General Notices and Requirements

USP 32 General Notices 1

General Notices and

Requirements

Applying to Standards, Tests,

Assays, and Other Specifications

of the United States Pharmacopeia

1. Title and Revision

.......................... 3

7. Test Results

................................ 7

7.10. Interpretation of Requirements .................. 7

7.20. Rounding Rules ............................ 7

2. Official Status and Legal Recognition

......... 3

2.10. Official Text .............................. 3

2.20. Official Articles ............................ 3

8. Terms and Definitions

....................... 8

2.30. Legal Recognition .......................... 3 8.10. Abbreviations ............................. 8

8.20. About .................................. 8

8.30. Alcohol Content ........................... 8

3. Conformance and Standards

................. 3

8.40. Atomic Weights ........................... 8

3.10. Applicability of Standards ..................... 3

8.50. Blank Determinations ....................... 8

3.20. Indicating Conformance ...................... 4

8.60. Concomitantly ............................ 8

8.70. Desiccator ............................... 8

4. Monographs and General Chapters

........... 4

8.80. Logarithms ............................... 8

4.10. Monographs ............................... 4

8.90. Microbial Strain ........................... 8

4.20. General Chapters ........................... 4

8.100. Negligible ............................... 8

8.110. NLT/NMT ............................... 8

5. Monograph Components

..................... 4

8.120. Odor ................................... 8

5.10. Molecular Formula .......................... 4

8.130. Percent ................................. 8

5.20. Added Substances, Excipients, and Ingredients ...... 4

8.140. Percentage Concentrations .................... 8

5.30. Description and Solubility ..................... 5

8.150. Pressure ................................. 8

5.40. Identification Test .......................... 5

8.160. Reaction Time ............................ 8

5.50. Assay ................................... 5

8.170. Specific Gravity ........................... 8

5.60. Impurities and Foreign Substances ............... 5

8.180. Temperatures ............................. 8

5.70. Performance Tests .......................... 6

8.190. Time ................................... 8

5.80. USP Reference Standards ..................... 6

8.200. Transfer ................................. 8

8.210. Vacuum ................................. 8

8.220. Vacuum Desiccator ......................... 8

6. Testing Practices and Procedures

............. 6

8.230. Water .................................. 8

6.10. Safe Laboratory Practices ..................... 6

8.240. Weights and Measures ...................... 9

6.20. Automated Procedures ....................... 6

6.30. Alternative and Harmonized Methods and

Procedures .............................. 6

9. Prescribing and Dispensing

.................. 9

6.40. Dried, Anhydrous, Ignited, or Solvent-Free Basis ..... 6

9.10 Use of Metric Units ......................... 9

6.50. Preparation of Solutions ...................... 6

9.20 Changes in Volume .......................... 9

6.60. Units Necessary to Complete a Test .............. 7

6.70. Reagents ................................. 7

10. Preservation, Packaging, Storage

6.80. Equipment ................................ 7

and Labeling

............................. 9

10.10. Storage Under Nonspecific

Conditions .............................. 9

2 General Notices USP 32

10.20. Containers ............................... 9 10.50. Guidelines for Packaging and Storage

Statements in USP–NF Monographs ........... 12

10.30. Storage Temperature and Humidity ............ 10

10.40. Labeling ............................... 11

USP 32 General Notices 3

General Notices and

Requirements

Change to read: dium when a monograph for the article is published in the compen-

dium and an official date is generally or specifically assigned to the

▲

The General Notices and Requirements section (the General monograph.

Notices) presents the basic assumptions, definitions, and default The title specified in a monograph is the official title for such

conditions for the interpretation and application of the United States article. Other names considered to be synonyms of the official titles

Pharmacopeia (USP) and the National Formulary (NF). may not be used as substitutes for official titles.

Requirements stated in these General Notices apply to all articles Official articles include both official substances and official

recognized in the USP and NF (the “compendia”) and to all general products. An official substance is a drug substance, excipient, diet-

chapters unless specifically stated otherwise. Where the require- ary ingredient, other ingredient, or component of a finished device

ments of an individual monograph differ from the General Notices for which the monograph title includes no indication of the nature

or a general chapter, the monograph requirements apply and super- of the finished form.

sede the requirements of the General Notices or the general chapter, An official product is a drug product, dietary supplement, com-

whether or not the monograph explicitly states the difference. pounded preparation, or finished device for which a monograph is

provided.

1. TITLE AND REVISION

The full title of this publication (consisting of three volumes and 2.30. Legal Recognition

including its Supplements), is The Pharmacopeia of the United The USP and NF are recognized in the laws and regulations of

States of America, Thirty-Second Revision and the National For- many countries throughout the world. Regulatory authorities may

mulary, Twenty-Seventh Edition. These titles may be abbreviated to enforce the standards presented in the USP and NF, but because

United States Pharmacopeia, Thirty-Second Revision (or to USP recognition of the USP and NF may vary by country, users should

32), to NF 27, and to USP 32–NF 27. The United States understand applicable laws and regulations. More information

Pharmacopeia, Thirty-Second Revision, and the National Formu- about the legal status of the USP and NF is provided in the Mission

lary, Twenty-Seventh Edition, supersede all earlier revisions. and Preface.

Where the terms “USP,” “NF,” or “USP–NF” are used without fur-

3. CONFORMANCE TO STANDARDS

ther qualification during the period in which these compendia are

3.10. Applicability of Standards

official, they refer only to USP 32, NF 27, and any Supplement(s)

Standards for an article recognized in a USP compendium are ex-

thereto. The same titles, with no further distinction, apply equally to

pressed in the article’s monograph, applicable general chapters, and

print or electronic presentation of these contents. Although USP and

these General Notices. Unless specifically exempted elsewhere in a

NF are published under one cover and share these General Notices,

compendium, the identity, strength, quality, and purity of an article

they are separate compendia.

are determined by the official tests, procedures, and acceptance cri-

This revision is official beginning May 1, 2009, unless otherwise

teria, whether incorporated in the monograph itself, in the General

indicated in specific text.

Notices, or in the applicable general chapters.

Supplements to USP and NF are published periodically.

The standards in the relevant monograph, general chapter(s), and

Interim Revision Announcements are revisions to USP and NF

General Notices apply at any time in the life of the article from

that are published in Pharmacopeial Forum. Interim Revision An-

production to expiration. The manufacturer’s specifications, and

nouncements contain official revisions and their effective dates, an-

good manufacturing practices generally, are developed and fol-

nouncements of the availability of new USP Reference Standards,

lowed to ensure that the article will comply with compendial stan-

and announcements of tests or procedures that are held in abeyance

dards until its expiration date, when stored as directed. Thus, any

pending availability of required USP Reference Standards.

official article tested as directed in the relevant monograph shall

Revision Bulletins are revisions to official text or postponements

comply.

that require expedited publication. They are published on the USP

At times, compendial standards take on the character of statistical

website and generally are official immediately unless otherwise

procedures, with multiple units involved and perhaps a sequential

specified in the Revision Bulletin.

procedural design to allow the user to determine that the tested arti-

Errata are corrections to items erroneously published that have

cle meets or does not meet the standard. The similarity to statistical

not received the approval of the Council of Experts and that do not

procedures may seem to suggest an intent to make inference to

reflect the official requirements. Errata are effective upon

some larger group of units, but in all cases, statements about

publication.

whether the compendial standard is met apply only to the units

2. OFFICIAL STATUS AND LEGAL RECOGNITION

tested. Repeats, replicates, statistical rejection of outliers, or extrap-

2.10. Official Text olations of results to larger populations, as well as the necessity and

Official text is text contained in USP and NF, including appropriate frequency of batch testing, are neither specified nor pro-

monographs, general chapters, and these General Notices. Revi- scribed by the compendia. First-party (manufacturer), second-party

sions to official text are provided in Supplements, Interim Revision (buyer), or third-party (regulator) compliance testing may or may

Announcements, and Revision Bulletins. General chapters numbered not require examination of additional specimens, in accordance

from 1000 to 1999 are considered interpretive and are intended to with predetermined guidelines or sampling strategies.

provide information on, give definition to, or describe a particular Official products other than dietary supplements are prepared

subject. They contain no mandatory requirements applicable to any from ingredients that meet USP or NF standards, where standards

official article unless specifically referenced in these General No- for such ingredients exist.

tices, a monograph, or a general chapter numbered below 1000. Official substances are prepared according to recognized princi-

General chapters numbered above 2000 apply only to articles that ples of good manufacturing practice and from ingredients comply-

are intended for use as dietary ingredients and dietary supplements. ing with specifications designed to ensure that the resultant sub-

stances meet the requirements of the compendial monographs.

2.20. Official Articles

An official article is an article that is recognized in USP or NF.

An article is deemed to be recognized and included in a compen-

4 General Notices USP 32

3.10.10. Applicability of Standards to Drug Products, Drug article. For general requirements relating to specific monograph

Substances, and Excipients sections, see section 5, Monograph Components.

The applicable USP or NF standard applies to any article mar- Because monographs may not provide standards for all relevant

keted in the United States that (1) is recognized in the compendium characteristics, some official substances may conform to the USP or

and (2) is intended or labeled for use as a drug or as an ingredient in NF standard but differ with regard to nonstandardized properties

a drug. The applicable standard applies to such articles whether or that are relevant to their use in specific preparations. To assure in-

not the added designation “USP” or “NF” is used. The standards terchangeability in such instances, users may wish to ascertain func-

apply equally to articles bearing the official titles or names derived tional equivalence or determine such characteristics before use.

by transposition of the definitive words of official titles or transpo-

4.10.10. Applicability of Test Procedures

sition in the order of the names of two or more active ingredients in

A single monograph may include several different tests, proce-

official titles.

dures, and/or acceptance criteria that reflect attributes of different

3.10.20. Applicability of Standards to Medical Devices, manufacturers’ articles. Such alternatives may be presented for dif-

Dietary Supplements, and Their Components and Ingredients ferent polymorphic forms, impurities, hydrates, and dissolution

An article recognized in USP or NF shall comply with the com- cases. Monographs indicate the tests, procedures, and/or acceptance

pendial standards if the article is a medical device, component in- criteria to be used and the required labeling.

tended for a medical device, dietary supplement, dietary ingredient,

4.10.20. Acceptance Criteria

or other ingredient that is intended for incorporation into a dietary

The acceptance criteria allow for analytical error, for unavoidable

supplement, and is labeled as conforming to the USP or NF.

variations in manufacturing and compounding, and for deterioration

Generally, dietary supplements are prepared from ingredients that

to an extent considered acceptable under practical conditions. The

meet USP, NF, or Food Chemicals Codex standards. Where such

existence of compendial acceptance criteria does not constitute a

standards do not exist, substances may be used in dietary supple-

basis for a claim that an official substance that more nearly ap-

ments if they have been shown to be of acceptable food grade qual-

proaches 100 percent purity “exceeds” compendial quality. Simi-

ity using other suitable procedures.

larly, the fact that an article has been prepared to tighter criteria

3.20. Indicating Conformance than those specified in the monograph does not constitute a basis

A drug product, drug substance, or excipient may use the desig- for a claim that the article “exceeds” the compendial requirements.

nation “USP” or “NF” in conjunction with its official title or else- An official product shall be formulated with the intent to provide

where on the label only when (1) a monograph is provided in the 100 percent of the quantity of each ingredient declared on the label.

specified compendium and (2) the article complies with the identity Where the minimum amount of a substance present in a dietary sup-

prescribed in the specified compendium. plement is required by law to be higher than the lower acceptance

When a drug product, drug substance, or excipient differs from criterion allowed for in the monograph, the upper acceptance crite-

the relevant USP or NF standard of strength, quality, or purity, as rion contained in the monograph may be increased by a correspond-

determined by the application of the tests, procedures, and accept- ing amount.

ance criteria set forth in the relevant compendium, its difference The acceptance criteria specified in individual monographs and

shall be plainly stated on its label. in the general chapters for compounded preparations are based on

When a drug product, drug substance, or excipient fails to com- such attributes of quality as might be expected to characterize an

ply with the identity prescribed in USP or NF or contains an added article compounded from suitable bulk drug substances and ingredi-

substance that interferes with the prescribed tests and procedures, ents, using the procedures provided or recognized principles of

the article shall be designated by a name that is clearly distinguish- good compounding practice, as described in these compendia.

ing and differentiating from any name recognized in USP or NF.

4.20. General Chapters

A medical device, dietary supplement, or ingredient or compo-

Each general chapter is assigned a number that appears in angle

nent of a medical device or dietary supplement may use the desig-

brackets adjacent to the chapter name (e.g., Chromatography

nation “USP” or “NF” in conjunction with its official title or else-

〈621〉). General chapters may contain the following:

where on the label only when (1) a monograph is provided in the

• Descriptions of tests and procedures for application through in-

specified compendium and (2) the article complies with the mono-

dividual monographs,

graph standards and other applicable standards in the compendium.

• Descriptions and specifications of conditions and practices for

The designation “USP” or “NF” on the label may not and does

pharmaceutical compounding,

not constitute an endorsement by USP and does not represent assur-

• General information for the interpretation of the compendial

ance by USP that the article is known to comply with the relevant

requirements,

standards. USP may seek legal redress if an article purports to be or

• Descriptions of general pharmaceutical storage, dispensing,

is represented as an official article in one of USP’s compendia and

and packaging practices, or

such claim is determined by USP not to be made in good faith.

• General guidance to manufacturers of official substances or of-

The designation “USP–NF” may be used on the label of an arti-

ficial products.

cle provided that the label also bears a statement such as “Meets NF

When a general chapter is referenced in a monograph, acceptance

standards as published by USP,” indicating the particular compen-

criteria may be presented after a colon.

dium to which the article purports to apply.

Some chapters may serve as introductory overviews of a test or

When the letters “USP,” “NF,” or “USP–NF” are used on the

of analytical techniques. They may reference other general chapters

label of an article to indicate compliance with compendial stan-

that contain techniques, details of the procedures, and, at times, ac-

dards, the letters shall appear in conjunction with the official title of

ceptance criteria.

the article. The letters are not to be enclosed in any symbol such as

5. MONOGRAPH COMPONENTS

a circle, square, etc., and shall appear in capital letters.

5.10. Molecular Formula

If a dietary supplement does not comply with all applicable com-

The use of the molecular formula for the active ingredient(s)

pendial requirements but contains one or more dietary ingredients

named in defining the required strength of a compendial article is

or other ingredients that are recognized in USP or NF, the individ-

intended to designate the chemical entity or entities, as given in the

ual ingredient(s) may be designated as complying with USP or NF

complete chemical name of the article, having absolute (100 per-

standards or being of USP or NF quality provided that the designa-

cent) purity.

tion is limited to the individual ingredient(s) and does not suggest

5.20. Added Substances, Excipients, and Ingredients

that the dietary supplement complies with USP standards.

Substances are regarded as unsuitable for inclusion in an official

4. MONOGRAPHS AND GENERAL CHAPTERS

article and therefore prohibited unless: (1) they do not exceed the

4.10. Monographs

minimum quantity required for providing their intended effect; (2)

Monographs set forth the article’s name, definition, specification,

their presence does not impair the bioavailability, therapeutic effi-

and other requirements related to packaging, storage, and labeling.

cacy, or safety of the official article; and (3) they do not interfere

The specification consists of tests, procedures, and acceptance crite-

with the assays and tests prescribed for determining compliance

ria that help ensure the identity, strength, quality, and purity of the

with the compendial standards.

USP 32 General Notices 5

The air in a container of an official article may, where appropri- ence table may indirectly assist in the preliminary evaluation of an

ate, be evacuated or be replaced by carbon dioxide, helium, argon, article, it is not intended to serve as a standard or test for purity.

or nitrogen, or by a mixture of these gases. The use of such gas The approximate solubility of a compendial substance is indi-

need not be declared in the labeling. cated by one of the following descriptive terms:

5.20.10. Added Substances, Excipients, and Ingredients in

Official Substances

Parts of Solvent Required

Official substances may contain only the specific added sub-

Descriptive Term for 1 Part of Solute

stances that are permitted by the individual monograph. Where such

Very soluble Less than 1

addition is permitted, the label shall indicate the name(s) and

Freely soluble From 1 to 10

amount(s) of any added substance(s).

Soluble From 10 to 30

5.20.20. Added Substances, Excipients, and Ingredients in

Sparingly soluble From 30 to 100

Official Products

Suitable substances and excipients such as antimicrobial agents,

Slightly soluble From 100 to 1,000

pharmaceutical bases, carriers, coatings, flavors, preservatives, sta-

Very slightly soluble From 1,000 to 10,000

bilizers, and vehicles may be added to an official product to en-

Practically insoluble, or Greater than or equal to

hance its stability, usefulness, or elegance, or to facilitate its prepa-

Insoluble 10,000

ration, unless otherwise specified in the individual monograph.

Added substances and excipients employed solely to impart color

5.40. Identification Test

may be incorporated into official products other than those intended

The compendial test titled Identification is provided as an aid in

for parenteral or ophthalmic use, in accordance with the regulations

verifying the identity of articles as they are purported to be, e.g.,

pertaining to the use of colors issued by the U.S. Food and Drug

those taken from labeled containers. Tests presented in the Identifi-

Administration (FDA), provided such added substances or excipi-

cation section shall be used to assist in establishing the identity of

ents are otherwise appropriate in all respects. (See also Added Sub-

the substance but are not necessarily sufficient to establish proof of

stances under Injections 〈1〉.)

identity. Other tests and specifications in the monograph often are

The proportions of the substances constituting the base in oint-

necessary to establish or confirm the identity of an article. Failure

ment and suppository products and preparations may be varied to

of an article to meet the requirements of a prescribed Identification

maintain a suitable consistency under different climatic conditions,

test may indicate that the article is mislabeled.

provided that the concentrations of active ingredients are not varied

and provided that the bioavailability, therapeutic efficacy, and

5.50. Assay

safety of the preparation are not impaired.

Assay tests for compounded preparations are not intended for

evaluating a compounded preparation before dispensing, but instead

5.20.20.1. In Compounded Preparations

are intended to serve as the official test in the event of a question or

Compounded preparations for which a complete composition is

dispute regarding the preparation’s conformance to official

given shall contain only the ingredients named in the formulas un-

standards.

less specifically exempted herein or in the individual monograph.

Deviation from the specified processes or methods of com-

5.50.10. Units of Potency (Biological)

pounding, although not from the ingredients or proportions thereof,

For substances that cannot be completely characterized by chemi-

may occur provided that the finished preparation conforms to the

cal and physical means, it may be necessary to express quantities of

relevant standards and to preparations produced by following the

activity in biological units of potency, each defined by an authorita-

specified process.

tive, designated reference standard.

Where a monograph for a compounded preparation calls for an

Units of biological potency defined by the World Health Organi-

ingredient in an amount expressed on the dried basis, the ingredient

zation (WHO) for International Biological Standards and Interna-

need not be dried before use if due allowance is made for the water

tional Biological Reference Preparations are termed International

or other volatile substances present in the quantity taken.

Units (IU). Monographs refer to the units defined by USP Refer-

Specially denatured alcohol formulas are available for use in ac-

ence Standards as “USP Units.” For biological products, units of

cordance with federal statutes and regulations of the Internal Reve-

potency are defined by the corresponding U.S. Standard established

nue Service. A suitable formula of specially denatured alcohol may

by FDA, whether or not International Units or USP Units have been

be substituted for Alcohol in the manufacture of official prepara-

defined (see Biologics 〈1041〉).

tions intended for internal or topical use, provided that the denatur-

5.60. Impurities and Foreign Substances

ant is volatile and does not remain in the finished product. A prepa-

Tests for the presence of impurities and foreign substances are

ration that is intended for topical application to the skin may

provided to limit such substances to amounts that are unobjection-

contain specially denatured alcohol, provided that the denaturant is

able under conditions in which the article is customarily employed

either a usual ingredient in the preparation or a permissible added

(see also Impurities in Official Articles 〈1086〉).

substance; in either case the denaturant shall be identified on the

Nonmonograph tests and acceptance criteria suitable for de-

label of the topical preparation. Where a process is given in the in-

tecting and controlling impurities that may result from a change in

dividual monograph, any preparation compounded using denatured

the processing methods or that may be introduced from external

alcohol shall be identical to that prepared by the monograph

sources should be employed in addition to the tests provided in the

process.

individual monograph, where the presence of the impurity is incon-

5.20.20.2. In Dietary Supplements

sistent with applicable good manufacturing practices or good phar-

Additional ingredients may be added to dietary supplement prod-

maceutical practice.

ucts provided that the additional ingredients: (1) comply with appli-

5.60.10. Other Impurities in USP and NF Articles

cable regulatory requirements; and (2) do not interfere with the as-

If a USP or NF monograph includes an assay or organic impurity

says and tests prescribed for determining compliance with

test based on chromatography, other than a test for residual sol-

compendial standards.

vents, and that monograph procedure does not detect an impurity

5.30. Description and Solubility

present in the substance, the amount and identity of the impurity,

Only where a quantitative solubility test is given in a monograph

where both are known, shall be stated in the labeling (certificate of

and is designated as such is it a test for purity.

analysis) of the official substance, under the heading Other

A monograph may include information regarding the article’s

Impurity(ies).

description. Information about an article’s “description and solubil-

The presence of any unlabeled other impurity in an official sub-

ity” also is provided in the reference table Description and Relative

stance is a variance from the standard if the content is 0.1% or

Solubility of USP and NF Articles. The reference table merely de-

greater. The sum of all Other Impurities combined with the mono-

notes the properties of articles that comply with monograph stan-

graph-detected impurities may not exceed 2.0% (see Ordinary Im-

dards. The reference table is intended primarily for those who use,

purities 〈466〉), unless otherwise stated in the monograph.

prepare, and dispense drugs and/or related articles. Although the in-

The following categories of drug substances are excluded from

formation provided in monographs and the information in the refer-

Other Impurities requirements:

6 General Notices USP 32

• fermentation products and semi-synthetics derived therefrom, method or procedure from one of these pharmacopeias, it should

• radiopharmaceuticals, comply with the requirements of the USP. When a difference ap-

• biologics, pears, or in the event of dispute, only the result obtained by the

• biotechnology-derived products, method and/or procedure given in the USP is conclusive.

• peptides,

6.40. Dried, Anhydrous, Ignited, or Solvent-Free Basis

• herbals, and

All calculations in the compendia assume an “as-is” basis unless

• crude products of animal or plant origin.

otherwise specified.

Any substance known to be toxic shall not be listed under Other

Test procedures may be performed on the undried or unignited

Impurities.

substance and the results calculated on the dried, anhydrous, or ig-

5.60.20. Residual Solvents in USP and NF Articles nited basis, provided a test for Loss on drying, or Water, or Loss on

All USP and NF articles are subject to relevant control of ignition, respectively, is given in the monograph. Where the pres-

residual solvents, even when no test is specified in the individual ence of moisture or other volatile material may interfere with the

monograph. If solvents are used during production, they must be of procedure, previous drying of the substance is specified in the indi-

suitable quality. In addition, the toxicity and residual level of each vidual monograph and is obligatory.

solvent shall be taken into consideration, and the solvents limited The term “solvent-free” signifies that the calculation shall be cor-

according to the principles defined and the requirements specified rected for the presence of known solvents as determined using the

in Residual Solvents 〈467〉, using the general methods presented methods described in Residual Solvents 〈467〉 unless a test for limit

therein or other suitable methods. of organic solvents is provided in the monograph.

The term “previously dried” without qualification signifies that

5.70. Performance Tests

the substance shall be dried as directed under Loss on Drying 〈731〉

Where content uniformity determinations have been made using

or Water Determination 〈921〉 (gravimetric determination).

the same analytical methodology specified in the Assay, with appro-

Where drying in vacuum over a desiccant is directed, a vacuum

priate allowances made for differences in sample preparation, the

desiccator, a vacuum drying pistol, or other suitable vacuum drying

average of all of the individual content uniformity determinations

apparatus shall be used.

may be used as the Assay value.

6.40.10. Ignite To Constant Weight

5.80. USP Reference Standards

“Ignite to constant weight” means that ignition shall be continued

USP Reference Standards are authentic specimens that have been

at 800 ± 25°, unless otherwise indicated, until two consecutive

approved by the USP Reference Standards Expert Committee as

weighings, the second of which is taken after an additional period

suitable for use as comparison standards in USP or NF tests and

appropriate to the nature and quantity of the residue, do not differ

assays. (See USP Reference Standards 〈11〉.) Current official lots of

by more than 0.50 mg per g of substance taken.

USP Reference Standards are published in the USP Reference Stan-

dards Catalog. Where a procedure calls for the use of a compendial 6.40.20. Dried To Constant Weight

article rather than for a USP Reference Standard as a material stan- “Dried to constant weight” means that drying shall be continued

dard of reference, a substance meeting all of the compendial mono- until two consecutive weighings, the second of which is taken after

graph requirements for that article shall be used. No new USP or an additional drying period appropriate to the nature and quantity of

NF standard or procedure requiring the use of a new USP Reference the residue, do not differ by more than 0.50 mg per g of substance

Standard shall be official until the specified USP Reference Stan- taken.

dard is available.

6.50. Preparation of Solutions

Unless a reference standard label bears a specific potency or con-

6.50.10. Filtration

tent, assume the reference standard is 100.0% pure in the official

Where a procedure gives direction to “filter” without further

application. Unless otherwise directed in the procedure in the indi-

qualification, the liquid shall be passed through suitable filter paper

vidual monograph or in a general chapter, USP Reference Standards

or equivalent device until the filtrate is clear. Due to the possibility

are to be used in accordance with the instructions on the label of the

of filter effects, the initial volumes of a filtrate may be discarded.

Reference Standard.

6.50.20. Solutions

6. TESTING PRACTICES AND PROCEDURES

Unless otherwise specified, all solutions shall be prepared with

6.10. Safe Laboratory Practices

Purified Water. Solutions for quantitative measures shall be pre-

In performing compendial procedures, safe laboratory practices

pared using accurately weighed or accurately measured analytes

shall be followed, including precautionary measures, protective

(see section 8.20, About).

equipment, and work practices consistent with the chemicals and

An expression such as “(1 in 10)” means that 1 part by volume of

procedures used. Before undertaking any procedure described in the

a liquid shall be diluted with, or 1 part by weight of a solid shall be

compendia, the analyst should be aware of the hazards associated

dissolved in, a sufficient quantity of the diluent or solvent to make

with the chemicals and the techniques and means of protecting

the volume of the finished solution 10 parts by volume. An expres-

against them. These compendia are not designed to describe such

sion such as “(20 : 5 : 2)” means that the respective numbers of

hazards or protective measures.

parts, by volume, of the designated liquids shall be mixed, unless

6.20. Automated Procedures otherwise indicated.

Automated and manual procedures employing the same basic

6.50.20.1. Adjustments to Solutions

chemistry are considered equivalent.

When a specified concentration is called for in a procedure, a so-

6.30. Alternative and Harmonized Methods and Procedures lution of other normality or molarity may be used, provided that

Alternative methods and/or procedures may be used if they pro- allowance is made for the difference in concentration and that the

vide advantages in terms of accuracy, sensitivity, precision, selec- change does not increase the error of measurement.

tivity, or adaptability to automation or computerized data reduction, Unless otherwise indicated, analyte concentrations shall be pre-

or in other special circumstances. Such alternative procedures and pared to within ten percent (10%) of the indicated value. In the spe-

methods shall be validated as described in the general chapter Vali- cial case in which a procedure is adapted to the working range of an

dation of Compendial Procedures 〈1225〉 and must be shown to instrument, solution concentrations may differ from the indicated

give equivalent or better results. Only those results obtained by the value by more than ten percent (10%), with appropriate changes in

methods and procedures given in the compendium are conclusive. associated calculations. Any changes shall fall within the validated

Alternative procedures should be submitted to USP for evalua- range of the instrument.

tion as a potential replacement or addition to the standard (see sec- When adjustment of pH is indicated with either an acid or base

tion 4.10, Monographs). and the concentration is not indicated, appropriate concentrations of

Certain general chapters contain a statement that the text in ques- that acid or base may be used.

tion is harmonized with the corresponding text of the European

6.50.20.2. Test Solutions

Pharmacopoeia and/or the Japanese Pharmacopoeia and that these

Information on Test Solutions (TS) is provided in the Test Solu-

texts are interchangeable. Therefore, if a substance or preparation is

tions portion of the Reagents, Indicators, and Solutions section of

found to comply with a requirement using an interchangeable

USP 32 General Notices 7

the USP–NF. Use of an alternative Test Solution or a change in the 6.80.20. Instrumental Apparatus

Test Solution used may require validation. An instrument may be substituted for the specified instrument if

the substitute uses the same fundamental principles of operation and

6.50.20.3. Indicator Solutions

is of equivalent or greater sensitivity and accuracy. These character-

Where a procedure specifies the use of an indicator TS, approxi-

istics shall be qualified as appropriate. Where a particular brand or

mately 0.2 mL, or 3 drops, of the solution shall be added unless

source of a material, instrument, or piece of equipment, or the name

otherwise directed.

and address of a manufacturer or distributor, is mentioned (ordina-

6.60. Units Necessary to Complete a Test

rily in a footnote), this identification is furnished solely for informa-

Unless otherwise specified, a sufficient number of units to ensure

tional purposes as a matter of convenience, without implication of

a suitable analytical result shall be taken.

approval, endorsement, or certification.

6.60.10. Tablets

6.80.20.1. Chromatographic Tubes and Columns

Where the procedure of a Tablet monograph directs to weigh and

The term “diameter” refers to internal diameter (ID).

finely powder not fewer than a given number of Tablets, a counted

6.80.20.2. Tubing

number of Tablets shall be weighed and reduced to a powder. The

The term “diameter” refers to outside diameter (OD).

portion of the powdered Tablets taken shall be representative of the

whole Tablets and shall, in turn, be weighed accurately. 6.80.20.3. Steam Bath

Where use of a steam bath is directed, use actively flowing steam

6.60.20. Capsules

or another regulated heat source controlled at an equivalent

Where the procedure of a Capsule monograph gives direction to

temperature.

remove, as completely as possible, the contents of not fewer than a

given number of the Capsules, a counted number of Capsules shall 6.80.20.4. Water Bath

be carefully opened and the contents quantitatively removed, com- A water bath requires vigorously boiling water unless otherwise

bined, mixed, and weighed accurately. The portion of mixed Cap- specified.

sules contents taken shall be representative of the contents of the

7. TEST RESULTS

Capsules and shall, in turn, be weighed accurately.

7.10. Interpretation of Requirements

6.70. Reagents

Analytical results observed in the laboratory (or calculated from

The proper conduct of the compendial procedures and the relia-

experimental measurements) are compared with stated acceptance

bility of the results depend, in part, upon the quality of the reagents

criteria to determine whether the article conforms to compendial

used in the performance of the procedures. Unless otherwise speci-

requirements.

fied, reagents conforming to the specifications set forth in the cur-

The reportable value, which often is a summary value for several

rent edition of Reagent Chemicals published by the American

individual determinations, is compared with the acceptance criteria.

Chemical Society (ACS) shall be used. Where such ACS reagent

The reportable value is the end result of a completed measurement

specifications are not available or where the required purity differs,

procedure, as documented.

compendial specifications for reagents of acceptable quality are

Where acceptance criteria are expressed numerically herein

provided (see the Reagents, Indicators, and Solutions section of the

through specification of an upper and/or lower limit, permitted val-

USP–NF). Reagents not covered by any of these specifications

ues include the specified values themselves, but no values outside

should be of a grade suitable to the proper performance of the

the limit(s). Acceptance criteria are considered significant to the last

method of assay or test involved.

digit shown.

Listing of these reagents, including the indicators and solutions

7.10.10. Equivalence Statements in Titrimetric Procedures

employed as reagents, in no way implies that they have therapeutic

The directions for titrimetric procedures conclude with a state-

utility; furthermore, any reference to USP or NF in their labeling

ment of the weight of the analyte that is equivalent to each mL of

shall include also the term “reagent” or “reagent grade.” USP may

the standardized titrant. In such an equivalence statement, the num-

supply reagents if they otherwise may not be generally commer-

ber of significant figures in the concentration of the titrant should

cially available.

be understood to correspond to the number of significant figures in

6.80. Equipment

the weight of the analyte. Corrections to calculations based on the

Unless otherwise specified, a specification for a definite size or

blank determination are to be made for all titrimetric assays where

type of container or apparatus in a procedure is given solely as a

appropriate (see Titrimetry 〈541〉).

recommendation. Other dimensions or types may be used if they are

7.20. Rounding Rules

suitable for the intended use.

The observed or calculated values shall be rounded off to the

6.80.10. Apparatus for Measurement

number of decimal places that is in agreement with the limit expres-

Where volumetric flasks or other exact measuring, weighing, or

sion. Numbers should not be rounded until the final calculations for

sorting devices are specified, this or other equipment of at least

the reportable value have been completed. Intermediate calculations

equivalent accuracy shall be employed.

(e.g., slope for linearity) may be rounded for reporting purposes, but

6.80.10.1. Pipet the original (not rounded) value should be used for any additional

Where a pipet is specified, a suitable buret may be substituted. required calculations. Acceptance criteria are fixed numbers and are

Where a “to contain” pipet is specified, a suitable volumetric flask not rounded.

may be substituted. When rounding is required, consider only one digit in the deci-

mal place to the right of the last place in the limit expression. If this

6.80.10.2. Light Protection

digit is smaller than 5, it is eliminated and the preceding digit is

Where low-actinic or light-resistant containers are specified, ei-

unchanged. If this digit is equal to or greater than 5, it is eliminated

ther containers specially treated to protect contents from light or

and the preceding digit is increased by 1.

clear containers that have been rendered opaque by application of a

suitable coating or wrapping may be used.

Illustration of Rounding Numerical Values

for Comparison with Requirements

Compendial Requirement Unrounded Value Rounded Result Conforms

Assay limit ≥98.0% 97.96% 98.0% Yes

97.92% 97.9% No

97.95% 98.0% Yes

Assay limit ≤101.5% 101.55% 101.6% No

101.46% 101.5% Yes

101.45% 101.5% Yes

8 General Notices USP 32

Illustration of Rounding Numerical Values

for Comparison with Requirements

Compendial Requirement Unrounded Value Rounded Result Conforms

Limit test ≤0.02% 0.025% 0.03% No

0.015% 0.02% Yes

0.027% 0.03% No

Limit test ≤3 ppm 3.5 ppm 4 ppm No

3.4 ppm 3 ppm Yes

2.5 ppm 3 ppm Yes

8. TERMS AND DEFINITIONS 8.130. Percent

“Percent” used without qualification means:

8.10. Abbreviations

• For mixtures of solids and semisolids, percent weight in

• RS refers to a USP Reference Standard.

weight;

• CS refers to a Colorimetric Solution.

• For solutions or suspensions of solids in liquids, percent weight

• TS refers to a Test Solution.

in volume;

• VS refers to a Volumetric Solution that is standardized in ac-

• For solutions of liquids in liquids, percent volume in volume;

cordance with directions given in the individual monograph or

• For solutions of gases in liquids, percent weight in volume.

in the Reagents, Indicators, and Solutions section of USP–NF.

For example, a 1 percent solution is prepared by dissolving 1 g of

8.20. About

a solid or semisolid, or 1 mL of a liquid, in sufficient solvent to

“About” indicates a quantity within 10%.

make 100 mL of the solution.

If the measurement is stated to be “accurately measured” or “ac-

8.140. Percentage Concentrations

curately weighed,” follow the statements in the general chapters

Percentage concentrations are expressed as follows:

Volumetric Apparatus 〈31〉 and Weights and Balances 〈41〉,

• Percent Weight in Weight (w/w) is defined as the number of g

respectively.

of a solute in 100 g of solution.

8.30. Alcohol Content

• Percent Weight in Volume (w/v) is defined as number of g of a

Percentages of alcohol, such as those under the heading Alcohol

solute in 100 mL of solution.

content, refer to percentage by volume of C

OH at 15.56°. Where

• Percent Volume in Volume (v/v) is defined as the number of

a formula, test, or assay calls for alcohol, ethyl alcohol, or ethanol,

mL of a solute in 100 mL of solution.

the USP monograph article Alcohol shall be used. Where reference

8.150. Pressure

is made to “C

OH,” absolute (100 percent) ethanol is intended.

Pressure is determined by use of a suitable manometer or barom-

Where a procedure calls for dehydrated alcohol, alcohol absolute,

eter calibrated in terms of the pressure exerted by a column of mer-

or anhydrous alcohol, the USP monograph article Dehydrated Alco-

cury of the stated height.

hol shall be used.

8.160. Reaction Time

8.40. Atomic Weights

Reaction time is 5 minutes unless otherwise specified.

Atomic weights used in computing molecular weights and the

factors in the assays and elsewhere are those established by the 8.170. Specific Gravity

IUPAC Commission on Atomic Weights and Isotopic Abundances. Specific gravity is the weight of a substance in air at 25° divided

by the weight of an equal volume of water at the same temperature.

8.50. Blank Determinations

Where it is directed that “any necessary correction” be made by a 8.180. Temperatures

blank determination, the determination shall be conducted using the Temperatures are expressed in centigrade (Celsius) degrees, and

same quantities of the same reagents treated in the same manner as all measurements are made at 25° unless otherwise indicated.

the solution or mixture containing the portion of the substance Where moderate heat is specified, any temperature not higher than

under assay or test, but with the substance itself omitted. 45°(113° F) is indicated.

8.60. Concomitantly 8.190. Time

“Concomitantly” denotes that the determinations or measure- Unless otherwise specified, rounding rules, as described in sec-

ments are to be performed in immediate succession. tion 7.20, Rounding Rules, apply to any time specified.

8.70. Desiccator 8.200. Transfer

The instruction “in a desiccator” indicates use of a tightly closed “Transfer” indicates a quantitative manipulation.

container of suitable size and design that maintains an atmosphere

8.210. Vacuum

of low moisture content by means of a suitable desiccant such as

“Vacuum” denotes exposure to a pressure of less than 20 mm of

anhydrous calcium chloride, magnesium perchlorate, phosphorus

mercury (2.67 kPas), unless otherwise indicated.

pentoxide, or silica gel. See also section 8.220, Vacuum Desiccator.

8.220. Vacuum Desiccator

8.80. Logarithms

“Vacuum desiccator” indicates a desiccator that maintains a low-

Logarithms are to the base 10.

moisture atmosphere at a reduced pressure of not more than 20 mm

8.90. Microbial Strain of mercury (2.67 kPas) or at the pressure designated in the individ-

A microbial strain cited and identified by its ATCC catalog num- ual monograph.

ber shall be used directly or, if subcultured, shall be used not more

8.230. Water

than five passages removed from the original strain.

8.230.10. Water as an Ingredient in an Official Product

8.100. Negligible

As an ingredient in an official product, water meets the require-

“Negligible” indicates a quantity not exceeding 0.50 mg.

ments of the appropriate water monograph in USP or NF.

8.110. NLT/NMT

8.230.20. Water in the Manufacture of Official Substances

“NLT” means “not less than.” “NMT” means “not more than.”

When used in the manufacture of official substances, water may

8.120. Odor meet the requirements for drinking water as set forth in the regula-

“Odorless,” “practically odorless,” “a faint characteristic odor,” tions of the U.S. Environmental Protection Agency (potable water).

and variations thereof indicate evaluation of a suitable quantity of

freshly opened material after exposure to the air for 15 minutes. An

odor designation is descriptive only and should not be regarded as a

standard of purity for a particular lot of an article.

USP 32 General Notices 9

8.230.30. Water in a Compendial Procedure 9.20 Changes in Volume

When water is called for in a compendial procedure, the USP ar- In the dispensing of prescription medications, slight changes in

ticle Purified Water shall be used unless otherwise specified. Defi- volume owing to variations in room temperatures may be

nitions for High-Purity Water and Carbon Dioxide–Free Water are disregarded.

provided in Containers—Glass 〈660〉. Definitions of other types of

10. PRESERVATION, PACKAGING, STORAGE, AND

water are provided in Water for Pharmaceutical Purposes 〈1231〉.

LABELING

8.240. Weights and Measures

10.10. Storage Under Nonspecific Conditions

In general, weights and measures are expressed in the Interna-

If no specific directions or limitations are provided in the Pack-

tional System of Units (SI) as established and revised by the Con-

aging and Storage section of an individual USP monograph or in

f´erence g´en´erale des poids et mesures. For compendial purposes,

the labeling of an article recognized in USP, the conditions of stor-

the term “weight” is considered to be synonymous with “mass.”

age shall include storage at controlled room temperature, protection

Molality is designated by the symbol m preceded by a number

from moisture, and, where necessary, protection from light. Such

that represents the number of moles of the designated solute con-

articles shall be protected from moisture, freezing, and excessive

tained in 1 kilogram of the designated solvent.

heat, and, where necessary, from light during shipping and distribu-

Molarity is designated by the symbol M preceded by a number

tion. Drug substances are exempt from the requirements in this

that represents the number of moles of the designated solute con-

paragraph.

tained in an amount of the designated solvent that is sufficient to

Regardless of quantity, where no specific storage directions or

prepare 1 liter of solution.

limitations are provided in an individual NF monograph or stated in

Normality is designated by the symbol N preceded by a number

the labeling of an article recognized in NF, the conditions of storage

that represents the number of equivalents of the designated solute

and distribution shall include protection from moisture, freezing,

contained in an amount of the designated solvent that is sufficient to

excessive heat, and, where necessary, from light.

prepare 1 liter of solution.

10.20. Containers

Symbols commonly employed for SI metric units and other units

The container is that which holds the article and is or may be in

are as follows:

direct contact with the article. The immediate container is that

which is in direct contact with the article at all times. The closure is

Bq = becquerel dL = deciliter

a part of the container.

kBq = kilobecquerel L = liter

Before being filled, the container should be clean. Special pre-

MBq = megabecquerel mL = milliliter

cautions and cleaning procedures may be necessary to ensure that

GBq = gigabecquerel µL = microliter

each container is clean and that extraneous matter is not introduced

into or onto the article.

Ci = curie Eq = gram-equivalent weight

The container does not interact physically or chemically with the

mCi = millicurie mEq = milliequivalent

article placed in it so as to alter the strength, quality, or purity of the

µCi = microcurie mol = gram-molecular weight

article beyond the official requirements.

(mole)

The compendial requirements for the use of specified containers

nCi = nanocurie Da = dalton (relative molecular

apply also to articles as packaged by the pharmacist or other dis-

mass)

penser, unless otherwise indicated in the individual monograph.

Gy = gray mmol = millimole

10.20.10. Tamper-Evident Packaging

The container or individual carton of a sterile article intended for

mGy = milligray Osmol = osmole

ophthalmic or otic use, except where extemporaneously com-

m = meter mOsmol = milliosmole

pounded for immediate dispensing on prescription, shall be so

dm = decimeter Hz = hertz

sealed that the contents cannot be used without obvious destruction

cm = centimeter kHz = kilohertz

of the seal.

Articles intended for sale without prescription are also required

mm = millimeter MHz = megahertz

to comply with the tamper-evident packaging and labeling require-

µm = micrometer (0.001mm) V = volts

ments of the FDA where applicable.

nm = nanometer

MeV = million electron volts

Preferably, the immediate container and/or the outer container or

kg = kilogram keV = kilo-electron volt

protective packaging used by a manufacturer or distributor for all

g = gram mV = millivolt

dosage forms that are not specifically exempt is designed so as to

show evidence of any tampering with the contents.

mg = milligram psi = pounds per square inch

10.20.20. Light-Resistant Container

µg; mcg = microgram

Pa = pascal

A light-resistant container (see Light Transmission Test under

ng = nanogram kPa = kilopascal

Containers—Performance Testing 〈671〉) protects the contents from

pg = pictogram g = gravity (in centrifugation)

the effects of light by virtue of the specific properties of the mate-

fg = femtogram

rial of which it is composed, including any coating applied to it.

Alternatively, a clear and colorless or a translucent container may

be made light-resistant by means of an opaque covering, in which

Previously the symbol mµ (for millimicron) was used.

case the label of the container bears a statement that the opaque

One milliliter (mL) is used herein as the equivalent of one cubic centimeter (cc).

covering is needed until the contents are to be used or administered.

The symbol µg is used in the USP and NF to represent micrograms, but micro-

Where it is directed to “protect from light” in an individual mono-

grams may be represented as “mcg” for labeling and prescribing purposes. The term

“gamma,” symbolized by γ, frequently is used to represent micrograms in biochemi-

graph, preservation in a light-resistant container is intended.

cal literature.

Where an article is required to be packaged in a light-resistant

container, and if the container is made light-resistant by means of

9. PRESCRIBING AND DISPENSING

an opaque covering, a single-use, unit-dose container or mnemonic

9.10 Use of Metric Units

pack for dispensing may not be removed from the outer opaque

Prescriptions for compendial articles shall be written to state the

covering before dispensing.

quantity and/or strength desired in metric units unless otherwise in-

10.20.30. Well-Closed Container

dicated in the individual monograph (see also Units of Potency, sec-

A well-closed container protects the contents from extraneous

tion 5.50.10 above). If an amount is prescribed by any other system

solids and from loss of the article under the ordinary or customary

of measurement, only an amount that is the metric equivalent of the

conditions of handling, shipment, storage, and distribution.

prescribed amount shall be dispensed. Apothecary unit designa-

tions on labels and labeling shall not be used.

10.20.40. Tight Container

A tight container protects the contents from contamination by ex-

traneous liquids, solids, or vapors; from loss of the article; and from

efflorescence, deliquescence, or evaporation under the ordinary or

10 General Notices USP 32

customary conditions of handling, shipment, storage, and distribu- ing as long as popular-size, special packages are also supplied. The

tion; and is capable of tight reclosure. Where a tight container is non–child-resistant package requires special labeling (16 CFR §

specified, it may be replaced by a hermetic container for a single 1700.5).

dose of an article. Various types of child-resistant packages are covered in ASTM

A gas cylinder is a metallic container designed to hold a gas International Standard D-3475, Standard Classification of Child-

under pressure. As a safety measure, for carbon dioxide, cyclopro- Resistant Packaging. Examples are included as an aid in the under-

pane, helium, nitrous oxide, and oxygen, the Pin-Index Safety Sys- standing and comprehension of each type of classification.

tem of matched fittings is recommended for cylinders of Size E or

10.30. Storage Temperature and Humidity

smaller.

Specific directions are stated in some monographs with respect to

[

NOTE

—Where packaging and storage in a tight container or a

the temperatures and humidity at which official articles shall be

well-closed container is specified in the individual monograph, the

stored and distributed (including the shipment of articles to the con-

container used for an article when dispensed on prescription meets

sumer) when stability data indicate that storage and distribution at a

the requirements under Containers—Performance Testing 〈671〉.]

lower or a higher temperature and a higher humidity produce unde-

10.20.50. Hermetic Container sirable results. Such directions apply except where the label on an

A hermetic container is impervious to air or any other gas under article states a different storage temperature on the basis of stability

the ordinary or customary conditions of handling, shipment, stor- studies of that particular formulation. Where no specific storage di-

age, and distribution. rections or limitations are provided in the individual monograph,

but the label of an article states a storage temperature that is based

10.20.60. Single-Unit Container

on stability studies of that particular formulation, such labeled stor-

A single-unit container is one that is designed to hold a quantity

age directions apply. (See also Pharmaceutical Stability 〈1150〉.)

of drug product intended for administration as a single dose or a

The conditions are defined by the following terms.

single finished device intended for use promptly after the container

is opened. Preferably, the immediate container and/or the outer 10.30.10. Freezer

container or protective packaging shall be so designed as to show “Freezer” indicates a place in which the temperature is main-

evidence of any tampering with the contents. Each single-unit tained thermostatically between −25° and −10° (−13° and 14°F).

container shall be labeled to indicate the identity, quantity and/or

10.30.20. Cold

strength, name of the manufacturer, lot number, and expiration date

Any temperature not exceeding 8° (46°F) is “cold.” A “refrigera-

of the article.

tor” is a cold place in which the temperature is maintained thermo-

10.20.70. Single-Dose Container statically between 2° and 8° (36° and 46°F).

A single-dose container is a single-unit container for articles in-

10.30.30. Cool

tended for parenteral administration only. A single-dose container is

Any temperature between 8° and 15° (46° and 59°F) is“cool.” An

labeled as such. Examples of single-dose containers include prefil-

article for which storage in a cool place is directed may, alterna-

led syringes, cartridges, fusion-sealed containers, and closure-

tively, be stored and distributed in a refrigerator, unless otherwise

sealed containers when so labeled. (See also Containers for Injec-

specified by the individual monograph.

tions under Injections 〈1〉.)

10.30.40. Controlled Cold Temperature

10.20.80. Unit-Dose Container

“Controlled cold temperature” is defined as temperature main-

A unit-dose container is a single-unit container for articles in-

tained thermostatically between 2° and 8° (36° and 46° F), that

tended for administration by other than the parenteral route as a sin-

allows for excursions in temperature between 0° and 15° (32° and

gle dose, direct from the container.

59° F) that may be experienced during storage, shipping, and distri-

10.20.90. Unit-of-Use Container bution such that the allowable calculated mean kinetic temperature

A unit-of-use container is one that contains a specific quantity of is not more than 8° (46° F). Transient spikes up to 25° (77° F)

a drug product and that is intended to be dispensed as such without may be permitted if the manufacturer so instructs and provided that

further modification except for the addition of appropriate labeling. such spikes do not exceed 24 hours unless supported by stability

A unit-of-use container is labeled as such. data or the manufacturer instructs otherwise.

10.20.100. Multiple-Unit Container 10.30.50. Room Temperature

A multiple-unit container is a container that permits withdrawal “Room temperature” indicates the temperature prevailing in a

of successive portions of the contents without changing the working area.

strength, quality, or purity of the remaining portion.

10.30.60. Controlled Room Temperature

10.20.110. Multiple-Dose Container “Controlled room temperature” indicates a temperature main-

A multiple-dose container is a multiple-unit container for articles tained thermostatically that encompasses the usual and customary

intended for parenteral administration only. (See also Containers working environment of 20° to 25° (68° to 77°F); that results in a

for Injections under Injections 〈1〉). mean kinetic temperature calculated to be not more than 25°; and

that allows for excursions between 15° and 30° (59° and 86°F) that

10.20.120. Requirements under the Poison Prevention

are experienced in pharmacies, hospitals, and warehouses. Provided

Packaging Act (PPPA)

the mean kinetic temperature remains in the allowed range, tran-

This act (see the website, www.cpsc.gov/businfo/pppa.html) re-

sient spikes up to 40° are permitted as long as they do not exceed

quires special packaging of most human oral prescription drugs,

24 hours. Spikes above 40° may be permitted if the manufacturer so

oral controlled drugs, certain non-oral prescription drugs, certain di-

instructs. Articles may be labeled for storage at “controlled room

etary supplements, and many over-the-counter (OTC) drug prepara-

temperature” or at “up to 25°”, or other wording based on the same

tions in order to protect the public from personal injury or illness

mean kinetic temperature. The mean kinetic temperature is a calcu-

from misuse of these preparations (16 CFR § 1700.14).

lated value that may be used as an isothermal storage temperature

The immediate packaging of substances regulated under the

that simulates the nonisothermal effects of storage temperature vari-

PPPA shall comply with the special packaging standards (16 CFR §

ations. (See also Pharmaceutical Stability 〈1150〉.)

1700.15 and 16 CFR § 1700.20). The PPPA regulations for special

An article for which storage at controlled room temperature is

packaging apply to all packaging types including reclosable, non-

directed may, alternatively, be stored and distributed in a cool

closable, and unit-dose types.

place, unless otherwise specified in the individual monograph or on

Special packaging is not required for drugs dispensed within a

the label.

hospital setting for inpatient administration. Manufacturers and

packagers of bulk-packaged prescription drugs do not have to use 10.30.70. Warm

special packaging if the drug will be repackaged by the pharmacist. Any temperature between 30° and 40° (86° and 104°F) is

PPPA-regulated prescription drugs may be dispensed in non–child- “warm.”

resistant packaging upon the request of the purchaser or when di-

10.30.80. Excessive Heat

rected in a legitimate prescription (15 U.S.C. § 1473).

“Excessive heat” means any temperature above 40° (104°F).

Manufacturers or packagers of PPPA-regulated OTC prepara-

tions are allowed to package one size in non–child-resistant packag-

USP 32 General Notices 11

10.30.90. Protection From Freezing Na and K are intended for use in abbreviating names of the salts of

Where, in addition to the risk of breakage of the container, freez- organic acids, but these symbols are not used where the word So-

ing subjects an article to loss of strength or potency, or to destruc- dium or Potassium appears at the beginning of an official title (e.g.,

tive alteration of its characteristics, the container label bears an ap- Phenobarbital Na is acceptable, but Na Salicylate is not to be

propriate instruction to protect the article from freezing. written).

10.30.100. Dry Place 10.40.40. Labeling Vitamin-Containing Products

The term “dry place” denotes a place that does not exceed 40% The vitamin content of an official drug product shall be stated on

average relative humidity at Controlled Room Temperature or the the label in metric units per dosage unit. The amounts of vitamins

equivalent water vapor pressure at other temperatures. The determi- A, D, and E may be stated also in USP Units. Quantities of vitamin

nation may be made by direct measurement at the place or may be A declared in metric units refer to the equivalent amounts of retinol

based on reported climatic conditions. Determination is based on (vitamin A alcohol). The label of a nutritional supplement shall bear

not less than 12 equally spaced measurements that encompass either an identifying lot number, control number, or batch number.

a season, a year, or, where recorded data demonstrate, the storage

10.40.50. Labeling Botanical-Containing Products

period of the article. There may be values of up to 45% relative

The label of an herb or other botanical intended for use as a diet-

humidity provided that the average value is 40% relative humidity.

ary supplement bears the statement, “If you are pregnant or nursing

Storage in a container validated to protect the article from mois-

a baby, seek the advice of a health professional before using this

ture vapor, including storage in bulk, is considered storage in a dry

product.”

place.

10.40.60. Labeling Parenteral And Topical Preparations

10.40. Labeling

The label of a preparation intended for parenteral or topical use

The term “labeling” designates all labels and other written,

states the names of all added substances (see 5.20., Added Sub-

printed, or graphic matter upon an immediate container of an article

stances, Excipients, and Ingredients and see Labeling under Injec-

or upon, or in, any package or wrapper in which it is enclosed, ex-

tions 〈1〉), and, in the case of parenteral preparations, also their

cept any outer shipping container. The term “label” designates that

amounts or proportions, except that for substances added for adjust-

part of the labeling upon the immediate container.

ment of pH or to achieve isotonicity, the label may indicate only

A shipping container containing a single article, unless such

their presence and the reason for their addition.

container is also essentially the immediate container or the outside

10.40.70. Labeling Electrolytes

of the consumer package, is labeled with a minimum of product

The concentration and dosage of electrolytes for replacement

identification (except for controlled articles), lot number, expiration

therapy (e.g., sodium chloride or potassium chloride) shall be stated

date, and conditions for storage and distribution.

on the label in milliequivalents (mEq). The label of the product

Articles in these compendia are subject to compliance with such

shall indicate also the quantity of ingredient(s) in terms of weight or

labeling requirements as may be promulgated by governmental bod-

percentage concentration.

ies in addition to the compendial requirements set forth for the

10.40.80. Labeling Alcohol

articles.

The content of alcohol in a liquid preparation shall be stated on

10.40.10. Amount of Ingredient Per Dosage Unit

the label as a percentage (v/v) of C

OH.

The strength of a drug product is expressed on the container label

10.40.90. Special Capsules and Tablets

in terms of micrograms or milligrams or grams or percentage of the

The label of any form of Capsule or Tablet intended for adminis-

therapeutically active moiety or drug substance, whichever form is

tration other than by swallowing intact bears a prominent indication

used in the title, unless otherwise indicated in an individual mono-

of the manner in which it shall be used.

graph. Both the active moiety and drug substance names and their

10.40.100. Expiration Date and Beyond-Use Date

equivalent amounts are then provided in the labeling.

The label of an official drug product or nutritional or dietary sup-

Official articles in capsule, tablet, or other unit dosage form shall

plement product shall bear an expiration date. All articles shall dis-

be labeled to express the quantity of each active ingredient or rec-

play the expiration date so that it can be read by an ordinary indi-

ognized nutrient contained in each such unit; except that, in the case

vidual under customary conditions of purchase and use. The

of unit-dose oral solutions or suspensions, whether supplied as liq-

expiration date shall be prominently displayed in high contrast to

uid preparations or as liquid preparations that are constituted from

the background or sharply embossed, and easily understood (e.g.,

solids upon addition of a designated volume of a specific diluent,

“EXP 6/08,” “Exp. June 08,” or “Expires 6/08”). [

NOTE

—For addi-

the label shall express the quantity of each active ingredient or rec-

tional information and guidance, refer to the Consumer Healthcare

ognized nutrient delivered under the conditions prescribed in Deliv-

Products Association’s Voluntary Codes and Guidelines of the Self-

erable Volume 〈698〉. Official drug products not in unit dosage form

Medication Industry.]

shall be labeled to express the quantity of each active ingredient in

The monographs for some preparations state how the expiration

each milliliter or in each gram, or to express the percentage of each

date that shall appear on the label shall be determined. In the ab-

such ingredient (see 8.140., Percentage Concentrations), except

sence of a specific requirement in the individual monograph for a

that oral liquids or solids intended to be constituted to yield oral

drug product or nutritional supplement, the label shall bear an expi-

liquids may, alternatively, be labeled in terms of each 5-mL portion

ration date assigned for the particular formulation and package of

of the liquid or resulting liquid. Unless otherwise indicated in a

the article, with the following exception: the label need not show an

monograph or chapter, such declarations of strength or quantity

expiration date in the case of a drug product or nutritional supple-

shall be stated only in metric units. See also 5.50.10., Units of Po-

ment packaged in a container that is intended for sale without pre-

tency (Biological).

scription and the labeling of which states no dosage limitations, and

10.40.20. Use of Leading and Terminal Zeros

which is stable for not less than 3 years when stored under the pre-

To help minimize the possibility of errors in the dispensing and

scribed conditions.

administration of drugs, the quantity of active ingredient when ex-

Where an official article is required to bear an expiration date,

pressed in whole numbers shall be shown without a decimal point

such article shall be dispensed solely in, or from, a container la-

that is followed by a terminal zero (e.g., express as 4 mg [not

beled with an expiration date, and the date on which the article is

4.0 mg]). The quantity of active ingredient when expressed as a

dispensed shall be within the labeled expiry period. The expiration

decimal number smaller than 1 shall be shown with a zero preced-

date identifies the time during which the article may be expected to

ing the decimal point (e.g., express as 0.2 mg [not .2 mg]).

meet the requirements of the compendial monograph, provided it is

10.40.30. Labeling of Salts of Drugs

kept under the prescribed storage conditions. The expiration date

It is an established principle that official articles shall have only

limits the time during which the article may be dispensed or used.

one official title. For purposes of saving space on labels, and be-

Where an expiration date is stated only in terms of the month and

cause chemical symbols for the most common inorganic salts of

the year, it is a representation that the intended expiration date is the

drugs are well known to practitioners as synonymous with the writ-

last day of the stated month. The beyond-use date is the date after

ten forms, the following alternatives are permitted in labeling offi-

which an article shall not be used. The dispenser shall place on the

cial articles that are salts: HCl for hydrochloride; HBr for

label of the prescription container a suitable beyond-use date to

hydrobromide; Na for sodium; and K for potassium. The symbols

12 General Notices USP 32

limit the patient’s use of the article based on any information sup- the date after which a compounded preparation is not to be used.

plied by the manufacturer and the General Notices. The beyond-use Because compounded preparations are intended for administration

date placed on the label shall not be later than the expiration date on immediately or following short-term storage, their beyond-use dates

the manufacturer’s container. may be assigned based on criteria different from those applied to

For articles requiring constitution before use, a suitable beyond- assigning expiration dates to manufactured drug products.

use date for the constituted product shall be identified in the The monograph for an official compounded preparation typically

labeling. includes a beyond-use requirement that states the time period fol-

For all other dosage forms, in determining an appropriate period lowing the date of compounding during which the preparation,

of time during which a prescription drug may be retained by a pa- properly stored, may be used. In the absence of stability information

tient after its dispensing, the dispenser shall take into account, in that is applicable to a specific drug and preparation, recommenda-

addition to any other relevant factors, the nature of the drug; the tions for maximum beyond-use dates have been devised for non-

container in which it was packaged by the manufacturer and the sterile compounded drug preparations that are packaged in tight,

expiration date thereon; the characteristics of the patient’s light-resistant containers and stored at controlled room temperature

container, if the article is repackaged for dispensing; the expected unless otherwise indicated (see Stability Criteria and Beyond-Use

storage conditions to which the article may be exposed; any unusual Dating under Stability of Compounded Preparations in the general

storage conditions to which the article may be exposed; and the ex- test chapter Pharmaceutical Compounding—Nonsterile Prepara-

pected length of time of the course of therapy. The dispenser shall, tions 〈795〉).

on taking into account the foregoing, place on the label of a multi-

10.50. Guidelines for Packaging and Storage Statements in

ple-unit container a suitable beyond-use date to limit the patient’s

USP–NF Monographs

use of the article. Unless otherwise specified in the individual mon-

In order to provide users of the USP and NF with proper gui-

ograph, or in the absence of stability data to the contrary, such be-

dance on how to package and store official articles, every mono-

yond-use date shall be not later than (a) the expiration date on the

graph in the USP and NF shall have a packaging and storage

manufacturer’s container, or (b) 1 year from the date the drug is

specification.

dispensed, whichever is earlier. For nonsterile solid and liquid dos-

For the packaging portion of the statement, the choice of contain-

age forms that are packaged in single-unit and unit-dose containers,

ers is given in this section 10, Preservation, Packaging, Storage,

the beyond-use date shall be 1 year from the date the drug is pack-

and Labeling, and includes Light-Resistant Container, Well-Closed

aged into the single-unit or unit-dose container or the expiration

Container, Tight Container, Hermetic Container, Single-Unit

date on the manufacturer’s container, whichever is earlier, unless

Container, Single-Dose Container, Unit-Dose Container, and Unit-

stability data or the manufacturer’s labeling indicates otherwise.

of-Use Container. For most preparations, the choice is determined

The dispenser shall maintain the facility where the dosage forms

by the container in which it shall be dispensed (e.g., tight, well-

are packaged and stored, at a temperature such that the mean kinetic

closed, hermetic, unit-of-use, etc.). For drug substances, the choice

temperature is not greater than 25°. The plastic material used in

would appear to be tight, well-closed, or, where needed, a light-

packaging the dosage forms shall afford better protection than poly-

resistant container. For excipients, given their typical nature as

vinyl chloride, which does not provide adequate protection against

large-volume commodity items, with containers ranging from

moisture permeation. Records shall be kept of the temperature of

drums to tank cars, a well-closed container is an appropriate default.

the facility where the dosage forms are stored, and of the plastic

Therefore, in the absence of data indicating a need for a more pro-

materials used in packaging.

tective class of container, the phrase “Preserve in well-closed con-

10.40.100.1. Compounded Preparations tainers” should be used as a default for excipients.

▲USP32

The label on the container or package of an official compounded

preparation shall bear a beyond-use date. The beyond-use date is