GROWTH – DEDICATED CALL – 10/00 TOPIC IV.30 The European virtual institute for industrial chemometrics and metrology 1. CONFORMITY WITH THE WORK PROGRAMME Network proposals are requested for this topic which is in conformity with objective 1.1.3-7.2 "Setting up of Virtual Institutes" section of the activity "Support to Research Infrastructure" within the GROWTH programme, for which Expressions of Interest have been called. 2. KEYWORDS Chemometrics, metrology, quality, uncertainty statements, method validation, expert systems, chemical measurements, guidelines, calibration. 3. SUMMARY OF OBJECTIVES AND JUSTIFICATION Good quality chemical measurements in applied and basic research are needed to maintain and control quality of products and processes, to ensure compliance with European and national regulations, to develop the standard reference materials and methods required for a European measurement system. More generally, they are needed to support European industry in developing a sustainable and environmentally responsible economic growth. The mission of the proposed institute is to promote more cost-effective chemical measurement practices by making use of modern chemometric procedures and to develop procedures for adequate assessment of the quality of methods and measurement results. It will bring together European competences to : - - - establish fundamental knowledge about chemical measurement and chemometrical techniques to exploit in an optimal way analytical signals and transform them in measurements by adequate calibration, to validate analytical methods, evaluate their fitness-for-purpose and assess the uncertainty of the measurement results obtained; prepare tools (e.g guidelines, measurement expertise, statistical software) that allow to put into practice the fundamental knowledge in specific areas of chemical analysis; assist in transferring the knowledge to those who apply chemical measurement in industry, service laboratories, governmental agencies. DC 10/00/Topic IV.30/ Pg 2 4. BACKGROUND The quality of a chemical measurement method depends on appropriate selection of the method, optimal treatment of the analytical signal, correct calibration and adequate quality assessment. 4.1 Selection of measurement methods Methods should be capable, to put it into process terms, or fit-for-purpose in metrological terms, they should be cost-effective and they should be robust or reliable. How to assess that criteria for capability or fitness-for-purpose are fulfilled is discussed under 4.3. Robustness can be determined using experimental design methodologies. Whether a method will be cost-effective depends very much on the initial selection of the techniques and on the optimisation of its parameters. Proper selection and optimisation help to render this process more reliable, more rapid and less costly. Expert system technology and experimental design are applied in chemometrics for this purpose. An example is the selection of chiral separation methods. In industrial pharmaceutical practice, many such separations must be developed at different stages. Expert systems have been developed that decide whether e.g. capillary zone electrophoresis with a specific chiral selector is the best starting point and experimental design helps to decide rapidly what the best pH, reagent concentration, etc. are. 4.2 Signal processing and calibration Nearly all analytical methods transform signals by a process called calibration. Recent developments in chemometrics have considerably enhanced the capabilities of analysts by using better procedures for signal processing (using e.g. wavelets) or more complex calibration procedures (using e.g. latent variable methods or neural nets for multivariate calibration). The development of rapid but robust measurement methods places the emphasis on obtaining as much information as possible from complex signals with a minimum of pretreatment. Such methods are used for instance for direct measurements on the product or in- or on-line for a process (e.g near infra red spectroscopy, acoustic emission, …) and replace slow off-line methods, with as a result better process control and better product quality. They are also used for measurements that relate more directly to consumer satisfaction (such as the electronic nose). The application of sophisticated chemometric methods such as wavelets, neural nets, etc. has proved essential for the development of such measurement methods. Chemometrics has been and is developing at a rapid pace. Several of the larger chemical industries have chemometric groups, but for many other analysts in industry or service laboratories and also for instrument makers it has become very difficult to understand the mathematics employed. Help is needed at different levels, namely for the proper selection of algorithms, their implementation in software (because many chemometrical methods are not available in standard software or need to be customized for specific applications) and the interpretation of results. Moreover for many of the newer methods such as monitoring of processes with N-way methods, further theoretical development is needed. DC 10/00/Topic IV.30/ Pg 3 4.3 Quality assessment of methods and results Measurement methods must be validated and/or shown to be fit-for-purpose. The uncertainty on measurement results obtained by individual laboratories should be known. This requires the use of statistics and chemometrics. To ensure that they provide data of the required quality, analytical laboratories must take appropriate measures including the use of validated methods of analysis. Full validation requires an examination of the characteristics of the method in an interlaboratory method performance (or collaborative study). Internationally accepted protocols have been proposed for full method validation, such as the ISO standard 5725.1 to 6. While collaborative studies are standard practice in certain areas of chemical analysis such as food analysis, there are many areas where they are not relevant, for instance when an industry is the only one to produce certain chemicals or drugs. In-house validation is then needed. Recently, IUPAC (International Union for Pure and Applied Chemistry) released a draft guideline for in-house validation of methods of analysis, which may provide a basis for protocols for single laboratory method validation. Several other organisations, e.g ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - topic Q2A and 2B), have developed guidelines for method validation. To ensure that a measurement method is fit-for-purpose it should be decided what criteria the method should fulfil. IUPAC defines fitness-for-purpose as the degree to which data produced by a measurement process enable a user to make correct decisions for a stated purpose. CCMAS (Codex Committee on Methods of Analysis and Sampling) has proposed that, instead of prescribing official methods, one should prescribe the criteria that a method must fulfill for a certain application, meaning that the method must be shown to be fit-for-purpose. Eurachem has proposed a guide with general principles and organisational details concerning fitness-for-purpose. The ISO approach for quantifying uncertainty resulted in the GUM, the Guide to the expression of Uncertainty in Measurement. It was adapted by Eurachem for chemical measurements. A different approach, based on the information gathered from interlaboratory experiments was proposed by the Analytical Methods Committee (of the Royal Society of Chemistry). In both cases the method applied should have been validated prior to the measurements and information from the method validation is used in the statement of uncertainty. Although it can be concluded that there is a considerable body of guidelines and related material available, much more work is needed, essentially at four levels: - Implementation in practice of the existing guidelines. With the exception of the document on collaborative trials, all the above mentioned approaches and guidelines are general and generic. In practice the implementation depends on the type of measurement method and the application area. For instance, the practical implementation of the validation of the analysis of a drug in a pharmaceutical form is different when the measurement is done directly by near infrared spectroscopy or after dissolution by HPLC. The validation of the analysis of a drug by HPLC is different when it is performed in a pharmaceutical formulation or in a biological sample. The existing guidelines cannot give all details and must be adapted to specific situations. It is left to individual users to adapt them to their type of application. They have difficulties to do this, because most chemists do not have the required statistical background. DC 10/00/Topic IV.30/ Pg 4 - Theoretical developments: Several new statistical /chemometric procedures have recently emerged. They are more sophisticated than was usual in this field and require further study. For instance, bootstrapping is a simulation procedure that allows to determine parameters such as confidence intervals without the prior definition of a statistical distribution. Until now insufficient use has been made of the methodology in chemical metrology, where it seems indicated for more complex situations, in which it is difficult to derive theoretical distributions. The use of interval hypothesis tests as applied in the ISO standard 5725-6 for the comparison of two methods combined with -statistics allows to predict how many replicates have to be measured to be able e.g. to see a given bias. The theory needs development for many other techniques applied in method validation such as e.g. standard addition. Moreover there are many specific questions, such as how to determine the uncertainty for a standard reference material when different measurement methods are applied to measure the concentration of the substance to be certified. Should one take into account that the methods have different precisions (as NIST does), or not? The questions can be more process-oriented such as: how does one derive the precision needed to monitor a process from its product quality specifications, i.e. on what criteria is a fitness-for-purpose statement based in such cases. - - Other types of measurement results. The guidelines all adress univariate quantitative measurements, but there are many other possibilities, such as qualitative mesurements, multivariate quantitative measurements such as those resulting from the methods mentioned under 4.2. Tools. Among the most important tools in a chemical measurement system are reference materials, substances and methods. The institute will stimulate the use and the production of such materials, substances and methods by providing assistance in their development and particularly in validating them. To enable chemists to include such materials and to implement statistical/chemometric methodology developed in the framework of their quality plans, dedicated software will be made available. One of the major problems being the relatively limited knowledge of chemometric/statistical methodology and validation procedures, course programs will be developed. 5. ECONOMIC AND SOCIAL BENEFITS The Institute is intended to benefit the end-users of chemometrics and metrology applied to chemistry, namely the industry, instrument makers, service laboratories, governmental agencies. The proper use of chemometrics and chemical metrology principles leads to enhanced measurement capabilities and more confidence in measurement results. Indeed, the problem of the agreement between analytical results and their mutual recognition (for checking product specifications, adherence to regulations,..) concerns everybody who is involved in a buyer-supplier or industryregulatory agency relationship. The Institute must have the ambition to become the place where users can turn to solve on demand questions related to chemometrics, to help implement its use in chemical measurement, aid in the validation of methods and the practical preparation for accreditation, to assist users in finding their way to and through the existing guidelines. In particular, it is the intention to lower the threshold for access to chemometrical, DC 10/00/Topic IV.30/ Pg 5 statistical and metrological help for SME, who at this stage find the use of such methods daunting. 6. SCIENTIFIC AND TECHNOLOGICAL OBJECTIVES The virtual institute will take advantage of the Internet to structure itself in a costeffective way. It will be based on existing centres of excellence, both industrial and academic, such that the application domain should be covered as well as possible. Its clients will therefore be: - - individual industries or other organisations that need implementation of chemometrics in their analytical labs or in/on line production, want to implement existing guidelines or need their own customized guidelines for validation and uncertainty statement and/or the software tools to make the implementation possible; European and national regulatory bodies that can for instance entrust the institute with the theoretical work that may be needed in connection with the way the measurement results should be treated when reference materials and methods are prepared. The Institute should not substitute itself for organisations such as ISO, Eurachem, industry wide organisations such as the ICH or national organisations such as AFNOR but be available for advice of a more fundamental or technical nature to these organisations when needed. 7. TIME SCALE After the setting up period, the Institute should be self-financing through, for example providing services and consultancy for European customers – industry, including SME’s, and governmental bodies - on a commercial basis. The access threshold should be kept as low as possible, to stimulate customers to profit from the facilities, knowhow, and technologies available in the European Virtual Institute for Tribology, and beyond. 8. IMPORTANT ADDITIONAL INFORMATION Proposers should address as wide a selection as possible of the potential areas of application. It is not mandatory to address all areas, but expertise in enough types of measurement techniques (e.g. spectroscopists, separation scientists,…), application domains (chemicals, polymers, pharmaceuticals, agro-food,…) and chemometrics should be present in the Institute. It is essential to demonstrate sufficient links with the industrial end-users and, to avoid problems with differing industrial cultures, to ensure a good geographical coverage of the participants. Proposers of the network must provide in detail an explanation of how their network will become self supporting in the form of a business plan. Envisaged legal structures (not required at the launch) should be described.