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 provides manu facturers of chewable tablets for huma n use with theCenter for Drug Evaluation and Research s (CDER) currentthinking on the critical quality attributes that should be assessed during the developme nt of these drug This guida ne

2、e also provides recomme ndati ons about submitti ng developme ntal, manu facturi ng, and labeli ng in formatio n for chewable tablets that must be approved by CDER before they can be distributed.The recommendations in this guidanee applymainly to new drug applications(NDAs),abbreviated new drug appl

3、ications3(ANDAs), and certain chemistry, manufacturing, and controls (CMC) supplements to these some of there commendations about the submission of developmental information mayalso apply to investigational new drug applicati ons (INDs). The recomme ndatio ns about assess ing critical quality attrib

4、utes apply to all chewable tablets for humanuse, in clud ing non-applicati on products.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CDERg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对新 药申请(NDAs、仿制药申请(ANDA)3和一些化学、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，INDs)。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

5、。Ingeneral, FDA s guidanee documents do not establish legally en forceableresp on sibilities. In stead, guida nces describe the Age ncy scurrent thinking ona topic and should be viewed only as recommendations, uni ess specificregulatory or statutory requireme nts are cited. The use of the word shoul

6、d 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FDA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 an immediate release (IR) oral dosage form inten ded to be cheweda nd the n swallo

7、wed by the patie nt rather tha n swallowed whole. They should be desig ned to have a pleasa nttaste and be easily chewed and swallowed. Chewable tablets should be safe and easyto use in a diverse patientpopulation, pediatric, adult, or elderly patie nts,who are un able or un willi ngtoswallow in tac

8、t tablets due to thesize of the tablet or difficulty withswallowing. The availability of safe, easy-to-use dosage forms is importa nt in cli nical practice. Chewable tablets are available for many over-the-co un ter(OTC) and prescripti on drug products.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

9、。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 Pharmacopeia (USP) recog ni zes and differe ntiates betwee n twotypes of chewable tablets:(1) thosethat may be chewed forease of adm ini strati on, and (2) those that must bechewedor cr

10、ushed before swallowi ng to avoid chok ing an d/or to en sure therelease of the active The con cepts in this guida nee are applicable to both types of chewabletablets.USF药典中识别和区分两种类型的咀嚼片：(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。Adverseevents for chewable tablets can

11、 include gastrointestinal(Gl)obstructi on result ing from patie nts swallowi ng whole or in completely chewedtablets, as wellas tooth damageand denture breakage resultingfromexcessive tablet A related pote ntial adverse eve nt thatsp on sors should also consider is esophageal irritation from chewabl

12、etablets. A review of numerous approveddrug product applicationsfor chewable tabletsrevealed that in certain casescritical quality attributes such as hard ness, dis in tegratio n, and dissolutio nwere not give n as much con sideratio n as may have bee n warra nted.This was evide need byin sta nces o

13、f in completem on itori ng of all releva nt critical quality attributes or the use of widelyranging values that were not justified as accepta nee criteria.In additi on, a wide variati on inan alyticalprocedures has bee n,8,9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(GI)阻塞，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

14、。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。Thisguidanee describes the critical quality attributes that should be con sideredwhe n develop ing chewable tablets and recomme nds that the selected acceptancecriteriabe appropriate

15、 and meaningful indicatorsofproduct performa ncethroughout the shelf life of the product.本指南建议了开发咀嚼片时应考虑的关键质量属性、可选择的合适的可接受标准、产品有效期内的有意义的产品性能指标。III. 讨论Avariety of physical characteristics should be con sidered in themanu facturi ngprocess for chewable tablets.An idealchewable tabletshould be:? Easy t

16、o chew? Palatable (taste masked or of acceptable taste)10? Of appropriate size and shape? Able to dis in tegrate readily to mini mize aspirati 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

17、should in cludehardness,disintegration,and dissolution,as well as all factors that mayin flue nee drugbioavailability and bioequivale nee.In additi on,carefulattention should be given to tablet size, thickness, andfriability, as well as taste, which may impact the ability or willi ngn ess of apatie

18、nt to chew the chewable tablet ., a patie nt may swallow whole, rathertha n chew, a bad tasting tablet). Nosingle quality characteristicshould becon sidered sufficie nt to con trol theperforma nee of a chewable tablet.In stead, the goal should be to develop theproper comb in ati on of these attribut

19、es to en sure the performa nee of thechewable tablet for its inten ded use.咀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. Hard nessA.硬度Thehardness of chewable tablets should be

20、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 expressed in a vari

21、ety of units. Applications submitted to FDAshould 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 = N = scu. Publicstandards also exist to ensure consistent measurement 11of the t

22、ablet hardness(Tablet Breaking Force ). 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 =

23、 1 kgf = N = scu。有公共标准(据参考文献是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. DisintegrationB. 崩解时限Thetime required for a tablet to break up into small particles is itsdisintegration time.For chewabletablets, disintegration timeshould be short enough to prevent GI obstructionin the event a t

24、ablet is not completely chewed by the patient. Usually, thepresence of the correct type and amount of a disintegrant facilitates rapiddisintegration of the In vitro disintegration testing should beconducted using intact tablets in suitable medium using established disintegrationequipment (such as US

25、P Disintegration Apparatus) and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13。C. DissolutionC.溶出度Drugabsorption from chewable tablets depends on the release of the drugsubstance(s) from the intact or the ch

26、ewed tablets; therefore, in vitrodissolution testing of chewable tablets should follow the principles of dissolutiontesting of conventional IRThat is, the activepharmaceuticalingredient（s） of the chewable tablets should adequately dissolve out of thetablet with or without chewing.咀嚼片的吸收取决于整片或咀嚼后的药物释

27、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。Forproduct characterization during development in vitro dissolution testing shouldbe conducted on intact tablets in at least four media, such as water, aqueousmedia at pH , buffer pH , and buffer pH , with establisheddissolutionmethod

28、s using equipment such as USPApparatus 1 (basket), USP 15Apparatus 2(paddle), or USP Apparatus 3 (reciprocating cylinder).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、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） 。D. Performance in Simulated Physiological MediaD.生理介质模拟实验Chewabletablets should also

29、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)exposures to small quantities (1-2mL) of human or simulated saliva. Suchstudies may provide a bett

30、er understanding of in vivo performance of thechewable tablets16. In vitro testing inphysiological media,consistent with the targeted patient population characteristics may supportfurther characterization of the drug product 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。

31、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 Postapproval ConsiderationsE.生物等效性豁免及上市后的注意事项Thesolubility and permeability characteristics of the drug substance may be usedto determine where the drug fits withi

32、n the Biopharmaceutics ClassificationSystem (BCS). Depending on the BCS classification of the drug substance,proposals for waiver of bioequivalence (BE) studies may17be considered forchewable tablets . Changes in the chemistry, manufacturing andcontrols after approval of the chewable tablets should

33、be made in conformancewith the principles outlined in the Scale-up and 18Post-Approval ChangesImmediate Release (SUPAC IR) guidance document .药物的溶解度和渗透性可以用来确定药物的生物药剂学分类系统（BCS o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17o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18oIV. RECOMMENDATIONSIV.建议Thefo

34、llow ing gen eral and specific recomme ndati ons should becon sidered duri ng thedevelopme nt phase of a chewable tablet.下面的一般和具体建议，应在咀嚼片的开发阶段考虑。Pote ntialproduct desig n and developme nt con siderati ons shouldinclude: disintegrant(s)tofacilitate release of the active ingredient,and sweete ners and

35、 flavori ngage nts for taste-mask ing19. The possibilityof the in teracti on ofexcipie nts with each other an d/or the drug substance(s), and their likelyimpact on the manufacturing process, 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19o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

36、能对生产工艺的影响。Thefollow ing in formati on should be collected either duri ng the con duct of pivotalcli ni cal studies and reported in the subseque nt NDA: the chewable tablets swallowed in tact ., without break ing) or afterbe ing thoroughly chewedswallowed in tact, does the shape and size of chewable

37、tablet posea chok in gor bowel obstruct ion risk20water was used to aid swallowi ng, what was the volume was the subject s sensory experienee ., taste, mouth feel, an daftertaste)21,22下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202. 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3. 如果患者可以用水帮助吞咽，水的用

38、量是多少4. 患者用药的感官体验如何(例如，味觉、口感、余味)21,22ForANDAapplications,general information such as subject s sensoryexperie nce(acceptability of taste, mouthfeel, and aftertaste) and easeof swallowi ng - in case of tablets swallowed in tact- can be collectedduri ng the con duct ofbioequivale nee studies and report

39、ed in the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)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。Thepote ntial for buccal absorpti on of the drug substa nee should be evaluated anddeseribed in the NDA.The importanee of any bueeal absorption may depend on thesolubility and permeability eharaeteristies of the

40、drug substanee, itsstability in saliva (over a pH range to , and whether it undergoesextensive first-pass 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()，以及药物是否有首过代谢。Stabilityin the bueeal environment can usually be assessed in vitro. For example,studies at the applieabl

41、e pH range over a short period of time ., 5min) showing minimal drug substanee release or laek 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. Crit

42、ieal Quality AttributesA.关键质量属性Thehard ness, dissoluti on,and dis in tegrati onof the ehewable tabletshould beestablished early in developme nt. FDA reeomme nds that multiple attributes bestudied to address the performa nee of the ehewable tablet and in eorporated in the produet speeifieati on. Reli

43、a nee 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 produets that require filingof an applieationwith the Agen（thedevelopme nt in formati on should be provided in seeti on (PharmaeeutiealDevelopme nt) of a eom mon teeh ni eal doeume

44、 nt (CTD) formatted submissi on. Thein formati on on tablet hard ness and ehew ingdiffieultyindex (see Appendix I)should be provided in seetion (Controlor seetion (Speeifieation)of aof Critieal Steps an di ntermediates)23formattedapplieatio n对于需要在FDA申请的药品，应在 在CTD文件（关键步骤和中间体的控制） 难度指数的信息（见附录I） 23。CTD文

45、件（药品开发）中提供研发信息 或（质量标准）中提供片剂硬度和咀嚼TheAge ncy en courages manu facturers of curre ntly approved chewable tablets andnonapplicationchewable tablets to reevaluatethe criticalquality attributes and en sure appropriate specificati ons are in place. Should the Agency have reason to determine that a marketed

46、 chewabletablet poses a particular risk to public health because it is difficult to chew., causes damage to the teeth or den tal prosthetics, or GI obstruction）,appropriate action will be taken to alleviate the risk to public 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

47、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 applicati ons and literature sources, the Age ncyrecomme nds that hard ness for chewable tablets be kept low ., 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， 12 kp） may be con sidered if brief（approximately 30 sec on ds

48、） exposure to saliva before chew ing results in sig ni fica nt dis in tegrati on an d/or reducti on in hard ness of these tablets. Thestudy may be performed in vivo using huma n volun teers or in vitro for 30seconds exposure, using 1 mLof simulated salivary fluid （see Appe ndix II）.如果咀嚼片在短时（约30秒）暴露于

49、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 ）。oln all other cases, the sponsor should provide justificationfor theproposedhard ness, in clud ing studies dem on strat ing that the tablet can be safely chewedbythe intended population without damageto teeth, dentures

50、, 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 sponsor shouldconsider evaluating the tablets for the chewing difficulty in dex （see Appe ndixl）

51、 both before and after exposure 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)。Disintegration and Dissolution崩解时限和溶出度oChewable tablets should typically meet the same dis in tegrati on and dissoluti on specificati 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

52、testi ng should be con ducted on in tact chewable tabletssinceit is possible that somepatientsmight swallow the tabletswithoutchew ing. Crush ing of the chewable tablets prior to con duct ing in vitrodissolutio n testi ng gen erally is not recomme nded since there is no reportedvalidated method for

53、this process to date. Furthermore, this approach would beunlikely to result in experimental conditions simulating a range of chew in gpatter ns that might be observed in differe nt patie nt populatio ns.However,additi onaldissoluti onassessme nts maybe n eeded ona case-by-case basis 24based on produ

54、ct-specific 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 OoIt is possible to use other methods, as long as the proposed methods aredem on strated to be equivale nt or superior to t

55、he existi ng approaches.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 applicable to a particular chewable tabletshould be evaluated using Age ncy recomme nded methods or using methods that aredem on strated to be equivale nt or superior to

56、 the exist ing approaches.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或优于现有方法的方法进行评价。B. Nome nclaturea nd Labeli ngB.命名和标识Aspreviously stated, the USP recog ni zes and differe ntiates betwee n two types ofchewable tablets: (1) those that may bechewed for ease of adm ini strati on,and (2) those that must be chewed an d/or crushed befores