A Phase-Appropriate Risk Assessment Strategy in Support of the Safety of Peptide and Oligonucleotide-Related Impurities

Food and Drug Administration (FDA) Center for drug evaluation and research. ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of rDNA origin. 2021.

European Medicines Agency. Draft guideline on the development and manufacture of Synthetic Peptides. 2023. https://www.ema.europa.eu/en/development-and-manufacture-synthetic-peptides-scientific-guideline. Accessed 16 Oct 2024. 

European Medicines Agency. Draft guideline on the development and manufacture of oligonucleotides. 2024. https://www.ema.europa.eu/en/development-manufacture-oligonucleotides-scientific-guideline. Accessed 16 Oct 2024. 

European Directorate for the Quality of Medicines & HealthCare, Substances for Pharmaceutical Use. European Pharmacopeia. 2034.

Food and Drug Administration (FDA). Draft guidance on nusinersin sodium. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_209531.pdf. Accessed 16 Oct 2024.

Food and Drug Administration (FDA). Draft Guidance on inclisiran sodium. 2023. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_214012.pdf. Accessed 16 Oct 2024.

Graham JC, Powley MW, Udovic E, Glowienke S, Nicolette J, Parris P, et al. Calculating qualified non-mutagenic impurity levels: Harmonization of approaches. Regul Toxicol Pharmacol. 2021;126:105023. https://doi.org/10.1016/j.yrtph.2021.105023.

Article  PubMed  Google Scholar 

Zushin PH, Mukherjee S, Wu JC. FDA Modernization Act 2.0: transitioning beyond animal models with human cells, organoids, and AI/ML-based approaches. J Clin Invest. 2023;133(21):e175824. https://doi.org/10.1172/jci175824.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Hubrecht RC, Carter E. The 3Rs and Humane Experimental Technique: Implementing Change. Animals (Basel). 2019;9(10):754. https://doi.org/10.3390/ani9100754.

Article  PubMed  Google Scholar 

Mitra MS, Datta K, Hutchinson R, Nicolette JJ, Pettersen JC, Wegesser TC, et al. Harmonized 3Rs-based non-mutagenic impurity qualification study designs developed using the results of an IQ consortium survey. Regul Toxicol Pharmacol. 2021;122:104895. https://doi.org/10.1016/j.yrtph.2021.104895.

Article  PubMed  Google Scholar 

Leach MW, Rana P, Hu W, Mittapalli RK, Pinkstaff J, Potter D, et al. Translation of nonclinical to clinical safety findings for 27 biotherapeutics. Toxicol Appl Pharmacol. 2024;484:116854. https://doi.org/10.1016/j.taap.2024.116854.

Article  PubMed  CAS  Google Scholar 

International Conference on Harmonisation. (ICH) Q3C (R9) Impurities: guideline for residual solvents. 2024;Step 4.

International Council for Harmonisation. (ICH) Q3D guideline for elemental impurities. 2022.

International Council for Harmonisation. (ICH) M7 (R2). Assessment and control of DNA reactive (Mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. 2023.

The Pharmacopeia of the United States of America and the National Formulary (USP–NF) USP-NP. General Chapter, 〈1469〉 Nitrosamine Impurities. 2024.

Munro IC, Ford RA, Kennepohl E, Sprenger JG. Correlation of structural class with no-observed-effect levels: a proposal for establishing a threshold of concern. Food Chem Toxicol. 1996;34(9):829–67. https://doi.org/10.1016/s0278-6915(96)00049-x.

Article  PubMed  CAS  Google Scholar 

Munro IC, Renwick AG, Danielewska-Nikiel B. The Threshold of Toxicological Concern (TTC) in risk assessment. Toxicol Lett. 2008;180(2):151–6. https://doi.org/10.1016/j.toxlet.2008.05.006.

Article  PubMed  CAS  Google Scholar 

Tluczkiewicz I, Buist HE, Martin MT, Mangelsdorf I, Escher SE. Improvement of the Cramer classification for oral exposure using the database TTC RepDose–a strategy description. Regul Toxicol Pharmacol. 2011;61(3):340–50. https://doi.org/10.1016/j.yrtph.2011.09.005.

Article  PubMed  CAS  Google Scholar 

Graham JC, Powley MW, Udovic E, Glowienke S, Nicolette J, Parris P, et al. Calculating qualified non-mutagenic impurity levels: Harmonization of approaches. Regul Toxicol Pharmacol. 2021;126:105023. https://doi.org/10.1016/j.yrtph.2021.105023.

Article  PubMed  Google Scholar 

Internatioal Confeence on Harmonisation. (ICH) Q3A (R2) Impurities in new drug substances 2006;Step 4.

Kroes R, Renwick AG, Cheeseman M, Kleiner J, Mangelsdorf I, Piersma A, et al. Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem Toxicol. 2004;42(1):65–83. https://doi.org/10.1016/j.fct.2003.08.006.

Article  PubMed  CAS  Google Scholar 

Harvey J, Fleetwood A, Ogilvie R, Teasdale A, Wilcox P, Spanhaak S. Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development. Regul Toxicol Pharmacol. 2017;84:116–23. https://doi.org/10.1016/j.yrtph.2016.12.011.

Article  PubMed  CAS  Google Scholar 

Wu LC, Chen F, Lee SL, Raw A, Yu LX. Building parity between brand and generic peptide products: Regulatory and scientific considerations for quality of synthetic peptides. Int J Pharm. 2017;518(1):320–34. https://doi.org/10.1016/j.ijpharm.2016.12.051.

Article  PubMed  CAS  Google Scholar 

Bugelski PJ, Treacy G. Predictive power of preclinical studies in animals for the immunogenicity of recombinant therapeutic proteins in humans. Curr Opin Mol Ther. 2004;6(1):10–6.

PubMed  CAS  Google Scholar 

Rozman KK. The role of time in toxicology or Haber’s c×t product. Toxicology. 2000;149(1):35–42. https://doi.org/10.1016/S0300-483X(00)00230-4.

Article  PubMed  CAS  Google Scholar 

Gaylor DW. The use of Haber’s Law in standard setting and risk assessment. Toxicology. 2000;149(1):17–9. https://doi.org/10.1016/S0300-483X(00)00228-6.

Article  PubMed  CAS  Google Scholar 

Capaldi D, Teasdale A, Henry S, Akhtar N, den Besten C, Gao-Sheridan S, et al. Impurities in Oligonucleotide Drug Substances and Drug Products. Nucleic Acid Ther. 2017;27(6):309–22. https://doi.org/10.1089/nat.2017.0691.

Article  PubMed  CAS  Google Scholar 

Roers A, Hiller B, Hornung V. Recognition of Endogenous Nucleic Acids by the Innate Immune System. Immunity. 2016;44(4):739–54. https://doi.org/10.1016/j.immuni.2016.04.002.

Article  PubMed  CAS  Google Scholar 

Meng Z, Lu M. RNA Interference-Induced Innate Immunity, Off-Target Effect, or Immune Adjuvant? Front Immunol. 2017;8:331. https://doi.org/10.3389/fimmu.2017.00331.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Bano N, Ehlinger C, Yang TY, Swanson M, Allen S. Considerations in the Immunogenicity Assessment Strategy for Oligonucleotide Therapeutics (ONTs). Aaps j. 2022;24(5):93. https://doi.org/10.1208/s12248-022-00741-x.

Article  PubMed  CAS  Google Scholar 

Yu RZ, Wang Y, Norris DA, Kim T-W, Narayanan P, Geary RS, et al. Immunogenicity Assessment of Inotersen, a 2′-O-(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety. Nucleic Acid Ther. 2020;30(5):265–75. https://doi.org/10.1089/nat.2020.0867.

Article  PubMed  CAS  Google Scholar 

Dintzis HM, Dintzis RZ, Vogelstein B. Molecular determinants of immunogenicity: the immunon model of immune response. Proc Natl Acad Sci U S A. 1976;73(10):3671–5. https://doi.org/10.1073/pnas.73.10.3671.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Rosenberg AS. Effects of protein aggregates: an immunologic perspective. Aaps j. 2006;8(3):E501–7. https://doi.org/10.1208/aapsj080359.

Article  PubMed  PubMed Central  Google Scholar 

Cohen JR, Brych SR, Prabhu S, Bi V, Elbaradei A, Tokuda JM, et al. A High Threshold of Biotherapeutic Aggregate Numbers is Needed to Induce an Immunogenic Response In Vitro, In Vivo, and in the Clinic. Pharm Res. 2024;41(4):651–72. https://doi.org/10.1007/s11095-024-03678-2.

Article  PubMed  CAS  Google Scholar 

Meunier S, De Bourayne M, Hamze M, Azam A, Correia E, Menier C. Maillère B specificity of the T Cell response to protein biopharmaceuticals. Front Immunol. 2020;11:1550.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Backert L, Kohlbacher O. Immunoinformatics and epitope prediction in the age of genomic medicine. Genome Medicine. 2015;7(1):119. https://doi.org/10.1186/s13073-015-0245-0.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Holley CK, Cedrone E, Donohue D, Neun BW, Verthelyi D, Pang ES, et al. An In Vitro Assessment of Immunostimulatory Responses to Ten Model Innate Immune Response Modulating Impurities (IIRMIs) and Peptide Drug Product, Teriparatide. Molecules. 2021;26(24):7461. https://doi.org/10.3390/molecules26247461.

Article 

Comments (0)

No login
gif