1、fda發布咀嚼片關鍵質量屬性指導原則（中英文對照）i. introductioni 引言this guidance provides manufacturers of chewable tablets for human use with the center for drug evaluation and research's (cder) current thinking on the critical quality attributes that should be assessed during the development of these drug products.2

2、 this guidanee also provides recommendations about submitting developmental, manufacturing, and labeling information for chewable tablets that must be approved by cder before they can be distributed. the recommendations in this guidance apply mainly to new drug applications(ndas), abbreviated new dr

3、ug applications (andas),3 and certain chemistry, manufacturing, and controls (cmc) supplements to these applications4 some of there commendations about the submission of developmental information may also apply to investigational new drug applications (inds). the recommendations about assessing crit

4、ical quality attributes apply to all chewable tablets for human use, including non-application products.本指南向生產者提供了藥品審評研究中心(cder )對人用咀嚼片在研發過 程中應評估的關鍵質量屬性的當前想法2。該指南也提供了必須向cder提交并 被其批準的咀嚼片的研發、生產及說明書信息的建議。該指南的這些建議主要針 對新藥申請(ndas )、仿制藥申請(andas尸和一些化學、生產和質控(cmc ) 補充申請°。某些建議同樣適合于硏究性新藥申請(即新藥臨床申請，inds )。

5、關于評估關鍵質量屬性的建議適用于所有人用咀嚼片,包括非申請產品。inge neral, fda's guidance docume nts do not establish legally enforceableresponsibilities instead, guidances describe the agency's current thinking ona topic and should be viewed only as recommendations, unless specificregulatory or statutory requirements are

6、 cited. the use of the word should inagency guidances means that something is suggested or recommended, but notrequired.通常,fda的指導文件不具有法律強制性，指南中描述的主題僅代表fda 機構目前的看法，只作為建議，除非是引用具體的法規或條例要求。建議或推薦 使用該指導原則，但不是必須的。ii. backgroundii 背景chewabletablets are an immediate release (ir) oral dosage form intended to

7、be chewedand then swallowed by the patient rather than swallowed whole. they should be designed to have a pleasanttaste and be easily chewed and swallowed. chewable tablets should be safe and easy to use in a diverse patientpopulation, pediatric, adult, or elderly patients, who are unable or unwilli

8、ngto swallow intact tablets due to the size of the tablet or difficulty withswallowing. the availability of safe, easy-touse dosage forms is important in clinical practice. chewable tablets are available for many over-the-counter(otc) and prescription drug products.咀嚼片是患者經咀嚼后立即釋放的口服劑型，而不是整個吞咽。其應被設計

9、為可口的味道且易于咀嚼和吞咽。咀嚼片應是安全的，易于那些因片子大小或吞 咽困難導致不能或不愿吞服的特殊人群、兒童、成年、或老年患者服用。能獲得 安全的、易于服用的劑型在臨床實踐中非常重要。在許多otc和處方藥中均有 咀嚼片。thellnited states pharmacopeia (usp) recognizes and differentiates between twotypes of chewable tablets: (1) thosethat may be chewed for ease of administration, and (2) those that must bec

10、hewed or crushed before swallowing to avoid choking and/or to ensure therelease of the active ingredient.5 the concepts in this guidanee are applicable to both types of chewabletablets.usp藥典中識別和區分兩種類型的咀嚼片：(1 )可以咀嚼以方便服用的咀 嚼片；(2 )必須咀嚼或壓碎以避免吞咽窒息和/或確保活性成分充分釋放的咀嚼 片5。本指南中的概念適用于這兩種類型的咀嚼片。adverseevents for

11、chewable tablets can include gastrointestinal (gl) obstructionresulting from patients swallowing whole or in completely chewed tablets, as wellas tooth damage and denture breakage resulting from excessive tablet hardness* a related potential adverse event thatsponsors should also consider is esophag

12、eal irritation from chewabletablets. a review of numerous approveddrug product applications for chewable tablets revealed that in certain casescritical quality attributes such as hardness, disintegration, and dissolutionwere not give n as much con sideration as may have been warranted. this was evid

13、enced by instances of incompletemonitoring of all relevant critical quality attributes or the use of widelyranging values that were not justified as acceptance criteria. in addition, a wide variation in analyticalprocedures has been reported.7,8,9咀嚼片的不良反應包括患者整片吞咽或不完全咀嚼導致的胃腸道(gi )(5且塞, 以及片劑過硬導致牙齒損傷和假

14、牙破損6o也應考慮咀嚼片引起的食道刺激這一 潛在不良事件。從過去批準的很多咀嚼片來看，許多產品對硬度、崩解時限、溶 出度等關鍵質量屬性的考察仍不充分，例如，對所有相關的關鍵質量屬性監管不 完全，或質量指標范圍很寬泛但未證明其在可接受的標準之內。此外，據報道, 分析方法也存在很大差異了吧thisguidanee describes the critical quality attributes that should be consideredwhen developing chewable tablets and recommends that the selected acceptancec

15、riteria be appropriate and meaningful indicators of product performancethroughout the shelf life of the product.本指南建議了開發咀嚼片時應考慮的關鍵質量屬性、可選擇的合適的可接受 標準、產品有效期內的有意義的產品性能指標。iii. discussioniii 討論avariety of physical characteristics should be considered in the manufacturingprocess for chewable tablets. an i

16、dealchewable tablet should be:easy to chewpalatable (taste masked or of acceptable taste) of appropriate size and shape10able to disintegrate readily to minimize aspiration and facilitate dissolution.在咀嚼片劑生產工藝中，應考慮各種物理特性。理想的咀嚼片應為:易于咀嚼味道可口(掩味或可接受的味道)尺寸及形狀適中10易崩解，以方便吞咽和活性成分溶岀criticalquality attributes

17、 for chewable tablets should include hardness,disintegration, and dissolution, as well as all factors that may in fluence drugbioavailability and bioequivale nee. in addition, careful attention should be given to tablet size, thickness, andfriability, as well as taste, which may impact the ability o

18、r willingness of apatient to chew the chewable tablet (i.e., a patient may swallow whole, ratherthan chew, a bad tasting tablet). nosingle quality characteristic should be considered sufficient to control theperformance of a chewable tablet .in stead, the goal should be to develop theproper combi na

19、tion of these attributes to en sure the performance of thechewable tablet for its intended use.咀嚼片的關鍵質量屬性包括硬度、崩解時限、溶出度以及其他影響生物利用 度和生物等效性的因素。另外，應重視片劑的形狀、厚度、脆碎度和味道，這些 會影響患者服用咀嚼片的能力和意愿(即：患者因味道不好可能整個吞咽，而不 是咀嚼)。充分控制咀嚼片的性能，不能只考慮單一的質量屬性，而應考慮質量 屬性的合適組合，從而確保咀嚼片達到預期的用途。a. hardnessa.硬度thehardness of chewable t

20、ablets should be such that they withstand the rigors ofmanufacturing, packaging, shipping, and distribution, as well as be easilychewed by the intended patient population. hardness is generally measured asthe force needed to break the tablet in a specific plane. tablet hardness maybe measured and ex

21、pressed in a variety of units. applications submitted to fda should use thesame unit of measure in reporting results and specifications. including: kilopond (kp), kilogram-force(kgf), newton (n), and strong-cobb units(scu). 1 kp = 1 kgf = 9.8 n = 1.4 scu. publicstandards also exist to ensure consist

22、ent measurement of the tablet hardness(tablet breaking force11). tablet hardness may be used to determinethe chewing difficulty index (see appendix i).咀嚼片的硬度要求既能承受生產、包裝、運輸、分發過程中的外力沖擊,又 要求便于目標患者人群的咀嚼。硬度通常是測定在特定平面上使藥片破裂所需力 的大小。硬度可以用多種單位表示。向fda提交申請時，在報告結果和說明中， 應使用相同的度量單位。包括：千克磅(kp),干克力(kgf),牛頓(n)和 stro

23、ng-cobb 單位(scu)。換算關系為 1 kp = 1 kgf = 9.8 n = 1.4 scuo 有公共標 準(據參考文獻是usp藥典標準)來確保片劑硬度測量的一致性(片劑脆碎度 11 ) ”片劑硬度可用于確定咀嚼難度指數(見附錄i ) ob disintegrationb崩解時限thetime required for a tablet to break up into small particles is itsdisintegration time. for chewabletablets, disin teg rati on time should be short enou

24、gh to prevent gl obstructionin the event a tablet is not completely chewed by the patient. usually, thepresence of the correct type and amount of a disintegrant facilitates rapiddisintegration of the tablet.12 in vitro disin tegration testing should beconducted using in tact tablets in suitable medi

25、um using established disintegrationequipment (such as usp disintegration apparatus) and methods.13崩解時限是指藥片從整片破碎成細小微粒的時間。對于咀嚼片,崩解時間應 足夠短，以免患者沒有充分咀嚼發生胃腸道阻塞。通常，選用正確類型及使用量 的崩解劑有利于片劑迅速崩解12。體外崩解試驗應使用完整片劑、在適當的介質、 用已確立的崩解裝置(例如usp崩解儀)和方法進行13oc dissolutionc溶出度drugabsorption from chewable tablets depends on th

26、e release of the drugsubstance(s) from the intact or the chewed tablets; therefore, in vitrodissolution testing of chewable tablets should follow the principles of dissoluti on testing of conventional ir tablets.14 that is, the active pharmaceuticalingredient(s) of the chewable tablets should adequa

27、tely dissolve out of thetablet with or without chewing.咀嚼片的吸收取決于整片或咀嚼后的藥物釋放。因此，咀嚼片的體外溶出試 驗應當遵循常規速釋片的溶出試驗原則匕即：咀嚼片中的活性成分在咀嚼或未 咀嚼情況下都應充分溶出。forproduct characterization during development in vitro dissolution testing shouldbe conducted on intact tablets in at least four media, such as water, aqueousmedia

28、 at ph 1.2, buffer ph 4.5, and buffer ph 6.8, with established dissoluti on methods using equipment such as usp apparatus 1 (basket), usp apparatus 2(paddle), or usp apparatus 3 (reciprocating cylinder).15開發過程中的體外溶出試驗應當使用完整片劑在至少4種介質中進行例如 水、ph12 ph4.5、ph6.8緩沖液；采用usp藥典公認的溶出方法試驗，例如 方法1(轉籃法)、方法2 (槳法)或方法

29、3 (往復筒法)1d. performance in simulated physiological mediad住理介質模擬實驗chewabletablets should also be evaluated using dissolution media such as simulatedfasted and fed state gastric and intestinal fluids with enzymes (biorelevantdissolution media). hardness should also be tested after brief (30 120s)expos

30、ures to small quantities (12ml) of human or simulated saliva. suchstudies may provide a better understanding of in vivo performance of thechewable tablets16 .in vitro testi ng in physiological media,c on siste nt with the targeted patient population characteristics may supportfurther characterizatio

31、n of the drug product and its critical qualityattributes.咀嚼片劑應當使用模擬空腹和餐后胃腸生理環境的溶出介質(生物相關介質) 進行評價。硬度測試，應短時(30-120s )暴露于少量(1-2ml )人類或模擬唾 液后進行。這些硏究可以更好的了解咀嚼片的體內性能。1 &在體外生理介質模擬 實驗中，采用與目標患者人群一致的生理介質可能會對該藥品進一步的鑒定和關 鍵質量屬性提供數據支持。e biowaiver and postapproval considerationse生物等效性豁免及上市后的注意事項thesolubility a

32、nd permeability characteristics of the drug substanee may be usedto determine where the drug fits within the biopharmaceutics classificationsystem (bcs). depending on the bcs classification of the drug substanee,proposals for waiver of bioequivalenee (be) studies may be considered forchewable tablet

33、s17 changes in the chemistry, manufacturing andcontrols after approval of the chewable tablets should be made in conformancewith the principles outlined in the scale-up and post-approval changeslmmediate release (supac ir) guidanee document18.藥物的溶解度和滲透性可以用來確定藥物的生物藥劑學分類系統(bcs )。根據 藥物的bcs分類，咀嚼片可提岀生物等效

34、性(be )硏究豁免的申請"。咀嚼片 上市后發生化學、生產及質控工藝變更時，應遵從速釋口服固體制劑：放大生 產和批準后變更(supac ir )指南18oiv. recommendationsiv.建議thefollowing general and specific recommendations should be considered during thedevelopment phase of a chewable tablet.下面的一般和具體建議，應在咀嚼片的開發階段考慮。potentialproduct desig n and development con sider

35、ations should include: disintegrant(s)to facilitate release of the active ingredient, and sweeteners and flavoringagents for taste-masking19. the possibility of the interaction ofexcipients with each other and/or the drug substance(s), and their likelyimpact on the manufacturing process, should be e

36、xplored.產品設計和開發階段應考慮的方面包括:促進活性成分釋放的崩解劑，增甜 劑和用于掩味的調味劑1豊應研究可能出現的輔料之間的相互作用和/或輔料與 藥物之間的相互作用，及這些相互作用可能對生產工藝的影響。thefollowing information should be collected either during the conduct of pivotalclinical studies and reported in the subsequent nda:1 .were the chewable tablets swallowed in tact (i.e., without

37、 breaking) or afterbeing thoroughly chewed?2f swallowed in tact, does the shape and size of chewable tablet pose a chokingor bowel obstruction risk? 203f water was used to aid swallowing, what was the volume?4.what was the subject's sensory experience (e.g., taste, mouth feel, andaftertaste)? 21

38、,22下面的信息應該在臨床研究期間收集并在隨后的nda申請資料中報告：1 該咀嚼片可以完整吞服(不破壞)還是應該徹底咀嚼后吞服?2. 如果完整吞服，該咀嚼片的形狀和大小是否有造成窒息或腸梗阻的風險？203. 如果患者可以用水幫助吞咽，水的用量是多少？4. 患者用藥的感官體驗如何(例如，味覺、口感、余味)？2但foranda applications, general information such as subjects sensory experience(acceptability of taste, mouthfeel, and aftertaste) and ease of swal

39、lowi ng - in case of tablets swallowed in tact -can be collected during the conduct ofbioequivalence studies and reported in the subsequent anda submissi ons.對于anda申請,一般要求在生物等效性研究期間收集患者的用藥體隸味 道可接受性、口感和余味)和在片劑整個吞服時的吞咽改善，在后續anda申報 資料中報告。thepotential for buccal absorption of the drug substance should b

40、e evaluated anddescribed in the nda. the importance of any buccal absorption may depend on thesolubility and permeability characteristics of the drug substanee, itsstability in saliva (over a ph range 6.0 to 7.5), and whether it undergoesextensive first-pass metabolism.對于藥物潛在的口腔吸收應評估并在nda申請中說明。藥物口腔吸

41、收的重 要性主要取決于藥物的溶解性和滲透性，藥物在唾液中的穩走性(ph6.07.5 ), 以及藥物是否有首過代謝。stabilityin the buccal environment can usually be assessed in vitro. for example,studies at the applicable ph range over a short period of time (e.g., <5min) showing minimal drug substance release or lack of degradation of the drugsubstance

42、 may be adequate to demonstrate short-term stability in the buccale nvironment.通常，可以采用體外研究評估藥物在口腔環境中的穩定性。例如，在合適的ph值范圍內,研究短時間內(例如，5分鐘)藥物的最小釋放或降解可得出口 腔環境的短期穩定性。a. critical quality attributesa關鍵質量屬性thehardness, dissolution, and disintegration of the chewable tablet should beestablished early in develop

43、ment. fda recommends that multiple attributes bestudied to address the performs nee of the chewable tablet and in co rpo rated inthe product specification. reliance on only one attribute should beavoided.咀嚼片研發早期應該硏究硬度、溶解度、崩解時限。fda建議研究多個屬性, 來了解咀嚼片的質量，并在質量標準中制訂。應避免只依賴一個屬性。fordrug products that require

44、 filing of an application with the agency, thedevelopment information should be provided in section 3.2.p.2 (pharmaceuticaldevelopme nt) of a comm on tech nical docume nt (ctd) formatted submission. theinformation on tablet hardness and chewing difficulty index (see appendix l)should be provided in

45、section 3.2.p.3.4 (control of critical steps and intermediates) or section 3.2.p.5.1 (specification) of a ctd formattedapplication23.對于需要在fda申請的藥品，應在ctd文件3.2.p.2 (藥品開發)中提供研 發信息。在ctd文件3.2.p.3.4 (關鍵步驟和中間體的控制)或3.2.p.5.1 (質量 標準)中提供片劑硬度和咀嚼難度指數的信息(見附錄i ) 2theagency encourages manufacturers of currently ap

46、proved chewable tablets and nonapplication chewable tablets to reevaluatethe critical quality attributes and en sure appropriate specificati ons are in place. should the agency have reason to determine that a marketed chewabletablet poses a particular risk to public health because it is difficult to

47、 chew(e.g., causes damage to the teeth or dental prosthetics, or gl obstruction),appropriate action will be taken to alleviate the risk to public health.fda鼓勵目前已批準的咀嚼片和非申請的咀嚼片的生產商重新評價其關鍵質量屬性，并確保適當的質量標準。fda須確定市售咀嚼片是否因咀嚼困難帶來公共健康風險（例如，對牙齒或假牙的損傷，或胃腸阻塞）,并采取適當的措施 來降低公共健康風險。hard ness硬度obased on the review

48、of applications and literature sources, the agencyrecommends that hardness for chewable tablets be kept low (e.g., < 12 kp).基于申請資料和文獻資料綜述，fda建議，咀嚼片硬度應保持較低(例如z <12kp)。oa higher hardness value (e.g., >12 kp) may be considered if brief(approximately 30 sec on ds) exposure to saliva before chew

49、ing results insignificant disintegration and/or reduction in hardness of these tablets. thestudy may be performed in vivo using human volunteers or in vitro for 30seconds exposure, using 1 ml of simulated salivary fluid (see appendix ii).如果咀嚼片在短時(約30秒)暴露于唾液中崩解和/或硬度顯著降低z可以 考慮較高的硬度值(例如，>12kp )。這項研究

50、可以利用人類志愿者體內進行或 在體外30秒暴露于1 ml模擬唾液來進行(見附錄ll)ooln all other cases, the sponsor should provide justification for the proposedhard ness, includi ng studies dem on strati ng that the tablet can be safely chewedby the intended population without damage to teeth, dentures, or other adverseeffects related to

51、 chewing these tablets.在其他情況下,申請者應對所提出的硬度提供理由,包括硏究，來表明該片 劑可以被預期人群安全地咀嚼,而對牙齒、假牙無損害,或無其他與咀嚼相關的 不良影響。oln addition to evaluating the hardness of chewable tablets, the sponsor shouldconsider evaluating the tablets for the chewing difficulty index (see appendixl) both before and after exposure to human sa

52、liva.除了評估咀嚼片的硬度外，申請者應考慮評估咀嚼片暴露于人的唾液前后的 咀嚼難度指數（見附錄i）odisintegration and dissolution 崩解時限和溶出度ochewable tablets should typically meet the same disintegration and dissoluti on specifications as ir tablets.咀嚼片的崩解時限和溶解度通常應符合相同的速釋片的標準要求。oln vitro dissolution testing should be con ducted on intact chewable

53、tabletssince it is possible that some patients might swallow the tablets withoutchewing. crushing of the chewable tablets prior to conducting in vitrodissolution testing generally is not recommended since there is no reportedvalidated method for this process to date furthermore, this approach would

54、beunlikely to result in experimental conditions simulating a range of chewingpatterns that might be observed in d if fere nt patient populations. however,additional dissolution assessments may be needed on a case-by-case basis24based on product-specific information.體外溶出度試驗應該采用完整的咀嚼片進行，因為一些患者可能會不經咀嚼

55、而整個吞服。原來的體外溶出試驗通常將咀嚼片破碎后進行，不推薦該方式，因 為破碎過程未經過驗證。此外，這種方法無法模擬多種試驗條件，不能考察不同 的患者群體中的咀嚼模式。然而,可能需要基于特定產品的信息，根據具體情況 逐進行溶出評估24oolt is possible to use other methods, as long as the proposed methods aredemonstrated to be equivale nt or superior to the existing approaches.可以使用其他方法，只要可以證明該方法等同或優于現有的方法。 other cri

56、tical quality attributes其他關鍵質量屬性oother critical quality attributes applicable to a particular chewable tabletshould be evaluated using agency recommended methods or using methods that aredemonstrated to be equivalent or superior to the existing approaches.咀嚼片的其他關鍵質量屬性應使用fda建議的方法”或使用被證明是等同 或優于現有方法的方法進行評價。b. nomenclatureand labelingb.命名和標識aspreviously stated, the usp recognizes and differentiates between two types ofchewable tablets: (1) those that may bechewed for ease of administration, and (2) those that must be chewed an