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. 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 inAgencyguidances 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