fda发布咀嚼片关键质量属性指导原则(1)

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 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 This gu

2、idance 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 applymainly to new drug applications(NDAs), abbreviated new drug applica

3、tions (ANDAs),3 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 applications (INDs). The recommendations about assessing critical quality attributes a

4、pply to all chewable tablets for humanuse, including non-application 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CDEFW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(ANDAs 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) o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。Ingene

5、ral, FDA ' s guidance documents do not establish legally enforceableresponsibi lities. Instead, guidances describe the Agency' scurrent thinking ona topic and should be viewed only as recommendations, unless specificregulatory or statutory requirements are cited. The use of the word should i

6、nAgency guidances means that something is suggested or recommended, but notrequired.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 FDAW 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 . BACKGROUNDIII 目兄Chewabletablets are an immediate release (IR) oral dosage form intended to be chewedand then swallowed by t

7、he 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 unwillingto swallow intact tablets due t

8、o the size of the tablet or difficulty withswallowing. The availability of safe, easy-to-use dosage forms is important inclinical practice. Chewable tablets are available for many over-the-counter(OTC) and prescription 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。咀嚼片应是安全的，易于那些因片子大小或

9、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OTCffi处方药中均有咀 嚼片。TheUnited States Pharmacopeia (USP) recognizes and differentiates between twotypes of chewable tablets:(1) thosethat may be chewed forease of administration, and (2) those that must bechewedor crushed before swallowing to

10、 avoid choking and/or to ensure therelease of the active The concepts in this guidance are applicable to both types of chewabletablets.USP§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 include gastrointestinal (

11、GI) obstructionresulting from patients swallowing whole or incompletely chewedtablets, as wellas tooth damageand denture breakage resulting from excessive tablet A related potential adverse event thatsponsors should also consider is esophageal irritation from chewabletablets. A review of numerous ap

12、proveddrug product applications for chewable tablets revealed that in certain casescritical quality attributes such as hardness, disintegration, and dissolutionwere not given as much consideration as may have been warranted. This was evidenced by instances of incompletemonitoring of all relevant cri

13、tical quality attributes or the use of widelyranging values that were not justified as acceptance criteria. In addition, a wide variation in analyticalprocedures has been ,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60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

14、，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。止匕外，据报道， 分析方法也存在很大差异7,8,9。Thisguidance describes the critical quality attributes that should be consideredwhen developing chewable tablets and recommends that the selected acceptancecriteria be appropriate and meaningful indicators of product performanceth

15、roughout 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。IV I.讨论Avariety of physical characteristics should be considered in theAn idealchewable tabletmanufacturingprocess for chewable tablets. should be:? Easy to chew? Palatable (taste masked or of acceptable tas

16、te)10? Of appropriate size and shape? Able to disintegrate readily to minimize aspiration and facilitate dissolution.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(掩昧或可接受的味道)?尺寸及形状适中10?易崩解，以方便吞咽和活性成分溶出that maycarefulshould beCriticalquality attributes for chewable tablets should include hardness,disintegr

17、ation, and dissolution, as well as all factors influence drugbioavailability and bioequivalence. Inaddition, attention should be given to tablet size, thickness, andfriability, as well as taste, which may impact the ability or willingness of apatient to chew the chewable tablet ., a patient may swal

18、low whole, ratherthan chew, a bad tasting tablet). Nosingle quality characteristic considered sufficient to control theperformance of a chewable tablet.Instead, the goal should be to develop theproper combination of these attributes to ensure the performance of thechewable tablet for its intended us

19、e.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. HardnessA.硬度Thehardness of chewable tablets should be such that they withstand the rigors ofmanufacturing, packaging, shipping, and

20、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 variety of units. Applications submitted to FDAshould use thesame unit of measure

21、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 of the tablet hardness(Tablet Breaking Force11). Tablet hardness may beused to determineth

22、e 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 = 1 kgf = N = scu 。有公共标准(据参考文献是US呦典标准)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

23、)。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 tablet is not completely chewedby the patient. Usually, thepresence of the correct

24、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 USP 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

25、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 chewed tablets; therefore, in vitrodissolution testing of chewable tablets should follow t

26、he principles of dissolutiontesting of conventional IRThat is, the activepharmaceuticalingredient(s) of the chewable tablets should adequately dissolve out of thetabletwith or without chewing.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。dissolution media, such es

27、tablishedForproduct characterization during development in vitro testing shouldbe conducted on intact tablets in at least four as water, aqueousmedia at pH , buffer pH , and buffer pH , with dissolutionmethods using equipment such as USPApparatus 1 (basket), USP15 Apparatus 2(paddle), or USP Apparat

28、us 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US哨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)15。D. Performance in Simulated Physiological MediaD.生理介质模拟实验16. In vitro testing inChewabletablets should also be evaluated using dissolution media such as simulatedfasted and fed state

29、 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 better understanding of in vivo performance of thechewable tabletsphysiologica

30、l media,consistent with the targeted patient population characteristicsmay supportfurthercharacterization of the drug productand 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

31、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 within the Biopharmaceutics ClassificationSystem (BCS). Depending on the BCS classification of the drug subs

32、tance,proposals for waiver of bioequivalence (BE) studies may be considered forchewable tablets17. 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 ChangesImmediate Re

33、lease (SUPAC IR) guidance document18.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。根据药物的BCS分类，咀嚼片可提出生物等效性（B6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Thefollowing general and specific recommendations should be considered during thedevelopment phase of a chewabl

34、e tablet.下面的一般和具体建议，应在咀嚼片的开发阶段考虑。Potentialproduct design and development considerations should include: disintegrant(s)to facilitate release of the active ingredient, and sweeteners and flavoringagents for taste-masking19. The possibilityof the interaction ofexcipients with each other and/or the dru

35、g 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。Thefollowing information should be collected either during the conduct of pivotalclinical studies and reported i

36、n the subsequent NDA: the chewable tablets swallowed intact ., without breaking) or afterbeing thoroughly chewedswallowed intact, does the shape and size of chewable tablet pose20 a chokingor bowel obstruction riskwater was used to aid swallowing, what was the volume was the subject ' s sensory

37、experience ., taste, mouth feel, andaftertaste) 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23 .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） 21,22ForANDAapplications, general information such as subject ' s sensory一can be collectedexperi

38、ence(acceptability of taste, mouthfeel, and aftertaste) and ease of swallowing incase of tablets swallowed intact during the conduct ofbioequivalence studies and reported in the subsequent ANDA submissions.对于ANDAH青，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AND刖报资料中报告。Thepotential for

39、 buccal absorption of the drug substance should be evaluated anddescribed in the NDA.The importance of any buccal absorption may depend on thesolubility and permeability characteristics of the drug substance, itsstability in saliva （over a pH range to , and whether it undergoesextensive first-pass m

40、etabolism.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 buccal environment can usually be assessed in vitro. For example,studies at the applicable pH range over a short period of time ., <5min） showing minimal drug substance release or lack of degra

41、dation of the drugsubstance may be adequate to demonstrate short-term stability in the buccalenvironment.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 Quality AttributesA.关键质量属性Thehardness, dissolution, and disintegration of the chewable tablet should

42、 beestablished early in development. FDA recommends that multiple attributes bestudied to address the performance of the chewable tablet and incorporated inthe product specification. Reliance 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。Fo

43、rdrug products that require filing of an application with the Agency, thedevelopment information should be provided in section （PharmaceuticalDevelopment） of a common technical document （CTD） formatted submission. Theinformation on tablet hardness and chewing difficulty index （see Appendix I）should

44、be provided in section （Control of Critical Steps andIntermediates） or section （Specification） of a CTD formattedapplication 23.对于需要在FDA申请的药品，应在CTD文件（药品开发）中提供研发信息。 在CTD文件（关键步骤和中间体的控制）或（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 ）23oTheAgency encourages manufacturers of currently approved chewable tablets and nona

45、pplication chewable tablets to reevaluatethe critical quality attributes and ensure appropriate specifications are inplace. Should the Agency have reason to determine that a marketed chewabletablet poses a particular risk to public health because it is difficult to chew., causes damage to the teeth

46、or dental 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。Hardness硬度oBased on the review of applications and literature sources

47、, the Agencyrecommends that hardness 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仍。oA higher hardness value ., >12 kp） may be considered if brief（approximately 30 seconds） exposure to saliva before chewing results insignificant disintegration and/or re

48、duction in hardness of these tablets. Thestudy may be performed in vivo using human volunteers or in vitro for 30seconds exposure, using 1 mLof simulated salivary fluid （see Appendix 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 o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 ） ooIn all

49、other cases, the sponsor should provide justification for the proposedhardness, including studies demonstrating that the tablet can be safely chewedbythe intended population without damageto teeth, dentures, or other adverseeffects related to chewing 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

50、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。oIn addition to evaluating the hardness of chewable tablets, the sponsor shouldconsider evaluating the tablets for the chewing difficulty index （see AppendixI） both before and after exposure to human 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

51、tegration and Dissolution崩解时限和溶出度oChewable tablets should typically meet the same disintegration and dissolutionspecifications 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。oIn vitro dissolution testing should be conducted on intact chewable tabletssince it is possible that somepatients might swallow t

52、he 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 beunlikely to result in experimental conditions simulating a

53、range of chewingpatterns that might be observed in different patient populations. However,additional dissolution assessments maybe needed on a case-by-case basis 24based on product-specific information.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。止匕外，这种方法无法模拟多种试验条件

54、，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240oIt is possible to use other methods, as long as the proposed methods aredemonstrated to be equivalent or superior to the existing 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 attribut

55、es 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. Nomenclatureand LabelingB.命名和标识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 and/or crushed before swallowing