Precision of the reportable result. Simultaneous optimisation of number of preparations and injections for sample and reference standard in quantitative liquid chromatography.

In pharmaceutical analysis, the precision of the reportable result, i.e. the result which is to be compared to the specification limit, is relevant for the evaluation of the suitability of the analytical procedure. But also for other applications, the precision of the result is important and an optimisation often of interest. However, increasing the number of determinations (e.g. injections or preparations) will reduce only the variability (or standard error) of the corresponding precision level. Therefore, the knowledge of the individual variance contributions, obtained from reliable precision studies is important to determine on a scientific basis which format of the (reportable) result, i.e. the number of injections and sample preparations (or even series), should be used. In case of relative analytical procedures such as LC, the calibration model and format, i.e. the number of determinations of the reference standard is one of the factors (besides instrument, operator, reagents, etc.) affecting the between-series variance contribution at intermediate precision/reproducibility level. Consequently, the precision of the reportable result is only valid for the calibration format used to obtain intermediate precision/reproducibility. Instead of repeating the whole precision study to optimize the calibration format, the present paper describes a statistical approach using variability results from the original precision study.

Transfer of analytical procedures: a panel of strategies selected for risk management, with emphasis on an integrated equivalence-based comparative testing approach.

In 2001, a multidisciplinary team made of analytical scientists and statisticians at Sanofi-aventis has published a methodology which has governed, from that time, the transfers from R&D sites to Manufacturing sites of the release monographs. This article provides an overview of the recent adaptations brought to this original methodology taking advantage of our experience and the new regulatory framework, and, in particular, the risk management perspective introduced by ICH Q9. Although some alternate strategies have been introduced in our practices, the comparative testing one, based equivalence testing as statistical approach, remains the standard for assays lying on very critical quality attributes. This is conducted with the concern to control the most important consumer's risk involved at two levels in analytical decisions in the frame of transfer studies: risk, for the receiving laboratory, to take poor release decisions with the analytical method and risk, for the sending laboratory, to accredit such a receiving laboratory on account of its insufficient performances with the method. Among the enhancements to the comparative studies, the manuscript presents the process settled within our company for a better integration of the transfer study into the method life-cycle, just as proposals of generic acceptance criteria and designs for assay and related substances methods. While maintaining rigor and selectivity of the original approach, these improvements tend towards an increased efficiency in the transfer operations.

Accurate topological comparison of two recombinant human growth hormones by optical surface plasmon resonance.

A strategy for the comparison of two recombinant derived human growth hormones (r-hGH) has been developed using surface plasmon resonance (SPR). Statistical analysis was systematically used on the results obtained with several batches derived from two different Escherichia coli strains. Monoclonal antibodies (MAb) directed against four different domains in the tertiary structure of natural human growth hormone were used to compare the epitopic maps of the three (two recombinant and one natural) hGH by SPR analysis. Topological studies show the homogeneity of the epitopic maps of the three hGH. The kinetic parameters, association rate, and dissociation rate constants were also analyzed for the binding of each hGH batch to all MAbs. They were found to be homogeneous between the three hormones. Furthermore, the two r-hGH were compared by more classical approaches examining recognition of lactogenic or somatogenic receptors using, respectively, a bioassay of Nb2 cell proliferation and binding to rat liver microsomes. Specific bioactivities and IC50 values calculated in radioreceptor assays did not significantly differ between different r-hGH. The method was sensitive enough to show slight differences on koff value for one MAb (3C11) between (natural) hormone and two r-hGH. These differences are discussed in relation to previous observation made in the literature and the presence of isoforms in the natural product. The strategy developed here was very useful as a new tool to establish the equivalence of the two r-hGH.