Skip to main content
SpringerLink
Log in

Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape

  • 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

REFERENCES

  1. United States Food and Drug Administration. How drugs are developed and approved-types of applications. 2010. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/default.htm. Accessed 2013

  2. United States Pharmacopeia and National Formulary (USP 36-1159NF 31). Rockville, MD: United States Pharmacopeia Convention; 2013.

  3. United States Government. Title 21—Food and Drugs Section 330.1: general conditions for general recognition as safe, effective and not misbranded. Code of Federal Regulations (annual edition); 2011.

  4. United States Pharmacopeial Convention. Key Issue: Monograph Modernization. 2012. Available from: http://www.usp.org/usp-nf/key-issues/monograph-modernization. Accessed 2013

  5. United States Pharmacopeial Convention. Pharmacopeial Forum (PF). Available from: http://www.usp.org/usp-nf/pharmacopeial-forum. Accessed 2013

  6. United States Pharmacopeial Convention. White Paper: Modernization of Organic Impurities Testing in USP Drug Product Monographs. 2013 [cited 2013]; Available from: http://www.usp.org/usp-nf/key-issues/monograph-modernization/organic-impurities-drug-monographs/white-paper-modernization-organic-impurities.

  7. United States Pharmacopeial Convention. Over-the-Counter (OTC) Drug Substances and Drug Products Workshop. 2011. Available from: http://www.usp.org/meetings-courses/workshops/over-counter-otc-drug-substances-and-drug-products-workshop. Accessed 2013

  8. Argentine M, Owens P, Olsen B. Strategies for the investigation and control of process-related impurities in drug substances. Adv Drug Deliv Rev. 2007;59(1):12–28.

    Article  CAS  PubMed  Google Scholar 

  9. Pilaniya K, Chandrawanshi H, Pilaniya U, Manchandani P, Jain P, Singh N. Recent trends in the impurity profile of pharmaceuticals. J Adv Pharm Technol Res. 2010;1(3):302–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Li Y, Liu D, Yang S, Sudini R, McGuire M, Bhanushali D, et al. Analytical control of process impurities in Pazopanib hydrochloride by impurity fate mapping. J Pharm Biomed Anal. 2010;52(4):493–507.

    Article  CAS  PubMed  Google Scholar 

  11. Teasdale A, Elder D, Chang S, Wang S, Thompson R, Benz N, et al. Risk assessment of genotoxic impurities in new chemical entities: strategies to demonstrate control. Org Process Res Dev. 2013;17(2):221–30.

    Article  CAS  Google Scholar 

  12. Chan Li Q, Qiu F, Cohen K, Tougas T, Li J, McCaffrey J, et al. Best practices for drug substance stress and stability studies during early-stage development part I—conducting drug substance solid stress to support phase Ia clinical trials. J Pharm Innov. 2012;7:214–24.

    Article  Google Scholar 

  13. Chan Li Q, Qiu F, Cohen K, Tougas T, Li J, McCaffrey J, et al. Best practices for drug substance stress and stability studies during early-stage development part II—conducting abbreviated long-term and accelerated stability testing on the first clinical drug substance batch to confirm and adjust the drug substance retest period/powder for oral solution shelf life. J Pharm Innov. 2013;8:56–65.

    Article  Google Scholar 

  14. 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.

  15. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guidance for Industry Q3B Impurities in New Drug Products (Revision 2). ICH Harmonized Tripartite Guidelines; 2006.

  16. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guidance for Industry Q3A Impurities in New Drug Substances (Revision 2). ICH Harmonized Tripartite Guidelines; 2008.

  17. United States Pharmacopeial Convention. General Chapters. Available from: http://www.usp.org/usp-nf/harmonization/general-chapters. Accessed 2013

  18. United States Pharmacopeial Convention. Monographs. [cited 2013]; Available from: http://www.usp.org/usp-nf/harmonization/monographs 2012.

  19. United States Pharmacopeial Convention. USP Reference Standards. Available from: http://www.usp.org/store/products-services/reference-standards. Accessed 2013

  20. 21 CFR 314 Applications for FDA Approval to Market a New Drug,” [Content and Format of an Abbreviated New Drug Application, Sec. 314.94 (9)].

  21. Food and Drug Administration (FDA). Guidance for Industry, ANDAs: impurities in Drug Substances (R1) 2009.

  22. Food and Drug Administration (FDA). Guidance for Industry: ANDAs: Impurities in Drug Products 2010.

  23. Crowley P, Martini LG. Drug-excipient interactions. Pharm Tech. 2001.

  24. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guidance for the Industry Q3C: Impurities: Residual Solvents. ICH Harmonized Tripartite GuidelinesJune 1997. p. 1–2.

  25. United States Pharmacopeia and National Formulary (USP 35-NF 30). Rockville, MD: United States Pharmacopeia Convention; 2012. p. 5089.

  26. Food and Drug Administration (FDA). OPS, MAPP 5015.8 Acceptance criteria for residual solvents. 2009.

  27. Food and Drug Administration (FDA). Questions and Answers on Residual Solvents in ANDAs: Guidance, Compliance, & Regulatory Information [Internet]. 2008. Available from: http://www.fda.gov/downloads/AboutFDA/CentersOffices/CenterforDrugEvaluationandResearch/ucm119607.pdf.

  28. European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents. Doc Ref EMEA/CHMP/SWP/4446/2000 February 2008. p. 1–2.

  29. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guidance for the Industry:Q8: Pharmaceutical Development (R2). ICH Harmonized Tripartite Guidelines 2009. pp. 1–2.

  30. Committee for Medicinal Products for Human Use (CHMP). Guideline on the Limits of Genotoxic Impurities. In: European Medicines Agency (EMEA), editor. London UK 2006.

  31. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guidance for industry-genotoxic and carcinogenic impurities in drug substances and products: recommended approaches (Draft Guidance). ICH Harmonized Tripartite Guidelines 2008.

  32. Snodin DJ, McCrossen SD. Guidelines and pharmacopoeial standards for pharmaceutical impurities: overview and critical assessment. Regul Toxicol Pharmacol. 2012;63(2):298–312.

    Article  CAS  PubMed  Google Scholar 

  33. Olsen BA, Baertschi SW. Strategies for investigation and control of process and degradation-related impurities. In: Ahuja S, Alsante K, editors. Handbook of isolation and characterization of impurities in pharmaceuticals. San Diego: Academic; 2003. p. 89–117.

    Google Scholar 

  34. Argentine MD, Owens PK, Olsen BA. Strategies for the investigation and control of process-related impurities in drug substances. Adv Drug Deliv Rev. 2007;59(1):12–28.

    Article  CAS  PubMed  Google Scholar 

  35. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guidance for the Industry Q3D: Impurities: Guideline for Metal Impurities (Final Concept Paper). ICH Harmonized Tripartite Guidelines; 2009. p. 1–2.

  36. United States Pharmacopeial Convention. Key Issue: Elemental Impurities. USP-NF Key Issues (http://wwwusporg/usp-nf/key-issues/elemental-impurities) [Internet]. 2013. Available from: http://www.usp.org/usp-nf/key-issues/elemental-impurities.

  37. International Pharmaceutical Excipients Council of the Americas. Press Release-Coalition for Rational Implementation of the USP Elemental Impurities Requirements. IPEC-Americas Insider [Internet]. Available from: http://ipecamericas.org/Press-release-coalition. 2012.

  38. Snodin DJ, Elder DP. Genotoxic Impurities Part 1: General Overview. Pharmaceutical Outsourcing [Internet]. 2012. Available from: http://www.pharmoutsourcing.com/Featured-Articles/113769-Genotoxic-Impurities-Part-1-General-Overview/.

  39. Stress Testing: Predictive or Overkill? Informa Life Sciences 5th Annual Conference on Forced Degradation; London, UK; 2011.

  40. Reid DL, Calvitt CJ, Zell MT, Miller KG, Kingsmill CA. Early prediction of pharmaceutical oxidation pathways by computational chemistry and forced degradation. Pharm Res. 2004;21(9):1708–17.

    Article  CAS  PubMed  Google Scholar 

  41. Boccardi G. Autoxidation of drugs: prediction of degradation impurities from results of reaction with radical chain initiators. Farmaco. 1994;49(6):431–5.

    CAS  PubMed  Google Scholar 

  42. Yao J, Dokuru DK, Noestheden M, Park SS, Kerwin BA, Jona J, et al. A quantitative kinetic study of polysorbate autoxidation: the role of unsaturated fatty acid ester substituents. Pharm Res. 2009;26(10):2303–13.

    Article  CAS  PubMed  Google Scholar 

  43. 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. pp. 10–48.

  44. Watkins MA, Pitzenberger S, Harmon PA. Direct evidence of 2-cyano-2-propoxy radical activity during AIBN-based oxidative stress testing in acetonitrile-water solvent systems. J Pharm Sci. 2013;102(5):1554–68.

    Article  CAS  PubMed  Google Scholar 

  45. Niu QJ, Mendenhall GD. Yields of singlet molecular oxygen from peroxyl radical termination. J Am Chem Soc. 1992;114(1):165–72.

    Article  CAS  Google Scholar 

  46. Brustugun J, Tonnesen HH, Klem W, Kjonniksen I. Photodestabilization of epinephrine by sodium metabisulfite. PDA J Pharm Sci Technol. 2000;54(2):136–43.

    CAS  PubMed  Google Scholar 

  47. Seburg RA, Ballard JM, Hwang TL, Sullivan CM. Photosensitized degradation of losartan potassium in an extemporaneous suspension formulation. J Pharm Biomed Anal. 2006;42(4):411–22.

    Article  CAS  PubMed  Google Scholar 

  48. Goldstein S, Meyerstein D, Czapski G. The Fenton reagents. Free Radic Biol Med. 1993;15(4):435–45.

    Article  CAS  PubMed  Google Scholar 

  49. Baertschi S, Draper J, Jansen P, Smith W, editors. Oxidative susceptibility testing: rapid, comprehensive screening techniques. 3rd Annual Forced Degradation Conference Institute for International Research, Short Hills, NJ. 2006.

  50. Wagner T, Martin W, Lipp R, Iffert B, Michel H, Westermann J, et al., inventors. Antioxidant in manufacture of prostane pharmaceuticals. 1999.

  51. United States Pharmacopeia and National Formulary (USP 27-NF 22): Monograph 27 “Containers for Dispensing Capsules and Tablets”. 22nd ed. Rockville, MD: United States Pharmacopeial Convention; 2004.

  52. Fasani E, Albini A. Photostability Stress Testing (Chapter 7). 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. 192–217.

  53. Clapham D, Templeton A, Klein L, Kleinman MH. Practical aspects of conducting photostability stress testing (Chapter 8). 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. 218–32.

  54. Thatcher SR, Mansfield RK, Miller RB, Davis CW, Baertschi SW. Pharmaceutical photostability: a technical and practical interpretation of the ICH guideline and its application to pharmaceutical stability: part I. Pharm Tech. 2001;25(3):98–110.

    CAS  Google Scholar 

  55. Thatcher SR, Mansfield RK, Miller RB, Davis CW, Baertschi SW. Pharmaceutical photostability: a technical and practical interpretation of the ICH guideline and its application to pharmaceutical stability: part II. Pharm Tech. 2001;25(4):50–62.

    CAS  Google Scholar 

  56. 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 

  57. Baertschi S, Clapham D, Foti C, Jansen P, Kristensen S, Reed R, et al. Implications of in use Photostability: Proposed Guidance for Photostability Testing and Labeling to Support the Administration of Photosensitive Pharmaceutical Products Part I. Drug Products Administered by Injection. J Pharm Sci. 2013;(in press).

  58. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Stability Testing: Photostability Testing of New Drug Substances and Products Q1B (Step 4 Version). ICH Harmonized Tripartite Guidelines; 1996.

  59. Kristensen S. Photostability of Parenteral Products (Chapter 14). In: Tonnesen H, editor. Photostability of Drugs and Drug Formulations. Second ed. Boca Raton, Florida: CRC Press; 2004. p. 448.

  60. Brustugun J, Tonnesen HH, Edge R, Navaratnam S. Formation and reactivity of free radicals in 5-hydroxymethyl-2-furaldehyde—the effect on isoprenaline photostability. J Photochem Photobiol B. 2005;79(2):109–19. Epub 2005 Jan 26.

    Article  CAS  PubMed  Google Scholar 

  61. 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 

  62. Lu Y, Bowen WE, Reed RA. Titanium Dioxide Induced Photo-oxidation in Pharmaceutical Formulation Solutions. In: The Photostability of Drugs Interest Group, editor. 5th International Conference on Photostability of Drugs and Drug Products (PPS'04); London, UK; 2004.

  63. Paul IC, Curtin DY. Thermally induced organic reactions in the solid state. Acc Chem Res. 1973;6(7):217–25.

    Article  CAS  Google Scholar 

  64. Carstensen JT. Solid pharmaceutics: mechanical properties and rate phenomena. New York: Academic; 1980. 259 p.

    Google Scholar 

  65. Morawetz H. Reactivity of organic crystals. Science. 1966;152(3723):705–11.

    Article  CAS  PubMed  Google Scholar 

  66. Guerrieri PP, Smith DT, Taylor LS. Phase behavior of ranitidine HCl in the presence of degradants and atmospheric moisture–impact on chemical stability. Langmuir. 2008;24(8):3850–6.

    Article  CAS  PubMed  Google Scholar 

  67. Shalaev EY, Zografi G. How does residual water affect the solid-state degradation of drugs in the amorphous state? J Pharm Sci. 1996;85(11):1137–41.

    Article  CAS  PubMed  Google Scholar 

  68. Schmidt GMJ. Photodimerization in the solid state. Pure Appl Chem. 1971;27:647–78.

    Article  CAS  Google Scholar 

  69. Kearsley SK. The prediction of chemical reactivity within organic crystals using geometric criteria. In: Desiraju GR, editor. Organic solid-state chemistry. New York: Elsevier; 1987. p. 69–115.

    Google Scholar 

  70. Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17(4):397–404.

    Article  CAS  PubMed  Google Scholar 

  71. Govindarajan R, Zinchuk A, Hancock B, Shalaev E, Suryanarayanan R. Ionization states in the microenvironment of solid dosage forms: effect of formulation variables and processing. Pharm Res. 2006;23(10):2454–68.

    Article  CAS  PubMed  Google Scholar 

  72. Stephenson GA, Groleau EG, Kleemann RL, Xu W, Rigsbee DR. Formation of isomorphic desolvates: creating a molecular vacuum. J Pharm Sci. 1998;87(5):536–42.

    Article  CAS  PubMed  Google Scholar 

  73. Byrn SR, Sutton PA, Tobias B, Frye J, Main P. Crystal structure, solid-state NMR spectra, and oxygen reactivity of five crystal forms of prednisolone tert-butylacetate. J Am Chem Soc. 1988;110(5):1609–14.

    Article  CAS  Google Scholar 

  74. Merritt JM, Viswanath SK, Stephenson GA. Implementing quality by design in pharmaceutical salt selection: a modeling approach to understanding disproportionation. Pharm Res. 2013;30(1):203–17.

    CAS  PubMed  Google Scholar 

  75. Dotterer SK, Forbes RA, Hammill CL. Impact of metal-induced degradation on the determination of pharmaceutical compound purity and a strategy for mitigation. J Pharm Biomed Anal. 2011;54(5):987–94.

    Article  CAS  PubMed  Google Scholar 

  76. Yang S, Caltabiano A, Wu L, Shen J, Chen J, Kord A, et al. Identification and control of metal-chelating chromatographic artifacts in the analysis of a malonohydrazide derivative drug compound. J Pharm Biomed Anal. 2010;53(3):371–5.

    Article  CAS  PubMed  Google Scholar 

  77. Murahashi S, Komiya N, Hayashi Y, Kumano T. Copper complexes for catalytic, aerobic oxidation of hydrocarbon. Pure Appl Chem. 2001;73(2):311–4.

    Article  CAS  Google Scholar 

  78. Petrier C, Jeunet A, Luche JL, Reverdy G. Unexpected frequency effects on the rate of oxidative processes induced by ultrasound. J Am Chem Soc. 1992;114(8):3148–50.

    Article  CAS  Google Scholar 

  79. Li M, Ahuja ES, Watkins DM. LC-MS and NMR determination of a dichloromethane artifact adduct, cyproheptadine chloromethochloride. J Pharm Biomed Anal. 2003;31(1):29–38.

    Article  PubMed  Google Scholar 

  80. Skibic MJ, King LA, Khan M, Fox PJ, Winger BE, Baertschi SW. Artifactual formylation of the secondary amine of duloxetine hydrochloride by acetonitrile in the presence of titanium dioxide: implications for HPLC method development. J Pharm Biomed Anal. 2010;53(3):432–9.

    Article  CAS  PubMed  Google Scholar 

  81. Lin M, Li M, Rustum A. Identification of an unknown extraneous contaminant in pharmaceutical product analysis. J Pharm Biomed Anal. 2007;45(5):747–55.

    Article  CAS  PubMed  Google Scholar 

  82. Orford C, Webb ML, Cattanach KH, Cottee FH, Escott RE, Pitfield ID, et al. An analytical and structural study of the photostability of some leukotriene B4 antagonists. In: Albini A, Fasani E, editors. Drugs: photochemistry and photostability. Cornwall, UK: Royal Society of Chemistry; 1998. p. 182–93.

    Chapter  Google Scholar 

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

  2. Pharmalytik Newark, Newark, Delaware, USA

    Kim C. Huynh-Ba

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

    Steven W. Baertschi, Gregory A. Stephenson & Patrick Jansen

  4. Celsion Corporation, Lawrenceville, New Jersey, USA

    Robert A. Reed

  5. United State Food and Drug Administration, Washington, District of Columbia, USA

    Scott Furness & Robert Iser

  6. Olsen Pharmaceutical Consulting, LLC, West Lafayette, Indiana, USA

    Bernard Olsen

  7. Merck and Co., West Point, Pennsylvania, USA

    Mark Mowery

  8. United States Pharmacopeial Convention, Rockville, Maryland, USA

    Karen Russo

Authors
  1. Karen M. Alsante
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim C. 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. Scott Furness
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernard Olsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mark Mowery
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karen Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robert Iser
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gregory A. Stephenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Patrick Jansen
    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.C., Baertschi, S.W. et al. Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape. AAPS PharmSciTech 15, 237–251 (2014). https://doi.org/10.1208/s12249-013-0061-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-013-0061-z

Keywords

Search

Navigation