Implementation of ISO 9001 in a medical testing laboratory

 The Department of Clinical Chemistry and Molecular Genetics, within the Institute of Clinical Pathology and Medical Research at Westmead Hospital, is a medical testing laboratory operating within the public sector health system of New South Wales, Australia. It provides acute-care pathology services to Westmead Hospital (a 900-bed tertiary referral university teaching hospital) as well as to three district hospitals and three rural hospitals. In addition to these core clinical chemistry services, it offers approximately 150 specialised biochemistry, pharmacology, toxicology, trace metal and molecular genetics assays as a reference laboratory service. In 1993, the Department became Australia's first medical testing laboratory to be registered to ISO 9001-1987/AS3901-1987. In 1995, this certification was extended to AS/NZS ISO 9001-1994. We are currently preparing for further accreditation to ISO/IEC Guide 25-1990, with additional supplementary requirements for medical testing. This paper describes the Quality System that the Department developed and which has been successfully maintained and extended since original certification. Important features of the Quality System are: 1. Primary design of the Quality System to meet medical and customer needs, with subsequent addition of required ISO elements. 2. Use of national Quality Award criteria to identify key business processes. 3. Development of integrated technical non-conformance, customer complaint, staff suggestion, and quality system corrective action procedures. 4. Implementation without external resources. Our conclusions are that ISO 9000 Quality Systems can be applied to medical testing laboratories, and can be implemented with minimum resource costs. Improvements in technical and service quality and business performance have resulted from this process. However, implementation of ISO 9000 at the level of individual Departments is not ideal. Greater improvements are possible when this process is undertaken at the level of the entire organisation. Received: 9 September 1996 Accepted: 5 October 1996     

Point-of-care testing of proteins

Point-of-care testing (POCT) is a fast developing area in clinical diagnostics that is considered to be one of the main driving forces for the future in vitro diagnostic market. POCT means decentralized testing at the site of patient care. The most important POCT devices are handheld blood glucose sensors. In some of these sensors, after the application of less than 1 μl whole blood, the results are displayed in less than 10 s. For protein determination, the most commonly used devices are based on lateral flow technology. Although these devices are convenient to use, the results are often only qualitative or semiquantitative. The review will illuminate some of the current methods employed in POCT for proteins and will discuss the outlook for techniques (e.g., electrochemical immunosensors) that could have a great impact on future POCT of proteins.     

Patient self-testing and self-management of oral anticoagulation

The development of portable instruments for measuring the prothrombin time (PT) in capillary whole blood has made it possible for patients on lifelong coumarin therapy to monitor the effect of the anticoagulant themselves (patient self-testing) and to adjust the dosage if necessary on their own (patient self-management). Dosage variations between individual patients and the narrow therapeutic range of the anticoagulant account for the need to monitor its effect, in order to minimize the risk of thromboembolism resulting from inadequate anticoagulation as well as the risk of bleeding due to overanticoagulation. This review focuses on the prerequisites for the successful implementation of patient self-testing and self-management, such as the selection of eligible patients, appropriate training and the reliability of available instruments. The outcomes of relevant clinical studies involving patient self-testing and self-management are also discussed.     

Quality assurance in the microbiology laboratory

 The pertinent issues necessary for the establishment of quality assurance in the microbiology laboratory are discussed. Quality assurance is a planned system of control measures that enables management to ensure that the analytical data produced in the laboratory are valid. To introduce quality assurance, all activities in the laboratory that affect the production of analytical data must be documented and controlled. These include sampling, method selection, laboratory environment, equipment, reagents and media, staff, reference materials and internal and external quality control. Laboratory accrediation in accordance with EN45001 and ISO Guide 25 enables laboratories demonstrate to an external agency their ability to perform analytical work and produce valid analytical data. This gives creditability to the laboratory and allows management to have confidence in the data produced. Received: 6 June 1995 Accepted: 3 July 1995     

Quality in point-of-care testing: taking POC to the next level

Point-of-care testing (POCT) is a complex system with many opportunities for error. Delivering quality POCT requires multidisciplinary coordination and an understanding of the preanalytic, analytic, and postanalytic processes that are necessary to deliver a test result and take clinical action. Most errors in laboratory testing occur in the pre and postanalytical phases and many mistakes that are referred to as lab error are actually due to poor communication, actions by others involved in the testing process, or poorly designed processes outside the laboratory's control. POCT requires significant operator interaction with analysis and documentation of calibration and quality control, unlike other medical devices. Clinicians often interpret POCT as equivalent to core laboratory testing, only faster, and mistakenly utilize the results interchangeably despite the differences in test methodologies. Taking quality of POCT to the next level involves looking beyond the analytical phase and integration of POCT into the entire pathway of patient care to understand how POCT relates to medical decision-making at specific points during the patient's care. A systematic review of the literature by the National Academy of Clinical Biochemistry is currently being conducted to draft guidelines for best practice that link the use of POCT to improved patient outcomes.Presented at the 10th Conference Quality in the Spotlight, March 2005, Antwerp, Belgium.     

Quality assurance in the view of a commercial analytical laboratory

 The necessity for analytical quality assurance is primarily a feature of the analytical process itself. With the full establishment of the EU domestic market, it is also becoming a legal necessity for an increasing number of analytical laboratories. The requirements which laboratories will need to fulfil are stipulated in DIN EN 45 001. Accredited testing laboratories must in fact provide evidence that they work solely in accordance with this standard. National and EU commissions, which are legislative authorities, tend therefore to specify analytical methods, e.g. in the form of regulations or appendices thereto, intended to ensure that results from different laboratories will be comparable and hence will stand up in a court of law. The analytical quality assurance system (AQS), introduced by the Baden-Württemberg Ministry for the Environment in 1984, obliges laboratories to regularly participate in collaborative studies and thereby demonstrate their ability to provide suitably accurate analyses. This alone, however, does not sufficiently demonstrate the competence of a laboratory. Only personal appraisal of the laboratory by an auditor, together with the successful analysis of a sample provided by the same and performed under his observation, can provide proof of the competence of the laboratory. From an analytical point of view, the competence of a laboratory must be regarded as the decisive factor. Competence can only be attained through analytical quality assurance, which thus must be demanded of all laboratories. Received: 4 October 1996 Accepted: 15 January 1997     

ISO compliant laboratory quality systems and incident monitoring improve the implementation of laboratory information systems

Quality systems can provide a means of measuring the rate of occurrence of defined incidents and non-conformities. We have studied the application of laboratory quality systems to monitoring the implementation of laboratory information systems (LIS) in two similar size tertiary hospital pathology laboratories in Australia. At one site, one department implemented a quality system accredited to ISO 9001–1987 and ISO 9001–1994 while the rest of the organisation did not have a formal quality system; this site implemented the Cerner PathNet LIS. At the other site, the organisation was in the process of implementing ISO/IEC Guide 25–1990 and ISO/IEC 17025–1999; this site implemented the PJACC AUSLAB LIS. The rate of quality system incidents and non-conformities was used to track the progress of implementation of the LIS. We found that different quality systems appeared equally useful in monitoring the rate of occurrence of incidents. However, the presence of a formal quality system greatly improved the proportion of incidents that could be investigated and resolved at root cause level. Incident monitoring, as part of a formal quality system, proved to be a useful tool in monitoring and managing the implementation of these LIS. Received: 4 August 2001 Accepted: 21 March 2002     

Traceability in laboratory medicine

In laboratory medicine meaningful measurements are essential for diagnosis, risk assessment, treatment and monitoring of patients. Thus methods applied in diagnostic measurements must be accurate, precise, specific and comparable among laboratories. Inadequate or incorrect analytical performance has consequences for the patients, the clinicians, and the health care system. One key element of metrology is the traceability of a measurement result to the SI system ensuring comparable results. This principle is described in the ISO/TC 212/WG2 N65 prEN 17511 Standard. In addition to the principles of metrology, the clinical usefulness, the diagnostic needs, and the biological and disease associated variations in patients' specimens have to be considered when the analytical biases for diagnostic purposes are defined. It must be the general goal of diagnostic laboratories to produce results that are true and comparable worldwide. The recent European in vitro diagnostic (IVD) Directive 98/79 EC follows the above mentioned standard of the International Organization for Standardization (ISO) and the European Committee for Standardization (CEN) requesting its application for all IVD reagents used within the European Union. This new European legislation will have a worldwide impact on manufacturers and clinical laboratories and will be implemented in 2003. It states that "traceability of values assigned to calibrators and/or control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order". Thus a worldwide reference system needs to be established by collaboration and mutual recognition between the United States National Institute of Standards and Technology (NIST), European Metrology Institutes (EUROMET), regulatory bodies (e.g. United States Food and Drug Administration, FDA) the IVD industry and professional organizations (e.g. International Federation of Clinical Chemistry and Laboratory Medicine, IFCC). In June 2002, in Paris, representatives of international and regional organizations and institutions decided to form the "Joint Committee on Traceability for Laboratory Medicine" (JCTLM), which will support industry in registration and licensing of the "CE" label to test systems conforming to the IVD Directive.Presented at the International ILAC/IAF Conference on Accreditation in Global Trade, 23–25 September 2002, Berlin, Germany     

Complementary use of molecular and element-specific mass spectrometry for identification of selenium compounds related to human selenium metabolism

The aim of this paper is to give an overview of analytical data on the identification of selenium compounds in biological samples with relevance for selenium metabolism. Only studies applying the combination of element-specific inductively coupled plasma mass spectrometry as well as molecular electrospray mass spectrometry detection have been included. Hence, selenium compounds are only considered identified if molecular mass spectra obtained by analysis of the authentic biological sample have been provided. Selenium compounds identified in selenium-accumulating plants and yeast are included, as extracts from such plants and yeast have been widely used for examination of the cancer-preventive effect of selenium in cell lines, animal models and human intervention trials. Hence, these selenium compounds are available for absorption and further metabolism. Identification of selenium metabolites in simulated gastric and intestinal juice, intestinal epithelial tissue, liver and urine is described. Hence, selenium metabolites identified in relation to absorption, metabolism and excretion are included.     

Atomic spectrometry and trends in clinical laboratory medicine

Increasing numbers of clinical laboratories are transitioning away from flame and electrothermal AAS methods to those based on ICP-MS. Still, for many laboratories, the choice of instrumentation is based upon (a) the element(s) to be determined, (b) the matrix/matrices to be analyzed, and (c) the expected concentration(s) of the analytes in the matrix. Most clinical laboratories specialize in measuring Se, Zn, Cu, and Al in serum, and/or Pb, Cd, Hg, As, and Cr in blood and/or urine, while other trace elements (e.g., Pt, Au etc.) are measured for therapeutic purposes. Quantitative measurement of elemental species is becoming more widely accepted for nutritional and/or toxicological screening purposes, and ICP-MS interfaced with separation techniques, such as liquid chromatography or capillary electrophoresis, offers the advantage of on-line species determination coupled with very low detection limits. Polyatomic interferences for some key elements such as Se, As, and Cr require instrumentation equipped with dynamic reaction cell or collision cell technologies, or might even necessitate the use of sector field ICP-MS, to assure accurate results. Nonetheless, whatever analytical method is selected for the task, careful consideration must be given both to specimen collection procedures and to the control of pre-analytical variables. Finally, all methods benefit from access to reliable certified reference materials (CRMs). While a variety of reference materials (RMs) are available for trace element measurements in clinical matrices, not all can be classified as CRMs. The major metrological organizations (e.g., NIST, IRMM, NIES) provide a limited number of clinical CRMs, however, secondary reference materials are readily available from commercial organizations and organizers of external quality assessment schemes.     

Benchmarking and quality management indicators in three medical laboratories

The aim of this study was to calculate various annual quality management indicators and implement them as a management tool in laboratories. The study was performed in three laboratories over five years, from 2000 to 2004. These laboratories are part of the XHUP (Public Hospital Network in Catalonia). We collected 20 annual items over five years and calculated 20 annual indicators. The Laboratory Manual Index Program from the College of American Pathologists was used as a reference. We also compared an analytical quality indicator versus productivity and calculated annual budget laboratory deviation. The information obtained from these indicators provides laboratories with a useful benchmarking tool to determine the results of management change and understand the real situation in laboratories. We found a lack of standardisation in management data. A future area of work could involve unifying some of the different characteristics. Presented at the Conference Quality in the Spotlight, March 2006, Antwerp, Belgium.     

Internal audits in private medical laboratory practice – a Finnish experience in 1996–2000

Internal audits inherently effect quality improvement, and concrete results can be expected by careful planning. As audits should improve the quality system in situ, the development of audits should not be neglected. ISO/IEC 17025 describes the objectives of internal audits and management reviews in more detail compared to the former standards EN 45001 and ISO/IEC Guide 25, although the main features are unchanged. This addresses continuous surveillance of the current practice. A brief questionnaire on vertical audits was distributed to 74 of 120 employees at a Finnish private medical laboratory, Medix Laboratories Ltd. A positive feed-back was received from the current management of audits. However, the study revealed that continuous supervision of audits is needed. Many employees were not willing to perform audits if they had no previous experience. Additionally, audits performed at the workbench were not considered as the best possible for fruitful discussions. Received: 20 February 2001 Accepted: 30 November 2001     

Quality specifications for evaluation and comparison of performance among external quality assessment schemes in occupational and environmental laboratory medicine

Quality specifications (QS) are proposed for lead in blood and for aluminium, copper, selenium and zinc in serum as part of the aim to set standards of performance for laboratories so that results can be demonstrated to be fit for the purpose to which they are applied. The QS were established taking account of the analytical state-of-the-art, physiological variations in the concentrations of the analyte and the clinical purpose for which the assay is to be used. A procedure was devised that uses these QS to give equivalence of assessment among external quality assessment schemes (EQAS), thus avoiding conflicting information which has been demonstrated in the past. Advantages of this procedure are: to provide direct comparison of performance of laboratories taking part in different schemes, to provide equivalence of assessment of laboratory performance necessary to establish mutual recognition agreements, and to demonstrate the fitness for purpose of results from participants.Presented at the Eurachem PT Workshop September 2005, Portorož, Slovenia     

Single molecule detection in nanofluidic digital array enables accurate measurement of DNA copy number

Digital polymerase chain reaction (PCR) is a promising technique for estimating target DNA copy number. PCR solution is distributed throughout numerous partitions, and following amplification, target DNA copy number is estimated based on the proportion of partitions containing amplified DNA. Here, we identify approaches for obtaining reliable digital PCR data. Single molecule amplification efficiency was significantly improved following fragmentation of total DNA and bias in copy number estimates reduced by analysis of short intact target DNA fragments. Random and independent distribution of target DNA molecules throughout partitions, which is critical to accurate digital PCR measurement, was demonstrated by spatial distribution analysis. The estimated relative uncertainty for target DNA concentration was under 6% when analyzing five digital panels comprising 765 partitions each, provided the panels contained an average of 212 to 3,365 template molecules. Partition volume was a major component of this uncertainty estimate. These findings can be applied to other digital PCR studies to improve confidence in such measurements. Figure Digital PCR amplification plot (left) and panel read out (right) of HindIII-digested pIRMM69. pIRMM69 contains one HindIII restriction enzyme site outside the hmg and transgene fragments used as targets in PCR. Red boxes with white shade denote positive hits containing one or more target DNA molecules, and white boxes with grey shade refer to no target being amplified.     

GC-MS with ethyl chloroformate derivatization for comprehensive analysis of metabolites in serum and its application to human uremia

An optimized method based on GC-MS with ethyl chloroformate derivatization has been developed for the comprehensive analysis of endogenous metabolites in serum. Twenty-two reference standards and serum samples were used to validate the proposed method. The correlation coefficient was higher than 0.9900 for each of the standards, and the LOD varied from 125 to 300 pg on-column. The analytical equipment exhibited good repeatability (RSD<10%) for all of the standards. Both the repeatability and the within-48-h stability of the analytical method were satisfactory (RSD<10%) for the 18 metabolites identified in the serum samples. Mean recovery was acceptable for the 18 metabolites, ranging from 70% to 120% with RSDs of less than 10%. Using the optimized protocol and a subsequent multivariate statistical technique, complete differentiation was achieved between the metabolic profile of uremic patients and that of age- and sex-matched normal subjects. Significantly decreased levels of valine, leucine, and isoleucine and increased levels of myristic acid and linoleic acid were observed in the patient group. This work demonstrated that this method is suitable for serum-based metabolic profiling studies.     

mRNA transport to and translation in neuronal dendrites

Transport of mRNA is an important biological process in all cells that sets up gradients of translated protein from the site of mRNA docking and translation. Neurons are highly polarized cells where the targeted movement of RNAs and local translation at that site have been shown to be integral to the proper functioning of the neuron. Indeed, this specialized biological function for localized RNAs in particular neurons may in part confer a selective advantage on these cells such that they "out-compete" others in the race to establish synaptic connectivity. In this mini-review we highlight some of the salient features of RNA targeting and translation in neurons.     

Statistical analysis of findings in external and internal audits and assessments in a testing laboratory

A statistical analysis of findings in assessments by an accreditation body, external audits and internal audits in an accredited testing laboratory for gamma-ray spectrometry is presented. The frequencies of observations reported in different areas were examined and analysed. The differences are interpreted in terms of the varying importance associated with the different areas as perceived by auditors and assessors.     

Parallel analysis of stimulants in saliva and urine by gas chromatography/mass spectrometry: perspectives for "in competition" anti-doping analysis

Stimulants are banned by the World Anti-Doping Agency (WADA) if used “in competition”. Being the analysis of stimulants presently carried out on urine samples only, it might be useful, for a better interpretation of analytical data, to discriminate between an early intake of the substance and an administration specifically aimed to improve the sport performance. The purpose of the study was to investigate the differences, in terms of excretion/disappearance of drugs, between urine and oral fluid, a sample that can reflect plasmatic concentrations.Oral fluid and urine samples were collected following oral administration of the following stimulants: modafinil (100 mg), selegiline (10 mg), crotetamide/cropropamide (50 mg each), pentetrazol (100 mg), ephedrine (12 mg), sibutramine (10 mg), mate de coca (a dose containing about 3 mg of cocaine); analysis of drugs/metabolites was carried out by gas chromatography/mass spectrometry (GC/MS) in both body fluids.Our results show that both the absolute concentrations and their variation as a function of time, in urine and in oral fluid, are generally markedly different, being the drugs eliminated from urine much more slowly than from oral fluid. Our results also suggest that the analysis of oral fluid could be used to successfully complement the data obtained from urine for “in competition” anti-doping tests; in all those cases in which the metabolite(s) concentration of a substance in urine is very low and the parent compound is not detected, it is indeed impossible, relying on urinary data only, to discriminate between recent administrations of small doses and remote administrations of higher doses.