William Brown and Margareth Marques
The following questions
have been submitted by readers of Dissolution Technologies. Margareth
Marques, Ph. D. and Will Brown, United States Phamacopeia, authored
responses to each of the questions.
*Note: These are opinions and interpretations of the authors,
and are not necessarily the official viewpoints of the USP
Email for correspondence:
web@usp.org
Q
What are the required number of samples
when evaluating dissolution of multi-dose and
single-dose units of oral suspensions?
A
The required number of individual dissolution results is
defined by the acceptance table. The current USP general
chapter <711> Dissolution does not specify the number of
containers of suspension, or powder or granulate for
suspension, that should be used as the source of the
samples for dissolution testing. The recommendation is to
transfer to the vessel an amount of product equivalent to
one dose or the amount specified in the particular
monograph. The product must be reconstituted as
directed on the label instructions. If the product has
several different doses (e.g., dosing according to age or
body weight), the test should be developed for the
highest dose.
Q
On what basis is the total volume of dissolution
medium for a particular product defined?
A
The volume of medium is usually determined so that sink
conditions are maintained. The solubility of the drug
substance in different media should be determined.
Based on this information, the volume of medium needed
to obtain a saturated solution, considering the highest
dose that will be marketed, should be defined. The
recommendation is to work with volumes at least three
times the one necessary to obtain a saturated solution.
In some cases, it may be appropriate to work with higher
volumes, such as 5 or even 10 times the saturation volume
based on other considerations. The definition of the
medium volume is determined case by case and should
be part of a discriminative procedure for a particular
product. Keep in mind that there are some instances
where the most discriminative condition may not conform
to sink conditions.
Q
How is the apparatus rotation speed selected for
a particular drug product?
A
Dissolution profiles should be obtained at different
rotation speeds, and the most discriminative condition
should be selected. Ideally, the dissolution results
will reflect in vivo performance. In most cases, the
recommended rotation speed is between 50 and 100 rpm.
Some products, like suspensions, may use rotation speeds
as low as 25 rpm. In general, rotation speeds less than
25 rpm or greater than 150 rpm are not recommended.
The selection of the rotation speed is done case by case.
Q
We are relocating several dissolution apparatus.
Some are going to be moved to a new position on
the same bench, others are going to be moved to
other benches in the same lab. Should we go
through the performance verification for all of
these test assemblies?
A
Every time a dissolution apparatus is moved or
serviced, a complete requalification of the equipment is
recommended. During the relocation of the equipment,
parts of it may be dislodged, unleveled, or even damaged.
Sources of vibration at the new location are another
critical point. If servicing is needed, parts of the equipment
may be replaced. In any case, it is necessary to verify
that the performance of the equipment is still within
acceptable limits. Recommendations on how to
qualify a dissolution apparatus are available at
http://www.usp.org/pdf/EN/dissolutionProcedureToolkit2007-10-04.pdf
Q
Are 2-L dissolution vessels widely accepted by
regulatory agencies around the world?
A
The USP general chapter <711> Dissolution was
harmonized for the U.S. Pharmacopeia (USP), the European
Pharmacopoeia, and the Japanese Pharmacopoeia, but
there are certain parts of the text, specially marked, that
were not harmonized. One example of this situation is
the volume of dissolution vessels. Only 1-L vessels are
harmonized among the three pharmacopeias. It does not
necessarily mean that 2-L and 4-L will not be accepted, but
good justification for using high volumes of dissolution
media should be part of the documentation submitted to
the regulatory agency in the region where the product
will be marketed. The most common use for a high volume
of dissolution medium is for poorly soluble drugs. There
are some USP monographs and products approved by
FDA that use volumes higher than 1 L (see
http://www.accessdata.fda.gov/scripts/cder/dissolution
).
Q
If both manual and automated procedures are
used for sampling in dissolution testing, both of
them should be evaluated in the performance
verification of the equipment. How is �automated
system" defined? Is an online HPLC UV detector part
of the system, or is it only the dissolution sampling
station?
A
A manual system is one in which the dosage units
are introduced by hand, the timing is by an external
chronometer, the test solution is taken up by hand using a
syringe or other similar device, and manipulations
required for spectrophotometric or chromatographic
analysis are done by hand. Some degree of automation is
inferred for systems where any of the above processes are
under immediate control of a microprocessor. The
Performance Verification Test (PVT) is a measure of the
suitability of a dissolution test assembly to produce
acceptably similar dissolution samples in comparison with
laboratories worldwide. All laboratories who participate in
the collaborative study conducted by USP to determine
the acceptance ranges for each lot of USP Reference
Standard tablets are expected to perform the testing
manually. Automated sampling brings additional variables
in sample preparation. Although manual and automated
sampling should produce similar results, USP does not
specifically certify that its ranges are suitable for automati-
cally sampled systems.
Q
According to the General Notices, numbers are
not rounded until the final calculation for the
reportable values. The acceptance tables in <711>
Dissolution have criteria for several levels such as
S1, S2 or L1, L2, L3. Dissolution values are obtained
from each unit tested. When calculating the aver-
age for L2 or L3, is the average calculated from the
rounded individual number results reported or
from the unrounded results?
A
Use section 7.20 of the General Notices as a guide on
rounding. For the limit expressions in <711> Dissolution, it
is apparent that several limits may be encountered when
working through the stages (or levels) given in
Acceptance Tables 1, 2, 3, or 4. At each stage of all of the
tables, individual unit values need to be compared with
limits that are given at a whole-number level of signifi-
cance. Therefore, the values are rounded to whole num-
bers for that comparison. Where an average of unit values
is needed, the original unrounded data are used to
compute the average and then rounded to the whole-
number level of significance of the limit.