Evaluation of measurement uncertainty of laboratory endocrine test items / 中国现代医生

Objective To evaluate the measurement uncertainty of endocrine test items by"top-down"method.Methods The"top-down"method in the technical report of CNAS-CL01-G003:2021"Medical Laboratory-Evaluation and Expression of Measurement Uncertainty"was used,collecting the laboratory's internal quality control data and the external quality assurance results of Beijing Clinical Laboratory Center from 2019 to 2021.To evaluate the measurement uncertainty of 11 endocrine tests including free triiodothyronine(FT3),total triiodothyronine(TT3)and free thyroxine(FT4).Results The relative expanded uncertainties of 11 endocrine test items in laboratory were FT3:12.658％,TT3:13.372％,FT4:10.468％,total thyroxine(TT4):32.382％,thyroid stimulating hormone(TSH):8.594％,estradiol(E2):18.656％,follicle-stimulating hormone(FSH):14.650％,luteinizing hormone(LH):29.384％,progesterone(PRO):28.806％,prolactin(PRL):13.810％and testosterone(TESTO):31.610％.At the normal concentration level,the relative expanded uncertainties were FT3:12.424％,TT3:12.462％,FT4:8.606％,TT4:14.130％,TSH:12.536％,E2:19.586％,FSH:14.382％,LH:23.400％,PRO:38.346％,PRL:16.014％and TESTO:39.352％.The relative expanded uncertainties at high concentration levels are FT3:13.882％,TT3:14.096％,FT4:11.040％,TT4:8.614％,TSH:7.782％,E2:14.366％,FSH:13.436％,LH:14.804％,PRO:11.574％,PRL:17.742％,TESTO:39.322％.The relative extended measurement uncertainty of TT4,LH near low concentration levels,PRO near low and normal concentration levels,and TESTO near three concentration levels was higher than the target uncertainty(25％),and the remaining items are less than the target uncertainty.Conclusion The quality control data in the laboratory can reflect the measurement uncertainty of 11 endocrine detection items including FT3,TT3 and FT4 in Abbott i2000SR automatic chemiluminescence immunoassay analyzer,which has important clinical application value.

Multivariate guard-bands and total risk assessment on multiparameter evaluations with correlated and uncorrelated measured values

Abstract The quality, efficacy, and safety of medicines are usually verified by analytical results. Measurement uncertainty is a critical aspect for the reliability of these analytical results. The pharmacopeial compendia usually adopt a simple acceptance rule that does not consider information from measurement uncertainty. In this work, we compared decision-making using simple acceptance and decision rules with the use of guard-band for multiparameter evaluation of ofloxacin ophthalmic solution and acyclovir topical cream. Ciprofloxacin ophthalmic solution and acyclovir topical cream samples were subject to pharmacopeial tests and assays. Multivariate guard-band widths were calculated by multiplying the standard uncertainty (u) by an appropriate multivariate coverage factor (k'). The multivariate coverage factor (k') was obtained by the Monte Carlo method. According to the simple acceptance rule, all the results obtained for ciprofloxacin ophthalmic solution and acyclovir topical cream are within the specification limits. However, the risk of false conformity decisions increases for ciprofloxacin tests. Decisions made using the simple acceptance rule and decision rules with the use of guard-band may differ. The simple acceptance rule may increase the risk of false conformity decisions when the measured value is close to the regulatory specification limits and/or when the measurement uncertainty value is inappropriately high. Nevertheless, the guard-band decision rule will always reduce the risk of false conformity decisions. Therefore, using information on measurement uncertainty in conformity assessment is highly recommended to ensure the proper efficacy, safety, and quality of medicines.

Risk of false conformity decisions due to measurement uncertainty of Active Pharmaceutical Ingredient: A multiparametric evaluation

Abstract Medicines must be subject to physical, chemical, and biological analysis to guarantee their quality, safety, and effectiveness. Despite the efforts to ensure the reliability of analytical results, some uncertainty will always be associated with the measured value, which can lead to false decisions regarding conformity/non-conformity assessment. This work aims to calculate the specific risk of false decisions regarding conformity/non-conformity of acetaminophen oral solution dosage form. The acetaminophen samples from five different manufacturers (A, B, C, D, and E) were subject to an active pharmaceutical ingredient assay, density test, and dose per drop test according to the official compendia. Based on measured values and their respective uncertainties, the risk values were calculated using the Monte Carlo method implemented in an MS Excel spreadsheet. The results for two acetaminophen oral solution samples (C and D) provided an increased total risk value of false acceptance (33.1% and 9.6% for C and D, respectively). On the other hand, the results for the other three acetaminophen samples (A, B, and E) provided a negligible risk of false acceptance (0.004%, 0.025%, and 0.045% for A, B, and E, respectively). This indicates that measurement uncertainty is very relevant when a conformity assessment is carried out, and information on the risks of false decisions is essential to ensure proper decisions.

Evaluation on measurement uncertainty of correction factors of fluconazole impurities determined by HPLC standard curve method / 中国药科大学学报

@#In this paper, the uncertainties of correction factors of fluconazole impurities determined by HPLC standard curve method were evaluated, and the main common factors affecting the accuracy of standard curve method were found, so as to improve the accuracy of the method.In this study, the corresponding fitting lines of fluconazole and its impurities A, B, C, D, F and I were established respectively, and the ratio of the slope of fitting lines of each impurity and its corresponding principal component was calculated as the correction factor of the impurity.Then on the basis of GUM method, the uncertainty of each impurity correction factor determined by standard curve method was evaluated according to the established uncertainty evaluation scheme of correction factor determination process.The correction factor and uncertainty of fluconazole impurities A, B, C, D, F and I were 1.068 ± 0.046, 0.102 ± 0.005, 0.0582 ± 0.0031, 1.382 ± 0.121, 0.802 ± 0.067 and 1.383 ± 0.119, respectively, and the coverage factor k was 2.Finally, the contribution rate of each uncertainty component was calculated.In the relative combined standard uncertainties urel(f) of fluconazole impurities A, B, C, D, F and I correction factors, the sum of contribution rate of slope uncertainty urel(K) of the linear equation of principal component and its impurity is more than 85%; in the slope uncertainties urel(K) of linear equation, the contribution rates of uncertainties of solution concentration in 8 of 12 data groups are more than 80%, and the contribution rates of uncertainties introduced by reference substance content in solution concentration are about 80%.It can be seen that the preparation of linear solution concentration is the most influential factor in the determination of impurity correction factor by standard curve method, followed by the linear fitting process.In the preparation process of linear solution concentration, the purity of reference substance is the most influential factor, followed by weighing and pipetting times.The conclusion can help the experimenters to better formulate experimental plans and ensure the accuracy of the results when doing similar work.

Incerteza de medição associada à contagem microbiana de produtos farmacêuticos / Measurement uncertainty associated with microbial count of pharmaceutical products

A contaminação microbiana pode comprometer a eficácia e a segurança dos produtos farmacêuticos. Os testes de contagem microbiana são utilizados para avaliar a qualidade microbiológica de produtos farmacêuticos não estéreis, exigidos pela maioria dos compêndios farmacopeicos. Apesar disso, raramente é considerada a avaliação da incerteza de medição para testes de contagem microbiana, o que pode levar a falsas decisões quanto à conformidade/nãoconformidade. Neste trabalho avaliamos os efeitos de matriz nos testes de contagem microbiana e sua avaliação de incerteza top-down, e avaliamos a incerteza da medição utilizando a abordagem bottom-up, além de que estimamos os riscos do consumidor ou do produtor devido à incerteza da medição. As incertezas combinada e expandida são calculadas empregando-se a abordagem topdown consideraram a exatidão (recuperação) e a precisão como os principais componentes de incerteza. O componente de incerteza da exatidão foi o mais relevante em 59% das amostras estudadas, enquanto a precisão foi a principal fonte de incerteza em apenas 41% das amostras, sendo observado que quanto maior a interferência da matriz, maior o fator de incerteza e, consequentemente, maior a assimetria para o intervalo em torno da medida. A partir da abordagem bottom-up, foram identificadas e quantificadas três principais fontes de incerteza: fator de diluição, volume plaqueado e contagem das placas. A contribuição dessas fontes de incerteza depende do valor medido da carga microbiana em produtos farmacêuticos, a contribuição do fator de diluição e das incertezas do volume plaqueado aumentam com o aumento do valor medido, enquanto a contribuição da contagem das placas diminui com o aumento do valor medido. Foi possível avaliar o risco de decisões falsas devido à incerteza de medição, por meio das estimativas dos riscos do consumidor ou do produtor. Os riscos foram avaliados utilizando-se o método Monte Carlo. Portanto, foi demonstrado a relevância da avaliação da incerteza de medição para garantir a confiabilidade dos resultados dos testes de contagem microbiana e a apoiar a tomada de decisões quando a avaliação da conformidade/não-conformidade dos produtos farmacêuticos não estéreis

Microbial contamination can compromise the efficacy and safety of pharmaceutical products. Microbial counting tests are used to assess the microbiological quality of non-sterile pharmaceutical products required by most pharmacopoeia compendiums. Despite this, measurement uncertainty assessment for microbial count tests is rarely considered, which can lead to false compliance/non-compliance decisions. In this work we evaluated the matrix effects on microbial counting tests and their top-down uncertainty assessment, and evaluated measurement uncertainty using the bottom-up approach, inaddition to estimating the consumer's or producer's risks due to measurement uncertainty. The combined and expanded uncertainties calculated using the top-down approach considered accuracy (recovery) and accuracy as the main components of uncertainty. The uncertainty component of accuracy was the most relevant in 59% of the samples studied, while accuracy was the main source of uncertainty in only 41% of the samples, being observed that the greater the interference of the matrix, the greater the uncertainty factor and, consequently, the greater the asymmetry for the interval around the measurement. From the bottom-up approach, three main sources of uncertainty were identified and quantified: dilution factor, platelet volume and plaque count. The contribution of these sources of uncertainty depends on the measured value of microbial load in pharmaceutical products, the contribution of the dilution factor and uncertainties of the plated volume increase with the increase in the measured value, while the contribution of plate counting decreases with the increase of the measured value. It was possible to assess the risk of false decisions due to measurement uncertainty by estimating consumer or producer risks. The risks were evaluated using the Monte Carlo method. Therefore, the relevance of measuring uncertainty assessment has been demonstrated to ensure the reliability of microbial count test results and to support decision-making when assessing non-sterile pharmaceutical conformity/non-compliance

Desenvolvimento de métodos microbiológicos rápidos (MMRs) para avaliação da potência de agentes antimicrobianos e suas incertezas de medição / Development of rapid microbiological methods (RMMs) for evaluation of potency of antimicrobial agents and their measurement uncertainties

O método de difusão em ágar tem sido utilizado na avaliação da atividade antimicrobiana desde a descoberta da penicilina. Apesar disso, pouco avanço ocorreu no sentido de reduzir o tempo necessário para a determinação dos halos de inibição de crescimento. O objetivo deste projeto foi desenvolver, otimizar e validar métodos microbiológicos rápidos (MMRs) para a avaliação da potência de agentes antimicrobianos, além de identificar, quantificar e avaliar as principais fontes de incerteza associadas à determinação da potência. O projeto foi dividido em quatro etapas: 1) influência da composição do meio de cultura na formação dos halos de inibição; 2) estudo da incerteza de medição associada à determinação da potência de agentes antimicrobianos; 3) desenvolvimento, otimização e validação de métodos microbiológicos rápidos (MMRs) para determinação da potência de agentes antimicrobianos e 4) determinação dos parâmetros envolvidos na formação dos halos de inibição de crescimento e estudo dos mecanismos de difusão e crescimento microbiano. Os resultados deste projeto possibilitaram a redução do tempo necessário para a determinação do tamanho dos halos de inibição. Adicionalmente, contribuiu com a elucidação dos mecanismos de difusão e crescimento microbiano, possibilitando identificar e quantificar as principais fontes de incerteza de medição associadas à formação dos halos de inibição

Agar diffusion method has been used in the evaluation of antimicrobial activity since the discovery of penicillin. Nevertheless, little progress has occurred in order to reduce the time required for the determination of growth inhibition zones. The goal of this project was to develop, optimize and validate rapid microbiological methods (RMMs) for evaluation of potency of antimicrobials, as well as to identify, quantify and assess the main sources of uncertainty associated with potency. The project was divided into four steps: 1) influence of culture medium composition on inhibition zones; 2) study of measurement uncertainty associated with antimicrobials potencies; 3) development, optimization and validation of rapid microbiological methods (RMMs) for the determination of antimicrobials potencies and 4) determination of the parameters involved in the formation of inhibition zones and study of mechanisms of diffusion and microbial growth. The results of this project allowed the reduction of the time required for the determination of inhibition zone sizes. Additionally, it contributed to the elucidation of the mechanisms of diffusion and microbial growth, making it possible to identify and quantify the main sources of measurement uncertainty associated with formation of inhibition zone sizes

Desarrollo de un material de referencia certificado para análisis elemental de agua potable / Development of a certified reference material for elemental analysis of drinking wáter / Desenvolvimento de um material de referência certificado para análise elementar de água potável

Resumen La producción de un material de referencia (MR) es un proceso en el que se realizan estudios relacionados con la preparación, envasado y caracterización (incluye homogeneidad y estabilidad). En este trabajo se presentan los resultados del desarrollo de un MR de agua potable. El envasado se realiza aplicando dos procedimientos (envasado convencional e inmersión). La caracterización se realizó por Absorción Atómica, ICPMS y Cromatografía iónica. La evaluación de homogeneidad del material se realizó para Na, Mg, Ca, Fe, K, Co, Pb, Mo, As, Ni, Se, Cu, Al, Cr Zn y aniones como NO3 - y Cl-. La estabilidad se evaluó a corto (condiciones aceleradas) y largo plazo por ICPMS y CI, además se realizó seguimiento gravimétrico. La homogeneidad y estabilidad se evaluaron con base en su incertidumbre. La incertidumbre asociada a la homogeneidad y estabilidad MR evidenció resultados aceptables para la mayoría de los analitos. Los resultados del seguimiento gravimétrico permitieron detectar pérdidas de masa del material, por lo que se planteó un nuevo esquema para evaluar la estabilidad a través de métodos gravimétricos. Finalmente, se encontró que el MR presenta incertidumbres expandidas entre el 0,93% y el 4,38%, siendo apto para el uso previsto.

Abstract The production of reference materials (RM) is a process that involves carrying out different studies related to the preparation, packaging and chemical stability of the analytes. This paper presents the results of the development of a drinking water RM. The packaging is done by applying two procedures (conventional packaging and immersion). The characterization of this material was carried out through atomic absorption, ICPMS and ion chromatography. The assessment of the homogeneity of the material was carried out for Na, Mg, Ca, Fe, K, Co, Pb, Mo, As, Ni, Se, Cu, Al, Cr Zn and anions as NO3 - y Cl-. The stability studies were evaluated in the short term (accelerated conditions), and long term by ICPMS and IC, and gravimetric monitoring was also performed. Homogeneity and stability were evaluated based on their uncertainty. The uncertainty associated with homogeneity and MR stability evidenced acceptable results for most analytes. The results of the gravimetric monitoring allowed to detect losses of mass of the material, reason why a new scheme was proposed to evaluate the stability through gravimetric methods. Finally, it was found that the RM presents expanded uncertainties between 0,93% and 4,38%, which makes it suitable for the intended use.

Resumo Este artigo apresenta os resultados do desenvolvimento de um MR de água potável. A embalagem é feita aplicando dois procedimentos (embalagem convencional e imersão). A caracterização foi realizada por Absorção Atômica, ICPMS e Cromatografia Iônica. A avaliação da homogeneidade do material foi realizada para Na, Mg, Ca, Fe, K, Co, Pb, Mo, As, Ni, Se, Cu, Al, Cr Zn e ânions como NO3 - y Cl-. A estabilidade foi avaliada em curto prazo (condições aceleradas) e em longo prazo pelo ICPMS e IC, e também foi realizada monitoração gravimétrica. A homogeneidade e estabilidade foram avaliadas com base na incerteza. A incerteza associada à homogeneidade e estabilidade da RM evidenciou resultados aceitáveis para a maioria dos analitos. Os resultados do monitoramento gravimétrico permitiram detectar perdas de massa do material, pelo que foi proposto um novo esquema para avaliar a estabilidade por métodos gravimétricos. Por fim, verificou-se que o RM apresenta incertezas expandidas entre 0,93% e 4,38%, sendo adequado para o uso pretendido.

Uncertainty analysis for detecting methyl mercury in fish tissue with liquid chromatography-atomic fluorescence spectrometry / 中国医学装备

Objective: To establish a method of liquid chromatography-atomic fluorescence spectrometry (LC-AFS), and carry out uncertainty analysis of detecting methyl mercury in fish tissue. Methods: LC-AFS method was adopted to determine the content of methyl mercury in fish tissue. And the theory of assessment and expression about uncertainty measurement based on JJF1059.1-2012 of State Administration for Market Regulation was applied to analyze the source of factors that affect its uncertainty. Through evaluated various factors of uncertainty and calculated and combined uncertainty to obtain the extended uncertainty of measurement results. Results: The content of methyl mercury in fish tissue by using LC-AFS wasω=(817.94±105.02)μg/kg (k=2, confidence level was 95%). Conclusion: The measurement uncertainty assessment can be used in the uncertainty analysis that LC-AFS measure content of methyl mercury in fish tissue. Therefore, the results are more reliable.

Further Understanding of Measurement Uncertainty in Clinical Laboratory Medicine / 现代检验医学杂志

In clinical laboratory medicine,measurement uncertainty (MU) is a fixed property of testing results in the measuring system.As an important part of ISO 15189,it is necessary for clinical laboratories to determine MU during the period of validation and verification for each measurement procedure and to review MU over time.Now,testing reports provided by clinical laboratories usually do not offer MU,but some clinical laboratories have already estimated MU in their routine work.Estimation andmonitoring of MU can help clinical laboratories offering more accurate results and provide objective tools for clinicians used in result intcrpretatinn.Generally,result interpretation can be achieved by the result comparison with three main comparators,including a previous result from the same patient,a population reference interval and a clinical decision point.The means of true value and the components contributing to the estimation of MU are both different when the com parison is conducted between testing results and different comparators,so the optimum estimation method of MU is accordingly different,which will subsequently affect the MU value and the determination of clinical decisions.Obviously,depending on the actual clinical uses,laboratories can choose appropriate comparators to the result interpretation and the determination of optimum estimation method of MU.For different clinical uses (diagnosis or monitoring) of the same mearurands,the adoption of different estimation methods should be used to acq uire reasonable MU.By interpreting the concept,characteristics,estimation,and uses of MU,as well as explaining how three main comparison methods of results exploit their own traceable chain to get MU,this paper intends to help clinical laboratories get further understanding of the importancc of MU and provide guidance for the MU estimation in routine work.

Measurement uncertainty of dissolution test of acetaminophen immediate release tablets using Monte Carlo simulations

ABSTRACT Analytical results are widely used to assess batch-by-batch conformity, pharmaceutical equivalence, as well as in the development of drug products. Despite this, few papers describing the measurement uncertainty estimation associated with these results were found in the literature. Here, we described a simple procedure used for estimating measurement uncertainty associated with the dissolution test of acetaminophen tablets. A fractionate factorial design was used to define a mathematical model that explains the amount of acetaminophen dissolved (%) as a function of time of dissolution (from 20 to 40 minutes), volume of dissolution media (from 800 to 1000 mL), pH of dissolution media (from 2.0 to 6.8), and rotation speed (from 40 to 60 rpm). Using Monte Carlo simulations, we estimated measurement uncertainty for dissolution test of acetaminophen tablets (95.2 ± 1.0%), with a 95% confidence level. Rotation speed was the most important source of uncertainty, contributing about 96.2% of overall uncertainty. Finally, it is important to note that the uncertainty calculated in this paper reflects the expected uncertainty to the dissolution test, and does not consider variations in the content of acetaminophen.