Industrial Production and Quality Control of Snake Antivenoms

  • Guillermo León
  • Álvaro Segura
  • Aarón Gómez
  • Andrés Hernandez
  • Diego Navarro
  • Mauren Villalta
  • Mariángela Vargas
  • María Herrera
  • José María Gutiérrez
Reference work entry
Part of the Toxinology book series (TOXI)

Abstract

The production of snake antivenoms involves stages such as production of venom, immunization of animals to generate hyperimmune plasma, immunoglobulin purification, viral inactivation (or removal), and stabilization of the formulation. In order to manufacture products of satisfactory effectiveness and safety, antivenom design must be validated by preclinical and clinical studies. Moreover, during the industrial production, the quality of the products and of the entire manufacturing process (including management of clean rooms, production of water for injection, and sterilization or sanitization of the equipment) must be strictly evaluated. This chapter presents a practical description of the stages involved in the design, production, and quality control of snake antivenoms.

Keywords

West Nile Virus Ammonium Sulfate Snake Venom Caprylic Acid Snake Species 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Abubakar IS, Abubakar SB, Habib AG, Nasidi A, Durfa N, Yusuf PO, Larnyang S, Garnvwa J, Sokomba E, Salako L, Theakston RD, Juszczak E, Alder N, Warrell DA, Nigeria-UK EchiTab Study Group. Randomised controlled double-blind non-inferiority trial of two antivenoms for saw-scaled or carpet viper (Echis ocellatus) envenoming in Nigeria. PLoS Negl Trop Dis. 2010;4(7):e767.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Al-Abdulla I, Garnvwa JM, Rawat S, Smith DS, Landon J, Nasidi A. Formulation of a liquid ovine Fab-based antivenom for the treatment of envenomation by the Nigerian carpet viper (Echis ocellatus). Toxicon. 2003;42:399–404.CrossRefPubMedGoogle Scholar
  3. Andya JD, Hsu CC, Shire SJ. Mechanism of aggregate formation and carbohydrate excipient stabilization of lyophilized humanized monoclonal antibody formulations. AAPS Pharm Sci. 2003;5(2):1–11.CrossRefGoogle Scholar
  4. Angulo Y, Estrada R, Gutiérrez JM. Clinical and laboratory alterations in horses during immunization with snake venoms for the production of polyvalent (Crotalinae) antivenom. Toxicon. 1997;35:81–90.CrossRefPubMedGoogle Scholar
  5. Burnouf T, Griffiths E, Padilla A, Seddik S, Stephano MA, Gutiérrez JM. Assessment of the viral safety of antivenoms fractionated from equine plasma. Biologicals. 2004;32(3):115–28.CrossRefPubMedGoogle Scholar
  6. Burnouf T, Terpstra F, Habib G, Seddik S. Assessment of viral inactivation during pH 3.3 pepsin digestion and caprylic acid treatment of antivenoms. Biologicals. 2007;35:329–34.CrossRefPubMedGoogle Scholar
  7. Calvete JJ. Proteomic tools against the neglected pathology of snake bite envenoming. Expert Rev Proteomics. 2011;8:739–58.CrossRefPubMedGoogle Scholar
  8. Camey KU, Velarde DT, Sanchez EF. Pharmacological characterization and neutralization of the venoms used in the production of Bothropic antivenom in Brazil. Toxicon. 2002;40:501–9.CrossRefPubMedGoogle Scholar
  9. Caricati C, Oliveira-Nascimento L, Yoshida J, Stephano M, Caricati A, Raw I. Safety of snake antivenom immunoglobulins: efficacy of viral inactivation in a complete downstream process. Biotechnol Prog. 2013;29(4):972–79CrossRefPubMedGoogle Scholar
  10. Carneiro SM, Zablith MB, Kerchove CM, Moura-da-Silva AM, Quissell DO, Markus RP, Yamanouye N. Venom production in long-term primary culture of secretory cells of the Bothrops jararaca venom gland. Toxicon. 2006;47:87–94.CrossRefPubMedGoogle Scholar
  11. Chippaux JP, Williams V, White J. Snake venom variability: methods of study. Toxicon. 1991;29:1279–303.CrossRefPubMedGoogle Scholar
  12. Chotwiwatthanakun C, Pratapaphon R, Akesowan S, Sriprapat S, Ratanabangkoon K. Production of potent polyvalent antivenom against three elapid venoms using a low dose, low volume, multi-site immunization protocol. Toxicon. 2001;39:1487–94.CrossRefPubMedGoogle Scholar
  13. Dichtelmüller H, Rudnick D, Kloft M. Inactivation of lipid enveloped viruses by octanoic acid treatment of immunoglobulin solution. Biologicals. 2002;30:135–42.CrossRefPubMedGoogle Scholar
  14. Duddu S, Dal MP. Effect of glass transition temperature on the stability of lyophilized formulations containing a chimeric therapeutic monoclonal antibody. Pharm Res. 1997;14(5):591–5.CrossRefPubMedGoogle Scholar
  15. EMEA (The European Agency for the Evaluation of Medicinal Products). Note for guidance on virus validation studies: the design, contribution and interpretation of studies validating the inactivation and removal of viruses. London: EMEA; 1996.Google Scholar
  16. EMEA (The European Agency for the Evaluation of Medicinal Products). Note for guidance on the production and quality control of animal immunoglobulins and immunosera for human use. London: EMEA; 2002.Google Scholar
  17. Feige K, Ehrat FB, Kästner SB, Schwarzwald CC. Automated plasmapheresis compared with other plasma collection methods in the horse. J Vet Med A Physiol Pathol Clin Med. 2003;50:185–9.CrossRefPubMedGoogle Scholar
  18. Gutiérrez JM, Avila C, Rojas G, Cerdas L. An alternative in vitro method for testing the potency of the polyvalent antivenom produced in Costa Rica. Toxicon. 1988;26:411–3.CrossRefPubMedGoogle Scholar
  19. Gutiérrez JM, Lomonte B, León G, Alape-Girón A, Flores-Díaz M, Sanz L, Angulo Y, Calvete JJ. Snake venomics and antivenomics: proteomic tools in the design and control of antivenoms for the treatment of snakebite envenoming. J Proteomics. 2009;72:165–82.CrossRefPubMedGoogle Scholar
  20. Gutiérrez JM, Sanz L, Flores-Díaz M, Figueroa L, Madrigal M, Herrera M, Villalta M, León G, Estrada R, Borges A, Alape-Girón A, Calvete JJ. Impact of regional variation in Bothrops asper snake venom on the design of antivenoms: integrating antivenomics and neutralization approaches. J Proteome Res. 2010;9:564–77.CrossRefPubMedGoogle Scholar
  21. Gutiérrez JM, León G, Lomonte B, Angulo Y. Antivenoms for snakebite envenomings. Inflamm Allergy Drug Targets. 2011;10:369–80.CrossRefPubMedGoogle Scholar
  22. Gutiérrez JM, Solano G, Pla D, Herrera M, Segura A, Villalta M, Vargas M, Sanz L, Lomonte B, Calvete JJ, León G. Assessing the preclinical efficacy of antivenoms: from the lethality neutralization assay to antivenomics. Toxicon. 2013;69:168–79.CrossRefPubMedGoogle Scholar
  23. ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use). Quality of biotechnological products: stability testing of biotechnological/biological products Q5C. ICH; 1996. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5C/Step4/Q5C_Guideline.pdf
  24. Kempf C, Stucki M, Boschetti N. Pathogen inactivation and removal procedures used in the production of intravenous immunoglobulins. Biologicals. 2007;35:35–42.CrossRefPubMedGoogle Scholar
  25. Kim H, Nakai S. Simple separation of immunoglobulin from egg yolk by ultrafiltration. J Food Sci. 1998;63:485–90.CrossRefGoogle Scholar
  26. Ko KY, Ahn DU. Preparation of immunoglobulin Y from egg yolk using ammonium sulfate precipitation and ion exchange chromatography. Poult Sci. 2007;86:400–7.CrossRefPubMedGoogle Scholar
  27. Lazar A, Epstein E, Lustig S, Barnea A, Silberstein L, Reuveny S. Inactivation of West-Nile virus during peptic cleavage of horse plasma IgG. Biologicals. 2002;30:163–5.CrossRefPubMedGoogle Scholar
  28. León G, Sánchez L, Hernández A, Villalta M, Herrera M, Segura A, Estrada R, Gutiérrez JM. Immune response towards snake venoms. Inflamm Allergy Drug Targets. 2011;10:381–98.CrossRefPubMedGoogle Scholar
  29. Macedo SM, Lourenço EL, Borelli P, Fock RA, Ferreira Jr JM, Farsky SH. Effect of in vivo phenol or hydroquinone exposure on events related to neutrophil delivery during an inflammatory response. Toxicology. 2006;220:126–35.CrossRefPubMedGoogle Scholar
  30. Meier J, Adler C, Hösle P, Cascio R. The influence of three different drying procedures on some enzymatic activities of three Viperidae snake venoms. Mem Inst Butantan. 1991;53(1):119–26.Google Scholar
  31. Niinistö K, Raekallio M, Sankari S. Storage of equine red blood cells as a concentrate. Vet J. 2008;176:227–31.CrossRefPubMedGoogle Scholar
  32. Pikal MJ. Mechanism of protein stabilization during freeze-drying and storage: the relative importance of thermodynamic stabilization and glassy state relaxation dynamics. In: Rey L, May JC, editors. Freeze-drying/lyophilization of pharmaceutical and biological products. 2nd ed. New York: Marcer Dekker Inc; 2004.Google Scholar
  33. Rial A, Morais V, Rossi S, Massaldi H. A new ELISA for determination of potency in snake antivenoms. Toxicon. 2006;48:462–6.CrossRefPubMedGoogle Scholar
  34. Rojas G, Jiménez JM, Gutiérrez JM. Caprylic acid fractionation of hyperimmune horse plasma: description of a simple procedure for antivenom production. Toxicon. 1994;32:351–63.CrossRefPubMedGoogle Scholar
  35. Sampaio SC, Rangel-Santos AC, Peres CM, Curi R, Cury Y. Inhibitory effect of phospholipase A2 isolated from Crotalus durissus terrificus venom on macrophage function. Toxicon. 2005;45:671–6.CrossRefPubMedGoogle Scholar
  36. Sarciaux JM, Mansour S, Hageman MJ, Nail SL. Effects of buffer composition and processing conditions on aggregation of bovine IgG during freeze-drying. J Pharm Sci. 1999;88(12):1354–61.CrossRefPubMedGoogle Scholar
  37. Schersch K, Betz O, Garidel P, Muehlau S, Bassarab S, Winter G. Systematic investigation of the effect of lyophilizate collapse on pharmaceutically relevant proteins I: stability after freeze-drying. J Pharm Sci. 2010;99(5):2256–78.CrossRefPubMedGoogle Scholar
  38. Segura Á, León G, Su C-Y, Gutiérrez J-M, Burnouf T. Assessment of the impact of solvent/detergent treatment on the quality and potency of a whole IgG equine antivenom. Biologicals. 2009a;37:306–12.CrossRefPubMedGoogle Scholar
  39. Segura Á, Herrera M, González E, Vargas M, Solano G, Gutiérrez JM, León G. Stability of equine IgG antivenoms obtained by caprylic acid precipitation: towards a liquid formulation stable at tropical room temperature. Toxicon. 2009b;53:609–15.CrossRefPubMedGoogle Scholar
  40. Segura A, Herrera M, Villalta M, Vargas M, Gutiérrez JM, León G. Assessment of snake antivenom purity by comparing physicochemical and immunochemical methods. Biologicals. 2012;41:93–7.CrossRefPubMedGoogle Scholar
  41. Solano S, Segura Á, León G, Gutiérrez JM, Burnouf T. Low pH formulation of whole IgG antivenom: impact on quality, safety, neutralizing potency and viral inactivation. Biologicals. 2012;40:129–33.CrossRefPubMedGoogle Scholar
  42. Teixeira C, Cury Y, Moreira V, Picolob G, Chaves F. Inflammation induced by Bothrops asper venom. Toxicon. 2009;54:988–97.CrossRefPubMedGoogle Scholar
  43. Theakston RD, Warrell DA, Griffiths E. Report of a WHO workshop on the standardization and control of antivenoms. Toxicon. 2003;41:541–57.CrossRefPubMedGoogle Scholar
  44. Wang W. Instability, stabilization and formulation of liquid protein pharmaceuticals. Int J Pharm. 1999;185:129–88.CrossRefPubMedGoogle Scholar
  45. Wang W, Singh S, Zeng D, King K, Nema S. Antibody structure, instability and formulation. J Pharm Sci. 2007;96(1):1–26.CrossRefPubMedGoogle Scholar
  46. Warrell DA. Snake bite. Lancet. 2010;375:77–88.CrossRefPubMedGoogle Scholar
  47. World Health Organization. Handbook for good clinical research practices (GCP). Geneva: WHO; 2005.Google Scholar
  48. World Health Organization. Guidelines for the production, control and regulation of snake antivenom immunoglobulins. Geneva: WHO; 2010.Google Scholar
  49. Xie G, Timasheff N. Mechanism of the stabilization of ribonuclease A by sorbitol: preferential hydration is greater for the denatured than for the native protein. Protein Sci. 1997;6:211–21.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Zychar BC, Castro Jr NC, Marcelino JR, Gonçalves LR. Phenol used as a preservative in Bothrops antivenom induces impairment in leukocyte-endothelial interactions. Toxicon. 2008;51:1151–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Guillermo León
    • 1
  • Álvaro Segura
    • 1
  • Aarón Gómez
    • 1
  • Andrés Hernandez
    • 1
  • Diego Navarro
    • 1
  • Mauren Villalta
    • 1
  • Mariángela Vargas
    • 1
  • María Herrera
    • 1
  • José María Gutiérrez
    • 1
  1. 1.Instituto Clodomiro Picado, Facultad de MicrobiologíaUniversidad de Costa RicaSan JoséCosta Rica

Personalised recommendations