Draft Guidance on Physical Attributes of Tabs & Caps

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

Drafted by Roohi Bano Obaid, Deputy Drugs Controller, DRAP for Policy, Training & Pharmacy Services, February 25th 2014 Page 2 of 14

Simple Attributes of Greater Impact on claim of Generic Drugs

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



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,



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



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.



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



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:



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



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)



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.



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.



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.



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.

Leadership & Management

Draft Guidance on Physical Attributes of Tabs & Caps