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Control Process for Manufacturing and Standardization of Allergenic Molecules

  • Immunologic/Diagnostic Tests in Allergy (M Chapman and A Pomés, Section Editors)
  • Published:
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Abstract

It is widely accepted that the success of the allergen immunotherapy (AIT), beyond clinical parameters such as dose, dosage regimen, or compliance, depends on the quality and composition of the final products used in the vaccines. Allergenic vaccines are pharmaceutical preparations derived from the natural sources which contain the allergenic components responsible for allergic sensitization. The selection of the appropriate allergenic sources must be a requirement. They suffer a dramatic transformation during the manufacturing process which renders a biologically standardized final product. The inclusion of the appropriate control analyses in the manufacturing process has demonstrated to be an efficient method to guarantee the quality and homogeneity of the final product as well as being a very useful tool for saving time and money. In this context, in the last years, the Regulatory Agencies have released specific guidelines to guarantee the manufacturing of the most appropriate products for the treatment of patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. European Pharmacopoeia, monograph “Allergen Products” (07/2014:1063). The document described all the regulatory requirements in Europe. It should be known by researchers in allergy and manufacturers.

  2. Noon L. Prophylactic inoculation against hay fever. Lancet. 1911;1:1572–3.

    Article  Google Scholar 

  3. Freeman J, Noon L. Further observation on the treatment of hay-fever by hypodermic inoculation of pollen vaccine. Lancet. 1911;2:814–7.

    Article  Google Scholar 

  4. Akdis M. New treatments for allergen immunotherapy. World Allergy Organ J. 2014;7(1):23. doi:10.1186/1939-4551-7-23.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Marth K, Focke-Tejkl M, Lupinek C, Valenta R, Niederberger V. Allergen peptides, recombinant allergens and hypoallergens for allergen-specific immunotherapy. Curr Treat Options Allergy. 2014;26(1):91–106. This is a clear revision for the understanding of the new tendencies in allergy and the products that we will have in the near future.

  6. EMA Guideline on Allergen Products: Production and Quality Issues. 2008. EMEA. CHMP/BWP/304831/2007. The document described all the Guidelines proposed by the EMA. It should be known by researchers in Allergy and manufacturers.

  7. Lorenz AR, Lüttkopf D, May S, Scheurer S, Vieths S. The principle of homologous groups in regulatory affairs of allergen products—a proposal. Int Arch Allergy Immunol. 2009;148(1):1–17. The study described the groups in which allergen extracts have been divided and included. The manuscript provides an idea about cross-reactivity, taxonomy, and other common points between allergens.

  8. U.S. Department of Health and Human Services. Food and Drug Administration. http://www.fda.gov/cvm/guidance/published.html. Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. Sept 2004.

  9. Esch RE. Allergen source materials: state-of-the-art. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2009;96:5–11. The document gives a clear information about raw material in allergy and the key points to take into account.

  10. Beck I, Jochner S, Gilles S, McIntyre M, Buters JTM, et al. High environmental ozone levels lead to enhanced allergenicity of birch pollen. PLoS ONE. 2013;8(11), e80147. doi:10.1371/journal.pone.0080147.

    Article  PubMed Central  PubMed  Google Scholar 

  11. García-Gallardo MV, Algorta J, Longo N, Espinel S, Aragones A, Lombardero M, et al. Evaluation of the effect of pollution and fungal disease on Pinus radiata pollen allergenicity. Int Arch Allergy Immunol. 2013;160(3):241–50. doi:10.1159/000341368.

    Article  PubMed  Google Scholar 

  12. Fernández-Caldas E, Carnés J, Iraola V, Casanovas M. Comparison of the allergenicity and Ole e 1 content of 6 varieties of Olea europaea pollen collected during 5 consecutive years. Ann Allergy Asthma Immunol. 2007;98(5):464–70.

    Article  PubMed  Google Scholar 

  13. Avula-Poola S, Morgan MS, Arlian LG. Diet influences growth rates and allergen and endotoxin contents of cultured Dermatophagoides farinae and Dermatophagoides pteronyssinus house dust mites. Int Arch Allergy Immunol. 2012;159(3):226–34. doi:10.1159/000336026.

    Article  CAS  PubMed  Google Scholar 

  14. Esch RE. Manufacturing and standardizing fungal allergen products. J Allergy Clin Immunol. 2004;113(2):210–5.

    Article  PubMed  Google Scholar 

  15. Farnell E, Rousseau K, Thornton DJ, Bowyer P, Herrick SE. Expression and secretion of Aspergillus fumigatus proteases are regulated in response to different protein substrates. Fungal Biol. 2012;116(9):1003–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Fernández-Caldas E, Carnés J, Gallego M, Mari A, Pagán Alemán JA. Standardization of animal epithelia. Arb Paul Ehrlich Inst Bundesamt Sera Impfstoffe Frankf A M. 2006;95:107–16.

    PubMed  Google Scholar 

  17. Vredegoor DW, Willemse T, Chapman MD, Heederik DJ, Krop EJ. Can f 1 levels in hair and homes of different dog breeds: lack of evidence to describe any dog breed as hypoallergenic. J Allergy Clin Immunol. 2012;130(4):904–9.

    Article  CAS  PubMed  Google Scholar 

  18. Bienboire-Frosini C, Cozzi A, Lafont-Lecuelle C, Vervloet D, Ronin C, Pageat P. Immunological differences in the global release of the major cat allergen Fel d 1 are influenced by sex and behaviour. Vet J. 2012;193(1):162–7.

    Article  CAS  PubMed  Google Scholar 

  19. Fernández-Rivas M, Garrido Fernández S, Nadal JA. Díaz de Durana MD, García BE, González-Mancebo E, Martín S, Barber D, Rico P, Tabar AI. Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract. Allergy. 2009;64(6):876–83.

    Article  PubMed  Google Scholar 

  20. Poms RE, Anklam E. Effects of chemical, physical, and technological processes on the nature of food allergens. J AOAC Int. 2004;87(6):1466–74.

    CAS  PubMed  Google Scholar 

  21. Carnés J, Fernández-Caldas E, Gallego MT, Ferrer A, Cuesta-Herranz J. Pru p 3 (LTP) content in peach extracts. Allergy. 2002;57(11):1071–5.

    Article  PubMed  Google Scholar 

  22. López-Matas MÁ, Larramendi CH, Ferrer A, Huertas AJ, Pagán JA, García-Abujeta JL, et al. Identification and quantification of tomato allergens: in vitro characterization of six different varieties. Ann Allergy Asthma Immunol. 2011;106(3):230–8.

    Article  PubMed  Google Scholar 

  23. Spillner E, Blank S, Jakob T. Hymenoptera allergens: from venom to “venome”. Front Immunol. 2014;5:77.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Carnés J, Fernández-Caldas E, Boluda L, Casanovas M, Sastre J, Lluch Bernal M, et al. Rapid release of Ole e 1 from olive pollen using different solvents. Allergy. 2002;57(9):798–804.

    Article  PubMed  Google Scholar 

  25. Oreste U, Santonastaso V, Ruffilli A. Effect of the time of extraction on the potency and allergenic composition of the extract of Parietaria officinalis pollen. Boll Ist Sieroter Milan. 1985;64(4):320–3.

    CAS  PubMed  Google Scholar 

  26. Jeong KY, Choi SY, Lee JH, Lee IY, Yong TS, Lee JS, et al. Standardization of house dust mite extracts in Korea. Allergy Asthma Immunol Res. 2012;4(6):346–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Casanovas M, Gómez MJ, Carnés J, Fernández-Caldas E. Skin tests with native, depigmented and glutaraldehyde polymerized allergen extracts. J Investig Allergol Clin Immunol. 2005;15(1):30–6.

    CAS  PubMed  Google Scholar 

  28. Patterson R, Suszko IM, Grammer LC, Shaughnessy MA. Polymerization of individual species of grass pollen allergens. J Allergy Clin Immunol. 1983;72(2):129–33.

    Article  CAS  PubMed  Google Scholar 

  29. Himly M, Carnés J, Fernández-Caldas E, Briza P, Ferreira F. Characterization of allergoids. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2009;96:61–9. The paper provides the information about the modern concept for the characterization of allergoids. The allergoids are the most frequently used product in AIT in Europe.

  30. Carnés J, Himly M, Gallego M, Iraola V, Robinson DS, Fernández-Caldas E, et al. Detection of allergen composition and in vivo immunogenicity of depigmented allergoids of Betula alba. Clin Exp Allergy. 2009;39(3):426–34.

    Article  PubMed  Google Scholar 

  31. Reuter A, Lüttkopf D, Vieths S. New frontiers in allergen standardization. Clin Exp Allergy. 2009;39(3):307–9. This editorial is discussing and open the options and necessities to a new and modern standardization of allergoids.

  32. Nordic Council on Medicines. NLN Publ. 1989;23:1–48.

    Google Scholar 

  33. van Ree R, Chapman MD, Ferreira F, Vieths S, Bryan D, Cromwell O, et al. The CREATE project: development of certified reference materials for allergenic products and validation of methods for their quantification. Allergy. 2008;63(3):310–26.

    Article  PubMed  Google Scholar 

  34. Chapman MD, Briza P. Molecular approaches to allergen standardization. Curr Allergy Asthma Rep. 2012;12(5):478–84.

    Article  CAS  PubMed  Google Scholar 

  35. Vieths S, Barber D, Chapman M, Costanzo A, Daas A, Fiebig H, et al. Establishment of recombinant major allergens Bet v 1 and Phl p 5a as Ph. Eur. reference standards and validation of ELISA methods for their measurement. Results from feasibility studies. Pharmeur Bio Sci Notes. 2012;2012:118–34. The study describes the results obtained in the ring trial project BSP090 and establish the start point for the quantification of two of the most important allergens in IAT.

  36. Esch RE, Plunkett GA. Immunotherapy preparation guidelines, rules, and regulation. Curr Allergy Asthma Rep. 2013;13(4):406–13. A clear discussion and revision about the allergen extracts in the USA.

  37. Turkeltaub PC. Biological standardization based on quantitative skin testing—the ID50 EAL method (intradermal dilution for 50 mm sum of erythema diameters determines the allergy unit). Arb Paul Ehrlich Inst Georg Speyer Haus Ferdinand Blum Inst Frankf A M. 1987;80:169–73.

    PubMed  Google Scholar 

  38. Chapman MD, Ferreira F, Villalba M, Cromwell O, Bryan D, Becker WM, et al. CREATE consortium. The European Union CREATE project: a model for international standardization of allergy diagnostics and vaccines. J Allergy Clin Immunol. 2008;122(5):882–9.

    Article  PubMed  Google Scholar 

  39. Cox L, Jacobsen L. Comparison of allergen immunotherapy practice patterns in the United States and Europe. Ann Allergy Asthma Immunol. 2009;103(6):451–9. This is a recent discussion and revision about the differences of the main consumers of AIT. The document highlights the similarities and differences.

  40. Esch RE. Allergen immunotherapy: what can and cannot be mixed? J Allergy Clin Immunol. 2008;122:659–60.

    Article  PubMed  Google Scholar 

  41. Pharmaceutical Compounding-Sterile Preparations. USP-NF General Chapter <797>. In: United States Pharmocopeia, 35th revision and the National Formulary. 30th ed. Rockville, MD: The United States Pharmacopoeia Convention; 2012.

  42. ICH Q2(R1) Validation of analytical procedures: text and methodology, 2005.

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Acknowledgments

The authors would like to thank Celia Sánchez for her support with the scientific documentation and bibliography.

Compliance with Ethics Guidelines

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Conflict of Interest

Jerónimo Carnés, Victor Iraola, Mayte Gallego, and José Ramón Leonor are employees of Laboratorios LETI S.L.U.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. R&D Department, Laboratorios LETI SLu, C/ Sol n° 5, Tres Cantos, Madrid, Spain

    Jerónimo Carnés, Víctor Iraola, Mayte Gallego & Jose R. Leonor

Authors
  1. Jerónimo Carnés
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  2. Víctor Iraola
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  3. Mayte Gallego
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  4. Jose R. Leonor
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Correspondence to Jerónimo Carnés.

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This article is part of the Topical Collection on Immunologic/Diagnostic Tests in Allergy

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Carnés, J., Iraola, V., Gallego, M. et al. Control Process for Manufacturing and Standardization of Allergenic Molecules. Curr Allergy Asthma Rep 15, 37 (2015). https://doi.org/10.1007/s11882-015-0541-1

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  • DOI: https://doi.org/10.1007/s11882-015-0541-1

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