Max Feinberg

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 Société Française 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.In the first two documents [Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewé, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, J. Pharm. Biomed. Anal. 36 (2004) 579-586; Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewé, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, E. Rozet, J. Pharm. Biomed. Anal., in press], a recent SFSTP Commission on the validation of analytical procedure has introduced a harmonized approach for the validation of analytical procedures. In order to complete this guide, the statistical methodology allowing to correctly conclude about the validity of a procedure is proposed in this third part of the guide. Indeed all the steps to obtain the decision tool namely the accuracy profile are described and illustrated step by step by a numerical example. This tool, based on the concept of total error (bias+standard deviation) build with a beta-expectation tolerance interval, allows to easily take the right decision and simultaneously minimizing the risk of the future use of the analytical procedure.

Bacillus Calmette guérin triggers the IL-12/IFN-γ axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes

The IL‐12/IFN‐γ axis is crucial for protective immunity to Mycobacterium in humans and mice. Our goal was to analyze the relative contribution of various human blood cell subsets and molecules to the production of, or response to IL‐12 and IFN‐γ. We designed an assay for the stimulation of whole blood by live M. bovis Bacillus Calmette‐Guérin (BCG) alone, or BCG plus IL‐12 or IFN‐γ, measuring IFN‐γ and IL‐12 levels. We studied patients with a variety of specific inherited immunodeficiencies resulting in a lack of leukocytes, or T, B, and/or NK lymphocytes, or polymorphonuclear cells, or a lack of expression of key molecules such as HLA class II, CD40L, NF‐κB essential modulator (NEMO), and IL‐1 receptor‐associated kinase‐4 (IRAK‐4). Patients with deficiencies in IL‐12p40, IL‐12 receptor β1 chain (IL‐12Rβ1), IFN‐γR1, IFN‐γR2, and STAT‐1 were used as internal controls. We showed that monocytes were probably the main producers of IL‐12, and that NK and T cells produced similar amounts of IFN‐γ. NEMO and IRAK‐4 were found to be important for IL‐12 production and subsequent IFN‐γ production, while a lack of CD40L or HLA class II had no major impact on the IL‐12/IFN‐γ axis. The stimulation of whole blood by live BCG thus triggers the IL‐12/IFN‐γ axis by an IRAK‐4‐ and NEMO‐dependent, non‐cognate interaction between monocytes, NK, and T lymphocytes.

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.

The effects of water residence time on the biological quality in a distribution network

Abstract This study analyses the interactions of water residence time with heterotrophic plate count (HPC) bacterial density, biodegradable dissolved organic carbon (BDOC) and disinfectant residuals within a full size distribution network. These results have demonstrated the different influences of residence time in reservoirs and in pipes on bacterial water quality. In this context, travel of water in the pipes has no significant influence on HPC bacterial density, the supply water can be regarded as “biologically stable”. However, reservoirs, in which water has an elevated residence time, have a significant impact on HPC bacterial density. The importance of regular reservoir and network maintenance is stressed. In spite of the “biological stability” of supply water, BDOC decrease vs residence time was observed for high water temperatures. Thresholds of nutrients for which no bacterial regrowth is observed must always be associated with temperature. Disinfectant residual, which rapidly disappears in the network, was seen to have a very limited role in “biological stability”.

Application of sensory analysis to champagne wine characterisation and discrimination

Abstract This study represents the first steps in the elaboration of a strategy devoted to control Champagne wine quality based on sensory analysis. A fixed choice profile technique was used to detect sensory differences by qualitatively and quantitatively characterising gustatory and olfactory properties of over 56 Champagne wines. 64 attributes were reduced to a working set of 19 objective attributes showing a good range of scores, low incidence of zeroes and no hedonic aspects. The trained panellist repeatability as well as their discriminative efficiency was estimated. During this 2-year study approximately 5400 ratings were made and stored in a database. Panel performance improved with time. Sensory profiles of samples changed with time, although not in the same way for each wine. It is concluded that the fixed choice technique is feasible for QA. Future studies will examine calibration studies. ©

The European Food Consumption Validation Project: conclusions and recommendations

Background/Objectives:To outline and discuss the main results and conclusions of the European Food Consumption Validation (EFCOVAL) Project.Subjects/Methods:The EFCOVAL Project was carried out within the EU Sixth Framework Program by researchers in 11 EU countries. The activities focused on (1) the further development of the EPIC-Soft software (the software developed to conduct 24-h dietary recalls (24-HDRs) in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study) and the validation of the 2-day non-consecutive 24-HDR method using EPIC-Soft, (2) defining and investigating the applicability of the most appropriate dietary assessment method to younger age groups and expanding the applicability of the software for use in exposure assessment of some potentially hazardous chemicals and (3) to improve the methodology and statistical methods that estimate usual intake distributions from short-term dietary intake information and develop a methodology to quantify uncertainty in usual intake distributions.Results:The preexisting EPIC-Soft application was reprogrammed into a Windows environment and more than 60 new specifications were implemented in the software. A validation study showed that two non-consecutive EPIC-Soft 24-HDRs are suitable to estimate the usual intake distributions of protein and potassium of European adult populations. The 2-day non-consecutive 24-HDRs in combination with a food propensity questionnaire also appeared to be appropriate to rank individuals according to their fish and fruit and vegetable intake in a comparable way in five European centers. Dietary intake of (young) children can be assessed by the combination of EPIC-Soft 24-HDRs and food recording booklets. The EPIC-Soft-standardized method of describing foods is useful to estimate dietary exposure to potentially hazardous chemicals such as specific flavoring substances. With the developed Multiple Source Method, repeated non-consecutive 24-HDR data in combination with food propensity data can be used to estimate the population distribution of the usual intake by estimating the individual usual intakes.Conclusions:The findings provide sufficient evidence to conclude that the repeated 24-HDR using EPIC-Soft for standardization in combination with a food propensity questionnaire and modeling of usual intake is a suitable method for pan-European surveillance of nutritional adequacy and food safety among healthy adults and maybe in children aged 7 years and older. To facilitate this methodology in other European countries, the next step is to provide and standardize an implementation plan that accounts for maintenance and updates, sampling designs, national surveillance programs, tailored capacity building and training, and linkage to food composition and occurrence databases.

Determination of complex polysaccharides by HPAE-PAD in foods: Validation using accuracy profile ☆

The increasing supplementation of foods with carbohydrates substitutes and the growing regulatory requirements for controlling these products, turn into the necessary development and validation of accurate analytical control techniques. This paper presents the simultaneous validation of two close analytical procedures for the determination of sucralose and fructooligosaccharides (FOS) in fruit juices using high-performance anion-exchange chromatography with pulsed amperometric detection (HPAE-PAD). This study consisted in applying the accuracy profile procedure with a three-level validation experimental design. Decision criteria, namely acceptability limits (+/-10%) and proportion of result contained in the calculated tolerance intervals (80%), were decided on a consensus basis with end-users, whereas no official references were available. In conclusion, the proposed analytical procedures were validated over the selected validation domains for fruit juices and came out on very capable techniques. Validation strategy was purposely oriented towards the ease of use in routine and the liability of the methods rather than extreme performances. This objective is consistent with this of contract laboratories which need to reach a known level of guarantee for the results which they produce. In that respect, accuracy profile represents a very convenient tool to ascertain such a goal.

Rationale and methods of the European Food Consumption Validation (EFCOVAL) Project

Background/Objectives:The overall objective of the European Food Consumption Validation (EFCOVAL) Project was to further develop and validate a trans-European food consumption method to be used for the evaluation of the intake of foods, nutrients and potentially hazardous chemicals within the European population.Subjects/Methods:The EFCOVAL Project was carried out by 13 institutes from 11 European countries. The main activities were centered on the three main objectives of the project organized in different sub-projects.Results:In EFCOVAL, EPIC-Soft (the software developed to conduct 24-h dietary recalls (24-HDRs) in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study) was reprogrammed and adapted according to prioritized specifications, resulting in a software program working under the Windows operating system. In parallel of the EPIC-Soft development, the repeated 24-HDR method using EPIC-Soft and a food propensity questionnaire was evaluated against biomarkers in 24-h urine collections and in blood samples among adults from Belgium, the Czech Republic, (the South of) France, the Netherlands and Norway. As a result from an expert workshop on a proposed dietary assessment method for children (4–12 years), the suggested method was tested in a feasibility study in Denmark and Spain among children of 4–5, 7–8 and 12–13 years. To ensure that collected data had sufficient detail in food description for the assessment of additives and contaminants to foods the EPIC-Soft databases were adapted. Finally, the EFCOVAL Consortium developed a statistical tool (Multiple Source Method) for estimating the usual intake and distribution, which has been tested using real food consumption data and compared with three other statistical methods through a simulation study. In addition, a methodology was developed to quantify uncertainty due to portion-size estimation in usual intake distributions.Conclusion:The findings of EFCOVAL provide sufficient evidence to conclude that the repeated 24-HDR using EPIC-Soft for standardization in combination with a food propensity questionnaire and modeling of usual intake is a suitable method for pan-European surveillance of nutritional adequacy and food safety among healthy adults and maybe in children aged 7 years and older.

New approach for the assessment of cluster diets

Dietary risk assessment is a major public health concern, positioned in the context of establishing overall food safety policy. It requires some understanding of population food choices although geographical location and social-cultural environment are variable. Several years ago, a cluster analysis based on FAO consumption data, ranging from 1990 to 1994, was at the origin of the 13, so called, GEMS/Food cluster diets. This analysis required the initial identification of 19 food markers based on geographical and cultural differences. This paper proposes a new modelling of FAO food consumption database in order to define new cluster diets based on updated consumption data from 2002 to 2007 and better adapted statistical methods. Two statistical methods were combined to extract, consumption systems that generate a substructure from the initial food consumption database and then by deriving a clustering of countries according to their consumption system profiles. The clustering resulted in 17 cluster diets composed of 2 up to 30 countries. The few discrepancies between these new clusters and former ones may be due to more recent data, and to the fact that the new approach is based on another mathematical modelling which does not require any initial identification of food markers.

Validation of Alternative Methods for the Analysis of Drinking Water and Their Application to Escherichia coli

ABSTRACT In Europe, the Drinking Water Directive of the European Commission indicates which methods (most of which are CEN/ISO-standardized methods) should be used for the analysis of microbiological parameters (European Commission, Environment, Council Directive 98/83/EC of 3 November 1998). According to the Directive, alternative methods “may be used, providing it can be demonstrated that the results obtained are at least as reliable as those produced by the methods specified.” The prerequisite for the routine use of any alternative method is to provide evidence that this method performs equivalently to the corresponding reference method. In this respect, the ISO 16140 standard (ISO, ISO 16140. Microbiology of Food and Animal Feeding Stuffs—Protocol for the Validation of Alternative Methods, 2003) represents a key issue in generating such a procedure based on an interlaboratory study. A new statistical tool, called the accuracy profile, has been developed to better interpret the data. The study presented here is based upon the enumeration of Escherichia coli bacteria in water. The reference method may require up to 72 h to provide a confirmed result. The aim of this publication is to present data for an alternative method by which results can be obtained in 18 h (Colilert-18/Quanti-Tray) based upon defined substrate technology (DST). The accuracy profile is a statistical and graphical decision-making tool and consists of simultaneously combining, in a single graphic, β expectation tolerance intervals (β-ETIs) and acceptability limits (λ). The study presents the validation criteria calculated at the three levels of contamination used in the trial for a β equal to 80% and a λ equal to ±0.3 and combines the accuracy profiles of Escherichia coli for a λ of ±0.3 log10 unit/100 ml, a λ of ±0.4 log10 unit/100 ml, and a β of 80% or 90%. Several interesting conclusions can be drawn from these data. The accuracy profile method has been applied to the validation of the Colilert-18/Quanti-Tray method against reference method ISO 9308-1 (ISO, ISO 9308-1. Water Quality—Detection and Enumeration of Escherichia coli and Coliform Bacteria. Part 1. Membrane Filtration Method, 2000), using a β of 80% and a λ of 0.4; the alternative method can be validated between 1.00 and 2.05 log10 units/100 ml, equivalent to 10 to 112 CFU/100 ml.