- Roles
of Dissolution Testing:
Regulatory, Industry and Academic Perspectives
- -Role of Dissolution
Testing in Pharmaceutical Industry
Martin Siewert
Hoechst Marion
Roussel, AG, Frankfurt, Germany
-
- Dissolution testing in pharmaceutical
industry is a very important tool in drug development and in
quality control. While traditionally developed for solid oral
dosage forms, in the last years, the use of dissolution testing
has been widened to a variety of dosage forms, such as semi-solid
or parenteral (e.g. implant) preparations.
- Scientifically, a lot of progress
has been made through more than three decades. Also, from the
perspective of (pharmacopoeial) standardization, international
harmonization of regulations, and thus consistent concepts and
test methods being applied around the world, we have reached
a high level.
- Does that mean that we have no
more questions, no more issues to be addressed? No, definitely
not!
The burning questions and issues are not necessarily new - it
is a set of aspects coming up again and again whenever experts
meet and discuss in vitro dissolution:
· Is there a value or need for calibrator tablets?
- · Is there a scientific
justification for further standardization of dissolution media?
- · Is there a scientific
rationale for standardization of dissolution specifications (e.g.
75% in 15 min; 75% in 45 min), or do we need to treat each product
on a case-by-case basis?
- · How important is stage
3 testing (especially when being strict in post-marketing stability
studies)?
- · Are we really having a
good understanding of which criteria would allow us to use in
vitro dissolution as a surrogate for bioequivalence studies-
Where are we too strict? Where are we not conservative enough?
- · What level of in-vitro-in-vivo-correlation
requirement is justified for validation of test method and specification?
For which type of products?
- · Is the basic concept of
searching for the most discriminating in vitro method justified,
when at the same time we continue to: face difficulties when
applying low rotation speeds with apparatus 2 (and 1)? learn
that typically, differences in vitro are more pronounced than
those in bioavailability, when comparing similar products?
- · Is there value in dissolution
testing, when an in-vivo-in-vitro-comparison has proven a non-correlation
(for any test condition considered reasonable)?
- Which concepts for comparison of
in vitro dissolution profiles are truly scientifically sound
and still pragmatic-to-handle in terms of being easily applied
and meaningful?
- This list is not at all meant to
be complete. Interesting enough, we are collecting more and more
examples, many of them supporting established concepts, many
other data sets raising these questions again. Sometimes we tend
to question the basic concepts of dissolution testing (completely
abstract, conventional method which we still believe to reflect
gastro-intestinal processes?).
- What are we really looking for?
Maybe we need further scientific studies and investigations.
But definitely, we need pragmatic approaches to make sure that
we are staying on scientific ground, have sufficiently (adequately!)
standardized tests in place, and still allow for enough flexibility
to handle specific products or situations. Industry needs to
focus on speed in registration of new products and in implementing
post approval changes/variations. The objective is the safety
and efficacy of our products for the patient. As long as regulatory
requirements are illustrated in guidelines rather than bureaucratic
directives, we will manage to the benefit of the patient, scientifically
sound, and still economically feasible.
- The SUPAC approach(es) and the
FIP-Guideline are going into the right direction. Not necessarily
all other recent proposals are obviously consolidating all available
experience. Reoccurring same or similar questions may also be
an indicator that, in some areas, we could be turning in circles
rather than adding value.
- A discussion forum for all the
scientific, regulatory and practical application aspects is the
best way to keep the dialogue running and to allow us to continue
to make progress. DISSOLUTION TECHNOLOGIES is a very valuable
forum in this regard.
- Happy Anniversary!