Maximum Allowable Uncertainty Research Articles

The role of analytical performance specifications in international guidelines and standards dealing with metrological traceability in laboratory medicine.

The goal of metrological traceability is to have equivalent results for a measurand in clinical samples (CSs) irrespective of the in-vitro diagnostic medical device (IVD-MD) used for measurements. The International Standards Organization standard 17511 defines requirements for establishing metrological traceability of values assigned to calibrators, trueness control materials and human samples used with IVD-MDs. Each step in metrological traceability has an uncertainty associated with the value assigned to a material. The uncertainty at each step adds to the uncertainty from preceding steps such that the combined uncertainty gets larger at each step. The combined uncertainty fora CS result must fulfil an analytical performance specification (APS) for the maximum allowable uncertainty (umax CS). The umax CS can be partitioned among the steps in a metrological traceability calibration hierarachy to derive the APS for maximum allowable uncertainty at each step. Similarly, the criterion for maximum acceptable noncommutability bias can be derived from the umax CS. One of the challenges in determining if umax CS is fulfilled is determining the repeatability uncertainty (u Rw) from operating an IVD-MD within a clinical laboratory. Most of the current recommendations for estimating u Rw from internal quality control data do not use a sufficiently representative time interval to capture all relevant sources of variability in measurement results. Consequently, underestimation of u Rw is common and may compromise assessment of how well current IVD-MDs and their supporting calibration hierarchies meet the needs of clinical care providers.

New, simple and express determination of lamotrigine in tablets by using diazole red 2J

Epilepsy is considered one of the most common chronic neurological diseases among humans. Lamotrigine is an effective new-generation anticonvulsant, which is widely introduced to the pharmaceutical market by various drug manufacturers. That is why the urgent aim for pharmaceutical analysis is developing of high precision, valid, accessible and quantitative methods for lamotrigine in pharmaceuticals.
 The aim of the work is to study the optimal conditions for the reaction between lamotrigine and diazole red 2J, to define the coefficients of stoichiometric relationships in the “pharmaceutical substance – reagent” system and to develop a valid, sensitive and easy-to-follow technique for the quantitative determination of lamotrigine in pharmaceutical forms.
 Material and methods. As reagent and solvent, diazole red 2J of AR grade and acetone of AR grade were used. Analytical equipment: Specord 200 spectrophotometer, ABT-120-5DM electronic scales, Elmasonic E 60H ultrasonic bath and measuring glassware of A class.
 Results. A new spectrophotometric method for the quantitative determination of lamotrigine in four pharmaceutical formulations based on interaction with diazole red 2J in acetone medium has been developed. The proposed method is valid according to such validation characteristics as linearity, precision, intra-laboratory precision, accuracy, application range and robustness. The subordination to Behr's law is in the range of concentrations of 2.20–3.36 mg/100 ml. The LOD and LOQ values based on the values of the calibration line were 0.00450 % and 0.0138 % respectively. It was found that the studied coloured solutions are stable for at least 60 min and fluctuations in the amount of added red diazole 2J solution within ±10 % do not significantly affect the value of optical density. The coefficients of stoichiometric ratios between the components of the “lamotrigine – diazole red 2J” reaction mixture were defined by three methods and are 1:1. The predicted complete uncertainty of the results of analysis for quantitative determination of lamotrigine in the pharmaceutical form (2.2 %) does not exceed the maximum allowable uncertainty for the technique (3.2 %) and meets the SPhU requirements.
 Conclusions. According to the experimental data, the technique can be correctly reproduced and it is suitable for using in laboratories of the State Inspection for Quality Control of Medicines and QCD of the chemicopharmaceutical enterprises

A probabilistic approach to assessment of the quality of drinking water

Abstract Knowledge of uncertainty in analytical results is of prime importance in assessments of compliance with requirements set out for the quality of water intended for human consumption. Assessments of drinking water quality can be performed using either a deterministic or a probabilistic method. In the former approach, every single result is referred directly to the parametric value, while in the probabilistic method uncertainty related to analytical results is taken into account during the decision-making process. In the present research, laboratory uncertainty and uncertainty determined on the basis of results of analyses of duplicate samples collected in two Polish cities were compared and used in the probabilistic approach of water quality assessment. Using the probabilistic method, more results were considered to be “above the parametric value”. Most excesses were observed when the maximum allowable uncertainty as set out in the Regulation of the Minister of Health of 7 December 2017 was used, which is due to the highest values of these uncertainties. The lowest values above parametric values in the probabilistic approach were observed when measurement uncertainty was considered.

Standardization of original medicine anti-alcohol action on assay of glycin

Aim. Development and validation of an accessible method for the quantitative determination of glycine in a new original drug used in condition of alcohol dependence.Methods. To quantify glycine in a drug in the form of an effervescent powder for the preparation of an oral solution, a spectrophotometric method was developed and validated using a Specord 200 spectrophotometer from “Analytik Jena”.Results. As a result of the study, a modified sensitive method for the quantitative determination of glycine by a spectrophotometric method was developed. The optimal conditions for carrying out the glycine – ninhydrin reaction were selected in order to obtain stable analysis results: analytical wavelength – 568 nm; heating the reaction mixture is carried out in a boiling water bath for 30 minutes; the volume of the buffer solution is 4 ml, the pH of the buffer solution is 6.8, and a reducing agent – ascorbic acid was introduced. It was established that the methodology does not have a systematic error; the relative uncertainty for the probability of 95 % does not exceed the maximum allowable uncertainty of the analysis results (1,77 % ≤ 2,4 %). Validation parameters such as specificity, linearity, accuracy, precision and robustness were studied for the glycine quantification procedure. It was established that all calculated validation parameters meet the acceptability criteria.Conclusions. An accessible sensitive spectrophotometric technique based on the ability of the products of the interaction of glycine with ninhydrin to absorb in the visible region of the spectrum has been developed and validated. All validation parameters meet the acceptability criteria

Output regulation in the presence of quadratically bounded parameter uncertainties

The problem of robust output regulation is studied for a class of parameter uncertain systems under unity output feedback control. The objective is tracking of the desired reference trajectory in the presence of the disturbance, both generated by a common exosystem. Because of the anti-stability of the exosystem and potentially unbounded reference trajectory, the output tracking error is employed as the measurement signal and used as the input to the feedback controller. The method of p-copy of the internal model is utilised to augment the plant dynamics. Assuming that the output regulation condition is satisfied for all the parameter uncertainties, it is shown that the problem of robust output regulation is equivalent to the problem of robust output stabilisation. Furthermore, for quadratically bounded parameter uncertainties, an application of the notion of the quadratic stability leads to H ∞ -based robust control, and the maximum allowable uncertainty bound can be computed, below which the robust output regulation can be achieved.

Output Regulation for a Class of Parameter Uncertain Systems

The problem of robust output regulation is studied for a class of parameter uncertain systems under unity output feedback control. The objective is tracking of the desired reference trajectory in the presence of the disturbance, both generated by a common exosystem. Because of the anti-stability of the exosystem and potentially unbounded reference trajectory, the output tracking error is employed as the measurement signal and used as the input to the feedback controller. The method of p-copy of the internal model is utilized to augment the plant dynamics. Assuming that the output regulation condition is satisfied for all the parameter uncertainties, it is shown that the problem of robust output regulation is equivalent to the problem of robust output stabilization. Furthermore for quadratically bounded parameter uncertainties, an application of the notion of the quadratic stability leads to H∞ based robust control, and the maximum allowable uncertainty bound can be computed, below which the robust output regulation can be achieved.

ВАЛІДАЦІЯ МЕТОДИКИ КІЛЬКІСНОГО ВИЗНАЧЕННЯ КРОМОГЛІКАТУ НАТРІЮ В ОЧНИХ КРАПЛЯХ ПРОТИАЛЕРГІЙНОЇ ДІЇ

<p align="left"><strong>Validation</strong><strong> </strong><strong>studies</strong><strong> </strong><strong>of</strong><strong> </strong><strong>cromoglicate</strong><strong> </strong><strong>sodium</strong><strong> </strong><strong>assay</strong><strong> </strong><strong>at</strong><strong> </strong><strong>eye</strong><strong> </strong><strong>drops</strong><strong> </strong><strong>with antiallergic action</strong><strong></strong></p><p><strong>Е. G. F</strong><strong>etisova</strong></p><p>NationalUniversityofPharmacy,Kharkov</p><p><strong>Introduction.</strong> Today during pharmaceutical development of drugs as well as at the all stage of product lifecycle, significant sense obtain analytical supporting of experiments and estimation of analytical methods which are necessary for control of process and finished products. The analytical methods, conditions of their carrying out, reagents and standard samples should be standardized with aim to obtain reproducing results that are required at the carrying out of drug pharmaceutical development and at the composition of drug registration materials. In accordance with the requirements of the State Pharmacopoeia of Ukraine (SPU) all methods of drug quality control should be validated and proved experimentally that the method is available for intended purposes. We have developed eye drops with antiallergic action based on cromoglicate sodium (CS) and the method of quantitative determination of cromoglicate sodium at the eye drops by the spectrophotometric method. The aim of the work is the determination of the method validation characteristics and experimental evidence that the method can make reliable and reproducing results for the test “Assay”.</p><p><strong>Materials and methods</strong>. The drug in the form of eye drops based on CS in the therapeutic concentration of 2% was the object of study. CS produced by company "Fermion" (Finland) and conformed to European Pharmacopoeia, was used for preparing of the eye drops. Absorption spectrophotometry in the UV region (SPU, 2.2.25) was the method of study. Analytical equipment: spectrophotometer UV-VIS HP 8453, company "Hewlett Packard" (USA); laboratory digital scales VA-210S, firm "Sartorius" (Germany); measuring vessels accuracy class A.</p><p><strong>R</strong><strong>esults and discussion</strong>. Validation of the developed method of quantitative determination of CS have been conducted in accordance with the requirements of SPU by major validation characteristics: specificity, accuracy, precision (convergence), linearity, range, intermediate precision. Also, the calculation of estimated total uncertainty of the analysis have been carrying out. According to the requirements of SPU the concentrations range for the study of linearity, accuracy and convergence has been ranged from 80 % to 120 % in increments of 5 %, the eligibility criteria was designed for B = 5 %, so the maximum uncertainty analysis should not exceed 1.6 %. Method characterized by sufficient convergence and accuracy throughout the range of concentrations studied. Found the relative size of the confidence interval (Δ<sub>Ζ</sub> = 1,23 %) is less than the critical value for the convergence of the results (1,6 %). Systematic error of the method (δ = 0,04 % < 0,41) is almost insignificant. Specificity is confirmed by insignifican deposit "placebo" in the total amount of background absorption compared with the maximum allowable uncertainty analysis (∆<sub>As</sub> = 1,6 %) and excipients do not interfere with the quantitative determination of CS in the preparation. Intermediate precision of the analysis have been confirmed by the compliance of the relative confidence interval for 6 replicates of a series of eye drops with 2 % CS (Δ<sub>Ζ</sub> = 0,62 %) to acceptance criteria (≤ 1,6 %). Full predicted uncertainty of the test results for the "Assay" of cromoglicate sodium (Δ<sub>As </sub>= 1,42 %) is less than critical value (1,6 %), so the method will give correct results in other laboratories on this indicator.</p><p><strong>Conclusion</strong>. The method of quantitative determination of CS at the eye drops by the spectrophotometric method has been validated in accordance with the requirements of the State Pharmacopoeia of Ukraine. For the test it has been established accordance to specified acceptance criteria for the assay limits ±5% by the validation parameters: specificity, linearity, precision (precision), accuracy within the using range (80-120% of the nominal contents). The complete uncertainty forecast of the method was carried out in order to confirm it correctness when reproduce at other laboratories and it was established that the projected total uncertainty of the results wasn’t exceed the required acceptance criteria. Based on the results of validation studies it has been substantiated and verified experimentally that the test can make reliable results, can be correctly reproduced and be suitable for quality control of 2% eye drops based on CS during differing stage of product lifecycle.</p>

Calibration of imprecise and inaccurate numerical models considering fidelity and robustness: a multi-objective optimization-based approach

Traditionally, model calibration is formulated as a single objective problem, where fidelity to measurements is maximized by adjusting model parameters. In such a formulation however, the model with best fidelity merely represents an optimum compromise between various forms of errors and uncertainties and thus, multiple calibrated models can be found to demonstrate comparable fidelity producing non-unique solutions. To alleviate this problem, the authors formulate model calibration as a multi-objective problem with two distinct objectives: fidelity and robustness. Herein, robustness is defined as the maximum allowable uncertainty in calibrating model parameters with which the model continues to yield acceptable agreement with measurements. The proposed approach is demonstrated through the calibration of a finite element model of a steel moment resisting frame.

Study of the uncertainty in NO2 chemiluminescence measurements due to the NO–O3 reaction in sampling lines

The change in light intensity that takes place when an ambient air sample is drawn into the detection chamber of a chemiluminescence monitor generates changes in the concentrations of several species, such as NO(2), NO and O(3). Although this phenomenon has been known for several decades, there is still no commonly accepted approach on when or how to correct for it in NO(2) and O(3) readings. In this work, we have assessed the expanded uncertainty of two chemiluminescence NO( x ) analysers commercially available according to EN 14211:2005, with the aim of establishing the maximum allowable standard uncertainty due to the reaction between NO and O(3) in the sampling system. Although this maximum allowable uncertainty cannot be a universal value-as it will depend on the performance of each analyser-our results have led us to propose the conservative value of 2%. We have also proposed a methodology for improving data quality which could be easily implemented by those responsible for air quality data validation.

Existence, stability and robustness analysis of limit cycles in hybrid anti-lock braking systems

We investigate the stability and robustness properties of anti-lock braking systems (ABS) based on actuators with on/off dynamics. Namely, we propose a hybrid ABS controller which gives rise to an asymptotically stable limit cycle on the wheel slip. The proposed approach allows to derive exact information on the maximum allowable uncertainty in the measured variables which guarantee the cycle stability. Moreover, a structural stability analysis is performed with respect to different road conditions and to the actuator rate limit.

Robust optimal solution to the attitude/force control problem

Many spacecraft have an orbit control subsystem (OCS) which applies forces in order to maintain the orbital parameters within certain bounds. On the other hand, the attitude control subsystem (ACS) applies torques so that the spacecraft keeps its desired orientation. We explore the interaction of an orbital control maneuver with the attitude of a spacecraft. We propose to use the thrusters that provide the force for the orbit control as actuators to control the attitude as well. We obtain the conditions on the thruster configuration which guarantee that any perturbation torque can be compensated while performing the orbit control maneuver. We prove that the minimum number of thrusters which solve this problem is 4. Furthermore, we prove that the same problem can be solved with a minimum of 6 thrusters if a single failure in any thruster is accepted. We compute a robustness index which measures the maximum allowable uncertainty in the thruster configuration while still solving the problem stated previously. In the case of 4 thrusters with bounded thrusts, we solve the problem of maximizing the resulting force in a certain direction.

6.2.4 A Nordic Reference Serum Suitable for Use as Trueness Control in the Clinical Routine Laboratory

The described reference serum is characterized by: liquid human serum at "normal" level stored in frozen state at -80 degrees C; minimum damage of proteins; aseptic preparation; cryoprecipitate and excess fibrin removed; serum cleared by ultracentrifugation; pH at 7.2-7.6; available in sealed glass ampoules with inert gas (one ml serum in each); specified components among most frequently analyzed analytes; homogeneity assured and stability monitored; produced under strict rules for good manufacturing practices (GMP). The assigned values are traceable to reference measurement procedures and reference materials of highest achievable metrological level; according to the present proposal the maximum allowable uncertainty of the assigned value is based on biological variation (shared common reference intervals); the uncertainty should ideally not exceed 1/5 of the maximum allowable bias of results obtained on patients samples (even 1/2 would theoretically be acceptable and, for a practical guide approximately < 1% may suffice). The present document provides some guidance of how the reference serum could be established in practice. The document also indicates the use of the material and further extension of the concept. The present work is done as a NORDKEM project.

An analysis of the lead-angles necessary for tracking and pointing at distant targets

A rigorous analysis is made of the lead-ahead problem that arises when a moving observer must track and point at a moving target at long range. The effect of errors in the predict-ahead time and in the range upon lead-angles is studied. For general target and observer motions in three dimensions, sufficient conditions are exhibited under which the relative error in the lead-angles is, to good approximation, directly proportional to the relative error in range. It is further shown how lead-angle requirements impose a constraint upon the maximum allowable uncertainty in range. Finally, the analysis is applied to a numerical example.