Measurement Uncertainty and Conformity Assessment Applied to Drug and Medicine Analyses - A Review.

Analytical results are often used in scientific research, industrial and clinical applications to support decision making. Despite all efforts to ensure the reliability of analytical results (including method validation, internal quality control, use of certified reference materials, proficiency tests, and ISO 17025 accreditation), there will always be an uncertainty associated with the measured value. The measurement uncertainty expresses the quality of the analytical result and allows the comparability between analytical results or between the measured value and the specification limit(s). This work discusses the importance of measurement uncertainty, including the steps involved in the measurement uncertainty evaluation, the bottom-up and top-down approaches used in measurement uncertainty calculation, the measurement uncertainty evaluation in drug and medicine analyses, and the application of measurement uncertainty in conformity assessment for quality control, stability studies, and pharmaceutical equivalence.

Frequentist approach for estimation of false decision risks in conformity assessment based on measurement uncertainty of liquid chromatography analytical procedures.

The measurement uncertainty (MU) related to analytical results can lead to false decisions in conformity assessment, such as accepting or rejecting incorrectly a medicine lot (consumer's and producer's risks, respectively). These risks can be global or specific. It is important to understand the different types of conformity decision risks, and the different approaches to estimate them to ensure the reliability of the analytical results. Thus, the aim of this work was to estimate the specific consumer's and producer's risks from the MU values of 64 liquid chromatography analytical procedures for antibiotic or antifungal assays, in order to evaluate their performances in conformity assessment. The specific risks of the analytical procedures were estimated by the frequentist approach following normal distribution using Microsoft Excel® software, and in addition a spreadsheet was created to be available as supplementary material to estimate specific risks by this approach. Moreover, the global risks of the analytical procedures were estimated using Bayesian approach, assuming a uniform scenario of production process. And finally, the estimation of specific risks by Bayesian and frequentist approaches was compared. Only 39 % of the evaluated analytical procedures had MU within the recommended. When the result is close to the specification limit, the risk can be significant, in such cases, a strategy is to adopt guard bands to reduce or expand the specification limits, minimizing the risks. The spreadsheet created shows the risk of false decision for a MU value, considering results within and outside the specification limits, allowing to verify the risk according to the analytical result obtained. The global risks values were practically equal to the expanded uncertainty values, as there is no tendency of the production process between lots within or outside the specification, but once the analytical result is known, the frequentist approach provides a more reliable risk estimate (specific risk). The specific risks estimated by Bayesian and frequentist approaches were divergent by the influence of the production process information on the first approach, which may overestimate or underestimate the consumer's and producer's risks regarding the frequentist approach. Failures in medicine conformity assessment can cause much damage, therefore, preventive actions such as developing, evaluating and/or optimizing analytical procedures, are essential in order to guarantee measurement uncertainties below or equal to the target and adopt routine strategies to minimize the risk of false decisions in conformity assessment.

Measurement uncertainty and risk of false conformity decision in the performance evaluation of liquid chromatography analytical procedures.

Liquid chromatography is one of the main techniques used in pharmaceutical quality control analytical procedures. However, there will always be a measurement uncertainty (MU) associated with them, that can lead to the approval of an out of specification lot (consumer risk) or rejection of a lot within specification (producer risk). Thus, the aim of this study was to evaluate the performance of liquid chromatography analytical procedures based on their measurement uncertainty and to estimate the risk of false conformity decisions. The uncertainties of the analytical procedures were estimated based on the results of validation (trueness and precision). Then, the ratio between overall uncertainty and specification range (U/T%) was calculated. It was noted that in most cases (73%), random errors (precision) contributes more significantly to the overall uncertainty when compared to systematic errors (trueness). Monte Carlo method was used, generating different manufacturing processes scenarios, and analytical results based on the MU of each analytical procedure. Then, consumer's and producer's risks were estimated from the simulated values. Pharmaceutical dosage forms that require more steps in sample preparation had higher measurement uncertainties, often above the recommended target uncertainty. As most of the analytical procedures showed U/T% values above recommended, the majority presented high estimated risk values and did not fit for purpose. Therefore, it is important to considerate the measurement uncertainty as part of analytical procedures validation, since trueness and precision values affect directly the measurement uncertainty and the risk of false conformity decisions.

Biscoitos de polvilho do comércio do estado de São Paulo, Brasil: composição da gordura com destaque para os ácidos graxos trans / Cassava biscuits from the market of São Paulo State, Brazil: fat composition with emphasis on trans fatty acids

A redução dos níveis de ácidos graxos trans (AGT) em produtos de panificação tem sido uma meta do setor produtivo brasileiro. A fim de avaliar a composição da gordura de biscoitos de polvilho, foram analisados produtos comerciais do estado de São Paulo, em 2009 (14 amostras) e 2013 (11 amostras). A gordura foi determinada por gravimetria (hidrólise prévia) e os ácidos graxos, por cromatografia em fase gasosa. Em ambos os períodos, os níveis médios de gordura total (17 e 18%) e AGT (3%) foram elevados. Pelo menos um dos componentes variou mais do que 20% do declarado, em 86% (2009) e 55% (2013) das amostras. Das 25 amostras analisadas, 20 continham gordura hidrogenada e altos teores de AGT; três amostras (com óleos de palma/ láuricos) apresentaram baixos teores de AGT, porém elevados de ácidos graxos saturados (AGS). Outras duas amostras, contendo óleo vegetal, apresentaram quantidades insignificantes de AGT e consideráveis de ácidos graxos poli-insaturados, benéficos à saúde, porém susceptíveis à oxidação. Os resultados indicam a necessidade de continuidade no monitoramento deste produto e do desenvolvimento de alternativas tecnológicas para adequá-lo às recomendações de redução dos componentes relacionados ao risco de doenças cardiovasculares, especialmente os AGT.