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

1、Size,Shape,andOtherPhysical Attributes ofGenericTablets and CapsulesGuidance for Industry大小，形狀，和其他物理屬性通用片和膠囊 工業(yè)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 介紹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 在尺寸和形狀方面的差異之間的藥片和膠囊上市藥品和藥品的引用一個縮寫新藥申請 21. Size 尺寸22. Shape形狀33. Patient Factors 患者因素4B. Other Physical Attribute Considerations 其他物理屬性4III. RECOMMENDATIONS 建議4A. Size 尺寸4B. Shape形狀5C. Other Physical Attributes其他物理屬性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藥物管理局（FDA或機構(gòu)）對這個話題目前的想法。它不會賦予任何人的任何權(quán)利，而不是對FDA或公眾具有約束力。您可以用另一

7、種方法，如果它滿足適用法規(guī)和規(guī)章的規(guī)定。至討論的另一種方法，請聯(lián)系FDA工作人員負責(zé)本指南的標(biāo)題列出頁面。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 片劑和膠囊劑被廣泛制造并規(guī)定，并且可以提供多個優(yōu)于其它劑型，包括便于儲存，便攜，易于施用，和準確性的劑量。 盡管這些藥物產(chǎn)品的通用配方都必須既藥學(xué)和治療上等同于一個參考列出的藥物（RLD）， 我們關(guān)心的是在差異物理特性（例如，大小和片劑或膠囊形狀）可能會影響患者合規(guī)性和用藥方案的接受程度

14、或可能導(dǎo)致用藥錯誤。我們相信這些病人的安全問題是重要的，而我們推薦的仿制藥廠家考慮的物理屬性，當(dāng)他們制定質(zhì)量目標(biāo)產(chǎn)品概況（QTPPs）為他們的通用產(chǎn)品候選人。 本指南中的建議適用于簡化新藥申請（ANDA的）和他們提交到仿制藥辦公室補充額外的優(yōu)勢（OGD）。 本指南不適用于批準的仿制藥申請（仿制藥）已經(jīng)在市場上。 但是，如果該機構(gòu)判斷為經(jīng)批準的產(chǎn)品應(yīng)該修改，因為尺寸產(chǎn)品或形狀構(gòu)成公共衛(wèi)生風(fēng)險，我們將通知ANDA的持有人。這個指導(dǎo)并不旨在適用于其他口服劑型（例如，咀嚼片，口服對于懸浮液/溶液的片劑，口服崩解片劑，舌下片劑，錠劑，樹膠）。 在一般情況下，F(xiàn)DA

15、的指導(dǎo)性文件不具有法律強制性責(zé)任。相反，指南描述的是FDA當(dāng)前思考的話題，應(yīng)該只被看作作為建議，除非有具體的法規(guī)或法定要求被引用。用法FDA指南的話應(yīng)該是指一些建議或推薦，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 一個參考之間的尺寸和

16、平板電腦的外形與膠囊的差異A.上市藥品和藥物產(chǎn)品除簡化新藥應(yīng)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 吞咽困難的片劑和膠囊劑可以是用于許多個人的問題，并可能導(dǎo)致各種不良反應(yīng)和治療方案的患者不遵守。據(jù)估計有超過1600萬人在美國有一定的吞咽困難，也被稱為吞咽困難。對于這些人，吞咽片劑或膠囊劑可以是特別具有挑戰(zhàn)性的。成年人對吞咽困難

20、，片劑和膠囊的一項調(diào)查表明，這問題遠遠超出了患者人群臨床公認吞咽困難和可能影響的美國人多達40。那些誰遇到吞咽困難藥物治療，不到四分之一與醫(yī)療保健專業(yè)，8的討論問題承認跳繩處方藥的劑量，和4的已停止治療因為片劑和/或膠囊難以下咽。  個人誰也很難吞服片劑和膠囊劑經(jīng)常引用的大小為主要原因的難度吞咽。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大小和片劑和膠囊的形狀影響產(chǎn)品的過境咽和食道和可能直接影響患者的吞咽特定的藥物產(chǎn)品的能力。較大的片劑和膠囊劑已被證明具有延長食管運送時間。此外還可導(dǎo)致食管和/或造成傷害的產(chǎn)物崩解到食道，導(dǎo)致疼痛和局部食管炎和嚴重后遺癥的可能性，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. 潰瘍，狹窄和穿孔。  其他不良反應(yīng)，如疼痛，窒息，窒息，和愿望在吞咽的口咽階段與吞咽困難和越來越多發(fā)生在較大的片劑和膠囊的大小。    成人研究評估對易于吞咽的片劑和膠囊大小的效果建議這增加規(guī)模與增長相關(guān)的患者吞咽相關(guān)投訴在片劑困難尺寸大于約

28、8毫米的直徑  的大小片劑或膠囊的影響，不論患者因素和管理食道中轉(zhuǎn)，技術(shù)（即，使用液體，病人位置）。較小的片劑通常已經(jīng)顯示有顯著更快的運輸時間在這些研究中。 Channer和Virjee比較明確8毫米直徑圓形片劑的過境時間至11毫米直徑的圓形片劑和14毫米×9毫米橢圓形片，發(fā)現(xiàn)了運輸時間為8毫米圓形片劑是顯著短超過11毫米圓形和14mm×9mm的橢圓形片（P <0.02或P <0.04，分別）。  在此外，顯著更多的患者都知道的大輪片（> 8 MM）在粘食道與8毫米圓形片劑相比。  雖然有研究較少

29、量化大小差異的影響吞咽的口咽階段，增加片劑或膠囊的大小被認為與關(guān)聯(lián)難度加大口咽轉(zhuǎn)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.形狀 對于任何給定的尺寸，某些形狀可以更容易地吞咽比其他。體外研究表明該單位藥片有更多的國家加入到食道比膠囊形片。  在研究人類也建議橢圓形片可能會更

31、容易吞咽并具有更快食道運輸時間比同等重量的圓形片劑。 患者的順從性與用藥方案可以通過以片劑或膠囊的大小和形狀的影響。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 該機構(gòu)承認，各種其他因素可能影響患者的吞咽能力的一個片劑或膠囊劑。例如，年齡可能是一個因素。兒童和青少年，還有

35、老年人，更可能有吞咽困難的片劑或膠囊。體位，流體攝入，和某些醫(yī)療條件（例如，多發(fā)性硬化的存在下，肌肉營養(yǎng)不良，帕金森氏?。┮部赡苡绊懟颊叩耐萄仕幤哪芰湍z囊。 雖然不是所有的患者因素可以通過藥物設(shè)計來解決，制造，產(chǎn)品的物理特性可以得到解決。這些物理特征影響某些患者的能力吞下制品，特別是在弱勢群體。我們認為，片劑和膠囊劑可以有效地開發(fā)和制造，以盡量減少吞咽困難，這可以鼓勵并提高患者遵守用藥方案。 FDA建議申請人設(shè)計和開發(fā)仿制藥考慮到這一點。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.其他物理屬性的思考 一涂層的存在和組

39、合物還可以潛在地影響易于吞咽片劑或膠囊。膜包衣的缺乏可減少或防止片劑的流動性比較具有相同的尺寸和形狀的包衣片劑。涂層還可能影響其他因素有助于患者接受，如適口性和嗅覺。片劑或膠囊的重量也可能影響運輸時間，用較重的片劑或膠囊相比于同樣大小，重量更輕片劑或膠囊具有更快的傳輸時間。表面積，崩解時間，并傾向吞咽時腫脹是附加參數(shù)是可以影響食管過境時間，并有會影響藥物的性能的潛在產(chǎn)品預(yù)期用途。這些物理屬性也應(yīng)考慮當(dāng)開發(fā)QTPP對于準備吞噬完整的仿制藥產(chǎn)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。建議 本指南中的建議是基于公開發(fā)表的文獻關(guān)于患者經(jīng)驗吞咽片劑和膠囊及代理經(jīng)驗，新發(fā)展區(qū)和仿制藥申請?zhí)峤挥诳诜瑒┖湍z囊劑。如果片劑或膠囊劑供使用者吞咽完整不同于建議本指導(dǎo)文件中的標(biāo)準，則申請人應(yīng)與建立QTPP前支持性信息和理由聯(lián)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、和遵守治療方案，該機構(gòu)建議，一般口服片劑和膠囊的意圖是吞咽完整應(yīng)該是相似的大小，以相應(yīng)的RLD的。該機構(gòu)建議限制治療等效片之間的尺寸上的差異如下：·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， 通用的產(chǎn)品應(yīng)該是：l 比RLD大不超過20的任何單一尺寸（得到的通用的單一尺寸應(yīng)不超過17mm）的。l 比RLD的體積大40以上。    如果RLD等于或大于17毫米的最大尺寸，通用產(chǎn)品應(yīng)該：l 不超過任何單一維度的RLD較大。l 不超過RLD的體積。 我們建議，片劑

46、或膠囊的最大尺寸應(yīng)不超過毫米和膠囊劑不應(yīng)超過標(biāo)準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. 額外的給予尺寸靈活性可為那些在其最大8毫米或更小的產(chǎn)品，但應(yīng)努力開發(fā)片劑和膠囊是一個同樣大小的和形狀上RLD下的標(biāo)準膠囊尺寸慣例，上述的津貼將通常允許增加一個膠囊的大小，當(dāng)RLD膠囊大小為3或更小。當(dāng)RLD膠囊是大小為2或更大，增加了一個膠囊大小應(yīng)該只能算是當(dāng)充分的理由可以提供的尺寸增加。這些建議將使增加了一個膠囊大小時的膠囊大小小于膠囊尺寸00。 該機構(gòu)承認兩個藥物的產(chǎn)品可能有不同的建議上限大小限制，但尺寸應(yīng)被視為

50、單一產(chǎn)品的風(fēng)險/益處配置文件的一部分。什么時候建立治療等效的，申請人應(yīng)在其通用產(chǎn)品相比只該RLD。173B.Shape 形狀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議，建議制造片劑并具有類似的形狀或膠囊有已被發(fā)現(xiàn)是更容易的形狀燕子與RLD的形狀比較。評審和比較的最大橫在RLD和通用產(chǎn)品的橫截面積是一種策略，量化形狀變化。  具有更大的橫截面面積（例如，片劑是圓）片劑和膠囊劑將通常更加難以下咽比相同體積的但與片劑或膠囊較小的橫截面面積。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. 有多種技術(shù)可被用于確定一個體積測量片劑或膠囊劑，其中包括使用比重瓶，或計算的基于物理測量片劑或用于生產(chǎn)片劑的模具。對于本指南，空間的目的成像和/或使用計算機模型的建

56、議，因為它們更精確和適用于各種形狀，盡管其它適當(dāng)驗證方法可以如果使用正確合理的。 應(yīng)在共同的技術(shù)文件中提供的片劑或膠囊的尺寸（CTD）格式， 部分3.2.P.1，說明ANDA的藥物產(chǎn)品和成分。任何研究和/或相關(guān)的信息，應(yīng)在CTD部分，提供，比較生物利用度和生物等效性研究報告。該機構(gòu)可要求樣品評價片劑或膠囊劑的物理屬性。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.其他物理屬性 片劑和膠囊等物理屬性應(yīng)在其