Regulatory aspects of Impurity profiling
Quality, safety and efficacy of pharmaceuticals play an important role in drug therapy. The safety attribute of drug is established by its pharmacological or toxicological profile along with adverse effects caused by impurities in bulk and dosage form. Impurities present in drug often possess undesired pharmacological or toxicological effects which outweighs the benefits of drug therapy. Recently, many impurity cases have been reported for e.g. NDMA (N-nitroso dimethylamine) impurity in drug product Ranitidine. This may be due to inappropriate follow of impurity related regulatory guidelines or critical voids in regulatory control of impurities or may be lack of appropriate analytical technique for impurity detection. Moreover, in June 2007, EMA became aware of contamination of Viracept® tablets. It was detected with presence of ethyl mesylate impurity, a known genotoxic substance in Nelfinavir mesylate (Viracept®). Due to this, the product was recalled from EU market.
An impure drug is devoid of safety, quality and efficacy and can lead to adverse events. So, drugs of required quality standards should reach the market for patient’s safety. Therefore it is important and becomes mandatory to submit impurity data related to isolation, identification, qualification and control of impurities to respective regulatory authorities. This article is an attempt to deliver comprehensive understanding related to various attributes and details about impurity profiling in context with regulatory guidelines along with detail description of impurity data submission to regulatory authority for drug substance (API) to get market approval. This article also focus on ICH impurity guidelines ,sources, classification and quality control of impurities.
2. Agasti W. Impurity Profiling and Quality by Design. Indo American Journal of Pharmaceutical Research.2019; 38(4):22-35.
3. Prasad P.B.N, Satyanarayana K, Mohan GK. Impurity Profiling and Regulatory aspects of Sitagliptin Active Pharmaceutical Ingredient. International Journal of Scientific Research.2008;54(6):8-17.
4. ICH Q3A (R2): Guideline for Impurities in New Drug Substances [Internet]. ICH; 2006 Oct. [cited 2020 Jan. 2]. Available from:
5. Gupta R, Dr. Jain S,Gupta A. A Review on the Impurity profile of Pharmaceuticals. International Journal of drug formulation and research. 2014; (2):53–83.
6. Huber L, Chebolu R. Genotoxic impurities in pharmaceutical products. Regulation and Analysis, Agilent Technologies, Primer; The Measure of Confidence; 2013:1-32.
7. Maithani M, Raturi R, Gupta V, Bansal P. Evolution of regulatory aspects of genotoxic impurities in pharmaceuticals: Survival of the fittest. Journal of Liquid Chromatography and Related Technologies. 2017 Sep.14; 40(15):759-69.
8. Rawat S, Kumar V. Impurity Profiling: Overview on Impurity Profiling and Reporting Methodologies Adopted by United States and Europe. World Journal of Pharmaceutical Research. 2017;206(6).
9. Ruhela G, Kaushik D. Regulatory Aspects for Impurity Profiling of Pharmaceutical Products: An Overview. International Journal of Pharmaceutical Sciences and Research. 2017;8(7):8-14.
10. ICH: Guideline for Residual Solvents Q3C (R6) [Internet]. ICH; 2016 Oct.20 [cited 2020 Jan.22]. Available from:
11. ICH: Guideline for Elemental Impurities Q3D [Internet]. ICH; 2019 Mar.22 [cited 2020 Feb.2].Available from: https://www.ich.org/page/quality-guidelines.
12. Patil Pradeep, Dr Vaidya I. Overview on Impurity Profiling. International Journal for Pharmaceutical Research Scholars (IJPRS). 2013;2(2):1-12.
13. EMA (European Medicines Agency) [Internet]. EMA; 2008 May 21 [cited 2020 Mar.4]. Available from:
14. Venkatesan P, Valliappan K. Impurity profiling: Theory and practice. Journal of Pharmaceutical Sciences and Research. 2014;6(7):9-254.
15. Bari S, Kadam B, Jaiswal Y, Shirkhedkar A. Impurity profile: Significance in Active Pharmaceutical Ingredient. Eurasian Journal of Analytical Chemistry. 2007;2(1):32-53.
16. Abhijit Chanda, N.Ramalakshmi, C.N Nalini SM. Impurity profiling an emerging trend in Pharmaceuticals: A Review. World Journal of Pharmaceutical Research. 2018;7(9):11-20.
17. Kątny M, Frankowski M. Impurities in Drug Products and Active Pharmaceutical Ingredients. Critical Reviews in Analytical Chemistry. 2017;47(3):187-93.
18. Müller L, Mauthe RJ, Riley CM, Andino MM, Antonis D de, Beels C, et al. A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regulatory Toxicology and Pharmacology. 2006; 44(3):198–211.
19. Raman NVVSS, Prasad AVSS, Ratnakar Reddy K. Strategies for the identification, control and determination of genotoxic impurities in drug substances: A pharmaceutical industry perspective. Journal of Pharmaceutical and Biomedical Analysis. 2011; 55(4):662-7.
20. Humfrey CDN. Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances. Toxicological Sciences. 2007;100(1):8-24.
21. Giordani A, Kobel W, Gally HU. Overall impact of the regulatory requirements for genotoxic impurities on the drug development process. European Journal of Pharmaceutical Sciences.2011;43(2):1-15.
22. Reddy AVB, Jaafar J, Umar K, Majid ZA, bin Aris A, Talib J, et al. Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review. Journal of Separation Science. 2015;38(5):64-79.
23. Jacobson-Kram D, McGovern T. Toxicological overview of impurities in pharmaceutical products. Advanced Drug Delivery Reviews. 2007;59(1):38-42.
24. Charde MS, Kumar J, Welankiwar AS, Chakole RD. Recent approaches for impurity profiling of pharmaceuticals. International Journal of Advances in Pharmaceutics. 2013;2(3):25-33.
25. Ayre A, Varpe D, Nayak R, Vasa N. Impurity profiling of pharmaceuticals. Advance research in pharmaceuticals and biologicals. 2011;1(2):76-90.
26. Jadhav GP. Drug Impurity Profiling: A Scientific Approach. Journal of Pharmacy Research. 2014;8(6):696–706.
27. Ramachandra B. Development of Impurity Profiling Methods Using Modern Analytical Techniques. Critical Reviews in Analytical Chemistry, Taylor and Francis Ltd. 2017;47(4):24-36.
28. Gad SC, Vales T. Recalls, Drugs and Consumer Products. Encyclopedia of Toxicology: Third Edition.2014; 12(4):54-58.
29. Sadhna D, Nagaich U. Drug recall: An incubus for pharmaceutical companies and most serious drug recall of history. International Journal of Pharmaceutical Investigation. 2015;5(1):1-13.
30. Charoo NA, Ali AA, Buha SK, Rahman Z. Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities. AAPS PharmSciTech. 2019;20(5):1-6.
31. WHO. WHO Information Note [Internet].WHO; 2019 [cited 2020 May 22]. Available from:
32. Leclerc J. Recall of N-Nitrosodimethylamine–Contaminated Pseudogeneric Valsartan: Best Generics Finally No Better Than Others?.Canadian Journal of Cardiology. 2018;34(10):7-13.
33. Gillette M, Taylor A, Butulija D, Kadiyala H, Jneid H. Reflections of the Angiotensin Receptor Blocker Recall by the FDA and Repercussions on Healthcare. Cardiovascular Drugs and Therapy. 2020; 32(4):42-58.
34. Byrd JB, Chertow GM, Bhalla V. Hypertension hot potato - Anatomy of the angiotensin-receptor blocker recalls. New England Journal of Medicine (“N Engl J Med”). 2019;380(17):89-91.
35. Hall K, Stewart T, Chang J, Kelly Freeman M. Characteristics of FDA drug recalls: A 30-month analysis. American Journal of Health-System Pharmacy. 2016;73(4):35-40.
36. Gunasekaran PM, Chertow GM, Bhalla V, Byrd JB. “Current Status of Angiotensin Receptor Blocker Recalls” .New England Journal of Medicine (“N Engl J Med”).2019;220(11):1-3.
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