Research design formation to determine quality indicators of potential API, 2. Quality risks arising in the process of scaling the synthesis procedure

Abstract

Within the framework of the current pharmaceutical legislation, harmonized as much as possible with the EU and the USA to ensure the import / export of high-quality medicines (within the framework of the ICH and the positions of the global pharmaceutical sector), the transfer of technology for obtaining an active pharmaceutical ingredient requires taking into account many factors. Particular attention should be paid to identifying and eliminating risks that may arise when transferring a compound synthesis procedure to an industrial site. The scaling up of the synthesis procedure is accompanied by risks that can affect the quality of the final product, its safety and effectiveness.

The aim. The aim of this work is to summarize information regarding the emergence of risks that may arise when scaling the method of synthesis of active biological substances and quality control methods that allow avoiding the emergence of risks in production, studying stability and further application in medical practice.

Materials and methods. To carry out the research, we used the collection and analysis of data presented in modern scientific literature and documents of regulatory bodies and the results of our own experimental studies. With the help of FMEA analysis, the stages of scaling of the synthesis technique are identified, which are the most critical, and appropriate measures are proposed to reduce them. Based on the results of a survey of experts in the field of organic synthesis and pharmaceutical production, an appropriate matrix was drawn up and the priority number of risks was calculated according to three criteria: the severity of the consequences, the likelihood of influencing the stages of scaling up the synthesis method, and the degree of probability of detecting a hazard.

Results. The risks arising from changes in the synthesis technology during the transfer of a laboratory procedure to a pilot and/or industrial site (simplification of the synthesis scheme, use of reagents and solvents of a different purity class, replacement of a compound isolation method, etc.) have been identified and can affect the pharmacological action, efficiency, safety and storage conditions of biologically active substances. On the basis of risk analysis, it is proposed to use quality control techniques that allow avoiding these risks in the future in the production of a biologically active compound.

Conclusions. The stages of scaling up the methodology for the synthesis of a potential active compound for transfer to clinical and preclinical trials are determined, the reasons for the emergence of risks that must be taken into account in the industrial synthesis of BAS, the development of quality control methods and the preparation of an appropriate “certificate of quality” for a new biologically active compound are considered