Validation of quantitative analytical procedure, Harmonization of approaches

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Harmonization of strategies for the validation of quantitative analytical procedures - A SFSTP proposal - part I

This paper is the first part of a summary report of a new commission of the Societe Francaise des Sciences et Techniques Pharmaceutiques (SFSTP). The main objective of this commission was the harmonization of approaches for the validation of quantitative analytical procedures. Indeed, the principle of the validation of theses procedures is today widely spread in all the domains of activities where measurements are made. Nevertheless. this simple question of acceptability or not of an analytical procedure for a given application, remains incompletely determined in several cases despite the various regulations relating to the good practices (GLP, GMP,...) and other documents of normative character (ISO, ICH. FDA,...). There are many official documents describing the criteria of validation to be tested, but they do not propose any experimental protocol and limit themselves most often to the general concepts. For those reasons, two previous SFSTP commissions elaborated validation guides to concretely help the industrial scientists in charge of drug development to apply those regulatory recommendations. If these two first guides widely contributed to the use and progress of analytical validations, they present, nevertheless, weaknesses regarding the conclusions of the performed statistical tests and the decisions to be made with respect to the acceptance limits defined by the use of an analytical procedure. The present paper proposes to review even the bases of the analytical validation for developing harmonized approach, by distinguishing notably the diagnosis rules and the decision rules. This latter rule is based on the use of the accuracy profile, uses the notion of total error and allows to simplify the approach of the validation of an analytical procedure while checking the associated risk to its usage. Thanks to this novel validation approach, it is possible to unambiguously demonstrate the fitness for purpose of a new method as stated in all regulatory documents. (C) 2004 Elsevier B.V. All rights reserved

Harmonization of strategies for the validation of quantitative analytical procedures - A SFSTP proposal - Part II

As reported in a previous paper[1], the main objective of the new commission of the Societe Francaise des Sciences et Techniques Pharmaceutiques (SFSTP) was the harmonisation of approaches for the validation of quantitative analytical procedures. In a series of meetings, members of this Commission have first tried to review the objectives of analytical methods and the objectives of validation methods and to recommend the use of two-sided beta-expectation tolerance intervals for total error of validation samples (accuracy profile) in the acceptance/rejection of analytical method in validation phase. In the context of the harmonization, the other objectives were: (i) to propose a consensus on the norms usually recognized, while widely incorporating the ISO terminology; (ii) to recommend to validate the analytical procedure accordingly to the way it will be used in routine; (iii) to elaborate a rational, practical and statistically reliable strategy to assure the quality of the analytical results generated. This strategy has been formalised in a guide and the three latter objectives made by the Commission are summarised in the present paper which is the second part of summary report of the SFSTP commission. The SFSTP guide has been produced to help analysts to validate their analytical methods. It is the result of a consensus between professionals having expertise in analytical and/or statistical fields. The suggestions presented in this paper should therefore help the analyst to design and perform the minimum number validation experiments needed to obtain all the required information to establish and demonstrate the reliability of its analytical procedure. (C) 2007 Elsevier B.V. All rights reserved

Harmonization of strategies for the validation of quantitative analytical procedures: a SFSTP proposal part IV. Examples of application.

A harmonized approach for the validation of analytical methods based on accuracy profile was introduced by a SFSTP commission on the validation of analytical procedure. This fourth and last document aims at illustrating this methodology and the statistics used. Therefore the validation of real case methods are proposed such as methods for the quality control of drugs, for the quantitation of impurities in drug substances, for bioanalysis or for the determination of nutriments. Furthermore, different types of analytical methods are used in order to demonstrate the applicability of the proposed approach to a wide range of methods such as liquid chromatography (LC-UV, LC-MS), spectrophotometry or ELISA

Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation Concordance With Clinical Outcomes

Background-Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation. Methods and Results-Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo. Conclusions-Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309.Funding Agencies|F. Hoffmann-La Roche</p

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