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Meeting Report: N-Nitrosamine Impurity Control Strategies in the Pharmaceutical and Biotechnology Industries

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Abstract

The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Control (CMC) Community hosted a virtual panel discussion on December 9, 2020, to provide a forum to discuss N-nitrosamine control strategies in the pharmaceutical and biotechnology industries. The panel included staff from the US Food and Drug Administration (FDA) and industry subject matter experts. Meeting topics included acceptable intake levels for nitrosamine impurities, definitions of “acceptable level of risk,” water as a contributor in nitrosamine risk assessments, nitrosamine impurity control strategies based upon fate/purge data, early vs. late development assessment expectations, application to oncology programs developed under ICH S9, and Drug Master File (DMF) regulatory expectations. During the meeting, divergence in global health authority expectations was additionally discussed. One of the most important outputs from this AAPS panel discussion was the criticality of continued dialog between industry and health authorities to help understand actual versus perceived risks and provide pragmatic, scientifically justified solutions to ensure patients are provided with an uninterrupted supply of safe medicines based on globally harmonized requirements.

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References

  1. (a) Nitrosamine Impurities in Human Medicinal Products, EMA/369136/2020, European Medicines Agency, June 25, 2020. (b) Questions and Answers for Marketing Authorisation Holders/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on Nitrosamine Impurities in Human Medicinal Products, European Medicines Agency, February 26, 2021.

  2. ICH Guideline M7(R1) on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, EMA/CHMP/ICH/83812/2013; European Medicines Agency, August 25, 2015.

  3. FDA Guidance for Industry on Control of Nitrosamine Impurities in Human Drugs, September 2020.

  4. (a) Cheung, P. C. W. “A Historical Review of the Benefits and Hypothetical Risks of Disinfecting 310 Drinking Water by Chlorination” J. Ecology. Environ. 2017, 8, 2157–6092. (b) Yang, C. S.; Yoo, J.-S. H., Ishizaki, H.; Hong, J. “Cytochrome P450IIe1: Roles in Nitrosamine Metabolism and Mechanisms of Regulation”, Drug Metabolism Reviews, 1990, 22, 147–159.

  5. For further discussion of the role of the alpha-hydrogen in the metabolic activation to generate N-nitrosamines, see: (a) Reference 1, (b) Lijinsky W. “Chemical Structural Effects in Carcinogenesis by Nitrosamines”, IARC Sci Publ. 1982, 41, 533–542. (c) Maekawa A.; Takahashi M.; Kurokawa Y.; Kokubo T.; Ogiu T.; Odashima S.; Mochizuki M.; Anjo T.; Okada M. “Carcinogenicity of Alpha-Oxidized Nitrosamines (Alpha-Acyloxy, Alpha-Hydroperoxy, and Alpha-Oxo Nitrosamines) in F-344 Rats”, IARC Sci Publ. 1982, 41, 619–624. (d) Mochizuki, M.; Osabe, M.; Anjo, T. “Mutagenicity of α-Hydroxy N-Nitrosamines in V79 Chinese Hamster Cells”, J Cancer Res Clin Oncol. 1984, 108, 290–295.

  6. Ashworth IW, Dirat O, Teasdale A, Whiting M. Potential for the formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water. Org. Process Res. Dev. 2020;24:1629–46.

    Article  CAS  Google Scholar 

  7. (a) ICH Guideline Q3A(R2) on Impurities in New Drug Substance, CPMP/ICH/2737/99; European Medicines Agency, October 2006. (b) ICH Guideline Q3B(R2) on Impurities in New Drug Products, CPMP/ICH/2738/99; European Medicines Agency, June 2006.

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Authors and Affiliations

  1. Novo Nordisk A/S, Vandtårnsvej 114, DK-2860, Søborg, Denmark

    Scott W. Roberts

  2. Amgen Ltd., Uxbridge, UK

    Andrew Lennard

  3. Merck & Co., Inc., Kenilworth, New Jersey, USA

    Ganapathy Mohan & Cheenu Murti

  4. Live Oak Pharmaceutical Consulting, Inc., Raleigh, North Carolina, USA

    James Bernstein, Steve Cole & Noreen Curristin

  5. Amgen Inc., Thousand Oaks, California, USA

    Nina S. Cauchon

  6. Pharmalytik, LLC, Newark, Delaware, USA

    Kim Huynh-Ba

  7. Pfizer Inc., Groton, Connecticut, USA

    Christine N. Kolz

  8. Genentech, Inc., South San Francisco, California, USA

    Kin Tang

Authors
  1. Scott W. Roberts
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  2. Andrew Lennard
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  3. Ganapathy Mohan
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  4. James Bernstein
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  5. Nina S. Cauchon
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  6. Steve Cole
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  7. Noreen Curristin
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  8. Kim Huynh-Ba
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  9. Christine N. Kolz
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  10. Cheenu Murti
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  11. Kin Tang
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Corresponding author

Correspondence to Scott W. Roberts.

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Conflict of Interest

Hasmukh Patel and Wendy Wilson-Lee from the US Food and Drug Administration (FDA) participated in this panel discussion but are not authors of this meeting report.

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The views expressed in this article are those of the authors and do not necessarily reflect the opinions of their companies/institutions or the official policy of the US Food and Drug Administration (FDA). No official endorsement by the FDA is intended or should be inferred.

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Roberts, S.W., Lennard, A., Mohan, G. et al. Meeting Report: N-Nitrosamine Impurity Control Strategies in the Pharmaceutical and Biotechnology Industries. AAPS J 23, 94 (2021). https://doi.org/10.1208/s12248-021-00618-5

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  • DOI: https://doi.org/10.1208/s12248-021-00618-5

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