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Research ArticleResearch

Development of Duration-Based Non-Mutagenic Thresholds of Toxicological Concern (TTCs) Relevant to Parenteral Extractables and Leachables (E&Ls)

Melisa J. Masuda-Herrera, Joel P. Bercu, Thomas H. Broschard, Anders Burild, Catrin Hasselgren, Patricia Parris, Lucie C. Ford, Jessica Graham, Brad Stanard, Michele Comerford, Daniel Lettiere, Steffen Erler, Courtney M. Callis, Eric Morinello, Wolfgang Muster, Elizabeth A. Martin, Troy R. Griffin, Lee Nagao and Maureen Cruz
PDA Journal of Pharmaceutical Science and Technology September 2022, 76 (5) 369-383; DOI: https://doi.org/10.5731/pdajpst.2021.012693
Melisa J. Masuda-Herrera
1Nonclinical Safety and Pathobiology (NSP), Gilead Sciences, Inc., Foster City, CA, USA;
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  • For correspondence: Melisa.Masuda-Herrera@gilead.com
Joel P. Bercu
1Nonclinical Safety and Pathobiology (NSP), Gilead Sciences, Inc., Foster City, CA, USA;
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Thomas H. Broschard
2Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany;
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Anders Burild
3Safety Sciences, Imaging and Data Management, Novo Nordisk A/S, Novo Nordisk Park 2760 Måløv, Denmark;
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Catrin Hasselgren
4Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080;
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Patricia Parris
5Pfizer Worldwide Research and Development, Sandwich, United Kingdom;
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Lucie C. Ford
6Department of Veterinary Integrative Biosciences, Interdisciplinary Faculty of Toxicology Program, Texas A&M University, 4466 TAMU, College Station, TX, 77843-4466;
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Jessica Graham
4Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080;
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Brad Stanard
7Ultragenyx Pharmaceutical Inc., Novato, CA;
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Michele Comerford
8Pfizer Global Research & Development, Groton, CT, 06340;
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Daniel Lettiere
8Pfizer Global Research & Development, Groton, CT, 06340;
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Steffen Erler
9Wella Company, Berliner Allee 65, 64295 Darmstadt, Germany;
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Courtney M. Callis
10Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN;
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Eric Morinello
4Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080;
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Wolfgang Muster
11Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland;
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Elizabeth A. Martin
12Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom;
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Troy R. Griffin
13Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, 19380; and
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Lee Nagao
14Faegre Drinker Biddle & Reath LLP, Washington, DC
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Maureen Cruz
14Faegre Drinker Biddle & Reath LLP, Washington, DC
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Abstract

The threshold of toxicological concern (TTC), i.e., the dose of a compound lacking sufficient experimental toxicity data that is unlikely to result in an adverse health effect in humans, is important for evaluating extractables and leachables (E&Ls) as it guides analytical testing and minimizes the use of animal studies. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium, which consists of member companies that span biotechnology, pharmaceutical, and medical device industries, brought together subject matter expert toxicologists to derive TTC values for organic, non-mutagenic E&L substances when administered parenterally. A total of 488 E&L compounds from the ELSIE database were analyzed and parenteral point of departure (PPOD) estimates were derived for 252 compounds. The PPOD estimates were adjusted to extrapolate to subacute, subchronic, and chronic durations of nonclinical exposure and the lower fifth percentiles were calculated. An additional 100-fold adjustment factor to account for nonclinical species and human variability was subsequently applied to derive the parenteral TTC values for E&Ls. The resulting parenteral TTC values are 35, 110, and 180 μg/day for human exposures of >10 years to lifetime, >1-10 years, and ≤1 year, respectively. These parenteral TTCs are expected to be conservative for E&Ls that are considered non-mutagenic per ICH M7(R1) guidelines.

  • Leachables
  • Extractables
  • Parenteral
  • Point of departure
  • Threshold of toxicological concern
  • ELSIE
  • © PDA, Inc. 2022
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PDA Journal of Pharmaceutical Science and Technology: 76 (5)
PDA Journal of Pharmaceutical Science and Technology
Vol. 76, Issue 5
September/October 2022
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Development of Duration-Based Non-Mutagenic Thresholds of Toxicological Concern (TTCs) Relevant to Parenteral Extractables and Leachables (E&Ls)
Melisa J. Masuda-Herrera, Joel P. Bercu, Thomas H. Broschard, Anders Burild, Catrin Hasselgren, Patricia Parris, Lucie C. Ford, Jessica Graham, Brad Stanard, Michele Comerford, Daniel Lettiere, Steffen Erler, Courtney M. Callis, Eric Morinello, Wolfgang Muster, Elizabeth A. Martin, Troy R. Griffin, Lee Nagao, Maureen Cruz
PDA Journal of Pharmaceutical Science and Technology Sep 2022, 76 (5) 369-383; DOI: 10.5731/pdajpst.2021.012693

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Development of Duration-Based Non-Mutagenic Thresholds of Toxicological Concern (TTCs) Relevant to Parenteral Extractables and Leachables (E&Ls)
Melisa J. Masuda-Herrera, Joel P. Bercu, Thomas H. Broschard, Anders Burild, Catrin Hasselgren, Patricia Parris, Lucie C. Ford, Jessica Graham, Brad Stanard, Michele Comerford, Daniel Lettiere, Steffen Erler, Courtney M. Callis, Eric Morinello, Wolfgang Muster, Elizabeth A. Martin, Troy R. Griffin, Lee Nagao, Maureen Cruz
PDA Journal of Pharmaceutical Science and Technology Sep 2022, 76 (5) 369-383; DOI: 10.5731/pdajpst.2021.012693
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Keywords

  • leachables
  • extractables
  • Parenteral
  • Point of departure
  • Threshold of toxicological concern
  • ELSIE

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