发布于: 2016-06-23 22:10

This  draft guidance, when finalized, will represent the current thinking of the  Food and Drug  Administration (FDA or  Agency) on this topic.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.  




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.


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.




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.


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.


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   


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. 





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.






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. 


A. Hardness


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)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)。

B. Disintegration


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


C. Dissolution


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.


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 


D. Performance in Simulated Physiological Media


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.


E. Biowaiver and Postapproval Considerations


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. 建议

Thefollowing general and specific recommendations should be considered during thedevelopment phase of a chewable tablet.


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.


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






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.


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.


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.


A. Critical Quality Attributes


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. 


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.


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.




oBased on the review of applications and literature sources, the Agencyrecommends that hardness for chewable tablets be kept low (e.g., < 12 kp).


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).


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.


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.


Disintegration and Dissolution


oChewable tablets should typically meet the same disintegration and dissolutionspecifications as IR tablets.


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.


oIt is possible to use other methods, as long as the proposed methods aredemonstrated to be equivalent or superior to the existing approaches.


• Other Critical Quality Attributes


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.


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.


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.


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.


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:


Chewor crush tablets completely before swallowing.


Ifspace permits, it is recommended that the following statement be displayed withlesser prominence to reinforce the importance of chewing the tablets:


Donot swallow tablets whole.


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.