FDA发布咀嚼片关键质量属性指导原则

1、FDA发布咀嚼片关键质量属性指导原则（中英文对照）I. INTRODUCTIONI.引言This guida nee p rovides manu facturers of chewable tablets forhuma n use with the Cen ter for Drug Evaluatio n and Research's (CDER)curre nt thi nking on the critical quality attributes that should be assessedduri ng the devel opment of these drug p r

2、oducts.2 This guida nee alsopro vides recomme ndati ons about submitti ng devel opmen tal,manu facturi ng, and labeli ng in formati on for chewable tablets that mustbe app roved by CDER before they can be distributed. Therecomme ndati ons in this guida nee apply main ly to new drugapp licatio ns(NDA

3、s), abbreviated new drug app licatio ns (ANDAs),3 andcerta in chemistry, manu facturi ng, and con trols (CMC) supp leme nts tothese app licati ons 必 some of there comme ndati ons about the submissi onof devel opmen tal in formatio n may also apply to inv estigatio nal newdrug app licati ons (INDs).

4、The recomme ndati ons about assess ing criticalquality attributes apply to all chewable tablets for huma n use, in cludi ngnon-app licati on p roducts.本指南向生产者提供了药品审评研究中心（CDER ）对人用咀嚼片在研发过程中应评估的关键质量属性的当前想法 2。该指南也提供了必须向CDER提交并被其批准的咀嚼片的研发、生产及说明书信息的建议。该指南的这些建议主要针INDs )。FDA对新药申请（NDAs ）、仿制药申请（ANDAs ） 3和一些化

5、学、生产和质控（CMC ）补充申请4。某些建议同样适合于研究性新药申请（即新药临床申请,关于评估关键质量属性的建议适用于所有人用咀嚼片，包括非申请产品。Ingeneral, FDA ' s guidanee documents do not establish legally en forceableres pon sibilities. In stead, guida nces describe the Age ncy curre nt thi nking ona topic and should be viewed only as recomme ndati ons, uni es

6、s sp ecificregulatory or statutory requireme nts are cited. The use of the word should in Age ncy guida nces mea ns that someth ing is suggested or recomme nded, but no trequired.通常，FDA的指导文件不具有法律强制性，指南中描述的主题仅代表机构目前的看法，只作为建议，除非是引用具体的法规或条例要求。 建议或推荐使用该指导原则，但不是必须的。II. BACKGROUNDII.背景Chewabletablets are

7、an immediate release (IR) oral dosage form inten ded to be cheweda nd the n swallowed by the p atie nt rather tha n swallowed whole. They should be desig ned to have a p leasa nttaste and be easily chewed and swallowed. Chewable tablets should be safe and easy to use in a diverse p atie ntpopu lati

8、on, p ediatric, adult, or elderly p atie nts, who are un able or un willi ngto swallow in tact tablets due to the size of the tablet or difficulty withswallowi ng. The availability of safe, easy-to-use dosage forms is imp orta nt in cli nical p ractice. Chewable tablets are available for many over-t

9、he-co un ter(OTC) and p rescri pti on drug p roducts.咀嚼片是患者经咀嚼后立即释放的口服剂型， 而不是整个吞咽。其应被设计为可口的味道且易于咀嚼和吞咽。 咀嚼片应是安全的，易于那些因片子大小或吞咽困难导致不能或不愿吞服的特殊人群、儿童、成年、或老年患者服用。能获得安全的、易于服用的剂型在临床实践中非常重要。在许多OTC和处方药中均有咀嚼片。TheU nited States P harmac op eia (US P) recog ni zes and differe ntiates(1) thosethat may be chewed fo

10、rbetwee n twot ypes of chewable tablets: ease of adm ini strati on, and (2) those that must bechewed or crushed before swallow ing to avoid chok ing an d/or to en sure therelease of the active in gredie nt. 5 The concepts in this guida nee are app licable to both types of chewabletablets.USP药典中识别和区分

11、两种类型的咀嚼片：（1）可以咀嚼以方便服用的咀嚼片；（2）必须咀嚼或压碎以避免吞咽窒息和/或确保活性成分充分释放的咀嚼片5。本指南中的概念适用于这两种类型的咀嚼片。Adverseeve nts for chewable tablets can in clude gastr oin testi nal (Gl) obstructi on result ing from p atie nts swallowi ng whole or incomp letely chewed tablets, as wellas tooth damage and den ture breakage result i

12、ngfrom excessive tablet hard ness.6 A related poten tial adverse eve nt thats pon sors should also con sider is esop hageal irritatio n from chewabletablets. A review of nu merous appro veddrug p roductapp licati ons for chewable tablets revealed that in certa in casescriticalThis wasquality attribu

13、tes such as hard ness, dis in tegrati on, and dissoluti on were not give n as much con siderati on as may have bee n warra nted.evide need by in sta nces of incomp letem on itori ng of all releva nt criticalquality attributes or the use of widelyra nging values that were notjustified as acce ptance

14、criteria.In additi on, a wide variati on in7,8,9(GI)阻塞,an alytica Ip rocedures has bee n rep orted.咀嚼片的不良反应包括患者整片吞咽或不完全咀嚼导致的胃肠道以及片剂过硬导致牙齿损伤和假牙破损 6。也应考虑咀嚼片引起的食道刺激这一潜在不良事件。从过去批准的很多咀嚼片来看，许多产品对硬度、崩解时限、溶出度等关键质量属性的考察仍不充分， 例如，对所有相关的关键质量属性监管不完全，或质量指标范围很宽泛但未证明其在可接受的标准之内。此外，据报道,分析方法也存在很大差异7,8,9。Thisguida nee

15、describes the critical quality attributes that should be con sideredwhe n devel oping chewable tablets and recomme nds that the selected acce ptan cecriteria be approp riate and mea nin gful in dicators of p roduct p erforma ncethroughout the shelf life of the p roduct.本指南建议了开发咀嚼片时应考虑的关键质量属性、 可选择的合适

16、的可接受标准、产品有效期内的有意义的产品性能指标。HI.DISCUSSIONIII.讨论An idealchewable tabletAvariety of p hysical characteristics should be con sidered in the manu facturi ngp rocess for chewable tablets.should be:?Easy to chew?Palatable (taste masked or of acce ptable taste)?Of approp riate size and sha pe 10?Able to disi

17、ntegrate readily to mi ni mize aspi rati on and facilitate dissoluti on.在咀嚼片剂生产工艺中，应考虑各种物理特性。理想的咀嚼片应为:?易于咀嚼?味道可口（掩味或可接受的味道）?尺寸及形状适中10?易崩解，以方便吞咽和活性成分溶出Criticalquality attributes for chewable tablets should in clude hard ness,dis in tegrati on, and dissoluti on, as well as all factors that mayIn addit

18、i on, carefulin flue nee drugbioavailability and bioequivale nee.atte nti on should be give n to tablet size, thick ness, an dfriability, as well as taste, which may impact the ability or willi ngn ess of ap atie nt to chew the chewable tablet (i.e., a p atie nt may swallow whole, rathertha n chew,

19、abad tasti ng tablet).Nosin gle quality characteristic should be con sidered sufficie nt to con trol the performa nee of a chewable tablet. In stead, thegoal should be to devel op the proper comb in ati on of these attributes to en sure the p erforma nee of thechewable tablet for its inten ded use.咀

20、嚼片的关键质量属性包括硬度、崩解时限、溶出度以及其他影响生物利用度和生物等效性的因素。另外，应重视片剂的形状、厚度、脆碎度和味道，这些会影响患者服用咀嚼片的能力和意愿 （即：患者因味道不好可能整个吞咽，而不是咀嚼）。充分控制咀嚼片的性能，不能只考虑单一的质量属性，而应考虑质量属性的合适组合，从而确保咀嚼片达到预期的用途。A. Hardn essA.硬度Thehard ness of chewable tablets should be such that they withsta nd the rigors ofma nu facturi ng, p ackagi ng, shi pping,

21、 and distributi on, as well as be easilychewed by the inten ded p atie nt popu lati on. Hardn ess is gen erally measured asthe force n eeded to break the tablet in a sp ecific plane. Tablet hard ness maybe measured and exp ressed in a variety of un its. App licati ons submitted to FDA should use the

22、same unit ofin clud ing: kil opond (kp),measure in reporting results and sp ecificatio ns.kilogram-force(kgf), Newton (N), and Stro ng-Cobb Un its(scu). 1 kp = 111). Tabletkgf = 9.8 N = 1.4 scu. P ublicsta ndards also exist to en sure con siste nt measureme nt of the tablet hard ness(Tablet Break in

23、g Force hard ness may be used to determ in ethe chew ing difficulty in dex (seeAppen dix I).咀嚼片的硬度要求既能承受生产、包装、运输、分发过程中的外力冲击，又要求便于目标患者人群的咀嚼。硬度通常是测定在特定平面上使药片破裂所需力的大小。硬度可以用多种单位表示。向FDA提交申请时，在报告结果和说明中,应使用相同的度量单位。包括：千克磅（kp）,千克力（kgf）,牛顿（N）和Strong-Cobb单位(scu)。换算关系为 1 kp = 1 kgf = 9.8 N = 1.4 scu 。有公共标准（据参考文

24、献是USP药典标准）来确保片剂硬度测量的一致性（片剂脆碎度11），片剂硬度可用于确定咀嚼难度指数（见附录I）。B. Disi ntegrati onB.崩解时限Thetime required for a tablet to break up into small p articles isitsdis in tegratio n time.For chewabletablets, dis in tegratio n time should be short eno ugh to p reve nt GI obstruct ionin the eve nt a tablet is not co

25、mp letely chewed by the p atie nt. Usually, the prese nee of the correct type and amount of a dis in tegra nt facilitates rapi ddis in tegratio n of the tablet. 12 In vitro dis in tegrati on test ing should bec on ducted using in tact13tablets in suitable medium using established dis in tegratio neq

26、uipment (such as USP Disin tegrati on App aratus) and methods.崩解时限是指药片从整片破碎成细小微粒的时间。对于咀嚼片，崩解时间应足够短，以免患者没有充分咀嚼发生胃肠道阻塞。 通常，选用正确类型及使用量的崩解剂有利于片剂迅速崩解12。体外崩解试验应使用完整片剂、在适当的介质、用已确立的崩解装置（例如USP崩解仪）和方法进行13C. Dissoluti onC.溶出度Drugabsor pti on from chewable tablets depends on the release of the drugsubsta nce(s)

27、 from the in tact or the chewed tablets; therefore, in14 That is, the activevitrodissolutio n test ing of chewable tablets should follow the principles of dissoluti on testi ng of conven ti onal IR tablets.p harmaceuticali ngredie nt(s) of the chewable tablets should adequatelydissolve out of thetab

28、letwith or without chew ing.咀嚼片的吸收取决于整片或咀嚼后的药物释放。因此，咀嚼片的体外溶出试验应当遵循常规速释片的溶出试验原则 14，即：咀嚼片中的活性成分在咀嚼或未咀嚼情况下都应充分溶出。Forp roduct characterizati on duri ng devel opment in vitro dissoluti on test ing shouldbe con ducted on in tact tablets in at least four media, such as water, aqueousmedia at pH 1.2, buffer

29、 pH 4.5, and buffer pH 6.8, with established dissoluti onm ethods using equipment such as USP App aratus 1 (basket), USP App aratus 2(p addle), or USP App aratus 3 (reci procati ng cyli nder). 15开发过程中的体外溶出试验应当使用完整片剂在至少 4种介质中进行，例如水、pH1.2、pH4.5、pH6.8缓冲液；采用USP药典公认的溶出方法试验，例如方法1 （转篮法）、方法2 （桨法）或方法3 （往复筒法）

30、15。D. P erforma nee in Simulated P hysiological MediaD.生理介质模拟实验Chewabletablets should also be evaluated using dissoluti on media such as simulatedfasted and fed state gastric and in testi nal fluids with en zymes (bioreleva ntdissoluti on media). Hardn ess should also be tested after brief (30-120s)

31、ex posures to small qua ntities (1-2mL) of huma n or16. In vitro test ing insimulated saliva. Suchstudies may pro vide a better un dersta nding of in vivo p erforma nee of thechewable tablets p hysiological media,c on siste nt with the targeted p atie nt popu latio n characteristics may supp ortfurt

32、her characterizati on of the drug p roduct and its critical qualityattributes.咀嚼片剂应当使用模拟空腹和餐后胃肠生理环境的溶出介质（生物相关介质）进行评价。硬度测试，应短时（30-120S ）暴露于少量（1-2ml ）人类或模拟唾液后进行。这些研究可以更好的了解咀嚼片的体内性能。16在体外生理介质模拟实验中，采用与目标患者人群一致的生理介质可能会对该药品进一步的鉴定和关键质量属性提供数据支持。E. Biowaiver and Po sta pp roval Con siderati onsE.生物等效性豁免及上市后的

33、注意事项Thesolubility and p ermeability characteristics of the drug substa nee may be usedto determ ine where the drug fits with in theBiop harmaceutics Classificati on System (BCS). Depending on the BCS classificatio n of the drug substa nce,prop osals for waiver of bioequivale nee (BE) studies may be

34、con sidered forchewable tabletsChan ges in the chemistry, manu facturi ng andcon trols after appro val ofthe chewable tablets should be made in con forma ncewith the princip les outl ined in the Scale-up and Po st-A pp roval Chan gesImmediate Release(SUPAC IR) guida nee docume nt18药物的溶解度和渗透性可以用来确定药物

35、的生物药剂学分类系统（BCS）。根据药物的BCS分类，咀嚼片可提出生物等效性（BE）研究豁免的申请17。咀嚼片上市后发生化学、生产及质控工艺变更时，应遵从速释口服固体制剂：放大生产和批准后变更（SUPAC IR）指南18。IV. RECOMMENDATIONSIV.建议Thefollow ing gen eral and sp ecific recomme ndati ons should be con sidered duri ng thedevel opment p hase of a chewable tablet.F面的一般和具体建议，应在咀嚼片的开发阶段考虑。Poten tia Ip

36、 roduct desig n and devel opment con siderati ons should19. The P ossibility ofin clude: disi ntegra nt(s)to facilitate release of the active in gredie nt, and sweete ners and flavori ngage nts for taste-mask ing the in teractio n ofexci pients with each other an d/or the drug substa nce(s), and the

37、ir likelyi mpact on the manu facturi ng p rocess, should be explored.产品设计和开发阶段应考虑的方面包括： 促进活性成分释放的崩解剂，增甜剂和用于掩味的调味剂19。应研究可能出现的辅料之间的相互作用和/或辅料与药物之间的相互作用，及这些相互作用可能对生产工艺的影响。Thefollow ing in formati on should be collected either duri ng the con duct of piv otalcii ni cal studies and rep orted in the subseq

38、ue nt NDA:I.Were the chewable tablets swallowed in tact (i.e., without break ing) or afterbe ing thoroughly chewed?202.lf swallowed in tact, does the sha pe and size of chewable tablet pose a chok in gor bowel obstructi on risk?3.If water was used to aid swallowi ng, what was the volume?4.What was t

39、he subject ' s sensory experienee (e.g., taste, mouth feel,an daftertaste)?21,22F面的信息应该在临床研究期间收集并在随后的 NDA申请资料中报告:1. 该咀嚼片可以完整吞服（不破坏）还是应该彻底咀嚼后吞服?2. 如果完整吞服，该咀嚼片的形状和大小是否有造成窒息或肠梗阻的风险?203. 如果患者可以用水帮助吞咽，水的用量是多少?4. 患者用药的感官体验如何（例如，味觉、口感、余味）？21,22ForANDA app licati ons, gen eral in formatio n such as subj

40、ect sen sory exp erie nce(acce ptability of taste, mouthfeel, and aftertaste) and-can beease of swallow ing- in case of tablets swallowed in tact collected duri ng the con duct ofbioequivale nee studies and rep orted in the subseque nt ANDA submissi ons.对于ANDA申请，一般要求，在生物等效性研究期间收集患者的用药体验（味道可接受性、口感和余味

41、）和在片剂整个吞服时的吞咽改善，在后续ANDA申报资料中报告。The poten tial for buccal absor pti on of the drug substa nee should be evaluated an ddeseribed in the NDA. The imp orta nee of any bueeal absor pti on may depend on thesolubility and p ermeability eharaeteristies of the drug substa nee, itsstability in saliva (over a

42、pH range 6.0 to 7.5), and whether it un dergoesexte nsive first -p ass metabolism.对于药物潜在的口腔吸收应评估并在 NDA申请中说明。药物口腔吸收的重要性主要取决于药物的溶解性和渗透性，药物在唾液中的稳定性(pH6.07.5 ),以及药物是否有首过代谢。Stabilityin the bueeal environment can usually be assessed in vitro.For exa mp ©studies at the app licable pH range over a shor

43、t p eriod of time (e.g., <5m in) show ing mini mal drug substa nee release or lack of degradati on of the drugsubsta nee may be adequate to dem on strate short-term stability in the bueeale nvir onment.通常，可以采用体外研究评估药物在口腔环境中的稳定性。例如，在合适的pH值范围内，研究短时间内(例如，5分钟)药物的最小释放或降解可得出口腔环境的短期稳定性。A. Critical Quali

44、ty AttributesA .关键质量属性Thehard ness, dissoluti on, and dis in tegrati on of the chewable tablet should beestablished early in devel opment. FDA reeomme nds that mult iple attributes bestudied to address the p erforma nee of thechewable tablet and incorpo rated in the p roduct sp ecificati on. Relia n

45、ee on only one attribute should beavoided.咀嚼片研发早期应该研究硬度、溶解度、崩解时限。FDA建议研究多个属性，来了解咀嚼片的质量，并在质量标准中制订。应避免只依赖一个属性。Fordrug p roducts that require fili ng of an app licati on with theAge ncy, thedevel opment in formati on should be pro vided in secti on 3.2 .P.2 (P harmaceuticalDevelo pment) of a com mon te

46、ch ni cal docume nt (CTD) formatted submissi on. Thei nformatio n on tablet hard ness and chew ing difficulty in dex (see Appen dix I)should be pro vided in sect ion233.2 .P .3.4 (Co ntrol of Critical Ste ps an dI ntermediates) or sectio n 3.2. P.5.1 (Sp ecificati on) of a CTD formatteda pp licatio

47、n对于需要在FDA申请的药品，应在CTD文件3.2.P.2 （药品开发）中提供研发信息。在CTD文件3.2.P.3.4 （关键步骤和中间体的控制）或 3.2.P.5.1 （质量标准）中提供片剂硬度和咀嚼难度指数的信息（见附录I） 23 0TheAge ncy en courages manu facturers of curre ntly app roved chewable tablets and nonapp licati on chewable tablets to reevaluatethe critical quality attributes and en sure approp

48、riate sp ecificatio ns are inp lace. Should the Age ncy have reas on to determ ine that a marketed chewabletablet po ses a p articular risk to p ublic health because it is difficult to chew(e.g., causes damage to the teeth or den tal p rosthetics, or GI obstructio n),a pprop riate acti on will be ta

49、ke n to alleviate the risk to p ublic health.FDA鼓励目前已批准的咀嚼片和非申请的咀嚼片的生产商重新评价其关键质量属性，并确保适当的质量标准。FDA须确定市售咀嚼片是否因咀嚼困难带来公共健康风险（例如，对牙齿或假牙的损伤，或胃肠阻塞），并采取适当的措施来降低公共健康风险。Hardn ess硬度oBased on the review of app licati ons and literature sources, theAge ncyrecomme nds that hard ness for chewable tablets be kep t

50、low (e.g.< 12 kp).基于申请资料和文献资料综述，FDA建议，咀嚼片硬度应保持较低（例如,<12KP )。oA higher hard ness value (e.g., >12 kp) may be con sidered if brief(a pp roximately 30 sec on ds) expo sure to saliva before chew ing results in sig nifica nt dis in tegrati on an d/or reduct ion in hard ness of these tablets. The

51、study may be p erformed in vivo using huma n volun teers or in vitro for 30sec onds exp osure, using 1 mL of simulated salivary fluid (seeAppen dix II).如果咀嚼片在短时（约30秒）暴露于唾液中崩解和/或硬度显著降低，可以考虑较高的硬度值（例如，12KP ）。这项研究可以利用人类志愿者体内进行或在体外30秒暴露于1ml模拟唾液来进行（见附录II）0oln all other cases, the spon sor should pro vide

52、justificatio n for the prop osedhard ness, in cludi ng studies dem on strati ng that the tablet can be safely chewedby the inten ded popu lati on without damage to teeth, den tures, or other adverseeffects related to chew ing these tablets.在其他情况下，申请者应对所提出的硬度提供理由， 包括研究，来表明该片剂可以被预期人群安全地咀嚼，而对牙齿、假牙无损害，或

53、无其他与咀嚼相关的不良影响。oln additi on to evaluat ing the hard ness of chewable tablets, the spon sor shouldc on sider evaluat ing the tablets for the chew ing difficulty in dex (see Appen dixI) both before and after exp osure to huma n saliva.除了评估咀嚼片的硬度外，申请者应考虑评估咀嚼片暴露于人的唾液前后的咀嚼难度指数（见附录I）。Disin tegrati on and

54、Dissolutio n崩解时限和溶出度oChewable tablets should typi cally meet the same dis in tegrati on and dissoluti onsp ecificati ons as IR tablets.咀嚼片的崩解时限和溶解度通常应符合相同的速释片的标准要求。oln vitro dissoluti on test ing should be con ducted on in tact chewable tabletss ince it is p ossible that some p atie nts might swallo

55、w the tablets withoutchew ing. Crush ing of the chewable tablets p rior to con duct ing in vitrodissolutio n testi ng gen erally is not recomme nded since there is no rep ortedvalidated method for this p rocess to date. Furthermore, this app roach would beun likely to result in exp erime ntal con di

56、ti ons simulat ing a range of chew ingp atter ns that might be observed in24based ondiffere nt p atie nt popu lati ons. However,additi onal dissolutio n assessme nts may be n eeded on a case-by-case basis p roduct-s pecific in formatio n.体外溶出度试验应该采用完整的咀嚼片进行， 因为一些患者可能会不经咀嚼而整个吞服。原来的体外溶出试验通常将咀嚼片破碎后进行，不

57、推荐该方式，因为破碎过程未经过验证。此外，这种方法无法模拟多种试验条件， 不能考察不同的患者群体中的咀嚼模式。然而，可能需要基于特定产品的信息，根据具体情况逐一进行溶出评估24。oIt is p ossible to use other methods, as long as the prop osed methods aredem on strated to be equivale nt or sup erior to the exist ing app roaches.可以使用其他方法，只要可以证明该方法等同或优于现有的方法。? Other Critical Quality Attributes其他关键质量属性oOther critical quality attributes app licable to a p articular chewable tabletshould be evaluated using Age ncy recomme nded methods or using methods that aredem on strated to be equivale nt or sup erior to the exist ing app roaches.咀嚼片的其他关键质量属性应使用 FDA建议的方法，或使用被证明是等同