In France, blood donations are tested in pools of 96 samples for parvovirus B19 (B19V) DNA to discard plasma for fractionation when it contains high viral loads. Between January 2015 and March 2024, B19V-positive donations decreased during the COVID-19 pandemic, followed by a strong rebound in 2023 and unusually high circulation during winter 2023/24 (ca 10 times higher December 2023-March 2024 vs the pre-pandemic period). Variations over time are probably related to measures implemented to limit SARS-CoV-2 spread.

Introduction: This paper describes the peculiarities of the plasma-derived medicinal product (PDMP) market and illustrates the results of a review of the literature on policies aimed at counteracting the shortage of PDMPs. Characteristics of PDMPs: Plasma is primarily used for the industrial production of blood products (80%). The demand for PDMPs, particularly immunoglobulins (IGs), is increasing. However, the production of PDMPs is complex, long (7-12 months), and expensive, accounting, according to US estimates, for 57% of the total costs of PDMPs compared to 14% for small molecules. PDMP market: Unexpected increases in clinical need cannot be addressed in the short term. Once the demand for some diseases is satisfied, the collection and fractionation of plasma will only be used to supply some specific patients. Hence, the full weight of the marginal costs, which remain constant, are borne by a few products. According to last liter economics, the industry stops producing when the marginal revenue equals the marginal cost, thereby reducing the convenience of producing the most commonly used PDMPs (albumin and IG). The imbalance between the demand and supply of PDMPs was exacerbated by the COVID-19 pandemic, which further increased the cost of plasma collection. Shortage issue and possible solutions: Policies to counteract this imbalance have also been discussed. If the demand is inappropriate, it should be reduced. If the demand is appropriate and supply cannot be increased, the demand should be prioritized for patients for whom PDMPs are the only available treatment. If the shortage depends on insufficient supply and technical and allocative efficiency, both production and supply should be improved, together with incentives for all stakeholders involved in the PDMP market to increase the sustainability of production/supply. The paper is focused on this second issue, that is supply-driven unbalance.

Plasma-derived medicinal products (PDMPs) are essential in the treatment of acute and chronic life-threatening diseases. The Korea Ministry of Food and Drug Safety has conducted a national lot release (NLR) of PDMPs since 2012 based on a summary protocol review system and lot release testing. However, few studies have investigated the performance or characteristics of the NLR framework. Over the past decade, the NLR of PDMPs was approximately 1000 per year, including mainly albumins, immunoglobulins, fibrin sealant kits, and coagulation factors, among others. The NLR system for PDMPs is similar to that for vaccines, except that PDMPs are manufactured using human plasma, which requires strict safety management. This study describes the status of NLR procedures for PDMPs and outlines the regulatory requirements needed to safely manage plasma for fractionation in Korea. This study can aid national control laboratories and marketing authorization holders in developing regulatory systems that assure the availability of safe and effective PDMPs.

Several analytical procedures are described in the European Pharmacopoeia (Ph. Eur.) to determine total protein content. However, the method for the determination of protein content in therapeutic immunoglobulins prescribed in the Ph. Eur. monographs is the Kjeldahl method. The Kjeldahl method is time-consuming and requires the use of large amounts of hazardous reagents, which also results in the production of a large amount of hazardous chemical waste. The purpose of this work was to validate an alternative chromatographic method that requires no hazardous reagents and saves time, using the same instrumental conditions specified in the Ph. Eur. for the human immunoglobulin size-exclusion high-performance liquid chromatography (SEC-HPLC) molecular-size distribution assay. The chromatographic separation was achieved with a TSKgel G3000SW (600 × 7.5 mm, 10 µm) column, using an isocratic elution, with detection at 280 nm wavelength. The mobile phase consisted of an aqueous solution of 0.03 M disodium hydrogen phosphate dehydrate, 0.01 M sodium dihydrogen phosphate monohydrate, 0.2 M sodium chloride and 1 mM sodium azide. The protein content of the test samples was determined referring to a standard with a known protein concentration (i.e. Human immunoglobulin (molecular size) Biological Reference Preparation). The method was validated evaluating the characteristics precision and trueness according to the ICH Q2 guideline, and the goodness of linear fit for the signal response was assessed (given for information only). In addition, the equivalence of methods was evaluated with two one-sided t-tests (TOST) analysis with the Kjeldahl method mentioned in Ph. Eur. monographs on therapeutic immunoglobulins, and with Bland-Altman analysis of SEC-HPLC and manufacturers\' data (Kjeldahl and biuret methods). The uncertainty of measurement was also calculated in order to evaluate the accuracy and quality of the results, thus facilitating a reliable compliance/non-compliance decision. Based on the outcome, the method is proposed as a suitable and convenient alternative for the determination of protein content in human immunoglobulins.

While the COVID-19 pandemic has impacted many aspects of healthcare, including routine blood donations, the impact of COVID-19 on the donation of source plasma critical to many aspects of patient care, including apheresis procedures, has been more difficult to define. As production of plasma-derived medicinal products (PDMPs) can take up to a year, shortages in source plasma donations may not be immediately appreciated. Given current shortages in PDMPs, in particular albumin, we examined the impact of COVID-19 on source plasma donations. Our data demonstrate that source plasma donations were disproportionately impacted by COVID-19 and that these shortages remained until the latter half of 2022. Given the time delay in PDMP manufacturing, these results suggest that while source plasma donation levels are returning to pre-pandemic levels, shortages in PDMPs may not be quickly overcome. These results also highlight the unique vulnerabilities in plasma sourcing that may continue to manifest as PDMP shortages for years to come.

The currently ongoing outbreak of monkeypox virus in many non-endemic countries around the world has also raised concerns about the safety of plasma-derived medicinal products. Based on what is known about the poxviridae, that is, that members are exceedingly large and carry a lipid envelope, effective removal and inactivation by plasma product manufacturing processes is expected. For the widely used solvent-detergent (S/D) treatments, however, poxviruses have been reported as potentially being a bit more resistant.
Using a S/D mixture comprising tri-n-butyl-phosphate, polysorbate 80 and Triton X-100 (TX-100), inactivation of vaccinia virus (a model closely resembling monkeypox virus, both within the same genus, i.e., Orthopoxvirus) in a plasma-derived process intermediate was analyzed over 60 min. As use of Triton X-100 will, based on environmental concerns, be restricted, similar experiments were conducted with a physicochemically virtually identical alternative, Nereid.
Fast inactivation of vaccinia virus to the assay detection limit, that is, reduction of infectivity by greater than 4 log10 within 10-20 min, was measured for the TX-100 S/D mixture. The alternative S/D mixture (Nereid instead of TX-100) was found fully equivalent.
As for other lipid-enveloped viruses, treatment of process intermediates with S/D mixtures containing TX-100 or the closely related detergent Nereid are highly effective in inactivating poxviruses. Thus, the current spread of monkeypox virus does not compromise the viral safety margins of plasma-derived medicines.

Chikungunya virus (CHIKV) and Mayaro virus (MAYV) are closely related members of the Semliki Forest complex within the genus alphavirus and are transmitted by arthropods, causing acute febrile illness in humans. CHIKV has spread to almost all continents, whereas autochthonous MAYV infections have been reported in South America and in the Caribbean. Nevertheless, there was concern about potential spread of MAYV to other regions similar to CHIKV in the past. The risk for transmission of emerging viruses by blood transfusion and the safety of plasma-derived medicinal products (PDMPs) are constant concerns. The manufacturing processes of PDMPs include procedures to inactivate/remove viruses.
In this study, we investigated the reduction of MAYV and CHIKV by heat inactivation in various matrices, solvent/detergent treatment and nanofiltration.
Unexpectedly, MAYV was significantly more resistant to heat and solvent/detergent treatment compared to CHIKV. However, being similar in size, both MAYV and CHIKV were removed below the detection limit by 35 nm virus filters.
The inactivation profiles of different alphavirus members vary considerably, even within the Semliki Forest Complex. However, robust dedicated viral inactivation/removal procedures commonly used in the plasma product industry are effective in inactivating or removing MAYV and CHIKV.

Here, we describe a straightforward sample pretreatment step for the colorimetric cobaltthiocyanate determination of polysorbate, which circumvents the assay\'s shortcomings due to interference of protein and does not require complex instrumentation. Protein-containing test samples are hydrolyzed with strong alkali at 100 °C, neutralized and clarified by filtration before applying the colorimetric assay. The modified method performs with appropriate accuracy and precision, allowing specific polysorbate measurement in the presence of Triton X-100 during virus inactivation, determination of residual amounts of polysorbate in the final products and measurement of polysorbate 80 in final formulated products. The alkaline hydrolysis step, primarily designed to provide the assay\'s reliability in the presence of protein, also enhances its selectivity towards interference by the non-ionic detergent Triton X-100 and increases its robustness against changes in the fatty acid moiety of polysorbate as it released the fatty acid essentially contributing to the known heterogeneity of polysorbates. These results demonstrate that with sample pretreatment the handy colorimetric assay, not requiring complex instrumentation, can be used to measure polysorbate 80 concentrations in intermediates and final products of therapeutic protein solutions.

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Risk of transmission of Creutzfeldt-Jakob disease (infectious agent, responsible of spongiform encephalopathy) via blood and blood components (including the plasma-derived medicinal products such as coagulation factors and immunoglobulins) have been a subject of concern for Health authorities since the early 1980s, with a regain of interest in the 1990s, with the bovine spongiform encephalopathy outbreak followed few years after with the notification of the first cases of variant Creutzfeldt-Jakob disease in humans. The risk-analysis and measures taken by the French authorities in the period 1990-2010 will be described with the various assumptions and working hypothesis used and revisited as new findings become available.