The top trends for plasma protein manufacturing are driven by a need to meet greater global demand in the face of a plasma shortage.
Global demand for plasma-derived therapies continues to expand due to an aging population, clinical successes, and recent applications for both widespread diseases and many rare conditions. On the flip side, the pandemic caused a 20% decrease in plasma donations in 2020 and 2021. A plasma shortage paired with increased need has manufacturers struggling to meet the demand. In response, the plasma industry is exploring ways to reduce fractionation scale, adopting new technologies, and employing more automation to increase efficiency and reduce the costs of plasma fractionation. In this article, we explore all these current- and future-state plasma-derived therapy manufacturing trends.
The current state of plasma-derived therapies:
- Growing demand for plasma-derived therapies
- Plasma shortage worldwide
Future trends of plasma-derived therapies:
- Regional self-sufficiency
- Small-scale fractionation
- Novel technologies in plasma fractionation
- Automation of plasma facilities
Before getting into these trends, let’s start with a short plasma refresher:
Plasma 101: How are plasma-derived therapies manufactured?
Each plasma protein—there are more than 4,000 proteins in human blood plasma—has an important physiological function and potential therapeutic benefit. Of those thousands of proteins, roughly 20 are currently isolated from plasma and manufactured into concentrated plasma protein therapies with a wide variety of clinical indications.
Plasma-derived therapies protect patients with immune deficiencies against pathogens and treat common neurological diseases, autoimmune disorders, and less common indications, such as bleeding disorders, chronic obstructive pulmonary disease (COPD), and treatment of shock in emergency rooms.
Manufacturers start with donated plasma pooled from thousands of donors. Desirable plasma proteins are isolated from plasma pools through a process known as fractionation, which involves altering the plasma’s physical and/or chemical properties. This causes the desired proteins to precipitate and allows them to be separated by mechanical methods, such as centrifugation or filtration. The fractionation process results in several process intermediates known as fractions, with each fraction containing a specific subset of plasma proteins. Variation in the fractionation process results in different quantities of fractions and mixtures of proteins within each fraction.
Plasma fractions undergo additional downstream processing to further isolate and purify the target plasma protein, followed by an aseptic filling process that puts the therapeutic protein product into its final state for delivery into the patient.
1. The demand for plasma proteins continues to grow
The global demand for plasma-derived therapies, particularly immunoglobulin G (IgG), continues to increase.
Healthcare professionals are unlocking new potential for IgG therapy
The treatment of primary immune deficiency has always been a leading contributor to global IgG demand. While demand has steadily grown year over year due to increased awareness and better diagnosis, much of the recent growth in IgG demand is due to newly identified indications for IgG therapy. Today, a significant portion of IgG usage is in specialties outside of immunology, such as neurology, hematology, oncology, and rheumatology.
Among those, neurology is the fastest growing specialty largely due to its approved on-label use for chronic inflammatory demyelinating polyneuropathy (CIDP). Following closely behind is the off-label use in secondary immune deficiency as a side effect of immunosuppressive diseases, such as lymphoma, myeloma, and leukemia, and immunosuppressive therapies that include the growing range of B-cell targeting therapies. The wide range of IgG usage and indications, both on-label and off-label, will continue to expand and drive IgG demand, especially as the population increases.
Convalescent plasma and H-Ig for infectious diseases
Convalescent plasma is donor plasma that contains relatively high titers of antibodies against an infectious disease. Convalescent plasma can be infused directly into a patient who is actively fighting a disease (convalescent plasma therapy). Alternatively, it can be pooled, fractionated, and purified to create concentrated doses of the antibody of interest, producing hyperimmune globulin (H-Ig).
The use of convalescent plasma and H-Ig is not new, but it has experienced renewed focus in light of the COVID-19 pandemic since it can serve as a first line of defense in an emerging disease when a vaccine is not available. Early on, there were high hopes that convalescent plasma or H-Ig from recovered COVID-19 patients could treat the newly infected. However, the US National Institutes of Health found insufficient data to recommend for or against the use of hyperimmune therapy and the World Health Organization advised against using it to treat COVID-19. Despite the limited success of H-Ig for COVID-19, H-Ig could still play an important role in future pandemics. Efforts to produce H-Ig for COVID-19 led to an unprecedented collaboration between major players in the plasma industry—a trend that, should it continue, could help us tackle other major challenges.
Subcutaneous Ig (SCIG) usage is growing
Historically, most patients received Ig therapies through intravenous Ig (IVIG) at a hospital or clinic. In contrast, subcutaneous Ig (SCIG) therapies can typically be administered at home by the patient at their own convenience. Social distancing practices during the COVID-19 pandemic have led many IVIG patients to opt for SCIG administration of their therapy. In addition to the convenience and safety of at-home administration, SCIG has been shown to be less likely to cause adverse drug reactions than IVIG. SCIG use is expected to continue to grow at a faster rate than IVIG, and manufacturers are starting to ramp up their SCIG production.
2. Plasma shortage continues to be a problem
Prior to the COVID-19 pandemic, global plasma collection volumes were steadily increasing year over year. Even this steadily increasing plasma supply was not enough to keep up with the product demand, especially for Ig therapies. The pandemic greatly reduced plasma donations and further compounded product supply deficiencies.
Manufacturers anticipate the return of plasma donations to pre-pandemic levels and beyond as COVID-19 restrictions subside. Until the plasma shortage is behind us, the industry is focused on minimizing plasma waste and maximizing product yields.
The plasma shortage is a main contributor to many of the following trends.
3. Regional self-sufficiency of plasma is on the rise
The US is the primary supplier of plasma and plasma-derived drug products to the world with plasma sourced solely from US donors. Almost every other country manufacturing plasma-derived therapies relies on importing plasma, plasma fractions, and plasma drug products from the US. While those countries have always wanted to eliminate their US plasma dependence, the current plasma shortage is causing renewed scrutiny. Outdated policies with restrictions on plasma collection are also going under the microscope.
In 2021, the UK lifted the ban on domestic blood plasma for clinical use—brought in two decades ago in response to mad cow disease (BSE, or bovine spongiform encephalopathy). This policy change boosted the UK’s annual plasma collection volume, supporting greater plasma-derived product manufacturing potential for local patient needs. Germany, Austria, Hungary, and the Czech Republic account for 40% of plasma collection for fractionation in the rest of Europe. There is an on-going revision to the EU Blood, Tissues, and Cells (BTC) legislation that many hope will lead to other countries ramping up plasma collection and fractionation.
While policy change may open the door, developing a domestic supply of plasma and manufacturing capacity for plasma products can’t be done with the flip of a switch. Here are some of the hurdles to clear before we can sufficiently fight the plasma shortage and attain regionally reliable inventories of plasma:
Plasma collection for fractionation is logistically and technically complex
Any country wanting to collect its own plasma needs a national regulatory body capable of overseeing the regulatory and safety compliance of its collection centers and logistics providers in keeping with the strict international guidelines and regulations for plasma for fractionation. Coupled with the significant financial investment needed to build and staff collection centers, this becomes a substantial burden, particularly for low- and middle-income countries.
Plasma storage and transport rely on cold chain management
Maintaining low temperatures during plasma fractionation is essential for plasma-derived products’ yield, safety, and effectiveness. From the time plasma is first collected and frozen, it must be fully traceable and monitored for any temperature variations. This adds complexity and cost to the overall plasma collection and manufacturing infrastructure.
Plasma fractionation facilities are complex and expensive to design and build
The large volume of a traditional batch process inherently leads to large, complex, and expensive stainless steel equipment and piping systems. Common fractionation methods use large quantities of flammable liquids, carrying unique building code requirements, and add to construction costs. While manufacturers can minimize some of these challenges with smart approaches in design and construction, a domestic fractionation facility will still come with a significant capital cost.
Plasma fractionation facilities require a large, qualified labor force
Safe and efficient operations of these large-scale facilities, and their production of safe for consumption products, requires a large, experienced team of well-trained staff. It also requires a robust framework and team dedicated to quality assurance and control.
The capital expenditure associated with designing and building a fractionation facility is arguably the most difficult of these challenges to overcome. Ultimately, this is driving the industry to take a closer look at novel plasma fractionation methods and facility design.
4. The need for small-scale plasma fractionation
Small-scale fractionation processes are an option for countries that can’t collect large volumes of plasma to support traditional approaches.
Small-scale fractionation with flexible batch sizes reduces strain on plasma collection
A fractionation facility designed to not only process smaller volumes of plasma, but also to have the flexibility to process a range of starting batch volumes, reduces the strain on less mature plasma collection infrastructures that may be more prone to volatile plasma collection volumes throughout the year.
Small-scale fractionation reduces facility capital cost
Small-scale fractionation reduces the size of process equipment, and in turn, reduces the size of the facility that must house the process. This leads to a lower capital investment; however, this is not a linear function. In other words, reducing the process scale by 50% does not result in a facility with 50% less capital or operational cost.
Small-scale fractionation simplifies design and construction
The large-scale traditional fractionation and purification processes can contribute to a high degree of customization in process equipment and supporting utility equipment. Reducing the scale of the process can make it easier to utilize standard, off-the-shelf equipment that is cheaper and more readily available. Simplifying the process design can also simplify facility construction and open the door to modular construction, potentially accelerating the deployment of fractionation facilities.
Small-scale plasma fractionation avoids large volumes of ethanol
Building code requirements vary depending on the quantity of flammable and hazardous materials stored within the facility. Small-scale fractionation could reduce the amount of flammable material like ethanol below the threshold that triggers more stringent building codes, which ultimately reduces facility cost and complexity. But operating below that threshold reduces the potential scale of the fractionation process, which limits the patient population served. This smaller-scale still might be feasible in a remote part of the world. This could allow, for example, fractionation of small pools of convalescent plasma during the early outbreak of an infectious disease.
Single-use equipment fits nicely with small-scale plasma fractionation
It’s unlikely that ethanol fractionation processes would ever transition completely to single-use equipment; traditional large-scale fractionation puts it outside the range of most single-use equipment. Standard single-use equipment also fails to meet code requirements for the handling of flammable liquids. However, small-scale fractionation starts to open the door for more single-use applications. The process volumes start to fall within the range of standard equipment. In some cases where ethanol is handled, simple modifications–such as placing a single-use bag into a modified stainless-steel drum so spills are completely contained–can reduce cost and complexity.
Going small scale can help reduce the burden of capital cost for a new fractionation facility, though this ultimately comes at the expense of overall facility throughput. New approaches to fractionation and purification could play a key role in reducing facility complexity while maintaining efficiency.
5. Novel technologies are emerging in plasma
While traditional batch ethanol fractionation processes continue to dominate plasma-derived therapy manufacturing as they have for decades now, the industry is also exploring alternative manufacturing technologies to improve the efficiency of fractionation facilities. Here are a few examples of novel manufacturing technologies that could change the plasma manufacturing landscape in the coming years:
Flammable material-free fractionation
As discussed in previous sections, the use of ethanol as a precipitation agent carries several unique design considerations that ultimately increase the cost and complexity of the facility and process design. Removing ethanol can open up other possibilities, such as a small-scale fractionation process done completely in single-use equipment for quick and efficient deployment in nearly any part of the world.
Continuous manufacturing is a trend that is not unique to plasma-derived therapies, and is of great interest in many biopharmaceutical processes. Applying elements of continuous manufacturing to plasma fractionation could be key to reducing process and facility scale without sacrificing throughput capacity and economic efficiency.
6. Automation is a key element to future plasma facilities
As we see throughout the biopharma industry, manufacturers are looking for ways to automate manufacturing processes as much as possible and remove manual intervention from operating personnel. Manual intervention is often a safety hazard for operators and can introduce errors that ultimately impact product quality and yield.
Increased automation is a trend that will likely appear in future plasma fractionation and purification facilities. Some plasma manufacturers are still using equipment technologies that are decades old, such as solid bowl centrifuges and plate and frame filter presses that must be manually harvested and cleaned. Equipment manufacturers are developing improved systems that automate some or all of the harvesting and cleaning operations. Transfer panels in process piping systems have also been a mainstay in many plasma and biopharmaceutical facilities. Still, the frequency of errors and safety incidents attributed to transfer panels is leading some manufacturers to remove them completely, replacing them with automated valve systems.
Your plasma manufacturing horizon
The plasma industry is experiencing a new level of disruption from the plasma shortage, market demand and industry innovation. In fact, the constraints of rising demand and dwindling supply are forcing manufacturers to expand their horizons. If you’re designing a new plasma fractionation facility or updating an existing one in response to these trends, CRB’s plasma experts understand your engineering needs and can help guide the way.
Curious about how to adopt new plasma-derived therapy manufacturing practices within your facility? Let’s talk.