INTRODUCTION
Topically
applied drug products fall into two general categories: those applied to
achieve local action and those applied to achieve systemic effects after
absorption through the skin into the blood circulation. Local action can occur
at or on the surface of the application site (e.g., stratum corneum); in the
underlying tissues (e.g., epidermis and/or dermis); and in subcutaneous tissues
(e.g., muscle or joint). Topically applied drug products include, but are not
limited to, creams, gels, ointments, pastes, suspensions, lotions, foams,
sprays, aerosols, solutions, and transdermal delivery systems (TDS). The
definitions and descriptions of these dosage forms, as well as brief information
on their composition and/or manufacturing processes, can be found in Pharmaceutical Dosage Forms 〈1151〉.
Procedures
and acceptable criteria for testing topically applied drug products can be
divided into those that assess general product quality attributes and those
that assess product performance. The product quality attributes include the
following: description, identification, assay (strength), impurities,
physicochemical properties, uniformity of dosage units, water content, pH,
apparent viscosity, microbial limits, antimicrobial preservative content,
antioxidant content, sterility (if applicable), and other tests that may be
product specific. Product performance testing assesses drug release and other
attributes that affect drug release from the finished dosage form.
This
chapter provides lists of consolidated common product quality test requirements
in a concise and coherent fashion. This chapter applies, in whole or in part,
when referenced in a drug product monograph (see General Notices, 3.10 Applicability of Standards)
and includes the quality tests for the specific route of administration. The
quality tests listed can be used as appropriate by manufacturers toward the
development of new drug product monographs for submission to USP–NF.
TDS release
their active ingredients by different mechanisms. They can be passive or
active. This chapter covers only the tests related to passive TDS.
PRODUCT QUALITY TESTS FOR
TOPICAL AND TRANSDERMAL DRUG PRODUCTS
Additional Procedure for Products Packaged in Containers
with a Non-Metered Pump
For some
tests (e.g., viscosity, assay, etc.), with the exception of the uniformity in
containers test, samples need to be collected from the pumped-out product. In
these instances, the samples should be collected as follows:
1. Remove cap from container.
2. Fully depress and release the
actuator, disposing of any material dispensed, and allowing the pump actuator
to return to the initial position after each actuation. Repeat the sequence, as
indicated in the patient instructions, until a full amount of material is
dispensed.
3. Collect the next material
dispensed as the sample. Generally, collect NMT the amount needed to perform a
single analysis (for the assay test, typically NMT 2 actuations).
Universal Tests
Universal
tests [see International Council for Harmonisation (ICH) guidance Q6A—Specifications:
Test Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances, available at www.ich.org]
are listed as follows and are applicable to all topically applied drug
products.
description
A
qualitative description of the drug product should be provided. The acceptance
criteria should include the final acceptable appearance of the finished dosage
form and packaging. A visual examination should identify changes in color,
adhesive migration (i.e., cold flow; see Cold Flow Test) for TDS,
separations, crystallization, and others that are specific to the drug product.
The description should specify the content or the label claim of the article.
For TDS, a visual examination should also be done to assess potential use
issues with the product. The examination should include an assessment of the
difficulty of removing the TDS from the pouch (e.g., due to adhesive migration adhering
the system to the pouch); inability to remove the TDS from the pouch without
damage to the system; and adhesive residue remaining on the pouch after removal
of the TDS. This is not a compendial test but is part of the manufacturer’s
specification for the drug product.
identification
Identification
tests are discussed in General Notices, 5.40 Identification.
Identification tests should establish the identity of the drug or drugs present
in the article and should discriminate between compounds of closely related
structures that are likely to be present. Identification tests should be
specific for the drug substance(s) (e.g., infrared spectroscopy). Near-infrared
(NIR) or Raman spectrophotometric methods also could be acceptable for the
identification of the drug product (for additional information, see Near-Infrared Spectroscopy—Theory and Practice 〈1856〉 and ▲Raman Spectroscopy—Theory and Practice 〈1858〉▲ (CN 1-Aug-2020)). Identification
solely by a single chromatographic retention time is not specific.
assay
A specific
and stability-indicating test should be used to determine the strength
(content) of the drug product. This assay requirement can be satisfied for
topical products containing antibiotics by a standard microbiological method
(see Antibiotics—Microbial Assays 〈81〉). In cases when
the use of a nonspecific assay (e.g., Titrimetry 〈541〉) is justified, other supporting
analytical procedures should be used to achieve overall specificity.
impurities
Process
impurities, synthetic byproducts, impurities associated with the adhesive
(e.g., residual monomers), residual solvents (see Residual Solvents 〈467〉), and other
inorganic and organic impurities may be present in the drug substance and in
the excipients used in the manufacture of the drug product and should be
assessed and controlled. Impurities arising from the degradation of the drug
substance and those arising during the manufacturing process of the drug
product also should be assessed and controlled.
Specific Tests
In addition
to the Universal Tests listed previously, the following Specific
Tests should be considered on a case-by-case basis.
uniformity of dosage units
This test
is applicable for TDS and for topical dosage forms intended for systemic
delivery, or where tight control of the dose is necessary to limit local
irritation or undesired systemic exposure, packaged in single-unit containers,
such as packets (see Uniformity of Dosage Units 〈905〉).
The uniformity of dosage units specification is not intended to apply to
solutions, suspensions, emulsions, ointments, or gels in single-unit containers
intended for local action following external, cutaneous administration.
water content
A test for
water content should be included when appropriate (see Water Determination 〈921〉). This test is
generally formulation dependent. Therefore, it is not included in the
compendial drug product monograph but is part of the manufacturer’s
specification for the drug product.
microbial limits
Microbial
examination of nonsterile drug products is performed according to the methods
given in Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉,
unless the formulation itself is demonstrated to have antimicrobial properties.
Acceptance criteria for nonsterile pharmaceutical products based on total
aerobic microbial count and total combined yeasts and molds count are given
in Microbiological Examination of Nonsterile Products:
Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical
Use 〈1111〉.
antimicrobial preservative content
Acceptance
criteria for antimicrobial preservative content in multi-unit products should
be established. They should be based on the levels of antimicrobial
preservative necessary to maintain the product’s microbiological quality at all
stages throughout its proposed usage and shelf life (see Antimicrobial Effectiveness Testing 〈51〉).
antioxidant content
If
antioxidants are present in the drug product, tests of their content should be
established unless oxidative degradation can be detected by another test method
such as impurity testing. Acceptance criteria for antioxidant content should be
established. They should be based on the levels of antioxidant necessary to
maintain the product’s stability at all stages throughout the product’s
proposed usage and shelf life.
sterility
Depending
on the use of the dosage form (e.g., products that will be applied to open
wounds or burned areas), sterility of the product should be demonstrated as
appropriate (see Sterility Tests 〈71〉).
pH
When
applicable, topically applied drug products should be tested for pH. Because
some topically applied drug products contain very limited quantities of water
or aqueous phase, pH measurements may not always be warranted. This test is
generally formulation dependent. Therefore, it is not included in the
compendial drug product monograph but is part of the manufacturer’s
specification for the drug product.
particle size
When the
finished product contains a suspended solid drug substance, the product should be
examined for particle size. The particle size of the active drug substance(s)
in topically applied drug products is usually established and controlled at the
formulation development stage. However, topically applied drug products should
be examined for evidence of particle alteration (i.e., drug polymorphic form,
appearance of particles, size, shape, morphology, agglomeration, or
aggregation) of the drug substance that may occur during the course of product
processing and storage. These types of tests are generally formulation
dependent. Therefore, such tests are not included in compendial drug product
monographs but are part of the manufacturer’s specification for the drug
product.
crystal formation
When the
drug substance is dissolved in the finished product, the product should be
microscopically examined for evidence of crystal formation of the active drug
substance. This test is generally formulation dependent. Therefore, it is not
included in the compendial drug product monograph but is part of the manufacturer’s
specification for the drug product. It is recommended that the potential for
the drug product to form crystals of drug substance be examined during product
development.
IN VITRO DRUG RELEASE TEST
For TDS,
the in vitro drug release test is required as a batch-to-batch quality control.
See Drug Release 〈724〉 for apparatus and test conditions.
The development and validation report of the in vitro drug release test needs
to include sufficient detail and data to facilitate the assessment of whether
the method is adequate as a quality control test for batch release and
stability testing.
For
semisolid dosage forms, in vitro drug release testing is currently not required
for batch release. See Semisolid Drug Products—Performance Tests 〈1724〉 for
apparatus, test conditions, and test applicability.
SPECIFIC TESTS FOR OPHTHALMIC
DRUG PRODUCTS
See Ophthalmic Products—Quality Tests 〈771〉.
SPECIFIC TESTS FOR TOPICAL
AEROSOLS
SPECIFIC TESTS FOR TOPICALLY
APPLIED SEMISOLID DRUG PRODUCTS
Minimum Fill
Single- and
multiple-unit containers must meet minimum fill requirements as established by
testing described in Minimum Fill 〈755〉. For single-unit containers where the
test for 〈905〉 is
applied, the test for 〈755〉 is
not required.
Apparent Viscosity
Viscosity
is a measure of a formulation’s resistance to flow and is an assessment of a
rheological property of a semisolid dosage form. The term “apparent viscosity”
applies to non-Newtonian fluids, which comprise the majority of semisolid
pharmaceutical dosage forms.
Measurement
procedures should be developed as outlined in Viscosity—Capillary Methods 〈911〉, Viscosity—Rotational Methods 〈912〉, and Viscosity—Rolling Ball Method 〈913〉. For semisolids
that show thixotropy and/or irreversible changes in viscosity after shearing,
specific attention should be given to sample preparation procedures to minimize
variability in the measurement of apparent viscosity caused by variable shear
histories (e.g., mixing speed and temperature, filling operation, and sample
handling). Furthermore, for some products it may be warranted to have apparent
viscosity specifications at more than one stage of the manufacturing process or
with more than one set of test conditions (e.g., bulk in-process stage, final
packaged product, high and low shear rates, and different temperatures).
Apart from
single-point viscosity measurements, more advanced rheological techniques
(flow, oscillatory, creep, and stress relaxation testing) can be applied to
develop a mechanistic understanding of a formulation and its structure. These
techniques may be useful for product development using the principles of
quality by design or for comparative physicochemical characterization of the
test and reference formulations in the case of a biowaiver argument in a
generic drug application. However, these techniques are not generally suitable
for routine quality testing. Common parameters derived from rheological testing
of semisolid pharmaceutical dosage forms that may be useful for
characterization and comparison are the storage modulus, loss modulus,
relaxation modulus, compliance, thixotropic index, and yield stress.
Acceptance
criteria are product specific and defined to ensure that the apparent viscosity
of each batch of semisolid drug product is within the range defined by the
product design and is consistent between batches based on the product
development specifications and statistical assessment of multiple product
batches over the product’s shelf life.
Uniformity in Containers
Topically
applied semisolid drug products may show physical separation during
manufacturing processes and during their shelf life. To ensure the integrity of
the drug product, it is essential to evaluate the uniformity of the finished
product. This test applies only to multiple-unit containers, such as tubes and
jars. This test does not apply to more fluid topical drug products in
multiple-unit containers, such as emulsions, lotions, two-phase gels, or
topical suspensions, in which the labeling directs the user to mix the product
(e.g., shake well) before use.
products packaged in tubes
Visual uniformity:
Carefully remove or cut off
the bottom tube seal and make a vertical cut from the bottom to the top of the
tube. Carefully cut the tube around the upper rim, open the two flaps, and lay
the flaps open to expose the product.
Inspect the
product visually for the presence of phase separation, change in physical
appearance and texture (e.g., color change, crystallization, lumping), and
other properties described in the product specification for Description.
If there is no significant phase separation or change in physical appearance
and texture, and if the product meets the Description criteria,
the product passes the test. If the product exhibits significant phase
separation or change in physical appearance or texture, the product fails the
test.
Uniformity of active
ingredient(s):
The following procedures can
be modified depending on the sensitivity of the quantitative procedure used to
determine the amount of the drug substance(s) present in the formulation.
For multiple-unit tubes that
contain 5 g or more of product
stage 1:
1. Using a single tube, after
performing the test for Visual uniformity, remove an appropriate
amount of the product from the top (i.e., cap end), middle, and bottom (i.e.,
seal end) portions of the tube. The sample size should be sufficient for at
least one quantitative determination of the active ingredient(s) and should not
exceed the maximum dose recommended by the product labeling for a single
application.
2. Determine the amount of the
active ingredient(s) in each portion of the product using any appropriate
validated quantitative procedure, and evaluate the test results from the single
tube using the Stage 1 acceptance criteria outlined in
number 3.
3. Stage 1 acceptance criteria are
met if:
·
None of the
three results are outside of the product assay range, and
·
The maximum
difference in the amount of active ingredient(s) determined within the tube is
NMT 10.0%. For example, if the three measurements within the tube are 97.0%,
95.2%, and 99.7%, the maximum difference would be 4.5% (i.e., 99.7% − 95.2% =
4.5%).
4. Proceed to Stage 2 testing
if Stage 1 acceptance criteria are not met and none of the
test results are outside the product assay range by more than 5.0% (e.g., if
the product assay range is 90.0%−120%, the range will be 85.0%−125.0%), and the
maximum difference in the amount of active ingredient(s) measured within the
tube is NMT 10.0%. An example of a product that fails to meet Stage 1 criteria:
if the highest and lowest assay values were 106.0% and 94.7% of label claim,
then the difference would be 106.0% − 94.7% = 11.3%.
5. Proceed to Stage 3 testing
if Stage 1 acceptance criteria are not met, Stage 2 acceptance
criteria cannot be met, NMT one of the three test results is outside of the
product assay range by more than ±5.0%, and the maximum difference of the
amount of active ingredient(s) measured within the tube is NMT 15.0%.
stage 2:
1. Test an additional 2 tubes
for Visual uniformity and Uniformity of active
ingredient(s) for a total of 3 samples each from 3 tubes.
2. Determine the amount of the
active ingredient(s) in each portion of the product using any appropriate
validated quantitative procedure, and evaluate the test results from the 3
tubes using the Stage 2 acceptance criteria.
3. Stage 2 acceptance criteria are
met if:
·
The Visual
uniformity test is met for all tubes;
·
None of the
9 results (i.e., 3 each from 3 tubes) are outside of the product assay range by
NMT 5.0%; and
·
The maximum
difference of the amount of active ingredient(s) measured within each tube, for
each of the samples tested, is NMT 10.0%.
4. Proceed to Stage 3 testing
if NMT one of the 9 test results is outside of the product assay range by ±5.0%
and the maximum difference of the amount of active ingredient(s) measured
within each tube is NMT 15.0%.
stage 3:
1. If Stage 2 has
been completed, test an additional 7 tubes for Visual uniformity and Uniformity
of active ingredient(s) for a total of 3 samples each from 10 tubes.
If Stage 2 was skipped, test an additional 9 tubes for Visual
uniformity and Uniformity of active ingredient(s) for
a total of 3 samples each from 10 tubes.
2. Determine the amount of active
ingredient(s) in each portion of the product using any appropriate validated
quantitative procedure, and evaluate the test results from the 10 tubes using the Stage
3 acceptance criteria as outlined in number 3.
3. Stage 3 acceptance criteria are
met if:
·
The Visual
uniformity test is met for all tubes;
·
NMT 1 of
the 30 test results is outside of the product assay range by ±5.0%; and
·
The maximum
difference of the amount of active ingredient(s) measured within each tube, for
each of the 10 tubes tested, is NMT 15.0%.
For multiple-unit tubes that
contain less than 5 g of product
stage 1:
1. Using a single tube, after
performing the test for Visual uniformity, remove an appropriate
amount of product from the top (i.e., cap end) and bottom (i.e., seal end)
portions of the tube. The sample size should be sufficient for at least one
quantitative determination of the active ingredient(s) and should not exceed
the maximum dose recommended by the product labeling for a single application.
2. Determine the amount of the
active ingredient(s) in each portion of the product using any appropriate
validated quantitative procedure, and evaluate the test results from the tube
using the Stage 1 acceptance criteria outlined in number 3.
3. Stage 1 acceptance criteria are
met if:
·
Neither
result is outside of the product assay range; and
·
The
difference between the amount of active ingredient(s) determined for the 2
samples within the tube tested is NMT 10.0%. For example, if the two
measurements within a tube were 95.2% and 89.7%, the difference would be 5.5%.
4. Proceed to Stage 2 testing
if Stage 1 acceptance criteria are not met and neither of the
test results are outside the product assay range by more than ±5.0% (e.g., if
the product assay range is 90.0%−120.0%, the range will be 85.0%−125.0%), and
the difference between the amounts of active ingredient(s) measured within the
tube is NMT 10.0%.
5. Proceed to Stage 3 testing
if Stage 1 acceptance criteria are not met, Stage 2 acceptance
criteria cannot be met, NMT one of the test results is outside of the product
assay range by more than ±5.0%, and the difference between the amounts of
active ingredient(s) measured within the tube is NMT 15.0%.
stage 2:
1. Test an additional 2 tubes
for Visual uniformity and Uniformity of active
ingredient(s) for a total of 2 samples each from 3 tubes.
2. Determine the amount of the
active ingredient(s) in each portion of the product using any appropriate
validated quantitative procedure, and evaluate the test results from the 3
tubes using the Stage 2 acceptance criteria as outlined in
number 3.
3. Stage 2 acceptance criteria are
met if:
·
The Visual
uniformity test is met for all tubes;
·
None of the
6 test results (i.e., 2 each from 3 tubes) are outside of the product assay
range by ±5.0%; and
·
The
difference between the amount of active ingredient(s) determined for the 2
samples within each tube, for each of the 3 tubes tested is NMT 10.0%.
4. Proceed to Stage 3 testing
if NMT one of the 6 test results is outside of the product assay range by
±5.0%, and the difference between the amounts of active ingredient(s) measured
within each tube is NMT 15.0%.
stage 3:
1. If Stage 2 has
been completed, test an additional 7 tubes for Visual uniformity and Uniformity
of active ingredient(s) for a total of 2 samples each from 10 tubes.
If Stage 2 was skipped, test an additional 9 tubes for Visual
uniformity and Uniformity of active ingredient(s) for
a total of 2 samples each from 10 tubes.
2. Determine the amount of active
ingredient(s) in each portion of the product using any appropriate validated
quantitative procedure, and evaluate the test results from the 10 tubes using
the Stage 3 acceptance criteria as outlined in number 3.
3. Stage 3 acceptance criteria are
met if:
·
The Visual
uniformity test is met for all tubes;
·
19 of 20
test results are within ±5.0% of the product assay range; and
·
The
difference between the amount of active ingredient(s) determined for the 2
samples within each tube, for each of the 10 tubes tested, is NMT 15.0%.
products packaged in containers other than tubes
For
semisolid products packaged in a container other than a tube when the sampling
method presented previously cannot be used, other sampling methods are
acceptable, such as this method described for a jar:
1. Select a suitable syringe of
sufficient length to extend to the bottom of the container.
2. Remove and set aside the
syringe plunger, and cut off the bottom of the syringe barrel. Sampling should
take place from a location to the left or right of the mid-line of the jar
surface to preserve an undisturbed region on the other side for any additional
investigation (see Figure 1).
Figure 1. Sampling from a jar
container.
3. Slowly push the syringe barrel
into the container until it reaches the bottom. Then twist the syringe barrel
containing the sample core, and remove the syringe from the container.
4. Insert the syringe plunger
into the barrel, and carefully extrude the sample core onto a clean surface in
three equal portions to represent the top, middle, and bottom portions of the
container.
5. Remove an appropriate sample
representative of the top, middle, and bottom portions of the container
samples, and test according to the instructions outlined in Products
Packaged in Tubes.
Delivered-Dose Uniformity in Metered Dose Containers
The test
for delivered-dose uniformity is required for drug products contained either in
metered-dose containers or in premetered unit presentations. The test for
delivered-dose uniformity includes dose uniformity over the entire unit shelf
life. Select 1 container. Using separate collection vessels, quantitatively
collect delivered doses representing the initial, middle, and the final dose
from the container. Appropriately discard doses not collected for testing.
Determine the drug substance content of each of the 3 collected samples using
an appropriate and validated quantitative procedure or the procedure indicated
in the individual monograph. A dose in this test is defined as the minimum
recommended number of actuations specified in the product labeling or in the
instructions for use but NMT 2 actuations. The target-delivered dose is
specified by the product label claim, unless otherwise specified in the
individual monograph.
In-Process Testing
pump functionality test for metered and non-metered
dose container closures
This test
is conducted during product development to establish that the airless pumps are
performing as intended. This test is product dependent. Therefore, it is part
of the manufacturer’s controls for the drug product and it is not included in
compendial drug product monographs.
During the
filling process for semisolid or liquid products packaged in a non-metered dose
container closure requiring an actuator to dispense the product (for example,
an airless pump container), in-process testing to verify pump functionality
should be examined. Example tests include pumps to prime and total amount
dispensed.
SPECIFIC TESTS FOR TDS
TDS are
formulated with an adhesive layer to ensure intimate contact with the skin and
allow the delivery of the desired dose of the drug. Adhesives in TDS must
permit easy removal of the release liner before use, adhere properly to human
skin upon application, maintain adhesion to the skin during the prescribed
period of use, and permit easy removal of the TDS at the end of use without
leaving a residue or causing damage to the skin or other undesirable effect(s).
Additionally, adhesives must be able to maintain the performance of the TDS
throughout the shelf life of the drug product.
Testing of
the physical properties of the TDS generally include peel adhesion, release
liner peel, tack, cold flow, shear, and crystal formation (see Crystal
Formation). The peel adhesion, release liner peel, and tack tests measure
the adhesion properties of the TDS. Each of these tests measures the force
required to separate the TDS from another surface. The cold flow and shear
tests measure the cohesive properties of the TDS. These latter tests measure
the resistance to flow of the adhesive matrix.
Acceptance
criteria are product specific and defined to ensure that adhesion of each batch
of TDS is within the range defined by the product design and is consistent
between batches based on the product development specifications and statistical
assessment of multiple product batches over the product’s shelf life.
In addition
to physical testing, this section also discusses the Leak Test applicable
to form-fill-seal-type (reservoir or pouched) TDS.
Peel Adhesion Test
This test
measures the force required to remove (peel away) a TDS attached to a standard
substrate surface (e.g., polished stainless steel). The TDS is applied to the
substrate using specified techniques for application and is conditioned at a
specified temperature and time. Then the TDS is peeled away from the substrate
with an instrument that allows for control of the peel angle (e.g., 90° or
180°) and peel rate (e.g., 300 mm/min), and the force profile is recorded. This
procedure is repeated using a minimum of 5 independent samples yielding results
from a suitable method (see Development of Peel Adhesion and Static
Shear Test Methods). The in vitro adhesive properties of the drug product
should thus be characterized with the specifications limits for the specified
tests in accordance with the results obtained on clinical batches for which
satisfactory in vivo adhesive properties under product use have been
demonstrated and used to support their justification of the drug product
specification. Release and shelf life limits should be the same, unless
justified by reference to clinical batches.
The
geometry of a TDS (e.g., round or rectangular shaped) and its design (e.g., TDS
with different surfaces such as an inner part and with a peripheral adhesive
ring) should be considered in the method.
The
substrate surface should be cleaned regularly and checked for scratches, as
this may influence test results.
Development of Peel Adhesion and Static Shear Test
Methods
During
method development, suitable methods (including test panel surface) need to be
identified. For peel adhesion testing, the method should allow the TDS to be
removed entirely and cleanly, leaving no visually noticeable matrix residue on
the substrate surface (i.e., cohesive failure).
In
contrast, for static shear testing, cohesive failure (i.e., adhesive is left on
the TDS and on the substrate plate) should occur.
Suitable
peel adhesion and static shear test methods do not result in undesired adhesive
failures. Undesired adhesive failure occurs when the TDS delaminates at an
interface (e.g., between a membrane and an adhesive layer, or between two
different adhesive layers of a bilayer product). During peel adhesion testing,
transfer of adhesive to the test panel (i.e., cohesive failure) is an
additional undesired adhesive failure mode.
Release Liner Peel Test
This test
measures the force required to separate the release liner from the adhesive
layer of the TDS. The test is performed with a finished product sample. The
test sample is conditioned using specific procedures (temperature and time).
Then, the release liner is pulled away from the TDS with an instrument that
allows for control of the peel angle (e.g., 90° or 180°) and peel rate (300
mm/min), and the force profile is recorded. This procedure is repeated using a
minimum of 5 independent samples. The product fails the test if the mean peel
force is outside the acceptable range determined during product development and
based on statistical assessment of multiple product batches over the product’s
shelf life.
Tack Test
A few tack
test methods have been developed and the current predominantly used method is
the Probe Tack Method. It is up to the TDS manufacturer to decide
which tack test is most appropriate for each drug product.
probe tack method
This test
measures the force required to separate the tip of the test probe from the
adhesive layer of the TDS. This test uses an instrument designed to create a
bond between the tip of the stainless steel test probe (of defined geometry)
and the TDS using a controlled force (light pressure) and specified test
conditions (i.e., rate, contact time, contact pressure, and temperature). Then
while controlling the rate of probe removal, the test measures the force
required to separate the probe tip from the TDS and the maximum force required
to break the bond (tack). This procedure is repeated using a minimum of 5
individual samples. The product fails the test if the mean test result is
outside the acceptable range determined during product development and based on
statistical assessment of multiple product batches over the product’s shelf
life.
The probe
head surface should be cleaned regularly and checked for scratches, as this may
influence the test results.
Cold Flow Test
Cold flow
is the migration of the adhesive matrix beyond the edge of the TDS backing, and
through the slit in the release liner, which may occur during the course of
product processing and storage. Cold flow is an inherent property of TDS due to
the use of pressure-sensitive adhesives that flow when force is applied (i.e.,
if the adhesive matrix did not flow, the TDS would not stick). The magnitude of
the cold flow is generally dependent on the product formulation, packaging
design, storage conditions, and storage time. Cold flow should be assessed
using a combination of quantitative and qualitative methods. No single
quantitative method has been identified to work universally for all TDS. The
TDS manufacturer should determine the most suitable cold flow test, or tests,
as cold flow may manifest differently for different products. Several different
cold flow tests have been developed. Examples include:
· Linear measurement of the
radial cold flow using microscopy
· Measuring the distance of
migrated adhesive matrix at predefined and evenly spaced positions of a TDS
· Measuring cold flow by
applying a reference plate in the size of the TDS plus the acceptable cold flow
· Swabbing and stripping the
migrated part of the matrix and determining it gravimetrically or by assay of
the drug substance
· Die cutting and punching out
the original size of the TDS and determining the amount of migrated matrix on
the outside
· Overall area determining
methods of cold flow using image analysis tools
Acceptance
criteria are product specific and defined to ensure that the cold flow of each
batch of TDS is within the range defined by the product design and is
consistent between batches based on the product development specifications and
statistical assessment of multiple batches over the product’s shelf life.
Shear Test
The shear
test measures the cohesive strength of a TDS. It can be measured under static
(see Static Shear Test) or dynamic conditions. Shear testing may
not be feasible for all TDS because the presence of multiple layers of adhesive
in the system, the presence of a membrane or scrim, or the use of an emulsion
adhesive system may result in the inability to achieve cohesive failure. TDS
that are constructed with a peripheral adhesive ring or form-fill-seal TDS may
not be suitable for this test. The TDS manufacturer should decide if a shear
test is appropriate, and if so, which shear test is most appropriate for each
drug product. Acceptance criteria are product specific and defined to ensure
that the shear of each batch of TDS is within the range defined by the product
design and is consistent between batches based on the product development
specifications and statistical assessment of multiple product batches over the
product’s shelf life.
Static Shear Test
For the
static shear test, the time required to remove a standard area of the TDS from
the substrate (i.e., stainless steel test panel) under a standard load (e.g.,
250 g) is measured. The TDS is applied to a test panel, and the sample is
subjected to a shearing force by means of a given weight suspended from the
TDS. The test apparatus holds the test panels at 0°− 2° from vertical to ensure
that the TDS will not experience peeling action when the weight is attached.
Dwell time, weight used, test panel type, mode of failure, and sample size
should be noted; the time taken for the TDS sample to detach from the test
panel is reported. This procedure is repeated using a minimum of 5 independent
samples yielding results from a suitable method (see Development of
Peel Adhesion and Static Shear Test Methods). The product fails the test if
the mean shear force (i.e., arithmetic mean or geometric mean as determined by
the manufacturer) is outside the acceptable range determined during product
development and based on statistical assessment of multiple product batches
over the product’s shelf life.
Leak Test
This test
is applicable only for form-fill-seal-type (reservoir or pouched) TDS.
Form-fill-seal TDS must be manufactured with zero tolerance for leaks because
of their potential for dose dumping if leaking occurs.
In-process
control methods to examine TDS for leaks or potential leaks are needed and
require considerable development on the part of TDS manufacturers.
in-process testing
During the
manufacturing process, the presence of leakage (or potential for leakage) due
to TDS perforation, cuts, and faulty seals resulting from failures such as air
bubbles, gel splash, or misalignment of a TDS backing and release liner layers
must be examined. Unless automated process analytical technology is
implemented, in-process testing to identify these defects should be performed
using the following test procedures.
Visual inspection:
·
A specified
number of TDS, defined on the basis of batch size, should be examined randomly
·
Each
sampled TDS should be thoroughly visually inspected for leakage
·
The product
fails if any of the TDS examined are detected with a leak
Seal integrity:
TDS seals should be stress
tested to ensure that the application of pressure does not force seals to open,
thereby leading to leakage.
·
A specified
number of TDS, defined on the basis of batch size, should be randomly examined.
·
Each
sampled TDS should be thoroughly visually inspected for leakage.
·
Each
sampled TDS is placed on a hard, flat surface and overlaid with a weight so
that it is subjected to 13.6 kg. The weight should be left in place for 2 min.
Upon removal of the weight, the TDS should be visually inspected for leakage.
·
The product
fails if the number of TDS detected with a leak is greater than the acceptable
limit established by the manufacturer.
Packaged product testing:
TDS may leak after they have
been individually placed in the primary packaging material as a result of the
packaging operation itself or by a user opening the packaging. Therefore, TDS
should be tested for leakage after they have been manufactured and packaged in
their primary packaging material.
·
A specified
number of TDS, defined on the basis of batch size, should be randomly examined
after they have been placed in their primary packaging material.
·
The sampled
TDS should be removed from their packaging and thoroughly visually inspected
for leakage.
·
Each
sampled TDS should then be uniformly wiped with a solvent-moistened swab. Both
the backing side and the release liner side of the TDS should be wiped. The
inside surface of the pouch should also be wiped. The swab(s) is then extracted
and assayed for the drug.
·
The product
fails if the total amount of drug from the TDS, and the corresponding pouch,
exceed the acceptable limit established by the manufacturer.
No comments:
Post a Comment