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 Researchs (CDER) current thinking on the critical quality attributes that should be assessed during the development of these drug products.2 Thi
2、s guidance 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 apply mainly to new drug applications(NDAs), abbreviated new drug a
3、pplications (ANDAs),3 and certain chemistry, manufacturing, and controls (CMC) supplements to these applications.4 some of there commendations about the submission of developmental information may also apply to investigational new drug applications (INDs). The recommendations about assessing critica
4、l quality attributes apply to all chewable tablets for human 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
5、的建议适用于所有人用咀嚼片，包括非申请产品。Ingeneral, FDAs guidance documents do not establish legally enforceableresponsibilities. Instead, guidances describe the Agencys current thinking ona topic and should be viewed only as recommendations, unless specificregulatory or statutory requirements are cited. The use of th
6、e 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. BACKGROUNDII.背景Chewabletablets are an immediate release (IR) oral dosage form intended to be chewedand then swa
7、llowed 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 t
8、ablets 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
9、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
10、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 inc
11、lude 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 chew
12、abletablets. 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 inco
13、mpletemonitoring 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。
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。Thisguidance describes the critical quality attributes that should be consideredwhen developing chewable tablets and recommends that the selected acceptancecriteria be appropriate and
15、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
16、be:Easy to chewPalatable (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 sho
17、uld 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
18、 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 en
19、sure 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. HardnessA.硬度Thehardness of chewable tablets should be such that they wi
20、thstand 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. App
21、lications 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 hard
22、ness(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
23、 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. DisintegrationB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 e
24、vent 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 disintegrationequ
25、ipment (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. DissolutionC.溶出度Drugabsorption from chewable tablets depends on the release of the drugsubstance(s) f
26、rom 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 o
27、r 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 buffe
28、r 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 S
29、imulated Physiological MediaD.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
30、-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
31、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 t
32、he 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, manuf
33、acturing 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
34、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
35、 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
36、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 chew
37、ed? 2.If swallowed intact, does the shape and size of chewable tablet pose a chokingor bowel obstruction risk? 203.If water was used to aid swallowing, what was the volume? 4.What was the subjects 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
38、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？203.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）？ 21,22ForANDA applications, general information such as subjects sensory experience(acceptability of taste, mouthfeel, and aftertaste) and ease of swallowing incase of tablets swallowed in
39、tact 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
40、 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
41、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., 12 kp) may be considered if brief(approximately 30 seconds) exposure to saliva before chewing results insignificant disintegration
42、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
43、）。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
44、，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
45、附录）。Disintegration 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 some patients mig
46、ht 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 s
47、imulating 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
48、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 qual
49、ity 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
