QUALITY RISK ASSESSMENT OF A DIRECT COMPRESSION TECHNOLOGY FOR LOZENGES CONTAINING AJANIA FRUTICULOSA (LEDEB.) POLJAK EX-TRACT WITHIN THE QUALITY BY DESIGN FRAMEWORK

Relevance. Direct compression enables lozenge manufacturing without wet granulation and drying. However, variability in the properties of herbal extracts may affect the reproducibility of critical quality attributes. Quality risk management within the Quality by Design framework supports systematic identification of variability sources and justification of a control strategy.

Objective. To identify and assess quality risks during the development of a direct compression technology for lozenges containing dry Ajania fruticulosa (Ledeb.) Poljak extract.

Materials and methods. Potential sources of variability were structured using an Ishikawa cause-and-effect diagram. Risks were ranked using Failure Mode and Effects Analysis. Severity, occurrence, and detectability were assessed using five-point scales, and Risk Priority Numbers (RPNs) were calculated. Residual risks were predicted by expert reassessment of occurrence and detectability under the proposed mitigation scenario, while severity scores remained unchanged.

Results. Thirty-six potential variability factors were identified, and seven priority failure modes were selected for Failure Mode and Effects Analysis. Initial RPNs ranged from 18 to 48. Powder blend segregation during feeding into the hopper zone had the highest initial RPN. Under the proposed mitigation scenario, predicted residual RPNs ranged from 6 to 24. Six of the seven failure modes were classified as low risk, including five initially classified as medium risk. Powder blend segregation remained a medium risk requiring continued monitoring.

Conclusions. The proposed control strategy provides a basis for further process development, technology transfer, and scale-up. Risk reduction represents an expert prediction and requires experimental confirmation through measurement of the corresponding critical quality attributes.

1. International Council for Harmonisation. ICH Q8(R2): Pharmaceutical Development. Geneva: International Council for Harmonisation, 2009.

2. International Council for Harmonisation. ICH Q9(R1): Quality Risk Management. Geneva: International Council for Harmonisation, 2023.

3. International Council for Harmonisation. ICH Q10: Pharmaceutical Quality System. Geneva: International Council for Harmonisation, 2008.

4. Yang S., Hu X., Zhu J., Zheng B., Bi W., Wang X., Wu J., Mi Z., Wu Y. Aspects and implementation of pharmaceutical Quality by Design from conceptual frameworks to industrial applications. Pharmaceutics, 2025, vol. 17, no. 5, article 623. DOI: 10.3390/pharmaceutics17050623.

5. Gurski C.S., Luna Lazo R.E., Gelinski M.A., Alves L.A., Sovinski M.S., Sari M.H.M., Borba H.H.L., Tonin F.S., Pontarolo R., Ferreira L.M. Quality by Design applied to pediatric-friendly formulations: a scoping review-based manufacturing process mapping for solid dosage forms. Journal of Drug Delivery Science and Technology, 2025, vol. 108, article 106915. DOI: 10.1016/j.jddst.2025.106915.

6. Simão J., Chaudhary S.A., Ribeiro A.J. Implementation of Quality by Design for development of bilayer tablets. European Journal of Pharmaceutical Sciences, 2023, vol. 184, article 106412. DOI: 10.1016/j.ejps.2023.106412.

7. Casian T., Iurian S., Bogdan C., Rus L., Moldovan M., Tomuta I. Quality by Design for pediatric oral lyophilisates development: risk assessment followed by screening and optimization. Drug Development and Industrial Pharmacy, 2017, vol. 43, no. 12, pp. 1932–1944. DOI: 10.1080/03639045.2017.1350702.

8. Kaljević O., Djuriš J., Djurić Z., Ibrić S. Application of failure mode and effects analysis in Quality by Design approach for formulation of carvedilol compression coated tablets. Journal of Drug Delivery Science and Technology, 2016, vol. 32, pp. 56–63. DOI: 10.1016/j.jddst.2016.02.004.

9. Naman S., Madhavi N., Singh B., Madan J., Baldi A. Implementing risk-based Quality by Design for development and optimization of flavored oral disintegrating mini tablets. Journal of Drug Delivery Science and Technology, 2021, vol. 66, article 102799. DOI: 10.1016/j.jddst.2021.102799.

10. Tafere C., Yilma Z., Abrha S., Yehualaw A. Formulation, in vitro characterization and optimization of taste-masked orally disintegrating co-trimoxazole tablet by direct compression. PLOS ONE, 2021, vol. 16, no. 3, article e0246648. DOI: 10.1371/journal.pone.0246648.

11. Nait Bachir Y., Said R.M., Terki N.Z., Antar R., Slamani M., Gharbi D., Foligni R. Biopharmaceutical and pharmacotechnical characterization of plant powder tablets obtained by direct compression process: the case of Atriplex halimus. Applied Sciences, 2025, vol. 15, no. 15, article 8623. DOI: 10.3390/app15158623.

12. Pham E.C., Vo Van L., Nguyen C.V., Nguyen Duong N.T., Le Thi T.V. Formulation development, optimization, in vivo antidiabetic effect and acute toxicity of directly compressible herbal tablets containing Merremia tridentata (L.) extract. Journal of Drug Delivery Science and Technology, 2023, vol. 84, article 104445. DOI: 10.1016/j.jddst.2023.104445.

13. Jakiyanov A.M., Ridvanov Ch.I., Isaev Zh.N., Zhumashova G.T., Bekezhanova T.S., Kulmanbetov R.I., Talgaeva E.V., Turuspaeva Zh.Zh., Sakipova Z.B., Suleimenov M.K. Razrabotka sostava i tekhnologii tabletok dlya rassasyvaniya s ekstraktom Ajania fruticulosa (Ledeb.) Poljak s primeneniem kontseptsii Quality by Design [Development of the composition and technology of lozenges with Ajania fruticulosa (Ledeb.) Poljak extract using the Quality by Design concept]. Razrabotka i registratsiya lekarstvennykh sredstv, 2026, vol. 15, no. 1, pp. 85–95. DOI: 10.33380/2305-2066-2026-15-1-2233. (In Russian).

14. Liang J., Lu P., Ning A., Yang Y., Shao Y., Xu J. Chemical constituents from the aerial parts of Ajania fruticulosa. Biochemical Systematics and Ecology, 2020, vol. 92, article 104124. DOI: 10.1016/j.bse.2020.104124.

15. Min X., Chen J., Mu W., Huang J., Huang G., Cao J. A new dimeric sesquiterpenoid from Ajania fruticulosa. Phytochemistry Letters, 2025, vol. 66, pp. 60–65. DOI: 10.1016/j.phytol.2025.02.001.

16. Jakiyanov A.M., Sakipova Z.B., Ibragimova L.N., Ibraeva M.B., Kaldybaeva A.M., Ensebaeva G.B. Farmatsevticheskaya kompozitsiya iz rastitel'noi substantsii s antibakterial'nym i protivogribkovym deistviem i sposob ee polucheniya [Pharmaceutical composition from a plant substance with antibacterial and antifungal activity and a method for its preparation]. Republic of Kazakhstan utility-model patent No. 11229, Bulletin No. 40, 3 October 2025. (In Russian).