Nitrosamine and Nitrosamine Drug Substance-Related Impurities (NDSRIs.pptx

Nitrosamine and Nitrosamine Drug Substance-Related Impurities (NDSRIs.pptx

1. Nitrosamines and Nitrosamine Drug Substance-Related Impurities (NDSRIs)  By Kedar Nimba Chaudhari (Reg. No.: M.S.Pharm/2023-24/PA/13) Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 1 Seminar presented as a part of curricular requirement for M.S. (Pharm.)- 1 st year – 1 st semester

2. Introduction Nitrosamines Nitrosamine Drug Substance-Related Impurities (NDSRIs) Analytical method for detection and quantitation of nitrosamine impurities Conclusion References Contents Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 2

3. Introduction Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 3

4. Nitrosamines Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 4

5. N-Nitrosamines are a class of organic impurities that includes highly potent mutagenic substances which are classified as probable human carcinogens. The nitrosamine is a class of compounds having the chemical structure of a nitroso group bonded to an amine. The compounds can form by a nitrosating reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions). Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Fig.1. Nitrosamine Fig.2. Reaction to Form Nitrosamines 28/1/2024 5

6. NDMA: N- nitrosodimethylamine NDEA: N- nitrosodiethylamine NMBA: N-nitroso-N-methyl-4-aminobutanoic acid NIPEA: N- nitrosoisopropylethyl amine NDIPA : N- nitrosodiisopropylamine NDBA: N- nitrosodibutylamine NMPA : N- nitrosomethylphenylamine Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Type of nitrosamine impurities that theoretically could be present in drug products (by FDA) 28/1/2024 6

7. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Figure 3. Chemical Structures of Seven Potential Nitrosamine Impurities in APIs and Drug Products 28/1/2024 7

8. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Table 1. N-nitrosamine formation routes and classification of reaction types 28/1/2024 8

9. General conditions that lead to nitrosamine formation Formation of nitrosamines is possible in the presence of secondary, tertiary, or quaternary amines under acidic reaction conditions. Nitrite salts may form nitrous acid and nitrous acid react with amine form nitrosamine. Sources of secondary, tertiary, and quaternary amines that can form nitrosamines Amines may be present in a manufacturing process for a variety of reasons. The API (or API degradants), intermediates, or starting materials may contain secondary or tertiary amine functional groups. All of these types of amines can react with nitrous acid or other nitrosating agents to form nitrosamines . Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR General Root Causes for the Presence of Nitrosamine Impurities in APIs Figure 4. Formation of NDMA from N,N- dimethylformamide 28/1/2024 9

10. Contamination in vendor-sourced raw materials Contamination of fresh solvent during shipment from vendor. Ex: ortho -xylene, toluene, and methylene chloride Nitrate-containing raw materials. Ex: Potassium nitrite Sodium nitrite. Recovered solvents, catalysts, and reagents as sources of contamination May pose a risk of nitrosamine impurities due to the presence of residual amines. Ex.Trimethylamine Diisopropylethylamine . Quenching process as a source of nitrosamine contamination When nitrous acid is added to the reaction mixture to decompose residual azide. This allows nitrous acid to come into direct contact with residual amines in the raw materials used in the manufacturing process. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 10

11. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Fig.5. Classification of Nitrosamine impurities based on manufacturing steps. Fig.6. Pathways of formation of nitrosamines. 28/1/2024 11

12. FDA recommends the following acceptable intake (AI) limits for the nitrosamine impurities NDMA, NDEA, NMBA, NMPA, NIPEA , and NDIPA. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Acceptable Intake Limits Nitrosamine AI Limit (ng/day) NDMA 96 NDEA 26.5 NMBA 96 NMPA 26.5 NIPEA 26.5 NDIPA 26.5 Table 2. AI Limits for NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA in Drug Products. For drug products with an MDD of less than 880 mg/day, a recommended limit for total nitrosamines of 0.03 ppm is not more than 26.5 ng/day and is considered acceptable. For drug products with an MDD above 880 mg/day, the limit for total nitrosamines should be adjusted so as not to exceed the recommended limit of 26.5 ng/day. 28/1/2024 12

13. Nitrosamine Drug Substance-Related Impurities (NDSRIs) Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 13

14. Nitrosamine impurities have been detected in various sartan’s products, ranitidine, nizatidine , and metformin. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Nitrosamine Drug Substance-Related Impurities (NDSRIs)  Fig.6. Chemical structure of (a) Ranitidine, (b) Nizatidine , (c) Metformin, (d) Valsartan (e) Candesartan (f) Irbesartan , and (g) Olmesartan . 28/1/2024 14

15. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Metformin Metformin is the most widely prescribed orally active anti-hyperglycemic drug. Synthesis of Metformin hydrochloride: Dimethylamine (DMA) hydrochloride and 2-cyanoguanidine Excipients: Povidone Hydroxypropyl methylcellulose Packing material: Nitrocellulose + Secondary amine Figure: Metformin Nitrosamine 28/1/2024 15

16. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 16

17. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Ranitidine Ranitidine is H2 receptor antagonist and widely used to treat peptic ulcer disease. Nitrosamine drug impurity forms due to the intermolecular degradation reaction of ranitidine molecule that occurs primarily in the solid state. The degradation proceeds without participation of any extraneous impurities. NDMA levels in drug substances start to increase at a slow rate from the point of manufacture; both elevated temperature and RH contribute to an increase in the rate of degradation. Fig.7. Ranitidine 1 2 Degradation Ranitidine NDMA 28/1/2024 17

18. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 18

19. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Valsartan Fig. 8. Tetrazole ring synthesis of valsartan using sodium azide. Sodium azide used for formation of tetrazole ring. Sodium azide is highly toxic and explosive. Sodium azide has limited solubility in DMF. Excess/unreacted sodium azide removed by adding Sodium nitrite. That’s form nitrogen and dinitrogen oxide and reacts with DMF and form Nitrosamine impurity Fig. 9. Removal of untreated excess sodium azide by addition of sodium nitrite 28/1/2024 19

20. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR 28/1/2024 20

21. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Analytical method for detection and quantitation of nitrosamine impurities  28/1/2024 21

22. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Conclusion Nitrosamines are highly potent carcinogens whose exposure through medicines need to be monitored and reduced to the possible extent. It is necessary to systematically identify the source of contamination to reduce the nitrosamine impurities in final finished products. Finished pharmaceutical products can get contaminated with nitrosamines through API synthesis and formulation manufacturing. Screening the excipients for precursors of nitrosamines, monitoring the stability of the formulation and migration of nitrosamines during printing and packaging operations will mitigate the formulation side contamination of finished products. The pharmaceutical industry to set limits for nitrosamine contamination and surveillance of existing marketed product. The products found to contain higher than maximum allowable doses of nitrosamines have been recalled from the market. 28/1/2024 22

23. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR References Agency, E. M. (2020, June 25). Nitrosamine impurities in human medicinal products . https://www.ema.europa.eu/en/homepage Food and Drug Administration ( n.d. ). Impurities in Human Drugs . https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs Schlingemann J, Boucley C, Hickert S, Bourasseau L, Walker M, Celdran C, Chemarin T, Pegues C, Fritzsche M, Keitel J, Goettsche A. Avoiding N- nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite. International Journal of Pharmaceutics. 2022 May 25;620:121740. Akkaraju H, Tatia R, Mane SS, Khade AB, Dengale SJ. A comprehensive review of sources of nitrosamine contamination of pharmaceutical substances and products. Regulatory Toxicology and Pharmacology. 2023 Feb 13:105355. King FJ, Searle AD, Urquhart MW. Ranitidine—investigations into the root cause for the presence of N-nitroso-N, N-dimethylamine in ranitidine hydrochloride drug substances and associated drug products. Organic Process Research & Development. 2020 Dec 1;24(12):2915-26. Shaik KM, Sarmah B, Wadekar GS, Kumar P. Regulatory updates and analytical methodologies for nitrosamine impurities detection in sartans , ranitidine, nizatidine, and metformin along with sample preparation techniques. Critical reviews in analytical chemistry. 2022 Jan 2;52(1):53-71. 28/1/2024 23

24. Dept. of Pharmaceutical Analysis, NIPER-HAJIPUR, Bihar, India NIPER-HAJIPUR Thank You ! 28/1/2024 24