The global biologics market is on track to grow from $382 billion in 2022 to $417 billion by the end of this year and is expected to reach $599.62 billion by the end of 2027.
In addition to a renewed focus on vaccines driven by the pandemic, many pharmaceutical companies are turning their attention to developing a new generation of biopharmaceutical therapies to treat rare and orphan diseases. More than 700 medicines were in the 2021 rare diseases development pipeline, accounting for 31% of all treatments in development. Many of these rare disease therapies harness innovative biopharma technologies, such as cell and gene therapy.
Taking it all into account, it is no surprise that increasing numbers of pharmaceutical companies are seeking to harness the benefits of biologics in their own development. Nor is it surprising that a growing number of contract development and manufacturing organizations (CDMOs) are investing in their manufacturing capacity to support commercial production of biopharmaceuticals.
However, the manufacture of biologic treatments poses containment and product purity challenges, due to the number of processes requiring fluid management. Fluids present a different array of problems compared with dry powders that add complexity to both containment and quality protocols. Failure to consider these can result in breaches that impact on worker health, or issues that undermine the safety and efficacy of the final product.
Carefully selecting the right liquid processing equipment is key to addressing these manufacturing issues while optimizing production line efficiency.
Overcoming liquid processing issues
Liquid — or fluid — processing and management is an essential feature of most biopharmaceutical production lines. Biologics often require purified water and other liquid processing due to the media used to culture the active molecules. Harsh liquids can also be used as solvents or raw materials in the manufacturing process for many excipients used in biological formulations.
A number of key procedures within biopharma production are commonly grouped under the heading of fluid management. These include the processing of liquids and other ingredients in mixers, their storage in containers for later use, or even the transfer of liquid material from one process to another in dedicated bottles or other vessels. The fluids involved can come in a variety of forms, from purified water to a high salt content buffer solution, to reactive hydrochloric and sulphuric acid, and high-pH alkalis.
The presence of fluids in the production process — regardless of their nature — poses specific efficiency, safety, and product quality issues that need to be addressed. The choice of the right transfer tote, storing or freezing cart, mixing vessels, and other components is not an easy task. Ensuring the right connections between equipment can hold the key to effective liquid processing.
Understanding the issues
Whatever the nature of the liquids being used in the process — even pH neutral purified water is reactive — it is vital that they are compatible with key manufacturing infrastructure they can come into direct contact with, and with the vessels used to transfer or store them in particular.
Manufacturers must carefully consider how the fluid will interact with any production system or component. Standard stainless steel vessels — and the accompanying seals connecting them with surrounding equipment — may react with the acid or alkali, pitting, corroding, or dissolving over time. This has a number of implications:
- Containment for worker safety: Containment is a key component of effective fluid management on any biopharmaceutical production line, regardless of the liquid in question or the stage in the manufacturing process. Containment breach of common biological actives, such as hormones, can pose a threat to the health and wellbeing of line operatives working in the vicinity. Harsh fluids and solvents used in the production of excipients for biological formulations can also cause serious injury to team members if they leak from production line equipment. In both scenarios, there are serious legal and financial ramifications resulting from regulatory non-compliance. If line components are incompatible with the fluids they are handling, they may weaken or become brittle over time, increasing the risk of breaches.
- Sterile integrity for patient health: Biopharma treatments are particularly reliant on sterile processing for a key reason. These therapies are most often administered parenterally to patients, which means that additional steps must be taken to ensure the drugs and the packaging and devices they come in remain sterile and safe for patients to use. Terminal sterilizsation using x-ray or gamma radiation — commonly used in manufacturing small-molecule formulations — is rarely an option for biologics. This is because the process of irradiating the formulation can damage the active molecules, negatively impacting on the efficacy of the finished formulation. Using aseptic processing throughout the fluid management and wider manufacturing process, through the use of cleanrooms and isolator equipment, is key to preventing microbial ingress and contamination.
- Impact of high component replacement frequency on production output: If line equipment, such as storage or transfer vessels, is incompatible with the fluids being processed, it may be necessary to replace it more often to maintain containment as well as sterile integrity. This can increase the processing downtime needed to remove worn parts and install new equipment, which can negatively impact on the productivity of the site, and on profit margins.
- Quality and purity of the end product: If the fluids being processed are incompatible with the surrounding equipment, compounds can leach out from the containers to contaminate material downstream. This could have ramifications for the efficacy of the finished product, or even for patient safety. It is possible to filter out chemical contaminants from drug formulations prior to finishing, but this is an additional step with cost and time implications.
The right equipment key to fluid management issues
Taking this into account, manufacturers — whether drug companies themselves or their CDMO partners — need to find equipment solutions to ensure effective liquid processing. Increasing the maintenance frequency for mixing, storage, and transport of vessels on a line, or adding in filtration steps downstream is becoming less and less desirable. All these actions reduce manufacturing efficiency, making it harder for companies to succeed in a fast-growing and competitive market. Selecting the right components for the fluid being handled can remove the need for adding costly and time-consuming processes.
Companies can explore a number of equipment options to help achieve efficiency goals, particularly when it comes to liquid mixing, transfer, and storage vessels. For example, they can opt for vessels made of super-alloys that are chemically inert in the presence of many liquids used in biopharma processing — not just acids and alkalis, but also purified water. However, they can be very expensive to source, with long lead times for delivery that can delay installation timelines.
It is possible to source specialist plastic mixing, transfer, and storage vessels for liquids, which offer the same performance as those made of super-alloys, but are more cost effective, with shorter delivery lead times. Vessels made using USP Class VI polypropylene are particularly useful for liquid processing throughout the biopharmaceutical production process.
These vessels are chemically inert, so they do not react with the fluids they are intended to handle, and therefore don’t weaken and break down prematurely. They can be used for an extended time, which lowers maintenance downtime, reduces costs, and optimizes productivity. They ensure effective containment and sterile integrity by preventing egress of fluid or ingress of microbial contamination. Their USP classification, meanwhile, means that they pose no leachable risk, so no contaminants affect product purity, eliminating any quality fears or the need for additional filtration steps.
Pharmaceutical manufacturers can source turn-key USP-certified plastic solutions, but working with suppliers with experience in designing custom-made mixing, transfer, and storage vessels can ensure that any new equipment is perfectly suited to the line’s unique needs. For example, particularly on bioprocessing lines, where sterile environments are of paramount importance, vessels can be designed to integrate seamlessly with existing cleanroom or isolator equipment. They can also optimize efficiency during washdown procedures, minimising unnecessary downtime and maximizing the effectiveness of the cleaning.
For added worker protection, vessels can be customized to integrate seamlessly with existing equipment to minimize risk of containment breaches at the connectors. Secondary vessels can be designed to fit beneath primary containers as an emergency safeguard against overspill, protecting workers in the vicinity.
In addition, it is possible to customize these components to address the scalability needs of a production line. Companies can source 10-20 liter mixers, containers and transfer bottles for low-volume production or they can opt for process tanks and storage vessels capable of holding tens of thousands of litres liters for large-scale commercial manufacturing. Whatever the requirements of the biopharmaceutical project, expert suppliers can provide tailor-made vessels quickly so that any line upgrade runs smoothly and efficiently.
Partnering to meet goals
From the complexities of synthesizsing the actives — whether proteins or complete cells — to logistical issues of getting these treatments to patients within often narrow timeframes, there are multiple factors that need to be considered in biopharmaceutical production. Nevertheless, effective fluid management is vital to ensure treatments are manufactured to the highest possible standards while maintaining optimum production efficiency, all while safeguarding employees.
The right infrastructure is essential to achieve these goals, but to find the ideal solutions for the needs of the line and the product, manufacturers must work with expert equipment partners. With this specialist support, they can be confident that they have the guidance required to address issues associated with processing fluids used in biologics production. This can help companies meet efficiency and workplace safety targets, all while delivering great quality treatments for patients.