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

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

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 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）。

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