Guidelines for Bacteriophage Product Certification

  • Alan Fauconnier
Part of the Methods in Molecular Biology book series (MIMB, volume 1693)


Following decades in the wilderness, bacteriophage therapy is now appearing as a credible antimicrobial strategy. However, this reemerging therapy does not rekindle without raising sensitive regulatory concerns. Indeed, whereas the European regulatory framework has been basically implemented to tackle ready-to-use pharmaceuticals produced on a large scale, bacteriophage therapy relies on a dynamic approach requiring a regulation on personalized medicine, nonexistent at present. Because of this, no guideline are currently available for addressing the scientific and regulatory issues specifically related to phage therapy medicinal products (PTMP).

Pending to the implementation of an appropriate regulatory framework and to the development of ensuing guidelines, several avenues which might lead to PTMP regulatory compliance are explored here. Insights might come from the multi-strain dossier approach set up for particular animal vaccines, from the homologous group concept developed for the allergen products or from the licensing process for veterinary autogenous vaccines. Depending on national legislations, customized preparations prescribed as magistral formulas or to be used on a named-patient basis are possible regulatory approaches to be considered. However, these schemes are not optimal and should thus be regarded as transitional.

Key words

Phage therapy medicinal product Magistral formula Named-patient Autogenous vaccine Homologous group Multi-strain dossier Regulatory framework Personalized medicine 



The author would like to thank Sofie Termont and Daniel De Vos for critical reading of the manuscript and valuable editorial comments. Conflict of interests: The author declares no competing financial interests. Although the author works for regulatory authorities, the views expressed in this chapter are his personal opinion. As such, they may not be understood, interpreted, or quoted as being made on behalf of, or reflecting the position of, any agency or institution.


  1. 1.
    European Parliament and Council of the European Union (2012) Directive 2001/83/EC on the community code relating to medicinal products for human use, as amended. Accessed 24 Aug 2016
  2. 2.
    Chan BK, Abedon ST, Loc-Carillo C (2013) Phage cocktails and the future of phage therapy. Future Microbiol 8:769–783. doi: 10.2217/fmb.13.47 CrossRefPubMedGoogle Scholar
  3. 3.
    Huys I, Pirnay JP, Lavigne R, Jennes S, De Vos D, Casteels M, Verbeken G (2013) Paving a regulatory pathway for phage therapy. EMBO Rep 14:951–954. doi: 10.1038/embor.2013.163 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pirnay JP, De Vos D, Verbeken G, Merabishvili M, Chanishvili N, Vaneechoutte M, Zizi M, Laire G, Lavigne R, Huys I, Van den Mooter G, Buckling A, Debarbieux L, Pouillot F, Azeredo J, Kutter E, Dublanchet A, Górski A, Adamia R (2011) The phage therapy paradigm: prêt-à-porter or sur-mesure? Pharm Res 28:934–937. doi: 10.1007/s11095-010-0313-5 CrossRefPubMedGoogle Scholar
  5. 5.
    Chan BK, Abedon ST (2012) Phage therapy pharmacology phage cocktails. Adv Appl Microbiol 78:1–23. doi: 10.1016/B978-0-12-394805-2.00001-4 CrossRefPubMedGoogle Scholar
  6. 6.
    Appropriate ICH Expert Working Group (2000) ICH Q7 Good manufacturing practice guide for active pharmaceutical ingredients. Accessed 25 Nov 2016
  7. 7.
    European Commission (2014) Basic requirements for active substances used as starting materials. Accessed 25 Nov 2016
  8. 8.
    European Medicines Agency (EMA) Compliance and Inspections Department (2014) Guidance for the template for the qualified person’s declaration concerning GMP compliance of active substance manufacture “The QP declaration template”. Accessed 25 Nov 2016
  9. 9.
    Verbeken G, De Vos D, Vaneechoutte M, Merabishvili M, Zizi M, Pirnay JP (2007) European regulatory conundrum of phage therapy. Future Microbiol 2:485–491. doi: 10.2217/17460913.2.5.485 CrossRefPubMedGoogle Scholar
  10. 10.
    Henein A (2013) What are the limitations on the wider therapeutic use of phage? Bacteriophage 3:e24872-1–e24872-7CrossRefGoogle Scholar
  11. 11.
    Verbeken G, Pirnay JP, Lavigne R, Jennes S, De Vos D, Casteels M, Huys I (2014) Call for a dedicated European legal framework for bacteriophage therapy. Arch Immunol Ther Exp 62:117–129. doi: 10.1007/s00005-014-0269-y CrossRefGoogle Scholar
  12. 12.
    Verbeken G, Pirnay JP, De Vos D, Jennes S, Zizi M, Lavigne R, Casteels M (2012) Huys I. Optimizing the European regulatory framework for sustainable bacteriophage therapy in human medicine 60:161–172. doi: 10.1007/s00005-012-0175-0 Google Scholar
  13. 13.
    Cooper CJ, Khan Mirzaei M, Nilsson AS (2016) Adapting drug approval pathways for bacteriophage therapeutics. Front Microbiol 7:article 1209. doi: 10.3389/fmicb.2016.01209 PubMedGoogle Scholar
  14. 14.
    Fauconnier A (2017) Regulating phage therapy. EMBO Rep 2117:e201643250Google Scholar
  15. 15.
    European Medicines Agency (2015) Workshop on the therapeutic use of bacteriophages. Accessed 16 Nov 2016
  16. 16.
    Pelfrene E, Willebrand E, Cavaleiro Sanches A, Sebris Z, Cavaleri M (2016) Bacteriophage therapy: a regulatory perspective. J Antimicrob Chemother 71:2071–2074. doi: 10.1093/jac/dkw083 CrossRefPubMedGoogle Scholar
  17. 17.
    International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (2003–2004) M4: the common technical document. Accessed 23 Aug 2016
  18. 18.
    appropriate ICH Expert Working Group (1997) ICH Q5D derivation and characterisation of cell substrates used for production of biotechnological/biological products. Accessed 6 Dec 2016
  19. 19.
    Food and Drug Administration - Center for Biologics Evaluation and Research (2010) Characterization and qualification of cell substrates and other biological materials used in the production of viral vaccines for infectious disease indications. Accessed 6 Dec 2016
  20. 20.
    appropriate ICH Expert Working Group (2005) ICH Q2(R1) validation of analytical procedures : text and methodology. Accessed 6 Dec 2016
  21. 21.
    European Parliament and Council of the European Union (2015) Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC, as amended. Accessed 24 Aug 2016
  22. 22.
    CVMP Immunologicals Working Party (2010) Guideline on data requirements for multi-strain dossiers for inactivated vaccines against avian influenza (AI), bluetongue (BT) and foot-and-mouth disease (FMD). Accessed 6 Dec 2016
  23. 23.
    CHMP Biologics Working Party (2009) Guideline on allergen products: production and quality issues. Accessed 25 Aug 2016
  24. 24.
    Lorenz AR, Lüttkopf D, May S, Scheurer S, Vieths S (2009) The principle of homologous groups in regulatory affairs of allergen products – a proposal. Int Arch Allergy Immunol 148:1–17. doi: 10.1159/000151243 CrossRefPubMedGoogle Scholar
  25. 25.
    Artu Biologicals Europe b.v. (2014) Package leaflet for artuvetrin therapy. Accessed 16 Nov 2016
  26. 26.
    Committee for Human Medicinal Products (CHMP) (2008) Guideline on human cell-based medicinal products. Accessed 16 Nov 2016
  27. 27.
    Appropriate ICH Expert Working Group (2009) ICH Q8(R2) pharmaceutical development. Accessed 30 Aug 2016
  28. 28.
    Medicines and Healthcare Products Regulatory Agency (MHRA) (2014) The supply of unlicensed medicinal products (“specials”), MHRA guidance note 14. Accessed 18 Nov 2016
  29. 29.
    Medicines and Healthcare Products Regulatory Agency (MHRA) (2013) .MHRA questions and answers for specials manufacturer’s Accessed 18 Nov 2016
  30. 30.
  31. 31.
    Leyens L, Richer É, Melien Ø, Ballensiefen W, Brand A (2015) Available tools to facilitate early patient access to medicines in the EU and the USA: analysis of conditional approvals and the implications for personalized medicine. Public Health Genomics 18:249–259. doi: 10.1159/000437137 CrossRefPubMedGoogle Scholar
  32. 32.
    Johnston JD, Feldschreiber P (2013) Proposal for new European pharmaceutical legislation to permit access to custom-made anti-sense oligo-nucleotide medicinal products. Br J Clin Pharmacol 77:939–946. doi: 10.1111/bcp.12250 CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Lacroix AS (2013) Place des autovaccins dans la lutte contre les maladies chez la animaux de rente. Dissertation, Ecole nationale vétérinaire d'Alfort and Faculté de médecine de Créteil. Accessed 21 Nov 2016
  34. 34.
  35. 35.
    Legifrance (2005) Décret n° 2005–374 du 20 avril 2005 relatif aux autovaccins à usage vétérinaire et modifiant le code de la santé publique (partie réglementaire). Accessed 1 Sep 2016
  36. 36.
    Legifrance (2008) Arrêté du 6 mars 2008 relatif aux bonnes pratiques de préparation des autovaccins à usage vétérinaire. Accessed 1 Sep 2016
  37. 37.
    Justel (2002) Royal Decree of 19 December 2016, as amended Accessed 21 Nov 2016
  38. 38.
    Federal Agency for Medicines and Health Products (2016) Liste des laboratoires agréés belges., Accessed 21 Nov 2016
  39. 39.
    Scientific Institute of Public Health (2014) Accessed 21 Nov 2016
  40. 40.
    Federal Agency for Medicines and Health Products (2016) Scientific-technical advice Accessed 22 Nov 2016
  41. 41.
    Committee for Human Medicinal Products (CHMP) (2015) Guideline on influenza vaccines – submission and procedural requirements Accessed 24 Nov 2016

Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  1. 1.Federal Agency for Medicines and Health ProductsBrusselsBelgium
  2. 2.Culture in vivo ASBLNivellesBelgium

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