Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Size, Shape, and Other
Physical Attributes of
Generic
Tablets and Capsules
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 2022
Pharmaceutical Quality/CMC
Revision 1

Size, Shape, and Other
Physical Attributes of
Generic Tablets and
Capsules
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 2022
Pharmaceutical Quality/CMC
Revision 1

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
A. 	Differences in Size and Shape of Tablets and Capsules between a Reference Listed Drug
and a Drug Product Subject to an Abbreviated New Drug Application ........................................... 2
1. Size ................................................................................................................................................... 2
2. Shape................................................................................................................................................ 3
3. Patient Factors ................................................................................................................................ 4
B. 	Other Physical Attribute Considerations .................................................................................... 4
III. 	RECOMMENDATIONS .................................................................................................. 4
A. 	Size................................................................................................................................................... 4
B. 	Shape ............................................................................................................................................... 5
C. 	Other Physical Attributes.............................................................................................................. 6
D. 	Biowaivers....................................................................................................................................... 6

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Size, Shape, and Other Physical Attributes of Generic
Tablets and Capsules
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. 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 office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
Tablets and capsules are widely manufactured and prescribed and may provide a number of
advantages over other dosage forms, including ease of storage, portability, ease of
administration, and accuracy in dosing.
While generic formulations of these drug products are required to be both pharmaceutically and
therapeutically equivalent to a reference listed drug (RLD),2 we are concerned that differences in
physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient
compliance and acceptability of medication regimens or could lead to medication errors. We
believe these patient safety concerns are important, and we are recommending that generic drug
manufacturers consider physical attributes when they develop quality target product profiles
(QTPPs) for their generic product candidates.
The recommendations in this guidance apply to abbreviated new drug applications (ANDAs) and
their 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.3
However, if the Agency determines that an approved product should be modified because the
1 This guidance has been prepared by the Office of Generic Drugs and the Office of Pharmaceutical Quality in the
Center for Drug Evaluation and Research at the Food and Drug Administration.
2 Reference listed drug means the listed drug identified by FDA as the drug product upon which an applicant relies
in seeking approval of its ANDA. See 21 CFR 314.3(b). FDA publishes the identification of RLDs in the Approved
Drug Products with Therapeutic Equivalence Evaluations (i.e., Orange Book), available at
https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-
evaluations-orange-book.
3 If the manufacturer of an RLD makes a postapproval change to the size or shape of a previously approved tablet or
capsule, the generic versions generally will not need to be modified. However, the Agency could ask for
modifications to the product if there are safety concerns because of the differences in physical characteristics.

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size 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, oral
tablets for suspension/solution, orally disintegrating tablets, sublingual tablets, troches, gums).
This guidance revises the guidance of the same name issued in June 2015 to clarify that the
largest dimension of a tablet should not exceed 22 mm and that capsules should not exceed a
standard 00 size. This guidance also includes updated references.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
A. 	Differences in Size and Shape of Tablets and Capsules between a Reference
Listed Drug and a Drug Product Subject to an Abbreviated New Drug
Application
1. 	Size
Difficulty swallowing tablets and capsules can be a problem for many individuals and can lead to
a variety of adverse events and patient noncompliance with treatment regimens. It is estimated
that over 16 million people in the United States have some difficulty swallowing, also known as
dysphagia.4,5 For these individuals, swallowing a tablet or a capsule can be particularly
challenging. A survey of adults on difficulties swallowing tablets and capsules suggests that this
problem goes well beyond the patient population with clinically recognized dysphagia and may
affect as many as 40 percent of Americans. Of those who experience difficulty swallowing
medications, less than a quarter discuss the problem with a health care professional, 8 percent
admit to skipping a dose of prescribed medication, and 4 percent have discontinued therapy
because the tablets and/or capsules were difficult to swallow.6 Individuals who find it difficult to
swallow tablets and capsules frequently cite the size as the main reason for the difficulty in
swallowing.7,8
Size and shape of tablets and capsules affect the transit of the product through the pharynx and
esophagus and may directly affect a patient’s ability to swallow a particular drug product.
Larger tablets and capsules have been shown to have a prolonged esophageal transit time. This
4 Agency for Health Care Policy and Research, 1999, Diagnosis and Treatment of Swallowing Disorders
(Dysphagia) in Acute-Care Stroke Patients: Summary, Evidence Report/Technology Assessment: Number 8.
5 Robbins J, Langmore S, Hind JA, and Erlichman M, 2002, Dysphagia Research in the 21st Century and Beyond:
Proceedings From Dysphagia Experts Meeting, J Rehabil Res Dev, 39(4):543–548.
6 Harris Interactive Inc., 2003, Pill-Swallowing Problems in America: A National Survey of Adults, New York, NY:
Harris Interactive Inc. for Schwarz Pharma, 1–39.
7 See footnote 4.
8 Bhosle M, Benner J, DeKoven M, and Shelton J, 2009, Difficult to Swallow: Patient Preferences for Alternative
Valproate Pharmaceutical Formulations, Patient Prefer Adherence, 3:161–171.

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can 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 serious sequelae including
ulceration, stricture, and perforation.9,10 Other adverse events such as pain, gagging, choking,
and aspiration are related to swallowing difficulties in the oropharyngeal phase of swallowing
and increasingly occur at larger tablet and capsule sizes.11,12
Studies in adults evaluating the effect of tablet and capsule size on ease of swallowing suggest
that increases in size are associated with increases in patient complaints related to swallowing
difficulties at tablet sizes greater than approximately 8 mm in diameter.13,14,15 The size of the
tablet or capsule influences esophageal transit, irrespective of patient factors and administration
techniques (i.e., use of fluids, patient position). Smaller tablets generally have been shown to
have significantly faster transit times in these studies. Channer and Virjee specifically compared
the transit time of 8 mm diameter round tablets to 11 mm diameter round tablets and 14 mm x 9
mm oval tablets and found the transit times for the 8 mm round tablet to be significantly shorter
than for 11 mm round and 14 mm x 9 mm oval tablets (p<.02 and p<.04, respectively).16 In
addition, significantly more patients were aware of the larger round tablets (>8 mm) sticking in
the esophagus compared with the 8 mm round tablets.17 Although there has been less research
quantifying the effects of size difference on the oropharyngeal phase of swallowing, increasing
tablet or capsule size is believed to correlate with increasing difficulty with oropharyngeal
transfer.
2. 	Shape
For any given size, certain shapes may be easier to swallow than others. In vitro studies suggest
that flat tablets have greater adherence to the esophagus than capsule-shaped tablets.18 Studies in
humans have also suggested that oval tablets may be easier to swallow and have faster
esophageal transit times than round tablets of the same weight.19,20 Patient compliance with
medication regimens may be influenced by the size and shape of a tablet or capsule.
9 Drug and Therapeutics Bulletin, 1981, Tablets and Capsules that Stick in the Oesophagus, Drug Ther Bull,
19(9):33–34.
10 Channer K and Virjee JP, 1986, The Effect of Size and Shape of Tablets on their Esophageal Transit, J Clin
Pharmacol, 26(2):141–146.
11 Kelly J, D’Cruz G, and Wright D, 2010, Patients With Dysphagia: Experiences of Taking Medication, J Adv
Nurs, 66(1):82–91.
12 Jackson LD, Little J, Kung E, Williams EM, Siemiatkowska K, and Plowman S, 2008, Safe Medication
Swallowing in Dysphagia: A Collaborative Improvement Project, Healthc Q, 11:110–116.
13 See footnote 10.
14 Wamberg T, Jorgensen F, Hasselbalch H, and Hey H, 1983, The Prejudgement of the Esophageal Transfer of
Tablets and Capsules, Archiv der Pharmazie Chemistry in Life Sciences, Ed., 11:24–31.
15 Brotherman DP, Bayraktaroglu TO, and Garofalo RJ, 2004, Comparison of Ease of Swallowing of Dietary
Supplement Products for Age-Related Eye Disease, J Am Pharm Assoc, 44(5):587–593.
16 See footnote 10.
17 Ibid.
18 Marvola M, Rajaniemi M, Marttila E, Vahervuo K, and Sothmann A, 1983, Effect of Dosage Form and
Formulation Factors on the Adherence of Drugs to the Esophagus, J Pharm Sci, 72(9):1034–1036.
19 See footnote 10.
20 Hey H, Jorgensen F, Sorensen K, Hasselbelch H, and Wamberg T, 1982, Oesophageal Transit of Six Commonly
Used Tablets and Capsules, Br Med J, 285(6356):1717–1719.

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3. 	Patient Factors
The Agency recognizes that a variety of other factors may affect a patient’s ability to swallow a
tablet or a capsule. For example, age could be a factor. Children and adolescents, as well as the
elderly, are more likely to have difficulty swallowing tablets or capsules. Body position, fluid
intake, and the presence of certain medical conditions (e.g., multiple sclerosis, muscular
dystrophy, Parkinson's disease) may also affect a patient’s ability to swallow tablets and
capsules.
Although not all patient factors can be addressed through pharmaceutical design and
manufacture, the physical characteristics of a product can be addressed. These physical
characteristics influence the ability of certain patients to swallow the product, particularly in
vulnerable populations. We believe that tablets and capsules can be effectively developed and
manufactured to minimize swallowing difficulties, which can encourage and improve patient
compliance with medication regimens. FDA recommends that applicants design and develop
generic drugs with this in mind.
B. 	Other Physical Attribute Considerations
The presence and composition of a coating can also potentially affect the ease of swallowing
tablets or capsules. The lack of a film coating can decrease or prevent tablet mobility compared
with a coated tablet of the same size and shape. Coating also can affect other factors that
contribute to patient acceptance, such as palatability and smell.
The weight of the tablet or capsule also may affect transit time, with heavier tablets or capsules
having faster transit times compared to similarly-sized, lighter tablets or capsules. Surface area,
disintegration time, and propensity for swelling when swallowed are additional parameters that
can influence esophageal transit time and have the potential to affect the performance of the drug
product for its intended use. These physical attributes should also be considered when
developing a QTPP for generic drug products intended to be swallowed intact.
III. 	RECOMMENDATIONS
The recommendations in this guidance are based on published literature regarding patient
experiences swallowing tablets and capsules and Agency experience with NDAs and ANDAs
submitted for oral tablets and capsules. If a tablet or capsule intended to be swallowed intact
differs from the criteria recommended in this guidance document, then the applicant should
contact OGD with supportive information and justification before establishing the QTPP.
A. 	Size
For comparable ease of swallowing as well as patient acceptance and compliance with treatment
regimens, the Agency recommends that generic oral tablets and capsules intended to be
swallowed intact should be of a similar size to the corresponding RLD. The Agency recommends
limiting size differences between therapeutically equivalent tablets as follows:

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• 	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 (the
resulting single dimension of the generic should not exceed 17 mm).
o 	No more than 40 percent larger than the volume of the RLD.22
• 	If the RLD is equal to or greater than 17 mm in its largest dimension, the generic product
should be:
o 	No larger than the RLD in any single dimension.
o 	No larger than the volume of the RLD.
• 	We recommend that the largest dimension of a tablet should not exceed 22 mm and that
capsules should not exceed a standard 00 size.23
Additional flexibility may be given for products that are 8 mm or smaller in their largest
dimension, but efforts should be made to develop tablets and capsules that are of a similar size
and shape to the RLD.
Under the standard capsule size convention, the allowances described above will generally allow
an increase of one capsule size, when the RLD capsule is of size 3 or smaller. When the RLD
capsule is of size 2 or larger, an increase of one capsule size should only be considered when
adequate justification can be provided for the size increase. These recommendations would allow
an increase of one capsule size when the capsule size is less than capsule size 00.
The Agency recognizes that two drug products may have different recommended upper size
limits, but size should be considered as part of a single product risk/benefit profile. When
establishing therapeutic equivalence, the applicant should compare their generic product only to
the RLD.
B. 	Shape
In addition to the size recommendations described above, we recommend manufacturing tablets
and capsules that have a similar shape or have a shape that has been found to be easier to
swallow compared with the shape of the RLD. Evaluating and comparing the largest cross
sectional areas of the RLD and generic product is one strategy to quantify changes in shape.24
Tablets and capsules that have a larger cross sectional area (e.g., tablets that are rounder) would
generally be more difficult to swallow than tablets or capsules of the same volume but with
smaller cross sectional areas.
21 The largest dimension refers to the length of oval or capsule shaped tablets or the diameter of round tablets.
22 For the purposes of this guidance, volume refers to the volume occupied by the tablet or capsule.
23 An internationally accepted numbering system for capsule sizes is used in approved U.S. drug products. For the
purpose of this guidance, a liquid fill capsule is considered a capsule.
24 For the purposes of this guidance, the largest cross sectional area is defined by the largest cross sectional area of
the tablet that lies in a plane perpendicular to the longest axis of the tablet. If the shape of tablet is unconventional
(e.g., pentagon, triangle, diamond, heart), then the largest cross sectional area will be defined as the area of the
smallest circle, oval, or ellipse that would completely enclose this largest cross sectional shape.

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There are a variety of techniques that may be used to determine the volume measurements of a
tablet or capsule, including use of pycnometers, or calculations based on physical measurements
of the tablet or the die used to produce the tablet. For the purpose of this guidance, spatial
imaging and/or the use of computer models is recommended, because they are more accurate and
applicable to a variety of shapes, although other appropriately validated methods may be used if
properly justified.
The 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. Any
studies and/or related information should be provided in the CTD section, 5.3.1.2, Comparative
Bioavailability and Bioequivalence Study Reports. The Agency may request samples for
evaluation of the physical attributes of a tablet or capsule.
C. 	Other Physical Attributes
Other physical attributes of tablets and capsules should be considered in the context of their effect
on 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.
Description of these physical characteristics should be provided in the CTD section 3.2.P.1,
Description and Composition of the Drug Product of the ANDA. A summary of any studies to
support sizes outside the recommendation provided in this guidance should be provided in the
CTD section 3.2.P.2, Pharmaceutical Development or CTD section 3.2.P.5.6, Justification of
Specifications.
D. 	Biowaivers
A biowaiver (i.e., the waiver of in vivo bioequivalence data) for additional strengths of a solid
oral dosage form is generally granted if it meets one of the criteria set forth in the regulations,26
one of which is proportional similarity between strengths in active and inactive ingredients.
Compositional proportionality may be particularly relevant when considering tablet size and
tablet formulation for other strengths (both lower and higher) of the same dosage form to be
considered for a waiver of the in vivo bioequivalence study requirement. Although
compositional proportionality may exist when all active and inactive ingredients are in the same
proportion between different strengths, other methods of achieving compositional proportionality
may be more amenable to maintaining appropriate tablet sizes for generic products when
compared with the RLD. A detailed description of how the Agency defines proportional
similarity can be found in the draft guidance for industry Bioequivalence Studies With
Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (August 2021).27
25 See the International Council for Harmonisation (ICH) guidance for industry M4Q: The CTD — Quality (August
2001). We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web
page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
26 See 21 CFR 320.22(d).
27 When final, this guidance will represent the FDA’s current thinking on this topic.

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FDA recommends that applicants consider Agency published guidance, product specific
guidance,28 and relevant regulations29 on the waiver process when designing and formulating
other strengths of the same dosage form that will be studied with bioequivalence studies. For
specific questions related to biowaivers, you should contact the appropriate review division
within OGD.
28 Available at https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development.
29 See 21 CFR 320.22.