As part of the research work for the doctoral thesis, we applied the approach of theoretical purge factor (TPF) determination for the evaluation of mutagenic impurities in the synthesis of vortioxetine drug substance, which was developed at the pharmaceutical company Lek d.d. The approach is described in ICH M7 guideline: “Assessment and Control of DNA Reactive (Mutagenic) Impurities and Pharmaceuticals to Limit Potential Carcinogenic Risk”, which entered the implementation phase by regulatory authorities in June 2014. In addition to monitoring and declaring mutagenic impurities on the specification of active substance, starting material or intermediate, the pharmaceutical industry, through the ICH M7 guideline, has a fourth option which is based on an understanding of the synthesis process and on the assessment of the impact of process parameters on the level of impurities obtained and generated. Namely, the physicochemical parameters of impurities affect the degree of their removal; such as their chemical reactivity, solubility, volatility, ionizability, and other properties that allow the removal of impurities through physical processes (e.g., chromatography). By assigning numerical values to these parameters, we can thus calculate the purge factor, based on which we can determine the likelihood that a certain impurity will be removed throughout the synthesis process. This approach was proposed and first described by A. Teasdale et al. If the approach were accepted by regulatory authorities, this would mean for the pharmaceutical industry to reduce the time and financial risk and burden of developing sophisticated analytical methods for evaluating mutagenic impurities. The proposed TPF calculation approach has been used in a number of practical examples in recent years. The results indicate that this approach can pretty well predict the ability to purge impurities through the process and that theoretically determined values are quite conservative, especially in the case of solubility-based separation. This means that the likelihood of overestimating the process's purification capability with this approach is highly unlikely. The suitability and applicability of the described approach was evaluated in the doctoral thesis in the case of vortioxetine synthesis. In the first part of the doctoral thesis, TPF was calculated for four potentially mutagenic impurities that can be formed in the synthesis of vortioxetine. Based on the knowledge and monitoring of the synthesis process and the characteristics of the input materials, we determined values for the following physicochemical properties: chemical reactivity, solubility, volatility, ionizability, and recrystallization ability. Although, according to the principal approach proposed by Teasdale, recrystallization is covered under solubility term, in the case of vortioxetine, recrystallization process was considered to be an individual physical process for purification, since it was introduced in the synthesis for this purpose. Theoretical calculations were then compared with analytically determined values, which were obtained on the basis of practical research of process's purification ability (depletion studies). The calculated TPFs have been shown to be very conservative, especially in the case of solubility-based separation. The conservatism of the approach is very important because of potential deviations in the process, and using conservative values also reduces the likelihood of overestimating the ability of the process to purge impurities. In the practical example, we have shown that the TPF determination approach is a good support in choosing the appropriate control strategy for certain impurities. Based on the calculated TPF for one of the impurities, we can predict a good ability to purge the impurity through the process, and the TPFs for the other impurities indicate the need for further analysis and control in the process. In the second part of the doctoral thesis, we extended the use of the TPF determination approach to use in the selection and justification of appropriate starting materials (SMs). Two of the three regulatory SMs in vortioxetine synthesis are mutagenic, and due to their presence, other mutagenic impurities can be formed. In accordance with curently valid regulations, the possibility of the formation and purification of impurities that may arise from the selected SMs is one of the main criteria in selecting the appropriate SMs. As part of the research work for the doctoral thesis, we have shown that based on the calculated TPF for the mutagenic SM 1 and its related mutagenic impurities, we can predict their high purge ability. The same can be argued for all impurities that may arise from SM 3, whereas, based on the calculated TPF for SM 3 itself, the possibility of its presence in the final drug substance cannot be ruled out. Therefore, further analysis and process control are required for SM 3. In the continuation of the research work, the TPF determination approach was also applied to the non-mutagenic SM 2 and its related non-mutagenic impurities, using the impurity limits according to the ICH Q3A guideline to determine the required purge. Again, we have shown that recrystallization introduced into the vortioxetine synthesis process has a major impact on impurity purification, and we have suggested that recrystallization as a purification step would represent an additional criterion in justifying the selection of SMs. In the last part of the doctoral thesis, we assessed the acceptability of the TPF determination approach, based on the response received from the US health authorities to the registration dossier for obtaining a marketing authorization. Namely, the TPF determination approach was used as a control strategy for most of the potential mutagenic impurities in vortioxetine synthesis. Based on the response received from the FDA, we can see that the TPF determination approach is acceptable, but additional justification for the determination of individual factors was required, together with all available experimental data. The agency also seems to be very cautious when dealing with mutagens or carcinogens entering or resulting from the final steps of drug substance synthesis. In the case of mutagenic SM 3, the results of the calculated TPF indicated the need for further analyses, which were also performed. The results of the impurity carry over study showed that the content of SM 3 in vortioxetine is below 30 % of the acceptable limit, which means there is no need to include routine testing on the specification of the final drug substance. However, the justification of ICH M7 control strategy 4 based on these results was not accepted by the FDA. In this doctoral thesis, we have successfully demonstrated the applicability of the TPF approach on vortioxetine case, and its acceptability by the authorities, which for the time being require additional justifications for the calculated factors. The principle of the approach is very simple, however, a great deal of knowledge and understanding of the process is required to determine the correct values, especially in determining the reactivity and solubility factors which have the greatest impact on the removal of impurities. The manner in which TPFs are determined and the resulting acceptance by the authorities is likely to increase with the use of in silico tool for the determination of TPFs. The latter is based on a database containing data on the reactivity of certain substances under certain conditions and types of reactions. In this way, the determined TPFs are thus based on sound scientific evidence supporting the predicted factors.
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