Opinion on the elimination of the leukocyte depletion step of plasma for fractionation collected in France
Date du document : 26/06/2025 Date de mise en ligne : 17/07/2025
Although there is no European regulatory threshold or recommendation for residual leukocyte count regarding plasma for fractionation (PFF) intended for the manufacture of plasma-derived medicinal products (PDMP), France has recommended since 1998 a leukoreduction step requiring a residual leukocyte count of less than 1.0 x 106 per liter, for at least 90% of the production. The reason for this measure is related to the elective tropism for the lymphoid system of prions responsible for the variant form of Creutzfeldt-Jakob disease (vCJD). Leukocyte depletion of PFF is estimated to reduce their infectivity to prions by a factor comprised between 0.3 and 1 log10. With regard to this benefit, leukocyte depletion represents a significant constraint for PPF collectors, with in particular a very limited choice of suppliers of apheresis machines capable of filtering plasma with such performance, the impossibility of using mobile machines allowing collections at a distance from donation centers, a loss of raw material linked to the filtration stage and significant additional costs of PFF compared to the competition.
The High Council for Public Health (HCSP) has been asked whether it is appropriate to amend this regulatory requirement without compromising health safety in relation to prion risk. To support its opinion, the HCSP convened a working group comprising, in addition to members from the French Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM), the Etablissement français du sang (EFS) and the Laboratoire Français de Fractionnement et des Biotechnologies (LFB), a panel of prion disease specialists. The elements that were analyzed to form the basis of this opinion are based on epidemiological considerations concerning the "epidemic tail" of the vCJD episode, on a benefit-risk analysis of the elimination of the leukocyte depletion step, on a critical study of the effectiveness of the alternative methods claimed by the LFB to inactivate prions, on a probabilistic modeling work conducted within the working group to evaluate the safety impact of the elimination of the leukocyte depletion step in the manufacture of PFF, on a study conducted in Great Britain which led to the reintegration of British donors for the production of immunoglobulins and finally on the public health issue represented by the national "Ambition plasma" project intended to increase the health autonomy of France and Europe in the production of PDMP and in particular of immunoglobulins.
In light of all these elements, the HCSP decides on the advisability of eliminating the leukocyte depletion step during the manufacture of the 14 PDMPs manufactured by the LFB, whose residual infectivity threshold for prions, in a worst-case scenario, is considered negligible because it falls below the threshold of 0.01 50% infectious doses for each product administration. The HCSP ultimately recommends applying the current European standard for fresh frozen plasma to the PPF, i.e., a residual leukocyte count < 0.1 x 109 per liter for at least 90% of the production. The HCSP supplements this opinion with additional recommendations aimed at (i) using methodological approaches by the LFB in accordance with the current state of knowledge on prions for the evaluation of alternative methods to leukocyte depletion intended for prion inactivation, (ii) strengthening epidemiological vigilance with regard to the occurrence of new cases of vCJD or atypical cases of prion diseases, and (iii) re-evaluating the strategy mentioned in the opinion every 3-4 years to ensure its relevance. Furthermore, the HCSP reiterates the need to maintain the current leukocyte depletion requirements for labile blood products, including plasma for therapeutic use, as this measure is the only one capable of reducing a residual prion risk in these products.
Lire en français : Déleucocytation du plasma pour fractionnement collecté en France du 26 juin 2025
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