FDA发布咀嚼片关键质量属性指导原则（中英文对照）
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This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page. 该指南草案定稿后，代表FDA对这一主题当前的想法，并未赋予任何人权利，且对FDA或公众不具有任何约束力。如果满足适用的法规和条例要求，也可以使用另外一种方法。如需讨论另外一种方法，请与本指南封面中列出的FDA工作人员联系。 |
I. INTRODUCTION
I.引言
Thisguidance provides manufacturers of chewable tablets for human use with theCenter for Drug Evaluation and Research’s (CDER) current thinking on thecritical quality attributes that should be assessed during the development ofthese drug products.2 This guidance also provides recommendationsabout submitting developmental, manufacturing, and labeling information forchewable 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 drug applications (ANDAs),3 and certainchemistry, manufacturing, and controls (CMC) supplements to these applications.4 some of therecommendations about the submission of developmental information may alsoapply to investigational new drug applications (INDs). The recommendationsabout assessing critical quality attributes apply to all chewable tablets forhuman use, 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）。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 guidance documents 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 cited. The use of the word should inAgency 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. BACKGROUND
II.背景
Chewabletablets are an immediate release (IR) oral dosage form intended to 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 unwillingto swallow intact tablets due to 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。
TheUnited 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 bechewed or crushed before swallowing to avoid choking and/or to ensure therelease of the active ingredient.5 The concepts in this guidance are applicable to both types of chewabletablets.
USP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 include gastrointestinal (GI) obstructionresulting from patients swallowing whole or incompletely chewed tablets, as wellas tooth damage and denture breakage resulting from excessive tablet hardness.6 A related potential adverse event thatsponsors should also consider is esophageal 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 given as much consideration as may have been warranted. This was evidenced 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。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。
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 performancethroughout 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.DISCUSSION
III.讨论
Avariety of physical characteristics should be considered in the manufacturingprocess for chewable tablets. An idealchewable tablet should be:
•Easy to chew
•Palatable (taste masked or of acceptable taste)
•Of appropriate size and shape10
•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 include hardness,disintegration, and dissolution, as well as all factors that may influence drugbioavailability and bioequivalence. Inaddition, careful 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 (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. Instead, the goal should be to develop theproper combination of these attributes to ensure the performance of thechewable tablet for its intended 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. Hardness
A.硬度
Thehardness of chewable tablets 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 expressed 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 consistent 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. Disintegration
B．崩解时限
Thetime required for a tablet to break up into small particles is itsdisintegration time. For chewabletablets, disintegration time should be short enough to prevent GI 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 disintegration testing should beconducted using intact tablets in suitable medium using established disintegrationequipment (such as USP Disintegration Apparatus) and methods.13
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. Dissolution
C.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 the principles of dissolutiontesting of conventional IR tablets.14 That is, the active 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 Biopharmaceutics ClassificationSystem (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）。
Disintegration and Dissolution
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 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 beunlikely to result in experimental conditions simulating a range of chewingpatterns that might be observed in different patient populations. However,additional dissolution assessments may be needed on a case-by-case basis24based 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。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 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 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 Labeling
B. 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 toavoid choking and to ensure the release of the active ingredient.25These two types of chewable tablets are differentiated by the way they arenamed and labeled.
如前所述，USP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）必须咀嚼和/或压碎以避免吞咽窒息和确保活性成分充分释放的咀嚼片25。这两种类型的咀嚼片由它们的命名和标签来区分。
•The format “[DRUG] Tablets” will be used for tablets that MAY be chewed orswallowed in their entirety. The labels and labeling for these products willalso include a labeling statement indicating that the tablets MAY be chewed.
格式为“【药品】片”将用于可以咀嚼或整个吞服的片剂。对这些产品的标签和标签说明书将包括该片剂可以咀嚼的标记语句。
•The format “[DRUG] Chewable Tablets” will be used for tablets that MUST bechewed and for which there is no alternative route of administration. Thelabels and labeling for these products will also include a labeling statementindicating that the tablets MUST be chewed.
•格式为“【药品】咀嚼片”将用于必须咀嚼且除了咀嚼无其他任何可替代服用方法的片剂。对这些产品的标签和标签说明书将包括该片剂必须咀嚼的标记语句。
Tohelp prevent patients from swallowing intact “[DRUG] Chewable Tablets,” it isstrongly recommended that the principle display panel of the container labeland the carton labeling (if applicable) prominently state the following:
为防止患者整个吞咽“【药品】咀嚼片”，强烈建议容器标签的主要展示面上和纸箱标签（若适用）上明确声明如下：
Chewor crush tablets completely before swallowing.
吞咽前彻底咀嚼或彻底粉碎药片。
Ifspace permits, it is recommended that the following statement be displayed withlesser prominence to reinforce the importance of chewing the tablets:
如果空间允许，则建议下面的语句稍突出显示，以加强咀嚼片剂的重要性：
Donot swallow tablets whole.
不要整个吞服药片。
Additionally,language similar to the previously mentioned statements should appear in the professionallabeling (Highlights of Prescribing Information; Section 2 Dosage andAdministration, and Section 17 Patient Counseling Information), as well as inany accompanying patient information or Medication Guide, if applicable.
此外，类似于前面声明的语言应该出现在专业说明书（处方信息的要点；第2部分剂量和用法，第17部分患者咨询资料），任何附带的患者信息或用药指南（若适用）。
