Application of a risk-based approach to determine critical parameters of the process of obtaining a lyophilisate based on a derivative of LCS-1269

Introduction. Maintaining the basic quality parameters of a drug is the key to its successful use in clinical practice. Productive use of the results of risk identification and assessment allows us to guarantee the effectiveness and safety of medicines through preventive measures to identify and eliminate potential threats to quality during their development and production.

Aim. The aim of the study was to identify critical points in the technological process of obtaining a lyophilized dosage form of a compound from the class of indolocarbazoles LCS-1269 using a risk-based approach.

Materials and methods. To analyze the risks in the technology for obtaining a lyophilisate based on LCS-1269, the risk management analysis tools and methods presented in the ICH Q8, Q9, Q10, State Pharmacopoeia of Russia XV ed. and ISO 31000-2019 guidelines were used.

Results and discussion. When identifying risks of the production process, the main critical process parameters and critical control points were identified, among which the most important are compliance with the mode of dissolution of the pharmaceutical substance and excipients, filtration of the resulting solution and its lyophilization, as well as control over the main quality indicators characteristic of lyophilized dosage forms for parenteral use.

Conclusion. The application of the selected approach made it possible to identify and assess possible risks to product quality at different stages of production of the drug "LCS-1269, lyophilisate for preparation of injection solution 25 mg" and to develop a strategy to eliminate or mitigate these risks and achieve the necessary goals, namely, obtaining high-quality, effective and safe drugs.

1. Tishkov S. V., Blynskaya E. V., Alekseev K. V., Alekseev V. K. Risk management aspects for quality in pharmaceutical development. Problems of biological, medical and pharmaceutical chemistry. 2023;26(3):3-10. (In Russ.) DOI: 10.29296/25877313-2023-03-01

2. Srishti S. A., Pinky P. P., Taylor R., Guess J., Karlik N., Janjic J. M. Quality by Design (QbD)-Driven Development and Optimization of Tacrolimus-Loaded Microemulsion for the Treatment of Skin Inflammation. Pharmaceutics. 2024;16(12):1487. DOI: 10.3390/pharmaceutics16121487.

3. Tabibzadeh M., Muralidharan A. Reducing Medication Errors and Increasing Patient Safety: Utilizing the Fault Tree Analysis. In: Lightner N. J., editor. Advances in Human Factors and Ergonomics in Healthcare and Medical Devices. Cham: Springer; 2019. P. 207–218. DOI: 10.1007/978-3-319-94373-2_23.

4. Glevitzky M., Glevitzky I., Mucea-Ștef P., Popa M., Dumitrel G.-A., Vică M. L. Integrated Risk Framework (IRF) – Interconnection of the Ishikawa Diagram with the Enhanced HACCP System in Risk Assessment for the Sustainable Food Industry. Sustainability. 2025;17(2):536. DOI: 10.3390/su17020536.

5. Gehring K. B., Kirkpatrick R. Hazard analysis and critical controlpoints (HACCP). In: Demirci A., Feng H., Krishnamurthy K., editors. Food safety engineering. Cham: Springer; 2020. P. 191-204. DOI: 10.1007/978-3-030-42660-6_8.

6. Lauri R., Incocciati E., Pietrangeli B., Tayou L. N., Valentino F., Gottardo M., Majone M. Hazop Analysis of a Bioprocess for Polyhydroxyalkanoate (PHA) Production from Organic Waste: Part B. Fermentation. 2023;9(2):154. DOI: 10.3390/fermentation9020154.

7. Signoret J. P., Leroy A. Hazard and operability study (HAZOP). In: Signoret J.-P., Leroy A. Reliability assessment of safety and production systems: analysis, modelling, calculations and case studies. Cham: Springer; 2021. P. 157–164. DOI: 10.1007/978-3-030-64708-79.

8. Blynskaya E. V., Tishkov S. V., Alekseyev K. V., Minaev S. V. Features pharmaceutical development lyophilisate GK-2 for parenteral use. Russian Journal of Biotherapy. 2018;17(4):81–90. (In Russ.) DOI: 10.17650/1726-9784-2018-17-4-81-90.

9. Beregovykh V. V., Spitskii O. R. Application of risk-based approach for determination of critical factors in technology transfer of production of medicinal products. Annals of the Russian academy of medical sciences. 2014;69(9–10):117–122. (In Russ.) DOI: 10.15690/vramn.v69i9-10.1140.

10. Tishkov S. V., Blynskaya E. V., Alekseev K. V., Alekseev V. K. Features of risk analysis, assessment and control methods in pharmaceutical development. Russian Journal of Biotherapy. 2023;22(1):28–41. (In Russ.) DOI: 10.17650/1726-9784-2023-22-1-28-41

11. Nikolaeva L. L., Lantsova A. V., Sanarova, E. V., Orlova O. L., Oborotov A. V., Ignatieva E. V., Shprakh Z. S., Kulbachevskaya N. Yu., Konyaeva O. I. Development of the Composition and Technology for Obtaining a Model of an Injection Form of an Indolocarbazole Derivative. Pharmaceutical Chemistry Journal. 2023;57:874–878. DOI: 10.1007/s11094-023-02962-6.

12. Ignatieva E. V., Yartseva I. V., Shprakh Z. S., Kolpaksidi A. P., Dmitrieva M. V., Lantsova A. V., Nikolaeva L. L., Prosalkova I. R. Quantitative determination of the N-glycoside derivative of substituted indolo[2,3a]carbazole in innovative dosage forms. Russian Journal of Biotherapy. 2022;21(3):61–71. (In Russ.) DOI: 10.17650/1726-9784-2022-21-3-61-71.

13. Mazumder S., Pavurala N., Manda P., Xu X., Cruz C. N., Krishnaiah Y. S. R. Quality by Design approach for studying the impact of formulation and process variables on product quality of oral disintegrating films. International Journal of Pharmaceutics. 2017;527(1–2):151–160. DOI: 10.1016/j.ijpharm.2017.05.048.