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Comments
on Mechanical & Chemical Calibration by an Instrument Manufacturer
By Royal Hanson, 3/21/07
To be reprinted in Dissolution
Technologies, May 2007
"My dissolution tester failed the USP calibrator tablet test.
What do I do?”
This is a dreaded
phone call that every instrument manufacturer has received at one time
or another, perhaps more than some care to admit.
Indeed, what do you do?
First of all, you
approach it with a rigorous, systematic procedure reviewing all
critical steps in test set-up and test run.
This includes a thorough review of “mechanical
calibration”, including paddle/basket/vessel alignment, centering,
speed and temperature, vibration, etc.
You evaluate the requirement for deaeration, as well as
cleanliness and appropriateness of glassware, flow cells and
accessories. You also
review what might be called the “human factor”.
This includes the proper execution of procedures and protocols,
preparation of standards, manual sampling technique, filtration, and
method of analysis. You
strive to isolate variables, and by so doing you ultimately identify
the problem(s). You then
establish corrective action as required.
Hanson Research
manufactures 200-250 dissolution testers each year.
As our equipment is designed for longevity, we have a working
installed base that well exceeds 3,000 units worldwide.
Some in our industry (for example, the recent ASTM Proposal
E55.03), have proposed the elimination of calibrator tablets (i.e.
“reference standard tablets”) in favor of a more comprehensive
mechanical calibration procedure.
You may think that elimination of calibrator tablets (and hence
elimination of those dreaded phone calls), would make our job easier.
However, I strongly support the use of calibrator tablets,
which essentially constitutes “chemical calibration” of the
instrument.
As an instrument
designer and manufacturer, I require an industry “standard” to
prove the efficacy and performance of the instrument for its intended
use. Mechanical
calibration is a critical component therein, as it qualifies and
proves the mechanical specifications of the instrument design and its
manufacture. But I also
want a “performance” standard, one that qualifies the instrument in
use. For dissolution
testing, this requires chemical calibration with calibrator tablets.
To wit: If we designed and manufactured aircraft, I would
certainly demand rigorous mechanical calibration of design
specifications and operation. But
I would want more. I would
also require performance qualification.
I would want to put that plane up in the air in a performance
test to ensure it safely took off, flew and landed as intended, before
I ever allowed passengers to get on board.
We call this “PQ”.
This leads to a
discussion of “IQ/OQ/PQ” (Installation, Operational and
Performance Qualification). IQ
and OQ (often combined during execution) are essential to prove
mechanical calibration, and should be mandatory in every lab, for each
instrument used.
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Within this context,
the current ASTM E55.03 proposal attempts to establish a comprehensive
IQ/OQ procedure and check list for mechanical specifications and
tolerances. This offers
inherent value as it strives for a better understanding and definition
of the critical aspects of mechanical calibration (although the
current proposal, in my judgment, needs refinement and collaboration
before it may fulfill its potential as a useful and practical tool in
the dissolution lab.)
However, PQ
(performance qualification), in addition to IQ/OQ, must also be
evaluated. PQ will test
the instrument in use.
It confirms not only mechanical calibration, but actual
performance in the real world (in this case, the working dissolution
laboratory). PQ will
monitor performance variables that mechanical calibration alone
cannot. Every lab must
institute training requirements for dissolution test methods and
protocols. PQ can catch
any lapses in training or execution; mechanical calibration cannot.
PQ (chemical calibration) is therefore vital to ensure and
maintain quality control.
Every instrument
manufacturer, and perhaps every expert in this industry, has seen
examples of calibrator tablet failures where the instrument was fine
but a human mistake caused a failure.
In one sense, this means calibrator tablets have done their
job. Calibrator tablets
have shown to be discriminating beyond mechanical problems, and may
also catch performance errors in test method or protocol.
One reason for this
debate is that USP calibrator tablets have not been perfect.
Some are therefore considering in-house calibrator tablets as
an alternative. My primary
concern here is that USP calibrator tablets, as an industry-wide
standard, have provided an extensive knowledge and data base.
This is scientifically valuable when conducting collaborative
dissolution test studies and comparing results.
A common, industry-wide standard (USP) provides
“apples-to-apples” comparisons.
A vast array of uncontrolled in-house calibrator tablets would
provide “apples-to-oranges” comparisons, and may tend to constrain
and limit relevant scientific inquiries.
Of our 3,000-plus
dissolution testers mentioned above, a significant inventory is based
in developing nations. In
many such cases, dedicated and ethical scientists are working to
establish viable quality control specifications for medicines, often
in an environment rife with substandard and counterfeit drugs.
Dissolution testing provides a relatively low cost tool for
pharmaceutical quality control. In
the absence of extensive and costly product testing, dissolution
testing may be the only bastion of defense in providing safe medicines
to local populations. Quality
verification of this fundamental, basic test must not be reduced or
marginalized. A full IQ/OQ/PQ
regimen is paramount for ensuring ongoing drug quality control.
***
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