RT Journal Article
SR Electronic
T1 Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis
JF PDA Journal of Pharmaceutical Science and Technology
JO PDA J Pharm Sci Technol
FD Parenteral Drug Association (PDA)
SP 399
OP 444
DO 10.5731/pdajpst.2022.012811
VO 78
IS 4
A1 Parris, Patricia
A1 Whelan, Geraldine
A1 Burild, Anders
A1 Whritenour, Jessica
A1 Bruen, Uma
A1 Bercu, Joel
A1 Callis, Courtney
A1 Chilton, Martyn L.
A1 Graham, Jessica
A1 Johann, Esther
A1 Johnson, Candice
A1 Griffin, Troy
A1 Kohan, Martin
A1 Martin, Elizabeth A.
A1 Masuda-Herrera, Melisa
A1 Stanard, Brad
A1 Cruz, Maureen T.
A1 Nagao, Lee
YR 2024
UL http://journal.pda.org/content/78/4/399.abstract
AB 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 analyzed 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.