Review and assessment of the donor safety among plasma donors.

Human plasma-derived medicinal products (PDMPs) are unique biological therapies derived from human plasma that are used to treat patients with rare, often genetic and chronic, conditions with a high disease burden, as well as acute indications. Despite decades of effective therapeutic use in the United States (US) and Europe and demonstrable clinical and societal value, these treatments still face numerous challenges pertaining to the plasma supply relative to growing demand, the donation landscape, regulatory and reimbursement frameworks, and treatment paradigms.1 As new indications arise and more patients are diagnosed with diseases requiring PDMP treatment, there is a growing clinical need for PDMPs, and considerably more plasma must be collected. Manufacturing from plasma collection to finished product generally takes 7 to 12 months. Plasma used for manufacturing PDMPs may be derived from whole blood donations (recovered plasma) or may be collected by apheresis for the sole purpose of fractionation (source plasma). Source plasma comprises more than 80% of the plasma fractionated in the US, totaling more than 53 million donations in 2019, with recovered plasma representing only 20%. The US currently collects approximately 70% of the world's supply, partly because the regulatory environment supports high-frequency donations and pays donors for their time and incidental expenses.2 Patients who require therapies manufactured from human plasma rely on the donations of many individuals. The PDMP manufacturing process starts with the collection of human plasma from healthy donors. This initial phase is complex and heavily regulated by multiple authorities around the world to ensure both plasma safety and donor well-being. While donor health is routinely monitored to ensure that donors are not at risk from donating plasma, published data on the health of frequent donors is limited. To protect the donor's health and well-being, there are numerous regulations worldwide concerning plasmapheresis center requirements (quality assurance, infrastructure, and personnel), as well as the frequency and volume of donations for each donor. Beyond donor safety regulations, centers, and manufacturers follow rigorous plasma quality and safety measures. The initial step in donation takes place even before source plasma is collected. For their donations to be used to manufacture PDMPs, individuals must pass a health assessment that includes a brief physical examination and a comprehensive health screening, as well as testing negative for specific viruses and having a normal protein electrophoresis and a negative syphilis test. Furthermore, new donors must successfully pass the full questionnaire and testing for transmissible diseases twice before their donations can be used. If these requirements are not met, the donations cannot be used to further manufacture injectable products. A summary of the PDMP manufacturing process is presented in Figure 1.1 Processes for manufacturing synthetic small molecules, which result in most common medications prescribed, are different and faster than this process. There are significant differences between countries regarding payment, donation frequency, and upper limits for the total annual number of donations. In most countries, this ranges from 20 to 60 times per year (Australia, 24 donations; Austria and Canada, 50 donations; Germany, 60 donations). Individuals in the US can donate source plasma up to twice per week with a minimum of 48 h between donations, or a maximum of 104 times per year if all eligibility criteria are met. Table 1 provides a summary of worldwide regulations for plasma donations.1 Payment of donors is permitted in only six countries: the US, China, Germany, Hungary, Austria, and the Czech Republic.3 Plasmapheresis in a healthy donor population was first described in 1952. Since then, the plasma products industry has carefully monitored the safety of repeated plasma donations on short- and long-term donors. Industry experience over the years has demonstrated that plasmapheresis is generally a safe process, with the most common adverse events (AEs) being related to phlebotomy, transient hypotension, or a mild vasovagal response.4 Studies continue to confirm that donors undergoing plasmapheresis, under regulated parameters, do not report significant repeated short-term or cumulative long-term donation-related AEs. Donors generally experience a low incidence of AEs, and most dropouts are due to nonmedical reasons or medical reasons unrelated to plasma donation.4 Approximately 10% of donors who present are deferred, most commonly because of unacceptable screening results, high blood pressure (BP), elevated pulse rate, low protein, and/or low hematocrit.5 It is our hypothesis that frequent plasmapheresis does not adversely affect donors' overall functional health and well-being. The purpose of this review is to discuss the regulatory and scientific basis for volume and frequency of plasma donations in the US and the European Union (EU) and to summarize the scientific knowledge available for donor health. While there is no evidence that health risks are associated with the frequency and volume of donations in the US, published data on the health status of frequent and long-term donors are limited. Long-term donors may be a self-selected group able to sustain plasma donation without deleterious effects, real or perceived. A few publications provide anecdotal information about the health status of donors, typically indicating that the donors have not demonstrated any adverse health effects considered to be related to donation. Most investigators studied donors at one time point and, according to the available published reports, did not always obtain health history data. A literature search of the EMBASE and MEDLINE databases was performed. The first search strategy focused on looking for publications with a mention of the effects of plasmapheresis on donor serum proteins, cholesterol levels, lymphocyte phenotype, iron levels, BP, and bone density. The second search strategy focused on recent publications. The abstracts from the results of database searches were then screened to determine whether the content reported on a possible safety concern associated with plasmapheresis. During screening, duplicates found in both the literature searches were excluded. The final list of abstracts and articles identified for potential inclusion in the review was then retrieved for a full-text review, during which any articles needing translation and conference abstracts with no full text were further excluded. During the preparation of the review, additional articles of interest identified by internal CSL teams as relevant to the discussion were added to the final list of full-text articles included in the analysis and incorporated into the review after excluding duplicates. Source plasma donors in the US are permitted to donate twice per week with at least 2 days between donations and no long-term cumulative volume limits. Maximal volumes collected at individual donations are regulated according to the weight of the donor (Table 1).1 The long-term record of safety for this industry, which has been collecting plasma donations at this frequency for decades and with the allowed volume allowances since 1992, would seem to allay these concerns.6, 7 Since proteins and immunoglobulins are removed with each donation (the sources of protein production in the body are not removed) along with other constituents of plasma, protein loss in plasma donors is one of the well-studied issues. In the US, this is monitored by determining the total plasma protein level before each donation and performing a protein electrophoresis every 4 months. In Europe, immunoglobulin G (IgG) levels as well as total plasma protein levels are monitored. Serum IgG has a delayed recovery after it is removed, which is the basis of this additional test. The degree of protein loss varies among individuals, but limits on volume per donation are intended to prevent hypovolemia or clinically significant protein loss. The effects of long-term intensive plasmapheresis on donor serum proteins remain a controversial issue despite many detailed studies.8 In 1963, studies at the National Institutes of Health showed that chronic plasmapheresis for up to 23 weeks with maximum rates not exceeding 1.5 L of plasma withdrawn per week (slightly less than the currently approved maximum) produced no changes in formed elements and only minor changes in serum protein levels. By contrast, an experimental study of five donors subjected to 5 L of plasma removal in 5 days did show serum protein depletion,9 but the collection of volumes as high as these is not practiced anywhere in the world. A study at the University of Michigan in 1970 showed no major serum protein depletion with donations of plasma equivalent to 4 units of whole blood per week (somewhat less than the maximum currently allowed).10 Investigators at the University of California, Los Angeles, and a commercial source of plasma products also showed no adverse effect on plasma protein homeostasis from long-term plasmapheresis at volumes somewhat less than currently allowed.11 In 1991, a study of Canadian Red Cross plasma donors who, on average, donated 550 mL once every 2 to 3 weeks concluded that when donations were made at these intervals, levels of plasma protein, albumin, IgG, and immunoglobulins A and M all remained within normal ranges.12 A similar low risk was found by Canadian investigators in 1993, but their protocol was weekly plasmapheresis at volumes about a third of what is currently allowed. Although a statistically significant decline in total protein levels was observed in most donors having 2 to 2.5 L of plasma drawn monthly for 6 months, its concentration was maintained well above the lower limit of the normal range.8 A comprehensive study of the removal and recovery of normal plasma constituents after plasma exchange, where larger volumes are removed, showed that immunoglobulin, complement, fibrinogen, and cholesterol had marked reductions in concentrations after high-volume plasma exchange. Interestingly, newly synthesized antibodies after the exchange may have increased biologic activity, indicating that immunoglobulin depletion did not necessarily correspond to a reduction in antibody activity or functional protection. Since albumin replacement was used, neither albumin nor total protein declined.13 Significant differences can be found in plasma protein levels in plasma collected with different techniques and frequencies.14 Laub et al. (2010) compared levels of various plasma proteins in plasma for fractionation obtained by pooling source plasma donations from either “compensated” German donors (Group III) or “paid” US (Group IV) donors with the levels observed in recovered and source plasma collected from unpaid donors in the EU (Group I) and recovered plasma in the US (Group II). No statistically significant differences (p > .05) were observed for any tested protein marker between plasma pools made with recovered plasma and source plasma (Figure 2).14 To determine whether IgG subclasses were affected, the IgG1, IgG2, IgG3, and IgG4 concentrations were also measured and compared (Figure 3). As the total IgG recovery calculated by summing the results for the individual IgG subclasses exceeded 90% of the independently measured total IgG, further comparison was possible. No significant difference was found between donations collected from EU (Group I) (unpaid donors of recovered + source plasma) and US (Group-II) (unpaid recovered plasma) donors. In the German compensated donors (Group III), the IgG1 and IgG2 levels were significantly lower (p < .0001) than in Groups I or II. In the US paid source plasma batches (Group IV), the IgG3 concentration was 8% lower, but the IgG1 and IgG4 concentrations were respectively 27% and 26% lower (all p < .0001) than in Groups I and II. A slightly greater difference was found for IgG2, whose average concentration in the US plasma batches (Group IV) reached only 70% of that measured in the EU plasma pools (p < .0001).14 The evidence of IgG subclass depletion led to concern that immune surveillance might be compromised in long-term plasma donors, impacting general health. Industry conducted two studies: one, a retrospective review of records of over 500 remunerated donors who participated in plasmapheresis programs at various frequencies for 10 years or more, and a second one determining the reasons for cessation of participation in serial plasmapheresis programs.4, 15 Neither study found evidence that long-term plasmapheresis impacted the donors' health. There are no published data documenting any increase in infections in donors. The reasons for dropping out of plasmapheresis programs were not medically related. Statistical analyses of total and serum protein electrophoretic groups of serum protein test results (Table S1) appeared to indicate that mean serum protein electrophoretic findings rose (with the exception of α1-globulin, which declined slightly) between the test result on record at the time of the last donation results and samples drawn for the follow-up survey;15 on average 124 days after their last donation. These results suggest that although there may be statistically significant decreases in total protein, albumin, and γ-globulins while donors are actively donating, these are not likely to be of clinical significance and recover quickly when repeated donation ceases. A comprehensive study of proteins and lymphocyte subsets showed decreased levels of serum protein, globulin, and IgG, accompanied by increased percentages of B (CD19) cells and decreased percentages of suppressor T (CD8+/CD11b+) and natural killer cells.6 Two groups of long-term plasma donors, source plasma donors (n = 20) and Rh immune globulin plasma donors (n = 26), were compared with whole blood donors (n = 29) and nondonor controls (n = 30). An analysis of lymphocyte data for the whole blood and plasma donors revealed no differences among the groups in the total white blood cell count, percentage of lymphocytes, or absolute number of lymphocytes. When the percentages of T (CD3) cells and B (CD19) cells were compared between source plasma donors, whole blood donors, and nondonor controls (Table S2), the only significant difference was in the percentage of B cells, which was higher in the source plasma donors. A more detailed comparison of suppressor T (CD8+/CD11b+) cells and cytotoxic T (CD8+/CD11b-) cells (Figure 4) revealed a significant decrease in the percentage of suppressor T (CD8+/CD11b+) cells in source plasma donors as compared to the percentage of those cells in either whole blood donors or non-donor controls. Although both plasma donor groups exhibited fewer CD8 cells and increased percentages of CD8+/CD11b+, no significant differences existed among plasma donors, whole blood donors, and nondonor controls in CD8+/CD11b- cells.6 When the focus began on iron depletion in blood donors, it was suggested this would be a possible issue for long-term plasma donors due to the accumulated loss of red cells with donation at the maximum frequency. The loss of 10 to 11 cc of red cells per donation with most of the automated equipment is reduced to about 5 cc when saline reinfusion is employed, which has become standard practice. The saline infusion rinses some of the red cells in the tubing back into the donor. Theoretically, a plasma donor could have the equivalent loss of 2 units of red cells per year. The Ferritin Levels in Plasma Donors (FLIPID) study studied ferritin levels in 1254 donors in the US.16 This study compared male and female donors at different donation frequencies with new donors. Donors who had ferritin levels less than 12 ng/mL were classified as having absent iron stores. Overall, <1% of male donors and 4% of female donors had absent iron stores.16 Some of the earlier studies have shown no change in cholesterol levels in the donor populations examined.17, 18 In 2013, a study was conducted across nine plasma donation centers in the US to assess the effect of plasmapheresis on total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels in a plasma donor population.19 The data showed a significant decrease in total and LDL cholesterol for both genders and all baseline cholesterol levels (p < .01). The greatest total cholesterol decreases (women, −46.8 mg/dL; men, −32.2 mg/dL) were associated with high baseline levels and 2 to 4 days between donations. Small but statistically significant increases in HDL cholesterol were predicted for donors with low baseline levels (Figure 5). A study in Austria found bone demineralization presumed to be due to the long-term impact of citrate infusion in long-term apheresis donors.20 Most of the data is related to platelet-pheresis donors, but the authors extended their conclusions to plasma-pheresis donors. In the plasma collection procedure, most of the citrate goes into the plasma collection bottle or bag and is not returned to the donor. An analysis of data (unpublished by the Plasma Protein Therapeutics Association [PPTA]) did not support the conclusion, and no other data has indicated bone mineral density losses in plasmapheresis donors. Rosa-Bray et al. (2013) performed a study to determine the possible effects of plasmapheresis on BP in 666 donors (18 to 69 years old; 407 males and 259 females) across nine centers in the US.21 The results (Figure 6) indicate that in donors with baseline Stage 1 or Stage 2 hypertensive levels, BP may be lowered following plasma donation at intervals of <14 days. When donations were less frequent (intervals of about 14 days), BP returned to near baseline levels. This effect was not seen following plasmapheresis in donors with normal baseline BP. Plasma donor recruitment and retention depend on a safe and positive donor experience. Even minor adverse reactions are significantly correlated with a decreased likelihood of subsequent donation, while major reactions might lead to substantially lower rates of return, although these are relatively minor reasons for donor attrition.22 The plasma-vigilance program collects, analyzes, and monitors donor AEs across the source plasma industry to continuously improve processes that contribute to donor health and safety. Schreiber et al (2021) compiled AEs reported by three PPTA member companies that represented 72% of the plasma donations made in the US.22 Donation data was collected between May 1 and August 31, 2018, from 3 PPTA member companies: CSL Plasma, Grifols, and Takeda BioLife. Donations were made at 513 plasma centers in 41 states. A total of 12,330,000 donations collected from 1,076,469 unique plasma donors who made at least one donation during the 4-month data collection period were analyzed. The International Quality Plasma Program (IQPP) Standard for Recording Donor AEs was used to classify AEs into 10 detailed categories with applicable subcategories. The donor population was approximately 62% male and 38% female, with an average donor age of 35.6 years. Nearly 93% of the donations were from repeat donors. The overall AE rate was 15.85/104 donations. The 2 AEs with the highest rates were transient hypotensive and phlebotomy events (8.32 and 5.91/104 donations, respectively) (Figure 7). Females had higher overall AE rates than males (25.76 vs. 9.85/104 donations), and first-time donors had higher overall AE rates than repeat donors (136.66 vs. 12.37/104 donations). Low weight, body mass index, and pre-donation estimated blood volume, along with advanced age, were also predictors of AEs.22 Following PPTA standards, all major events were reportable. No fatalities or life-threatening events during or within 24 h that were attributed to the donation occurred. Serious AEs, such as major cardiovascular or respiratory events, were very rare and not specifically enumerated. Three PPTA member companies are currently conducting a study in the US to assess the health status of donors with various donation frequencies. In this current longitudinal cohort study conducted by the PPTA, the functional health and well-being of a minimum of 4000 source plasma donors in 4 donation frequency groups were evaluated using the Short Form 36 Health Survey version 2.0. In addition, a second survey evaluated the occurrence of current or recent illnesses, infections, and fevers to examine whether donation frequency is associated with conditions that could be related to depleted immunoglobulins. The reasons donors stop donating for a period of at least 6 months were also assessed. Data from this study are not yet available. Previous studies have reported that the reason donors stop donating is not due to health status related to being a plasma donor.15 Potential safety hazards to the plasmapheresis donor, including protein depletion, iron depletion, and significant acute AEs after donations, are discussed in this review. The concern about the health of source plasma donors, particularly in the US, relates to both the frequency and amount collected at each donation and the fact that donors are compensated for their time and personal expenses. The data available suggest that there are not major health-related issues with this donor population. However, the PPTA is addressing this concern in the US with short- and long-term studies of the donor population's health. These longitudinal studies are ongoing, and no data have yet been presented or published. US Food and Drug Administration (FDA) reviews all donor fatality reports that it receives on an annual basis. Reports issued by the agency (reported on the FDA website)23 have not resulted in any changes to the regulatory paradigm. Although there is little information on the reasons for the dropout of long-term donors, the available information suggests that the reasons are not health-related. To address the issue of immune sequelae more accurately in long-term donors, it would be helpful to conduct follow-up studies, as planned by the PPTA. Reported studies of reduced immunoglobulin levels and changes in lymphocyte phenotypes have not been correlated with donor health and do not necessarily imply any true health impairment.6 There is a need for country-level awareness campaigns promoting the critical importance of plasma donations and their impact on patients' well-being. This can be achieved by a joint effort from industry and patient associations as well as governments and supranational bodies. We thank Dr. Debbie Bensen-Kennedy and Dr. David Gardiner for their support in critically reviewing this manuscript and providing feedback. We thank Kate McDonald and Stewart Barnett in Medical Writing for performing a Quality Control check on this document. CSL Behring. The authors have disclosed no conflicts of interest. MP and RM are full-time employees of CSL Behring. TS is a full-time employee of CSL Plasma. MB is an independent consultant who was compensated for effort on this project. Table S1. Total and individual serum protein statistics. Table S2. Lymphocyte Phenotypes in Donors and Nondonor Controls. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.