Advertisement

AAPS PharmSciTech

, Volume 18, Issue 5, pp 1692–1698 | Cite as

Accelerated Stability Modeling for Peptides: a Case Study with Bacitracin

  • Robin Waterman
  • Jennifer Lewis
  • Kenneth C. WatermanEmail author
Research Article

Abstract

The Accelerated Stability Assessment Program (ASAP) was applied for the first time to a peptide, the antibiotic active pharmaceutical ingredient bacitracin. Bacitracin and its complex with zinc were exposed to temperature and relative humidity conditions from 50 to 80°C and from 0 to 63% for up to 21 days. High-performance liquid chromatography was used to analyze the stressed samples for both degradant formation and loss of the active (bacitracin A) and two inactive isoforms, with identities confirmed by mass spectrometry. These data were then analyzed using a humidity-corrected Arrhenius equation and isoconversion approach to create a shelf-life predicting model for typical storage conditions. Model fitting was found to be good with low residuals in both temperature and relative humidity axes for all parameters examined. The generated model’s predictions for both the native and zinc complex of bacitracin for both formation of the major degradation product (F) and loss of the active isoform (A) were consistent with longer-term measured values at 30°C/53%RH and 40°C/75%RH, validating this approach for accelerating the determination of long-term stability of a peptide.

KEY WORDS

accelerated stability peptide stability solid-state stability stability modeling 

Notes

Acknowledgments

The authors would like to acknowledge the following scientists from FreeThink Technologies, who helped considerably on this project: Alisa Waterman, Philip Waterman, Tom Sharp, Michael Grabowski, Nick Sinchuk, and Teslin Botoy.

References

  1. 1.
    International Conference on Harmonization Guideline Q1A(R2): stability testing of new drug substances and drug Products 2003.Google Scholar
  2. 2.
    Waterman KC, Adami RC. Accelerated aging: prediction of chemical stability of pharmaceuticals. Int J Pharm. 2005;293:101–25.CrossRefPubMedGoogle Scholar
  3. 3.
    Waterman KC. The application of the Accelerated Stability Assessment Program (ASAP) to quality by design (QbD) for drug product stability. AAPS PharmSciTech. 2011;12:932–7.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Waterman KC, MacDonald BC. Package selection for moisture protection for solid, oral drug products. J Pharm Sci. 2010;99:4437–52.CrossRefPubMedGoogle Scholar
  5. 5.
    Waterman KC. 2009.Understanding and predicting pharmaceutical product shelf-life. In Huynh-Ba K, editor. Handbook of Stability Testing in Pharmaceutical Development, Springer, p 115–135.Google Scholar
  6. 6.
    Waterman KC, Colgan ST. A science-based approach to setting expiry dating for solid drug products. Regul Rapp. 2008;5(7):9–14.Google Scholar
  7. 7.
    Waterman KC, Carella AJ, Gumkowski MJ, Lukulay P, MacDonald BC, Roy MC, et al. Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm Res. 2007;24(4):780–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Cleland JL, Powell MF, Shire SJ. The development of stable protein formulations: a close look at protein aggregation, deamidation, and oxidation. Crit Rev Ther Drug Carrier Syst. 1993;10(4):307–77.PubMedGoogle Scholar
  9. 9.
    Yoshioka S, Aso Y, Izutsu K, Terao T. Application of accelerated testing to shelf-life prediction of commercial protein preparations. J Pharm Sci. 1993;83(3):454–6.CrossRefGoogle Scholar
  10. 10.
    Yoshioka S, Aso Y, Izutsu K, Kojima S. Is stability prediction possible for protein drugs? Denaturation kinetics of β-galactosidase in solution. Pharm Res. 1994;11(12):1721–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Franks F. Accelerated stability testing of bioproducts: attractions and pitfalls. Trends Biotechnol. 1994;12:114–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Jaenicke R. Stability and folding of domain proteins. Prog Biophys Mol Biol. 1999;71:155–241.CrossRefPubMedGoogle Scholar
  13. 13.
    Shnyrov VL, Zhadan GG. Irreversible thermal denaturation of complex biological structures. 2000;4:351–67.Google Scholar
  14. 14.
    Reithmeier H, Dickes M, Winer G, Knoll AG. Accelerated isothermal and non-isothermal stability studies of aqueous protein formulations. Proc Int Symp Control Rel Bioact Mater. 2001;28:896–7.Google Scholar
  15. 15.
    Roberts CJ. Kinetics of irreversible protein aggregation: analysis of extended Lumry-Eyring models and implications for predicting protein shelf life. J Phys Chem B. 2003;107:1194–207.CrossRefGoogle Scholar
  16. 16.
    Weiss WF, Young TM, Roberts CJ. Principles, approaches, and challenges for predicting protein aggregation rates and shelf life. J Pharm Sci. 2009;98:1246–77.CrossRefPubMedGoogle Scholar
  17. 17.
    Sanchez-Ruiz JM. Protein kinetic stability. Biophys Chem. 2010;148:1–15.CrossRefPubMedGoogle Scholar
  18. 18.
    Ikai Y, Oka H, Hayakawa J, Matsumoto M, Saito M, Harada K-I, et al. Total structures and antimicrobial activity of bacitracin minor components. J Antibiot (Tokyo). 1995;48:233–42.CrossRefGoogle Scholar
  19. 19.
    United States Pharmacopeia. 2008. Bacitracin Monograph. In USP 31-NF, p 1483–1485.Google Scholar
  20. 20.
    Stone KJ, Strominger JL. Mechanism of action of bacitracin: complexation with metal ion and C55-isoprenyl pyrophosphate. Proc Natl Acad Sci U S A. 1971;68:3223–7.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhao W, Qiao J, Song Q, Lian H. Characterization of bacitracin zinc by matrix-assisted laser desorption ionization–tandem time-of-flight mass spectrometry. Instrum Sci Technol. 2015;43:453–68.CrossRefGoogle Scholar
  22. 22.
    Pavli V, Kmetec V. Pathways of chemical degradation of polypeptide antibiotic bacitracin. Biol Pharm Bull. 2006;29:2160–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Potts AR, Psurek T, Jones C, Parris L, Wise A. Validation of a quantitative HPLC method for bacitracin and bacitracin zinc using EDTA as a mobile-phase modifier. J Pharm Biomed Anal. 2012;70:619–23.CrossRefPubMedGoogle Scholar
  24. 24.
    Consonni V, Ballabio D, Todeschini R. Comments on the definition of the Q2 parameter for QSAR validation. J Chem Inf Model. 2009;49:1669–78.CrossRefPubMedGoogle Scholar
  25. 25.
    Consonni V, Ballabio D, Todeschini R. Evaluation of model predictive ability by external validation techniques. J Chemometrics. 2010;24:194–201.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • Robin Waterman
    • 1
  • Jennifer Lewis
    • 1
  • Kenneth C. Waterman
    • 1
    Email author
  1. 1.FreeThink Technologies, Inc.BranfordUSA

Personalised recommendations