483’s

• The dissolution testing machine was

observed to be sitting on a bench top
that was vibrating.
• The dissolution test apparatus could be
felt to be vibrating when a hand was
placed on the dissolution tank surface.
• The vibration was being caused by
two continuously operating bench top
stability chambers located on the same
lab bench.
• Calibration of the dissolution units are deficient in that:
• Only 2 of the 4 USP calibrator tests (for units utilizing
paddles and baskets) are performed to qualify a new
dissolution apparatus of an existing apparatus being returned
to service after a major repair. For example, apparatus… which
used both paddles and baskets, was repaired. This unit was
calibrated for baskets with prednisone tablets and for paddles
with prednisone tablets. Calibration with salicylic acid tablets
was not performed.  
• Calibration is not performed at a minimum every 6-months
using all 4 USP calibrator tests if the unit is used for paddles
and baskets and using 2 USP calibrator tests of the unit is
dedicated to paddles or baskets. Rather calibration is
performed using 1 USP calibrator test for non-dedicated units
or is performed every …using 1 USP calibrator test for
dedicated units.
• The amount of alcohol used to bring the predinisone
standard into solution is not recorded in the calibration data.
(No more than 5% of the total volume of the standard solution
may be used).
• Calibration does not include testing of the baskets on the
dissolution units for wobble; only the shaft wobble is tested.
• The serial number of the thermometer used in
calibration of the dissolution units is not recorded.
For example, the thermometer used during
calibration of dissolution units … was not recorded.
• A stopwatch is used to calibrate the rotation of
the dissolution apparatus. However, the time from
the stopwatch is not recorded in the raw data; only
the units’ RPMS are recorded. Also, the serial
number of the stopwatch used is not recorded.
• The actual temperature from the thermometer
used to calibrate the units is not recorded in the raw
data. According to management, the data recorded
is the temperature after an adjustment for the
thermometer’s correction factor.
• ….The procedure for calibration of the
laboratory dissolution units is
outdated and unclear as follows:
• The procedure does not describe
how to prepare the standard solution
used in calibration testing.
• The procedure does not specify how
to prepare the medium used in
testing, i.e. graduated cylinders.
• The procedure does not describe
how to check the centering.
• ….The filters used in dissolution testing
and in calibration of the dissolution units
have not been evaluated for the adsorption
of the active drug.
• ….The 1,000 ml plastic graduated cylinders
used in dissolution testing are not
calibrated.
• ….The dissolution paddles are rotating
while tablets are dropped in the medium
and this allowed by procedure… The USP
24 requires the tablet to sink to the bottom
of the vessel before rotation of the blade is
started.
….Quality Unit review of Analytical
Laboratory Investigation Reports
(ALIRs) failed to confirm the accuracy
and completeness of the finished
reports in that additional information
had to be added and clarified in the
ALIRs during the inspection. For
example, for …capsule questionable
dissolution results, bracketing
standard failures and equipment
malfunctions required a clarification
memo.
• ….The firm failed to adequately follow
SOP…”Dissolution Apparatus Calibration and
Testing” in that the composition and concentration
of the standard solution should be a close
approximation of that of the sample solution. A
review of the firm’s dissolution raw data laboratory
books, revealed that the concentrations of the
standard and sample solutions used for the analysis
were not the same. The standard solutions
absorbencies used by the firm are about four times
the absorbency of the sample solutions.
49. ….The firm’s conclusion in investigation
deviation states that “it was suspected that
the analyst did not properly deaerate the
dissolution medium” and that resulted in
the higher values. This conclusion of the
investigation is inaccurate in that
undeaerated dissolution median doesn’t
give a higher value that deaerate
dissolution median. Actually a
tablet/capsule doesn’t dissolve as fast if an
air bubble adhesives to a tablet/capsule.
…The … multi-bath dissolution systems
have remained in use over the past four
years although they have had
numerous and frequent malfunctions
and the reliability of the system
software has been questioned. These
malfunctions have impeded quality
control procedures and monitoring.
• The firm lacks systems to ensure that
all electronic data generated in the QC
laboratory is secure and remains
stored unaltered. For example:
• The multi-bath dissolution system
allows analysts to modify, overwrite,
and delete original raw data files.
89. …The serial number of the
thermometer used to measure the
temperature of the dissolution vessel
medium is not recorded during
dissolution testing.
89. …The date the temperature probe was
replaced on electronic digital
thermometer serial number …, was
not recorded in the thermometer’s
calibration log and the reason for
replacement was not recorded. This
thermometer is used in the calibration
of dissolution units in the laboratory.
91. ….The volume of medium used in
dissolution testing is measured at …C
rather than 250C as required by the
USP 24.
• …The firm has failed to adequately investigate and
implement corrective actions for malfunctioning laboratory
equipment.
• The …Multidose Dissolution Workstations used to drop
samples into dissolution bath vessels malfunctioned
approximately 15 times per month over the past two years.
This malfunction has resulted in what appears to be OOS
dissolution results and samples must be retested.
• The … robot sample station used to inject samples into
the UV Vis Spectrophotometer routinely malfunctions due to
air bubbles in the sample lines. This results in what appears
to be OOS data and samples are routinely retested without
an investigation.
• ….Calibration of the dissolution units are deficient I that:
• Only two of the four USP calibrator tests (for units utilizing
paddles and baskets) are performed to quality a new
dissolution apparatus or an existing apparatus being
returned to service after a major repair.
• Calibration is not performed at a minimum every six
months using all four USP calibrator tests if the unit is used
for paddles and baskets. Rather calibration is performed
using one USP calibrator test of non-dedicated units or is
performed every … using one USP calibrator test for
dedicated units.
• the amount of alcohol used to bring the prednisone
standard into solution is not recorded in the calibration data.
(No more than 5% of the total volume of the standard
solution may be used.)
• Calibration does not include testing of the baskets on the
dissolution units for wobble; only the shaft wobble is tested.
• The serial number of the thermometer used in
calibration of the dissolution units is not recorded.
For example, the thermometer used during the
calibration of dissolution units …. was not recorded.
• A stopwatch is used to calibrate the rotation of
the dissolution apparatus. However, the time from
the stopwatch is not recorded in the raw data; only
the unit’s RPMs are recorded. Also, the serial
number of the stopwatch used is not recorded.
• The actual temperature from the thermometer
used to calibrate the laboratory units is not recorded
in the raw data. According to management, the data
recorded is the temperature after an adjustment for
the thermometer’s correction factor.
• …The procedure for calibration of the
laboratory dissolution units is outdated and
unclear as follows.
• The procedure does not describe how t
prepare the standard solution used in
calibration testing.
• The procedure does not specify how to
measure the medium used in testing, I.e.,
graduated cylinders.
• The procedure does not describe how to
check the centering.
• ….The filters used in dissolution testing and in
calibration of the dissolution units have not been
evaluated for the adsorption of the active drug.
• ….The dissolution paddles are rotating while
tablets are dropped in the medium and this is
allowed by procedure….The USP 24 requires the
tablet to sink to the bottom of the vessel before
rotation of the blade is started.
• …..The 1,000ml plastic graduated cylinders used in
dissolution testing are not calibrated.
Product performance was not evaluated
with respect to the use of alternatively
sourced excipient in the production of
…… tablets. Subsequent batches had
marginal dissolution results which
were attributed to the use of this raw
material.