Stepwise options for preparing therapeutic plasma proteins from domestic plasma in low- and middle-income countries.

Industrial plasma fractionation, a complex and highly regulated technology, remains largely inaccessible to many low- and middle-income countries (LMICs). This, combined with the limited availability and high cost of plasma-derived medicinal products (PDMPs), creates deficiency of access to adequate treatment for patients in resource-limited countries, and leads to their suffering. Meanwhile, an increasing number of LMICs produce surplus plasma, as a by-product of red blood cell preparation from whole blood, that is discarded because of the lack of suitability for fractionation. This article reviews pragmatic technological options for processing plasma collected from LMICs into therapies and supports a realistic stepwise approach aligned with recent World Health Organization guidance and initiatives launched by the Working Party for Global Blood Safety of the International Society of Blood Transfusion. When industrial options based on contract or toll plasma fractionation programme and, even more, domestic fractionation facilities require larger volumes of quality plasma than is produced, alternative methods should be considered. In-bag minipool or small-scale production procedures implementable in blood establishments or national service centres are the only realistic options available to gradually reduce plasma wastage, provide safer treatments for patients currently treated with non-pathogen-reduced blood products and concurrently improve Good Manufacturing Practice (GMP) levels with minimum capital investment. As a next step, when the available volume of quality-assured plasma reaches the necessary thresholds, LMICs could consider engaging with an established fractionator in a fractionation agreement or a contract in support of a domestic fractionation facility to improve the domestic PDMP supply and patients' treatment.

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.

Stepwise access to safe plasma proteins in resource-constrained countries: Local production and pathways to fractionation-Report of an International Society of Blood Transfusion Workshop.

BACKGROUND AND OBJECTIVES: Actions are needed to improve access to safe plasma-derived medicinal products (PDMPs) in low- and middle-income countries (LMICs). MATERIALS AND METHODS: The International Society of Blood Transfusion (ISBT) Working Party for Global Blood Safety organized an on-line workshop during 21-23 September 2021 to advance access to safe plasma proteins in resource-constrained countries, consistent with recent World Health Organization (WHO) guidance documents. RESULTS: The meeting drew attention to the considerable unmet needs for access to essential PDMPs in LMICs, in particular coagulation factors and immunoglobulins, and stepwise actions to address these deficits. First, improved access to safe plasma protein therapies requires blood component separation with prevention of wastage of recovered plasma. Quality and safety of collected blood and plasma must be assured so that plasma in excess of transfusion needs can be processed into safe plasma proteins. Second, local production of safe plasma proteins can be implemented using available technologies to locally obtain pathogen-reduced plasma and prepare pathogen-reduced cryoprecipitate and immunoglobulins from small plasma pools. Third, when a sufficient, stable volume of quality-assured plasma is available (approximately 50,000 L/year), contract or toll fractionation by a foreign plasma fractionator can expand the supply of PDMPs. Fourth, when the national infrastructure supports high-technology industrial production and stable volumes of quality plasma reach at least 200,000 L/year, technology transfer for domestic fractionation can be considered. CONCLUSION: Action is needed including commitments of the organizations that made the workshop possible (WHO, ISBT, World Federation of Haemophilia [WFH], Plasma Protein Therapeutics Association [PPTA], International Plasma Fractionation Association [IPFA], International Patient Organization of Primary Immunodeficiencies [IPOPI] and International Federation of Blood Donor Organizations [FIODS]).

Rationale for supporting stepwise access to safe plasma proteins through local production in low- and middle-income countries: A commentary of an international workshop.

This document provides a commentary and further elaboration on the conclusions reached during a recent international workshop on plasma protein therapies organized by the Working Party for Global Safety of the International Society of Blood Transfusion (ISBT). The workshop addressed the profound deficiency in access to safe plasma protein therapies that persists in low- and middle-income countries (LMICs). We provide additional factual economic and technological information that highlights why local production of small-scale virus-inactivated concentrates of clotting factors and immune globulins from domestic recovered plasma through stepwise introduction of available validated technologies is a pragmatic approach to gradually improve the care of patients with bleeding disorders and immune deficiencies in LMIC while supporting progress toward fractionation of plasma. This strategy is in line with a recent WHO guidance. We stress that the active involvement of international blood donor and blood transfusion organizations, patient organizations, governments and industry will be essential in supporting stepwise and sustainable improvements in access to safe, effective, and quality assured plasma protein therapies.

Plasma fractionation in countries with limited infrastructure and low-/medium income: How to move forward?

Although therapeutic drivers are changing over the years, and innovative biotech products are continuously modifying the clinical landscape, there is an increasing need for plasma protein therapies obtained by the fractionation of human plasma. Plasma-derived protein products therefore continue to play vital roles in the therapeutic management of various immunological disorders, deficiencies in coagulation factors or protease inhibitors, viral or bacterial infections, and trauma. Plasma fractionation is a biotechnology industry that has increased in complexity over the last 30 years to ensure that plasma-derived protein therapies exhibit optimal quality and pathogen safety profiles. Plasma-derived products are among the safest biological therapies available; in industrialized countries they are strictly and efficiently regulated in all aspects of their production chain and clinical use. Conversely, due to some technological complexities and strict adherence to regulatory requirements, a substantial barrier to entry into the field of plasma fractionation exists. Although various plasma-derived protein products are on the WHO model list of essential medicines, dramatic shortages of these products exist, especially in low-/medium income countries, while at the same time more than 9 million liters of recovered plasma in these countries are wasted annually. Lack of plasma protein products results mainly from three factors: (a) cost of imported products, (b) insufficient local supply of quality plasma for fractionation, or (c) lack of domestic industrial fractionation capacity. As the understanding of critical quality and safety factors has dramatically improved over the years, there is a need to rethink how affordable, scalable, and reliable purification and virus inactivation technologies could be introduced in countries with poor relevant infrastructures and low-/medium income. Such technologies, when properly validated and implemented, could help ensure local availability of essential plasma protein therapies and gradually fill the gap in product supply, safety and affordability that exists relative to advanced economies.

The Evolving Role of Information Technology in Haemovigilance Systems.

This work provides an overview and appraisal of the general evolution of IS/IT in haemovigilance, from which lessons can be learned for its future strategic management. An electronic survey was conducted among the members of the International Haemovigilance Network to compile information on the mechanisms implemented to gather, process, validate, and store these data, to monitor haemovigilance activity, and to produce analytical reports. Survey responses were analysed by means of descriptive statistics, and comments/observations were considered in the final discussion. The answers received from 23 haemovigilance organizations show a direct relationship between the number of collected notifications (i.e., communication of adverse effects and events) and the technical specifications of the haemovigilance system in use. Notably, IT is used in the notification reception of 17 of these systems, out of which 8 systems are exclusively based on Web solutions. Most assessments of the evolution of IS/IT tend to focus on the scalability and flexibility of data gathering and reporting, considering the ever-changing requirements of haemovigilance. Data validation is poorly implemented, and data reporting has not reached its full potential. Web-based solutions are seen as the most intuitive and flexible for a system-user interaction.

Traceability of Blood Transfusions and Reporting of Adverse Reactions in Developing Countries: A Six-Year Postpilot Phase Experience in Burkina Faso.

Traceability is an essential tool for haemovigilance and transfusion safety. In Burkina Faso, the implementation of haemovigilance has been achieved as part of a pilot project from 2005 to 2009. Our study aims to evaluate the traceability of blood transfusions and reporting of adverse reactions over the 6-year postpilot phase. A cross-sectional study including all blood units ordered between 2010 and 2015 has been conducted in public and private health care facilities supplied with blood products by the transfusion center of Bobo-Dioulasso. The complete traceability was possible for 83.5% of blood units delivered. Adverse reactions were reported in 107 cases representing 2.1/1,000 blood units per annum. Transfusions of wrong blood to wrong patient were reported in 13 cases. Our study shows that the haemovigilance system in Burkina Faso must be improved. Healthcare workers have to be sensitized on how traceability and haemovigilance could impact the quality of care provided to patients.

Involvement of the RNAse L gene in prostate cancer.

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Identification of genetic susceptibility loci for prostate cancer has however been extremely difficult, and only in 1996 was the first prostate cancer susceptibility locus HPC1 mapped to chromosome 1q24-25. Since, several additional putative loci have been identified by genetic linkage analysis on chromosome 1, 17, 20 and X (reviewed in). For three of these loci, family-based studies have identified three genes associated with inherited prostate cancer: the 3' processing endoribonuclease ELAC2/HPC2 gene, the macrophage scavenger receptor 1 gene (MSR1), and the endoribonuclease RNase L gene (RNAse L/HPC1). Here we will focus our review on the RNAse L gene and its involvement in prostate cancer and other diseases.

Worldwide overview of existing haemovigilance systems.

Haemovigilance is a "quality process" with the aim to improve quality and increase safety of blood transfusion, taking into account that haemovigilance covers and surveys all activities of the blood transfusion chain from donors to recipients. Haemovigilance is indispensable when it comes to safety and quality of blood transfusions. Within the European Union (EU), the European Blood Directive requires haemovigilance in each Member State: the intention has been to rely on the existing or developing national systems. There are significant differences in haemovigilance around the world, in terms of definition, organisational schemes, state of development and implementation. These differences are more pronounced outside the EU: in some countries, even basic traceability causes a problem while in others systems similar as the most developed ones in the EU are implemented.

Work of the European Haemovigilance Network (EHN).

Haemovigilance has become a crucial part of the blood safety concept. In the Member States of the European Union, national haemovigilance systems are already in place or are developing. With the coming into force of the European Blood Directive 2002/98/EC, Community haemovigilance has become a priority: cooperation between the national haemovigilance systems will be of vital interest. The process of collaboration has already been initiated some years ago by the European Haemovigilance Network (EHN) with the following objectives: to favour the exchange of valid information between its members, to increase rapid alert/early warning between the members, to encourage joint activities between the members and to undertake educational activities relating to haemovigilance. This has been achieved by the EHN by developing and maintaining a website [http://www.ehn-org.net], by establishing a system for rapid alert and early warning (RAS), by discussing on all kinds of definitions relevant to haemovigilance, initiating standardisation of processes and forms (developing a common "mother matrix"), by starting with the compilation and analysis of European data (generated by the national haemovigilance systems in Europe) and by organising annual European Haemovigilance Seminars, where all these items are discussed. As in the past, the EHN will continue in the future to play a major role in promoting European haemovigilance.