FDA发布咀嚼片关键质量属性指导原则.docx

1、FDA发布咀嚼片关键质量属性指导原则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 dr

2、ug This 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

3、drug applications (ANDAs),3 and certain chemistry, manufacturing, and controls (CMC)supplements to these some of there commendations about the submission of developmental information may also apply to investigational new drug applications (INDs). The recommendations about assessing critical quality

4、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的建议适用于所有人用咀嚼片，包括

5、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 the word should in

6、Agency 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 swallowed by the pati

7、ent 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 s

8、ize 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

9、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 c

10、hoking and/or to ensure therelease of the active 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) obstruction

11、resulting from patients swallowing whole or incompletely chewed tablets, as wellas tooth damage and denture breakage resulting from excessive tablet A related potential adverse event thatsponsors should also consider is esophageal irritation from chewabletablets. A review of numerous approveddrug pr

12、oduct 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

13、 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

14、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 sh

15、elf 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.讨论Avariety of physical characteristics should be considered in the manufacturingprocess for chewable tablets. An idealchewable tablet should be:Easy to chewPalatable (taste masked or of acceptable taste)Of appropriate

16、 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 t

17、hat 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 ., a patient may swallow whole, ratherthan chew, a b

18、ad 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

19、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 distribution, as well

20、 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

21、 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 be used to determinethe chewing difficu

22、lty 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

23、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

24、 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道阻塞。通常，选用正确类型及使用量的

25、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 the principles of diss

26、olutiontesting of conventional IR 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 developmen

27、t in vitro dissolution testing shouldbe conducted on intact tablets in at least four media, such as water, aqueousmedia at pH , buffer pH , and buffer pH , with established dissolutionmethods using equipment such as USP Apparatus 1 (basket), USP Apparatus 2(paddle), or USP Apparatus 3 (reciprocating

28、 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、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 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 enzy

29、mes (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,consiste

30、nt 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

31、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,propos

32、als 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 c