Calibration
Another notable debate right now that will affect manufacturers, analysts, and regulatory agencies deals with the calibration
of dissolution equipment. An industry accepted recommendation is to calibrate the equipment every six months, and for many
years, the industry practice was to conduct both a simple mechanical test and a chemical test. The mechanical calibration
test evaluated parameters such as centering, temperature, and rotation speed. The chemical calibration test (i.e., now called
a performance verification test) used USP calibration tablets (now performance-verification standards).
However, recently there has been a push from industry, regulatory agencies, and other collaborative groups to eliminate the
chemical calibration portion of the testing. Some believe it is sufficient to forego the performance test and run a rigorous
mechanical check of the instrument. One of the suggested is the accepted standard ASTM E2503-07, "Standard Practice for Qualification
of Basket and Paddle Dissolution Apparatus). Mechanical calibration would involve system evaluation of various points through
the dissolution instrument with appropriate measurement tools and documenting all set-up parameters (e.g., centering of the
vessel, the straightness of the shaft of the paddle, and the proper depth position).
One reason in favor of only requiring mechanical calibration is that it is a routine that is faster than running performance
tests. Performance tests are run with a group of six samples (sometimes extra if the method calls for a control or blank).
Testing takes at least a couple of hours, says Hanson, and it may be expensive to devote a piece of equipment and an analyst
for a long period of time, instead of having the analyst do something more productive. Sometimes, if there is variation in
the test results, tests take an even longer period of time to complete.
FDA is not opposed to the idea. The agency has released a draft guidance related to the mechanical calibration of Apparatus
1 and 2, which says a firm can use an "appropriately rigorous method" of mechanical calibration (6). One example of a rigorous
method is CDER's "Mechanical Qualification of Dissolution Apparatus 1 and 2" procedure that is used by its Division of Pharmaceutical
Analysis (DPA, St. Louis, MO) to set up, calibrate, and maintain its dissolution units. DPA procedures suggest reviewing vessel,
paddle, and basket dimensions. In addition, the calibration portion of this document includes measurements of the following:
shaft wobble, paddle and basket shaft verticality, basket wobble, vessel centering and verticality, basket and paddle depth,
and rotational speed.
According to the FDA draft guidance, the use of USP calibration tablets can lead to variability in the dissolution measurement
system. Specifically, the document states, "The newer USP [prednisone] 10-mg tablet tends to give lower dissolution results
with the paddle method and higher results with the basket method over time." Moreover, other studies have been conducted on
the variabililty of USP prednisone reference standard tablets (7). The variability in the USP calibrator tablets led the agency
to develop the guidance for mechanical calibration.
In addition, according to Buhse, the draft guidance would "meet or exceed" the criteria for mechanical calibration proposed
in USP General Chapter ‹711›. "The dissolution test general chapter is part of the ICH Q4B (Evaluation and Recommendation
of Pharmacopoeial Texts for Use in the ICH Regions) work plan, but a final annex describing how this chapter can be used as
interchangeable in the ICH regions is still pending publication of final versions of the chapter by the pharmacopeia," says
Buhse.
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