Skip to main content

Advertisement

SpringerLink
Log in

Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms

  • Meeting Report
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Scheme 1
Scheme 2
Scheme 3

References

  1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Stability Testing of New Drug Substances and Products Q1A (R2). ICH Harmonized Tripartite Guidelines. 2003.

  2. Parenty ADC, Button WG, Ott MA. An expert system to predict the forced degradation of organic molecules. Molecular Pharmaceutics. 2013;in press.

  3. Baertschi SW, Reynolds DW, Jansen P, Alsante K, Santafianos D, Kimmer Smith W, et al. Pharmaceutical stress testing: predicting drug degradation. Second ed. Baertschi SW, Alsante KM, Reed RA, editors: InformaHealth Sciences; 2011. 624 p.

  4. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guideline on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals ICH M3 (R2). ICH Harmonized Tripartite Guidelines. 2009.

  5. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Photosafety Evaluation of Pharmaceuticals S10: Draft ICH Consensus Guideline. ICH Harmonized Tripartite Guidelines. 2013.

  6. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guideline on assessment and control of dna reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk M7: Draft Consensus Guideline. ICH Harmonized Tripartite Guidelines. 2013.

  7. Reynolds DW, Galvani M, Hicks SR, Joshi BJ, Kennedy-Gabb SA, Kleinman MH, et al. The use of N-methylpyrrolidone as a cosolvent and oxidant in pharmaceutical stress testing. J Pharm Sci. 2012;101:761–76.

    Article  CAS  PubMed  Google Scholar 

  8. Kleinman MH, Smith MD, Kurali E, Kleinpeter S, Jiang K, Zhang Y, et al. An evaluation of chemical photoreactivity and the relationship to phototoxicity. Regul Toxicol Pharmacol. 2010;58:224–32.

    Article  CAS  PubMed  Google Scholar 

  9. Onoue S, Hosoi K, Wakuri S, Iwase Y, Yamamoto T, Matsuoka N, et al. Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation. J Appl Toxicol. 2012;13(10).

  10. Spielmann H, Balls M, Brand M, Doring B, Holzhutter HG, Kalweit S, et al. EEC/COLIPA project on in vitro phototoxicity testing: first results obtained with a Balb/c 3T3 cell phototoxicity assay. Toxicol In Vitro. 1994;8(4):793–6.

    Article  CAS  PubMed  Google Scholar 

  11. Henry B, Foti C, Alsante K. Can light absorption and photostability data be used to assess the photosafety risks in patients for a new drug molecule? J Photochem Photobiol B. 2009;96(1):57–62.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. Baertschi SW, Jansen PJ, Alsante KM. Stress testing: a predictive tool (Chapter 2). In: Baertschi SW, Alsante KM, Reed RA, editors. Pharmaceutical Stress Testing: Predicting Drug Degradation: Informa Life Sciences; 2011. 10-48.

  14. Baertschi SW, Alsante KM, Tonnesen HH. A critical assessment of the ICH guideline on photostability testing of new drug substances and products (Q1B): Recommendation for revision. J Pharm Sci. 2010;99(7):2934–40.

    CAS  PubMed  Google Scholar 

  15. Jansen PJ, Smith WK, Baertschi SW. Stress testing: Analytical considerations (Chapter 4). In: Baertschi S, Alsante K, Reed R, editors. Pharmaceutical Stress Testing. New York, NY: Informa Healthcare; 2011.

    Google Scholar 

  16. Lhasa Limited. Zeneth. Leeds UK: Lhasa Limited,; 2013; Version 5:(Available from: www.lhasalimited.org/zeneth/.

  17. Albini A, Anderson NH, Baertschi S, Boxhammer J, Byard SJ, Carter PL, et al. In: Tonnesen H, editor. Photostability of drugs and drug formulations. 2nd ed. Boca Raton, Florida: CRC Press; 2004. 448 p.

    Google Scholar 

  18. Piechocki JT, Tonnesen H, Allen JM, Allen SK, Gauglitz G, Hubig SM, et al. In: Piechocki JT, Thoma K, editors. Pharmaceutical photostability and stabilization technology. 1st ed. New York, NY: Informa Healthcare; 2007. 445 p.

    Google Scholar 

  19. Lukulay P, Hokanson G. Reconciling mass balance in forced degradation studies. Pharm Tech. 2005; 106-12.

  20. Baertschi SW. Analytical methodologies for discovering and profiling degradation-related impurities. TrAC Trends Anal Chem. 2006;25(8):758–67.

    Article  CAS  Google Scholar 

  21. Nussbaum MA, Kaerner A, Jansen PJ, Baertschi SW. Role of "mass balance" in pharmaceutical stress testing (Chapter 9). In: Baertschi SW, Alsante KM, Reed RA, editors. Pharmaceutical Stress Testing: Predicting Drug Degradation (Drugs and the Pharmaceutical (Sciences). Second Edition ed: Informa Life Sciences; 2011. p. 233-53.

  22. Nursten HE, Royal Society of Chemistry. The Maillard Reaction: Chemistry, Biochemistry, and Implications: Royal Society of Chemistry; 2005.

  23. Nussbaum MA, Baertschi SW, Jansen PJ. Determination of relative UV response factors for HPLC by use of a chemiluminescent nitrogen-specific detector. J Pharm Biomed Anal. 2002;27(6):983–93.

    Article  CAS  PubMed  Google Scholar 

  24. Baertschi SW, Alsante KM, Santafianos D. The chemistry of drug degradation (Chapter 3). In: Baertschi SW, Alsante KM, Reed RA, editors. Pharmaceutical Stress Testing: Predicting Drug Degradation: Informa Life Sciences; 2011. p. 49-141.

  25. Alsante KM, Baertschi SW, editors. Reviewing Advances in Knowledge of Drug Degradation Chemistry. Forced Degradation for Pharmaceuticals : Conference Proceedings; 2012 January 18-19, 2012; United Kingdom.

  26. Alsante KM, Ando A, Brown R, Ensing J, Hatajik TD, Kong W, et al. The role of degradant profiling in active pharmaceutical ingredients and drug products. Adv Drug Del Rev. 2007;59:29–37.

    Article  CAS  Google Scholar 

  27. Reynolds DW, Facchine KL, Mullaney JF, Alsante KM, Hatajik TD, Motto MG. Available guidance and best practices for conducting forced degradation studies. Pharm Tech. 2002;26(2):48–54.

    Google Scholar 

  28. Alsante KM, Snyder KD, Swartz M, Parks C. Applications development using out-of-the-box software: a structure searchable degradation/impurity database. Scientific Computing and Instrumentation. June 2012:30-7.

  29. Boyd DB, Sharp TR. The Power of Computational Chemistry to leverage Stress Testing of Pharmaceuticals. In: Baertschi SW, Alsante KM, Reed RA, editors. Pharmaceutical stress testing. Predicting Drug Degradation: Informa Life Sciences; 2011.

    Google Scholar 

  30. Handbook of Pharmaceutical Excipients. Seventh ed. Rowe RC, Sheskey PJ, Cook WG, Fenton ME, editors: Pharmaceutical; 2012.

  31. Wasylaschuk W, Harmon P, Wagner G, Harman AB, Templeton AC, Xu H, et al. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 2007;96(1):106–16.

    Article  CAS  PubMed  Google Scholar 

  32. Yue H, Bu X, Huang M-H, Young J, Raglione T. Quantitative determination of trace levels of hydrogen peroxide in crospovidone and a pharmaceutical product using high performance liquid chromatography with coulometric detection. Int J Pharm. 2009;375:33–40.

    Article  CAS  PubMed  Google Scholar 

  33. Li Z, Jacobus LK, Wuelfing WP, Golden M, Martin GP, Reed RA. Detection and quantification of low-molecular-weight aldehydes in pharmaceutical excipients by headspace gas chromatography. J Chromatogr A. 2006;1104(1–2):1–10.

    Article  CAS  PubMed  Google Scholar 

  34. Li Z, Kozlowski BM, Chang EP. Analysis of aldehydes in excipients used in liquid/semi-solid formulations by gas chromatography-negative chemical ionization mass spectrometry. J Chromatogr A. 2007;1160(1–2):299–305.

    Article  CAS  PubMed  Google Scholar 

  35. Hartauer KJ, Arbuthnot GN, Baertschi SW, Johnson RA, Luke WD, Pearson NG, et al. Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: identification and control of an oxidative degradation product. Pharm Dev Technol. 2000;5(3):303–10.

    Article  CAS  PubMed  Google Scholar 

  36. Waterman KC. The application of the Accelerated Stability Assessment Program (ASAP) to quality by design (QbD) for drug product stability. AAPS PharmSciTech. 2011;12(3):932–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Glodek M, Liebowitz S, McCarthy R, McNally G, Oksanen C, Schultz T, et al. Product robustness—a PQRI white paper. Pharm Eng. 2006;26(6):1–11.

    Google Scholar 

  38. Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility. AAPS PharmSciTech. 2011;12(4):1248–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Kensil CR, Dennis EA. Alkaline hydrolysis of phospholipids in model membranes and the dependence on their state of aggregation. Biochemistry. 1981;20(21):6079–85.

    Article  CAS  PubMed  Google Scholar 

  40. Zuidam NJ, Crommelin DJ. Chemical hydrolysis of phospholipids. J Pharm Sci. 1995;84(9):1113–9.

    Article  CAS  PubMed  Google Scholar 

  41. Schnitzer E, Pinchuk I, Lichtenberg D. Peroxidation of liposomal lipids. Eur Biophys J. 2007;36(4–5):499–515.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang JA, Pawelchak J. Effect of pH, ionic strength and oxygen burden on the chemical stability of EPC/cholesterol liposomes under accelerated conditions. Part 1: Lipid hydrolysis. Eur J Pharm Biopharm. 2000;50(3):357–64.

    Article  CAS  PubMed  Google Scholar 

  43. Food and Drug Administration (FDA). Guidance for Industry: Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation (Draft Guidance). 2002.

  44. Moll KP, Stosser R, Herrmann W, Borchert HH, Utsumi H. In vivo ESR studies on subcutaneously injected multilamellar liposomes in living mice. Pharm Res. 2004;21(11):2017–24.

    Article  CAS  PubMed  Google Scholar 

  45. Zuidam NJ, Gouw HK, Barenholz Y, Crommelin DJ. Physical (in) stability of liposomes upon chemical hydrolysis: the role of lysophospholipids and fatty acids. Biochim Biophys Acta. 1995;22(1):101–10.

    Article  Google Scholar 

  46. Grit M, Crommelin DJ. The effect of surface charge on the hydrolysis kinetics of partially hydrogenated egg phosphatidylcholine and egg phosphatidylglycerol in aqueous liposome dispersions. Biochim Biophys Acta. 1993;17(1):49–55.

    Article  Google Scholar 

  47. MacLachlan I. Liposomal formulations for nucleic acid delivery (Chapter 9). In: Corooke ST, editor. Antisense drug technologies: principles, strategies, and applications. 2nd ed. Boca Raton, FL: CRC; 2007. p. 237–69.

    Chapter  Google Scholar 

  48. Li Z, Zhang Y, Wurtz W, Lee JK, Malinin VS, Durwas-Krishnan S, et al. Characterization of nebulized liposomal amikacin (Arikace) as a function of droplet size. J Aerosol Med Pulm Drug Deliv. 2008;21(3):245–54.

    Article  PubMed  Google Scholar 

  49. Abend A, Duersch B, Fiszlar K. Small molecule parenteral drugs: practical aspects of stress testing (Chapter 12). In: Baertschi SW, Alsante KM, Reed RA, editors. Pharmaceutical Stress Testing: Predicting Drug Degradation: Informa Life Sciences; 2011. p. 322-42.

  50. Abend A, Templeton A. The impact of stopper drying for lyophilized drug products. Am Pharm Rev. 2010;25(6):201–6.

    Google Scholar 

  51. Carlisle CB, Cooper DE. Tunable diode laser frequency modulation spectroscopy through an optical fiber: high‐sensitivity detection of water vapor. Appl Phys Lett. 1990;56:805–7.

    Article  CAS  Google Scholar 

  52. Templeton AC, Placek J, Xu H, Mahajan R, Hunke WA, Reed RA. Determination of the moisture content of bromobutyl rubber stoppers as a function of processing: implications for the stability of lyophilized products. PDA J Pharm Sci Technol. 2003;57(2):75–87.

    CAS  PubMed  Google Scholar 

  53. Reed RA, Harmon P, Manas D, Wasylaschuk W, Galli C, Biddell R, et al. The role of excipients and package components in the photostability of liquid formulations. PDA J Pharm Sci Technol. 2003;57(5):351–68.

    CAS  PubMed  Google Scholar 

  54. Faust BC, Zepp RG. Photochemistry of aqueous iron(III)-polycarboxylate complexes: roles in the chemistry of atmospheric and surface waters. Environ Sci Technol. 1993;27(12):2517–22.

    Article  CAS  Google Scholar 

  55. Haber F, Weiss J. Uber die Katalyse des Hydroperoxydes. Naturwissenschaften. 1932;20(51):948–50.

    Article  CAS  Google Scholar 

  56. Pilatti C, Torre MC, Chiale C, Spinetto M. Stability of pilocarpine ophthalmic solutions. Drug Dev Ind Pharm. 1999;25(6):801–5.

    Article  CAS  PubMed  Google Scholar 

  57. Al-Badr AA, Aboul-Enein HY. Pilocarpine. In: Florey K, editor. Analytical profiles of drug substances. Academic; 1983. p. 385–432.

  58. Singh S, Mariappan TT, Sharda N, Kumar S, Chakraborti AK. The reason for an increase in decomposition of rifampicin in the presence of isoniazid under acid conditions. Pharm Pharmacol Commun. 2000;6(9):405–10.

    Article  CAS  Google Scholar 

  59. Yoshioka S, Stella VJ. Stability of drugs and dosage forms. First ed: Springer; 2000.

  60. Food and Drug Administration (FDA). Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance—Laboratory Controls. Guidance, Compliance, & Regulatory Information [Internet]. 2011. Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124785.htm.

Download references

Acknowledgments

The organizing committee would like to thank all the speakers for sharing their work at this conference and through this publication.

Disclaimer

The views and opinions in this article are only those of the authors and do not necessarily reflect the views or policies of the companies, organizations or agencies cited herein.

Author information

Authors and Affiliations

  1. Pfizer Global Research and Development, Groton, Connecticut, USA

    Karen M. Alsante, Margaret S. Landis & Christopher Foti

  2. Pharmalytik, Newark, Delaware, USA

    Kim Huynh-Ba

  3. Eli Lilly and Company Lilly Research Laboratories, Indianapolis, Indiana, USA

    Steven W. Baertschi

  4. Celsion Corporation, Lawrenceville, New Jersey, USA

    Robert A. Reed

  5. GlaxoSmithKline, King of Prussia, Pennsylvania, USA

    Mark H. Kleinman

  6. Bristol-Myers Squibb, New Brunswick, New Jersey, USA

    Venkatramana M. Rao

  7. Rutgers University, New Brunswick, New Jersey, USA

    Paul Meers

  8. Merck, West Point, Pennsylvania, USA

    Andreas Abend

  9. GlaxoSmithKline, Research Triangle Park, North Carolina, USA

    Daniel W. Reynolds & Biren K. Joshi

Authors
  1. Karen M. Alsante
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim Huynh-Ba
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven W. Baertschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert A. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Margaret S. Landis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark H. Kleinman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christopher Foti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Venkatramana M. Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paul Meers
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andreas Abend
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniel W. Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Biren K. Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Margaret S. Landis.

Additional information

Dedication

This manuscript is dedicated to the memory of the late Karen Russo, Ph.D. (United States Pharmacopeial Convention)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alsante, K.M., Huynh-Ba, K., Baertschi, S.W. et al. Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms. AAPS PharmSciTech 15, 198–212 (2014). https://doi.org/10.1208/s12249-013-0047-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-013-0047-x

Keywords

Search

Navigation