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Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis

Patricia Parris, Geraldine Whelan, Anders Burild, Jessica Whritenour, Uma Bruen, Joel Bercu, Courtney Callis, Martyn L. Chilton, Jessica Graham, Esther Johann, Candice Johnson, Troy Griffin, Martin Kohan, Elizabeth A. Martin, Melisa Masuda-Herrera, Brad Stanard, Maureen T Cruz and Lee Nagao
PDA Journal of Pharmaceutical Science and Technology September 2023, pdajpst.2022.012811; DOI: https://doi.org/10.5731/pdajpst.2022.012811
Patricia Parris
1 Pfizer Worldwide Research, Development and Medical, Sandwich, UK;
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  • For correspondence: patricia.parris@pfizer.com
Geraldine Whelan
2 GlaxoSmithKline, Ware, UK;
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  • For correspondence: geraldine.b.whelan@gsk.com
Anders Burild
3 Novo Nordisk A/S, Safety Sciences and Imaging, Malov, Denmark;
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  • For correspondence: qabu@novonordisk.com
Jessica Whritenour
4 Pfizer Worldwide Research, Development and Medical, Groton, CT, USA;
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  • For correspondence: jessica.duffy-whritenour@pfizer.com
Uma Bruen
5 Organon USA Inc., Jersey City, NJ, USA;
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  • For correspondence: uma.bruen@organon.com
Joel Bercu
6 Gilead Sciences Inc., Foster City, CA, USA;
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Courtney Callis
7 Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN, USA;
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  • For correspondence: courtney.callis@lilly.com
Martyn L. Chilton
8 Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK;
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  • For correspondence: martyn.chilton@lhasalimited.org
Jessica Graham
9 Genentech, Inc., South San Francisco, CA, USA;
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  • For correspondence: graham.jessica@gene.com
Esther Johann
10 Merck KGaA, Darmstadt, Germany;
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  • For correspondence: esther.johann@merckgroup.com
Candice Johnson
11 Instem, 1393 Dublin Road, Columbus, Ohio USA;
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  • For correspondence: cjohnson@leadscope.com
Troy Griffin
12 Teva Branded Pharmaceutical Products R&D, West Chester, PA, USA;
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  • For correspondence: troy.griffin@tevapharm.com
Martin Kohan
13 formerly of Global Sustainability, AstraZeneca, Cambridge, UK;
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  • For correspondence: martin.kohan@safebridge.com
Elizabeth A. Martin
14 Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK;
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Melisa Masuda-Herrera
15 Gilead Sciences;
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  • For correspondence: melisa.masuda-herrera@gilead.com
Brad Stanard
16 Ultragenyx Pharmaceutical Inc., Novato, CA, USA;
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  • For correspondence: bstanard@ultragenyx.com
Maureen T Cruz
17 Faegre Drinker Biddle & Reath LLP;
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  • For correspondence: maureen.cruz@faegredrinker.com
Lee Nagao
18 Faegre Drinker Biddle & Reath
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Abstract

Quality by design is the foundation of the risk management framework for extractables and leachables (E&Ls) recommended by the Extractables and Leachables Safety Information Exchange (ELSIE). Following these principles during the selection of materials for pharmaceutical product development minimizes the presence of highly toxic substances and decreases the health risk of potential leachables in the drug product. Therefore, in the context of the broad arena of chemicals, it is important to distinguish E&Ls as a subset of chemicals and evaluate this relevant chemical space to derive appropriate analytical and safety thresholds. When considering the health hazards posed by E&Ls, one area presenting a challenge is understanding the sensitization potential and whether it poses a risk to patients. A dataset of E&Ls compiled by ELSIE (n=466) was analysed to determine the prevalence and potency of skin sensitizers in this chemical subset and explore a scientifically justified approach to the sensitization assessment of potential leachables in parenteral drug products. Approximately half of the compounds (56%, 259/466) had sensitization data recorded in the ELSIE database and of these, 20% (52/259) are potential skin sensitizers. Only 3% (8/259) of the E&L dataset with sensitization data were considered potent (strong or extreme) sensitizers following in silico analysis and expert review, illustrating that potent sensitizers are not routinely observed as leachables in pharmaceutical products. Our analysis highlights that in silico potency prediction and expert review are key tools during the sensitization assessment process for E&Ls. The results confirm where material selection is anticipated to mitigate the risk of presence of strong and/or extreme sensitizers (e.g., extractable testing via ISO 10993-10), and that implementing thresholds per ICH M7 and/or Masuda-Herrera et al. provides a reasonably conservative approach for establishing the analytical testing and safety thresholds.

  • extractables
  • in silico
  • leachables
  • potency
  • risk assessment
  • sensitization
  • Received December 7, 2022.
  • Accepted August 17, 2023.
  • Copyright © 2023, Parenteral Drug Association

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PDA Journal of Pharmaceutical Science and Technology: 79 (2)
PDA Journal of Pharmaceutical Science and Technology
Vol. 79, Issue 2
March/April 2025
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Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis
Patricia Parris, Geraldine Whelan, Anders Burild, Jessica Whritenour, Uma Bruen, Joel Bercu, Courtney Callis, Martyn L. Chilton, Jessica Graham, Esther Johann, Candice Johnson, Troy Griffin, Martin Kohan, Elizabeth A. Martin, Melisa Masuda-Herrera, Brad Stanard, Maureen T Cruz, Lee Nagao
PDA Journal of Pharmaceutical Science and Technology Sep 2023, pdajpst.2022.012811; DOI: 10.5731/pdajpst.2022.012811

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Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis
Patricia Parris, Geraldine Whelan, Anders Burild, Jessica Whritenour, Uma Bruen, Joel Bercu, Courtney Callis, Martyn L. Chilton, Jessica Graham, Esther Johann, Candice Johnson, Troy Griffin, Martin Kohan, Elizabeth A. Martin, Melisa Masuda-Herrera, Brad Stanard, Maureen T Cruz, Lee Nagao
PDA Journal of Pharmaceutical Science and Technology Sep 2023, pdajpst.2022.012811; DOI: 10.5731/pdajpst.2022.012811
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Keywords

  • Extractables
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  • Leachables
  • Potency
  • Risk assessment
  • Sensitization

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