Nonspecific Impurities in Pharmaceutical Substances: Characteristics of Test Methods

One of the prerequisites of efficacy and safety of finished pharmaceutical products is the quality of pharmaceutical substances used in their production. Criteria of assessment of pharmaceutical substance purity are determined by the substance composition and production technology, as well as by specific aspects of the finished pharmaceutical product production and use. It is necessary to control the content of nonspecific organic and inorganic impurities, impurities of microbial origin, and residual solvents. The aim of the study was to analyse characteristics of test methods used to determine nonspecific impurities in pharmaceutical substances. The State Pharmacopoeia of the Russian Federation describes various chemical, physical, physicochemical and biological tests for the analysis of nonspecific impurities. Determination of inorganic cations and anions usually includes comparison of test solutions with solutions of the corresponding reference standards, or checking the absence of a positive reaction in the test solution. Quantitative analysis of trace impurities largely relies on highly specific and sensitive test methods, such as atomic absorption spectrometry, atomic emission spectrometry and inductively coupled plasma mass spectrometry. The content of residual organic solvents is determined by gas chromatography or high-performance liquid chromatography. The purity and safety of pharmaceutical substances are ensured by biological tests: “Microbial quality”, “Sterility”, “Pyrogenicity”, “Bacterial endotoxins”. Specific characteristics of test methods used for determination of the content of nonspecific impurities in various pharmaceutical substances depend on physicochemical properties of the tested substances, toxicity of the analysed impurities, and content limits. The results of the study make it possible to formulate a methodological approach to the development of criteria for assessing the quality of pharmaceutical substances. This approach includes mandatory compliance with the basic principles of substance standardisation, as well as case-by-case selection of quality parameters, specific test conditions and content limits for impurities.

1. Olefir YuV, Sakanyan EI, Shemeryankina TB, Senchenko SP, Zaytsev SA, Barmin AV. Standardization of pharmaceutical substances with respect to purity. Khimiko-farmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal. 2018;52(8):56–60 (in Russ.) https://doi.org/10.30906/0023-1134-2018-52-8-56-60

2. Kovaleva EL. Standardization of pharmaceutical substances and preparations in the tablet form. Moscow: Grif i K; 2012 (In Russ.)

3. Bagirova VL, Kovaleva EL, Shanazarov KS. Pharmacopoeial article «Pharmaceutical substances». Khimiko-farmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal. 2007;41(1):35–7 (In Russ.) https://doi.org/10.30906/0023-1134-2007-41-1-35-37

4. Kovaleva EL, Bagirova VL, Shanazarov KS. Developing methodological approaches to standardization of pharmaceutical substances. Khimiko-farmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal. 2010;44(1):35–42 (In Russ.) https://doi.org/10.30906/0023-1134-2010-44-1-35-42

5. Bagirova VL, Kovaleva EL. On the issue of ensuring the pharmacopoeial quality of the original ingredients used to obtain drugs. Vestnik Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya Ministerstva zdravookhraneniya Rossiyskoy Federatsii = Тhе Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation. 2003;(1):46–8 (In Russ.)

6. Arzamastsev AP, Titova AV. The special features of substances standartisation in terms of market economy. Remedium = Remedium. 2006;(9):57–9 (In Russ.)

7. Matveeva OA, Kovaleva EL. Modern approach to estimating the content of genotoxic impurities in drugs (a review). Khimiko-farmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal. 2015;49(11):41–8 (In Russ.)

8. Narkevich IA. State Pharmacopoeia of Russian Federation in modern pharmaceutical analysis practice. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = Тhе Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2016;(2):35–7 (In Russ.)

9. Sakanyan EI, Shemeryankina TB, Barmin AV, Zaytsev SA, Yarushok TA. Pharmaceutical substances. Requirements of the State Pharmacopoeia for their standardization. Antibiotiki i khimioterapiya = Antibiotics and Chemotherapy. 2017;62(5–6):63–7 (In Russ.)

10. Skornyakov YuV, Skornyakova OV. The achievements and problems of the production of generic drug substances for pharmaceutical industry. Izvestiya Akademii nauk. Seriya khimicheskaya = Russian Chemical Bulletin. 2015;64(7):1696–9 (In Russ.)

11. Teryoshkina OI, Guskova TA. International experience in the safety evaluation of impurities in drugs. Toksikologicheskiy vestnik = Toxicological Review. 2010;(5):32–5 (In Russ.)

12. Kovaleva EL, Belanova AI, Panova LI, Zakharchenko AA. Current requirements for assessment of elemental impurities (heavy metals) in medicines. Khimiko-farmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal. 2018;52(1):54–9 (In Russ.)

13. Wills J, Kutscher D, Lecornet G. Analysis of Pharmaceutical Products for Their Elemental Impurities Using the Thermo Scientific iCAP Q ICP-MS. Analitika = Analytics. 2013;(6):36–43 (In Russ.)

14. Novoselov AN. Determination of lead, cadmium, arsenic and mercury in some pharmaceutical substances by atomic absorption spectrometry with electrothermal atomization. Nauka i sovremennost’ = Science and Modernity. 2010;(4–2):9–14 (In Russ.)

15. Chernyshova OV, Rodionova RA. Using the method of atomic absorption spectrometry in the analysis of drugs, food and other samples. Vestnik farmatsii = Bulletin of Pharmacy. 2006;(4):85–92 (In Russ.)

16. Teryoshkina OI, Guskova TA, Ramenskaya GV, Samylina IA. Pharmacopoeial approaches to rationing residual organic solvents in medicines. Farmatsiya = Pharmacy. 2017;66(1):9– 13 (In Russ.)

17. Moiseev SV, Krylov VI, Masterkova TV, Yashkir VA, Bunyatyan ND. Nuclear magnetic resonance spectroscopy for drug identification, characterization and quantification of impurities in substance of salicylic acid. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = Тhе Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2014;(1):15–9 (In Russ.)

18. Belikov VG, Borovsky BV, Rasskazov AG. Definition of residual organic solvents in some substances by means of gas-liquid chromatography method. Zhurnal novykh meditsinskikh tekhnologiy = Journal of New Medical Technologies. 2011;18(3):11–3 (In Russ.)

19. Voropaev AA, Fadeikina OV, Ermolaeva TN, Davydov DS, Volkova RA, Shvedov DV. Development and validation of a procedure for subvisible particles determination in water for injections by the Coulter principle (electrical sensing zone method). Biopreparaty. Profilaktika, Diagnostika, Lechenie = BIOpreparations. Prevention, Diagnosis, Treatment. 2018;18(2):98–105 (In Russ.) https://doi.org/10.30895/2221-996X-2018-18-2-98-105

20. Kachaput AI. Choice and justification of the method of bacterial purification of hormonal substances at production of medicinal preparations in suspension form for injections in rheumatology. Sibirskiy meditsinskiy vestnik = Journal of Siberian Medical Sciences. 2017;(2):40–6 (In Russ.)

21. Shapovalova OV, Neugodova NP, Sapozhnikova GA, Agashirinova AA, Gunar OV. Detection of bacterial endotoxins in drugs: Disturbing factors and their elimination. Farmatsiya = Pharmacy. 2017;66(6):9–14 (In Russ.)

22. Ustinnikova OB, Gayderova LA, Baykova ML, Lobanova TN, Shcherbachenko IM, Goloshchapova EO, Bondarev VP. Biopreparaty. Profilaktika, Diagnostika, Lechenie = BIOpreparations. Prevention, Diagnosis, Treatment. 2017;17(3):152–7 (In Russ.) https://doi.org/10.30895/2221-996X-2017-17-3-152-157

23. Ryabtseva MS, Filimonova IN, Osipova IG, Neugodova NP, Kovaleva EL, Sharoykina MV. Quality indicator «Abnormal toxicity» — one of the main components of safety of biological drugs. Mezhdunarodny zhurnal prikladnykh i fundamentalnykh issledovaniy = International Journal of Applied and Fundamental Research. 2016;(9–2):232–7 (In Russ.)