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A u t h o r M a n u f a c t u r i n g & P r o c e s s i n g
Dr Joachim Ermer is responsible for coordinating,
supporting, and advising the quality control departments
of Aventis in analytical aspects. This also includes the
establishment of company guidelines and training modules.
Ermer is deputy head of the working group in quality
control/pharmaceutical analytics of the German
Pharmaceutical Society and a member of the working
group quality assurance of the International Association
of Pharmaceutical Technology.
METHODS
Dr Joachim Ermer, director of analytical
limit. Selective methods such as high performance liquid
chromatography, gas chromatography, high performance thin layer
chromatography, and immuno assays are preferred for active (and
related) residues. Non-selective methods, such as pH-measurement,
conductivity and total organic carbon, are mainly used for detergents.
processes and technology for Aventis quality
operations, discusses the performance As a rapid, sensitive and selective method, ion mobility spectrometry
parameters for cleaning methods and suitable was introduced, particularly for cleaning verification. This technique
calculations, tests and acceptance criteria. (used in airports to detect explosives) is based on the ionisation of the
sample directly from the swab and measures the characteristic speed of
the ions moving through an electric field under atmospheric pressure.
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GDD002_008 Aventis 27/8/04 15:39 Page 130
but the latter is the primary objective. Therefore, the first step
should be to inspect the experimental data for systematic deviations
Paul GmbH from the applied regression function. Numerical parameters are
only suitable afterwards. The relative standard error of slope is
recommended because such a normalised (percentage) parameter
allows a straightforward evaluation by comparison with an
Recoveries
If relevant (with respect to the precision), the recovery factor should
be used to correct the results of the cleaning method. To allow a
straightforward evaluation, the recoveries are preferably presented
graphically as percentages with respect to the spiked concentration.
This plot should be inspected for a concentration-dependent
behaviour. In case of no or only slight dependency, the average and
the relative standard deviation of all recoveries can be calculated. If
the spikings are analysed in an independent series, the calculation
can be performed as an analysis of variances. Here, the precision
contributions within and between the series are obtained separately,
and conclusions can be drawn on the robustness of the procedure.
M a n u f a c t u r i n g & P r o c e s s i n g
recovery (%)
1-(p-chloro-a-phenyl-benzyl)-4-m-methylbenzyl)piperazine 96
Recovery from swabs: 88.5% (RSD 4.2%)
dihydrochloride, is practically insoluble in water and slightly 94
Recovery from plates: 89.2% (RSD 2.7%) 1.3%
soluble in diluted acids. The SRCL was established to 0.50µg/cm2. 92
The system precision of the LC assay of 0.21 per cent and 0.41 per 0.5%
cent was obtained from five repeated injections at a concentration 90
0.9%
corresponding to 200 per cent SRCL. The recoveries from five swabs 88
and five plates at each of the three concentration levels were obtained. 4.3%
0.9%
86
1.8% Spiked swabs
No relevant difference is observed between the recoveries from swabs 84
and plates. Therefore it can be concluded that meclizine can be Spiked plates
82
recovered almost completely from the stainless steel surface, and
the main loss is due to absorption on the swab material. However, 80
the recoveries are acceptable, with only a slight concentration 0 50 100 150 200 250
dependency. Therefore, overall parameters can be calculated. spiked concentration (% SRCL)
For the QL, various approaches can be applied, based either on the plates
blank (signal-to-noise ratio, standard deviation of the blank) or 100 swabs
extraction solution
analyses of the analyte in the low concentration range (standard
deviation of the intercept, residual standard deviation of the linear 90 Av.: 89.9%
regression). It is important to be aware that the determined limit RSD: 1.15%
(DL) is strongly dependent on the equipment and conditions as 80
well as on the calculation procedure applied. The minimum
requirement for QL is approximately 50 per cent of the SRCL.
70
When calculating DL/QL from a calibration line, a frequent
mistake is to use a too-large concentration range or even 60
extrapolation. Due to non-constant variances, higher 0 1 2 3 4
concentrations will dominate the dispersion parameters used to Storage time (d)
calculate QL. Therefore, the maximum concentration should not
exceed the 10- to 20-fold of DL. The range and mean of three determinations are indicated,
as well as the overall average and the relative standard
Stability considerations deviation of the swab samples.
An important aspect in cleaning validation is the ageing of the
sample at the various stages of the process to define the
conditions appropriately. In the given example, the ageing effect
was investigated with respect to the analyte on dry stainless steel such a case, the time between cleaning and sampling from the steel
plates, on moistened swabs, and in the extraction solution from surface and the shelf life of the extraction solution needs to be
the swabs (Figure 2). limited in the cleaning validation process. No changes were observed
for the storage of the moistened swabs. Due to the intermediate
Large effects can be observed for the ageing on plates and in the recovery conditions in the stability study, this average of 89.9 per
extraction solution, both with respect to recovery and variability. In cent is suitable to define the recovery factor. END
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