Size, Shape, and Other PhysicalAttributes of Generic Tablets and Capsules

1、Size,Shape,andOtherPhysical Attributes ofGenericTablets and CapsulesGuidance for Industry大小，形状，和其他物理属性通用片和胶囊 工业指南U.S. Department of Health and Human Services Food and Drug AdministrationCenter for Drug Evaluation and Research (CDER)June 2015 Pharmaceutical Quality/CMCGeneric Tablets andCapsules

2、Guidance for IndustryAdditional copies are available from:Office of Communications, Division of Drug Information Center for Drug Evaluation and ResearchFood and Drug Administration10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993Phone: 855-543-3784 or 301-796-3400; Fax: 3

3、01-431-6353/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmContains Nonbinding RecommendationsTABLE OF CONTENTSI. INTRODUCTION 介绍1II. BACKGROUND 背景2A. Differences in Size and Shape of Tablets and Capsules between a Reference Listed Drug and a D

4、rug Product Subject to an Abbreviated New Drug Application 在尺寸和形状方面的差异之间的药片和胶囊上市药品和药品的引用一个缩写新药申请 21. Size 尺寸22. Shape形状33. Patient Factors 患者因素4B. Other Physical Attribute Considerations 其他物理属性4III. RECOMMENDATIONS 建议4A. Size 尺寸4B. Shape形状5C. Other Physical Attributes其他物理属性6D. Biowaivers豁免生物等效性（研究）6

5、1 Size, Shape, and Other Physical Attributes of Generic2 Tablets and Capsules3 Guidance for Industry145This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not create any rights for any person and is not binding on FDA or the public

6、. 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.本指南代表了食品和药物管理局（FDA或机构）对这个话题目前的想法。它不会赋予任何人的任何权利，而不是对FDA或公众具有约束力。您可以用另一

7、种方法，如果它满足适用法规和规章的规定。至讨论的另一种方法，请联系FDA工作人员负责本指南的标题列出页面。678910111213141516I.INTRODUCTION17Tablets and capsules are widely manufactured and prescribed and may provide a number ofadvantages over other dosage forms, including ease of storage, portability, ease ofadministration, and accuracy in dosing. Whi

8、le generic formulations of these drug products are required to be both pharmaceutically andtherapeutically equivalent to a reference listed drug (RLD),2 we are concerned that differences inphysical characteristics (e.g., size and shape of the tablet or capsule) may affect patientcompliance and accep

9、tability of medication regimens or could lead to medication errors. Webelieve these patient safety concerns are important, and we are recommending that generic drugmanufacturers consider physical attributes when they develop quality target product profiles(QTPPs) for their generic product candidates

10、. The recommendations in this guidance apply to abbreviated new drug applications (ANDAs) andtheir supplements for additional strengths that are submitted to the Office of Generic Drugs(OGD). This guidance does not apply to approved ANDAs (generic drugs) already on the market.3However, if the Agency

11、 determines that an approved product should be modified because thesize or shape of a product poses a risk to public health, we will notify the holder of the ANDA.This guidance is not intended to apply to other oral dosage forms (e.g., chewable tablets, oraltablets for suspension/solution, orally di

12、sintegrating tablets, sublingual tablets, troches, gums). In general, FDAs guidance documents do not establish legally enforceable responsibilities.Instead, guidances describe the Agencys current thinking on a topic and should be viewed onlyas recommendations, unless specific regulatory or statutory

13、 requirements are cited. The use ofthe word should in Agency guidances means that something is suggested or recommended, butnot required. 引言 片剂和胶囊剂被广泛制造并规定，并且可以提供多个优于其它剂型，包括便于储存，便携，易于施用，和准确性的剂量。 尽管这些药物产品的通用配方都必须既药学和治疗上等同于一个参考列出的药物（RLD）， 我们关心的是在差异物理特性（例如，大小和片剂或胶囊形状）可能会影响患者合规性和用药方案的接受程度

14、或可能导致用药错误。我们相信这些病人的安全问题是重要的，而我们推荐的仿制药厂家考虑的物理属性，当他们制定质量目标产品概况（QTPPs）为他们的通用产品候选人。 本指南中的建议适用于简化新药申请（ANDA的）和他们提交到仿制药办公室补充额外的优势（OGD）。 本指南不适用于批准的仿制药申请（仿制药）已经在市场上。 但是，如果该机构判断为经批准的产品应该修改，因为尺寸产品或形状构成公共卫生风险，我们将通知ANDA的持有人。这个指导并不旨在适用于其他口服剂型（例如，咀嚼片，口服对于悬浮液/溶液的片剂，口服崩解片剂，舌下片剂，锭剂，树胶）。 在一般情况下，FDA

15、的指导性文件不具有法律强制性责任。相反，指南描述的是FDA当前思考的话题，应该只被看作作为建议，除非有具体的法规或法定要求被引用。用法FDA指南的话应该是指一些建议或推荐，不是必需的。46II.BACKGROUND4748 A.Differences in Size and Shape of Tablets and Capsules between a Reference49 Listed Drug and a Drug Product Subject to an Abbreviated New Drug50 Application51521.SizeII。背景 一个参考之间的尺寸和

16、平板电脑的外形与胶囊的差异A.上市药品和药物产品除简化新药应用Difficulty swallowing tablets and capsules can be a problem for many individuals and can lead toa variety of adverse events and patient noncompliance with treatment regimens. It is estimatedthat over 16 million people in the United States have some difficulty swallowin

17、g, also known asdysphagia.4,5 For these individuals, swallowing a tablet or a capsule can be particularlychallenging. A survey of adults on difficulties swallowing tablets and capsules suggests that thisproblem goes well beyond the patient population with clinically recognized dysphagia and mayaffec

18、t as many as 40 percent of Americans. Of those who experience difficulty swallowingmedications, less than a quarter discuss the problem with a health care professional, 8 percentadmit to skipping a dose of prescribed medication, and 4 percent have discontinued therapybecause the tablets and/or capsu

19、les were difficult to swallow.6 Individuals who find it difficult toswallow tablets and capsules frequently cite the size as the main reason for the difficulty inswallowing.7,81.尺寸 吞咽困难的片剂和胶囊剂可以是用于许多个人的问题，并可能导致各种不良反应和治疗方案的患者不遵守。据估计有超过1600万人在美国有一定的吞咽困难，也被称为吞咽困难。对于这些人，吞咽片剂或胶囊剂可以是特别具有挑战性的。成年人对吞咽困难

20、，片剂和胶囊的一项调查表明，这问题远远超出了患者人群临床公认吞咽困难和可能影响的美国人多达40。那些谁遇到吞咽困难药物治疗，不到四分之一与医疗保健专业，8的讨论问题承认跳绳处方药的剂量，和4的已停止治疗因为片剂和/或胶囊难以下咽。  个人谁也很难吞服片剂和胶囊剂经常引用的大小为主要原因的难度吞咽。Size and shape of tablets and capsules affect the transit of the product through the pharynx andesophagus and may directly affect a patients

21、ability to swallow a particular drug product.Larger tablets and capsules have been shown to have a prolonged esophageal transit time. Thiscan lead to disintegration of the product in the esophagus and/or cause injury to the esophagus,resulting in pain and localized esophagitis and the potential for

22、serious sequelae including大小和片剂和胶囊的形状影响产品的过境咽和食道和可能直接影响患者的吞咽特定的药物产品的能力。较大的片剂和胶囊剂已被证明具有延长食管运送时间。此外还可导致食管和/或造成伤害的产物崩解到食道，导致疼痛和局部食管炎和严重后遗症的可能性，包括ulceration, stricture, and perforation.9,10 Other adverse events such as pain, gagging, choking,and aspiration are related to swallowing difficulties in the o

23、ropharyngeal phase of swallowingand increasingly occur at larger tablet and capsule sizes.11,12Studies in adults evaluating the effect of tablet and capsule size on ease of swallowing suggestthat increases in size are associated with increases in patient complaints related to swallowingdifficulties

24、at tablet sizes greater than approximately 8 mm in diameter.13,14,15 The size of thetablet or capsule influences esophageal transit, irrespective of patient factors and administrationtechniques (i.e., use of fluids, patient position). Smaller tablets generally have been shown tohave significantly fa

25、ster transit times in these studies. Channer and Virjee specifically comparedthe transit time of 8 mm diameter round tablets to 11 mm diameter round tablets and 14 mm x 9mm oval tablets and found the transit times for the 8 mm round tablet to be significantly shorterthan for 11 mm round and 14 mm x

26、9 mm oval tablets (p<.02 and p<.04, respectively).16 Inaddition, significantly more patients were aware of the larger round tablets (>8 mm) sticking inthe esophagus compared with the 8 mm round tablets.17 Although there has been less researchquantifying the effects of size difference on the

27、 oropharyngeal phase of swallowing, increasingtablet or capsule size is believed to correlate with increasing difficulty with oropharyngealtransfer. 溃疡，狭窄和穿孔。  其他不良反应，如疼痛，窒息，窒息，和愿望在吞咽的口咽阶段与吞咽困难和越来越多发生在较大的片剂和胶囊的大小。    成人研究评估对易于吞咽的片剂和胶囊大小的效果建议这增加规模与增长相关的患者吞咽相关投诉在片剂困难尺寸大于约

28、8毫米的直径  的大小片剂或胶囊的影响，不论患者因素和管理食道中转，技术（即，使用液体，病人位置）。较小的片剂通常已经显示有显著更快的运输时间在这些研究中。 Channer和Virjee比较明确8毫米直径圆形片剂的过境时间至11毫米直径的圆形片剂和14毫米×9毫米椭圆形片，发现了运输时间为8毫米圆形片剂是显著短超过11毫米圆形和14mm×9mm的椭圆形片（P <0.02或P <0.04，分别）。  在此外，显著更多的患者都知道的大轮片（> 8 MM）在粘食道与8毫米圆形片剂相比。  虽然有研究较少

29、量化大小差异的影响吞咽的口咽阶段，增加片剂或胶囊的大小被认为与关联难度加大口咽转移。2.ShapeFor any given size, certain shapes may be easier to swallow than others. In vitro studies suggestthat flat tablets have greater adherence to the esophagus than capsule-shaped tablets.18 Studies inhumans have also suggested that oval tablets may be eas

30、ier to swallow and have fasteresophageal transit times than round tablets of the same weight.19,20 Patient compliance withmedication regimens may be influenced by the size and shape of a tablet or capsule. 982.形状 对于任何给定的尺寸，某些形状可以更容易地吞咽比其他。体外研究表明该单位药片有更多的国家加入到食道比胶囊形片。  在研究人类也建议椭圆形片可能会更

31、容易吞咽并具有更快食道运输时间比同等重量的圆形片剂。 患者的顺从性与用药方案可以通过以片剂或胶囊的大小和形状的影响。3.Patient FactorsThe Agency recognizes that a variety of other factors may affect a patients ability to swallow atablet or a capsule. For example, age could be a factor. Children and adolescents, as well as theelderly, are more likely to

32、 have difficulty swallowing tablets or capsules. Body position, fluidintake, and the presence of certain medical conditions (e.g., multiple sclerosis, musculardystrophy, Parkinson's disease) may also affect a patients ability to swallow tablets andcapsules. 107Although not all patient factors ca

33、n be addressed through pharmaceutical design andmanufacture, the physical characteristics of a product can be addressed. These physicalcharacteristics influence the ability of certain patients to swallow the product, particularly invulnerable populations. We believe that tablets and capsules can be

34、effectively developed andmanufactured to minimize swallowing difficulties, which can encourage and improve patientcompliance with medication regimens. FDA recommends that applicants design and developgeneric drugs with this in mind. 3.患者因素 该机构承认，各种其他因素可能影响患者的吞咽能力的一个片剂或胶囊剂。例如，年龄可能是一个因素。儿童和青少年，还有

35、老年人，更可能有吞咽困难的片剂或胶囊。体位，流体摄入，和某些医疗条件（例如，多发性硬化的存在下，肌肉营养不良，帕金森氏病）也可能影响患者的吞咽药片的能力和胶囊。 虽然不是所有的患者因素可以通过药物设计来解决，制造，产品的物理特性可以得到解决。这些物理特征影响某些患者的能力吞下制品，特别是在弱势群体。我们认为，片剂和胶囊剂可以有效地开发和制造，以尽量减少吞咽困难，这可以鼓励并提高患者遵守用药方案。 FDA建议申请人设计和开发仿制药考虑到这一点。116B.Other Physical Attribute Considerations117The presence and composit

36、ion of a coating can also potentially affect the ease of swallowingtablets or capsules. The lack of a film coating can decrease or prevent tablet mobility comparedwith a coated tablet of the same size and shape. Coating also can affect other factors thatcontribute to patient acceptance, such as pala

37、tability and smell. 122The weight of the tablet or capsule also may affect transit time, with heavier tablets or capsuleshaving faster transit times compared to similarly-sized, lighter tablets or capsules. Surface area,disintegration time, and propensity for swelling when swallowed are additional p

38、arameters thatcan influence esophageal transit time and have the potential to affect the performance of the drugproduct for its intended use. These physical attributes should also be considered whendeveloping a QTPP for generic drug products intended to be swallowed intact. B.其他物理属性的思考 一涂层的存在和组

39、合物还可以潜在地影响易于吞咽片剂或胶囊。膜包衣的缺乏可减少或防止片剂的流动性比较具有相同的尺寸和形状的包衣片剂。涂层还可能影响其他因素有助于患者接受，如适口性和嗅觉。片剂或胶囊的重量也可能影响运输时间，用较重的片剂或胶囊相比于同样大小，重量更轻片剂或胶囊具有更快的传输时间。表面积，崩解时间，并倾向吞咽时肿胀是附加参数是可以影响食管过境时间，并有会影响药物的性能的潜在产品预期用途。这些物理属性也应考虑当开发QTPP对于准备吞噬完整的仿制药产品。130III.RECOMMENDATIONS131The recommendations in this guidance are based on pu

40、blished literature regarding patientexperiences swallowing tablets and capsules and Agency experience with NDAs and ANDAssubmitted for oral tablets and capsules. If a tablet or capsule intended to be swallowed intactdiffers from the criteria recommended in this guidance document, then the applicant

41、shouldcontact OGD with supportive information and justification before establishing the QTPP.三。建议 本指南中的建议是基于公开发表的文献关于患者经验吞咽片剂和胶囊及代理经验，新发展区和仿制药申请提交于口服片剂和胶囊剂。如果片剂或胶囊剂供使用者吞咽完整不同于建议本指导文件中的标准，则申请人应与建立QTPP前支持性信息和理由联系OGD。A.SizeFor comparable ease of swallowing as well as patient acceptance and complia

42、nce with treatmentregimens, the Agency recommends that generic oral tablets and capsules intended to beswallowed intact should be of a similar size to the corresponding RLD. The Agency recommendslimiting size differences between therapeutically equivalent tablets as follows: A.尺寸 可比易于吞咽，以及患者的接受

43、和遵守治疗方案，该机构建议，一般口服片剂和胶囊的意图是吞咽完整应该是相似的大小，以相应的RLD的。该机构建议限制治疗等效片之间的尺寸上的差异如下：·If the RLD is less than 17 mm in its largest dimension,21 the generic product should be:o No more than 20 percent larger than the RLD in any single dimension (theresulting single dimension of the generic should not exceed

44、 17 mm).o No more than 40 percent larger than the volume of the RLD.22149·If the RLD is equal to or greater than 17 mm in its largest dimension, the generic productshould be:o No larger than the RLD in any single dimension.o No larger than the volume of the RLD. 154·We recommend that the l

45、argest dimension of a tablet or capsule should not exceed 22mm and that capsules should not exceed a standard 00 size如果RLD是小于17毫米的最大尺寸， 通用的产品应该是：l 比RLD大不超过20的任何单一尺寸（得到的通用的单一尺寸应不超过17mm）的。l 比RLD的体积大40以上。    如果RLD等于或大于17毫米的最大尺寸，通用产品应该：l 不超过任何单一维度的RLD较大。l 不超过RLD的体积。 我们建议，片剂

46、或胶囊的最大尺寸应不超过毫米和胶囊剂不应超过标准00尺寸。Additional flexibility may be given for products that are 8 mm or smaller in their largestdimension, but efforts should be made to develop tablets and capsules that are of a similar sizeand shape to the RLD. 161Under the standard capsule size convention, the allowances d

47、escribed above will generally allowan increase of one capsule size, when the RLD capsule is of size 3 or smaller. When the RLDcapsule is of size 2 or larger, an increase of one capsule size should only be considered whenadequate justification can be provided for the size increase. These recommendati

48、ons would allowan increase of one capsule size when the capsule size is less than capsule size 00. 167The Agency recognizes that two drug products may have different recommended upper sizelimits, but size should be considered as part of a single product risk/benefit profile. Whenestablishing therape

49、utic equivalence, the applicant should compare their generic product only tothe RLD. 额外的给予尺寸灵活性可为那些在其最大8毫米或更小的产品，但应努力开发片剂和胶囊是一个同样大小的和形状上RLD下的标准胶囊尺寸惯例，上述的津贴将通常允许增加一个胶囊的大小，当RLD胶囊大小为3或更小。当RLD胶囊是大小为2或更大，增加了一个胶囊大小应该只能算是当充分的理由可以提供的尺寸增加。这些建议将使增加了一个胶囊大小时的胶囊大小小于胶囊尺寸00。 该机构承认两个药物的产品可能有不同的建议上限大小限制，但尺寸应被视为

50、单一产品的风险/益处配置文件的一部分。什么时候建立治疗等效的，申请人应在其通用产品相比只该RLD。173B.Shape 形状174In addition to the size recommendations described above, we recommend manufacturing tabletsand capsules that have a similar shape or have a shape that has been found to be easier toswallow compared with the shape of the RLD. Evaluating

51、 and comparing the largest crosssectional areas of the RLD and generic product is one strategy to quantify changes in shape.24Tablets and capsules that have a larger cross sectional area (e.g., tablets that are rounder) wouldgenerally be more difficult to swallow than tablets or capsules of the same

52、 volume but withsmaller cross sectional areas. 182除了上述的大小的建议，建议制造片剂并具有类似的形状或胶囊有已被发现是更容易的形状燕子与RLD的形状比较。评审和比较的最大横在RLD和通用产品的横截面积是一种策略，量化形状变化。  具有更大的横截面面积（例如，片剂是圆）片剂和胶囊剂将通常更加难以下咽比相同体积的但与片剂或胶囊较小的横截面面积。There are a variety of techniques that may be used to determine the volume measurements of ata

53、blet or capsule, including use of pycnometers, or calculations based on physical measurementsof the tablet or the die used to produce the tablet. For the purpose of this guidance, spatialimaging and/or the use of computer models is recommended, because they are more accurate andapplicable to a varie

54、ty of shapes, although other appropriately validated methods may be used ifproperly justified. 189The size of a tablet or capsule should be provided in the common technical document (CTD)format,25 section 3.2.P.1, Description and Composition of the Drug Product of the ANDA. Anystudies and/or related

55、 information should be provided in the CTD section, , ComparativeBioavailability and Bioequivalence Study Reports. The Agency may request samples forevaluation of the physical attributes of a tablet or capsule. 有多种技术可被用于确定一个体积测量片剂或胶囊剂，其中包括使用比重瓶，或计算的基于物理测量片剂或用于生产片剂的模具。对于本指南，空间的目的成像和/或使用计算机模型的建

56、议，因为它们更精确和适用于各种形状，尽管其它适当验证方法可以如果使用正确合理的。 应在共同的技术文件中提供的片剂或胶囊的尺寸（CTD）格式， 部分3.2.P.1，说明ANDA的药物产品和成分。任何研究和/或相关的信息，应在CTD部分，提供，比较生物利用度和生物等效性研究报告。该机构可要求样品评价片剂或胶囊剂的物理属性。196C.Other Physical Attributes197Other physical attributes of tablets and capsules should be considered in the context of t

57、heir effecton ease of swallowing. For example, tablet coating, weight, surface area, disintegration time,and propensity for swelling should be considered when developing a QTPP for generic tablets. 201Description of these physical characteristics should be provided in the CTD section 3.2.P.1,Descrip

58、tion and Composition of the Drug Product of the ANDA. A summary of any studies tosupport sizes outside the recommendation provided in this guidance should be provided in theCTD section 3.2.P.2, Pharmaceutical Development or CTD section 3.2.P.5.6, Justification ofSpecifications. C.其他物理属性 片剂和胶囊等物理属性应在其