AAPS PharmSciTech

, Volume 15, Issue 1, pp 198–212 | Cite as

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

  • Karen M. Alsante
  • Kim Huynh-Ba
  • Steven W. Baertschi
  • Robert A. Reed
  • Margaret S. Landis
  • Mark H. Kleinman
  • Christopher Foti
  • Venkatramana M. Rao
  • Paul Meers
  • Andreas Abend
  • Daniel W. Reynolds
  • Biren K. Joshi
Meeting Report

References

  1. 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.Google Scholar
  2. 2.
    Parenty ADC, Button WG, Ott MA. An expert system to predict the forced degradation of organic molecules. Molecular Pharmaceutics. 2013;in press.Google Scholar
  3. 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.Google Scholar
  4. 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.Google Scholar
  5. 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.Google Scholar
  6. 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.Google Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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).Google Scholar
  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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.Google Scholar
  14. 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.PubMedGoogle Scholar
  15. 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. 16.
    Lhasa Limited. Zeneth. Leeds UK: Lhasa Limited,; 2013; Version 5:(Available from: www.lhasalimited.org/zeneth/.
  17. 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. 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. 19.
    Lukulay P, Hokanson G. Reconciling mass balance in forced degradation studies. Pharm Tech. 2005; 106-12.Google Scholar
  20. 20.
    Baertschi SW. Analytical methodologies for discovering and profiling degradation-related impurities. TrAC Trends Anal Chem. 2006;25(8):758–67.CrossRefGoogle Scholar
  21. 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.Google Scholar
  22. 22.
    Nursten HE, Royal Society of Chemistry. The Maillard Reaction: Chemistry, Biochemistry, and Implications: Royal Society of Chemistry; 2005.Google Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.Google Scholar
  25. 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.Google Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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. 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.Google Scholar
  29. 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. 30.
    Handbook of Pharmaceutical Excipients. Seventh ed. Rowe RC, Sheskey PJ, Cook WG, Fenton ME, editors: Pharmaceutical; 2012.Google Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 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. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 40.
    Zuidam NJ, Crommelin DJ. Chemical hydrolysis of phospholipids. J Pharm Sci. 1995;84(9):1113–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Schnitzer E, Pinchuk I, Lichtenberg D. Peroxidation of liposomal lipids. Eur Biophys J. 2007;36(4–5):499–515.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.Google Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.CrossRefGoogle Scholar
  46. 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.CrossRefGoogle Scholar
  47. 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.CrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.Google Scholar
  50. 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. 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.CrossRefGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. 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.PubMedGoogle Scholar
  54. 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.CrossRefGoogle Scholar
  55. 55.
    Haber F, Weiss J. Uber die Katalyse des Hydroperoxydes. Naturwissenschaften. 1932;20(51):948–50.CrossRefGoogle Scholar
  56. 56.
    Pilatti C, Torre MC, Chiale C, Spinetto M. Stability of pilocarpine ophthalmic solutions. Drug Dev Ind Pharm. 1999;25(6):801–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Al-Badr AA, Aboul-Enein HY. Pilocarpine. In: Florey K, editor. Analytical profiles of drug substances. Academic; 1983. p. 385–432.Google Scholar
  58. 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.CrossRefGoogle Scholar
  59. 59.
    Yoshioka S, Stella VJ. Stability of drugs and dosage forms. First ed: Springer; 2000.Google Scholar
  60. 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.

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  • Karen M. Alsante
    • 1
  • Kim Huynh-Ba
    • 2
  • Steven W. Baertschi
    • 3
  • Robert A. Reed
    • 4
  • Margaret S. Landis
    • 1
  • Mark H. Kleinman
    • 5
  • Christopher Foti
    • 1
  • Venkatramana M. Rao
    • 6
  • Paul Meers
    • 7
  • Andreas Abend
    • 8
  • Daniel W. Reynolds
    • 9
  • Biren K. Joshi
    • 9
  1. 1.Pfizer Global Research and DevelopmentGrotonUSA
  2. 2.PharmalytikNewarkUSA
  3. 3.Eli Lilly and Company Lilly Research LaboratoriesIndianapolisUSA
  4. 4.Celsion CorporationLawrencevilleUSA
  5. 5.GlaxoSmithKlineKing of PrussiaUSA
  6. 6.Bristol-Myers SquibbNew BrunswickUSA
  7. 7.Rutgers UniversityNew BrunswickUSA
  8. 8.MerckWest PointUSA
  9. 9.GlaxoSmithKlineResearch Triangle ParkUSA

Personalised recommendations