This document provides guidance on selecting physical parameters for designing and developing oral solid dosage forms (tablets and capsules) for generic drugs. It discusses key physical attributes like size, shape, tablet scoring and other factors and their impact on generic drug claims and therapeutic outcomes. The document recommends that generic drug manufacturers consider physical attributes like size, shape, scoring and other factors in developing their products to ensure equivalence to the reference brand drug. The physical attributes can impact patient acceptance and compliance. It provides recommendations and criteria for generic drugs to address physical attributes like having similar size and shape as the reference brand and consistent scoring.

1. PTPS-DG-12-2014
Simple Attributes of Greater
Impact on Claim of Generic
Drugs
Selection of Physical Parameters for
Designing & Development of
Oral Dosage Forms (Tablets and Capsules)
to demonstrate promised therapeutic outcome
with Reference Brand
Roohi Bano Obaid, Deputy Drugs Controller,
Drugs Regulatory Authority of Pakistan
For Policy, Training and Pharmacy Services
February 2014

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INDEX
S. No Title Page No
1 Introduction 3
2 Key Physical Attributes of Tablets and Capsules 4
3 Size, Shape, Patient Factors, Tablet Scoring 4-6
4 Other Physical Attributes 6
5 Recommendations 7
6 Size, Shape, Tablet Scoring, other Physical Attributes 7-10
7 Glossary 11
8 References 13

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Disclaimer
Rapid movement in science and parallel development in regulatory science discovers and opens
new ways to have an insight on potentials possessing greater impact on pharmaceutical
manufacturing activities and advancement in the field of public health. Based on extensive
review and professional judgment the topic was prioritized for issuance of guidance leading to
regulatory framework in appropriate period.
Referring guidance of United States-Food and Drug Administration (US-FDA) as a principle
source of information and knowledge and focusing on the significance of subject, a guidance
document is drafted and presented. Critical review and comments will be appreciated and
acknowledged if cross referred with specific reference or norms of good science.
1. Introduction:
Regular science based practice of pharmacy and medicine is fundamental for an efficient
pharmaceutical care system to deliver and ensure right dose in right dosage form.
Extemporaneous compounding to make available prescribed dose by dividing of tablets, dosage
titer and evidence based clinical judgment has great impact on primary to tertiary healthcare
system. For. e.g. tablet captopril 25 mg and tablet phenobarbitone 30 mg are the most regular
supplied among their strengths and a significant number of prescriptions direct patients to divide
tablet into half or quarter. As a matter of fact, there is no procedure to teach how this product or
other product which has narrow therapeutic index (NTI) can be divided by the patient at home.
Content uniformity is consistently challenged and stability after breaking of tablet into half or
quarter requires assessing and understanding. Nevertheless, scores on tablets play a vital role in
therapeutic outcome promised on the label claim.
Indeed, the final divided dose of a tablet taken by the patient is neither subject to verification of
its content nor studied for its stability on surface area exposed to temperature, light and moisture,
therefore, a risk assessment for particular cases need to be addressed in isolation while other
topics bearing significant amount of concern are the subject of document.
Tablets and capsules are manufactured and prescribed far and wide. They may provide a number
of advantages over other dosage forms, like ease of storage, portability, ease of administration,

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and accuracy in dosing. Generic formulations of these drug products must be pharmaceutically
and therapeutically equivalent to a Reference Innovator Drug (RID). Differences in physical
characteristics e.g. shape and size of a tablet or capsule can affect patient compliance and
acceptability of dosage regimens. It may also lead to medication errors. Hence, these safety
concerns are important. In line with development going around in the field of pharmaceutical
regulatory sciences, it is recommended that generic drug manufacturers should take into account
such physical attributes while developing their generic formulation’s Quality Target Product
Profiles (QTPP) interested in registration and market authorization of their product.
This document does not cover or extend to other oral dosage forms of different delivery systems
(e.g., chewable tablets, oral tablets for suspension/solution, orally disintegrating tablets,
sublingual tablets, troches, gums).
Glossary is given for cross-reference and precise elucidation of the matter related to this
guidance at the end.
2. Key Physical attributes of Tablets and Capsules:
a. Size:
Many people come across difficulty in swallowing tablets and capsules leading to a
number of adverse events and patient non-compliance with treatment regimens.
Difficulty in swallowing is known as dysphagia. People having difficulty in swallowing
tablets and capsules often hold responsible the size.1,2
The transit of the product through the pharynx and esophagus is affected by the size and
shape of tablets and capsules. This may directly affect a patient’s ability to swallow a
particular drug product. Larger tablets and capsules have been shown to prolong
esophageal transit time. This may cause the product to disintegrate in the esophagus
and/or cause injury to the esophagus, resulting in pain and localized esophagitis and the
potential for serious consequences like ulceration, stricture and perforation. 3, 4
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.5,6
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

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patient complaints related to swallowing difficulties at tablet sizes greater than
approximately 8 mm in diameter.4,7,8
Thus, the size of the tablet or capsule influences
esophageal transit
b. Shape:
, 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. Although research has shed minimal
light on 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.
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.4, 9
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.4,10
Patient compliance with medication regimens may be influenced by the size
and shape of a tablet or capsule.
c. Patient factors:
Various other factors may affect a patient’s ability to swallow a tablet or a capsule. E.g.
age of the patient may be a factor. Children and adolescents, as well as the elderly, are
more prone 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.
It is realized that several factors may affect the ability of a patient to swallow a tablet or
capsule. While, not all patient factors can be addressed through pharmaceutical design
and manufacture, the physical characteristics can be. These characteristics affect patient’s
ability to swallow tablet or a capsule especially in vulnerable populations. It is believed
that tablets and capsules can be effectively developed and manufactured to minimize
swallowing difficulties. This will in turn encourage and improve patient compliance with
medication regimens. Hence, the generic drug manufacturers should develop their
products taking into account these aspects.

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d. Tablet Scoring:
Science considers tablet scoring as an issue when determining whether a generic drug
product is the same as the Reference Innovator Drug (RID).
3. Other Physical Attributes:
A tablet dosage form may
be manufactured with or without a score or scores. This characteristic is useful as tablet
scoring can facilitate the splitting of tablet into fractions when less than a full tablet is
desired for a dose. Even though, there are no standards or regulatory requirements that
specifically address scoring of tablets, the current scientific thinking on the subject
emphasizes the need for consistent scoring between a generic product and its RID.
Consistent scoring ensures that the patient is able to adjust the dose, by splitting the
tablet, in the same manner as the RID. This enables the patient to switch between
products made by different manufacturers without encountering problems related to the
dose. In addition, consistent scoring ensures that neither the generic product nor the RID
has an advantage in the marketplace because one is scored and one is not.
The world’s leading Regulatory Agency (US-FDA) conducted internal research on tablet
splitting and concluded that in some cases, there are possible safety issues, especially
when tablets are not scored or evaluated for splitting. The Agency’s concerns with
splitting a tablet included variations in the tablet content, weight, disintegration, or
dissolution, which can affect how much drug is present in a split tablet and available for
absorption. In addition, there may be stability issues with splitting tablets.11,12
Tablet splitting also is addressed in pharmacopeial standards. The European
Pharmacopeia (EP) currently applies accuracy of subdivision standards for scored
tablets—and has at various times also included standards for content uniformity, weight
variation, and loss of mass—while the United States Pharmacopeia (USP) published a
Stimuli article in 2009 proposing criteria for loss of mass and accuracy of subdivision for
split tablets.13
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 increase the risk of tablet capture compared
with a coated tablet of the same size and shape. Coating also can affect other factors that

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contribute to patient acceptance, such as palatability and smell. It is pertinent to mention that
coating of the generic drug products should be the same as the RID.
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.
4. Recommendations:
a. Size:
In order to achieve patient acceptance and compliance with treatment regimens, it is
recommended that generic oral tablets and capsules intended to be swallowed intact
should be of a similar size to their corresponding RID or justified if deviates to prove the
equivalency in compliance and therapeutic outcome.
b. Shape:
It is recommended to manufacture tablets and capsules of similar shape or a shape that is
easier to swallow compared with that of the RID. Evaluating and comparing the largest
cross sectional areas of the RID and generic product is one strategy to quantify changes
in shape. 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. Volume measurement can be done
using various techniques like the use of pycnometers, calculations based on physical
measurements of the tablets or die used to produce the tablet. Spatial imaging and/or the
use of computer models is recommended, because they are accurate and applicable to a
variety of shapes, although other appropriately validated methods may be used if properly
justified. The same may be submitted for evaluation of physical attributes to the
concerned upon request.
c. Tablet Scoring:

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As a result of these thoughts on tablet scoring, some guidelines and criteria
I. The content of application regarding the scientific basis for functional scoring on
solid oral dosage form products to ensure the quality of generic scored tablet
products may be required to consider during the review of dossiers for generic
drugs.
from US-
FDA are reproduced below:
II. The dosage amount meant to be achieved after splitting the tablet should not be
below the minimum therapeutic dose indicated on the approved labeling.
III. The split tablet should be safe to handle and not pose risk of unintended drug
exposure.
IV. Modified release products for which the control of drug release can be
compromised by tablet splitting should not have a scoring feature.
V. The split tablet, when stored in pharmacy dispensing containers (no seal/no
desiccant), should demonstrate adequate stability for a period of 90 days at 25º C
+ 2º C/60% Relative Humidity (RH) +5 percent RH.
VI. The split tablet portions should meet the same finished-product testing
requirements as for a whole-tablet product with equivalent strength. A risk
assessment should be provided to justify the tests and criteria for product with the
proposed functional scoring. The resulting data may be submitted for evaluation
to the concerned upon request. The assessment should be undertaken on both
tablets that are split non-mechanically (by hand) and tablets that are split
mechanically (with a tablet splitter). Any recommended dissolution test data must
be generated on a minimum of 12 individual split tablet portions.
VII. Typical criteria related to the dosage form that should be assessed during
pharmaceutical development and during primary/ exhibit stability batches and

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scale-up by the manufacturers are described below. A risk assessment should be
performed to justify criteria for each product.
i. Immediate Release Solid Oral Dosage Forms:
USP General Chapter <905> Uniformity of Dosage Units - Testing for Weight
Variation is permitted for split tablet portions intended to contain 25 mg or more
of a drug substance that comprises 25 percent or more (by weight) of the split
tablet portion. Otherwise, the test for Content Uniformity should be used.
Tablet splitability at both ends of the proposed hardness range should be
demonstrated by:
 Testing 15 tablets to ensure a loss of mass of less than 3.0 percent between
the individual segments (30 for bisected tablets, 45 for trisected tablets,
etc.) when compared to the whole tablet. The resulting data for each tablet
may be submitted for evaluation to the concerned upon request.
 Confirming that the split tablet portions meet the USP Friability
requirement.14
Dissolution data on split tablet portions should meet finished-product release
requirements.
ii. Modified Release Solid Oral Dosage Forms (Using Matrix Technology)
 All above criteria for i of c of 3 should be met.
 Dissolution should be demonstrated at both ends of the hardness range.
 Dissolution on whole versus split tablet portions should meet the similarity
factor (f2) criteria.
iii. Modified Release Solid Oral Dosage Forms (Using Compressed Film
Coated Components)

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 All above criteria for i & ii of c of 3 should be met.
 Dissolution profile on pre-compressed beads versus post-compressed
whole and split tablet portions should meet similarity factor (f2) criteria to
ascertain the integrity of beads during compression.
Scoring configuration of generic drug products should be the same as the RID or justified
in terms of improved safety, quality and compliance if deviated.
iv. Nomenclature and Product Labeling:
The products that meet the above-referenced criteria will carry all current
scientific support to be labeled as having functional scoring.
For currently marketed products, manufacturers need to perform an assessment
followed by generation of relevant actual data for its evaluation under the
approach of continuous improvement required by Quality Management System
(QMS). Difference in scoring and functional scoring may carry weight to
strengthen the intent behind label claim if placed at a prominent place on the
label.
d. 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.

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5. Glossary:
The terms used in this guidance are defined for the ease of understanding:
a. Generic Drug:
A generic drug is the same as a brand name drug in dosage, safety, strength, how it is
taken, quality, performance, and intended use. A generic drug product must contain the
identical amounts of the same active ingredient(s) as the brand name product.
b. Pharmaceutical Equivalent:
Drug Products can be considered to be pharmaceutically equivalent if they meet the
following three criteria:
 they contain the same active ingredient(s)
 they are of the same dosage form and route of administration
 they are identical in strength or concentration
Pharmaceutically equivalent drug products may differ in characteristics such as:
 shape
 release mechanism
 labeling (to some extent)
 scoring
 excipients (including colors, flavors, preservatives)
c. Therapeutic Equivalent:
Drug products can be considered to be therapeutically equivalent only if they meet these
criteria:
 they are pharmaceutical equivalents (contain the same active
ingredient(s); dosage form and route of administration; and strength.)
 Designates a brand name drug to be the Reference Innovator Drug (RID).
 Scientifically demonstrate that the product is bioequivalent (i.e., performs in the
same manner as the Reference Innovator Drug).
d. Quality Target Product Profile (QTPP):
It is a prospective summary of the quality characteristics of a drug product that ideally
will be achieved to ensure the desired quality, taking into account safety and efficacy of
the drug product. The Quality Target Product Profile forms the basis of design for the

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development of the product. Considerations for the quality target product profile could
include:
 Intended use in clinical setting, route of administration, dosage form, delivery
systems
 Dosage strength(s)
 Container closure system
 Therapeutic moiety release or delivery and attributes affecting pharmacokinetic
characteristics (e.g., dissolution, aerodynamic performance) appropriate to the
drug product dosage form being developed
 Drug product quality criteria (e.g., sterility, purity, stability, and drug release)
appropriate for the intended marketed product.
e. Reference Innovator Drug (RID):
Innovator who developed the dosage form and entered in market after the approval of
regulatory agency is considered as innovator in developed country. Since, same formula
does not apply in Pakistan for every case, therefore first finished good of the particular
dosage form assessed against the aforementioned may be taken as Reference innovator
Drug (RID) for those products whose innovator reference is not available in Pakistan.
f. Largest cross-sectional area:
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, etc.), 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.
g. Split Tablet Portion:
Each split portion of a whole tablet is considered a unit of dose and should meet the
uniformity of dosage unit requirement.

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h. Functional Scoring:
Engraved mark capable to swiftly divide a tablet in equal doses from the mark precisely
upon application of finger force and demonstrated by sufficient amount of science based
working for the intended purpose.
i. Non-Functional Scoring:
A mark or engraved mark placed as a cosmetic attribute or a trade symbol and is not
studied for equal division of doses for a tablet.
6. References:
1. Agency for Health Care Policy and Research, March 1999, Diagnosis and Treatment of
Swallowing Disorders (Dysphagia) in Acute-Care Stroke Patients. Summary, Evidence
Report/Technology Assessment: Number 8, USA.
2. Bhosle M, Benner J, DeKoven M, Shelton J., 2009, Difficult to Swallow: Patient
Preferences for Alternative Valproate Pharmaceutical Formulations. Patient Prefer
Adherence 3, 161-171.
3. Drug and Therapeutics Bulletin, 1981; Tablets and Capsules that Stick in the
Oesophagus, 19(9), 33-34.
4. Channer, K, Virjee, JP. 1986, The Effect of Size and Shape of Tablets on their
Esophageal Transit. Journal of Clinical Pharmacology, 26, 141-146.
5. Kelly J, D’Cruz G, Wright D, 2010, Patients with Dysphagia: Experiences of Taking
Medication. Journal of Advanced Nursing 66(1), 82-91.
6. Jackson LD, Little J, Kung E, Williams EM, Siemiatkowska K, Plowman S, 2008, Safe
Medication Swallowing in Dysphagia; A Collaborative improvement Project. Healthcare
Quarterly 11, 110-116.

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7. Wamberg T., Jorgensen, F., Hasselbalch, H., Hey, H., 1983, The Prejudgement of the
Esophageal Transfer of Tablets and Capsules. Archiv der Pharmazie Chemistry in Life
Sciences, Ed. 11, 24-31.
8. Brotherman, DP,. Bayraktaroglu, T.O., Garofalo, R.J., 2004, Comparison of Ease of
Swallowing of Dietary Supplement Products for Age-Related Eye Disease. Journal of
American Pharmacists Association, 44, 587-593.
9. Marvola M., Rajaniemi M., Marttila E., Vahervuo K., Sothmann A., 1983, Effect of
Dosage Form and Formulation Factors on the Adherence of Drugs to the Esophagus.
Journal of Pharmaceutical Sciences 72(9), 1034-1036.
10. Hey H., Jorgensen F., Sorensen K., Hasselbelch H., Wamberg T., 1982, Esophageal
Transit of Six Commonly used Tablets and Capsules. British Medical Journal 285, 1717-
1719.
11. Na Zhao et al., 30 November 2010, 401(1-2), “Tablet Splitting: Product quality
assessment of metoprolol succinate extended release tablets,” International Journal of
Pharmaceutics.
12. Rakhi Shah et. al., 26 August 2010, “Tablet Splitting of a Narrow Therapeutic Index
Drug: A Case with Levothyroxine Sodium,” AAPS PharmSciTech.
13. Geoff Green et al., November-December 2009, 35(6), “Pharmacopoeial Standards for the
Subdivision Characteristics of Scored Tablets,” Pharmacopoeial Forum.
14. See USP General Chapter <1216> Tablet Friability.
15. United States-Food and Drug Administration.