Recommendations on the potency labelling of factor VIII and factor IX concentrates

Abstract

To cite this article: Hubbard AR, Dodt J, Lee T, Mertens K, Seitz R, Srivastava A, Weinstein M, On Behalf of the 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: 988-9.This document addresses two main objectives of product labelling -the first being to define the quantity of the active substance in the vial for manufacturing and marketing purposes, and the second to guide physicians on the dose to be used for treatment that would correlate with recovery data measured in clinical laboratories. For the latter to be effective, the labelling of potency needs to correlate with methods that are predominantly used in hospital laboratories. These correlations may be difficult to establish for individual products and should be resolved at the level of the manufacturers and regulators. This document relates to the potency labelling of all new factor VIII (FVIII) and factor IX (FIX) concentrate products, including plasma-derived, recombinant and modified products. The following recommendations are made in recognition that the potency measurement of some new products might be highly dependent on the choice of assay methods and reagents. Manufacturer's characterization of new product potencyDecisions on potency labelling should be supported by a thorough characterization of the in vitro properties of the new product. This will include testing against the current WHO International Standards (WHO IS) for FVIII or FIX concentrate to establish if valid estimates are possible using both one-stage clotting and chromogenic methods. Methodologies should follow the SSC recommendations and relevant monograph methods where applicable (e.g. pre-dilution in appropriate factor-deficient plasma; albumin in dilution buffers; specified activation times). Best practice for testing includes multiple dilutions (at least three) of standard and product samples to enable evaluation of statistical validity. Potency estimates based on single dilutions of test samples should be avoided and are not acceptable for product labelling. (Chromogenic assays for FIX should be included for information even though the method has only recently become available.)Evaluation by the one-stage clotting method should be performed using different APTT reagents (e.g. silica-based and ellagic acid). It is anticipated that the potency of modified products (e.g. pegylated molecules) by the onestage clotting method may be highly dependent on the choice of APTT reagent in some cases.In addition to potency assessment relative to the WHO IS Concentrate, assays should also be conducted using a plasma reference. This information may not be used in connection with product potency assignment but could be useful when considering the use of a plasma reference to monitor the recovery of new products in clinical laboratories. Data from other analytical methods (e.g. global tests...

A world‐wide survey and field study in clinical haemostasis laboratories to evaluate FVIII:C activity assay variability of ADYNOVATE and OBIZUR in comparison with ADVATE

“…The OBIZUR product insert recommends that the one-stage clotting assay is used to measure FVIII activity levels after OBIZUR dosing. Each vial of OBIZUR is labelled with the actual rpFVIII activity expressed in units following a recent recommendation [17] determined by a one-stage clotting assay, using a reference rpFVIII material calibrated against the World Health Organization (WHO) 8th International Standard for human FVIII concentrates.…”

Chromogenic assay for BAY 81‐8973 potency assignment has no impact on clinical outcome or monitoring in patient samples

“…Discrepancies between the one‐stage assay and the chromogenic assay have also been observed for some PEGylated rFVIII products in development, and one‐stage assay results may be highly dependent on the contact activator that is used . The ISTH Scientific and Standardization Committee has provided additional recommendations for potency labeling, recognizing that potency determination for new modified products may require specific assays and reagents . If there is significant discrepancy between the one‐stage assay and the chromogenic assay, an agreement between manufacturers and regulators on which assay to use for potency labeling will be needed .…”

Recombinant FIX Fc fusion protein activity assessment with the one‐stage clotting assay: A multicenter, assessor‐blinded, prospective study in Japan (J‐Field Study)

“…This method is based on the activated partial thromboplastin time (aPTT), for which a variety of activators, phospholipid components, calibrator plasmas, and instruments are commercially available. Although the calibrator plasmas are traceable to an international standard for FIX activity (commissioned by the World Health Organization), the diversity of available reagents and instruments has resulted in significant assay variability, particularly reported for recombinant FIX (rFIX) products . Furthermore, there is greater variability for some of the newer extended half‐life FIX products compared with the conventional rFIX products.…”

“…Such assay variability is of particular concern when accurate clinical monitoring is required (eg, during surgical procedures). Therefore, manufacturers of all FIX products must justify their choice of assay used for potency assignment and, when introducing a new FIX product into clinical practice, ensure that it can be measured with acceptable accuracy and reliability using one‐stage clotting assays, employing all commonly used aPTT reagents across multiple laboratories …”