Generating pathways to domestically sourced plasma-derived medicinal products: Report from a workshop by the International Plasma and Fractionation Association and the Working Party on Global Blood Safety of the International Society of Blood Transfusion.

Plasma-derived medicinal products (PDMPs) are recognized internationally as essential medicines required to treat various acute and chronic conditions including congenital deficiencies of plasma proteins in haemophilia and primary immune deficiency. Global provision of these medicines is dominated by a small number of commercial companies, influencing the price and availability of the products. Achieving a level of strategic independence from this dominance is now seen as a public health priority in many countries. During the Regional Congress of the International Society for Blood Transfusion (ISBT) in Cape Town, South Africa, in November 2023, around 50 delegates from 24 countries participated in a workshop (WS) organized jointly by the International Plasma and Fractionation Association (IPFA) and the ISBT Working Party on Global Blood Safety on pathways towards provision of PDMPs from domestic plasma independent of commercial purchase in the open market. The WS was structured around three themes, each addressed by a separate group: Quality/safety requirements for plasma for fractionation (PfF) Stepwise access for safe plasma proteins Approaching contract fractionation A synthesis of conclusions from these groups included the following: The need to acquire support from government authorities for a national plasma policy, recognizing the difficulties posed by unstable political and bureaucratic environments. The value of embedding plasma and PDMPs within a patient blood management (PBM) paradigm to promote optimal clinical use of PDMPs. Training of blood/plasma collection personnel in the relevant principles of Good Manufacturing Practice (GMP), coupled with regulatory oversight of plasma product production in the engaged jurisdictions. Appreciation that limited access to contract fractionation may necessitate a stepwise approach, which may include small-scale preparation of versions of essential plasma proteins as an intermediate phase towards the manufacture of industrial-scale PDMPs from domestic plasma.

The Evolution of the Safety of Plasma Products from Pathogen Transmission-A Continuing Narrative.

Chronic recipients of plasma products are at risk of infection from blood-borne pathogens as a result of their inevitable exposure to agents which will contaminate a plasma manufacturing pool made up of thousands of individual donations. The generation of such a pool is an essential part of the large-scale manufacture of these products and is required for good manufacturing practice (GMP). Early observations of the transmission of hepatitis by pooled plasma and serum led to the incorporation of heat treatment of the albumin solution produced by industrial Cohn fractionation of plasma. This led to an absence of pathogen transmission by albumin over decades, during which hepatitis continued to be transmitted by other early plasma fractions, as well as through mainstream blood transfusions. This risk was decreased greatly over the 1960s as an understanding of the epidemiology and viral aetiology of transfusion-transmitted hepatitis led to the exclusion of high-risk groups from the donor population and the development of a blood screening test for hepatitis B. Despite these measures, the first plasma concentrates to treat haemophilia transmitted hepatitis B and other, poorly understood, forms of parenterally transmitted hepatitis. These risks were considered to be acceptable given the life-saving nature of the haemophilia treatment products. The emergence of the human immunodeficiency virus (HIV) as a transfusion-transmitted infection in the early 1980s shifted the focus of attention to this virus, which proved to be vulnerable to a number of inactivation methods introduced during manufacture. Further developments in the field obviated the risk of hepatitis C virus (HCV) which had also infected chronic recipients of plasma products, including haemophilia patients and immunodeficient patients receiving immunoglobulin. The convergence of appropriate donor selection driven by knowledge of viral epidemiology, the development of blood screening now based on molecular diagnostics, and the incorporation of viral inactivation techniques in the manufacturing process are now recognised as constituting a "safety tripod" of measures contributing to safety from pathogen transmission. Of these three components, viral inactivation during manufacture is the major contributor and has proven to be the bulwark securing the safety of plasma derivatives over the past thirty years. Concurrently, the safety of banked blood and components continues to depend on donor selection and screening, in the absence of universally adopted pathogen reduction technology. This has resulted in an inversion in the relative safety of the products of blood banking compared to plasma products. Overall, the experience gained in the past decades has resulted in an absence of pathogen transmission from the current generation of plasma derivatives, but maintaining vigilance, and the surveillance of the emergence of infectious agents, is vital to ensure the continued efficacy of the measures in place and the development of further interventions aimed at obviating safety threats.

The legacy of haemophilia: Memories and reflections from three survivors.

Following the publication of a book of personal memories by one of us (CS1,2 ), we have attempted to synthesis our joint memories of three ageing men, born in the era preceding universal access to treatment, in an attempt to describe our experience, our challenges and our reflections on the development of therapies, which have ensured that our experience of growing up with haemophilia in the 1950s and 1960s has not been mirrored by the current generation of patients. We describe our upbringing in different parts of Europe in health care systems which, while of varying standards, were all unable to offer the kind of care which developed after the development of specific therapies. We assess the effect of the contamination of these therapies by blood-borne pathogens on our own development, and the development of our communities around us. In addition, we reflect on the lessons learnt, sometimes painfully, by our generation of people with haemophilia and how some of these enabled us to overcome substantial hurdles, survive and build productive lives. Finally, we survey the development of therapies in the past 20 years, and offer some reflections on how our experience can be integrated in a realistic expectation of what the future holds for our community, in our own affluent societies and in countries less advantaged economically. We hope that our thoughts may contribute to continued progress in the field of haemophilia care.

Therapeutic Solutions of Human Albumin - The Possible Effect of Process-Induced Molecular Alterations on Clinical Efficacy and Safety.

Human albumin solutions were developed as therapeutic during the Second World War to address blood loss due to battlefield injury. This indication was based on the recognition that albumin provided most of the oncotic capacity of human plasma. For the succeeding sixty years, this formed the basis for the use of albumin in traumatology and emergency medicine. In more recent times, the pharmacological properties arising from albumin's complex structure have become a focus of attention by clinical researchers. In particular, albumin, through anti-inflammatory and anti-oxidant properties, has been proposed as an agent for the treatment of sepsis, cirrhosis and other inflammatory states. Some evidence for these indications has accrued from a number of small clinical trials and observational studies. These studies have not been confirmed in other large trials. Together with other investigators, we have shown that the process of plasma fractionation results in alterations in the structure of albumin, including those parts of the molecule involved in anti-oxidant and anti-inflammatory effects. Albumin products from diverse manufacturers show heterogeneity in their ability to address these effects. In this article, we review the historical development of albumin solutions, pointing out the variations in fractionation chemistries which different manufacturers have adopted. We suggest ways by which the manufacturing processes have contributed to variations in the physico-chemical properties of molecule. We review the outcomes of clinical studies assessing the role of albumin in ameliorating conditions such as sepsis and cirrhosis, and we speculate as to the extent which heterogeneity in the products may have contributed to variable clinical outcomes. Finally, we argue for a change in the perception of the plasma product industry and its regulatory overseers. Historically, albumin has been viewed as a generic commodity, with different preparations being interchangeable in their clinical application. We suggest that this implied biosimilarity is not necessarily applicable for different albumin solutions. The use of albumin, in indications other than its historical role as a plasma expander, can only be validated by clinical investigation of each separate albumin product.

Estimation of the latent therapeutic demand for immunoglobulin therapies in autoimmune neuropathies in the United States.

BACKGROUND AND OBJECTIVES: The use of immunoglobulin (IG) solutions as an immunomodulatory therapy in certain neurological conditions has become an established modality and represents a significant proportion of total IG use. The estimation of the evidence-based potential demand designated as the latent therapeutic demand (LTD) for IG in these diseases is required for adequate planning of the plasma supply required to manufacture the product. MATERIALS AND METHODS: The diseases studied included chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome (GBS) and multifocal motor neuropathy (MMN). The LTD for IG was assessed using a decision analysis model, using Microsoft Excel. The model analysed the epidemiological and clinical factors contributing to IG usage. One-way sensitivity analysis and probabilistic sensitivity analysis derived the LTD in grams per 1000 inhabitants. The key variables included the treatment schedule and the prevalence of the disease. RESULTS: The model estimates that an average annual IG demand and standard deviation for CIDP, GBS and MMN in the United States is 83.05 ± 24.5, 6.1 ± 3.2 and 36.1 ± 25.5 g/1000 inhabitants, respectively. CONCLUSION: Together with previous work on the LTD for IG in immunodeficiencies, these results indicate that current IG usage reflects the estimated LTD for the main indications for IG in the United States The wide range of LTD found in all these studies emphasizes the need for more precise assessment of the underlying variables, particularly disease prevalence and dosage. Further studies on other indications such as secondary immunodeficiencies will augment these results and will assist in guiding demand planning for IG use and plasma collection in the United States and inform blood policy in other countries.

The art of the possible in approaching efficacy trials for COVID19 convalescent plasma.

COVID-19 convalescent plasma (CCP) is widely used as a treatment. While safety data are enough, high-level evidences of efficacy are still missing. We summarize here the results from randomized controlled trials (RCT) published to date and analyze their flaws and biases. We then provide suggestions for next round of CCP RCTs, discussing specification of CCP, therapeutic dose, timing, control arm, disease stage, and outcome measures.