Abstract Background Asymptomatic blood donors can transmit human parvovirus B19 (B19V). Methods We assessed the B19V prevalence among a large cohort of blood donations collected in Germany during 2015–2018. Results In total, 167 123 donations were screened for B19V deoxyribonucleic acid with 22 cases of viremia identified (0.013% positive). Infections peaked at a 4-year interval and the highest number of cases occurred in the summer months. All 22 infections were found in rhesus D-antigen-positive donations, suggesting a protective factor in donors who lack this antigen. Conclusions These findings contribute to our understanding of risk factors for B19V infection among central European blood and plasma donors.

Objectives: To provide detailed data on the tolerability and safety of octagam (R) 10%, a ready-to-use intravenous immunoglobulin, in a subgroup of patients with immune thrombocytopenia (ITP) involved in an integrated analysis of post-authorisation safety surveillance (PASS) studies. Methods: A subgroup analysis was conducted using data collected from two non-interventional studies that included patients with ITP treated with octagam (R) 10%. Patients were observed and monitored for possible adverse drug reactions (ADRs) during or after administration of octagam (R) 10%, with a particular focus on thromboembolic events (TEEs). ADRs were analysed at the case and event level. Results: In this analysis of 112 patients receiving octagam (R) 10% (mean dose 0.4g/kg/infusion), there were five cases with at least one adverse drug reaction (ADR) associated with 626 infusions of octagam (R) 10% (case incidence of 0.8% per infusion). ADRs were of mild or moderate severity. There were a total of 10 events, most commonly back pain (n=3) and headache (n=2). Nausea, dizziness and a sensation of heaviness were also reported. The remaining two events involved drug exposure during pregnancy. There were no TEEs or other serious ADRs. Discussion: In this subgroup analysis of patients who received octagam (R) 10% (manufactured using an amended process) in two PASS studies, the overall ADR rate was low, with ADRs occurring in only 0.8% of all infusions. No TEEs or other serious ADRs were reported. Conclusions: Routine clinical use of octagam (R) 10% was safe and well tolerated, with no unexpected safety issues, in patients with ITP. The two studies from which data were taken are registered with the International Standard Randomised Controlled Trial Number Registry, numbers ISRCTN58800347 and ISRCTN02245668.

Objective: To evaluate the tolerability and safety of Octagam® 5% and 10% across all indications, ages, and treatment regimens, using data from four non-interventional post-authorization safety studies (PASS); this analysis was performed following changes in the preparation of raw material used to manufacture Octagam. Methods: All four studies included in- and out-patients prescribed Octagam for treatment of their medical condition. Physicians used case report forms to document baseline demographics, Octagam treatment details, and data on the efficacy of Octagam, and recorded all adverse drug reactions (ADRs) and other safety data. Results: Altogether 21,780 infusions of Octagam in 2,397 patients were included in our analysis. The most frequent indication for Octagam was secondary immunodeficiencies (SID; n = 1,368, 11,348 infusions), followed by primary immunodeficiencies (PID; n = 363; 3,923 infusions). During the individual patient observation, 83% of SID and 67% of PID patients were free of any infection. In up to 85% of all investigator assessments, Octagam was rated to have a favorable effect. In autoimmune diseases, investigators assessed Octagam as being beneficial in 70% (immune thrombocytopenia) up to 100% (Guillain-Barré syndrome), depending on the indication. The majority of patients (92%) tolerated Octagam treatment without any ADR. The overall incidence of reported ADRs was 1.0% for all infusions. The majority of ADRs were considered non-serious (93%) and mild or moderate (87%) in severity. No unexpected ADR signal was detected. Conclusions: This analysis demonstrates that the changes in the preparation of raw material used to manufacture Octagam did not affect the safety profile of Octagam® 5% and 10%.

Background OctaplasLG® is a 2nd‐generation virus inactivated pooled plasma for infusion. Prions are removed by the principle of chromatography, utilizing an affinity ligand gel (LG) developed for binding of prion proteins and their infectivity. The goal of this study was to verify, using the gold standard animal bioassay system, whether or not prion infectivity can be removed by the LG affinity step under conditions used in the routine manufacturing process.Materials and methods Aliquots of pooled plasma were spiked with a microsomal/cytosolic (MIC) fraction of brain‐derived hamster‐adapted scrapie 263K and subjected to the OctaplasLG® manufacturing process. Validated Western blot tests and animal bioassays studies were performed to determine the logarithmic reduction factors (RF) and the prion infectivity binding capacity.Results Bioassay studies demonstrated different logarithmic RFs (i.e. 1·73 and 0·76 log10) at two different plasma‐to‐resin ratios, the latter one representing the actual manufacturing ratio of 100:1, which can be explained by the differences in the study design. However, both bioassay studies showed a reproducible and high prion infectivity binding capacity of ≥5·64 log10 ID50/ml gel.Conclusion Bioassay studies confirmed the capacity of the LG to bind brain‐derived MIC prion proteins spiked into plasma. Even through infectivity was still detected following passage over the LG, this can be attributed to the high loads used in the study design, and the binding capacity of the LG still ensures a significant safety margin – binding the prion agents at the levels of prion infectivity that might be present in plasma and beyond.

Background and ObjectivesA new chromatographic step for the selective binding of abnormal prion protein (PrPSc) was developed, and optimization for PrPSc capture was achieved by binding to an affinity ligand attached to synthetic resin particles. This step was implemented into the manufacturing process of the solvent/detergent (S/D)-treated biopharmaceutical quality plasma Octaplas (R) to further improve the safety margin in terms of risk for variant Creutzfeldt-Jakob disease (vCJD) transmission.Materials and MethodsIntermediates and Octaplas (R) final container material, spiked with hamster brain-derived PrPSc-containing fractions, were used for experiments to establish the feasibility of introducing this novel chromatography step. The binding capacity per millilitre of ligand gel was determined under the selected manufacturing conditions. In addition, the specificity of the ligand gel to bind PrPSc from human sources was investigated. A validated Western blot test was used for the identification and quantification of PrPSc.ResultsA reduction factor of >= 3 center dot 0 log(10) could be demonstrated by Western blotting, utilizing the relevant Octaplas (R) matrix from manufacturing. In this particular cell-free plasma solution, the PrPSc binding capacity of the selected gel was very high (>= 6 log(10) ID(50)/ml, equivalent to roughly 10 log(10) ID(50)/column at manufacturing scale). The gel binds specifically PrPSc from both animal (hamster and mouse) and human (sporadic and variant CJD) sources.ConclusionThis new single-use, disposable PrPSc-harvesting gel ensures a very high capacity in terms of removing the pathogenic agent causing vCJD from the new generation OctaplasLG (R), in the event that prions can be found in plasma from donors incubating the disease and thereby contaminating the raw material plasma used for manufacturing.

Background and ObjectivesA new chromatographic step for the selective binding of pathological prion proteins (PrPSc) to an affinity ligand, developed and optimized for PrPSc capture and attached to synthetic resin particles (PRDT, USA; ProMetic BioSciences Ltd, Isle of Man, UK) was implemented into the manufacturing process of the solvent/detergent (S/D) treated biopharmaceutical quality plasma Octaplas (R).Materials and MethodsPilot batches of Octaplas (R) with the implemented chromatographic step [labelled as OctaplasLG (R) (ligand gel)] were manufactured by Octapharma PPGmbH, Vienna, Austria. The biochemical quality was compared directly after manufacturing as well as after 18 months storage. All samples were tested on global coagulation parameters, fibrinogen levels, activities of coagulation factors and protease inhibitors, ADAMTS13 levels, as well as markers of activated coagulation and fibrinolysis. In addition, von Willebrand factor multimeric analysis was performed.ResultsThe incorporation of this novel chromatography into the large-scale routine manufacturing process was shown to be technically feasible and the performance of the column was assessed to be excellent. The biochemical studies showed that Octaplas (R) and OctaplasLG (R) produced without and with the new column, respectively, demonstrate an identical biochemical quality. OctaplasLG (R) remained stable over a period of 18 months stored frozen. A parallel reduction of the S/D virus inactivation step from 4-4 center dot 5 to 1-1 center dot 5 h led to significantly higher activities of plasmin inhibitor.ConclusionThe studies confirmed that the affinity ligand chromatography under the developed conditions can be introduced into the Octaplas (R) manufacturing process, as a mean to reduce potentially present PrPSc, without hampering the proven quality of this product.

Reports about transfusion-related transmissions of variant Creutzfeldt-Jakob disease have urged the need for more information regarding the risk for prion contaminated units in the blood supply and the safety of transfusion plasma and biopharmaceuticals derived from this precious raw material. According to a possible epidemiological model, the risk in many European countries is the same or lower than that of human immunodeficiency virus. Comprehensive investigations have shown that the prion safety margin of both single-donor and pooled solvent/detergent treated transfusion plasma is high. Furthermore, prophylactic treatment using plasma-derivatives poses a very low risk in terms of prion disease despite extensive lifetime exposure.

Background and Objectives The most common way to thaw frozen coagulation‐active plasma products for transfusion is the use of a water bath with good circulation at 30–37 °C. The aim of this study was to perform an extensive biochemical characterization of the pharmaceutically licenced solvent/detergent‐treated plasma, Octaplas®, thawed using the SAHARA‐III dry tempering system from the company Sarstedt GmbH, Austria. A regular water bath was used in parallel for comparison.Materials and Methods Six batches Octaplas® with different blood groups were thawed in a water bath or using the SAHARA‐III dry tempering system in parallel. Thawed plasma was investigated on screening tests for blood coagulation, as well as on the activities of important coagulation factors and protease inhibitors. In addition, markers of activated coagulation and fibrinolysis were tested and von Willebrand factor multimeric analysis was performed.Results There were neither significant differences in the blood coagulation parameters, coagulation factors, protease inhibitors, nor of markers of activated coagulation and fibrinolysis when Octaplas® thawed by the two different methods was tested. The von Willebrand factor analyses showed no influence on the overall profile of the multimeric pattern when using the SAHARA‐III dry tempering system.Conclusion Octaplas® can be thawed using the SAHARA‐III dry tempering system without any negative influences on the demonstrated quality of this product. The SAHARA‐III dry tempering system enables standardized thawing and warming procedure. Furthermore, tempering of Octaplas® in the emergency unit or operating theatre, where no water baths can be utilized, is safe and can be fully endorsed.