A Review on Forced Degradation and Its Regulatory Guidelines - a Reliable and Necessary Tool in Stability Studies and Development of Stability Indicating Methods
Corresponding Author(s) : Dr. Ameena Yasmeen
ameena2309@gmail.com
International Journal of Allied Medical Sciences and Clinical Research,
Vol. 9 No. 2 (2021): 2021 Volume - 9 Issue - 2
Abstract
Forced degradation is also known as,“Stress Testing” and “Purposeful Degradation” and it has long been recognized as an important part of the drug development process. Recent efforts by the International Conference on Harmonization (ICH) with regard to impurities and photo stability have brought an increased regulatory scrutiny of impurities, requiring identification and toxicological classification at very low levels. Efforts to improve and streamline processes related to early identification of potential problems are important to the goal of providing new, safe medicine, faster. Stress testing is the main tool that is used to predict stability problems, develop analytical methods, and identify degradation products/ pathways. Forced degradation studies also play a central role during analytical method development, setting specifications and design of formulations under the quality-by-design (QbD) paradigm. This review paper will provide the readers with a single source reference that bench marks the current best practices in stress testing and answers to questions like, “ How hot, How long, “How much humidity”, “What pH values to be used?,” “ What reagents/conditions for oxidative studies to be used”, What conditions are appropriate”, and topics such as mass balance, photo stability, oxidative susceptibility and the chemistry of drug degradation are addressed in an objective, detailed scientific manner, with an overview of the relevantguidelines governing stress testing. Prior to appropriate guidelines on stress testing coming into force, the stress testing had evolved into an artful science that was highly dependent on the experience of the company or the individuals directing the studies.
Keywords
Shelf-Life
Stability Studies
Stability Indicating Methods
Degradation Pathways
Degradation Products
Forced Degradation
1.
Dr. Ameena Yasmeen, Dr. Kaleemullah khan, Dr. Ghulam Mohammad Loan, Dr. Ghulamuddin Sofi. A Review on Forced Degradation and Its Regulatory Guidelines - a Reliable and Necessary Tool in Stability Studies and Development of Stability Indicating Methods. Int. J. of Allied Med. Sci. and Clin. Res. [Internet]. 2021 Jul. 7 [cited 2026 Apr. 19];9(2):356-64. Available from: https://ijamscr.com/ijamscr/article/view/1026
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References
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References
1. O’Donnell PB, Bosker AD. Stability of pharmaceutical products [Chapter]. 21st ed. Vol. 52 Remington- The Science and Practice of Pharmacy; 2006. p. Vol-1. BI Publications Pvt Limited P 1025-36.
2. Baertschi SW, Stress Testing Jansen. A predictive tool pharmaceutical stress testing- predicting drug degradation first Indian Reprint 2008. Boca Raton, Singapore: Taylor & Francis Group. p. 13, 16.
3. Anonymous. The United States pharmacopeia, the national formulary. Asian edition. 2004; By Authority ofthe United States Pharmacopeial Convention, Inc. 12601. Twin Brook. Rockville, MD: Parkway Publishers 20852. P 1191, 2605-8.
4. Huynh-Ba. Handbook of stability testing in pharmaceutical. Development. July 2008, 1st (edn.), New. York. Springer Link. p. 29.
5. Rawat T, Pandey IP. Forced degradation studies for Drug Substances and Drug Products- Scientific and Regulatory Considerations. J Pharm Sci Res. 2015; 7(5):238-41.
6. Baertschi SW, Reynolds DW. Introduction- pharmaceutical stress testing- predicting drug degradation first Indian Reprint 2008. Boca Raton, Singapore: Taylor & Francis Group. P. 2-4.
7. Baertschi SW. Forced degradation and its relation to real-time drug product stability [Chapter]-15 Pharmaceutical Stability Testing to Support Global Markets Huynh-Ba K, Springer P, editors; 2010. p. 108-14.
8. Aubry A, Tattersall P, Ruan J. Development of stability methods [Chapter]-7 Handbook of Stability Testing in Pharmaceutical Development Springer H-BK, editor; 2009 (India) Private Limited, 3rd. Floor GM, Deendayal Upadhyaya M. New Delhi, India. P: 146,147.
9. Sharma MK, Murugesan M. Forced degradation study an essential approach to develop stability indicating method. J Chromatogr Sep Tech. 2017; 08(1):349. Doi: 10.4172/2157-7064.1000349.
10. Shinde NG, Bangar BN, Deshmukh SM, Suyog P. Sulake S P and Sherekar DP. Pharmaceutical forced degradation studies with regulatory consideration. Asian J Res Pharm Sci. 2013; 3(4, October–December):178-88.
11. Nussbaum MA, Jansen PJ, Baertschi SW. Role of mass balance in pharmaceutical stress testing pharmaceutical stress testing- predicting drug degradation first Indian Reprint 2008. Boca Raton, Singapore: Taylor & Francis Group. P. 181-3.
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22. Available from: http://www.usp.org chapter -1086 Impurities in drug substances and drug products USP 37 page 828; July 2014 [cited 24/6/2021].
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27. Available from: http://www.ema.europa.eu. EMEA- note for guidance on in-use stability testing of human medicinal products CPMP/QWP/2934/99; March 2001 [cited 24/6/2021].
28. Available from: http://www.ema.europa.eu. EMEA-guideline on the chemistry of new active substances CPMP/QWP/130/96, Rev1; February 2004 [cited 24/6/2021].
29. Available from: http://www.fda.gov. FDA guidance for industry: analytical procedures and methods validation CDER; February 2014 [cited 24/6/2021].
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31. Carstensen JT, Rhodes CT. Drug stability: principles and practices. 3rd ed. New York: Marcel Dekker, Inc; 2000.
2. Baertschi SW, Stress Testing Jansen. A predictive tool pharmaceutical stress testing- predicting drug degradation first Indian Reprint 2008. Boca Raton, Singapore: Taylor & Francis Group. p. 13, 16.
3. Anonymous. The United States pharmacopeia, the national formulary. Asian edition. 2004; By Authority ofthe United States Pharmacopeial Convention, Inc. 12601. Twin Brook. Rockville, MD: Parkway Publishers 20852. P 1191, 2605-8.
4. Huynh-Ba. Handbook of stability testing in pharmaceutical. Development. July 2008, 1st (edn.), New. York. Springer Link. p. 29.
5. Rawat T, Pandey IP. Forced degradation studies for Drug Substances and Drug Products- Scientific and Regulatory Considerations. J Pharm Sci Res. 2015; 7(5):238-41.
6. Baertschi SW, Reynolds DW. Introduction- pharmaceutical stress testing- predicting drug degradation first Indian Reprint 2008. Boca Raton, Singapore: Taylor & Francis Group. P. 2-4.
7. Baertschi SW. Forced degradation and its relation to real-time drug product stability [Chapter]-15 Pharmaceutical Stability Testing to Support Global Markets Huynh-Ba K, Springer P, editors; 2010. p. 108-14.
8. Aubry A, Tattersall P, Ruan J. Development of stability methods [Chapter]-7 Handbook of Stability Testing in Pharmaceutical Development Springer H-BK, editor; 2009 (India) Private Limited, 3rd. Floor GM, Deendayal Upadhyaya M. New Delhi, India. P: 146,147.
9. Sharma MK, Murugesan M. Forced degradation study an essential approach to develop stability indicating method. J Chromatogr Sep Tech. 2017; 08(1):349. Doi: 10.4172/2157-7064.1000349.
10. Shinde NG, Bangar BN, Deshmukh SM, Suyog P. Sulake S P and Sherekar DP. Pharmaceutical forced degradation studies with regulatory consideration. Asian J Res Pharm Sci. 2013; 3(4, October–December):178-88.
11. Nussbaum MA, Jansen PJ, Baertschi SW. Role of mass balance in pharmaceutical stress testing pharmaceutical stress testing- predicting drug degradation first Indian Reprint 2008. Boca Raton, Singapore: Taylor & Francis Group. P. 181-3.
12. Maheswaran R. FDA perspectives: scientific considerations of forced degradation studies in ANDA submissions. Pharm Technol. 2012; 36:73-80.
13. Available from: http://www.ICH.org, International Conference on Harmonization, Stability testing of new drug substances and Products Q1A. Vol. R2 (February); 2003.
14. Available from: http://www.ICH.org, International Conference on Harmonization, Stability Testing: Photo Stability Testing of New Drug Substances and Products. Vol. Q1B; November 1996.
15. Available from: http://www.ICH.org, International Conference on Harmonization, Evaluation of stability data Q1E; February 2003.
16. Available from: http://www.ICH.org. Methodology, International Conference on Harmonization, Validation of Analytical Procedures. Vol. Q2; November 2005. (p. R1).
17. Available from: http://www.ICH.org, International Conference on Harmonization, Impurities in New Drug substances. Vol. Q3A; October 2006. (p. R2).
18. Available from: http://www.ICH.org, International Conference on Harmonization, Impurities in New Drug Products. Vol. Q3B; June 2006. (p. R2).
19. Available from: http://www.ICH.org, International Conference on Harmonization, Stability Testing of Biotechnological/Biological Products. Vol. Q5C; November 1995.
20. Available from: http://www.ICH.org, International Conference on Harmonization, Specifications: New Chemical Drug Substances and Products. Vol. Q6A (October); 1999.
21. Available from: http://www.ICH.org. Guide for active pharmaceutical ingredients, International Conference on Harmonization, Good Manufacturing Practice. Vol. Q7; November 2000.
22. Available from: http://www.usp.org chapter -1086 Impurities in drug substances and drug products USP 37 page 828; July 2014 [cited 24/6/2021].
23. Available from: http://www.usp.org. USP Reference standards USP. Vol. X; 1926 chapter-11.
24. Available from: http://www.drugfuture.com [cited 24/6/2021] chapter -1150 USP Pharmaceutical stability.
25. Available from: http://www.drugfuture.com chapter -1191 USP Stability Considerations in Dispensing Practice; May 2012 [cited 24/6/2021].
26. Available from: http://www.usp.org. USP Pharmaceutical Compounding-Sterile Preparations-Storage and Beyond -Use Dating USP 41 page 6554 and PF 41 (6) chapter-797; November–December 2015 [cited 24/6/2021].
27. Available from: http://www.ema.europa.eu. EMEA- note for guidance on in-use stability testing of human medicinal products CPMP/QWP/2934/99; March 2001 [cited 24/6/2021].
28. Available from: http://www.ema.europa.eu. EMEA-guideline on the chemistry of new active substances CPMP/QWP/130/96, Rev1; February 2004 [cited 24/6/2021].
29. Available from: http://www.fda.gov. FDA guidance for industry: analytical procedures and methods validation CDER; February 2014 [cited 24/6/2021].
30. Available from: http://www.fda.gov/CDER/guidance/3619fnl.pdf. FDA guidance for industry: INDs for Phase II and Phase III studies, chemistry manufacturing, and controls information 2003 [cited 24/6/2021].
31. Carstensen JT, Rhodes CT. Drug stability: principles and practices. 3rd ed. New York: Marcel Dekker, Inc; 2000.