TECHNICAL CONSIDERATIONS OF FORCED DEGRADATION STUDIES OF NEW DRUG SUBSTANCES AND PRODUCT: REGULATORY PERSPECTIVES
Forced degradation studies of new drug substances and drug product are important to help develop and demonstrate specificity of stability indicating methods and provide knowledge about possible degradation pathways and degradation products of the active ingredients and help elucidate the structure of the degradants. They were also useful in the investigation of chemical and physical stability of crystal forms. It is better to start degradation studies earlier in the drug development process to have sufficient time to gain more information about the stability of the molecule. This information will in turn help improve the formulation manufacturing process and determine the storage conditions. As no specific set of conditions is applicable to all drug products and drug substances and the regulatory guidance does not specify the conditions to be used, this study requires the experimenter to use common sense. The aim of any strategy used for forced degradation is to produce the desired amount of degradation i.e., 5â€“20%. Adequate degradation required to understand the probable degradants for the evaluation of stability indicating method. It has become mandatory to perform stability studies of new drug moiety before filing in registration dossier. The stability studies include long-term studies (12 months) and accelerated stability studies (6 months).
Key Words: Force Degradation, Stability Indicating, ICH, Drug substances, Drug product.
2. Reynolds DW, Facchine KL, Mullaney JF. Available guidance and best practices for conducting forced degradation studies. Pharmaceutical Technology, 2008; 26:48â€“56.
3. Singh R, Rehman Z. Current trends in forced degradation study for pharmaceutical product development. Journal of pharmaceutical and educational research, 2012; 2:54-63.
4. Maheswaran R. FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions. Pharmaceutical Technology, 2012; 36:73-80.
5. Singh S, Bakshi M. Guidance on conduct of stress tests to determine inherent stability of drugs. Phrama Technology, 2000, 24, 1-14.
6. Boccardi G. Oxidative susceptibility testing, pharmaceutical Stress Testing-Predicting Drug Degradation; Baertschi SW, editors, Taylor and Francis, New York. 2005.
7. Alsante KM, Hatajik TD, Lohr LL, Santafianos D Sharp TR. Solving impurity/degradation problems: case studies. In; handbook of Isolation and Characterization of impurities in Pharmaceutical, Ahuja S, Alsante K, editors, Academics Press, New York. 2003, 380-383.
8. Alan RO, Brigitte ES, Yanqiu SA, Polshyna NM, Dunphy R, Barbara LM. Forced degradation studies of rapamycin: Identification of autoxidation products. Journal Pharmaceutical and Biomedical analysis, 2012; 59:194-200.
9. Trabelsi H, Hassen IE, Bouabdallah S, Bouzouita K, Safta F. Stability indicating LC method for determination of Pipamperone. Journal of Pharmaceutical and Biomedical Analysis, 2005; 39:914-919.
10. Bojana P, Markus D, Kappe CO. Microwave-assisted forced degradation using high-throughput microtiter platforms. Journal of Pharmaceutical and Biomedical Analysis, 2011; 56:867-873.
11. Baertschi SW, Thatcher SR. Sample presentation for photostability studies: problems and solutions, In; Pharmaceutical Photostability and Stabilization Technology. Piechocki J, Editor, Taylor & Francis, New York. 2006; 445-450.
12. Baertschi SW, Alsante KM. Stress testing: the chemistry of the drug degradation, In; Pharmaceutical Stress Testing, Baertschi SW, editors, Taylor & Francis, New York. 2005; 99-101.
13. FDA Guidance for Industry, INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic Biotechnology Derived Products, Draft Guidance, Food and Drug Administration.
14. Jenke DR. Chromatographic method validation: a review of common practices and procedures II. Journal of Liquid Chromatography, 1996; 19:737-757.
15. Ali NW, Abbas AS, Zaazaa HE. Validated stability indicating methods for determination of Nitazoxanide in presence of its degradation products, Journal Pharmaceutical Analysis. 2012; 2:105-116.
16. Carstensen JT. Solution Kinetics; Kinetic pH profiles; Oxidation in solution; Catalysis, Complexation, and Photolysis, in Carstensen JT, Rhodes CT, Drug Stability, Principle and Practice, 3rd edition, Marcel Dekker, New York, 2000, 19-143.
17. David A, Alexander TF. Fast track: Physical Pharmacy, 1st edition, London, Pharmaceutical Press, 2008, 29-31.
18. ICH, Final Guidance on Stability Testing of Biotechnological/Biological Products Availability, International Conference on Harmonization, 1996.
19. ICH Guidance for Industry, Q1B: Photo stability testing of New Drug Substances and Product, International Conference on Harmonization, 1996.
20. ICH Guidance for Industry, Q2B: Validation of Analytical Procedures: Methodology, International Conference on Harmonization, 1996.
21. Ngwa G. Forced degradation studies as an integral part of HPLC stability indicating method development. Drug Delivery Technology, 2010; 10:56-59.
22. Sitaram C, Rupakula R, Reddy BN. Determination and characterization of degradation products of Anastrozole by LC MS/ MS and NMR spectroscopy. Journal of Pharmaceutical and Biomedical Analysis, 2011; 56:962-968.
23. Skoog DA. West DM Principles of Instrumental Analysis. Saunderg Golden, Japan, 1980, 2-3.
24. Dolan J. Stability-indicating assays: LC trouble shooting. LCGC, 2002; 20:346-349.
25. Smela JW. Regulatory considerations for stability indicating analytical methods in drug substance and drug product testing. Pharmaceutical Review, 2002; 8:51-54.
26. Maheswaran R. FDA perspectives: scientific considerations of forced degradation studies in ANDA submissions. Pharmaceutical Technology, 2012; 36:73-80.
27. Kovarikova P, Jiri K, Jiri D, Lucie T. HPLC study of glimepiride under hydrolytic stress conditions. Journal of Pharmaceutical and Biomedical Analysis, 2004; 36:205-209.
28. FDA Guidance for Industry, INDs for Phase II and III Studies- Chemistry, Manufacturing, and Controls Information. Food and Drug Administration, 2003, 1-27.
29. Singh S, Bakshi M. Guidance on conduct of stress tests to determine inherent stability of drugs. Pharmaceutical Technology, 2000, 24, 1-14.
30. Riddhiben MP, Piyushbhai MP, Natubhai MP. Stability indicating HPLC method development-a review. International Research Journal of Pharmacy, 2011; 2:79-87.
31. ICH Guidance for Industry, Q1B: Photo stability Testing of New Drug Substances and Product, International Conference on Harmonization.1996.
32. Baertschi SW, Thatcher SR. Sample presentation for photo stability studies: problems and solutions, in: J. Piechocki (Ed.), Pharmaceutical Photostability and Stabilization Technology, Taylor & Francis, New York, 2006, 445-450.
33. Allwood M, Plane J. The wavelength-dependent degradation of vitamin A exposed to ultraviolet radiation, International Journal of Pharmacy 1986; 31:1â€“7.
34. ICH Q3A (R2) Impurities in New Drug Substances and Products (Step 4), International Conference on Harmonization, 2006, 1-15.
35. Phale MD, Hamrapurkar PD. Optimization and establishment of a validated stability-indicating HPLC method for study of the stress degradation behavior of metoprolol succinate. Journal of AOAC International. 2010, 93, 911â€“916.
36. Wartz M, Krull I. Developing and Validating Stability-Indicating Methods. LCGC, 2005, 26, 23586-23593
37. Ngwa G. Forced Degradation Studies. Drug Delivery Technology, 2010, 10, 3, 0976-1225.
38. Reynolds DW. Forced Degradation of Pharmaceuticals. Pharmaceutical Review, 2004, 23, 56-61.
39. European Medicines Agency, Guidance for Industry Q2B Validation of Analytical Procedures: Methodology. 2011.
40. Alsante KM, Ando A, Brown R, Ensing J, Hatajik TD, Tsuda, Y. The Role of Degradant Profiling in Active Pharmaceutical Ingredients and Drug Products. Advance Drug Delivery Review, 2007, 1, 59-65.
41. Klick S, Muijselaar PG, Waterval J, Eichinger T, Korn C, Gerding TK, Debets AJ, Sanger-Van de Griend C, Van den Beld, C, Somsen GW, De Jong GJ. Toward a Generic Approach for Stress Testing of Drug Substances and Drug Products. Pharmaceutical Technology, 2005, 29, 48-57.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).