Other groups also have stated their opinion, including the International Pharmaceutical Federation (FIP), which published
a white paper titled "FIP Position Paper on Qualification of Paddle and Basket Dissolution Appartus." "The phrase that caught
my attention," says Hanson, "says 'any strict requirement on the use of a specific performance verification test tablet is
not recommended at this time.'"
But decisions on the "correct" physical specifications for the equipment are still under discussion. Gray points to the vessels,
for example. "It is well known, within the past five years, that vessels can be malformed. They can be made improperly or
differently so that a different vessel can have hydrodynamic forces that affect the dissolution." One of the efforts USP has
been involved is to make the vessel dimensions more uniform by developing specifications of the dimensions. "This is a big
effort that would affect dissolution equipment providers, so you can't go fast with something like this," says Gray. FDA also
has a task force looking into the effects of vibration of the equipment, how it may introduce variability, and how it might
be corrected. "The demands are up for better methods and people are really paying attention to it," says Gray. "In this way
we will understand more about what is going on with dissolution tests and how we can improve it and understand it."
Despite all the work on defining mechanical specifications, the industry doesn't appear to be ready to eliminate chemical
calibration altogether. A dissolution testing group from PhRMA, developed an enhanced mechanical calibration and conducted
a collaborative study, says Gray. This study showed the performance verification test tablets still had some value because
there are some aspects about the equipment that can't be picked up accurately through a mechanical method. According to Gray,
a lot of studies have shown that current performance verification standards are very sensitive to the attributes of the equipment
that can't be picked up mechanically. "That doesn't mean that someday it won't all be picked up mechanically, but at the moment
we are not there yet."
Hanson agrees, "In reality, laboratories are mostly still using the performance verification tablets because they aren't confident
that the mechanical calibration will pick up any problems with their equipment. And the bottom line is the onus is on their
shoulders." Chemical calibration captures some of the what-ifs, he says, such as analyst error, spectrophotometers set up
incorrectly, dirty flow cells, and so forth. "However, as mechanical calibration improves, my sense is that industry is going
to move away from chemical calibrator tablets and move toward rigorous mechanical calibration."
An alternative option to the chemical calibration method that has been suggested is to give companies the choice to develop
and use an in-house standard for performance verification. Currently USP has provides prednisone tablets for chemical calibration.
The tables come with a certificate that indicates the range of results that should be obtained if a test is performed in a
certain way with these tablets. An in-house tablet to use in performance-verification studies that would replace the commercially
available performance tablets would have to have prove that it is as sensitive to problems with the equipment (e.g., vibration,
centering, vessel asymmetry). The in-house standard also would have a method developed around it, which is not easy to do.
"There may some Big Pharma companies that have done it, but I don't see it as an easy option for contract laboratories and
smaller companies," says Gray. "It would definitely be work to come up with an in-house standard and my question would be,
why devote those resources when you have a proven performance-verification standard already available?"
Dissolution equipment has changed significantly since the 1970s (see sidebar, "Evolution of dissolution equipment"). Equipment
vendors continue to incorporate automated systems in their dissolution instruments, especially in the collection and sampling,
which are controlled by user interface systems on the units. Sophisticated equipment configurations are connected to a computer
with dissolution software running the tests. "I think as time goes by you are going to see that more. You can archive all
of your methods, cross reference, and download into your instruments," says Hanson. "You'll never be able to cut out analysts,
but you will definitely be able to make their lives easier."
Those who engineer dissolution equipment are also working on extending drug-release analysis to other dosage forms such as
skin permeation products, ointments, creams, stents, patches, and implants, including those with microchips (8). But does
this really qualify as dissolution? "If you take the strict definition of dissolution in USP, maybe not," says Hanson. "But
if you consider the general definition of dissolution to be testing the release rate of a pharmaceutical dosage delivery vehicle,
then that maybe something we see on the horizon."
1. USP 28–NF 23, General Chapter ‹711› "Dissolution," 2412–2414.
2. C. Sinko, "Quality by Design and Dissolution," presented at the Advisory Committee for the Pharmaceutical Science, Oct.
25, 2005, available at http://188.8.131.52/search?q=cache:f_JEWzBgEaEJ:www.fda.gov/ohrms/dockets/AC/05/slides/2005-4187S1_05_Sinko.ppt+dissolution+qbd&cd=3&hl=en&ct=clnk&gl=us/, accessed Sep. 1, 2009.
3. E. Jantratid and J. Dressman, "Biorelevant Dissolution Media Simulating the Proximal Human Gastrointestinal Tract: An
Update," Dissol. Technol. 21–25 (Aug. 2009).
4. H. Jogia, T. Mehta, and M. Patel, "Evaluation of Dissolution Media Containing a Novel Synthetic Surfactant by In Vivo
Testing of BCS Class II Drugs," Dissol. Technol. 14-19 (Aug. 2009).
5. W. Qingxi, N. Fotakl, and Yun Mao, "Biorelevant Dissolution: Methodology and Application in Drug Development," Dissol. Technol. 27–30 (Aug. 2009).
6. FDA, Draft Guidance for Industry: The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2, Current Good Manufacturing
Practice (Rockville, MD), Oct. 2007.
7. W.W. Hauck et al. "Variability of USP Lot P Prednisone Reference Standard Tablets," Pharm. Technol.
32 (7) 24–33 (2008).
8. FIP workshop, "In Vitro Release of Special Dosage Forms," Oct.20-21, London, England, http://www.fip.org/www/index.php?page=ps_sig_invitro/, accessed Oct. 2, 2009.