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26 by noah1 on Wed Oct 03 11:23:32 EDT 2012
USP 35
Labeling—The labeling requirements for a commercial
repackager and a pharmacist are different. For example, the
commercial repackager must comply with 21 CFR 201.1,
but the pharmacist or dispenser does not have to comply
with this requirement. If stability data are unavailable, the
dispenser shall repackage only an amount of stock sufficient
for a limited time and shall include product name and
strength, lot number, manufacturer, and appropriate be-
yond-use date on the label. When quantities are repackaged
in advance of immediate needs, each preparation must bear
an identifying label, and the dispenser is required to main-
tain suitable repackaging records showing the name of the
manufacturer, lot number, expiration date, date of repack-
aging, and designation of persons responsible for repack-
aging and for checking. The repackager or dispenser will
use documented controls to prevent labeling errors.
Materials—The repackager or dispenser shall place an
appropriate beyond-use date on the label and package in
appropriate materials. Materials used by the repackager shall
not be reactive, additive, or absorptive, and must meet the
requirements described in 21 CFR 175 and 177.
Storage—The dispenser shall rotate and monitor stock
closely to ensure that the dispensing of preparations is on a
first-in–first-out (FIFO) basis. The repackager or dispenser
shall store preparations under required environmental condi-
tions (e.g., controlled room temperature with a mean ki-
netic temperature not higher than 25°).
Drug Product—The repackager or dispenser shall ex-
amine preparations for evidence of instability such as
change in color or odor, and shall exercise professional
judgment as to the acceptability of a package.
Complaints—The repackager or dispenser will maintain
written procedures describing the handling of written and
oral complaints regarding a drug product and will ensure
that complaints are investigated and appropriately resolved.
Returned Goods—Policies and procedures relating to re-
turned goods should be developed to ensure proper
handling.
Reprocessing—Reprocessing of repackaged unit-dose
containers (i.e., removing medication from one unit-dose
container and placing it into another unit-dose container)
shall not be done. However, reprocessing of the secondary
package (e.g., removing the blister card from the cardboard
carrier and placing the blister card into another cardboard
carrier) is allowed provided the original beyond-use date is
maintained, and provided the integrity of the blister is
ensured.
Special Considerations—If a product is known to be ox-
ygen sensitive or if it exhibits extreme moisture or light sen-
sitivity (e.g., cold form foil), it shall not be repackaged. If a
product is refrigerated, it shall not be repackaged unless
proper environmental conditions and suitable materials are
available. Certain drug products (such as oncologic agents,
hormones, or penicillin derivatives) require special handling
because they are considered very potent or toxic, and be-
cause transfer of any portion of these products to another
product could have deleterious effects.
〈1150〉 PHARMACEUTICAL
STABILITY
The term “stability,” with respect to a drug dosage form,
refers to the chemical and physical integrity of the dosage
unit and, when appropriate, the ability of the dosage unit to
maintain protection against microbiological contamination.
Official from August 1, 2012
Copyright (c) 2012 The United States Pharmacopeial Convention. All rights reserved.
General Information / 〈1150〉 Pharmaceutical Stability 763
The shelf life of the dosage form is the time lapse from
initial preparation to the specified expiration date. The mon-
ograph specifications of identity, strength, quality, and pu-
rity apply throughout the shelf life of the product.
The stability parameters of a drug dosage form can be
influenced by environmental conditions of storage (tempera-
ture, light, air, and humidity), as well as the package com-
ponents. Pharmacopeial articles should include required
storage conditions on their labeling. These are the condi-
tions under which the expiration date shall apply. The stor-
age requirements specified in the labeling for the article
must be observed throughout the distribution of the article
(i.e., beyond the time it leaves the manufacturer up to and
including its handling by the dispenser or seller of the article
to the consumer). Although labeling for the consumer
should indicate proper storage conditions, it is recognized
that control beyond the dispenser or seller is difficult. The
beyond-use date shall be placed on the container label.
Stability Protocols
Stability of manufactured dosage forms must be demon-
strated by the manufacturer, using methods adequate for
the purpose. Monograph assays may be used for stability
testing if they are stability-indicating (i.e., if they accurately
differentiate between the intact drug molecules and their
degradation products). Stability considerations should in-
clude not only the specific compendial requirements, but
also changes in physical appearance of the product that
would warn users that the product’s continued integrity is
questionable.
Stability studies on active substances and packaged dos-
age forms are conducted by means of “real-time,” long-
term tests at specific temperatures and relative humidities
representing storage conditions experienced in the distribu-
tion chain of the climatic zone(s) of the country or region of
the world concerned. Labeling of the packaged active sub-
stance or dosage form should reflect the effects of tempera-
ture, relative humidity, air, and light on its stability. Label
temperature storage warnings will both reflect the results of
the real-time storage tests and allow for expected seasonal
excursions of temperature.
Controlled Room Temperature
Controlled room temperature (see Storage Temperature
and Humidity in Preservation, Packaging, Storage, and Label-
ing under General Notices and Requirements) delineates the
allowable tolerance in storage circumstances at any location
in the chain of distribution (e.g., pharmacies, hospitals, and
warehouses). This terminology also allows patients or con-
sumers to be counseled as to appropriate storage for the
product. Products may be labeled either to store at “Con-
trolled room temperature” or to store at temperatures “up
to 25°” where labeling is supported by long-term stability
studies at the designated storage condition of 25°. Con-
trolled room temperature limits the permissible excursions to
those consistent with the maintenance of a mean kinetic
temperature calculated to be not more than 25°. See Mean
Kinetic Temperature. The common international guideline for
long-term stability studies specifies 25 ± 2° at 60 ± 5% rela-
tive humidity. Accelerated studies are specified at 40 ± 2°
and at 75 ± 5% relative humidity. Accelerated studies also
allow the interpretation of data and information on short-
term spikes in storage conditions in addition to the excur-
sions allowed by controlled room temperature.
The term “room temperature” is used in different ways in
different countries, and for products to be shipped outside
the continental U.S. it is usually preferable for product label-
ing to refer to a maximum storage temperature or tempera-
ture range in degrees Celsius.
 Accessed from 206.192.168.26 by noah1 on Wed Oct 03 11:23:32 EDT 2012

764 〈1150〉 Pharmaceutical Stability / General Information USP 35

Table 1. International Climatic Zones

Calculated Data Derived Data
% %
Climatic Zone °C* °C MKT** RH mbar*** °C RH mbar
I. Temperate 20.0 20.0 42 9.9 21 45 11.2
Japan
United Kingdom
Northern Europe
Canada
Russia
United States
II. Mediterranean, Subtropical 21.6 22.0 52 13.5 25 60 19.0
United States
Japan
Southern Europe
(Portugal-Greece)
III. Hot, Dry 26.4 27.9 35 11.9 30 35 15.0
Iran
Iraq
Sudan
IV. Hot, Humid 26.7 27.4 76 26.6 30 70 30.0
Brazil
Ghana
Indonesia
Nicaragua
Philippines
* Data recorded as <19° calculated as 19°.
** Calculated mean kinetic temperature.
*** Partial pressure of water vapor.

Mean Kinetic Temperature
Mean Kinetic Temperature (MKT) is defined as the single
calculated temperature at which the total amount of degra-
dation over a particular period is equal to the sum of the
individual degradations that would occur at various temper-
atures. Thus, MKT may be considered as an isothermal stor-
age temperature that simulates the nonisothermal effects of
storage temperature variation. It is not a simple arithmetic
mean. MKT is calculated from temperatures in a storage fa-
cility. The temperatures for calculating MKT can be conven-
iently collected using electronic devices that measure tem-
peratures at frequent intervals (e.g., every 15 minutes). MKT
can be calculated directly or the data can be downloaded to
a computer for processing. For dispensing sites, such as
pharmacies and hospitals, where the use of such instru-
ments may not be feasible, devices such as high-low ther-
mometers capable of indicating weekly high and low tem-
peratures over a 52-week period may be employed. The
arithmetic mean of the weekly high and low temperatures is
then used in the calculation of MKT. MKT is calculated by
the following equation (derived from the Arrhenius
equation):
in which Tk is the mean kinetic temperature; ∆H is the heat
of activation, 83.144 kJ · mole−1 (unless more accurate infor-
mation is available from experimental studies); R is the uni-
versal gas constant, 8.3144 × 10−3 kJ · mole−1 · degree−1; T1 is
the value for the temperature recorded during the first time
period, e.g., the first week; T2 is the value for the tempera-
ture recorded during the second time period, e.g., second
week; and Tn is the value for the temperature recorded dur-
ing the nth time period, e.g., nth week, n being the total
number of storage temperatures recorded (minimum of 52
weekly entries) during the annual observation period.
[NOTE—All temperatures, T, are absolute temperatures in de-
grees Kelvin (K).]
The following is an example of a typical storage and dis-
tribution temperature range in Kelvin degrees and the con-
version factors used to convert this range into degrees Fah-
renheit and Celsius.
Kelvin (K) Fahrenheit (°F) Celsius (°C)
288.1–303.1 59–86 15–30
Conversion Factors:
Fahrenheit to Kelvin = {[(°F − 32) × 5/9] + 273.1}
Celsius to Kelvin = 273.1 + °C
Fahrenheit to Celsius = [(°F − 32) × 5/9]
Climatic Zones
For convenience in planning for packaging and storage,
and for stability studies, international practice identifies four
climatic zones, which are described in Table 1. The United
States, Europe, and Japan are characterized by zones I and
II. The values in Table 1 are based on observed temperatures
and relative humidities, both outside and in rooms, from
which mean kinetic temperatures and average humidity val-
ues are calculated.1 Derived values are based on inspection
of data from individual cities and on allowances for a mar-
gin of safety in assignment of these specified conditions.
A discussion of aspects of drug product stability that are
of primary concern to the pharmacist in the dispensing of
medications may be found under Stability Considerations in
Dispensing Practice 〈1191〉.
Inasmuch as this chapter is for purposes of general infor-
mation only, no statement herein is intended to modify or
supplant any of the specific requirements pertinent to phar-
1 The source of the data and information in Table 1 is the International Con-
ference on Harmonization sponsored by the International Federation of Phar-
maceutical Manufacturers Associations.

Official from August 1, 2012

Copyright (c) 2012 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 206.192.168.26 by noah1 on Wed Oct 03 11:23:32 EDT 2012
USP 35 General Information / 〈1151〉 Pharmaceutical Dosage Forms 765
maceutical preparations, which are given elsewhere in this
Pharmacopeia.
Change to read:
〈1151〉 PHARMACEUTICAL
DOSAGE FORMS
▲GENERAL CONSIDERATIONS
This chapter provides general descriptions of and defini-
tions for drug products, or dosage forms, commonly used
to administer the active pharmaceutical ingredient (API). It
discusses general principles involved in the manufacture or
compounding of these dosage forms and recommendations
for proper use and storage. A glossary is provided as a re-
source on nomenclature.
A dosage form is a combination of API and often excipi-
ents to facilitate dosing, administration, and delivery of the
medicine to the patient. The design and testing of all dos-
age forms target drug product quality.1 A testing protocol
must consider not only the physical, chemical, and biologi-
cal properties of the dosage form as appropriate, but also
the administration route and desired dosing regimen. The
interrelationships of dosage forms and routes of administra-
tion have been summarized in the compendial taxonomy
for pharmaceutical dosage forms (see Figure 1).2 The organ-
ization of this general information chapter is by the physical
attributes of each particular dosage form (Tier Two), gener-
ally without specific reference to route of administration. In-
formation specific to route of administration is given when
needed.
Tests to ensure compliance with Pharmacopeial standards
for dosage form performance fall into one of the following
areas.
Dose Uniformity (see also Uniformity of Dosage Units
〈905〉)—Consistency in dosing for a patient or consumer re-
quires that the variation in the API content of each dosage
unit be accurately controlled throughout the manufactured
batch or compounded lot of drug product. Uniformity of
dosage units typically is demonstrated by one of two proce-
dures: content uniformity or weight variation. The proce-
dure for content uniformity requires the assay of API content
of individual units and that for weight variation uses the
weight of the individual units to estimate their content.
Weight variation may be used where the underlying distri-
bution of API in the blend is presumed to be uniform and
well-controlled, as in solutions. In such cases the content of
API may be adequately estimated by the net weight. Con-
1 In the United States a drug with a name recognized in USP–NF must comply
with compendial identity standards or be deemed adulterated, misbranded,
or both. To avoid being deemed adulterated such drugs also must comply
with compendial standards for strength, quality, or purity, unless labeled to
show all respects in which the drug differs. See the Federal Food, Drug, and
Cosmetic Act (FDCA), Sections 501(b) and 502(e)(3)(b), and Food and Drug
Administration (FDA) regulations at 21 CFR 299.5. In addition, to avoid being
deemed misbranded, drugs recognized in USP–NF also must comply with
compendial standards for packaging and labeling, FDCA Section 502(g).
“Quality” is used herein as suitable shorthand for all such compendial require-
ments. This approach also is consistent with U.S. and FDA participation in the
International Conference on Harmonization (ICH). The ICH guideline on spec-
ifications, Q6A, notes that “specifications are chosen to confirm the quality of
the drug substance and drug product…” and defines “quality” as “The suita-
bility of either a drug substance or drug product for its intended use. This
term includes such attributes as identity, strength, and purity.”
2 Marshall K, Foster TS, Carlin HS, Williams RL. Development of a compendial
taxonomy and glossary for pharmaceutical dosage forms. Pharm Forum.
2003;29(5):1742–1752.
Official from August 1, 2012
Copyright (c) 2012 The United States Pharmacopeial Convention. All rights reserved.
tent uniformity does not rely on the assumption of blend
uniformity and can be applied in all cases. Successful devel-
opment and manufacture of dosage forms requires careful
evaluation of API particle or droplet size, incorporation tech-
niques, and excipient properties.
Stability (see also Pharmaceutical Stability 〈1150〉)—Drug
product stability involves the evaluation of chemical stability,
physical stability, and performance over time. The chemical
stability of the API in the dosage form matrix must support
the expiration dating for the commercially prepared dosage
forms and a beyond-use date for a compounded dosage
form. Test procedures for potency must be stability indicat-
ing (see Validation of Compendial Procedures 〈1225〉). Degra-
dation products should be quantified. In the case of dis-
persed or emulsified systems, consideration must be given
to the potential for settling or separation of the formulation
components. Any physical changes to the dosage form must
be easily reversed (e.g., by shaking) prior to dosing or ad-
ministration. For the example of tablets, capsules, and oral
suspensions, in vitro release test procedures such as dissolu-
tion and disintegration provide a measure of continuing
consistency in performance over time (see Dissolution 〈711〉,
Disintegration 〈701〉, and Drug Release 〈724〉).
Bioavailability (see also In Vitro and In Vivo Evaluation of
Dosage Forms 〈1088〉 and Assessment of Drug Product Perfor-
mance—Bioavailability, Bioequivalence, and Dissolution
〈1090〉)—Bioavailability is influenced by factors such as the
method of manufacture or compounding, particle size, crys-
tal form (polymorph) of the API, the properties of the excip-
ients used to formulate the dosage form, and physical
changes as the drug product ages. Assurance of consistency
in bioavailability over time (bioequivalence) requires close
attention to all aspects of the production (or compounding)
and testing of the dosage form. With proper justification, in
vitro release (e.g., disintegration and dissolution) testing
may sometimes be used as a surrogate to demonstrate con-
sistent availability of the API from the formulated dosage.
Manufacture—Although detailed instructions about the
manufacture of any of these dosage forms are beyond the
scope of this general information chapter, general manufac-
turing principles have been included, as well as suggested
testing for proper use and storage. Information relative to
extemporaneous compounding of dosage forms can be
found in Pharmaceutical Compounding—Nonsterile Prepara-
tions 〈795〉 and Pharmaceutical Compounding—Sterile Prepa-
rations 〈797〉.
Route of Administration—The primary routes of admin-
istration for pharmaceutical dosage forms can be defined as
mucosal, gastrointestinal, parenteral (by injection), inhala-
tion, and topical/dermal, and each has subcategories as
needed. Many tests used to ensure quality generally are ap-
plied across all of the administration routes, but some tests
are specific for individual routes. For example, products in-
tended for injection must be evaluated for Sterility Tests 〈71〉
and Pyrogen Test 〈151〉, and the manufacturing process (and
sterilization technique) employed for parenterals (by injec-
tion) should ensure compliance with these tests. Tests for
particulate matter may be required for certain dosage forms
depending on the route of administration (e.g., by injec-
tion—Particulate Matter in Injections 〈788〉, or mucosal—Par-
ticulate Matter in Ophthalmic Solutions 〈789〉). Additionally,
dosage forms intended for the inhalation route of adminis-
tration must be monitored for particle size and spray pattern
(for a metered-dose inhaler or dry powder inhaler) and
droplet size (for nasal sprays). Further information regarding
administration routes and suggested testing can be found in
the Guide to General Chapters, Charts 4–8 and 10–13.
An appropriate manufacturing process and testing regi-
men help ensure that a dosage form can meet the appropri-
ate quality attributes for the intended route of
administration.
Excess Volume in Injections—Each container of an Injec-
tion is filled with a volume in slight excess of the labeled
“size” or the volume that is to be withdrawn. The excess