The stability of vaccines is of great interest industries and government institutions. Accelerated stability studies are designed to determine the rate of vaccine degradation over time as a result of exposure to temperatures higher than those recommended for product storage. However, commonly applied stability predictions based on application of zero- or first order kinetics are very often too simplified for description of the degradation of biological products, which frequently undergo complex and multistep degradation reactions. We used an advanced kinetic approach mixing with statistical analysis to fit the forced degradation data (ELISA, NTA … ) by computed kinetic parameters, and finally, to predict valuable the long term stability of vaccine. The modeling approach is based on the selection of the most appropriate kinetic equations which fit the degradation rate of compounds subjected to elevated temperatures, accelerating the rate of the reaction.
Keywords Results for Prediction of Reaction Extent
Predictive modeling for assessing the long-term thermal stability of a new fully-liquid quadrivalent meningococcal tetanus toxoid conjugated vaccine
Establishing product stability is critical for pharmaceuticals. We used a modeling approach to predict the thermal stability of a fully-liquid quadrivalent meningococcal (serogroups A, C, W, Y) conjugate vaccine (MenACYW-TT; MenQuadfi®) at potential transportation and storage temperatures. Vaccine degradation was determined by measuring the rate of hydrolysis through an increase of free polysaccharide (de-conjugated or unconjugated polysaccharide) content during six months storage at 25°C, 45°C and 56°C. A procedure combining advanced kinetics and statistics was used to screen and compare kinetic models describing observed free polysaccharide increase as a function of time and temperature for each serogroup.
Accelerated Predictive Stability for Vaccines
The main challenge for the formulation of biologically derived products is to control the rate of degradation of their constituents to ensure an acceptable lifetime during storage and transport around the world [1-3]. The concept of stability of biological compounds (proteins, viruses, bacteria) is complex to understand, involving theoretically, concepts of both thermodynamics and advanced kinetics. one way of estimating protein stability is to study the denaturation when a protein is subjected to chemical stress (denaturing agents, pH) or physical stress (temperature, pressure…, etc.).
Continous Monitoring of Shelf Lives of Materials by Application of Data Loggers With Implemented Kinetic Parameters
The evaluation of the shelf life of, for example, food, pharmaceutical materials, polymers, and energetic materials at room or daily climate fluctuation temperatures requires kinetic analysis in temperature ranges which are as similar as possible to those at which the products will be stored or transported in. A comparison of …
Biophysical virus particle specific characterization to sharpen the definition of virus stability
Vaccine thermostability is key to successful global immunization programs as it may have a significant impact on the continuous cold-chain maintenance logistics, as well as affect vaccine potency. Modern biological and biophysical techniques were combined to in-depth characterize the thermostability of a formulated rabies virus (RABV) in terms of …
Accurate prediction of vaccine stability under real storage conditions and during temperature excursions
Due to their thermosensitivity, most vaccines must be kept refrigerated from production to use. To successfully carry out global immunization programs, ensuring the stability of vaccines is crucial. In this context, two important issues are critical, namely: (i) predicting vaccine stability and (ii) preventing product damage due to excessive temperature excursions outside of the recommended storage conditions (cold chain break) …
Thermal decomposition of AIBN, Part B: Simulation of SADT value based on DSC results and large scale tests according to conventional and new kinetic merging approach
The paper presents the results of the common project performed with the Federal Institute for Materials Research and Testing, Berlin, Germany (BAM) concerning the comparison of the experimental results with simulations based on the application of the kinetic-based method and heat balance of the system for the determination of the self accelerating decomposition temperature (SADT). The substantial potential of the kinetic-based method is illustrated by the results of the simulation of SADT of azobisisobutyronitrile (AIBN) …
Determination of Thermal Hazard from DSC measurements. Investigation of Self-Accelerating Decomposition Temperature (SADT) of AIBN
The method of determination of the thermal hazard properties of reactive chemicals from DSC experiments is illustrated by the results of SADT simulations performed with azobisisobutyronitrile (AIBN). The kinetics of decomposition of AIBN in the solid state was investigated in a narrow temperature window of 72-94 °C, just below the sample melting. The kinetic parameters of the decomposition were evaluated by differential isoconversional method. The very good fit of the experimental results by the simulation curves, based on the determined kinetic parameters, indicated the correctness of the kinetic description of the process …
Advanced Kinetic Analysis as a Tool for Formulation Development and Prediction of Vaccine Stability
We have used a protein-based vaccine, a live virus vaccine, and an experimental adjuvant to evaluate the utility of an advanced kinetic modeling approach for stability prediction. The modeling approach uses a systematic and simple procedure for the selection of the most appropriate kinetic equation to describe the degradation rate of compounds subjected to accelerated conditions. One-step and two-step reactions with unlimited combinations of kinetic models were screened for the three products under evaluation. The most appropriate mathematical model for a given product was chosen based on the values of residual sum of squares and the weight parameter w. A relatively simple n-th order kinetic model best fitted the degradation of an adjuvanted protein vaccine with a prediction error lower than 10% …
Prediction of Thermal Stability of Materials by Modified Kinetic and Model Selection Approaches based on Limited Amount of Experimental Points
The experimental data collected in the discontinuous mode are often used for the computation of reaction kinetics and, further, for the simulation of the thermal stability of materials. However, the kinetic calculations based on limited amount of sparse points require specific criteria allowing correct choice of the best kinetic model. We present the modified kinetic computations allowing considering one, two or even more reaction stages by applying unlimited amount of combinations of different kinetic models for the best description of the reaction course. The kinetic parameters are calculated using the truncated Šestâk-Berggren (SB) approach and further verified by using the Akaike and Bayesian information criteria (AIC and BIC, respectively) …
Parameters Influencing the Correct Thermal Safety Evaluations of Autocatalytic Reactions
The stability of live-attenuated viruses is very challenging due to thermal sensitivity; therefore, solid form is usually required (often freeze-dried products). Micropellet technology is a lyophilization technology that has the potential to provide greater flexibility in the presentation of a given vaccine particularly in multi-dose format or in combination of different vaccines. As a novel vaccine alternative process, this spray freeze-dried (SFD) micropellet technology was evaluated using as a model a yellow fever virus produced in Vero cells (vYF) …
Technical note in Japanese based on HPLC data (limited amount of data points)
Technical note in Japanese based on HPLC data (limited amount of data points)
Scale-up Based on Advanced Kinetics. Influence of DTBP/Toluene Ratio on the Thermal Behavior of Samples in mg, kg and ton-Scales
The runaway reactions are generally investigated by the time-consuming Accelerating Rate Calorimetry (ARC) or in isothermal (ISO-ARC) or heat-waitsearch (HWS) modes. In present poster we discuss the application of the Differential Scanning Calorimetry (DSC) for the determination of the Time to Maximum Rate under adiabatic conditions (TMRad) of various concentrations of Ditert- butyl peroxide (DTBP) in toluene. Additionally we present the method of simulation of the course of ARC experiments …
Consideration of Autocatalytic Behavior in Determination of Self Accelerating Decomposition Temperature
When determining Self Accelerating Decomposition Temperatures (SADT) for shipment purposes, the kinetics of the decomposition reaction of the materials must be known. The simplified models assuming the first order decomposition kinetics are generally applied, however this traditional approach fails in correct SADT determination for autocatalytic and multistage overlapped reactions. For these cases a more universal, yet easily implemented, advanced method will be presented in which the detailed kinetic mechanism does not need to be known to correctly predict SADT …
Optimization of Modeling of Propellants Aging Investigated According to NATO AOP-48 Ed.2 Test Procedure
The stability test procedure according to NATO-AOP 48 Ed. 2 commonly applied for the explosives and nitrocellulose-based propellants is based on the assumption that the kinetic description of the process of stabilizer depletion can be done by applying the reaction-order (RO) model for the fitting experimental data. In the present paper another procedure is proposed by application more general Prout-Tompkins (PT) model based on the autocatalytic character of the reaction. Presented computer simulations indicate that PT model allows much better fit of the processes which kinetics is not fully determined …
Estimation of Time to Maximum Rate under Adiabatic Conditions(TMRad) using Kinetic Parameters derived from DSC – Investigation of Thermal Behavior of 3-Methyl-4-Nitrophenol
Kinetic parameters of the decomposition of hazardous chemicals can be applied for the estimation of their thermal behavior under any temperature profile. Presented paper describes the application of the advanced kinetic approach for the determination of the thermal behavior also under adiabatic conditions occurring e.g. in batch reactors in case of cooling failure. The kinetics of the decomposition of different samples (different manufacturers and batches) of 3-methyl-4-nitrophenol were investigated by conventional DSC in non-isothermal (few heating rates varying from 0.25 to 8.0 K/min) and isothermal (range of 200-260°C) modes …
Determination of SADT and Cook-Off Ignition Temperature by Advanced Kinetic Elaboration of DSC Data
The exothermic decomposition parameters of a single-base propellant were obtained using differential scanning calorimeter (DSC) tests conducted at various heating rates. The DSC signals were processed using the Friedman isoconversional method to compute activation energy as a function of conversion. There was excellent agreement between the experimental and the simulation plots, which confirms the validity of the kinetic model used to describe the propellant’s exothermic decomposition. The kinetic parameters and heat balance were subsequently analyzed and used for a simulation of cookoff experiments conducted at different experimental rates (heating rates 3.3 – 1.0 K/h and a heat-wait-search mode) …
Prediction of the Thermal Behaviour of Energetic Materials by Advanced Kinetic Modelling of HFC and DSC Signals
High energetic materials can slowly decompose during storage or transport particularly at elevated temperatures which may result in reduced performance and correct functionality. Even very low decomposition progress of the exothermic reaction resulting in minor heat release can significantly change the properties of the propellants leading to shortening of the service life-time. The reaction progress influencing already the behaviour of the samples can be in the range of ca. 1-2% of the total decomposition degree …
Prediction of the Ageing of Rubber using the Chemiluminescence Approach and Isoconversional Kinetics
A common scepticism towards the application of many product formulations results from the fact that their long-term stability is difficult to predict. In the present study we report on a new approach of kinetic analysis of the oxidation reactions of natural rubbers with and without stabiliser in an oxygen atmosphere at moderate temperatures using CL measurements carried out on a newly-developed instrumentation. The kinetic parameters of the oxidation process, calculated from the chemiluminescence’s signals by means of the differential isoconversional method of Friedman, were subsequently applied for the simulation of the rubber aging under different temperature profiles …
The Simulation of the Thermal Behavior of Energetic Materials based on DSC and HFC Signals
Two small calibre and four medium calibre types of propellants were investigated non-isothermally (0.25-4 K min-1) by differential scanning calorimetry (DSC) in the range of RT-260-C and isothermally (60-100°C) by heat flow calorimetry (HFC). The data obtained from both techniques were used for the calculation and comparison of the kinetic parameters of the decomposition process. The application of HFC allowed to determine the kinetic parameters of the very early stage of the reaction (reaction progress below 0.02) what, in turn, made possible the precise prediction of the reaction progress under temperature mode corresponding to real atmospheric changes according to STANAG 2895 …
Evaluating SADT by Advanced Kinetics-based Simulation Approach
Present study depicts the extension of the method of the application of the advanced kinetic description of the energetic materials decomposition by its combination with the exact heat balance carried out by numerical analysis and the determination of the Self-Accelerating Decomposition Temperature (SADT). Moreover, the additional parameters such as thermal conductivity of the self-reactive substances, the type of containers and insulation layers, and different temperature profiles of the surrounding environment were taken into consideration …
Advanced Kinetics-based Simulation of Time to Maximum Rate under Adiabatic Conditions
An adiabatic calorimeter is very often used for the investigation of runaway of exothermic reactions. However the ideal adiabatic environment is a theoretical state which during laboratory scale testing cannot be obtained but may only be approached. Deviation from the fully adiabatic state comes from (i) the thermal inertia of the test system or heat lost into the sample container and (ii) the loss of heat from the container itself to the environment that reflects the ‘operational adiabaticity’ of the instrument…
Advanced Simulation of the Lifetime of Energetic Materials based on HFC Signals
The prediction of the shelf life of energetic materials requires the precise determination of the kinetics of their decomposition. Due to the fact that energetic materials decompose with the evolution of heat, the thermoanalytical methods such as Differential Scanning Calorimetry (DSC) and Heat Flow Calorimetry (HFC) are often used for the monitoring the reaction rate and the evaluation of the kinetic parameters of these reactions. In the present paper we describe the precise, advanced method of the evaluation of the kinetic parameters from HFC signals …
Prediction of Thermal Stability of Fresh and Aged Parchment
The hyphenated thermal analysis-mass spectrometry technique (TA-MS) was applied for the investigation of the thermal behavior of reference and aged parchment samples. The kinetic parameters of the process were calculated independently from all recorded TA and MS signals. The kinetic analysis showed the distinct dependence of the activation energy on the reaction progress. Such behavior is characteristic for the multistage mechanism of the reaction …
Up-Scaling of DSC Data of High Energetic Materials
Differential scanning calorimetry (DSC) carried out with few heating rates was applied in the studies of the thermal properties of four energetic materials: EI® propellant, high explosive PBXW-17, pyrotechnic mixtures with composition B/KNO3 (50:50) and B/KNO3 (30:70). DSC signals, after optimization of the baseline, were used for the calculation of the kinetic parameters (KP) of the decomposition process applying advanced kinetic software designed by AKTS. The determination of the kinetic parameters was based on the differential iso-conversional method of Friedman. The correctness of the estimation of KP was checked by the comparison of the experimental and predicted courses of the decomposition …
The Prediction of Thermal Stability of Self-Reactive Chemicals
An advanced study on the thermal behaviour of double base (boost and sustain propellant) rocket motor used in a ground to air missile has been carried out by differential scanning calorimetry (DSC). The presence of two propellants as well as the different experimental conditions (open vs. closed crucibles) influence the relative thermal stability of the energetic materials. Several methods have been presented for predictions of the reaction progress of exothermic reactions under adiabatic conditions. However, because decomposition reactions usually have a multi-step nature, the accurate determination of the kinetic characteristics strongly influences the ability to correctly describe the progress of the reaction …
Prediction of the Progress of Solid-State Reactions under Different Tempreature Modes
Using a computational method (AKTS-TA-Software) for solid-state kinetic analysis, the calculations of the progress of solid-state reactions were achieved employing temperature conditions different from those at which the experiments were carried out. The prediction of the solid-state reaction extent is illustrated by the results obtained during decomposition of hydromagnesite (component of some pharmaceuticals) …