pharmaceuticalingredient(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 1.2, buffer pH 4.5, and buffer pH 6.8, with established dissolutionmethods using equipment such as USP Apparatus 1 (basket), USP Apparatus 2(paddle), or USP Apparatus 3 (reciprocating cylinder).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）15。 D. Performance in Simulated Physiological Media D.生理介质模拟实验
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)exposures to small quantities (1-2mL) of human or simulated saliva. Suchstudies may provide a better understanding of in vivo performance of thechewable tablets16. In vitro testing in physiological 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。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 Considerations E.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
BiopharmaceuticsClassificationSystem (BCS). Depending on the BCS
classification of the drug substance,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 Release (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（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. RECOMMENDATIONS IV. 建议
Thefollowing general and specific recommendations should be considered during thedevelopment 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。
Potentialproduct design and development considerations 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 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 in the subsequent NDA:
1.Were the chewable tablets swallowed intact (i.e., without breaking) or afterbeing thoroughly chewed?
2.If swallowed intact, does the shape and size of chewable tablet pose a chokingor bowel obstruction risk? 20
3.If water was used to aid swallowing, what was the volume?
4.What was the subject’s sensory experience (e.g., taste, mouth feel, andaftertaste)? 21,22
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？
20
3.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）？21,22
ForANDA applications, general information such as subject’s sensory experience(acceptability of taste, mouthfeel, and aftertaste) and ease of swallowing – incase of tablets swallowed intact –can be collected during the conduct ofbioequivalence studies and reported in the subsequent ANDA submissions.
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。
Thepotential for 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 6.0 to 7.5), 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（pH6.0~7.5），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 (e.g., <5min) showing minimal drug substance release or lack of degradation 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 Attributes A．关键质量属性
Thehardness, dissolution, and disintegration of the chewable tablet should 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。 Fordrug products that require filing of an application with the Agency, thedevelopment information should be provided in section 3.2.P.2
(PharmaceuticalDevelopment) of a common technical document (CTD) formatted submission. Theinformation on tablet hardness and chewing
difficulty index (see Appendix I)should be provided in section 3.2.P.3.4 (Control of Critical Steps andIntermediates) or section 3.2.P.5.1 (Specification) of a CTD formattedapplication23.
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。
TheAgency encourages manufacturers of currently approved chewable tablets and nonapplication 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(e.g., causes damage to the teeth 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, the
Agencyrecommends that hardness for chewable tablets be kept 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 hardness value (e.g., >12 kp) may be considered if
brief(approximately 30 seconds) exposure to saliva before chewing 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）。
oIn all other cases, the sponsor should provide justification for the proposedhardness, including studies demonstrating that the tablet can be safely chewedby the intended population without damage to 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）。