Romel A. Altamirano

PRUEBAS QUE SE REALIZAN A FORMAS FARMACEUTICAS



The following list of parameters for each dosage form is
presented as a guide for the types of tests to be included
in a stability study. In general, appearance, assay, and degradation
products should be evaluated for all dosage forms.
The list of tests presented for each dosage form is not
intended to be exhaustive, nor is it expected that every
listed test be included in the design of a stability protocol
for a particular drug product (e.g., a test for odor should
be performed only when necessary and with consideration
for analyst safety). Furthermore, it is not expected that
every listed test be performed at each time point.

A. TABLETS
Tablets should be evaluated for appearance, color, odor,
assay, degradation products, dissolution, moisture, and
friability.

B. CAPSULES
Hard gelatin capsules should be evaluated for appearance
(including brittleness), color, odor of contents, assay, degradation
products, dissolution, moisture, and microbial
limits. Testing of soft gelatin capsules should include
appearance, color, odor of contents, assay, degradation
products, dissolution, microbial limits, pH, leakage, and
pellicle formation. In addition, the fill medium should be
examined for precipitation and cloudiness.

C. EMULSIONS
An evaluation should include appearance (including phase
separation), color, odor, assay, degradation products, pH,
viscosity, microbial limits, preservative content, and mean
size and distribution of dispersed phase globules.

D. ORAL SOLUTIONS AND SUSPENSIONS
The evaluation should include appearance (including formation
of precipitate, clarity for solutions), color, odor,
assay, degradation products, pH, preservative content, and
microbial limits.
In addition, for suspensions, redispersibility, rheological
properties, and mean size and distribution of particles
should be considered. After storage, samples of suspensions
should be prepared for assay according to the recommended
labeling (e.g., “shake well before using”).

E. ORAL POWDERS FOR RECONSTITUTION
Oral powders should be evaluated for appearance, odor,
color, moisture, and reconstitution time.
Reconstituted products (solutions and suspensions)
should be evaluated as described in Section VIII.D, after
preparation according to the recommended labeling,
through the maximum intended use period.

F. METERED-DOSE INHALATIONS AND
NASAL AEROSOLS
Metered-dose inhalations and nasal aerosols should be
evaluated for appearance (including content, container,
and the valve and its components), color, taste, assay,
degradation products, assay for cosolvent (if applicable),
dose content uniformity, labeled number of medication
actuations per container meeting dose content uniformity,
aerodynamic particle size distribution, microscopic evaluation,
water content, leak rate, microbial limits, valve
delivery (shot weight), and extractables and leachables
from plastic and elastomeric components. Samples should
be stored in upright and inverted/on-the-side orientations.
For suspension-type aerosols, the appearance of the
valve components and container’s contents should be evaluated
microscopically for large particles and changes in
morphology of the drug surface particles, extent of
agglomerates, crystal growth, and foreign particulate matter.
These particles lead to clogged valves or nonreproducible
delivery of a dose. Corrosion of the inside of the
container or deterioration of the gaskets may adversely
affect the performance of the drug product.
A stress temperature-cycling study should be performed
under the extremes of high and low temperatures
expected to be encountered during shipping and handling
to evaluate the effects of temperature changes on the quality
and performance of the drug product. Such a study
may consist of three or four 6-hour cycles per day, between
subfreezing temperature and 40°C (75–85% RH), for a
period of up to 6 weeks.
Because the inhalant drug products are intended for
use in the respiratory system, confirmation that initial
release specifications are maintained should be provided
to ensure both the absence of pathogenic organisms (e.g.,
Staphylococcus aureus, Pseudomonas aeruginosa,
Escherichia coli, and Salmonella species) and that the total
aerobic count and total mold and yeast count per canister
are not exceeded.

G. INHALATION SOLUTIONS AND POWDERS
The evaluation of inhalation solutions and solutions for
inhalation should include appearance, color, assay, degradation
products, pH, sterility, particulate matter, preservative
and antioxidant content (if present), net contents (fill
weight and volume), weight loss, and extractables or
leachables from plastic, elastomeric, and other packaging
components.
The evaluation of inhalation powders should include
appearance, color, assay, degradation products, aerodynamic
particle size distribution of the emitted dose, microscopic
evaluation, microbial limit, moisture content, foreign particulates,
content uniformity of the emitted dose, and number
of medication doses per device meeting content uniformity
of the emitted dose (device metered products).

H. NASAL SPRAYS: SOLUTIONS AND SUSPENSIONS
The stability evaluation of nasal solutions and suspensions
equipped with a metering pump should include appearance,
color, clarity, assay, degradation products, preservative
and antioxidant content, microbial limits, pH, particulate
matter, unit spray medication content uniformity,
number of actuations meeting unit spray content uniformity
per container, droplet or particle size distribution,
weight loss, pump delivery, microscopic evaluation (for
suspensions), foreign particulate matter, and extractables
and leachables from plastic and elastomeric components
of the container, closure, and pump.

I. TOPICAL, OPHTHALMIC, AND OTIC PREPARATIONS
Included in this broad category are ointments, creams,
lotions, pastes, gels, solutions, and nonmetered aerosols
for application to the skin.
Topical preparations should be evaluated for appearance,
clarity, color, homogeneity, odor, pH, resuspendability
(for lotions), consistency, viscosity, particle size distribution
(for suspensions, when feasible), assay,
degradation products, preservative and antioxidant content
(if present), microbial limits and sterility, and weight loss
(when appropriate).
Appropriate stability data should be provided for
products supplied in closed-end tubes to support the maximum
anticipated use period—during patient use—once
the tube seal is punctured, allowing product contact with
the cap and cap liner. Ointments, pastes, gels, and creams
in large containers, including tubes, should be assayed by
sampling at the surface, top, middle, and bottom of the
container. In addition, tubes should be sampled near the
crimp (see also Section VII.D.2).
Evaluation of ophthalmic or otic products (e.g.,
creams, ointments, solutions, and suspensions) should
include the following additional attributes: sterility, particulate
matter, and extractables.
Evaluation of nonmetered topical aerosols should
include appearance, assay, degradation products, pressure,
weight loss, net weight dispensed, delivery rate, microbial
limits, spray pattern, water content, and particle size distribution
(for suspensions).

J. TRANSDERMALS
Stability studies for devices applied directly to the skin
for the purpose of continuously infusing a drug substance
into the dermis through the epidermis should be examined
for appearance, assay, degradation products, leakage,
microbial limit and sterility, peel and adhesive forces, and
drug release rate.

K. SUPPOSITORIES
Suppositories should be evaluated for appearance, color,
assay, degradation products, particle size, softening range,
appearance, dissolution (at 37°C), and microbial limits.

L. SVPS
SVPs include a wide range of injection products such as
drug injection, drug for injection, drug injectable suspension,
drug for injectable suspension, and drug injectable
emulsion.
Evaluation of drug injection products should include
appearance, color, assay, preservative content (if present),
degradation products, particulate matter, pH, sterility, and
pyrogenicity.
Stability studies for drug for injection products should
include monitoring for appearance, clarity, color, reconstitution
time, and residual moisture content. The stability
of drug for injection products should also be evaluated
after reconstitution according to the recommended labeling.
Specific parameters to be examined at appropriate
intervals throughout the maximum intended use period of
the reconstituted drug product, stored under conditions
recommended in labeling, should include appearance,
clarity, odor, color, pH, assay (potency), preservative (if
present), degradation products and aggregates, sterility,
pyrogenicity, and particulate matter.
The stability studies for drug injectable suspension
and drug for injectable suspension products should also
include particle size distribution, redispersibility, and
rheological properties in addition to the parameters cited
above for drug injection and drug for injection products.
The stability studies for drug injectable emulsion products
should include, in addition to the parameters cited
above for drug injection, phase separation, viscosity, and
mean size and distribution of dispersed phase globules. The
functionality and integrity of parenterals in prefilled syringe
delivery systems should be ensured through the expiration
dating period with regard to factors such as the applied
extrusion force, syringeability, pressure rating, and leakage.
Continued assurance of sterility for all sterile products
can be assessed by a variety of means, including evaluation
of the container and closure integrity by an appropriate
challenge test or tests, or sterility testing as described
in Section VII.C. Stability studies should evaluate product
stability following exposure to at least the maximum specified
process lethality (e.g., F, Mrads).
Inclusion of testing for extractables and leachables in the
stability protocol may be appropriate in situations in which
other qualification tests have not provided sufficient information
or assurance concerning the levels of extractables and
leachables from plastics and elastomeric components.
Interaction of administration sets and dispensing
devices with parenteral drug products, where warranted,
should also be considered through appropriate-use test
protocols to assure that absorption and adsorption during
dwell time do not occur.

M. LVPS
Evaluation of LVPs should include appearance, color,
assay, preservative content (if present), degradation products,
particulate matter, pH, sterility, pyrogenicity, clarity,
and volume.
Continued assurance of sterility for all sterile products
may be assessed by a variety of means, including evaluation
of the container and closure integrity by an appropriate
challenge test or tests, or sterility testing as
described in Section VII.C. Stability studies should
include evaluation of product stability following exposure
to at least the maximum specified process lethality (e.g.,

F, Mrads).
Interaction of administration sets and dispensing
devices with this type of dosage form should also be
considered through appropriate-use test protocols to
ensure that absorption and adsorption during dwell time
do not occur.

N. DRUG ADDITIVES
For any drug product or diluent that is intended for use
as an additive to another drug product, the potential for
incompatibility exists. In such cases, the drug product
labeled to be administered by addition to another drug
product (e.g., parenterals, inhalation solutions) should be
evaluated for stability and compatibility in admixture with
the other drug products or with diluents both in upright
and inverted/on-the-side orientations, if warranted.
A stability protocol should provide for appropriate
tests to be conducted at 0-, 6 to 8-, and 24-hour time
points, or as appropriate over the intended use period at
the recommended storage and use temperature or temperatures.
Tests should include appearance, color, clarity,
assay, degradation products, pH, particulate matter, interaction
with the container and closure and device, and
sterility. Appropriate supporting data may be provided in
lieu of an evaluation of photodegradation. The compatibility
and the stability of the drug products should be
confirmed in all diluents and containers and closures as
well as in the presence of all other drug products indicated
for admixture in the labeling. Compatibility studies
should be conducted on at least the lowest and highest
concentrations of the drug product in each diluent as
specified in the labeling. The stability and compatibility
studies should be performed on at least three batches of
the drug product. Compatibility studies should be
repeated if the drug product or any of the recommended
diluents or other drug products for admixture are reformulated.
Testing for extractables and leachables on stability
studies may be appropriate in situations where other qualification
tests have not provided sufficient information or
assurance concerning the levels of extractables and leachables
from plastics and elastomeric components. Interaction
of administration sets and dispensing devices with
parenteral drug products, where warranted, should also be
considered through appropriate use test protocols to
ensure that absorption and adsorption during dwell time
do not occur.

O. IMPLANTABLE SUBDERMAL, VAGINAL, AND INTRAUTERINE DEVICES THAT DELIVER
DRUG PRODUCTS

A device containing a drug substance reservoir or matrix
from which drug substance diffuses should be tested for
total drug substance content, degradation products,
extractables, in vitro drug release rate, and as appropriate,
microbial burden or sterility. The stability protocol should
include studies at 37° or 40°C over a sufficient period of
time to simulate the in vivo use of the drug delivery
device.
Stability testing for intrauterine devices (IUDs) should
include the following tests: deflection of horizontal arms
or other parts of the frame if it is not a T-shaped device
(frame memory), tensile strength of the withdrawal string,
integrity of the package (i.e., seal strength of the pouch),
and sterility of the device.
Romel A. Altamirano