Plasma-derived Medicinal Products Research Articles

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.

Navigating the Asia-Pacific region plasma therapies landscape: Insights from the 2023 Asia-Pacific Plasma Leaders' Network meetings.

The Asia-Pacific Plasma Leaders' Network (APPLN) plays a crucial role in addressing the regional shortage of plasma-derived medicinal products (PDMPs), particularly in low- and middle-income countries (LMICs). It provides a platform for experts to share their expertise and drive multi-stakeholder collaborations. While several PDMPs are acknowledged by the World Health Organization (WHO) as life-saving therapeutics on the Model List of Essential Medicine for treating various chronic and acute life-threatening diseases, there are still many inadequacies in the availability and affordability of PDMPs. These challenges arise from insufficient domestic supplies of plasma suitable for fractionation, as well as a lack of technical and financial capabilities to implement contract or domestic plasma fractionation programmes. At two separate dialogue forums organized by the APPLN in 2023, experts discussed the unmet needs of PDMPs for individuals living with haemophilia and immunodeficiencies in the region. They also highlighted the limited access to early diagnosis and patient-centred care in several LMICs. To address these issues, there is an urgent need to increase the availability of high-quality domestic plasma for fractionation. Adopting a stepwise approach to utilize unused recovered plasma and establishing contract fractionation programmes could be viable strategies to potentially enhance PDMP availability in LMICs. However, achieving this goal requires improving existing domestic infrastructures for blood collection, implementing adequate policy reforms and fostering competent local leadership. Ultimately, there is no 'one-size-fits-all' strategy for securing safe plasma proteins for all patients in need. Collaborative efforts are essential for achieving progressive self-sufficiency in PDMPs.

Balancing Donor Health and Plasma Collection: A Systematic Review of the Impact of Plasmapheresis Frequency

Most plasma used for manufacturing plasma-derived medicinal products (PDMPs) such as albumin, immunoglobulin (Ig), and clotting factors is obtained from source plasma collected via plasmapheresis, the majority of which is contributed by the United States (US). While the demand for PDMPs continues to rise, it remains unclear whether high-frequency plasmapheresis, such as the twice-weekly plasma donation allowed in the US, may have any (long-term) adverse health effects on the donor. To investigate the frequency at which plasma can be donated without harm to the donor, the current systematic review explores the impact of plasma donation frequency on cardiovascular health, protein depletion, and adverse events in healthy plasma donors. We asked the following research question: What is the impact of plasmapheresis frequency (Intervention) on the safety or health (Outcome) of healthy donors (Population)? Six databases (PubMed, Embase, Web of Science, CINAHL, the Cochrane Library, and Transfusion Evidence Library), 2 clinical trial registries (ICTRP and clinicaltrials.gov), and the PROSPERO database were searched. Four observational and 2 experimental studies were included. The results showed that very high-frequency donation (twice per week) may result in a clinically relevant decrease in ferritin and bring IgG levels below the lower threshold of 6 g/l. However, the evidence is of low to very low certainty, and solid conclusions are hindered by the healthy donor effect and methodological limitations of the included studies. To determine a safe threshold donation frequency that minimizes any possible harmful effect on the donor, more high-quality prospective cohort studies and experimental studies are needed. We should expedite such studies to support recommendations, as conclusive evidence confirming or refuting the safety of maximum allowed donation frequencies is lacking. Donor protection is essential, given that healthy donors receive no direct medical benefit from donating plasma.

Overview of regulatory frameworks on the national lot release of plasma-derived medicinal products in Korea

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.

Accessibility to plasma-derived medicinal products in Malaysia: The challenges faced by patients with inborn errors of immunity.

Inborn errors of immunity (IEI) (also known as primary immunodeficiencies) is an umbrella term for a growing group of over 450 different disorders that are characterized by defects in some of the components of the immune system. IEI are chronic diseases of genetic origin that render individuals suffering from them susceptible to infections. The mainstay of treatments for most patients with IEI, that is, predominantly antibody deficiencies is immunoglobulin replacement therapy (IRT), which is commonly delivered intravenously. Immunoglobulin (IG) therapy contains antibodies to compensate for the defective immune system's inability to produce them. Individuals with IEI need IRT regularly throughout their lives to help combat infections and prevent organ damage. Without IRT, they are in danger of suffering from morbidity, poor quality of life, and reduced life expectancy. In the last 20 years, the use of IG preparation has tripled and this is partly attributed to the growing awareness and improved diagnoses of IEI cases. IG preparations are also used for the treatment of other medical conditions including secondary immunodeficiencies and autoimmune diseases. As IG is derived from human plasma, there are concerns about the availability of supply, particularly to treat life-threatening conditions that cannot be improved with other medications. It is estimated that 75% to 80% of IEI patients do not have access to adequate IG therapy throughout the world. This concern of supply and other challenges faced by patients with IEI in Malaysia are described from the patients' perspective.

Shortage of plasma-derived medicinal products: what is next? narrative literature review on its causes and counteracting policies in Italy.

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 (7-12months), 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.

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.

Large-scale real-world data analysis of source plasma collections using a novel technology-enabled nomogram.

Source plasma collections are needed to satisfy the growing demand for plasma-derived medicinal products. The US plasma collection target volume has been guided by a standard weight-based FDA-issued nomogram (STAN) since 1992. In this research, large-scale US-based real-world data (RWD) were analyzed to confirm the safety and volume gains of a newly introduced personalized nomogram (PERS) that was previously studied in a premarket randomized controlled environment. A non-inferiority (NI) analysis was conducted to compare the novel nomogram's significant hypotensive adverse event (AE) incidence rate with large historical standard nomogram AE datasets. Additionally, the average target volumes and donor return rates were compared for collections following PERS and STAN. A total of 4,816,784 donations (PERS) by 414,957 donors resulted in a rate of 0.0998% (95% CI [0.0970, 0.1027]) significant hypotensive AEs. NI analysis suggested strong non-inferiority of the new technology (Δ = -0.0082%, 95% CI [-0.0113, -0.0050], prespecified NI margin = 0.1080). Average plasma collection target volumes increased by 66.39 mL (8.49%; p < .0001). Consecutive weekly donor return rates were consistent between the two nomograms (PERS: 73.6%, 95% CI [69.6%-76.7%]; STAN: 74.1%, 95% CI [66.1%-77.2%]). This analysis confirms in a large-scale real-world dataset the key safety parameter and collection benefit of a novel, technology-enabled nomogram. The nomogram may help meet the growing demand for plasma-derived therapies by providing approximately 8.5% more plasma per donation on average while maintaining donor safety and return rates.

Report on the seventh meeting of national control laboratories for vaccines and biologicals of the WHO Western Pacific and South-East Asia member states

The Biregional Network of National Control Laboratories (NCLs) of the WHO Western Pacific and South-East Asia Regions has been meeting annually since 2018 to enhance NCLs' voluntary participation capacity. Its seventh meeting was hosted by the Korea National Institute of Food and Drug Safety Evaluation (NIFDS) of the Ministry of Food and Drug Safety (MFDS), in conjunction with the Global Bio Conference, in Seoul on September 6, 2022. Over 60 participants from seven countries, (India, Indonesia, Japan, Korea, Malaysia, the Philippines, and Vietnam) attended the meeting on-site and online. The theme of this meeting was ‘Quality Control Issues and International Trends for Biologicals including Vaccines and Plasma-Derived Medicinal Products.’ Three special speeches were presented on sharing the quality control system for biologicals, including NCLs' considerations in preparing the WHO Listed Authorities and sharing MFDS experiences. Furthermore, the participating NCLs shared country-specific issues related to national lot releases during the COVID-19 pandemic and acknowledged the meeting’s crucial role in response preparedness for pandemic emergencies and enhancing regulatory capacity through coalitions and information exchange among NCLs. The NIFDS will cooperate closely with other Asian NCLs to enhance biological product quality control, aiming to establish regional standards and standardize test methods through collaboration.

On assessing the viral safety of individual units of the substance "Human plasma for fractionation" by nucleic acid amplification

Scientific relevance. The absence of blood-borne viruses in human plasma-derived medicinal products must be ensured by the control of raw materials and the manufacturing process.Aim. This study aimed to analyse system suitability criteria for analytical procedures to assess the viral safety of individual units of the substance "Human plasma for fractionation" in terms of the content of nucleic acids of blood-borne viruses, considering the requirements of the European Pharmacopoeia.Materials and methods. The authors analysed individual units of the substance "Human plasma for fractionation" (hereinafter, plasma). The study used the International Standards (ISs) for human immunodeficiency virus RNA, hepatitis A virus (HAV) RNA, hepatitis C virus (HCV) RNA, hepatitis B virus (HBV) DNA, and parvovirus B19 DNA, as well as nucleic acid detection kits for these viruses based on polymerase chain reaction (PCR).Results. HCV RNA was not detected in any of the eight plasma samples studied, and parvovirus B19 DNA was detected in one of the samples at a concentration not exceeding 104 IU/mL. Three tests with the corresponding ISs showed that the studied reagent kits detected HCV RNA at a concentration of 102 IU/mL and parvovirus B19 DNA (M1 genotype) at a concentration of 104 IU/mL. In additional tests that were conducted in two samples considering the requirements of the European Pharmacopoeia for the detection of HCV RNA and parvovirus B19 DNA, a new batch of reagent kit I detected the HCV RNA IS at a concentration of 102 IU/mL only in one of three replicates, which did not correspond to the claimed sensitivity of the reagent kit. HCV RNA was not detected in either replicate in one of two plasma samples spiked with the HCV RNA IS at concentrations of 102 and 103 IU/mL, possibly because of plasma inhibitory properties. The sensitivity of the reagent kits to parvovirus B19 DNA corresponded to the label claims; the study did not show any inhibitory properties of the plasma samples.Conclusions. Polymerase chain reaction testing of the viral safety of plasma intended for manufacturing medicinal products should include control samples calibrated in IU/mL. Further research and appropriate pharmacopoeial reference materials are needed to set system suitability criteria for analytical procedures using such control samples.

Effects of donation frequency on U.S. source plasma donor health.

Plasma-derived medicinal products (PDMPs) are essential, life-saving medicines manufactured from plasma donated by healthy human volunteers. PDMPs are used to treat a range of rare, serious, and chronic conditions, often genetic in origin. Approximately 70% of the Source Plasma (SP) used for PDMP manufacturing comes from United States (US). The hypothesis of the study is that US donation frequency does not impair donor self-reported functional health and well-being. A total of 5608 SP donors from 14 US SP centers were enrolled in a cross-sectional study to assess self-reported health related quality of life (HRQoL) and well-being. By sex, donors were assigned to one of four groups, according to their frequency of SP donation in the 12 months before enrollment. The SF-36v2® Health Survey (SF-36v2) and a survey assessing the frequency of various health conditions that may be associated with impaired immune function over different time periods were used. There were no statistically significant differences in SF-36v2 scores between any of the donor frequency groups, compared with new donors after controlling for potential confounding and accounting for multiple comparisons among males and females. Cough, cold, occasional fatigue, and sore throat were the most reported health conditions or symptoms, but there was no clear difference among sex or frequency groups. The self-reported data in this study support the hypothesis that compensated donations at US FDA permitted frequencies and volumes are consistent with maintaining donor health. Compared with the general population, SP donors have comparable or better health than the general population.

Why do US source plasma donors stop donating?

In the United States, source plasma (SP) donors can donate up to 104 times per year. Considering the global need for SP and plasma-derived medicinal products, it is critical to maintain the health of frequent donors. This study explores SP donors' self-reported reasons for a lapse in donating. There were 5608 SP donors from 14 SP centers who enrolled in a longitudinal cohort study to assess self-reported functional health and well-being. Donors were assigned to one of four groups, according to the frequency of SP donation in the 12 months before enrollment. One thousand four hundred forty-eight SP donors who lapsed in donating during 6 months or greater during the study follow-up were asked to complete a survey. There were 545 lapsed SP donors who returned surveys (37.6%); 63% were female. Most responses given for stopping SP donation were categorized as convenience reasons (69.1%). Self-reported health concerns, including being deferred multiple times, which were categorized as possibly related or unable to determine a relationship to plasmapheresis, represented 45.5% of the responses. Primary reasons US SP donors report for a lapse in donation were categorized as convenience (e.g., schedule conflicts/lack of time). Donor responses categorized as health concerns which have a possible or uncertain relationship to plasmapheresis were less frequent but present in all frequency groups. This study adds to the body of evidence that SP donors cease donating for a variety of self-reported reasons with the majority not directly related to a perceived negative impact on their health.

The impact of the COVID-19 pandemic on source plasma donations.

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.

Plasma-Derived Medicinal Products in Nigeria

Plasma-Derived Medicinal Products in Nigeria

Plasma collection and supply in Europe: Proceedings of an International Plasma and Fractionation Association and European Blood Alliance symposium.

At the symposium organized by the International Plasma and Fractionation Association and European Blood Alliance, experts presented their views and experiences showing that the public sector and its blood establishments may strengthen the collection and increase the supply of plasma using the right strategies in plasma donor recruitment, retention and protection, scaling-up collection by increasing the number of donors within improved/new infrastructure, supportive funding, policies and legislation as well as harmonization of clinical guidelines and the collaboration of all stakeholders. Such approaches should contribute to increased plasma collection in Europe to meet patients' needs for plasma-derived medicinal products, notably immunoglobulins and avoid shortages. Overall, presentations and discussions confirmed that European non-profit transfusion institutions are committed to increasing the collection of plasma for fractionation from unpaid donors through dedicated programmes as well as novel strategies and research.

The future of plasma-derived medicinal products (PDMP)

The future of plasma-derived medicinal products (PDMP)

Review and assessment of the donor safety among plasma donors.

Review and assessment of the donor safety among plasma donors.

Plasma collection in Indonesia - a challenge to implement fractionation

In recent years, the national usage of Plasma Derived Medicinal Products (PDMPs), particularly albumin and immunoglobulin, has expanded due to a rise in disease prevalence, as well as enhanced patient management practices and broader assurance coverage. Now, Indonesia is a country that imports all of its PDMPs, resulting in high pricing and market reliance; nevertheless, barely a third of recovered plasma gets transfused to patients. The plasma that has not been used should be discarded, at a cost. The government intended to begin meeting the needs of the PDMP by implementing the plasma fractionation program. The decision was taken to use contract fractionation for three years, after which a national fractionation manufacturer was anticipated. The potential utility of recovered plasma and the prospective requirement for plasmapheresis collection have been assessed. The Minister of Health has enacted legislation concerning plasma fractionation, including the potential of establishing plasmapheresis centers to facilitate plasma collections. The Food and Drug Administration of Indonesia has also initiated a certification scheme for blood establishments (BEs), and only certified BEs can provide plasma for fractionation. After the epidemic, the government restarted the fractionation program by modifying existing laws to allow private manufacturers to participate. The difficulty was obtaining plasma from uncompensated donors, recruiting plasma donors, increasing the number of qualified biological examiners, of which only 19 out of 469 have been certified, and increasing technology and personnel capacities. Other significant obstacles were the harmonization or consolidation of existing biological entities (BEs) and the expense of paying for recovered and source plasma. The government and other parties involved had to make substantial efforts and collaborate to overcome these problems.

Safety profile of plasma for fractionation donated in the United Kingdom, with respect to variantCreutzfeldt–Jakobdisease

Plasma-derived medicinal products (PDMPs) are life-saving and life-improving therapies, but the raw material is in short supply: Europe depends on importation from countries including the United States. Plasma from donors resident in the United Kingdom has not been fractionated since 1999 when a precautionary measure was introduced in response to the outbreak of variant Creutzfeldt-Jakob disease (vCJD). Cases of vCJD have been far fewer than originally predicted in the 1990s. Since the introduction of leucodepletion in 1999, and accounting for the incubation period, more than 40 million UK-derived blood components have been issued with no reports of TT vCJD. In February 2021, the UK Government authorized manufacture of immunoglobulin from UK plasma. Following separate reviews concluding no significant difference in the risk posed, the United States, Australia, Ireland and Hong Kong also lifted their deferrals of blood donors with a history of living in the United Kingdom. Other countries are actively reviewing their position. Demand is rising for PDMPs, and Europe faces a threat of supply shortages. Industry and patient groups are clear that using UK plasma would bring significant immediate benefits to patients and to the resilience of the European supply chain. From this scientific review, we conclude that UK plasma is safe for fractionation and urge blood regulators and operators to take account of this safety profile when considering fractionation of UK plasma, and to revise their guidelines on the deferral of donors who have lived in, or received a transfusion in, the United Kingdom.

The impact of educating blood donors on plasmapheresis and plasma applications on the availability of plasma-derived medicinal products

Introduction: Human plasma contains valuable proteins such as albumin, globulins and coagulation factors. These ingredients are used to obtain medicinal products (PDMPs - plasma-derived medicinal products) used in many fields of medicine. The growing number of indications for their use causes an increase in the demand for plasma collected from blood donors. Most donors, however, choose to donate whole blood, which provides a lower amount of plasma than plasmapheresis.&#x0D; Purpose of the study: This study aims to indicate the reasons why donors do not decide to donate plasma by apheresis, to show the role of informing donors about the plasmapheresis, about the uses of plasma collected and about the safety of the process. The work also presents examples of PDMPs applications that can be used in the process of educating donors, which may contribute to increasing the number of plasma donors and, at the same time, the availability of PDMPs.&#x0D; Material and methods: A review of scientific research (using Pubmed, Google Scholar databases), medical books and materials published on websites of institutions related to blood donation regulations was conducted.&#x0D; Results: The reasons why blood donors do not decide to donate plasma include, among others, longer donation time and lack of knowledge about plasmapheresis. The decision to donate plasma via plasmapheresis is influenced not only by the fact of informing the donor about such a possibility, but also by the content and manner of providing the information. Due to the greater amount of plasma obtained each time by plasmapheresis compared to the separation of whole blood, an increase in the number of donors undergoing plasmapheresis may indirectly positively affect the availability of plasma-derived medicinal products