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74 á2ñ Oral Drug Products—Product Quality Tests / General Requirements USP 40

á2ñ ORAL DRUG PRODUCTS—PRODUCT QUALITY TESTS

INTRODUCTION

Oral delivery is the most common route of administration for drug products. All oral drug products lead to systemic and/or
local action in the oral cavity and/or gastrointestinal tract. Oral drug products fall primarily into two main categories: solids
and liquids. Solid oral drug products include but are not restricted to capsules, tablets, granules, and powders. Similarly, liquid
oral drug products include but are not restricted to solutions, suspensions, and emulsions. The definitions and descriptions of
these dosage forms and brief information about their composition and manufacturing process are found in Pharmaceutical
Dosage Forms á1151ñ. [NOTE—All references to chapters above á1000ñ are for informational purposes only, for use as a helpful
resource. These chapters are not mandatory unless explicitly called out for application.]
This chapter focuses on the product quality tests that are generally necessary for oral drug products for a single or combina-
tion of small molecules of active ingredients. Biologics in solid dosage forms are not considered. In this chapter, the terms
“drug substance” and “active ingredient” are used interchangeably. The contents of this chapter do not necessarily apply to
drug products that are intended for use other than by oral administration. For example, the chapter does not address oromu-
cosal dosage forms. Some of the tests indicated in this chapter may be performed on an in-process basis or omitted as routine
tests based on process validation. However, the product must meet USP compendial requirements when sampled and tested,
once the product is on the market.
This chapter provides lists of consolidated common product quality test requirements in a concise and coherent fashion. This
General Chapters

chapter applies, in part or whole, when referenced in a drug product monograph (see General Notices, 3.10 Applicability of
Standards). This chapter includes the quality tests for the specific route of administration. The quality tests listed can be used as
appropriate by manufacturers toward the development of new drug product monographs for submission to USP. If a validated
performance test procedure is available for the specific drug product, it is identified in a general chapter below á1000ñ. In cases
where a validated procedure cannot be recommended, but if the information is available for a product quality and/or product
performance test, it is described in an informational chapter above á1000ñ.

Drug Product Quality Tests and Performance Tests

Monograph tests, analytical procedures, and acceptance criteria for testing oral drug products are divided into two catego-
ries: 1) those that assess general product quality attributes, and 2) those that assess product performance, which is a specific
quality attribute typically linked to bioavailability and bioequivalence studies (see Assessment of Drug Product Performance—Bio-
availability, Bioequivalence, and Dissolution á1090ñ). Drug product quality tests are intended to assess attributes such as identifi-
cation, strength (assay), impurities (universal tests), dose content uniformity, pH, minimum fill, alcohol content, volatile con-
tent, and microbial content (specific tests). Drug product performance tests are designed to assess in vitro drug release from
dosage forms (e.g., Dissolution á711ñ and Drug Release á724ñ). For liquid oral drug products in solution, performance is consid-
ered optimal, and a monograph performance test is not included.
Each of these attributes is important for a primary understanding of the quality and performance of a drug product. Thus,
they form the basis for the monograph. A compendial product should meet all drug product quality tests and drug product
performance tests contained in its monograph.
[NOTE—Dissolution tests, specifically dissolution profile similarity between higher strengths and lower strengths of a given
manufacturer’s product and dissolution profile similarity between the generic product and the reference product, are used for
granting biowaivers. See á1090ñ.]

PRODUCT QUALITY TESTS FOR ORAL DRUG PRODUCTS

Drug product quality tests for oral drug products fall into two categories: 1) universal tests that are applicable to all oral drug
products and should be included in the monograph, and 2) specific tests that should be considered for inclusion for specific
types of oral products.

Universal Tests for Oral Drug Products

Product quality attributes for oral dosage forms are important to ensure that commercialized products meet minimum quali-
ty requirements. Universal tests should be applied to all oral dosage forms and include Description, Identification, Strength (As-
say test), and Impurities (organic, inorganic, and residual solvents).

DESCRIPTION

Description is general in nature and is not a standard in itself. It communicates the appearance of an article that complies
with monograph standards.

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USP 40 General Requirements / á2ñ Oral Drug Products—Product Quality Tests 75

IDENTIFICATION

The identification test is defined in General Notices, 5.40 Identity. It is included in a monograph as an aid to confirm that the
article contains the labeled drug substance by providing a positive identification of the drug substance or substances in a drug
product.
One method of confirming the identity is to compare the retention time of the sample with that obtained for the standard
injections in a chromatographic assay procedure. Other methods often used to orthogonally confirm the identity of the active
ingredient are: Thin-Layer Chromatographic Identification Test á201ñ, Spectrophotometric Identification Tests á197ñ, Nuclear Mag-
netic Resonance Spectroscopy á761ñ, Near-Infrared Spectroscopy á1119ñ, and Raman Spectroscopy á1120ñ, among others. The ana-
lytical procedure must be able to distinguish the active ingredient from all excipients that are present or from potential degra-
dation products likely to be present. Care must also be taken to ensure that the chromatographic system separates the article
from other closely related drug substances, impurities, and additives. Infrared and ultraviolet absorption also can be used for
identification (see á197ñ), if the procedure has been demonstrated to be selective for the drug substance via an appropriate
validation or verification study. The results of the identification test must be compared to the results obtained from a similarly
prepared, suitable Reference Standard.

ASSAY

The assay is a specific and stability-indicating test to determine the potency (content) of the drug product. When a nonspe-
cific assay (e.g., titration) is justified, other supporting analytical procedures should ensure that any interfering species can be

General Chapters
detected. In general the a priori acceptance of ±10% variation in limits of a quality attribute (e.g., assay) from the target label
claim (100%) in most cases is intended to account for manufacturing variability and shelf-life stability and is primarily based on
the notion that such variation in a quality attribute is less likely to have any noticeable adverse impact on the desired clinical
outcome. Acceptance criteria of 95.0%–105.0% are used with justification (e.g., for drug products with narrow therapeutic
index). Activity assays and absolute content assays also are acceptable when justified.

IMPURITIES

Process impurities, synthetic by-products, and other inorganic and organic impurities may be present in the drug substance
and in the excipients used in the manufacture of the drug product. These impurities are limited by drug substance and exci-
pient monographs. During product manufacture and over the shelf life of the product, degradation products can form. These
can be a result of degradation of the drug substance or from interactions between the drug substance and excipient(s),
among other factors. The procedures and acceptance criteria should specifically limit toxic materials. See specific requirements
in the General Notices 5.60, Impurities and Foreign Substances. [NOTE—For additional information, see Impurities in Drug Sub-
stances and Drug Products á1086ñ.]

Specific Tests for Tablets

In addition to the Universal Tests for Oral Drug Products described above, the following specific tests for tablets should be
considered, depending upon the nature of the drug substance and formulation.

VOLATILE CONTENT

The test and the specific method depend on the nature of the article. Special consideration should be given to dosage forms
for which water content has been shown to be a potential quality attribute and to products where solvent is used in the manu-
facture of the drug product.
When the presence of moisture or other volatile material may become critical, analysts must determine the amount of un-
bound volatile solvents or volatile matter of any kind that is driven off by Loss on Drying á731ñ or another suitable technique
(e.g., water activity). For substances that appear to contain water as the only volatile constituent, the procedure given in Water
Determination á921ñ may be appropriate. For drug products, analysts also should consult Residual Solvents á467ñ.

DISINTEGRATION

Disintegration is an essential attribute of oral solids, except for those intended to be chewed before being swallowed and for
delayed- or extended-release products. This test measures the time it takes for the dosage unit to disintegrate in an aqueous
medium and is described in detail in Disintegration á701ñ. For certain dosage forms (e.g., effervescent tablets, disintegrating
tablets, and others) the European Pharmacopoeia describes the disintegration test in great detail. The disintegration test for
some of the dosage forms in this chapter is included for completeness. For detailed procedures, please refer to á701ñ or the
European Pharmacopoeia. The disintegration test, if included, is used only as a quality control test and not as a product per-
formance test and should conform with the specifications in the monograph. Only when disintegration has been correlated

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76 á2ñ Oral Drug Products—Product Quality Tests / General Requirements USP 40

with dissolution of a dosage form can a disintegration test be used as a product performance test (ICH Guidance Q6A, availa-
ble at www.ich.org). In all other instances, a dissolution test should be considered as a product performance test.

TABLET FRIABILITY

The test procedure is applicable to most compressed, uncoated tablets. Friability determines the ability of tablets to with-
stand mechanical stresses and their resistance to chipping and surface abrasion. [NOTE—For additional information, see Tablet
Friability á1216ñ.]

TABLET BREAKING FORCE

Tablet breaking force measures the mechanical integrity of tablets, which is the force required to cause them to fail (i.e.,
break) in a specific plane. [NOTE—For additional information, see Tablet Breaking Force á1217ñ.]

UNIFORMITY OF DOSAGE UNITS

Uniformity of dosage units must be demonstrated by either content uniformity or weight variation. Content uniformity is
based on the assay of the individual content of drug substance(s) in a number of dosage units to determine whether the indi-
vidual contents are sufficiently close to label claim. Weight variation can be used as an alternative to estimate content uniform-
ity under certain conditions (see Uniformity of Dosage Units á905ñ).
General Chapters

Specific Tests for Uncoated Tablets

Uncoated tablets include single-layer tablets that result from a single compression of particles and multilayer tablets that
consist of concentric or parallel layers obtained by successive compression of particles of different composition. The excipients
used generally are not specifically intended to modify the release of the active substance in the digestive fluids. Uncoated tab-
lets include but are not limited to: effervescent tablets, buccal tablets, sublingual tablets, chewable tablets, disintegrating tab-
lets, orally disintegrating tablets, tablets for oral solution, and tablets for oral suspension. For uncoated tablets, disintegration
should be tested as directed in á701ñ.

BUCCAL, SUBLINGUAL, AND ORALLY DISINTEGRATING TABLETS

These dosage forms are discussed in Mucosal Drug Products—Product Quality Tests á4ñ. They are listed here for informational
purposes and completeness.

CHEWABLE TABLETS

Chewable tablets are not required to comply with the disintegration test. Chewable tablets (intact) should undergo dissolu-
tion testing, as a product performance test (if cited in the monograph), because they might be swallowed without proper
chewing by a patient. In general, the dissolution test conditions for chewable tablets should be the same as for nonchewable
tablets of the same active ingredient or moiety.

TABLETS FOR ORAL SOLUTION AND TABLETS FOR ORAL SUSPENSION

These are tablets intended to be dissolved or dispersed in water before administration, giving a homogeneous solution or
dispersion. They are listed here for informational purposes and completeness.

Specific Tests for Coated Tablets

Coated tablets are tablets covered with one or more layers of mixtures of various substances such as natural or synthetic
resins, gums, gelatin, inactive and insoluble excipients, sugars, plasticizers, polyols, waxes, coloring matter authorized by the
competent authority, and sometimes flavoring substances and active substances. Tablets coated by sugar or film include but
are not limited to: plain coated tablets, extended-release tablets, and delayed-release tablets. A disintegration test, when appli-
cable, should be performed as directed in á701ñ.
There are no additional specific quality tests for extended-release tablets and delayed-release tablets. Universal quality tests
should be applied to these products.

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USP 40 General Requirements / á2ñ Oral Drug Products—Product Quality Tests 77

Specific Tests for Capsules

In addition to the Universal Tests for Oral Drug Products described above, the specific tests included below should be consid-
ered, depending on the nature of the drug substance and formulation.
Product quality tests that are considered specific to the type of capsule include those for volatile content (á731ñ and á921ñ).
One-piece capsules typically are used to deliver a drug substance as a solution or suspension. Two-piece capsules consist of
two telescoping cap-and-body pieces that are used to deliver solid material as powder, granules, or small tablets. Modified-
release capsules include but are not limited to: delayed-release capsules and extended-release capsules.
Disintegration: Proceed as directed in Disintegration á701ñ, Soft Gelatin Capsules for one-piece capsules and Disintegration
á701ñ, Hard Gelatin Capsules for two-piece capsules. Disintegration for modified-release capsules is described in great detail in
the European Pharmacopoeia.
There are no additional specific quality tests for extended-release capsules and delayed-release capsules. Universal quality
tests should be applied to these products.

Specific Tests for Granules

In addition to the Universal Tests for Oral Drug Products described above, the specific tests included below should be consid-
ered, depending on the nature of the drug substance and formulation.
Granules are solid dosage forms that are composed of agglomerations of smaller particles. Granules include but are not limi-
ted to: effervescent granules, coated granules, extended-release granules, and delayed-release granules.

General Chapters
Tests that are considered specific to the type of granules include volatile content (á731ñ and á921ñ). Disintegration for effer-
vescent granules is described in great detail in the European Pharmacopoeia. On the basis of the nature of the article and scien-
tific criteria, additional tests may apply, including powder fineness and others.

Specific Tests for Powders

Oral powders should indicate: “For Oral Use Only”. Tests that are considered specific to the type of powders include: Mini-
mum Fill á755ñ and volatile content (á731ñ and á921ñ). Chapter á755ñ has specifications that apply to oral powders.
On the basis of the nature of the article and scientific criteria, additional tests may apply, including pH in an aqueous solu-
tion, powder fineness, microbial limits, and others.

Specific Tests for Liquids

The recommended product quality tests for a liquid drug product include the Universal Tests for Oral Drug Products described
above and the specific tests included below. Most of the quality tests for liquids require the evaluation of single-dose products
to estimate the quality attribute. Specific directions to perform the quality tests for either single-dose or multiple-dose products
are provided in the monograph or the general chapter. For example, weight variation may be used when adequacy of mix for
the active substance(s) and excipients in the blend is well controlled to ensure their uniform distribution, as in solutions.

DELIVERABLE VOLUME

When the liquid formulation is packaged in a multiple-dose container, compliance with Deliverable Volume á698ñ is required.

ALCOHOL DETERMINATION

If the liquid formulation contains a quantity of alcohol, Alcohol Determination á611ñ should be included. The limits may be an
absolute concentration, in percentage, or relative to a labeled content.

PH

Liquid oral products typically are aqueous formulations that are susceptible to pH changes from exposure to atmospheric
CO2. The uptake of atmospheric CO2 and consequent pH change of oral liquid products is only relevant to aqueous-based
products. The pH of an oral liquid formulation can affect flavor and stability. The pH range as outlined in pH á791ñ is indicated
in the monograph.

MICROBIAL CONTENT

The presence of certain microorganisms in nonsterile preparations may have the potential to reduce or even inactivate the
therapeutic activity of the product and has a potential to adversely affect the health of the patient. Some liquid oral products

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78 á2ñ Oral Drug Products—Product Quality Tests / General Requirements USP 40

can be subject to extreme microbiological control, and others require none. The needed microbial specification for a given
liquid oral product depends on its formulation and use and is indicated in the monograph.
[NOTE—For additional information, see Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceuti-
cal Preparations and Substances for Pharmaceutical Use á1111ñ.]

ANTIOXIDANT

Release testing should be performed. Shelf-life testing may be unnecessary where justified by development and stability data
(ICH Guidance Q6A).

EXTRACTABLES

Where development and stability data show no significant evidence of extractables, elimination of this test may be pro-
posed. Where data demonstrate the need and acceptance criteria for oral solutions—rubber stopper, cap liner, plastic bottle—
data should be collected as early in the development process as possible (ICH Guidance Q6A).

Types of Liquid Dosage Forms

Specific quality tests for these dosage forms are provided in their respective monographs.
General Chapters

SOLUTIONS, POWDERS, AND GRANULES FOR SOLUTION

Tests of “for Solution” formulations are conducted on a well-mixed solution of the drug product constituted as described in
the labeling.

EMULSIONS, SUSPENSIONS, AND POWDERS AND GRANULES FOR SUSPENSION

Tests of “for Suspension” formulations are conducted on a well-mixed suspension of the drug product constituted as descri-
bed in the labeling. Product quality tests for suspensions should include a test of suspendability.

POWDERS AND GRANULES FOR SOLUTIONS

After dissolution or suspension, they comply with monograph requirements for the final dosage form. Volatile content (á731ñ
and á921ñ) may be an additional quality test for powders and granules for reconstitution.

Specific Tests for Miscellaneous Oral Dosage Forms

LYOPHILIZED ORAL PRODUCTS

Water Determination á921ñ, Method Ia: Lyophilized oral products comply with the test. The limits are approved as indicated in
the specific monograph.

á3ñ TOPICAL AND TRANSDERMAL DRUG PRODUCTS—PRODUCT

QUALITY TESTS

INTRODUCTION

Topically applied drug products fall into two general categories: those applied to achieve local action and those applied to
achieve systemic effects after absorption through the skin into the blood circulation. Local action can occur at or on the sur-
face of the application site (e.g., stratum corneum ); in the underlying tissues (e.g., epidermis and/or dermis); and in subcuta-
neous tissues (e.g., muscle or joint). Topically applied drug products include, but are not limited to, creams, gels, ointments,
pastes, suspensions, lotions, foams, sprays, aerosols, solutions, and transdermal delivery systems (TDS ). The definitions and
descriptions of these dosage forms, as well as brief information on their composition and/or manufacturing processes, can be
found in Pharmaceutical Dosage Forms á1151ñ.
Procedures and acceptable criteria for testing topically applied drug products can be divided into those that assess general
product quality attributes and those that assess product performance. The product quality attributes include the following: de-

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