Human blood plays a crucial role not only in transfusions, but also as a component of specific medicines. So-called plasma derivatives, which are obtained from human blood, support the treatment of various diseases—from hemophilia and antigen defects to Covid-19. The products are in high demand and their manufacture involves complex processes. Precision throughout the value chain helps ensure that patients get the most out of every drop.

The market for blood plasma derivatives is growing steadily. This high demand is, among others, driven by advances in medical technology. More and more compounds can be produced recombinantly, i.e., through genetic engineering, and no longer require donated plasma. Technologies for fractionation—splitting plasma into its components—have also evolved, resulting in higher yields of valuable proteins such as albumin, immunoglobulins, and coagulation factors. In parallel, blood coagulation disorders, rare genetic defects, and immune diseases are on the rise worldwide, increasing the demand for plasma derivatives.

Before plasma can be transformed into safe and effective medicines, the raw material must go through several stages of processing. Manufacturers normally receive donated raw plasma in frozen form. It is then thawed, fractionated, purified, formulated, filled or freeze-dried, inspected, and in some cases pasteurized. Due to the complex nature of production and the limited availability of human plasma, pharmaceutical producers must ensure precise and reliable processes. Plasma loss is not only costly; it also means wasted therapeutic opportunities. In addition to high yields, flexible processes that deliver safe, high-quality products are paramount.

Thawing and fractionation

The frozen plasma that pharmaceutical manufacturers process is shipped in large bags or bottles containing donor material from several sources. Before fractionation, the raw plasma must be thawed gradually to avoid harming the temperature-sensitive proteins. This is done in specialized systems with mixing tools that exert low shear forces on the material and gradually raise the temperature. After thawing, the raw material is ready for fractionation, i.e., split into components such as albumin, immunoglobulins, and fibrinogens, which are among the coagulation factors. The fractionated plasma then undergoes several filtration steps that separate the target molecules according to size, electrical charge, and chemical affinity.

This highly complex step requires equipment that offers efficient and stable large-scale fractionation. All-in-one solutions from a single source form the basis for a seamlessly integrated, fully automated system infrastructure with continuous monitoring of critical parameters. Each extracted fraction must be stored and purified separately. Impurities and viruses are degraded chemically or using heat, while the concentration of each future active ingredient is increased. Various excipients including stabilizers are added to the fractions during formulation, while stabilizers ensure that the fractions remain effective throughout the subsequent process. A robust infrastructure for pure media complements these steps and enables a reliable supply of pure steam and purified or highly purified water.

Precise and gentle dosing

Plasma derivatives are mainly filled in glass vials of varying volumes, typically ranging from 2 to 500 milliliters, which are used for liquid and freeze-dried products alike. The demand for flexible filling systems that can accommodate different vial sizes and deliver precise filling volumes is high. Modern technologies rely on multi-stage filling and weighing processes to achieve high filling accuracy even with fast changeovers.

Peristaltic pumps, which are particularly suitable for shear-sensitive proteins such as coagulation factors, are first used to fill 95 percent of the product. The remaining 5 percent is filled in a second step—with a smaller filling needle and within more narrow tolerance limits. This main dosing and subsequent dosing make it possible to determine the optimal filling weight with 100 percent in-process control (IPC) and to achieve precisely dosed plasma derivatives. Moreover, advanced filling systems can avoid underfilled vials. If the weighing process reveals that certain containers do not yet hold the required amount of product, the filling needles swing to the corresponding containers to top them off.

Ensuring optimum aseptic conditions

Sensitive plasma derivatives are typically filled in isolators or RABS to ensure their safety. Both approaches to separate operating personnel and products have become even more important considering the revised version of EU GMP Annex 1. In terms of aseptic production, Annex 1 explicitly recommends both technologies in combination with a higher degree of automation to increase the quality of medicinal products. This includes effective bio-decontamination prior to the actual filling process.

Isolator systems from leading manufacturers use vaporized hydrogen peroxide (H2O2) as part of a multi-stage process that includes preparation, conditioning, and aeration in addition to bio-decontamination. The goal is six-log reduction of the biological indicator organism. The residual concentration should be less than 1 ppm (part per million), as proteins react sensitively to vaporized hydrogen peroxide; residual concentrations lower than 1 ppm can also be achieved.

Freeze-drying and inspection

Freeze-drying of plasma derivatives is characterized by long processing times. This alternative to the liquid dosage form has become the preferred method for preserving sensitive coagulation factors. Cycle times of several days are a common requirement for this production step, which makes it all the more important to ensure safe, monitored processes. Systems with redundant and high-quality components support fail-safe production. Modern freeze-dryers also rely on sophisticated, state-of-the-art sensor technology to keep key process parameters such as temperature and pressure stable. Advanced systems with optimized secondary processes such as CIP, SIP, filter sterilization, and WIT can save energy, time, and media.

Freeze-drying is followed by another important step: the visual inspection of liquid or lyophilized products, checking for the presence of particles and cosmetic defects, and container closure integrity testing (CCIT). State-of-the-art inspection systems efficiently combine the two processes on a single platform. Leak testing for lyophilized products is carried out using headspace analysis (HSA).

Pasteurization within a narrow temperature range

Some products require pasteurization, during which they are processed as gently as possible in tightly sealed containers and within strict temperature limits. As a rule, plasma derivatives are pasteurized at 60 degrees Celsius (140 degrees Fahrenheit), with deviations of only half a degree (approx. 32 Fahrenheit) permitted over a period of up to twelve hours. In addition to flow-optimized pasteurizers with corresponding baffles, suitable processes are key to maintaining the right temperature. The steam-air mixture principle provides a homogeneous flow through the pasteurizer by ensuring consistent conditions over extended processing times and within a narrow temperature range.

The ideal system configuration can be determined by simulating the process and comparing it with real values, an aspect that makes equipment manufacturers’ process expertise particularly important. These manufacturers involve customers in the analysis and design at an early stage. The same applies to the entire process: by working together closely from the outset, pharmaceutical companies and equipment manufacturers can define and implement optimum systems for precise processes throughout the value chain—so that patients gain the most from every drop of the precious plasma derivatives.

Sarah Springer is the global product manager for vials, ampoules and filling systems at Syntegon Technology, a supplier of process technology and packaging solutions for the pharmaceutical industry. She can be reached at sarah.springer@syntegon.com.