectly impact a CQA), and the results of critical in process tests (specifying the test procedure and acceptance criteria), yield, and reconciliation data. The table should also include links to any information referenced from other parts of the submission. It should also clarify whether these batches were packaged to completion at the die cutting and pouching stage

由于(yu) TDS 產品(pin)對制(zhi)造(zao)過程中(zhong)的微小(xiao)差異很敏感,應在申(shen)請書第3.2.P.2.3節(jie)(jie)中(zhong)包(bao)(bao)含一(yi)份比較臨床、BE、注冊/展示和(he)擬議商(shang)業批(pi)次(ci)的主(zhu)表(biao)。對于(yu)每個(ge)批(pi)次(ci),該表(biao)應詳細(xi)說明所使用的制(zhi)造(zao)工藝(yi)(包(bao)(bao)括設備、制(zhi)造(zao)規模以(yi)及可(ke)能直接或(huo)間(jian)接影(ying)響CQA的參數),以(yi)及關鍵過程中(zhong)測試(shi)的結果(guo)(規定測試(shi)程序和(he)驗收標準)、產量和(he)調(diao)節(jie)(jie)數據。該表(biao)還應包(bao)(bao)括提交文件其他部分引(yin)用的任何信(xin)息的鏈接。還應澄(cheng)清這些批(pi)次(ci)是否在模切和(he)裝袋階(jie)段包(bao)(bao)裝完(wan)成

3.Product Characterization Studies/產品特性研究

Because of the uniqueness of the TDS dosage form, specialized developmental studies and eva1uations are recommended to demonstrate full product understanding in both new and abbreviated new drug applications. Several such studies/eva1uations are discussed below.

由于(yu)TDS劑型的獨特性,建(jian)議(yi)進行專門的開發(fa)研究和(he)評估,以證明在NDA和(he)ANDA應(ying)用中(zhong)對(dui)產(chan)品的全面理解。以下討(tao)論了幾項此類研究/評估。

a.Skin Permeability/皮膚滲(shen)透(tou)性

Skin permeability is a function of permeant thermodynamic activity and degree of saturation of the drug substance in the TDS. The solubility and degree of saturation of the drug substance in the TDS should be eva1uated, and their impact on the performance of the TDS understood.

皮膚(fu)滲(shen)透(tou)性是(shi)滲(shen)透(tou)熱力學活性和(he)TDS中藥物(wu)飽和(he)程度(du)的(de)函(han)數。應(ying)評(ping)估藥物(wu)在TDS中的(de)溶解(jie)度(du)和(he)飽和(he)度(du),并了解(jie)其對TDS性能的(de)影響。

b.Crystallization/結(jie)晶

Generally, crystallization of the drug substance in the TDS product should be avoided. If crystallization occurs, studies should be conducted to assess its impact on the in vivo performance and adhesion of TDS.

通常,應(ying)(ying)避免 TDS 產品中API的(de)結(jie)晶。如果發(fa)生結(jie)晶,應(ying)(ying)進行研究以評(ping)估其對TDS體內性能(neng)和粘(zhan)附的(de)影(ying)響。

c.Thermodynamic Stability of Drug Substance/原(yuan)料藥的熱(re)力學穩定性

To confirm thermodynamic stability of the drug substance, the risk of precipitation or salt formation during manufacturing and storage should be eva1uated. If there is an equilibrium between different salt forms, the kinetics to reach this equilibrium should be thoroughly haracterized. The impact of this equilibrium on TDS performance should be eva1uated with relevant in vitro drug release, permeation, and/or clinical data.

為了確認藥(yao)物(wu)的熱力學穩定性,應評(ping)估生產和儲存(cun)過程中沉淀或(huo)鹽(yan)形(xing)成的風險。如果不同鹽(yan)形(xing)式之間存(cun)在平(ping)衡,則(ze)應徹底(di)描述達到該平(ping)衡的動力學。應使用相關的體外(wai)藥(yao)物(wu)釋(shi)放、滲(shen)透和/或(huo)臨床數據(ju)評(ping)估這種平(ping)衡對TDS性能(neng)的影響。

d.Strength/規(gui)格

The strength of a transdermal system should be expressed as a rate (e.g., XX mg/day), whereas the strength of a topical system should be expressed as a percent total drug load. For transdermal systems, the strength can be derived from and supported by either PK data or by residual drug analysis performed on used transdermal systems. The first approach involves the derivation of a clearance (Cl) value from absolute bioavailability of the drug and multiplying that by the concentration (Css) at the steady state. The second approach involves the measurement of the amount of drug left in the transdermal systems at the end of the wear period and dividing the “consumed amount” by the wear period.

透(tou)皮(pi)系(xi)統(tong)(tong)的(de)規格應(ying)(ying)表示為速(su)率(例如,XXmg/天(tian)),而局部(bu)系(xi)統(tong)(tong)的(de)強度(du)(du)則(ze)應(ying)(ying)表示為總(zong)藥物(wu)負荷的(de)百分(fen)比。對于透(tou)皮(pi)系(xi)統(tong)(tong),強度(du)(du)可以(yi)由PK數據或對使(shi)用(yong)過的(de)透(tou)皮(pi)系(xi)統(tong)(tong)進行(xing)的(de)殘留藥物(wu)分(fen)析得出并得到支持。第(di)一(yi)種(zhong)方法涉(she)及(ji)從藥物(wu)的(de)絕對生物(wu)利用(yong)度(du)(du)導出清除率(Cl)值,并將其乘(cheng)以(yi)穩定狀態下的(de)濃度(du)(du)(Css)。第(di)二種(zhong)方法涉(she)及(ji)在使(shi)用(yong)期結束時測量透(tou)皮(pi)系(xi)統(tong)(tong)中殘留的(de)藥物(wu)量,并將“消耗量”除以(yi)使(shi)用(yong)期。

Although the strength of a topical system is expressed as percent total drug load, a residual drug analysis should still be conducted.

盡管局部系(xi)統的強(qiang)度以總藥物(wu)負荷百分(fen)比表示,但仍(reng)應進(jin)行殘留藥物(wu)分(fen)析。

e.Residual Drug/殘留藥物

Consistent with FDA guidance for industry Residual Drug in Transdermal and Related Drug Delivery Systems (August 2011), scientific justification sufficient to support the amount of residual drug in a TDS should be included in the pharmaceutical development section of the application. To provide a robust analysis of the residual drug, we recommend the following:

根(gen)據FDA關于透皮(pi)和相關藥(yao)(yao)物(wu)輸送系統中殘留(liu)藥(yao)(yao)物(wu)的行(xing)業指南(nan)(2011年8月),申請的藥(yao)(yao)物(wu)開發部分(fen)(fen)應包含足以支持TDS中殘留(liu)藥(yao)(yao)物(wu)量(liang)的科學依據。為(wei)了對殘留(liu)藥(yao)(yao)物(wu)進行(xing)可靠(kao)分(fen)(fen)析,我們建議(yi)如下:

1.Data should be based on analysis of the used TDS and not on a theoretical calculation. 數(shu)據應基于(yu)對所用TDS的分析(xi),而非理論(lun)計(ji)算。

2.The amount of drug left on the skin surface should be assessed. Any drug that may have been transferred to packaging or other components of the TDS during storage or use should be accounted for in an attempt to perform a mass balance. 應(ying)(ying)評估殘留在(zai)皮(pi)膚表面的藥(yao)物量。在(zai)儲存或使用過程中可(ke)能轉(zhuan)移到包裝或 TDS 其他成分的任(ren)何藥(yao)物都應(ying)(ying)考慮在(zai)內,以嘗試進(jin)行(xing)質量平衡。

3.Tape or overlays should not be used in studies where the TDS is used to calculate residual drug在TDS用(yong)于計算殘留藥物的研(yan)究中,不應使(shi)用(yong)膠帶(dai)或(huo)覆蓋物

4.TDS adhesion assessments should be conducted over the entire period of wear to determine whether the TDS diffusional surface area remains in full contact with the skin during the entire period of the study. 應在(zai)整個(ge)使(shi)用(yong)期間進(jin)行(xing)TDS粘附(fu)評估(gu),以確定TDS擴散表(biao)面積(ji)在(zai)整個(ge)研究期間是否(fou)與皮膚(fu)完全接(jie)觸。

5.A control study should be performed to provide an estimate of drug load, rather than simply using the expressed label claim. This study should include analysis of a minimum of three unused products from the same lot of product used in the study. 應(ying)進行對(dui)照研究,以(yi)提(ti)供藥物負(fu)荷的(de)(de)估計(ji),而(er)不(bu)是簡單地使用(yong)表達的(de)(de)標簽要求。這項(xiang)研究應(ying)包括對(dui)研究中使用(yong)的(de)(de)相同產品的(de)(de)三種未(wei)使用(yong)產品的(de)(de)分析。

6.Sample storage conditions before and after application of the TDS on the skin should be validated. Photostability and thermal stability of the active ingredient(s) in the TDS should also be considered when selecting the appropriate storage conditions. 應驗證將TDS應用(yong)于(yu)皮膚之(zhi)前和(he)之(zhi)后(hou)的(de)(de)樣(yang)品存(cun)儲(chu)條(tiao)件。在選擇合適的(de)(de)儲(chu)存(cun)條(tiao)件時,還應考慮TDS中活性(xing)(xing)成分的(de)(de)光穩定(ding)(ding)性(xing)(xing)和(he)熱穩定(ding)(ding)性(xing)(xing)。

7.Appropriately sensitive and valid analytical methods should be used to assay the residual drug content for the purpose of calculating drug depletion and delivery. When estimating the amount of residual drug in the TDS, a drug extraction method with a target extraction efficiency close to 100 percent should be utilized to minimize error應使用適(shi)當敏感和(he)有效的(de)分析(xi)方(fang)法測定(ding)殘留藥(yao)物(wu)(wu)含量,以計算藥(yao)物(wu)(wu)消耗和(he)遞送。當估計TDS中殘留藥(yao)物(wu)(wu)的(de)量時,應使用目標提取效率接近100%的(de)藥(yao)物(wu)(wu)提取方(fang)法,將誤(wu)差(cha)降至(zhi)最低

f.In Vitro Permeation Testing/體外滲透測試

In vitro permeation testing (IVPT) with the use of excised human skin may be utilized to characterize the rate and extent of transdermal or topical drug delivery, and the study protocols and results should be described in the application. The following factors should be considered during IVPT model development:

使用(yong)離體人體皮膚(fu)的體外滲透(tou)試驗(IVPT)可用(yong)于(yu)表征透(tou)皮或局部藥物遞(di)送的速(su)率和程度,并且在(zai)應(ying)(ying)用(yong)中應(ying)(ying)描(miao)述研究方案和結果。IVPT模型開發過(guo)程中應(ying)(ying)考慮以(yi)下(xia)因素:

相關閱讀:《FDA IVPT 測試 工(gong)業指南翻譯稿(gao)》

• Selection of the diffusion apparatus and the operating conditions like stirring rate or flow rate, as well as temperature control to maintain the under-normal-conditions skin surface temperature (32°C ±1°C)

選(xuan)擇擴散(san)裝(zhuang)置和操作條(tiao)件,如攪拌速率或流速,以(yi)及溫度控制,以(yi)保(bao)持正常條(tiao)件下(xia)的皮膚表(biao)面溫度(32°C±1°C)

 

Source of the skin, skin storage conditions, choice of skin type (i.e., age range, sex , race, and consistent anatomical region) and the skin preparation technique (e.g., full-thickness, dermatomed, isolated epidermis)

皮(pi)(pi)膚(fu)來(lai)源(yuan)、皮(pi)(pi)膚(fu)儲存條(tiao)件、皮(pi)(pi)膚(fu)類型的選(xuan)擇(即(ji)年齡范圍、性(xing)別、種(zhong)族(zu)和(he)(he)一致的解剖(pou)區域(yu))和(he)(he)皮(pi)(pi)膚(fu)制備技術(例如全厚度、病理皮(pi)(pi)膚(fu)、分離表皮(pi)(pi))

The IVPT protocol should specify the nominal skin thickness and its range, details of the skin barrier integrity test, and any occlusion of the product during the IVPT. Visual observations alone are not sufficient to characterize the barrier integrity of the skin. Acceptable barrier integrity tests may be based on tritiated water permeation, trans-epidermal water loss (TEWL), or electrical impedance/conductance measured across the skin. The test parameters and acceptance criteria used for the skin barrier integrity test should be justified based on relevant literature references or other information

IVPT方案應規定標稱皮膚(fu)厚度及其(qi)范圍、皮膚(fu)屏(ping)障完(wan)整性(xing)(xing)測(ce)試(shi)的(de)(de)細節以(yi)及IVPT期(qi)間產品的(de)(de)任何遮(zhe)擋。僅憑視覺觀察不足(zu)以(yi)表征皮膚(fu)的(de)(de)屏(ping)障完(wan)整性(xing)(xing)。可接受(shou)的(de)(de)屏(ping)障完(wan)整性(xing)(xing)測(ce)試(shi)可基(ji)于氚化水滲透、經表皮失(shi)水(TEWL)或(huo)(huo)通過皮膚(fu)測(ce)量(liang)的(de)(de)電阻抗/電導。用于皮膚(fu)屏(ping)障完(wan)整性(xing)(xing)測(ce)試(shi)的(de)(de)測(ce)試(shi)參數和驗收標準應根據相關文獻參考或(huo)(huo)其(qi)他信息進行證明

相關閱(yue)讀:《IVPT測試(shi)中的(de)皮膚研(yan)究》

The IVPT protocol should also include details about the receptor solution, system equilibration, procedures for skin mounting and application of the TDS, as well as any measures to secure the TDS on the skin surface to prevent lifting. We recommend that an antimicrobial agent be included in the receptor solution (e.g., ~0.1 percent sodium azide or ~0.01 percent gentamicin sulfate).

IVPT方(fang)案還應(ying)包括受體溶(rong)液、系統平衡(heng)、皮膚安(an)裝(zhuang)程序(xu)和TDS應(ying)用程序(xu)的(de)(de)詳細信息,以及將TDS固定在皮膚表面以防止移(yi)動的(de)(de)任何(he)措施。我們建議在受體溶(rong)液中加入抗菌劑(例如,約(yue)0.1%的(de)(de)*或(huo)約(yue)0.01%的(de)(de)硫酸慶大(da)霉素)。

The IVPT study report should include dose duration, sampling duration, sampling time points, concentration of samples, concentration of the antimicrobial component, and the empirical stability (at relevant temperatures) and solubility of the active ingredient in the receptor solution. The study report should also include the number of individuals whose skin was eva1uated (i.e., skin donors) and the number of replicate skin sections per donor per treatment group

IVPT研究報告應包括(kuo)劑量(liang)持(chi)續(xu)時間、取樣持(chi)續(xu)時間、取樣時間點、樣品濃度、抗(kang)菌成(cheng)分(fen)濃度以(yi)及活性成(cheng)分(fen)在受(shou)體溶液中的經驗(yan)穩定(ding)性(在相(xiang)關(guan)溫度下)和(he)溶解度。研究報告還(huan)應包括(kuo)接受(shou)皮膚(fu)評估的個(ge)體數(shu)量(liang)(即,皮膚(fu)供體)以(yi)及每(mei)個(ge)治(zhi)療組每(mei)個(ge)供體的重復皮膚(fu)切片數(shu)量(liang)。

All treatment groups compared in an IVPT study should be dosed on the skin samples from the same set of donors, with the same number of replicates per donor per treatment group. These treatment groups should also use the skin samples from the same anatomical site from all donors, unless varying these parameters is essential to the design of the study and the eva1uation of the TDS. The study report should include the equilibrated skin surface temperature prior to dose application, and the ambient temperature and relative humidity in the laboratory, as well as the extent of qualification of the sample analytical methods (e.g., HPLC)

IVPT研(yan)究中比較的(de)(de)(de)所有(you)治(zhi)(zhi)療組(zu)應在同(tong)一組(zu)供體(ti)的(de)(de)(de)皮膚(fu)(fu)樣(yang)本(ben)上給藥,每個治(zhi)(zhi)療組(zu)每個供體(ti)的(de)(de)(de)重復次數(shu)相(xiang)同(tong)。這些治(zhi)(zhi)療組(zu)還(huan)應使用(yong)來自所有(you)供體(ti)的(de)(de)(de)相(xiang)同(tong)解剖部位的(de)(de)(de)皮膚(fu)(fu)樣(yang)本(ben),除(chu)非改變這些參數(shu)對研(yan)究設計(ji)和TDS評估至(zhi)關(guan)重要。研(yan)究報告應包括劑量應用(yong)前的(de)(de)(de)平衡(heng)皮膚(fu)(fu)表面溫度、實驗室的(de)(de)(de)環境溫度和相(xiang)對濕度,以及(ji)樣(yang)品分析方法(如HPLC)的(de)(de)(de)合格程度

g.Extractable and Leachable Testing/可(ke)提取(qu)且(qie)可(ke)浸出的測試

All TDS should be eva1uated for potential compounds that could be transferred from the product to the patient. This eva1uation should include assessments of extractables and leachables, consistent with USP and

應評(ping)估(gu)所有(you)TDS中(zhong)可能(neng)從產品轉移至(zhi)患者(zhe)的潛在化合物(wu)。該評(ping)估(gu)應包(bao)括與(yu)USP<1663>和<1664>一致的可提取物(wu)和可浸出物(wu)的評(ping)估(gu)

As defined in United States Pharmacopeia (USP)21 General Chapter Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, “extractables are organic and inorganic chemical entities that are released from a pharmaceutical packaging/ delivery system, packaging component, or packaging material of construction and into an extraction solvent under laboratory conditions.” The extraction conditions should “accelerate or exaggerate the normal conditions of storage and use for a packaged dosage form.”

如《美國藥典》(USP)第(di)21章“與藥物(wu)(wu)包(bao)裝(zhuang)/輸送系(xi)統(tong)相關的(de)可提(ti)取(qu)物(wu)(wu)評(ping)估”中所(suo)定義的(de),“可提(ti)取(qu)物(wu)(wu)是在(zai)實(shi)驗室(shi)條(tiao)件(jian)下(xia)從(cong)藥物(wu)(wu)包(bao)裝(zhuang)/運(yun)輸系(xi)統(tong)、包(bao)裝(zhuang)組件(jian)或包(bao)裝(zhuang)材料中釋放并進入(ru)提(ti)取(qu)溶劑(ji)的(de)有機和(he)無機化學(xue)物(wu)(wu)質(zhi)。提(ti)取(qu)條(tiao)件(jian)應“加速或放大包(bao)裝(zhuang)劑(ji)型(xing)的(de)正常儲(chu)存和(he)使用條(tiao)件(jian)”

As defined in USP General Chapter  Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems, “leachables are foreign organic and inorganic entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies.”

如USP通用章節與藥(yao)物(wu)(wu)包(bao)(bao)(bao)裝(zhuang)(zhuang)/輸(shu)送系(xi)統(tong)相關的藥(yao)品(pin)浸(jin)出(chu)物(wu)(wu)評估中所定義(yi),“可(ke)浸(jin)出(chu)物(wu)(wu)是指(zhi)包(bao)(bao)(bao)裝(zhuang)(zhuang)藥(yao)品(pin)中存在的外來有機和(he)無機物(wu)(wu)質,因為它們(men)在正常儲(chu)存和(he)使用條件下或在加(jia)速藥(yao)品(pin)穩定性研究期間從包(bao)(bao)(bao)裝(zhuang)(zhuang)/輸(shu)送系(xi)統(tong)、包(bao)(bao)(bao)裝(zhuang)(zhuang)組件或包(bao)(bao)(bao)裝(zhuang)(zhuang)材料中浸(jin)出(chu)到(dao)包(bao)(bao)(bao)裝(zhuang)(zhuang)藥(yao)品(pin)中。”

In the context of this guidance, extractable impurities are chemical entities that can be drawn out of the backing membrane, release liner, pouching material, printed ink, internal membranes, and components other than the drug substance and adhesive matrix by a solvent system.

在本指(zhi)南的(de)上下文(wen)中,可提取雜質(zhi)是可通過溶劑系(xi)統從背(bei)襯膜(mo)(mo)、釋放襯墊(dian)、袋材(cai)料、印刷(shua)油墨(mo)、內膜(mo)(mo)和(he)除藥物和(he)粘合劑基(ji)質(zhi)以(yi)外的(de)成(cheng)分中抽出的(de)化學物質(zhi)。

Additionally, an extraction study can detect compounds introduced into the TDS from the manufacturing process, which can impact the final impurity profile of the TDS product. In the context of this guidance, leachables are chemical entities present in a packaged TDS because they leached into the adhesive matrix (or where applicable, reservoir) under normal conditions of storage or during accelerated stability studies. These compounds may transfer from the adhesive matrix (or reservoir) to the patient during use.

此外,提取研(yan)究可(ke)(ke)(ke)以檢測從制造過程中引入(ru)TDS的(de)化合物,這(zhe)會影響TDS產品的(de)最終雜質(zhi)分(fen)布。在本指南中,可(ke)(ke)(ke)浸出物是(shi)包裝TDS中存在的(de)化學(xue)物質(zhi),因為它們在正常儲(chu)(chu)存條件下或在加速(su)穩定(ding)性(xing)研(yan)究期間(jian)浸出到粘(zhan)合劑(ji)(ji)基質(zhi)(或適(shi)用情況下的(de)儲(chu)(chu)層)中。在使(shi)用過程中,這(zhe)些化合物可(ke)(ke)(ke)從粘(zhan)合劑(ji)(ji)基質(zhi)(或貯層)轉(zhuan)移(yi)至患(huan)者。

Extractable studies are used to inform the leachable study design. The leachable data should be correlated, if possible, with the extractables profile(s) determined under the various control extraction study conditions. Both extractable and leachable studies should have adequate sensitivity to detect compounds potentially released at a level associated with patient exposure when a product is used at the maximum daily dose (e.g., 1.5 mcg/day for standard mutagenic compounds in a chronic-use drug product22 ), unless otherwise justified. For some products, the maximum daily dose may require applying more than one TDS.

可提(ti)取研(yan)究(jiu)用(yong)(yong)于(yu)告知可浸出研(yan)究(jiu)設計。如(ru)果可能(neng)(neng)的(de)話,在不同(tong)的(de)對照浸出研(yan)究(jiu)條件下確定浸出物(wu)的(de)分布。可提(ti)取和可浸出研(yan)究(jiu)應具有足夠的(de)靈敏度,以(yi)(yi)檢(jian)測(ce)當產品以(yi)(yi)最(zui)大(da)日劑量(liang)使(shi)用(yong)(yong)時(例如(ru),長期使(shi)用(yong)(yong)藥物(wu)產品中的(de)標準致突變化合物(wu)為1.5 mcg/天),可能(neng)(neng)釋放的(de)化合物(wu),除非另有證明。對于(yu)某些產品,最(zui)大(da)每日劑量(liang)可能(neng)(neng)需要應用(yong)(yong)一種以(yi)(yi)上的(de)TDS。

Adhesive impurities such as residual monomers, initiator byproducts, and aldehydes are not considered extractables or leachables because these impurities are present at peak concentrations before product manufacture. Control of adhesive impurities is discussed elsewhere in this guidance (see section IV. INFORMATION TO BE SUBMITTED IN AN APPLICATION, C. Control of TDS Product). However, the leachable studies discussed below may be leveraged to justify adhesive impurity limits or as part of the toxicological risk assessment for adhesive impurities because a leachable study is performed on the proposed commercial product.

粘(zhan)合劑(ji)(ji)(ji)雜質(zhi),如殘留單(dan)體(ti)、引(yin)發(fa)劑(ji)(ji)(ji)副產(chan)(chan)物和醛類,不(bu)被視為(wei)(wei)可(ke)(ke)(ke)提取或可(ke)(ke)(ke)浸出(chu)物,因為(wei)(wei)這些雜質(zhi)在(zai)產(chan)(chan)品(pin)(pin)制(zhi)造前以峰值濃度存在(zai)。本(ben)指南其他地方對(dui)(dui)粘(zhan)合劑(ji)(ji)(ji)雜質(zhi)的控制(zhi)進(jin)行(xing)了(le)討論(見第四節(jie)C申(shen)請中提交的信息TDS產(chan)(chan)品(pin)(pin)的控制(zhi))。然而,以下(xia)討論的可(ke)(ke)(ke)浸出(chu)性研(yan)究(jiu)可(ke)(ke)(ke)用(yong)于(yu)證明粘(zhan)合劑(ji)(ji)(ji)雜質(zhi)限值,或作為(wei)(wei)粘(zhan)合劑(ji)(ji)(ji)雜質(zhi)毒(du)理學風(feng)險評估的一部分,因為(wei)(wei)對(dui)(dui)擬議的商業(ye)產(chan)(chan)品(pin)(pin)進(jin)行(xing)了(le)可(ke)(ke)(ke)浸出(chu)研(yan)究(jiu)。

To aid in the extractable and leachable analyses described below, applicants should contact raw material suppliers to identify potential extractables of toxicological concern, such as residual monomers from backing materials.

為了(le)幫助進行下文所(suo)述的可(ke)提(ti)取和可(ke)浸(jin)出分析,申(shen)請人應聯(lian)系(xi)原材料供應商,以確定潛在(zai)的毒理學問題(ti)可(ke)提(ti)取物(wu),例如(ru)背(bei)襯材料中的殘(can)留(liu)單體。

lExtractable Studies

Extractable studies should be conducted early in the pharmaceutical development process to understand the potential leachables from components of the proposed commercial TDS. These studies should be conducted on components such as backing membrane, release liner, rate controlling or other internal membranes, ink and pouching. The testing components should be extracted in a variety of solvents with a range of polarities under vigorous laboratory extraction conditions to maximize the levels of extractables and identify as many potential leachables as possible. One of the extraction solvents used in the extractable studies should include the solvent of the proposed commercial adhesive(s) platform or the known residual solvents for the finished TDS. The choices of solvents used should be justified

可提取性研(yan)究

應在(zai)(zai)藥物(wu)開發過(guo)程早期進(jin)行可提(ti)取(qu)(qu)(qu)性(xing)研究(jiu)(jiu),以了解擬(ni)議商業(ye)(ye)TDS組分(fen)的(de)(de)(de)潛(qian)在(zai)(zai)浸出物(wu)。這些研究(jiu)(jiu)應在(zai)(zai)背(bei)襯膜(mo)、釋放襯墊、速率控制或其他內部膜(mo)、油墨和袋等組件(jian)上進(jin)行。測試(shi)組分(fen)應在(zai)(zai)各(ge)種極(ji)性(xing)不(bu)同的(de)(de)(de)溶(rong)(rong)劑中(zhong)(zhong),在(zai)(zai)劇烈的(de)(de)(de)實驗(yan)提(ti)取(qu)(qu)(qu)條件(jian)下提(ti)取(qu)(qu)(qu),以最(zui)大限度地提(ti)高可提(ti)取(qu)(qu)(qu)物(wu)的(de)(de)(de)水平,并盡(jin)可能多地確定潛(qian)在(zai)(zai)的(de)(de)(de)可浸出物(wu)。可提(ti)取(qu)(qu)(qu)性(xing)研究(jiu)(jiu)中(zhong)(zhong)使用的(de)(de)(de)提(ti)取(qu)(qu)(qu)溶(rong)(rong)劑之一(yi)應包括(kuo)擬(ni)定商業(ye)(ye)粘合劑平臺的(de)(de)(de)溶(rong)(rong)劑或成品TDS的(de)(de)(de)已知(zhi)殘留溶(rong)(rong)劑。所用溶(rong)(rong)劑的(de)(de)(de)選(xuan)擇應合理

 

可浸出研(yan)究

 

可浸(jin)出研究的(de)條(tiao)件(jian)應(ying)盡(jin)可能(neng)接(jie)近皮膚的(de)“最壞情況(kuang)”臨(lin)床條(tiao)件(jian)(例如,劇烈運動期(qi)間出汗)。應(ying)為(wei)研究選擇合理的(de)溶劑(ji)/溶液(如鹽(yan)濃度)、溫度、攪拌水(shui)平、暴露于(yu)溶劑(ji)的(de)時間等實(shi)驗條(tiao)件(jian)。在研究期(qi)間,應(ying)將隔離(li)襯墊從系統(tong)中移除,以使粘(zhan)合劑(ji)層充(chong)分(fen)暴露于(yu)生物相關溶劑(ji)。申(shen)請人(ren)應(ying)進行多時間點可浸(jin)出物分(fen)析(例如,0、6、12、24個(ge)月),以提供全面的(de)可浸(jin)出物概(gai)況(kuang),并確定可浸(jin)出物的(de)任何趨勢(shi),因為(wei)這些數據可能(neng)影響產品的(de)保(bao)質期(qi)。提交申(shen)請時,應(ying)提交在加速和(he)長期(qi)條(tiao)件(jian)下儲(chu)存至少6個(ge)月的(de)多批次樣品的(de)可浸(jin)出研究數據。我們建議對三種(zhong)不同(tong)的(de)TDS層壓(ya)板進行可浸(jin)出研究,并進行穩(wen)定性測試。

h.Assessing the Effects of Heat

Heat from external sources such as a heating blanket, and potentially from a rise in internal body temperature due to strenuous exercise or fever, may affect the rate of drug release from the TDS and the absorption of drug into and through the skin. We recommend that applicants study the impact of an elevated TDS/skin surface temperature on the delivery profile of TDS relative to its delivery profile at a normal TDS/skin surface temperature.

h.評估(gu)熱效應的影響

來自外部(bu)來源(yuan)(如加熱毯(tan))的(de)熱量,以及(ji)可(ke)能由于(yu)劇(ju)烈運動(dong)或發燒(shao)導致的(de)體內(nei)溫度升高,可(ke)能會影響(xiang)TDS中藥物(wu)(wu)釋放的(de)速率(lv)以及(ji)藥物(wu)(wu)進入和通過(guo)皮膚的(de)吸(xi)收。我們建議申請人研(yan)究相對(dui)(dui)于(yu)正常TDS/皮膚表面溫度下的(de)TDS釋放曲(qu)線(xian),升高TDS/皮膚表面溫度對(dui)(dui)TDS釋放曲(qu)線(xian)的(de)影響(xiang)。

For a TDS product to be submitted in an NDA, we recommend that the heat effect studies be conducted as part of a clinical study using the proposed commercial product. In designing the heat effect studies, critical factors such as appropriate elevated test temperature(s), heat exposure onset time(s), duration(s), and cycles (if any), as well as mechanisms of heat exposure (e.g., heating lamp, heating pad, etc.) should be identified

對于在NDA中提交的(de)(de)TDS產品,我們建議將熱效應研究作為臨(lin)床研究的(de)(de)一部分(fen),使用擬議的(de)(de)商(shang)業(ye)產品進行(xing)。在設計熱效應研究時,應確定關鍵因(yin)素,如適當升高的(de)(de)試(shi)驗(yan)溫度(du)、熱暴露開始時間、持續時間和周期(如有),以及(ji)熱暴露機(ji)制(如加熱燈、加熱墊等(deng))

For a TDS product to be submitted in an ANDA, the applicant should eva1uate whether the test TDS, used under elevated temperature conditions, increases drug delivery compared to the reference (R) TDS. The ANDA applicant should provide the results of an IVPT study comparing the drug delivery characteristics for the test TDS and the R TDS at normal and elevated temperatures using skin from multiple individuals (donors), with multiple replicate diffusion cells eva1uated per donor, per treatment (test versus R), and per temperature condition. An IVPT study with a sufficient number of donors and replicates per donor per treatment per temperature condition is recommended to obtain meaningful data. A study with fewer than four donors and four replicates per donor per treatment per temperature may be difficult to interpret.

對(dui)于(yu)將(jiang)在ANDA中提(ti)交的(de)(de)TDS產品,申請人應評估在高溫(wen)條(tiao)件下(xia)使用的(de)(de)測試TDS是(shi)否比參考(R)TDS增(zeng)加藥物遞送。ANDA申請人應提(ti)供(gong)一項IVPT研(yan)究(jiu)的(de)(de)結(jie)(jie)果,該(gai)研(yan)究(jiu)使用來自多(duo)個(ge)個(ge)體(供(gong)體)的(de)(de)皮膚(fu),在正常和升(sheng)高溫(wen)度(du)(du)下(xia)比較(T)TDS和(R)TDS的(de)(de)藥物遞送特性(xing),每個(ge)供(gong)體、每個(ge)治療(T與R)和每個(ge)溫(wen)度(du)(du)條(tiao)件下(xia)評估多(duo)個(ge)復制擴散池。建(jian)議進行(xing)IVPT研(yan)究(jiu),以獲(huo)得有意(yi)義的(de)(de)數據,該(gai)研(yan)究(jiu)具有足夠數量的(de)(de)供(gong)體,并在每個(ge)溫(wen)度(du)(du)條(tiao)件下(xia)對(dui)每個(ge)供(gong)體進行(xing)重復治療。如果一項研(yan)究(jiu)在每種溫(wen)度(du)(du)下(xia),每種處理的(de)(de)供(gong)體少于(yu)四個(ge),每個(ge)供(gong)體有四個(ge)重復,這可能很難(nan)對(dui)結(jie)(jie)果進行(xing)解釋。

We recommend a parallel eva1uation and comparison of the test and R TDS under the following baseline and elevated temperature conditions:

我們建議(yi)在以(yi)下基礎和(he)高溫條件下對試(shi)驗和(he)R TDS進行平行評(ping)估(gu)和(he)比較:

1.BASELINE: Both the test and R products should be maintained at a TDS/skin surface temperature of 32 ±1°C for the entire study duration. 基(ji)礎:在整個(ge)研(yan)究期間,T和R產品(pin)的TDS/皮膚表面溫度應保持在32±1°C。

2.ELEVATED TEMPERATURE: Both the test and R products should be maintained at a TDS/skin surface temperature of 32 ±1°C until a specified time, approximately when the peak flux is observed, and then maintained at a TDS/skin surface  temperature of 42 ±2°C for a period thereafter, which may be the remainder of the study duration升高的(de)溫度(du):T和(he)R產品應保持(chi)在32±1°C的(de)TDS/皮膚(fu)表面溫度(du),直到大約(yue)觀(guan)察到峰值通量時的(de)指定時間,然后(hou)在剩(sheng)余持(chi)續研究時間段保持(chi)在42±2°C的(de)TDS/皮膚(fu)表面溫度(du)

It should not be assumed that a set temperature for a circulating water bath will provide the target temperature at the TDS/skin surface. The TDS/skin surface temperature should be directly measured using an infrared thermometer or other temperature probe. The study duration for a 7-day wear TDS need not encompass the entire labeled duration of wear. It may be adequate to perform an IVPT study for a 48 or 72 hour duration, if that duration is sufficient to reach the peak drug delivery rate under baseline conditions. Alternatively, an applicant may justify eva1uating other conditions or scenarios of exposure to elevated temperatures that represent the worst-case scenario for a given TDS product or indicated patient population.

不應假(jia)設循環水浴(yu)的(de)(de)設定(ding)溫(wen)度(du)(du)可(ke)以提供TDS/皮(pi)膚表面的(de)(de)目標(biao)溫(wen)度(du)(du)。應使用紅外溫(wen)度(du)(du)計或(huo)其(qi)他溫(wen)度(du)(du)探頭直接測量TDS/皮(pi)膚表面溫(wen)度(du)(du)。7天使用TDS的(de)(de)研究(jiu)(jiu)(jiu)持(chi)續(xu)時間不需要(yao)包(bao)括整(zheng)個(ge)標(biao)示的(de)(de)使用持(chi)續(xu)時間。如(ru)果IVPT研究(jiu)(jiu)(jiu)的(de)(de)持(chi)續(xu)時間足以達(da)到基礎(chu)條(tiao)件下的(de)(de)峰值藥物輸送率,則進行(xing)48或(huo)72小時的(de)(de)IVPT研究(jiu)(jiu)(jiu)可(ke)能就足夠。或(huo)者(zhe),申請人可(ke)以評(ping)估(gu)證明暴露于高溫(wen)的(de)(de)其(qi)他條(tiao)件或(huo)情景是(shi)合理的(de)(de),這些條(tiao)件或(huo)情景代表給定(ding)TDS產品或(huo)指(zhi)定(ding)患者(zhe)人群的(de)(de)最壞情況。

i.Microscopic Matrix eva1uation

Due to complexities of many TDS formulations, adhesive matrices often do not form true solutions, rather they manifest as dispersions. If rearrangements of the dispersed-like system occur over time within the matrix, they can possibly lead to lack of adhesion or changes in drug delivery and release. As such, it is important to have a good understanding of the TDS formulation, the way the drug substance and excipients are dispersed within the adhesive matrix, and the tendency of the matrix to change over time from product release through its expiry period. Therefore, it is informative to assess surface and cross-sectional changes in the TDS matrix throughout the shelf life of the developmental batches using high-powered microscopy, elemental mapping, or other appropriate tools. These tools may not be appropriate for every TDS; applicants should provide a scientific justification for the tools used. These assessments  will help achieve comprehensive understanding of product and process, mitigate quality-related risks, and assure that the TDS meets the requisite quality attributes through its expiry period

i. 微觀基(ji)質評(ping)價

由于(yu)許(xu)多TDS配方(fang)的(de)(de)(de)復雜性(xing)(xing),粘合(he)劑(ji)基質(zhi)通常不(bu)會形成真正(zheng)的(de)(de)(de)溶液(ye),而(er)是表現(xian)為分(fen)散(san)體。如果分(fen)散(san)樣系統(tong)在(zai)(zai)基質(zhi)中隨著時(shi)間(jian)的(de)(de)(de)推移(yi)發生重排,它(ta)們可(ke)(ke)能導致(zhi)缺(que)乏粘附(fu)或(huo)藥物(wu)(wu)遞送和釋(shi)(shi)放的(de)(de)(de)變化(hua)(hua)。因此,需要充分(fen)了(le)解(jie)TDS配方(fang)、藥物(wu)(wu)和賦形劑(ji)在(zai)(zai)粘合(he)劑(ji)基質(zhi)中的(de)(de)(de)分(fen)散(san)方(fang)式,以及有效期內,隨著時(shi)間(jian)變化(hua)(hua)基質(zhi)從產(chan)品(pin)中釋(shi)(shi)放的(de)(de)(de)趨(qu)勢。因此,使(shi)用高(gao)性(xing)(xing)能顯微(wei)鏡、元素圖譜(pu)或(huo)其(qi)他(ta)適(shi)(shi)當的(de)(de)(de)工(gong)具(ju)評估TDS基質(zhi)在(zai)(zai)整個開發批(pi)次保質(zhi)期內的(de)(de)(de)表面(mian)和橫(heng)截面(mian)變化(hua)(hua)是有益的(de)(de)(de)。這些(xie)工(gong)具(ju)可(ke)(ke)能不(bu)適(shi)(shi)用于(yu)所有TDS;申請人應為所使(shi)用的(de)(de)(de)工(gong)具(ju)提供科學依據。這些(xie)評估將有助(zhu)于(yu)全面(mian)了(le)解(jie)產(chan)品(pin)和過(guo)程(cheng),降低質(zhi)量相(xiang)關風險,并確保TDS在(zai)(zai)其(qi)到期期間(jian)滿足必要的(de)(de)(de)質(zhi)量屬性(xing)(xing)

4.Proposed Manufacturing Changes

Scale-up proposals and other process changes may be proposed in an original NDA or ANDA, but the level of additional information needed to support these changes will generally be commensurate with the risk of the change to adversely impact product quality. In general, changes to TDS after the conduct of pivotal clinical studies should be avoided when possible because of the sensitivity of TDS to small changes in formulation and manufacturing process.

4.擬議的生(sheng)產變更

原NDA或ANDA中可能會提出比例放大建議和其他(ta)流程(cheng)變(bian)(bian)更,但支持這些(xie)變(bian)(bian)更所需的(de)(de)額外信息水平通常與變(bian)(bian)更對產品(pin)質量產生(sheng)不利影(ying)響(xiang)的(de)(de)風險(xian)相(xiang)當。一般來說,在(zai)進行關鍵臨(lin)床研究后,應盡可能避免TDS的(de)(de)變(bian)(bian)化,因為(wei)TDS對配方(fang)和制造過程(cheng)中的(de)(de)微小變(bian)(bian)化很敏感。

Low-risk changes may be adequately supported with updated master batch records and batch formulas. Examples include scale-up of solvent-based and aqueous mixtures within a factor of 10 using equipment of the same design and operating principles, or proposing a change to converting and pouching equipment of the same design and operating principle

可(ke)通過更新主批次(ci)記(ji)錄和批次(ci)方案得到(dao)充(chong)分支持低風險(xian)變更。例如,使(shi)用相(xiang)同設計和工作原(yuan)理(li)的(de)設備,將(jiang)溶劑(ji)基和水性混合物(wu)的(de)規模擴大10倍,或建議對相(xiang)同設計和工作原(yuan)理(li)的(de)轉換和裝袋設備進行更改(gai)

Moderate-risk changes may warrant additional developmental studies and stability data on commercial scale batches to demonstrate that they will not result in an adverse impact on the quality of the product. Examples of such changes may include scale-up of hot-melt mixtures within a factor of 10, scale-up of screw-based mixing processes, and changes to coating/drying/laminating equipment of the same design and operating principle

中等風險變(bian)化(hua)可能需要對商業規(gui)模批次進行額外的(de)(de)開(kai)發研究和穩定性數據,以(yi)證明(ming)它們不(bu)會對產(chan)品質(zhi)量產(chan)生(sheng)不(bu)利影響。這種變(bian)化(hua)的(de)(de)例(li)子可能包括(kuo)將熱熔混合物的(de)(de)比例(li)提(ti)(ti)高(gao)到10倍以(yi)內(nei),將螺桿混合工藝的(de)(de)比例(li)提(ti)(ti)高(gao),以(yi)及(ji)改變(bian)具有相同設(she)計(ji)和操作原理的(de)(de)涂層/干燥/層壓(ya)設(she)備

Changes that pose a high risk to quality may warrant additional in vivo studies. An example is changing the manufacturing process to incorporate equipment of a different design and operating principle.

對質量構(gou)成高風(feng)險的(de)(de)變(bian)化可(ke)能(neng)需要額外(wai)的(de)(de)體內研究。一個例子(zi)是(shi)改變(bian)制造(zao)工藝(yi),以(yi)采用不同設計和操作原理的(de)(de)設備。

B.Manufacture

As described in ICH M4Q, section 3.2.P.3 of the application should contain information about where and how the TDS product will be manufactured. The batch formula and a descr1ption of the manufacturing process and process controls should be provided. A detailed schematic diagram of the proposed production process, including descr1ptions of the equipment, operating conditions, and process controls, should also be provided.


B.生產

如ICH M4Q中所述,應(ying)用程(cheng)序的第3.2.P.3節應(ying)包含關(guan)于TDS產品將在何(he)(he)處以(yi)及(ji)如何(he)(he)制(zhi)造的信息。應(ying)提(ti)供(gong)批次配方以(yi)及(ji)制(zhi)造工(gong)(gong)藝(yi)和(he)工(gong)(gong)藝(yi)控制(zhi)的說明。還(huan)應(ying)提(ti)供(gong)擬定(ding)生產工(gong)(gong)藝(yi)的詳細示意圖,包括設(she)備(bei)、操作條(tiao)件和(he)工(gong)(gong)藝(yi)控制(zhi)的說明。

During process development, the applicant should identify process variables that have a potential to impact TDS product CQAs. These process development studies inform commercial process qualification and continued process verification later in the product life cycle.

在工藝開發過(guo)程中,申請人應(ying)確定可能影響TDS產(chan)品CQA的(de)工藝變量。這些工藝開發研(yan)究為商業(ye)工藝鑒定和產(chan)品生命周(zhou)期后(hou)期的(de)持續工藝驗證(zheng)提供了(le)信息。

Typical TDS manufacturing steps/unit operations are listed below (a non-exhaustive list). For processes that incorporate these steps, the applicant should describe how each operation and associated controls were developed, addressing the considerations below, specifically, the CQAs that may be impacted by the operation, and the relevant process parameters and material attributes that may impact the output of each operation:

下面(mian)列出(chu)了典型的(de)TDS制造步驟/裝(zhuang)置操(cao)(cao)(cao)作(zuo)(非(fei)詳(xiang)盡列表)。對于(yu)包含(han)這些步驟的(de)過(guo)程,申請(qing)人應說明每(mei)個操(cao)(cao)(cao)作(zuo)和(he)相關控(kong)制是如何制定的(de),并說明以(yi)下注意事(shi)項,特別是可能(neng)受(shou)操(cao)(cao)(cao)作(zuo)影響(xiang)的(de)CQA,以(yi)及可能(neng)影響(xiang)每(mei)個操(cao)(cao)(cao)作(zuo)輸(shu)出(chu)的(de)相關工藝參數(shu)和(he)材料屬性:

Mixing: Mixing operations produce bulk mixtures for the coating step. Mixing can impact CQAs such as assay, stability of drug substance and/or excipients, content uniformity, microscopic appearance, and physical properties of the adhesive. The control strategy should address the impact of equipment design, order of material addition, and process parameters (such as mixing speeds, mixing times, temperatures, redispersion or recirculation conditions, and deaeration conditions) on CQAs, and should be justified, as necessary, based on development studies. CMAs that can impact mixing include drug substance particle size, polymorphic form, raw material rheological attributes, and percent solids for materials supplied in solvent-based mixtures.

混(hun)合:混(hun)合操作產生用于涂層步驟的散裝混(hun)合物。混(hun)合可影響(xiang)(xiang)CQA,如(ru)含(han)量測(ce)定、原(yuan)(yuan)料藥(yao)和(he)/或(huo)賦形劑的穩定性(xing)、含(han)量均勻性(xing)、微觀形態(tai)(tai)和(he)粘合劑的物理性(xing)質。控制策略應(ying)(ying)解(jie)決設備設計、物料添(tian)加順序和(he)工藝參數(如(ru)混(hun)合速(su)度、混(hun)合時間、溫度、再(zai)分散或(huo)再(zai)循環條(tiao)件以(yi)及脫氣(qi)條(tiao)件)對(dui)CQA的影響(xiang)(xiang),并應(ying)(ying)根據開發研究在(zai)必要(yao)時予以(yi)證明。能夠影響(xiang)(xiang)混(hun)合的cma包括(kuo)原(yuan)(yuan)料藥(yao)粒(li)度、多(duo)態(tai)(tai)形態(tai)(tai)、原(yuan)(yuan)料流變特性(xing)和(he)溶劑型(xing)混(hun)合物中供(gong)應(ying)(ying)的材料的固體(ti)百分比。。

Coating, drying, and lamination: Coating is the application of a mixture to a substrate.  Depending on the equipment used, coating can impact CQAs such as content uniformity and microscopic appearance. Though CPPs are equipment dependent,  firms should demonstrate that the control strategy (e.g., process parameters to be controlled) is adequate to ensure content uniformity and microscopic appearance for the full duration of the coating operation. CMAs that can impact coating include the rheology of the bulk mixture and within-roll uniformity of the substrate to be coated

涂(tu)(tu)布、干燥和層壓:涂(tu)(tu)布是將混合物涂(tu)(tu)覆到基材(cai)上(shang)。根據使(shi)用的(de)設(she)備(bei),涂(tu)(tu)層可(ke)(ke)能會(hui)影(ying)響(xiang)CQA,如(ru)含(han)量均(jun)勻性和微觀(guan)外觀(guan)。盡管CPP依(yi)賴于設(she)備(bei),但企業應證明控(kong)(kong)制策略(例如(ru),要控(kong)(kong)制的(de)工藝參數)足以確(que)保(bao)涂(tu)(tu)布操作整個過程中的(de)含(han)量均(jun)勻性和微觀(guan)形態。可(ke)(ke)能影(ying)響(xiang)涂(tu)(tu)層的(de)CMA包括散裝混合物的(de)流變性和待(dai)涂(tu)(tu)層基材(cai)的(de)輥內均(jun)勻性

Drying involves the removal of solvent from the mixture following the coating process. This process step can impact CQAs such as assay, permeation enhancer content, antioxidant content, water content (for hydrogels), content uniformity, microscopic appearance, drug release, product stability, residual solvents, residual adhesive impurities, and physical properties of the adhesive matrix. Therefore, CPPs for drying that may need to be considered during process development include line speed, the pump or screw speed, zone temperatures, air flow rates, temperature of the drying air, and humidity of the drying air. Process development should also consider the CMAs that can impact drying such as solvent and adhesive impurity content in the bulk mixture. Applicants should also provide data to justify any drug substance overage or excipient excess that may be needed to compensate for any evaporation during drying

干(gan)燥(zao)(zao)包(bao)括在涂布過(guo)程(cheng)(cheng)之后從混合(he)(he)(he)物中除去溶劑(ji)(ji)。該工(gong)(gong)藝步驟可(ke)影響CQA,如(ru)測(ce)定(ding)(ding)、滲(shen)透促進劑(ji)(ji)含(han)量、抗(kang)氧化(hua)劑(ji)(ji)含(han)量、水(shui)含(han)量(用于水(shui)凝(ning)膠)、含(han)量均(jun)勻性(xing)、微觀外觀、藥物釋放(fang)、產品(pin)穩定(ding)(ding)性(xing)、殘留溶劑(ji)(ji)、殘留粘(zhan)合(he)(he)(he)劑(ji)(ji)雜(za)質和粘(zhan)合(he)(he)(he)劑(ji)(ji)基質的(de)物理(li)性(xing)質。因此,在工(gong)(gong)藝開發過(guo)程(cheng)(cheng)中可(ke)能需(xu)要考慮(lv)用于干(gan)燥(zao)(zao)CPP的(de)包(bao)括管線速度(du)、泵或螺桿速度(du)、區(qu)域溫度(du)、空氣流速、干(gan)燥(zao)(zao)空氣的(de)溫度(du)和干(gan)燥(zao)(zao)空氣的(de)濕度(du)。工(gong)(gong)藝開發還(huan)應考慮(lv)可(ke)能影響干(gan)燥(zao)(zao)的(de)CMA,如(ru)散裝(zhuang)混合(he)(he)(he)物中的(de)溶劑(ji)(ji)和粘(zhan)合(he)(he)(he)劑(ji)(ji)雜(za)質含(han)量。申請人還(huan)應提供數據,證明藥物和輔料可(ke)能需(xu)要過(guo)量,以補償干(gan)燥(zao)(zao)過(guo)程(cheng)(cheng)中的(de)蒸發損(sun)失。

Lamination involves the combining of multiple layers of a given transdermal system design into a single common laminate. Applicants should provide development data for corona treatments if such a process is used to bond the adhesive to a backing film or rate-controlling membrane

層(ceng)(ceng)壓(ya)包括將(jiang)(jiang)給定透皮系統(tong)設計的多個層(ceng)(ceng)組合成(cheng)單(dan)個普(pu)通(tong)層(ceng)(ceng)壓(ya)。如果使用電暈處理工(gong)藝將(jiang)(jiang)膠粘(zhan)劑粘(zhan)合到背膜或(huo)速(su)率(lv)控制膜上,則申請人應提(ti)供電暈處理的開(kai)發(fa)數(shu)據。

ØSlitting and Printing: The bulk product is typically slit longitudinally into narrower rolls of laminate for further processing. Slitting and printing are typically low risk steps; however, if certain aspects of the printing processes, e.g., excessive penetration depth or heat input, can adversely affect product quality, then printing processes should be characterized and controlled.

分切和印刷(shua)(shua):通常將散裝產品縱向(xiang)切成較窄(zhai)的層壓(ya)板卷,以便進(jin)(jin)一步加工。切片和印刷(shua)(shua)是(shi)典型的低風險步驟;然而,如果印刷(shua)(shua)過程的某些(xie)方面(mian),例(li)如過度的滲透深(shen)度或(huo)熱量輸入,會對產品質量產生不利影響,那么應對印刷(shua)(shua)工藝進(jin)(jin)行表征和控制(zhi)。

ØConverting and pouching: Converting and pouching typically involve cutting a  continuous laminate into individual units and sealing the unit in a heat-sealed pouch.  CQAs affected by these processes include usability of the product (e.g., the ability to remove a release liner) and pouch integrity. Common CPPs for these steps include heat sealing temperatures and dwell times.

轉換(huan)(huan)和封(feng)裝(zhuang):轉換(huan)(huan)和封(feng)裝(zhuang)通(tong)常涉及(ji)將連續層壓材料(liao)切割成單(dan)個單(dan)元,并將該單(dan)元密(mi)封(feng)在(zai)熱(re)密(mi)封(feng)袋中。受這些過程影響的(de)CQA包括產品(pin)的(de)可用性(xing)(例(li)如(ru),移除(chu)釋(shi)放襯墊的(de)能力)和袋的(de)完(wan)整性(xing)。這些步驟的(de)常見CPP包括熱(re)封(feng)溫度和停留時(shi)間。

Curing: Some TDS have processing steps to complete a curing reaction after drying or pouching. Curing time and curing conditions are common CPPs for this step. Curing should be completed before batch release testing if curing could impact test results.

固化:有(you)些(xie)TDS在干(gan)燥或裝袋后有(you)加工步驟來完成(cheng)(cheng)固化反應(ying)。固化時間和(he)固化條件是(shi)該步驟的常見(jian)CPPs。如(ru)果固化可能影響測試(shi)結果,則應(ying)在批放行測試(shi)前完成(cheng)(cheng)固化。

Hold times: Hold times must be defined and justified for in-process materials held between unit operations (21 CFR part 211.111). Applicants should use a risk-based approach to determine which CQAs to monitor during hold time studies.

保(bao)持(chi)時(shi)(shi)間(jian)(jian)(jian):必(bi)須定義和證明在(zai)單元操作之間(jian)(jian)(jian)保(bao)留的(de)過(guo)程中材料(liao)的(de)保(bao)留時(shi)(shi)間(jian)(jian)(jian)(21 CFR第211.111部分)。申請人應使(shi)用(yong)基于風險的(de)方法來確定在(zai)保(bao)持(chi)時(shi)(shi)間(jian)(jian)(jian)研究期(qi)間(jian)(jian)(jian)要監(jian)控(kong)哪(na)些CQA。

Other considerations: Tubing and other product-contact equipment must be qualified as non-reactive, non-additive, and non-absorptive (21 CFR part 211.65(a)). The selection of the tubing and certain product-contacting equipment should be risk based, i.e., dependent on the duration of contact, process temperature, solvent system,  material considerations, clearance of leachables during manufacturing, and clinical use considerations.

其他注意事項(xiang):管道(dao)和其他產品接觸設備必須經過非(fei)反應(ying)性、非(fei)添加劑和非(fei)吸收性(21 CFR第211.65(a)部分(fen))的認證。管道(dao)和某些產品接觸設備的選擇應(ying)基于風(feng)險,即取(qu)決(jue)于接觸持(chi)續時間、工藝(yi)溫(wen)度(du)、溶劑系統、材料考慮因素(su)、制(zhi)造過程中可(ke)浸出物(wu)的清除(chu)以及臨床使用考慮因素(su)。

In-process controls (IPCs) for TDS are an integral part of the control strategy. The descr1ption of the proposed IPCs should address the following:

TDS的過程(cheng)中控制(zhi)(IPC)是控制(zhi)策略的一個組成部分(fen)。擬議IPC方案的說(shuo)明應包括以下內容:

At the mixing stage, IPCs can provide assurance of assay, viscosity, uniformity, and pH for aqueous mixtures. If multiple samples are taken from a dispersed mixture, applicants should specify the mean, range for individual samples, and percent relative standard deviation.

在混(hun)合(he)階段,IPC可(ke)以保證水性(xing)混(hun)合(he)物的(de)含量、粘(zhan)度、均(jun)勻性(xing)和(he)pH值。如果從分散的(de)混(hun)合(he)物中(zhong)提取多個樣(yang)(yang)品(pin),申請(qing)人應指定(ding)平均(jun)值、單個樣(yang)(yang)品(pin)的(de)范圍和(he)相對標準偏(pian)差(cha)百分比。

IPCs for coating, drying, and lamination can provide assurance of uniformity across the laminate and throughout the run. For example, measurements for film appearance, coat weight, and/or a test for residual solvents may be applicable IPCs for coating and drying. Film appearance measurements that allow detection and rejection of defects affecting continuity of an adhesive laminate (e.g., streaks) should be described in the application. Additionally, for films that are dispersions at the microscopic scale (e.g.,  acrylic adhesive dispersed in silicone, povidone dispersed in silicone, or solid drug  substance dispersed in adhesive), applicants should describe the IPCs established to monitor uniformity throughout a coating run in the application. Samples for testing coat weight and uniformity should be representative of the full length and width of a laminate. Alternatively, these attributes can be monitored continuously (e.g., by the use of in-line coating measurement tools). In cases where the upstream controls can be used to confirm certain finished TDS specifications, such as residual solvents and  residual adhesive impurities, IPC testing can be used in lieu of release testing for these attributes.

用(yong)于涂(tu)布、干(gan)燥(zao)和(he)(he)層(ceng)壓的(de)(de)(de)(de)IPC可(ke)(ke)確保整(zheng)(zheng)個(ge)(ge)層(ceng)壓板和(he)(he)整(zheng)(zheng)個(ge)(ge)運(yun)行過程中(zhong)(zhong)(zhong)的(de)(de)(de)(de)均(jun)勻(yun)性。例(li)如(ru),薄膜外觀(guan)(guan)、涂(tu)層(ceng)質(zhi)(zhi)量(liang)的(de)(de)(de)(de)測(ce)(ce)量(liang)和(he)(he)/或殘(can)留溶劑的(de)(de)(de)(de)測(ce)(ce)試可(ke)(ke)能(neng)適(shi)用(yong)于涂(tu)層(ceng)和(he)(he)干(gan)燥(zao)的(de)(de)(de)(de)IPC。應(ying)在(zai)(zai)申(shen)請(qing)中(zhong)(zhong)(zhong)描述允(yun)許(xu)檢(jian)測(ce)(ce)和(he)(he)排除影響粘合(he)劑層(ceng)壓板連續性的(de)(de)(de)(de)缺陷(xian)(例(li)如(ru)條紋)的(de)(de)(de)(de)薄膜外觀(guan)(guan)測(ce)(ce)量(liang)。此外,對于在(zai)(zai)微(wei)觀(guan)(guan)尺度(du)上(shang)為分散體的(de)(de)(de)(de)薄膜(例(li)如(ru),分散在(zai)(zai)硅(gui)(gui)酮中(zhong)(zhong)(zhong)的(de)(de)(de)(de)丙(bing)烯酸粘合(he)劑,分散在(zai)(zai)硅(gui)(gui)氧烷中(zhong)(zhong)(zhong)的(de)(de)(de)(de)聚維(wei)酮,或分散在(zai)(zai)粘合(he)劑中(zhong)(zhong)(zhong)的(de)(de)(de)(de)固體藥物),申(shen)請(qing)人應(ying)描述為在(zai)(zai)應(ying)用(yong)中(zhong)(zhong)(zhong)監控整(zheng)(zheng)個(ge)(ge)涂(tu)層(ceng)運(yun)行的(de)(de)(de)(de)均(jun)勻(yun)性而建(jian)立(li)的(de)(de)(de)(de)IPC。用(yong)于測(ce)(ce)試涂(tu)層(ceng)質(zhi)(zhi)量(liang)和(he)(he)均(jun)勻(yun)性的(de)(de)(de)(de)樣品(pin)應(ying)代表層(ceng)壓板的(de)(de)(de)(de)整(zheng)(zheng)個(ge)(ge)長度(du)和(he)(he)寬(kuan)度(du)。或者,可(ke)(ke)以(yi)連續監測(ce)(ce)這些屬性(例(li)如(ru),通過使用(yong)在(zai)(zai)線涂(tu)層(ceng)測(ce)(ce)量(liang)工具)。如(ru)果(guo)上(shang)游控制可(ke)(ke)用(yong)于確認某些成(cheng)品(pin)TDS規范,如(ru)殘(can)留溶劑和(he)(he)殘(can)留粘合(he)劑雜質(zhi)(zhi),則可(ke)(ke)使用(yong)IPC測(ce)(ce)試代替(ti)這些屬性的(de)(de)(de)(de)釋放(fang)測(ce)(ce)試。

For converting and pouching, IPCs can provide assurance of pouch integrity, product placement within the pouch, and product appearance (e.g., adequacy of the printed label, die-cuts, and kiss-cuts). An automated system can perform in-process checks for product appearance in lieu of human operators if the automated system is demonstrated to be suitable for the intended task(s).

對于轉換和裝袋,IPC可以(yi)(yi)(yi)確保袋的(de)完整性、袋內的(de)產品放置以(yi)(yi)(yi)及產品外觀(例如,印刷標簽(qian)、模切和吻(wen)切的(de)充分性)。如果證明自動(dong)化系統適用(yong)于預期任務,自動(dong)化系統可以(yi)(yi)(yi)代替人(ren)工操作員對產品外觀進行過程中檢(jian)查。

C.Control of TDS Product

Section 3.2.P.5 of the application should contain the following information on control of the TDS product:

C.TDS產品控制(zhi)

申請書(shu)第3.2.P.5節(jie)應包(bao)含以下關于(yu)TDS產(chan)品(pin)控(kong)制的信(xin)息(xi):

Specification規格

Analytical procedures分析程序

Validation of analytical procedures分析程序的驗證

ØCharacterization of impurities雜質的表征

Batch analyses批次分析

Justification for the proposed specification擬定規范的理由

Typical CQAs included in TDS specification:

TDS規范中包含的典型CQA

Descr1ption說明

Identification鑒別

Assay含量測定

Impurities and degradation products雜質和降解產物

Uniformity of dosage units含量均勻度

Permeation enhancer content, when applicable促滲劑含量(如適用)

Adhesion粘合劑

Release liner peel釋放襯墊剝離

Tack黏著力

Shear剪切力

Cold flow冷流

In vitro drug release體外藥物釋放實驗

Drug substance crystal presence藥物晶態

Pouch integrity包裝完整性

Microbial limits, when applicable 微生物限度(如適用)

Moisture content, when applicable水分測定(如適用)

Residual solvents殘留溶劑

The proposed analytical procedures should be d0cumented in sufficient detail that they can be reviewed and reproduced in FDA laboratories. In some cases, if upstream controls can be used to confirm that a batch of product meets a CQA listed on the specification, that attribute may not need to be tested at release for every batch, but should be indicated as such on the specification. Applicants proposing a control strategy using such an approach should provide justification.

建議的分(fen)析程序(xu)應詳細記錄(lu),以(yi)便在(zai)(zai)FDA實驗室(shi)進(jin)行(xing)審(shen)查(cha)和復(fu)制。在(zai)(zai)某些情(qing)況(kuang)下,如果上游(you)控制可用于確認一批產(chan)品符(fu)合規(gui)范中列(lie)出的CQA,則該屬性可能不需要在(zai)(zai)每批產(chan)品放行(xing)時進(jin)行(xing)測試,但應在(zai)(zai)規(gui)范中注明。申(shen)請(qing)人(ren)提出使用這種方法的控制策略時應提供理由。

Some of the methods and criteria associated with CQAs typical for TDS are described below.

一些與(yu)CQAs相關的TDS典型(xing)方法和標準(zhun)如(ru)下所述。

a.Adhesive Impurities

Adhesives may contain residual monomers, initiator byproducts, aldehydes, etc. The safety of these compounds should be assessed, as some of these compounds are classified as neurotoxic (e.g., tetramethylsuccinonitrile) or mutagenic (e.g., crotonoaldehyde). Manufacturers are encouraged to contact the raw material suppliers to discuss the selected adhesive raw material  and all potential impurities, as some impurities may not be reported on the certificates of analysis provided by the supplier. Applicants should discuss the potential impurities arising from the raw material in the application. A control strategy for any impurity of toxicological relevance should be established and justified. The control strategy may include testing at the raw material stage,  demonstrating that the manufacturing process is capable of consistently removing the impurities of concern, testing of the final laminate, or a combination of the above.

a.粘合劑雜質

粘(zhan)合(he)劑(ji)可(ke)(ke)能含(han)有(you)(you)殘余單(dan)體、引(yin)發劑(ji)副(fu)產物、醛等。應(ying)評估這些化合(he)物的安全性,因為(wei)其中一些化合(he)物被分類(lei)為(wei)具有(you)(you)神(shen)經毒性(例(li)如,四甲基(ji)丁二腈)或致突變性(例(li)如巴豆醛)。鼓勵制造商(shang)與原(yuan)材料(liao)供(gong)應(ying)商(shang)聯(lian)系,討論所選(xuan)粘(zhan)合(he)劑(ji)原(yuan)材料(liao)和所有(you)(you)潛在雜質,因為(wei)供(gong)應(ying)商(shang)提供(gong)的分析證書中可(ke)(ke)能未報告某(mou)些雜質。申請(qing)人應(ying)在申請(qing)中討論原(yuan)材料(liao)可(ke)(ke)能產生的雜質。應(ying)制定(ding)并證明(ming)與毒理學相(xiang)關的任何雜質的控制策略。控制策略可(ke)(ke)包括在原(yuan)材料(liao)階段進行(xing)測(ce)試,證明(ming)制造過程能夠持(chi)續去除(chu)相(xiang)關雜質,測(ce)試最(zui)終(zhong)層壓板,或以上各項(xiang)的組合(he)。

To support a proposed control strategy based on the capability of the manufacturing process to consistently remove any impurities of concern, applicants should provide data to demonstrate a reduction in the level of the impurity in the final laminate (or finished product) compared to the level in the same batch of raw material.These data are necessary to quantitatively demonstrate effectiveness of the manufacturing process in removing the impurity and to establish controls for adhesive impurities based on levels in the raw material rather than on the final product.

為了支持(chi)基于制造工(gong)藝持(chi)續(xu)去除任(ren)何相關雜(za)質的(de)(de)(de)能力的(de)(de)(de)擬議控制策略,申請人(ren)應提供數據(ju)(ju),以證(zheng)(zheng)明最終層壓板(ban)(或(huo)成品)中(zhong)的(de)(de)(de)雜(za)質水平(ping)(ping)與同一批原材料(liao)中(zhong)的(de)(de)(de)水平(ping)(ping)相比有所降低。這些數據(ju)(ju)對于定量證(zheng)(zheng)明制造工(gong)藝去除雜(za)質的(de)(de)(de)有效(xiao)性以及(ji)根據(ju)(ju)原材料(liao)中(zhong)的(de)(de)(de)含(han)量而不是(shi)最終產品中(zhong)的(de)(de)(de)含(han)量建立粘(zhan)合劑雜(za)質控制是(shi)必要的(de)(de)(de)。

Applicants may consider leveraging the leachable study discussed in the pharmaceutical development section of this guidance by testing adhesive impurities in the leachate. The leachable information can be used to provide toxicological justification for impurity limits or the information can be included as part of the toxicological risk assessment.

申請人(ren)可(ke)考慮利用本指南藥物開(kai)發部分中討論的(de)(de)可(ke)浸(jin)出(chu)性研究,測(ce)試(shi)滲(shen)濾液中的(de)(de)粘(zhan)合劑雜質(zhi)。可(ke)浸(jin)出(chu)信(xin)息可(ke)用于為雜質(zhi)限值提供毒(du)理學依據,或將信(xin)息作為毒(du)理學風險評估(gu)的(de)(de)一部分。

b.Uniformity of Dosage Units

TDS specifications should include a test and acceptance criterion for content uniformity for the dosage units. If the finished TDS is designed to be cut by the user, uniformity should also be demonstrated among pieces cut from a single unit.

b.含(han)量均勻度

TDS規范應包括(kuo)劑量單(dan)位含量均(jun)勻性的(de)測試和(he)驗收標準。如(ru)果最終TDS設(she)計為由用戶切割,則(ze)還(huan)應證明從單(dan)個單(dan)元切割的(de)工件之間的(de)一致性。

c.Permeation Enhancer Content

Products that utilize permeation enhancers to establish or maintain drug delivery should include a test and acceptance criterion for permeation enhancers at release and throughout stability. An acceptance criterion that is wider than the typical range for a particular permeation enhancer may require in vivo justification in the absence of an in vitro in vivo correlation.

C.促滲劑含量(liang)

使用(yong)滲透(tou)促進劑(ji)建立或維持藥(yao)物遞送的產品應包(bao)括促滲劑(ji)在釋放和(he)整個穩定性試驗(yan)時的測試和(he)驗(yan)收標準(zhun)。在缺乏體外(wai)-體內相關性的情況下,比特(te)定促滲劑(ji)的典(dian)型范圍(wei)更寬的接(jie)受標準(zhun)可能(neng)需要(yao)體內研究證明。

d.Adhesion Testing (Peel Adhesion, Release Liner Peel, Tack, and Shear Tests)

Using currently available methods, in vitro adhesion testing does not correlate to in vivo adhesion, but in vitro adhesion testing can be useful for quality control (QC) purposes. In vitro adhesion testing should include peel adhesion, release liner removal, tack, and shear (dynamic or static). There are multiple methods and different experimental parameters for each of the tests.

D.黏附試驗(剝(bo)離粘(zhan)附、釋放襯墊剝(bo)離、粘(zhan)性和(he)剪切試驗)

使(shi)用當前可用的方法,體(ti)外(wai)(wai)粘附測試(shi)與體(ti)內粘附無關,但(dan)體(ti)外(wai)(wai)黏附測試(shi)可用于質(zhi)量(liang)控(kong)制(zhi)(QC)目的。體(ti)外(wai)(wai)黏附測試(shi)應包括剝離黏附、剝離襯墊移(yi)除(chu)、粘性和剪切(動態或靜(jing)態)。每個(ge)測試(shi)有多種(zhong)方法和不同的實驗參數。

The peel adhesion test measures the force required to remove (peel away) a TDS that has been applied to a standard test panel (e.g., polished stainless steel). The measurement of peel adhesion is influenced by the test parameters such as dwell time, substrate (e.g., stainless steel, high density polyethylene (HDPE)), peel angle, and peel speed.

剝離(li)附著(zhu)力(li)測(ce)(ce)試測(ce)(ce)量去(qu)除(剝離(li))已應(ying)用于標(biao)準(zhun)測(ce)(ce)試面板(例如(ru)拋光(guang)不(bu)(bu)銹(xiu)鋼)的TDS所(suo)需的力(li)。剝離(li)附著(zhu)力(li)的測(ce)(ce)量受(shou)測(ce)(ce)試參數的影響,例如(ru)停(ting)留時間(jian)、基材(cai)(例如(ru)不(bu)(bu)銹(xiu)鋼、高密(mi)度聚(ju)乙烯(HDPE))、剝離(li)角和剝離(li)速(su)度。

A release liner peel test measures the force required to separate a TDS from its release liner. The measurement of release liner peel is influenced by experimental parameters such as peel angle and peel speed.

釋放襯(chen)墊(dian)剝(bo)離(li)(li)測(ce)試用于測(ce)量(liang)將(jiang)TDS與釋放襯(chen)套分離(li)(li)所需的力。釋放襯(chen)墊(dian)剝(bo)離(li)(li)的測(ce)量(liang)受(shou)剝(bo)離(li)(li)角和剝(bo)離(li)(li)速度(du)等實驗(yan)參數的影響。

The probe tack test measures the force required to separate the test probe from the adhesive of the TDS. Tack measurement is influenced by the test parameters such as the contact area, the contact pressure, the time of contact (or dwell time), and rate of separation.

探針粘性測(ce)(ce)試(shi)測(ce)(ce)量(liang)將測(ce)(ce)試(shi)探針與TDS粘合(he)劑分離(li)所需的(de)力。粘性測(ce)(ce)量(liang)受測(ce)(ce)試(shi)參(can)數的(de)影響,如接(jie)觸面(mian)積、接(jie)觸壓力、接(jie)觸時間(jian)(或停留時間(jian))和分離(li)速度。

There are two categories of shear testing, namely dynamic and static. In the dynamic test, the TDS is pulled from a standard test panel (e.g., polished stainless steel). Dwell time, speed, type of test panel, mode of failure, and sample size are the typical test parameters reported for the dynamic shear test. In the static shear test, the TDS sample is applied to a test panel that is at an angle 2° from the vertical, and the sample is subjected to a shearing force by a means of a givenweight (e.g., 1000 g) suspended from the TDS; the time required to detach a standard area of the TDS from a stainless steel test panel under a standard load is measured. Dwell time, weight used, type of test panel, mode of failure, and sample size are the typical test parameters reported for the static shear test. The time taken for the TDS sample to detach from the test panel is also reported

剪切(qie)試(shi)驗(yan)有兩(liang)類(lei),即動(dong)態(tai)和靜(jing)態(tai)。在(zai)動(dong)態(tai)測(ce)試(shi)中(zhong),TDS從(cong)標準測(ce)試(shi)面板(ban)(ban)(例如,拋光(guang)不(bu)銹鋼(gang))中(zhong)拉(la)出。停留時(shi)間、速度、試(shi)驗(yan)板(ban)(ban)類(lei)型、失效模(mo)式(shi)和樣本(ben)大(da)小是動(dong)態(tai)剪切(qie)試(shi)驗(yan)報(bao)告(gao)的(de)(de)典(dian)型試(shi)驗(yan)參數(shu)。在(zai)靜(jing)態(tai)剪切(qie)試(shi)驗(yan)中(zhong),將TDS樣品(pin)施加到與(yu)垂直方向成2°角的(de)(de)試(shi)驗(yan)板(ban)(ban)上(shang)(shang),并通過懸(xuan)浮在(zai)TDS上(shang)(shang)的(de)(de)給定質(zhi)量(liang)(例如1000 g)對(dui)樣品(pin)施加剪切(qie)力(li);測(ce)量(liang)在(zai)標準負載下從(cong)不(bu)銹鋼(gang)測(ce)試(shi)面板(ban)(ban)上(shang)(shang)分離TDS標準區域所(suo)需的(de)(de)時(shi)間。靜(jing)態(tai)剪切(qie)試(shi)驗(yan)報(bao)告(gao)的(de)(de)典(dian)型試(shi)驗(yan)參數(shu)包(bao)括停留時(shi)間、所(suo)用質(zhi)量(liang)、試(shi)驗(yan)板(ban)(ban)類(lei)型、破壞(huai)模(mo)式(shi)和樣品(pin)尺(chi)寸。也需報(bao)告(gao)TDS樣品(pin)從(cong)測(ce)試(shi)面板(ban)(ban)上(shang)(shang)分離所(suo)需的(de)(de)時(shi)間

E.冷流

冷流是指粘合劑基質在(zai)背襯膜周(zhou)邊或通過(guo)剝離襯墊(dian)縫隙的流動或滲出。TDS、隔(ge)離襯(chen)墊、袋或(huo)一次性(xing)膜(mo)(有時稱為滑動片或(huo)保護膜(mo),例如背襯(chen)上(shang)的膜(mo)和隔(ge)離襯(chen)墊上(shang)的膜(mo))上(shang)可能存在(zai)冷流。盡管評估冷(leng)流的(de)定(ding)量方(fang)法可以提(ti)供有意義的(de)測(ce)量,但(dan)它可能無法描述從袋中(zhong)去(qu)除(chu)TDS或從TDS中(zhong)去(qu)除(chu)保護膜的(de)困難。TDS最準確的(de)冷流(liu)評(ping)估(gu)可能(neng)來自特定產品的(de)定量(liang)和(he)定性(xing)方法的(de)組合。

 

The test methods should be discriminating and scientifically justified. Manufacturers should propose product-specific acceptance criteria with justification supported by product development research.

測試方(fang)法應具有鑒別性和科學合理(li)性。制(zhi)造商應提出(chu)產(chan)品特(te)定的(de)驗(yan)收標準(zhun),并提供產(chan)品開發研究(jiu)支(zhi)持的(de)理(li)由。

f.In vitro Drug Release

USP General Chapter describes the apparatuses to use for in vitro release testing and the acceptance criteria for each apparatus; however, method development and validation is not addressed. General recommendations for in vitro release testing of TDS are described below along with considerations for method design and validation

F.體外(wai)藥(yao)物釋放

USP通則章節描述了用于體(ti)外釋放測(ce)試的(de)儀器以及每個(ge)儀器的(de)驗(yan)(yan)收(shou)標準;然(ran)而,方(fang)法(fa)開發和(he)驗(yan)(yan)證并未涉(she)及。TDS體(ti)外釋放試驗(yan)(yan)的(de)一(yi)般建議以及方(fang)法(fa)設計和(he)驗(yan)(yan)證的(de)注意事(shi)項如下(xia)所述

In vitro drug release testing of TDS products is typically performed using specific, qualified apparatus such as: Paddle over Disk (Apparatus 5), Cylinder (Apparatus 6), or Reciprocating Holder (Apparatus 7).

TDS產品的體外藥物(wu)釋放測試通(tong)常使用(yong)特定合格(ge)的設(she)備進(jin)行,例如:槳(jiang)碟法(fa)(裝置5)、轉(zhuan)筒法(fa)(裝置6)或往復支架(jia)法(fa)(裝置7)。

(圖(tu)片(pian)提供銳拓相應設備圖(tu)片(pian))

The NDA or ANDA submission for the TDS product should include a method development and validation report with complete information/data supporting the proposed drug release method and acceptance criteria.

TDS產品的NDA或ANDA提交文件(jian)應(ying)包(bao)括方法開發(fa)和驗證報(bao)告(gao),其中包(bao)含支持擬定藥物釋放方法和驗收(shou)標準的完整信息/數據。

Sufficient detail and data should be included in the method development and validation report so the adequacy of the method for batch release and stability testing can be properly assessed. Examples of parameters to eva1uate during method development include selection of USP apparatus/other equipment, drug release medium, rotation or agitation speed, temperature, pH,  sink conditions, use of a surfactant, and other technical aspects of the test. An in vitro drug release method should be simple, reliable, reproducible, discriminating, and robust. Applicants should strive to develop a method that releases as much drug as possible.

方(fang)法(fa)開(kai)(kai)發和驗證報告(gao)中應(ying)包含足(zu)夠的(de)(de)(de)細節和數據,以便(bian)能夠正確評估(gu)批放(fang)行和穩定性(xing)測(ce)試方(fang)法(fa)的(de)(de)(de)充分(fen)性(xing)。方(fang)法(fa)開(kai)(kai)發過程中要(yao)評估(gu)的(de)(de)(de)參(can)數示例包括USP儀器/其(qi)他設(she)備的(de)(de)(de)選擇(ze)、藥(yao)物(wu)釋(shi)放(fang)介質、旋轉或攪拌(ban)速(su)度(du)、溫度(du)、pH值、沉降條件、表(biao)面活性(xing)劑的(de)(de)(de)使用(yong)以及測(ce)試的(de)(de)(de)其(qi)他技術方(fang)面。體外(wai)藥(yao)物(wu)釋(shi)放(fang)方(fang)法(fa)應(ying)簡單、可靠、可重復、鑒別和耐用(yong)。申請人應(ying)努力開(kai)(kai)發一種釋(shi)放(fang)盡可能多藥(yao)物(wu)的(de)(de)(de)方(fang)法(fa)。

 

The validation section of the report should include complete information/data regarding: i) the discriminating ability of the selected method, ii) the validation of the drug release methodology, and iii) the validation/verification of the analytical method selected to assay the drug release samples. The selected method should be able to differentiate the release profiles of TDS that are intentionally manufactured with meaningful variations in critical process parameters and formulation components. Validation data should demonstrate the range and sensitivity of the  method for proportional drug release across different strengths of the TDS. In addition,  validation data should demonstrate reproducibility of the method for drug release across different runs of the same batch and its robustness, i.e., its capacity to remain unaffected by changes in receptor medium temperature, paddle rate, and other method parameters

報告的(de)驗(yan)證(zheng)(zheng)(zheng)部分(fen)應包括以下方(fang)面的(de)完整信(xin)息/數(shu)據(ju)(ju):i)所選(xuan)方(fang)法的(de)區分(fen)力,ii)藥(yao)物釋(shi)放(fang)方(fang)法的(de)驗(yan)證(zheng)(zheng)(zheng),以及(ji)iii)測定(ding)藥(yao)物釋(shi)放(fang)樣(yang)品所選(xuan)分(fen)析(xi)方(fang)法的(de)驗(yan)證(zheng)(zheng)(zheng)/驗(yan)證(zheng)(zheng)(zheng)。所選(xuan)方(fang)法應能夠(gou)區分(fen)有(you)意制造的(de)TDS的(de)釋(shi)放(fang)曲線,其(qi)關鍵工(gong)藝參數(shu)和(he)配方(fang)組分(fen)存(cun)在(zai)有(you)意義的(de)變(bian)化。驗(yan)證(zheng)(zheng)(zheng)數(shu)據(ju)(ju)應證(zheng)(zheng)(zheng)明(ming)該方(fang)法在(zai)TDS不同強度(du)(du)下的(de)比例藥(yao)物釋(shi)放(fang)范圍(wei)和(he)靈敏度(du)(du)。此外,驗(yan)證(zheng)(zheng)(zheng)數(shu)據(ju)(ju)應證(zheng)(zheng)(zheng)明(ming)藥(yao)物釋(shi)放(fang)方(fang)法在(zai)同一批次(ci)的(de)不同運行中的(de)再(zai)現性(xing)及(ji)其(qi)耐(nai)用性(xing),即其(qi)不受受體介質溫度(du)(du)、槳速率和(he)其(qi)他(ta)方(fang)法參數(shu)變(bian)化影響的(de)能力

相關閱讀:《FDA IVRT測試 工業指南翻譯稿》

The acceptance criteria for the in vitro drug release test should be based on the proposed TDS product batch release data, including data from bio-batches (e.g., BE, PK, Clinical), registration/exhibit batches, and commercial batches (if available). To set the acceptance criteria for the in vitro drug release test, a complete drug release profile should be established by collecting data until there is no increase in drug release over three consecutive time points (sampling every 2 hours). The drug release profile of TDS products typically encompasses  initial, middle, and terminal phases; thus, for setting the acceptance criteria, there should be at least one sampling time point covering each phase. The drug release data should be reported as  the cumulative percent of drug being released with time. The acceptance criteria range for each specific timepoint should be based on the mean percentage value of drug released ± 10 percent using the drug release data generated at these times. The percentage should be determined based  on the TDS product’s label claim. If less than 100 percent drug is released, but no drug increase is observed over three consecutive sampling timepoints (i.e., incomplete drug release), the amount of drug reached at the plateau should be considered 100 percent for the purposes of estimating the percent of drug release over time.

體外(wai)藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)試(shi)驗的(de)(de)驗收(shou)標(biao)(biao)準應(ying)(ying)(ying)基于擬定的(de)(de)TDS產品(pin)(pin)批(pi)放(fang)(fang)行數(shu)據,包括生物(wu)(wu)批(pi)次(ci)(如BE、PK、臨床)、注冊/展示批(pi)次(ci)和商業(ye)批(pi)次(ci)(如可用(yong)(yong))的(de)(de)數(shu)據。為了制定體外(wai)藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)試(shi)驗的(de)(de)驗收(shou)標(biao)(biao)準,應(ying)(ying)(ying)通過收(shou)集數(shu)據建(jian)立完整的(de)(de)藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)曲線,直到(dao)連(lian)(lian)續三(san)個(ge)(ge)時(shi)間(jian)點(dian)(dian)(每(mei)2小時(shi)取樣一次(ci))藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)量沒有(you)增加。TDS產品(pin)(pin)的(de)(de)藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)概(gai)況通常包括初期(qi)、中期(qi)和末期(qi);因此,為了設定驗收(shou)標(biao)(biao)準,每(mei)個(ge)(ge)階段(duan)至少(shao)(shao)應(ying)(ying)(ying)有(you)一個(ge)(ge)采(cai)樣時(shi)間(jian)點(dian)(dian)。藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)數(shu)據應(ying)(ying)(ying)報告為藥(yao)(yao)(yao)(yao)物(wu)(wu)隨(sui)時(shi)間(jian)釋(shi)(shi)(shi)(shi)放(fang)(fang)的(de)(de)累積百分比。每(mei)個(ge)(ge)特定時(shi)間(jian)點(dian)(dian)的(de)(de)驗收(shou)標(biao)(biao)準范圍應(ying)(ying)(ying)基于使用(yong)(yong)這(zhe)些(xie)時(shi)間(jian)生成的(de)(de)藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)數(shu)據的(de)(de)藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)的(de)(de)平均百分比值±10%。百分比應(ying)(ying)(ying)根據TDS產品(pin)(pin)的(de)(de)標(biao)(biao)簽聲(sheng)明確定。如果釋(shi)(shi)(shi)(shi)放(fang)(fang)的(de)(de)藥(yao)(yao)(yao)(yao)物(wu)(wu)少(shao)(shao)于100%,但在連(lian)(lian)續三(san)個(ge)(ge)采(cai)樣時(shi)間(jian)點(dian)(dian)內未觀察到(dao)藥(yao)(yao)(yao)(yao)物(wu)(wu)增加(即藥(yao)(yao)(yao)(yao)物(wu)(wu)釋(shi)(shi)(shi)(shi)放(fang)(fang)不完全),則應(ying)(ying)(ying)將(jiang)達到(dao)穩(wen)定期(qi)的(de)(de)藥(yao)(yao)(yao)(yao)物(wu)(wu)量視為100%,以估計藥(yao)(yao)(yao)(yao)物(wu)(wu)隨(sui)時(shi)間(jian)的(de)(de)釋(shi)(shi)(shi)(shi)放(fang)(fang)百分比。

Wider acceptance criteria range for the drug release test may be acceptable if they are supported by an approved in-vitro in-vivo correlation model.

如果有已批(pi)準的體外-體內相關模型支持,則藥物(wu)釋放試驗的接受(shou)標準范圍可能會更寬。

g.Crystal Presence

The presence of crystals or crystallization of the drug in the TDS over time can negatively impact the product performance. Therefore, it is important to establish a test and acceptance criteria to confirm the absence of crystals to be used at release and on stability. Microscopic and photometric methods are preferred rather than a simple visual count. It is recognized that some products are designed to be suspensions, however, this design does not preclude the need for a crystal specification. Suspension products should still include tests and acceptance criterion to ensure against crystal propagation, which may impact drug delivery or adhesion properties of the product.

g.析晶現象

隨(sui)著時間的推移(yi),TDS中析出藥物晶體(ti)或結晶會對產(chan)(chan)(chan)品(pin)性(xing)(xing)能產(chan)(chan)(chan)生負面影(ying)(ying)響。因此,建(jian)立(li)一個測(ce)試和(he)驗收標(biao)準,以(yi)確認釋放(fang)和(he)穩定性(xing)(xing)時不存在待(dai)使用的晶體(ti),這(zhe)(zhe)(zhe)一點很重要。最(zui)好使用顯(xian)微鏡和(he)光(guang)度法,而不是簡(jian)單的目視計(ji)數(shu)。人(ren)們(men)認識到,雖然有(you)些產(chan)(chan)(chan)品(pin)設計(ji)為懸浮液,但(dan)這(zhe)(zhe)(zhe)種設計(ji)并不排除(chu)對晶體(ti)規格的需求。懸浮產(chan)(chan)(chan)品(pin)仍(reng)應包(bao)括(kuo)測(ce)試和(he)驗收標(biao)準,以(yi)防(fang)止晶體(ti)化,這(zhe)(zhe)(zhe)可能會影(ying)(ying)響藥物輸送或產(chan)(chan)(chan)品(pin)的粘(zhan)附性(xing)(xing)能。

h.Pouch Integrity

The pouch for a TDS is critical to the stability and integrity of the product. Pouch integrity testing should be conducted as part of finished product release unless justification is provided for an alternative approach that assures the finished product specification is met.

h.袋的完整性

TDS袋(dai)(dai)對產品的穩(wen)定(ding)性(xing)(xing)和完整性(xing)(xing)至關重(zhong)要(yao)。袋(dai)(dai)完整性(xing)(xing)測試應作為成品放(fang)行(xing)的一部分進行(xing),除非為確保符合(he)成品規范的替代方法提(ti)供了理(li)由。

D.Additional Stability Studies

In addition to the standard battery of formal stability and photostability studies for drug substance and drug products discussed in ICH Q1A and ICH Q1B, TDS applicants and manufacturers should conduct stability studies under challenge conditions that include temperature excursions, freeze/thaw, and/or crystal seeding. These additional studies are intended to address certain product quality issues such as crystal formation and growth. Moreover, in-use photostability testing may be appropriate to conduct for certain TDS formulations, depending on backing membrane opacity, duration of wear, and its expected exposure to light when in use.


D.其他 穩定性研究

除(chu)了ICH Q1A和(he)ICH Q1B中討論(lun)的(de)(de)原料藥和(he)藥物(wu)產(chan)品(pin)的(de)(de)正(zheng)式(shi)穩(wen)定(ding)性(xing)(xing)和(he)光穩(wen)定(ding)性(xing)(xing)研究的(de)(de)標準(zhun)組外,TDS申(shen)請人和(he)制造商應在挑戰條件下進行穩(wen)定(ding)性(xing)(xing)研究,包(bao)括溫度漂移(yi)、冷凍/解凍和(he)/或(huo)晶種。這些(xie)額外的(de)(de)研究旨在解決某些(xie)產(chan)品(pin)質量(liang)問(wen)題,如晶體形成和(he)生長。此外,使用(yong)中的(de)(de)光穩(wen)定(ding)性(xing)(xing)測(ce)試可能適用(yong)于(yu)某些(xie)TDS制劑,這取決于(yu)背襯(chen)膜的(de)(de)不透明度、磨損(sun)持續時間以及使用(yong)時預(yu)期(qi)的(de)(de)光暴露。

A.Product Adhesion Considerations

In vivo adhesion studies provide the greatest prediction of adhesion, a CQA, for a proposed commercial product. Applicants should demonstrate that reasonable efforts were made to optimize adhesive characteristics of the TDS. This optimization should balance properties such as adhesiveness, cohesiveness, and stability to ensure a consistent and uniform adhesion of its entire surface area to the skin for the entire duration of wear. Applicants should develop a comprehensive strategy for assessing the adhesive attributes of the TDS. In vivo adhesion studies are necessary to demonstrate adequate adhesion of the TDS. Therefore, when possible, such as in efficacy studies for an NDA, subject diaries describing the actual in-use product adhesion performance should be used. This information bolsters adhesion data collected from the studies described below and in other guidances


A.產(chan)品附著力注意(yi)事項

體表粘附研究(jiu)為(wei)擬定的(de)商業產品提供了(le)最大的(de)粘附預測,即CQA。申請人應(ying)證明已作出(chu)合理(li)努力以優化TDS的粘合特性。這種優化(hua)應平衡諸如粘附(fu)性、內聚性和(he)穩(wen)定性等特(te)性,以確保(bao)在整個(ge)使用期間其(qi)整個(ge)表面區域與皮膚(fu)的一致(zhi)性和(he)均(jun)勻粘附(fu)力(li)。申請(qing)人應制(zhi)定全面的策略來評(ping)估TDS的粘性屬性。體內(nei)粘(zhan)附研究是證(zheng)明TDS充分粘(zhan)附的必要(yao)條件。因此(ci),在可能(neng)的情況下(xia),例如在NDA的療(liao)效研究(jiu)中(zhong),應使用(yong)描述實際在用(yong)產品(pin)粘附性能(neng)的受試者日記(ji)。該信息支持從以下研究和(he)其(qi)他指南中收集的粘附數據

 

Characterization of the adhesive properties of a TDS should demonstrate that the labelled uses are substantiated. For example, if the TDS is intended to be worn during bathing and showering, applicants should demonstrate that the TDS will continue to adhere during and after such incidental exposure to water. Product reinforcement, such as taping the edges or use of overlays, or occluding the product from water during bathing should not be permitted during the in vivo adhesion eva1uation

TDS粘附(fu)特性的表征(zheng)應證明標簽用(yong)途(tu)得(de)到(dao)證實(shi)。例如,如果TDS打算在(zai)沐浴和(he)淋(lin)浴時使用(yong),申請人應證明TDS在(zai)偶然接觸水期(qi)間和(he)之后將繼續保持(chi)粘附(fu)。在(zai)體內粘附(fu)性評(ping)估期(qi)間,不允許使用(yong)產品加固,例如貼邊或使用(yong)覆蓋物,或在(zai)沐浴期(qi)間將產品與水隔絕

We recommend that when assessing the adhesion of a TDS, applicants use a 5-point numerical scale in which each score corresponds to a specified range of adhered surface area of the TDS, as follows:

我們(men)建(jian)議(yi),在評估(gu)TDS粘(zhan)附(fu)性時,申請人(ren)使用5分制的數值量表,其中每個分數對應TDS粘(zhan)附(fu)表面積的指定范圍,如下所示(shi):

0 = ≥ 90% adhered (essentially no lift off the skin) 粘附(基本上不會剝離(li)皮膚)

1 = ≥ 75% to < 90% adhered (some edges only lifting off the skin) 粘附(fu)(某些邊緣僅從(cong)皮(pi)膚上剝離)

2 = ≥ 50% to < 75% adhered (less than half of the TDS lifting off the skin) 粘附(少于(yu)TDS的(de)一半(ban)剝(bo)離皮膚(fu))

3 = > 0% to < 50% adhered (not detached, but more than half of the TDS lifting off the skin without falling off) 粘附(未(wei)脫(tuo)落,但(dan)超過一(yi)半的(de)TDS從皮膚上(shang)剝離而(er)不脫(tuo)落)

4 = 0% adhered (TDS detached; completely off) 粘附(TDS分(fen)離;完全脫落(luo))

Additionally, the following information should be collected:

此(ci)外(wai),還(huan)應收集(ji)以(yi)下信息:

At each time point when adhesion is assessed on the above described 5-point scale, the scorer should also record their actual percent adherence estimate (e.g., if the observer scores the product as a two on the five point scale and estimates that the product appears to be 60 percent adhered, a score of two and a 60 percent should be recorded for that time point).

在(zai)以上(shang)述5分(fen)(fen)制評估(gu)(gu)粘(zhan)附(fu)力的每個時間點(dian),記(ji)分(fen)(fen)員還應記(ji)錄他(ta)們(men)的實際粘(zhan)附(fu)百分(fen)(fen)比估(gu)(gu)計值(例如,如果(guo)觀察者在(zai)5分(fen)(fen)制上(shang)將產品(pin)評分(fen)(fen)為2分(fen)(fen),并估(gu)(gu)計產品(pin)粘(zhan)附(fu)率為60%,則(ze)應記(ji)錄該時間點(dian)的2分(fen)(fen)和60%)。

Photographic evidence showing the extent of TDS adherence to the skin at each time point should be provided.

應提供照片證據,顯示(shi)在每個時間點TDS粘附到皮膚的程度(du)。

B.Product Storage and Disposal – Labeling Considerations

TDS storage conditions should be supported by stability data and stated in the label. Generally, we recommend controlled room temperature for the storage of TDS. Excursions, if permitted, should be indicated on the label. The label should also state that TDS should not be stored outside of the pouch if that is necessary to preserve the safety, efficacy, and quality of the TDS.

B.產品(pin)儲存(cun)和處理-標(biao)簽注意事(shi)項

TDS儲存條(tiao)件應(ying)得(de)到穩定性(xing)(xing)數據(ju)的支持,并在標簽(qian)中說明。通常,我們(men)建(jian)議在室溫下儲存TDS。如(ru)果允許(xu),應(ying)在標簽(qian)上注明。標簽(qian)還應(ying)說明,如(ru)果為了保(bao)持TDS的安全性(xing)(xing)、有效性(xing)(xing)和質量,TDS不(bu)應(ying)存放在袋外。

Transdermal and topical delivery systems often contain post-use residual drug in the delivery system. Considering the therapeutic nature of the drug compound and potential adverse events resulting from unintended exposure, the instruction for product disposal should be clearly outlined in the labeling. It is important that the disposal process prevents exposure of the residual drug to the environment and/or other people. Depending on the nature of the product, special instructions may be required to prevent exposure to children and caregivers, which could result in significant safety-related consequences

經皮和(he)局部遞送(song)系統使用后(hou),通(tong)常(chang)會有殘留的藥(yao)物(wu)。考慮到藥(yao)物(wu)的治療性質和(he)由于(yu)意外暴(bao)露引起的潛在不(bu)良事(shi)件,標簽中應(ying)明(ming)(ming)確列出產品處理事(shi)項(xiang)。處理過(guo)程必(bi)須(xu)防(fang)止殘余藥(yao)物(wu)暴(bao)露于(yu)環境和(he)/或其(qi)他人(ren)。根據產品的性質,可能(neng)(neng)需要特殊(shu)說明(ming)(ming),以防(fang)止兒童和(he)護理人(ren)員(yuan)接觸(chu),否(fou)則(ze)可能(neng)(neng)會導致(zhi)嚴重的安全相關(guan)后(hou)果

實驗(yan)儀(yi)器(qi):銳拓 RT800 自動取樣透皮擴散系統

 

 

 

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