Research design formation to determine quality indicators of potential api, 2. quality risks arising in the process of scaling the synthesis procedure
Keywords:active substance, scaling up of the synthesis method, risks, standardization, quality control methods
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
- Bevz, N., Mishchenko, V. (2019). Development of a design research for determining the quality indicators of potential API. 1. newly synthesized substances for primary pharmacological screening. ScienceRise: Pharmaceutical Science, 5 (21), 18–26. doi: http://doi.org/10.15587/2519-4852.2019.182279
- Pro derzhavne rehuliuvannia diialnosti u sferi transferu tekhnolohii (2006). Zakon Ukrainy No. 143-V. 14.09.2006. Available at: https://zakon.rada.gov.ua/laws/show/143-16
- McDonald, K., Ho, K. (2012). ICH Q11: development and manufacture of drug substances–chemical and biotechnological/biological entities. Generics and Biosimilars Initiative Journal, 1 (3-4), 142–144. doi: http://doi.org/10.5639/gabij.2012.0103-4.025
- Pro likarski zasoby (1996). Zakon Ukrainy No. 123/96-VR. 04.04.1996. Available at: http://zakon.rada.gov.ua/laws/main/123/96-%D0%B2%D1%80
- Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol. 2. Good manufacturing practices and inspection (2007). Geneva: World Health Organization, 46.
- DSTU ISO 9000:2015. Systemy upravlinnia yakistiu. Osnovni polozhennia ta slovnyk terminiv (ISO 9000:2015, IDT) (2016). Kyiv: Derzhspozhyvstandart Ukrainy, 45.
- Levin, M. (2005). Pharmaceutical Process Scale-Up. Drugs and the pharmaceutical sciences. Marcel Dekker, Inc., 588.
- Sobolieva, T. O. (2008). Upravlinnia formuvanniam ta realizatsiieiu innovatsiinoho potentsialu pidpryiemstva (za materialamy farmatsevtychnykh pidpryiemstv Ukrainy). Kyiv, 20.
- Raval, N., Tambe, V., Maheshwari, R., Deb, P. K., Tekade, R. K. (2018). Scale-Up Studies in Pharmaceutical Products Development. Dosage Form Design Considerations, 669–700. doi: http://doi.org/10.1016/b978-0-12-814423-7.00019-8
- Shanley, A. (2019). Scaling Up Right the First Time. Pharmaceutical Technology Europe, 31 (9), 10–14.
- Plane, G. (2018). Managing Process Scale-Up and Tech Transfer. Available at: https://www.merckmillipore.com/GB/en/20151116_192332?IdOfReferringPage=20150727_145042&Pname=108
- Derzhavna Farmakopeia Ukrainy. Vol. 1. (2015). Kharkiv: Derzhavne pidpryiemstvo «Ukrainskyi naukovyi farmakopeinyi tsentr yakosti likarskykh zasobiv», 1128.
- The European Pharmacopoeia (2018). European Directorate for the Quality of Medicines & HealthCare of the Council of Europe. Strasbourg, 6. Available at: http://online6.edqm.eu/ep900/
- The United States Pharmacopoeia, 41 – NF 36 (2018). The United States Pharmacopeial Convention. Rockville. Available at: https://opac.kku.ac.th/catalog/BibItem.aspx?BibID=b00420302
- EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev 1 (2014). Guideline on process validation for finished products – information and data to be provided in regulatory submissions.
- Liapunov, M., Bezuhla, O., Soloviov, O. et. al. (2012). Standartyzatsiia farmatsevtychnoi produktsii. Kharkiv: Morion, 728.
- Vetiutneva, N. O., Ubohov, S. H., Pylypchuk, L. B., Fedorova, L. O., Todorova, V. I., Budnikova, T. M. et. al. (2014). Suchasnyi stan ta tendentsii rozvytku normatyvno-pravovoho rehuliuvannia u sferi zabezpechennia yakosti likarskykh zasobiv. Farmatsevtychnyi zhurnal, 3, 66–74.
- Nor, A. M. Pilot plant scale up techniques contents: introduction on pilot plant and scale up. Available at: https://www.academia.edu/8939649/PILOT_PLANT_SCALE_UP_TECHNIQUES_CONTENTS_INTRODUCTION_ON_PILOT_PLANT_AND_SCALE_UP
- Felton, L. A. (2011). Pharmaceutical Process Scale-Up, 3rd edition. Drug Development and Industrial Pharmacy, 38 (4), 512–512. doi: http://doi.org/10.3109/03639045.2011.633523
- Lehmann, H., LaVecchia, L. (2010). Scale-Up of Organic Reactions in a Pharmaceutical Kilo-Lab Using a Commercial Microwave Reactor. Organic Process Research & Development, 14 (3), 650–656. doi: http://doi.org/10.1021/op900269y
- Tiberghien, A. C., von Bulow, C., Barry, C., Ge, H., Noti, C., Collet Leiris, F. et. al. (2018). Scale-up Synthesis of Tesirine. Organic Process Research & Development, 22 (9), 1241–1256. doi: http://doi.org/10.1021/acs.oprd.8b00205
- Gołofit, T., Maksimowski, P., Szwarc, P., Cegłowski, T., Jefimczyk, J. (2017). Scale-Up Synthesis of Hexabenzylhexaazaisowurtzitane, an Intermediate in CL-20 Synthesis. Organic Process Research & Development, 21 (7), 987–991. doi: http://doi.org/10.1021/acs.oprd.7b00101
- Guidance for industry: Q8 (R2) pharmaceutical development (2009). US FOOD AND DRUG ADMINISTRATION. Center for Drug Evaluation and Research: Silver Spring.
- Nogueira, R., Queiroz, S. M., Silva, G. E. B., Rocha, W. F. C., Sarmanho, G. F., Almeida, R. R. R., Moreira, G. F. (2012). Determination of volatiles in pharmaceutical certified reference materials. Journal of the Brazilian Chemical Society, 23 (9), 1636–1646. doi: http://doi.org/10.1590/s0103-50532012005000021
- ICH Harmonized Tripartite Guideline: Q3A (R2) Impurities in new substances (2016). The international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH), 15.
- ICH Harmonized Tripartite Guideline: Q3B (R2) Impurities in new drug products (2006). The international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH), 14.
- Ibrahim, M. M. (2015). Investigation on thermal stability and purity determination of two antihypertensive drugs, valsartan and losartan potassium. International Journal of Current Pharmaceutical Research, 7 (3), 64–69.
- Bevz, O. V., Ukrainets, I. V., Vashchenko, O. V., Georgiyants, V. A., Budianska, L. V. (2018). Obtaining of the pharmacopoeial reference sample of the mandelic acid isopropyl ester. Vìsnik Farmacìï, 1 (93), 3–11. doi: http://doi.org/10.24959/nphj.18.2196
- WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty- first report (2007). WHO Technical Report Series, No. 943. Geneva: World Health Organization.
- Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol. 2. Second updated edition. Good manufacturing practices and inspection. Geneva: World Health Organization, 46.
How to Cite
Copyright (c) 2020 Nataliia Bevz, Volodymyr Mishchenko, Viktor Khomenko, Victoriya Georgiyants
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our journal abides by the Creative Commons CC BY copyright rights and permissions for open access journals.