Accreditation and Quality Assurance (v.19, #5)

“Degrees of equivalence” for chemical measurement capabilities: primary pH by David L. Duewer; Kenneth W. Pratt; Chainarong Cherdchu; Nongluck Tangpaisarnkul; Akiharu Hioki; Masaki Ohata; Petra Spitzer; Michal Máriássy; Leoš Vyskočil (329-342).
The key comparison (KC) studies of the Consultative Committee for Amount of Substance—Metrology in Chemistry help ensure the reliability of chemical and biochemical measurements relevant to international trade and environmental-, health-, and safety-related decision making. The traditional final evaluation of each measurement result reported by a KC participant is a “degree of equivalence” (DEq) that quantitatively specifies how consistent each individual result is relative to a reference value. Recognizing the impossibility of conducting separate KCs for all important analytes in all important sample matrices at all important analyte levels, emphasis is now shifting to documenting broadly applicable critical or “core” measurement competencies elicited through a series of studies. To better accomplish the necessary synthesis of results, data analysis and display tools must be developed for objectively and quantitatively combining individual DEqs. The information detailed in the 11 KCs of primary method pH measurements publically available as of 2013 provides an excellent “best case” prototype for such analysis. We here propose tools that enable documenting the expected primary pH measurement performance of individual participants between pH 1 and pH 11 and from 15 °C to 37 °C. These tools may prove useful for other areas where the uncertainty of measurement is a predictable function of the measured quantity, such as the stable gases. That results for relatively simple measurement processes can be combined using relatively simple analysis and display methods does not ensure that similarly meaningful summaries can be devised for less well understood and controlled systems, but it provides the incentive to attempt to do so.
Keywords: CCQM; EAWG; Degree of equivalence; Key comparison; Leave-one-out strategy; Parametric Bootstrap Monte Carlo analysis; pH

The role of quality management system in the monitoring and continuous improvement of GMP-regulated short-lived radiopharmaceutical manufacture by M. Poli; D. Petroni; A. Berton; E. Campani; C. Felicini; S. Pardini; L. Menichetti; P. A. Salvadori (343-354).
The last decade has seen extraordinary growth in the clinical use of Positron Emission Tomography (PET), an in vivo molecular imaging modality widely used in oncology that requires the use of radiopharmaceuticals labeled with short-lived radionuclides. These medicinal products have found widespread application in Nuclear Medicine departments equipped with PET scanners. Due to the great increase in radiopharmaceutical demand, their production has been centralized and moved to industrial manufacturing sites in which Good Manufacturing Practice (GMP) principles and guidelines for medicinal products are to be applied. The production of PET radiopharmaceuticals features particular aspects such as the use of the lot before the completion of all tests, the multiplicity of batches produced per single day and the absence of product stock due to radionuclide short half-life. In this context, the application of quality principles to all stages of the process and the implementation of a quality management system (QMS) are of primary importance. This paper reports on the development of a QMS applied to a GMP manufacturing site of an in vivo PET diagnostic product, and on how its application can describe the performance of the site. Data were collected over a 6-year period (2008–2013) and demonstrate the ability of Key Performance Indicators, strictly related to the structure and organization of the QMS, and quality tools (data analysis, internal audit, etc.) to monitor process performance in terms of effectiveness, efficacy and stability.
Keywords: Radiopharmaceuticals; Process performance indicators; Quality management system; GMP; PET

The paper describes the activities carried out for the implementation of the quality management system (QMS) at the Laboratory of Radiological Protection and Safety (LPSR) in Portugal in order to achieve the management and technical requirements of ISO/IEC 17025:2005 and to get the accreditation for ten tests. The implementation of the QMS based on this international standard allowed LPSR to improve the methods, to identify problems, to implement preventive and corrective actions, to generate valid results and to achieve a stable level of high-quality output recognized by an independent body in the scope of waters, metrology, radiation and radiochemistry.
Keywords: Quality management system; ISO/IEC 17025:2005; Accreditation; Waters; Metrology; Radiation; Radiochemistry

A total of 54 scenarios of human errors in multi-residue analysis of pesticides in fruits and vegetables are mapped in a routine monitoring laboratory. The likelihood and severity of the errors and the ability of components of the laboratory quality system to prevent/block human errors, as well as the effectiveness of the quality system as a whole, are evaluated using expert judgments. It is shown that human errors in sampling are prevented less by the quality system than other steps of the analysis. Training and supervision are found as the quality system components having the highest priorities. Effectiveness of the quality system obtained a good score value of 71 % (in comparison with an ideal system preventing human errors with 100 % effectiveness). Variability of the score values resulting from changes of the expert judgments is discussed.
Keywords: Multi-residue analysis; Pesticides; Fruits; Vegetables; Quality assurance; Human error quantification

An interlaboratory comparison for the determination of aniline, nine methylated anilines and chlorinated anilines in contaminated groundwater (each compound between 1 µg L−1 and 750 µg L−1) was conducted as proficiency test for the selection of contract laboratories for a groundwater monitoring campaign. For the 13 participants, two different test sample series were prepared from a stabilized real case groundwater. Series A was the groundwater as sampled in the field and series B was prepared from series A by spiking with selected anilines. Homogeneity and stability investigations revealed that contaminated groundwater provides a viable basis for the preparation of ring test samples for the determination of anilines. Analytical procedures were limited to the standardized liquid–liquid extraction or solid-phase extraction in combination with gas chromatography/mass spectrometry (DIN 38407-16:1999). The robust consensus values were evaluated according to the standardized protocol of DIN 38402-45:2013. Robust reproducibility standard deviations ranged largely between 20 % and 60 % depending on the analyte. The proficiency assessment of individual participants combined the qualitative aspect of correct peak identification with the quantitative determination of individual concentrations within set limits in a unified approach. It could be shown that the accreditation status of laboratory and the existence of a standardized analytical procedure do not substitute a problem-related proficiency assessment of potential contractors.
Keywords: Aniline; Chloroanilines; Methylanilines; Groundwater; Interlaboratory comparison; Proficiency test

The gravimetric method specified by ISO 8655-6 is a standard method for calibrating piston pipettes (micropipettes). The quality of the calibration can be assessed by uncertainty evaluation, the procedure for which is described in ISO/Technical Report (TR) 20461. However, the existence of “method uncertainty” due to ambiguity in the calibration operation, which is not described in the TR, has been found in various experiments, such as the interlaboratory comparison of CCM.FF-K4.2.2011. In this report, the “method standard uncertainty” is quantified as exp(−4.51 + 0.36 ln(V nom/μL) + 0.05{ln(V nom/μL)}2) μL for a nominal volume, V nom, in the range from 2 μL to 10000 μL. Furthermore, the reported values in an interlaboratory comparison are confirmed to be consistent using the quantified method standard uncertainty.
Keywords: Piston pipette; Micropipette; ISO 8655; Calibration; Gravimetric method; Uncertainty

Development of a certified reference material for the determination of perfluorooctanoic acid by Nobuyasu Hanari; Taichi Yamazaki; Nobuyasu Itoh; Takashi Yarita; Naomi Fujiki; Ryoko Iwasawa; Yoshie Aoyagi; Masahiko Numata (391-396).
A certified reference material (CRM) for the determination of perfluorooctanoic acid (PFOA) has been issued as NMIJ CRM 4056-a by the National Metrology Institute of Japan, National Institute of Advanced Industrial Science and Technology (NMIJ/AIST). Purity (kg kg−1) based on a titration method was determined by subtracting the mass fractions of impurities measured using liquid chromatography/mass spectrometry (LC/MS) from those of acids expressed as PFOA measured by a neutralization potentiometric titration. To validate an obtained result, purity based on a mass balance method was determined by subtracting the mass fractions of impurities, measured using LC/MS, Karl-Fischer titration (KFT), and vacuum evaporation, from 1 kg kg−1. Results from both titration and mass balance methods were in agreement within the accepted limits of uncertainty. The certified purity of NMIJ CRM 4056-a was determined to be 0.959 kg kg−1, calculated as the mean of the results obtained with the two methods. The standard uncertainty of the certified purity was evaluated from purity evaluations as well as from sample homogeneity and stability obtained from LC/MS and KFT analyses. Consequently, the expanded uncertainty was estimated to be 0.005 kg kg−1 with a coverage factor of k = 2.
Keywords: Certified reference material (CRM); Perfluorooctanoic acid (PFOA); Potentiometric titration method; Mass balance method; SI

Application of ISO 13528 robust statistical method for external quality assessment of blood glucose measurements in China by Ya L. Xiao; Chuan B. Zhang; Hai J. Zhao; Feng F. Kang; Wei Wang; Kun Zhong; Shuai Yuan; Zhi G. Wang (397-401).
External quality assessment (EQA) including extensive participants often result in abnormal distribution. Robust statistical methods are insensitive to slight deviation for a given probability model and can estimate the population parameters utilizing robust algorithm. The aim of this study was to evaluate the blood glucose testing performance of EQA in China using ISO 13528 robust statistical method. A total of 4571 participants measured two lots of materials at different concentrations and submitted the results through the Clinet-EQA reporting system V1.5. Data were collected and analyzed by Clinet-EQA evaluating system and SPSS 13.0. Participants were classified by method principles they adopted. Acceptability of relative differences between each result and robust mean of the group was calculated using biological variation desirable quality specification for allowable total error. The kernel density plots and Youden Plot were also applied to show the distribution of z-scores. The robust means of the two lots were 6.31 mmol/L and 15.71 mmol/L, and the robust standard deviations were 0.23 mmol/L and 0.5 mmol/L, respectively. Acceptability of relative differences was more than 90 % among all groups. About 91.5% and 89.7 % of the participants out of the two lots fulfilled the condition of |z| ≤ 2. In addition, 87.2 % participants fell inside the confidence ellipse for probability levels of 95 % in Youden Plot. According to the statistical results, we can conclude that most participants are qualified for performing blood glucose test and ISO 13528 robust statistical method is appropriate for EQA result analysis.
Keywords: Blood glucose; Robust statistical method; z-scores; Youden Plot

Facility-based inspection training in a virtual 3D laboratory by C. Maderuelo; A. Martin-Suarez; J. S. Pérez-Blanco; H. Zazo; J. Cruz-Benito; A. Domínguez-Gil (403-409).
In order to train postgraduate students in the evaluation of a quality system in the pharmaceutical industry, it would be desirable to have installations constructed in accordance with the quality standards. This is very costly and unusual in universities. Virtual 3D worlds allow simulating immersive professional contexts for training. The first aim of this project is to design and construct a virtual analytical laboratory adapted to good laboratory practices (GLP) in the Second Life™ (SL) virtual world. The second aim is to set up a practice based on the inspection of the virtual laboratory installations. Finally, the students’ acquisition of knowledge and satisfaction were assessed. The laboratory is available online on the Usalpharma Island of SL. The installations, equipment and tools were created using SL’s building tools. During two academic years, a total of 30 students made an inspection of the laboratory to identify and classify nonconformities of a GLP quality system (supplementary video). They report the results in an assessment report. The following evaluation of the practice shows that the scores concerning the assessment of skills (7.1 ± 0.5 out of 10) and knowledge acquired (7.8 ± 0.3 out of 10) met the expectations of the authors. In an anonymous questionnaire, 81 % of the students assessed the experiment as satisfactory. The virtual laboratory allows, at very low cost, training postgraduate students in facilities not available at university. Tools like this could be implemented not only at universities, but in professional field in order to assess competencies or support the essential lifelong learning of the laboratory staff.
Keywords: GLP principles; Facility-based inspection; Virtual worlds; Virtual laboratory; Second Life; Pharmaceutical education