Download PDF
Semin Thromb Hemost 2015; 41(08): 849-854
DOI: 10.1055/s-0034-1395353
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Potency Labeling of Novel Factor VIII and Factor IX Concentrates: Past Experience and Current Strategy

Anthony R. Hubbard
1   Haemostasis Section, Biotherapeutics Group, National Institute for Biological Standards and Control, South Mimms, Potters Bar, Hertfordshire, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
19 February 2015 (online)

    Permissions and Reprints

Abstract

Various strategies to produce “longer-lasting” factor VIII and factor IX concentrates through chemical and genetic modifications are currently under evaluation. It is now clear that these new molecules are amenable to testing using conventional methods for biological activity (one-stage clotting and chromogenic) and there is a preference to maintain labeling in International Units (IU) traceable to the WHO International Standard Concentrates. This is an achievable goal; however, many of the new molecules are associated with potency discrepancies both between methods and also within methods, for instance, when different activated partial thromboplastin time reagents are used. In the interests of global harmonization, it is important for licensing authorities to reach agreement on the choice of the potency labeling method. This choice should be supported by a thorough characterization of product potency, both in vitro and in vivo, to anticipate future issues and with a view to maintaining equivalence of the IU compared with existing licensed products. In cases where the product potency is defined using specific reagents, the robustness of the manufacturer's product standard will be crucial for product consistency. The sensitivity of measured potency to different methodologies will require manufacturers to provide guidance to clinical laboratories on suitable postinfusion testing approaches.

Keywords

hemophilia - factor VIII - factor IX - coagulation
 

  • References

  • 1 Peyvandi F, Garagiola I, Seregni S. Future of coagulation factor replacement therapy. J Thromb Haemost 2013; 11 (Suppl. 01) 84-98
    CrossrefPubMedSearch in Google Scholar
  • 2 Shapiro AD. Long-lasting recombinant factor VIII proteins for hemophilia A. Hematology (Am Soc Hematol Educ Program) 2013; 2013: 37-43
    CrossrefPubMedSearch in Google Scholar
  • 3 Schaub RG. Recent advances in the development of coagulation factors and procoagulants for the treatment of hemophilia. Biochem Pharmacol 2011; 82 (2) 91-98
    CrossrefPubMedSearch in Google Scholar
  • 4 Oldenburg J, Albert T. Novel products for haemostasis - current status. Haemophilia 2014; 20 (Suppl. 04) 23-28
    CrossrefPubMedSearch in Google Scholar
  • 5 Gu JM, Ramsey P, Evans V , et al. Evaluation of the activated partial thromboplastin time assay for clinical monitoring of PEGylated recombinant factor VIII (BAY 94-9027) for haemophilia A. Haemophilia 2014; 20 (4) 593-600
    CrossrefPubMedSearch in Google Scholar
  • 6 Barrowcliffe TW, Hubbard AR, Kitchen S. Standards and monitoring treatment. Haemophilia 2012; 18 (Suppl. 04) 61-65
    CrossrefPubMedSearch in Google Scholar
  • 7 Hubbard AR. International biological standards for coagulation factors and inhibitors. Semin Thromb Hemost 2007; 33 (3) 283-289
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Assay of human coagulation factor VIII (2.7.4) In: European Pharmacopoeia. 8th ed. Strasbourg, France: Council of Europe; 2014. 8.0. 236
    Search in Google Scholar
  • 9 Langdell RD, Wagner RH, Brinkhous KM. Effect of antihemophilic factor on one-stage clotting tests; a presumptive test for hemophilia and a simple one-stage antihemophilic factor assy procedure. J Lab Clin Med 1953; 41 (4) 637-647
    PubMedSearch in Google Scholar
  • 10 Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin. A simple screening test for first stage plasma clotting factor deficiencies. Am J Clin Pathol 1961; 36: 212-219
    CrossrefPubMedSearch in Google Scholar
  • 11 Seghatchian MJ, Miller-Andersson M. A colorimetric evaluation of factor VIII: C potency. Med Lab Sci 1978; 35 (4) 347-354
    PubMedSearch in Google Scholar
  • 12 Rosén S. Assay of factor VIII: C with a chromogenic substrate. Scand J Haematol Suppl 1984; 40: 139-145
    PubMedSearch in Google Scholar
  • 13 Barrowcliffe TW. Standardization of FVIII & FIX assays. Haemophilia 2003; 9 (4) 397-402
    CrossrefPubMedSearch in Google Scholar
  • 14 Hubbard AR, Weller LJ, Bevan SA. Activation profiles of factor VIII in concentrates reflect one-stage/chromogenic potency discrepancies. Br J Haematol 2002; 117 (4) 957-960
    CrossrefPubMedSearch in Google Scholar
  • 15 Viuff D, Barrowcliffe T, Saugstrup T, Ezban M, Lillicrap D. International comparative field study of N8 evaluating factor VIII assay performance. Haemophilia 2011; 17 (4) 695-702
    CrossrefPubMedSearch in Google Scholar
  • 16 Mikaelsson M, Oswaldsson U, Sandberg H. Influence of phospholipids on the assessment of factor VIII activity. Haemophilia 1998; 4 (4) 646-650
    CrossrefPubMedSearch in Google Scholar
  • 17 Ingerslev J, Jankowski MA, Weston SB, Charles LA ; ReFacto Field Study Participants. Collaborative field study on the utility of a BDD factor VIII concentrate standard in the estimation of BDDr Factor VIII: C activity in hemophilic plasma using one-stage clotting assays. J Thromb Haemost 2004; 2 (4) 623-628
    CrossrefPubMedSearch in Google Scholar
  • 18 Barrowcliffe TW, Mertens K, Preston FE, Ingerslev J. Laboratory aspects of haemophilia therapy. Haemophilia 2002; 8 (3) 244-249
    CrossrefPubMedSearch in Google Scholar
  • 19 Finney DJ. Statistical method in biological assay. 3rd ed. London: Charles Griffin & Company Ltd.; 1978
    Search in Google Scholar
  • 20 Assay of human coagulation factor IX (2.7.11) In: European Pharmacopoeia 8th ed. Strasbourg, France: Council of Europe; 2014. 8.0. 248
    Search in Google Scholar
  • 21 Shapiro AD, Ragni MV, Valentino LA , et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood 2012; 119 (3) 666-672
    CrossrefPubMedSearch in Google Scholar
  • 22 Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 2009; 102 (4) 634-644
    PubMedSearch in Google Scholar
  • 23 Østergaard H, Bjelke JR, Hansen L , et al. Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood 2011; 118 (8) 2333-2341
    CrossrefPubMedSearch in Google Scholar
  • 24 Gray E, Pickering W, Hockley J , et al. Collaborative study for the establishment of replacement batches for human coagulation factor IX concentrate reference standards. Pharmeur Bio 2008; 2008 (1) 19-30
    PubMedSearch in Google Scholar
  • 25 Bangham DR, Brozović M. Factor VIII international units and reference materials. Thromb Diath Haemorrh 1974; 31 (1) 3-11
    PubMedSearch in Google Scholar
  • 26 Hubbard AR, Weller LJ, Bevan SA. A survey of one-stage and chromogenic potencies in therapeutic factor VIII concentrates. Br J Haematol 2002; 117 (1) 247-248
    CrossrefPubMedSearch in Google Scholar
  • 27 Raut S, Daniels S, Heath AB ; SSC Sub-Committee on Factor. Value assignment of the WHO 8th International Standard for factor VIII, concentrate (07/350). J Thromb Haemost 2012; 10 (6) 1175-1176
    CrossrefPubMedSearch in Google Scholar
  • 28 Lusher JM, Hillman-Wiseman C, Hurst D. In vivo recovery with products of very high purity—assay discrepancies. Haemophilia 1998; 4 (4) 641-645
    CrossrefPubMedSearch in Google Scholar
  • 29 Mikaelsson M, Oswaldsson U. Assaying the circulating factor VIII activity in hemophilia A patients treated with recombinant factor VIII products. Semin Thromb Hemost 2002; 28 (3) 257-264
    Thieme ConnectPubMedSearch in Google Scholar
  • 30 Hubbard AR, Bevan SA, Weller LJ. Potency estimation of recombinant factor VIII: effect of assay method and standard. Br J Haematol 2001; 113 (2) 533-536
    CrossrefPubMedSearch in Google Scholar
  • 31 Barrowcliffe TW. Clotting factor concentrates in clinical practice. Standardization and assay. Semin Thromb Hemost 1993; 19 (1) 73-79
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Barrowcliffe TW, Raut S, Hubbard AR. Discrepancies in potency assessment of recombinant FVIII concentrates. Haemophilia 1998; 4 (4) 634-640
    CrossrefPubMedSearch in Google Scholar
  • 33 Barrowcliffe TW. Factor VIII and factor IX Sub-Committee. Recommendations for the assay of high-purity factor VIII concentrates. Thromb Haemost 1993; 70 (5) 876-877
    PubMedSearch in Google Scholar
  • 34 Raut S, Sands D, Heath AB, Barrowcliffe TW. Variability in factor VIII concentrate measurement: results from SSC field collaborative studies. J Thromb Haemost 2003; 1 (9) 1927-1934
    CrossrefPubMedSearch in Google Scholar
  • 35 Lee CA, Owens D, Bray G , et al. Pharmacokinetics of recombinant factor VIII (recombinate) using one-stage clotting and chromogenic factor VIII assay. Thromb Haemost 1999; 82 (6) 1644-1647
    PubMedSearch in Google Scholar
  • 36 Farrugia A. Potency assessment of the new generation of coagulation factor concentrates—time for a new paradigm?. Thromb Haemost 2003; 90 (6) 968-970
    PubMedSearch in Google Scholar
  • 37 Christiansen ML, Balling KW, Persson E , et al. Functional characteristics of N8, a new recombinant FVIII. Haemophilia 2010; 16 (6) 878-887
    CrossrefPubMedSearch in Google Scholar
  • 38 White G, Shapiro A, Ragni M , et al. Clinical evaluation of recombinant factor IX. Semin Hematol 1998; 35 (2) (Suppl. 02) 33-38
    PubMedSearch in Google Scholar
  • 39 Ewenstein BM, Joist JH, Shapiro AD , et al; Mononine Comparison Study Group. Pharmacokinetic analysis of plasma-derived and recombinant F IX concentrates in previously treated patients with moderate or severe hemophilia B. Transfusion 2002; 42 (2) 190-197
    CrossrefPubMedSearch in Google Scholar
  • 40 Chevreux G, Faid V, Andre MH, Tellier Z, Bihoreau N. Differential investigations from plasma-derived and recombinant Factor IX revealed major differences in post-translational modifications of activation peptides. Vox Sang 2013; 104 (2) 171-174
    CrossrefPubMedSearch in Google Scholar
  • 41 Barrowcliffe TW. Insights from factor IX activation studies with chromogenic assays: implications of disparate product results. Haemophilia 2010; 16 (Suppl. 06) 9-12
    CrossrefPubMedSearch in Google Scholar
  • 42 Yu Y, Millar CM. Measurement of factor IX activity in plasma-derived and recombinant concentrates: insights from thrombin generation and activation-based assays. J Thromb Haemost 2014; 12 (1) 62-70
    CrossrefPubMedSearch in Google Scholar
  • 43 Wilmot HV, Hogwood J, Gray E. Recombinant factor IX: discrepancies between one-stage clotting and chromogenic assays (epub ahead of print). Haemophilia 2014;
    PubMedSearch in Google Scholar
  • 44 Kitchen S, Gray E, Mertens K. Monitoring of modified factor VIII and IX products. Haemophilia 2014; 20 (Suppl. 04) 36-42
    CrossrefPubMedSearch in Google Scholar
  • 45 Hubbard AR, Dodt J, Lee T , et al; Factor VIII and Factor IX Subcommittee of The Scientific and Standardisation Committee of The International Society on Thrombosis and Haemostasis. Recommendations on the potency labelling of factor VIII and factor IX concentrates. J Thromb Haemost 2013; 11 (5) 988-989
    CrossrefPubMedSearch in Google Scholar
  • 46 European Medicines Agency. Report of Workshop on Characterisation of New Clotting Factor Concentrates (FVIII, FIX) with Respect to Potency Assays Used for Labelling and Testing of Post Infusion Samples. 28-29 November 2013. Doc Ref. EMA/135928/2014. London, 26 June 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/07/WC500169760.pdf
    PubMed
  • 47 Powell JS, Josephson NC, Quon D , et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood 2012; 119 (13) 3031-3037
    CrossrefPubMedSearch in Google Scholar
  • 48 Product information for Alprolix (Coagulation factor IX, recombinant, Fc fusion protein). Cambridge, MA: Biogen Idec Inc.
    PubMed
  • 49 Sommer JM, Moore N, McGuffie-Valentine B , et al. Comparative field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical haemostasis laboratories. Haemophilia 2014; 20 (2) 294-300
    CrossrefPubMedSearch in Google Scholar