Donors to patients—a narrative review of safety and manufacturing of human serum albumin

Introduction

Background

Human serum albumin (HSA) is a key plasma protein synthesized exclusively by hepatocytes, accounting for 50–60% of the total proteins in the blood plasma. Its unique molecular structure allows it to perform various functions beyond its primary role in regulating oncotic pressure. These functions include transporting molecules, scavenging harmful substances, providing antioxidant activity, and exhibiting enzymatic properties. As a colloidal agent, it effectively restores fluid balance in conditions involving significant fluid loss, such as trauma, surgery, severe infections, burns, and organ dysfunction. Additionally, HSA functions as a sophisticated delivery system, wherein its ability to bind and transport various drugs enhances their therapeutic efficacy and duration of action. This combination of fluid management and drug delivery capabilities, along with its detoxification properties, makes HSA an invaluable tool in modern medicine, particularly in critical care and targeted drug therapy (1-5). It is currently used in greater volume than any other biopharmaceutical product, with worldwide manufacturing amounting to hundreds of tons each year (1-5). Given HSA’s versatile roles in critical care and therapeutic applications, its use has expanded across a range of clinical settings. Since its first documented clinical use in 1942, albumin has become central to managing hypovolemia and hypoalbuminemia related to burns, trauma, liver disease, and acute respiratory distress syndrome (ARDS), among others (6). The availability of both hyper-oncotic (20–25%) and iso-oncotic (4–5%) formulations allows clinicians to tailor treatment based on the clinical scenario (7). Additionally, HSA is an important excipient, stabilizer, and lyoprotectant for lyophilized powder used to formulate biopharmaceutical agents (8,9). However, as the global demand for HSA continues to rise, particularly in critical care settings, maintaining a stable supply of plasma-derived HSA (pdHSA) has become challenging, especially in emerging markets where plasma availability and the high costs of production remain limiting factors (5,10,11). This has led to the exploration of recombinant HSA (rHSA) derived from non-human sources; however, these alternatives are still in their nascent stages, and future studies are required to evaluate their clinical value for high-dosage use in established and promising indications of pdHSA (4,12).

Rationale and knowledge gap

Currently, human plasma is the main source of therapeutic HSA; therefore, ensuring its manufacturing and clinical safety remains paramount in the transfusion field with a special focus on transfusion-transmitted infections (TTIs). The coronavirus disease 2019 (COVID-19) pandemic has further underscored the need for vigilance against emerging pathogens. While current data suggest that established donor screening and pathogen inactivation protocols are effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (13), this presents an opportunity to reassess the adequacy of these safety measures in anticipation of future threats. This comprehensive review addresses critical gaps in the current literature of pdHSA manufacturing processes and clinical safety profile. The analysis is particularly timely given the increasing global demand, emerging therapeutic applications, and evolving safety considerations in the post-COVID-19 era. Understanding these safety parameters is crucial for healthcare providers and regulatory authorities as they navigate the expanding role of albumin therapy in clinical practice.

Objective

The objective of this study was to critically evaluate the modern manufacturing practices and pathogen safety controls employed in the commercial production of pdHSA. Furthermore, the review sought to offer evidence-based insights into the clinical safety of HSA, drawing upon data from clinical trials and post-marketing surveillance over the past seven decades. By doing so, the study aims to support informed clinical decision-making and address current challenges related to the safety and availability of this essential therapeutic product. We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-25-9/rc).

Methods

Articles describing pdHSA manufacturing, clinical safety, and comparisons between pdHSA and rHSA were identified through systematic searches in PubMed and Google Scholar. For this study, original research articles, reviews, meta-analyses, and relevant international guidelines published until November 2024 were selected. The literature search strategy for this narrative review is summarized in Table 1.

Pharmacovigilance data for Takeda’s albumin was extracted from the Periodic Benefit-Risk Evaluation Report (PBRER) [2024], provided by Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA. In the PBRER, a broad search was conducted using the MedDRA System Organ Class ‘Infections and Infestations’ to identify potential infection-related adverse events.

Manufacturing processes for plasma-derived albumin

Albumin manufacturing

The rich manufacturing history of pdHSA dates back to the 1940s when Dr. E. Cohn and colleagues pioneered the plasma fractionation process in Boston, MA, USA (14). Albumin can be purified from plasma either collected through plasmapheresis, called “source plasma”, or separated from whole blood donations, named “recovered plasma”. The former is the method of choice for industrial-scale manufacturing, yielding approximately 20–25 mg albumin/kg of plasma processed at >95% purity. Cohn’s cold ethanol fractionation separates albumin from other plasma proteins by leveraging its distinct biochemical and biophysical properties, such as high-water solubility, low isoelectric point, and structural stability through a series of precipitation steps (15,16). The cryoprecipitated plasma is subjected to an increasingly higher ethanol concentration (up to 40%) at low pH, temperature, and varying salt concentrations as albumin gets precipitated in the last fraction due to its high-water solubility. The excess water and ethanol are removed by the diafiltration/ultrafiltration method. For some albumin products, HSA is further subjected to one or more chromatographic processes (ion exchange and/or gel filtration) to reduce the concentration of contaminants and endotoxins. Finally, the purified albumin is aseptically filled in sterile containers and pasteurized at 60±0.5 °C for 10–11 hours in the presence of N-acetyl tryptophan or caprylate as stabilizers (16-18). Examples of different methods to obtain purified albumin products from human plasma are depicted in Figure S1.

Ensuring the safety of plasma-derived albumin

The pdHSA is manufactured using pooled plasma sourced from thousands of donors, the majority coming from the United States, followed by China and Europe (19). Pooling of plasma reduces the toxicity/immunogenicity of the HSA preparations; however, it is a cause of concern for exposure to TTIs and presents a key safety challenge during processing (20).

The safety of plasma-derived products is ensured using a three-tier process continuously being refined through rigorous scientific progress (Figure 1). The first tier involves screening potential plasma donors and deferring high-risk individuals before donation. Second, is the testing of plasma donors for the presence of selected TTIs to eliminate infectious donations before they enter the plasma pool. The third and most crucial tier involves pathogen reduction technologies (PRTs) during manufacturing (13,20,21).

Figure 1 Safety layers in pdHSA manufacturing. The safety layers for plasma-derived albumin manufacturing depicting the three levels of safety mechanisms that ensure pathogen safety. pdHSA, plasma-derived human serum albumin; TTI, transfusion-transmitted infection.

Donor selection and plasma testing

Plasmapheresis and blood donation centers are regulated by laws from regional health authorities, such as the European Medical Agency (EMA) and the United States Food and Drug Administration (FDA). These requirements detail criteria for donor selection and exclusion, plasma testing protocols, and guidelines for collecting epidemiological data about the donor population. They also outline safety measures to be followed during the manufacturing of plasma-derived products. Uniquely, EMA requires a dossier called the Plasma Master File to be implemented for manufacturing plasma products (15,22).

Potential donors of source plasma are provided educational material describing the risk of TTIs and a list of medication deferrals. Donor’s health is assessed through an annual physical exam along with medical screenings that include a focused physical assessment and a donor history questionnaire administered at each donation to gauge the TTI exposure risk (23). The list of donor inclusion/exclusion criteria is described in Table S1.

Source plasma donors who pass two separate medical screenings on two different occasions, including required viral testing, are termed “qualified donors”, and plasma is collected only from such donors at plasmapheresis centers under aseptic conditions. Donors not returning within the next six months lose their status as qualified donors. The donated plasma is tested for the TTIs required by the competent authority (Table 2). Donors/donations considered a potential risk based on the screening criteria are deferred, and their donations are excluded (including prior donations, if any) (15,22,26). The collected plasma is put on “inventory hold”, a quarantine (Q) for at least 45 and 20 days for source and recovered plasma, respectively. This allows sufficient time for testing and exclusion of donors in the “window period” when the viral load of the first tested donation is below the detection levels. After confirmed negative screening tests, individual plasma units are pooled and processed for albumin manufacturing (15,27).

Donor screening requirements significantly decrease the likelihood of pathogens in donated plasma, which is currently estimated at 8 cases per 100,000 donations [4 cases for hepatitis C virus (HCV), 1 for hepatitis B virus (HBV), and 3 for human immunodeficiency virus (HIV)]. This figure represents a remarkable 1,000-fold reduction compared to the incidence of these infections in the general population (21,24). The risk of TTIs is further minimized through PRTs during the albumin manufacturing process.

Pathogen removal and inactivation methods for albumin

Besides eliminating the risk of established TTIs, PRTs are essential for reducing the risk of emerging and unknown pathogens (28,29). The PRTs employed in albumin manufacturing are broadly categorized into pathogen removal and inactivation technologies. PRTs such as ethanol fractionation or chromatography reduce pathogen concentration by partitioning or retention, while pathogen inactivation methods such as pasteurization actively kill them (Table 3) (27,32,33).

Ethanol fractionation

Ethanol fractionation serves the dual purpose of protein purification and pathogen reduction. The increasingly higher concentration of ethanol (up to 40%) at low pH and temperature is extremely effective in pathogen removal (15,16). An analysis of 615 studies demonstrated a >10,000-fold (>4 log₁₀) reduction in viral load attributable to fractionation (34). Even the newly emerging Hepatitis E virus has been reported to be effectively eliminated through cold ethanol fractionation process (reduction factor >3.5 log₁₀) (35). Ethanol fractionation is also inherently effective (reduction factor >4.9 log₁₀) in removing prions from plasma products (36,37).

Chromatography

Chromatography with/without fractionation is an efficient method for reducing pathogens during albumin preparation. The bulk of pathogens gets evenly partitioned in the mobile phase and are likely not retained in the column bed. Validation studies on virus clearance have reported a 1.5 to >4.4 log₁₀ reduction of HBV and >10 log₁₀ reduction in HIV through chromatography (38,39). The reduction achieved for the non-enveloped viruses like HAV is in the range of 4–5 log₁₀ (40). It is also effective in reducing prions with studies demonstrating a reduction factor of over 3–4 log₁₀ when using ion-exchange chromatography (41).

Heat inactivation or pasteurization

Pasteurization is a robust method for pathogen inactivation and has been pivotal in ensuring albumin safety for the past 70 years (18,42). It is known to be highly effective against enveloped viruses (reduction factor >4 log₁₀) and some non-enveloped viruses like HAV (reduction factor >6 log₁₀) (43). The process is also considered the best bet against any unknown threats and is effective in combating emerging viruses such as flaviviruses [West Nile virus (WNV)], SARS-CoV-2, influenza, Zika, and chikungunya (43). Pasteurization was also reported to reduce the viral load of HEV by >3.1 log₁₀ (35). The combined viral reduction efficacy of fractionation and pasteurization is in the range of ~8–19 log₁₀ for enveloped viruses and ~4–11 log₁₀ for non-enveloped (13,15,16,44).

In addition to traditional TTIs, re-emerging and newly emerging pathogens—such as WNV, Dengue virus, Yellow Fever virus, and Japanese Encephalitis virus—pose important risks to transfusion medicine. While screening for these pathogens may vary based on local epidemiology, the manufacturing processes and virus inactivation steps used for plasma-derived products have been shown to be highly effective in eliminating these TTIs (45,46).

Human albumin quality criteria

As per the International Pharmacopeial Standards, clinical use HSA solutions contain a minimum of 95–96% albumin with <10% dimers/oligomers, sodium (87–160 mmol/L), potassium (<2 mmol/L), and stabilizers like sodium octanoate or acetyl tryptophan (47). The maximal levels allowed for contaminants like Prekallikrein activator (PKA) and aluminum are <35 IU/mL and <200 µg/L, respectively. The ethanol-fractionated pdHSA is free from oxygen carriers, coagulation factors, antibodies, and blood group antigens. Therefore, it can be administered regardless of the recipient’s blood group (15,16,48).

Safety evolution timeline for plasma-derived products

The evolution of pathogen safety in plasma-derived products reflects significant advances in both detection methodologies and virus clearance capacity. When albumin was first used in clinical settings in the early twentieth century, malaria and syphilis were the only known TTIs to humankind and were easily neutralized during ethanol fractionation (20). The first real concern for TTI arose in the 1950s when many cases of post-transfusion hepatitis were linked with blood transfusion. The causative agent, initially termed “serum hepatitis”, was later identified as HBV in the late 1960s, leading to the introduction of pasteurization in pdHSA manufacturing as a virus inactivation method (43,49,50). In the 1970s, HBV screening methods were developed, which played a crucial role in eliminating infected donors (20). However, HBV was not the only hepatitis-inducing TTI, and by the end of the 1970s, non-A non-B hepatitis (HCV) was discovered (51). The early 1980s saw cases of HIV transmission through specific plasma-derived products, particularly coagulation factors, which were the first-liter plasma-derived products. These products lacked viral inactivation, prompting the rapid development and implementation of screening tests in 1985 to enhance transfusion safety. The introduction of HIV screening in 1985 and donor deferral policies further reduced transmission risks and screening tests were quickly developed and implemented in 1985 (52,53). This led to the induction of deferral policies in blood and plasma donation. However, pasteurization was the savior in pdHSA production and was shown to be highly effective in reducing HIV risk (54). The next major TTI discovery was the pathogenic protein “prions” in the early 2000s. The ethanol fraction of immunoglobulins and albumin, however, did not demonstrate prion infectivity. There have been no documented cases of HIV or any other TTIs associated with pdHSA since the 1940s due to the induction of pasteurization in the manufacturing process (20). Pasteurization combined with good manufacturing practices (GMPs) used in pdHSA manufacturing is robust in eliminating known viral pathogens and is also effective against unknown/emerging threats (55).

The evolution of the transfusion field in the last two decades has resulted in recommendations to estimate potential virus input and virus inactivation/removal capacity in the manufacturing process (43). The contemporary approach involves systematically assessing the transmission potential of each pathogen, confirming pathogen elimination through PRTs, and developing screening methods when necessary. This was exemplified by SARS-CoV-2, where established manufacturing processes and PRTs effectively mitigated exposure risks to negligible levels (13).

pdHSA—clinical safety profile

The clinical safety of pdHSA has been systematically documented through rigorous pharmacovigilance and numerous clinical trials spanning more than seven decades, establishing it as one of the most well-characterized biological therapeutics with exceptional safety profiles in clinical practice.

Real-world evidence of albumin clinical safety

The most comprehensive clinical safety evidence comes from the pharmacovigilance data of albumin collected by manufacturers over long periods (Table 4). Spontaneous reporting defined as the voluntary reporting of clinical observations of suspected adverse drug reactions (ADRs) is an established tool for providing direct clinical safety evidence for pharmaceutical products (62). The first such large-scale study analyzed the spontaneously reported serious adverse event (SAE) data for human albumin from nine major global suppliers between 1990–1997. The study defined SAEs as an event involving death, a life-threatening clinical condition, hospitalization, disability, congenital anomaly, or intervention to prevent permanent impairment/damage. During 1990–1997, an estimated 95.4 million (40 g/dose) doses were supplied, and the SAE incidence rate was 1.29 per million doses [95% confidence interval (CI): 1.07 to 1.54] with 99 non-fatal and 24 fatal events. Notably, albumin was not attributed as a cause for any fatal SAE (58).

A subsequent study of pharmacovigilance data from ten major global suppliers from 1998 through 2000 confirmed the remarkable clinical safety of albumin. The combined total albumin doses distributed during this period was 16.2 million. The total SAEs reported were 211 with an incidence rate of 5.28 per million doses (95% CI: 1.60±17.4) (59). While an increased reporting rate was observed during 1998–2000 as compared to the 1990–1997 period, it was largely attributed to enhanced pharmacovigilance rather than changes in the product’s safety profile. The majority of reported AE were isolated incidents, primarily involving allergy-like responses such as erythema and anaphylaxis (63).

In line with these large-scale studies, the pharmacovigilance data for Takeda human albumin—the cumulative experience since product launch as well as the periodic evaluation reports—reflect a positive benefit-risk profile for its use. Takeda markets human albumin at 5%, 20%, and 25% (w/v) in 67 countries and has supplied more than 73.4 million doses for all albumin products since 1954. Cumulatively, from 1954–2024, 4,510 spontaneous AEs have been reported including 706 cases of hypersensitivity and 166 cases of TTIs, which amount to an incidence reporting rate of 9.62 and 2.26 per million doses, respectively. These TTIs reported over 70 years were attributed to patients’ underlying conditions, with no confirmed transmission linked to pdHSA. Since the introduction of pasteurization in the 1940s, no documented cases of TTIs have been associated with pdHSA. While two cases initially raised concerns, further investigation found no product-related transmission.

An analysis of the FDA adverse event reporting system for albumin between 2004 to 2022 showed only 535 reports. The most common AEs reported were chills, pruritus, hypotension, fever, and dyspnea, but no cases of TTI were documented (61). Another real-world study compiling published ADRs for HSA from the Chinese databases between 1990–2012 revealed 61 cases. Among these only 27 cases were attributed to albumin usage, none related to TTIs. The majority of ADRs were caused by inappropriate use of albumin such as off-label use or high infusion rates (60).

Safety evidence from clinical trials

Seven decades of pharmacovigilance safety data align well with evidence generated from several clinical studies that demonstrated the clinical safety of HSA. The first clinical studies were conducted in the early 1940s when albumin was being introduced for its hypovolemic application. The studies reported no adverse effects in about 800 participants (64). Albumin’s clinical safety in the first 35 years of usage was lauded as “so high, it rarely warrants discussion” (59).

Safety of pdHSA in critically ill patients

The SAFE trial, one of the largest clinical trials for HSA, involving 6,997 critically ill patients detected no safety difference between albumin and saline while comparing their clinical efficacy in critically ill patients (65). In a Cochrane analysis of 38 studies comparing albumin to crystalloids as volume expanders in 10,842 critically ill patients, albumin was shown to be a safe choice for hypovolemia and perhaps beneficial in a niche population of critically ill patients (66).

Safety of pdHSA in sepsis

The ALBIOS study, including data from 1,818 patients with severe sepsis/septic shock, did not report any worse adverse effects for albumin including renal replacement therapy or kidney injury, as compared to crystalloid (67). While isolated reports noted transient oxygenation decrements with hyperoncotic albumin administration, systematic evaluation has revealed no consistent adverse effects on pulmonary function. Furthermore, hyperoncotic albumin positively impacted fluid balance and shock resolution (68). A meta-analysis of 16 RCTs pooling data from 4,190 patients with sepsis/septic shock concluded albumin to be safe as a colloidal agent with no signal towards harm detected (69).

Safety of pdHSA in liver cirrhosis

The FRISC trial in liver cirrhosis patients with sepsis (N=154) demonstrated the superiority of albumin as a colloidal agent compared to saline with no additional safety concerns (70). Importantly, the ANSWER study has demonstrated that even long-term (up to 18 months) usage of albumin is safe in patients with liver cirrhosis (71).

Benefit-risk evaluation

The sub-group analysis of SAFE study demonstrated better clinical outcomes for albumin with no additional adverse effects as compared to saline in patients with severe sepsis, suggesting a better benefit-risk profile in these patients (72). A meta-analysis of 58 trials using data from 26,531 patients compared the survival benefits and adverse effects of seven crystalloids and colloidal agents for fluid resuscitation in sepsis, surgery, trauma, and brain injury. Among patients with sepsis and surgery but not with brain injury, albumin and balanced crystalloids were reported to achieve better clinical outcomes with fewer adverse renal events as compared to saline, gelatin, and hydroxyethyl starch. However, balanced crystalloids were reported to be required in larger volumes (73).

Plasma-derived and recombinant albumin—a comparison

Globally, the demand for HSA is rising due to its multifunctional nature and use in a wide range of therapies (10,74). While pdHSA has demonstrated a strong safety profile with low toxicity and immunogenicity over seven decades, reliance on human plasma has strained supply chains. This has led to interest in rHSA, which offers advantages such as controlled production and reduced risk of TTIs (4,12). The first report of rHSA production using Saccharomyces cerevisiae dates back to 1989, and multiple host expression systems have since been investigated. However, challenges related to achieving high purity and clinical-grade yields have limited its broader application (12,75). A detailed discussion of rHSA production hurdles, clinical trial data, and approved uses is beyond the scope of this review; interested readers may refer to recent comprehensive reviews by Wiedermann, 2024 and Chen et al. 2013 (4,12).

Comparison of plasma-derived and recombinant albumin safety profiles

The potential risk of TTI associated with pdHSA could be addressed by utilizing rHSA. rHSA, being a non-animal-derived alternative, enables large-scale and potentially cost-efficient production of pharmaceutical-grade albumin through various eukaryotic systems, including yeast and transgenic plants (76-78). Prokaryotic systems like E. coli and B. subtilis have shown limited success for rHSA production due to low secretion efficiency and accumulation in insoluble inclusion bodies, requiring complex refolding and purification processes that raise cost and complexity (79,80). Commercial production of rHSA primarily uses methylotrophic yeast Pichia pastoris as the expression system, resulting in a product that is structurally and functionally similar to pdHSA as demonstrated by in vitro and in vivo analysis (81,82). However, demonstrating comparable clinical efficacy to pdHSA has proven challenging, as the field is still in its early stages of clinical development, with no large-scale trials available comparing the efficacy of pdHSA and rHSA (4). Isolating and purifying rHSA from microorganisms to meet the clinical purity standards impacts production efficiency and presents additional challenges for its clinical applications. In contrast, pdHSA is allogenic and has an established safety profile of over seven decades backed by substantial clinical data, especially in high-volume therapeutic applications (12).

Alternative production methods for rHSA, such as transgenic rice (Oryza sativa), offer cost-effective and scalable manufacturing. However, they raise concerns about unintentional transgene transfer into the food supply and regarding variability in post-translational modifications (PTMs) (83-85). Plant-based systems often produce proteins with non-human glycosylation patterns—including plant-specific sugars α-1,3-fucose and ẞ-1,2-xylose—that have been linked to altered drug-binding properties and thermal stability and may lead to adverse immune reactions (83). In addition to glycosylation, other common degradation modification includes protein misfolding and aggregation, methionine oxidation, deamidation of asparagine and glutamine residues, and proteolysis, all of which can impact protein stability and function (86).

The detailed study analyzing Oryza sativa-derived recombinant HSA (OsrHSA) from various suppliers—including multiple lots from single supplier—noted extensive glycation at arginine and lysine residues, likely due to the expression system or purification processes. These modifications affected the protein’s biophysical properties and drug-binding behavior, with substantial lot-to-lot variability observed even among products from a single supplier. Such heterogeneity in PTMs—along with differences in thermal stability and fatty acid content—raises concerns about the reproducibility and immunogenic potential of rice-expressed rHSA for clinical use (83). The key differences between pdHSA and rHSA are described in Table 5.

Clinical and economic implications of using pdHSA vs. rHSA

A shift from pdHSA to rHSA has significant therapeutic and economic impacts. For therapies requiring small-scale use such as stabilizers or as excipients to biological products, rHSA presents a safety profile comparable to pdHSA (12). Clinical studies have reported rHSA to be safe and well-tolerated with no significant safety differences compared to pdHSA in healthy volunteers (88,90). A small phase III study in patients with liver cirrhosis found rHSA to be comparable to pdHSA (81). In another study in patients with liver cirrhosis, repeated administration of rHSA over three treatment courses at intervals of at least two weeks did not result in any serious allergic reactions (91). However, the safety and efficacy of rHSA in clinical settings require further investigation and its long-term safety data is currently unavailable. Due to the lack of efficacy and safety information, rHSA is only approved as a pharmaceutical excipient and is not used for high-volume clinical applications (85).

The choice between plasma-derived and recombinant products for small-scale therapeutic use also hinges on two key factors, accessibility and costs. Access to pdHSA is limited due to high demand and geographically constrained supply chains (74). In contrast, recombinant products could theoretically be readily available in well-funded healthcare systems. However, examples with other recombinant plasma products, such as coagulation factor VIII, have demonstrated that the supply of recombinant protein products can also face disruptions due to severe and prolonged manufacturing and supply issues (92).

The cost of producing pdHSA remains relatively low, contributing to its widespread clinical use. In contrast, achieving comparable cost-efficiency for rHSA continues to pose substantial challenges. Prokaryotic expression systems such as E. coli are hindered by complex protein refolding requirements and limited yields, resulting in high production costs. While animal bioreactors offer improved expression capabilities, they are resource-intensive and require significant time and capital investment for scalable production. Plant-based platforms, particularly transgenic rice, have shown promising advancements by surpassing industrial yield benchmarks and offering advantages in scalability, cost-effectiveness, and long-term storage (12).

Despite these advancements, the large-scale, cost-effective production of rHSA remains unfeasible at present. Additionally, the current regulatory approval status of rHSA restricts its use to small-volume clinical applications, positioning it more as a complementary than a replacement option for pdHSA. However, ongoing clinical use, even at a limited scale, continues to generate valuable safety and efficacy data. These insights are crucial for informing future regulatory considerations and broadening rHSA’s role in transfusion and biopharmaceutical practice (12).

Guidelines and recommendations for using pdHSA

National and international guidelines recommend using albumin, which is currently derived from donated plasma (Table 6). It is recommended in critical illnesses such as trauma, sepsis, surgery, burns, and liver diseases for managing hypovolemia and hypoalbuminemia. The Guidelines on the Use of Therapeutic Apheresis in Clinical Practice by the American Society for Apheresis recommends using albumin for therapeutic plasma exchange in over 160 indications (98). The International Collaboration for Transfusion Medicine recommends using HSA in liver cirrhosis with ascites during large-volume paracentesis to prevent circulatory dysfunction and in patients with spontaneous bacterial peritonitis to reduce mortality (93). Similarly, the European guidelines for the management of cirrhosis recommend HSA in refractory ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome (94). Expert consensus by Chinese cardiovascular surgeons recommends using HSA in cardiac surgery for volume replacement, pump priming, and pre/postoperative hypoalbuminemia (96). The Surviving Sepsis Campaign’s international guidelines also recommend albumin administration in adults with sepsis or septic shock (99). It is important to note that none of the guidelines yet recommend rHSA from non-human sources because of a lack of evidence for clinical use.

Conclusions

This review highlights the manufacturing and clinical safety of pdHSA in therapeutic applications supported by large-scale clinical trials and more than seven decades of pharmacovigilance data. The exceptionally low incidence of adverse events reported across different time periods, clinical settings, and patient populations strongly endorses the continued use of albumin in appropriate clinical contexts. Given the minimal pathogen risk, pdHSA remains a reliable choice for various biopharmaceutical applications.

Major international guidelines recommend pdHSA for hypovolemia and hypoalbuminemia for critical illnesses. Even though alternative sources like rHSA are emerging, their therapeutic use remains limited to low-volume applications, and the current research focused on enhancing their production efficiency and purity. The established safety record of pdHSA can serve as a benchmark for shaping policies that govern plasma-derived products and guide the development of regulatory frameworks for emerging alternatives like rHSA. The cold ethanol fractionation manufacturing process combined with pathogen removal and inactivation procedures, ensures robust safety against pathogens, effectively addressing both traditional and emerging infectious threats (100). Modern manufacturing facilities incorporate stringent quality control measures ensuring product purity and safety (18,42). The implementation of GMP standards has further enhanced the quality and safety profile of pdHSA.

While pdHSA has a remarkable safety and efficacy profile, ongoing research is necessary to address the evolving landscape of critical care medicine, along with advances in manufacturing technologies and increasing global demand. This requires continuous monitoring of safety parameters to ensure albumin therapy continues to evolve while maintaining the highest standards of safety and efficacy. A clear understanding of these safety parameters is vital for healthcare providers and regulatory authorities as they navigate the expanding role of albumin therapy (101).

Acknowledgments

The authors acknowledge the support provided by WNS Global Services Private Limited, Gurugram, India, in developing this manuscript. We also extend our appreciation to all contributors for their valuable insights and assistance throughout the drafting and review process.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Jan Hartmann) for the series “Source Plasma” published in Annals of Blood. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-25-9/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-25-9/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-25-9/coif). The series “Source Plasma” was commissioned by the editorial office without any funding or sponsorship. W.K. reports Takeda Stocks, consulting fees from Gerson Lehrman Group and Third Bridge Group, and payment for Speaker Bureau from Alexion Pharm. E.G. reports Takeda Stock options. W.E. is employee of Takeda Pharmaceuticals and shareholder. P.L.T. reports full time employee of Baxalta Innovations GmbH, a Takeda company, and Takeda Stocks. T.R.K. and U.U. also report being employed by Takeda and are Takeda stock owner. T.A.H. reports Takeda Stocks. R.P. also is employee of Takeda. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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