Lifting the Lid on Biopharmaceutical Manufacturing: Unlocking New Possibilities in Media and Buffer Preparation

Guy Matthews, Market Development, Single Use Technology, FUJIFILM Biosciences

Synopsis

The biopharmaceutical industry faces ongoing pressure to deliver new therapies to patients as quickly and efficiently as possible. To accomplish this, manufacturers need to develop and optimize cost-effective production processes without compromising quality or safety. Many resources have been invested into the optimization of both upstream and downstream processes to increase efficiency and lower costs of production, but one area that has been overlooked is dry powder media and buffer preparation.

While the preparation and use of media and feeds has remained largely unchanged, to improve the approach to buffer use, many manufacturers are embracing automation and single-use in the form of inline dilution or inline conditioning. Even with this technology shift, there is still a requirement to hydrate powders to produce liquid feedstocks. Conventional hydration processes are labor intensive, time consuming, and a known source of process variation. This article provides an overview of the current state of the industry, and reviews new technologies that are helping to transform the efficiency of this crucial aspect of biopharmaceutical manufacturing.

Introduction

It is no secret that biopharmaceuticals hold the potential to address some of the biggest health concerns of the modern age. Since the first monoclonal antibody (mAb) was developed in 1975¹, the idea of using the body’s own defense mechanisms to combat disease has gone from strength to strength, with the emergence of innovative new modalities including recombinant vaccines and cell and gene therapies. Estimated at a value of $263B as of 2022², the biopharmaceuticals industry is now firmly established as a major player in the global pharmaceutical market to address these concerns.

The production of therapeutics in a biological process can be subject to product variation in both yield and quality unless rigorously controlled. Removing process input variation is therefore an important first step to minimizing the variation in the output and creating efficient production processes. A large amount of time and resources have been put into cell line optimization, bioreactor configuration and control, chromatography and other downstream processes to optimize production. Some areas that have been overlooked are the supporting processes – such as the preparation of media and buffers. With conventional hydration methods we see variation in inputs so it should not be unexpected that the process gives variable outputs. Here, we explore the current state of this supporting but essential part of the bioprocessing industry, and the new strategies that hold the potential to unlock new possibilities for efficient production.

Media Formulation – The Key to Optimized Manufacture?

Cell culture medium is an integral part of biopharmaceutical manufacturing, and identifying the correct formulation is essential to ensuring an efficient, repeatable, and scalable process. Over the years, many high-performance media have been developed and are available off-the-shelf. As our understanding of how different media components impact different cells has expanded, the cell culture media market has made significant strides to develop tailored formulations – offering higher yields, less waste and, most importantly, more consistent results in terms of cell growth, yield, and product quality.

A strategic industry move to chemically defined media, arguably one of the most significant developments in the cell culture space seen in recent years, has supported this process. By eliminating the need for undefined supplements such as hydrolysates, the consistency of the media and the performance of cell lines have improved.

By moving to chemically defined formulations, media developers have gained the ability to optimize every component of a medium formulation, including trace elements. Consequently, easier access to consistent and high-quality platform media formulations provide therapeutic developers a streamlined route to manufacturing and producing therapies that meet regulatory requirements, while being produced in a cost and time efficient process.

What is the next step for the cell culture media market, and how do we continue to innovate and enhance the development and manufacture of new biopharmaceuticals? To answer that, we need to look to the tools and techniques that underpin the manufacturing process.

Liquid vs. Dry Media

Choosing between liquid and dry media formulations has been a key decision for drug developers and manufacturers for many years, with each having distinct advantages and specific use cases. Typically, a dry formulation is favored where large volumes of media are required, for example in the manufacture of biopharmaceuticals for commercial use. In these cases, dry media offer several important benefits, most notably in transport. Removing water from the product offers significant reductions in weight, improving handling ergonomics and reducing the costs associated with shipping. In addition, dry media are more temperature stable and do not usually require the strict environmental and handling controls needed to preserve liquid media. Similarly, dry formulations offer dramatic improvements to shelf life, making it feasible for companies (provided they have the facilities available) to purchase and store large quantities of media, essentially alleviating any risk of supply chain interruptions or the challenge of dealing with any unexpected changes in demand.

That is not to say that dry media formulations are not without their challenges. Being a typically hydroscopic powder, dry media are inherently susceptible to moisture, meaning they must be carefully packaged and have processes in place to ensure the powder is properly stored and quality maintained. Liquid media are favored when only small amounts are required, such as for personalized therapies like cell and gene therapies, or for drugs earlier in the development pipeline. In these cases, the resources associated with rehydrating and preparing dry media make them less viable when compared to liquid media, particularly as long-term storage is not usually a concern.

Drug developers are looking to reduce expenditure wherever possible, particularly given continuing temperamental market conditions and a maturing marketplace with the advent of the “patent cliff” and biosimilars on the horizon. Dry media formulations present an attractive, cost-saving solution, yet one that is sometimes hindered by the resource requirements for media preparation. In these cases, innovations in automation, and single-use technologies (SUTs)—techniques that have already proven revolutionary in other unit operations within bioproduction—may hold the key.

Technologies Driving Change

By now, most industries and processes have embraced the power of automation to optimize and standardize labor-intensive processes. Automating media hydration can help overcome many of the obstacles presented by dry media, producing a more consistent product faster and enabling users to prepare media on-demand and in precisely controlled amounts, reliably from beginning to end. Automation provides a clear route to efficient, high quality, and, more importantly, scalable, method of powder hydration.

One of the major benefits of automating media hydration comes from the substantial reduction in labor requirements. Aside from the obvious benefits of reducing costs, automation can also lead to notable increases in productivity—enabling operators to focus on more impactful work rather than media preparation tasks. Reducing the amount of manual handling required can also enhance environmental health and safety factors, improve space efficiency and equipment utilization, and make on-site media preparation more consistent, safer and more efficient throughout the process.

Innovations in SUTs continue to drive progress in the bioprocessing industry, and vice versa. For media preparation specifically, SUTs enable users to focus on process development knowing that the inputs into that process are consistent. Refining the process is futile if you cannot recreate the process with optimal conditions (media / feed / buffer make up), from the lab into the development suite and finally onto the production floor. The use of automation also helps to address manufacturing’s sustainability footprint and any related issues. It is well established that SUT can reduce the environmental impact of biomanufacturing, by reducing water, electrical power, and chemical use. It is also worth noting that if by utilizing a more efficient and consistent process, a facility can move from producing 25 batches a year to 27 or 28, those two or three extra batches can also help to reduce the overall carbon footprint of a manufacturing facility. Additionally, several initiatives are already in place to offset plastic waste management, including using waste materials for energy generation, or recycling waste into usable materials, for example so-called ‘plastic lumber’. Structurally designed sustainability procedures all contribute to minimizing environmental impacts while enhancing access to life saving drugs and vaccines to a wider patient population.

Conclusion

Dry powder remains the leading physical format for cell culture media used in biopharmaceutical production. Developing a method to prepare dry media quickly and consistently is critical to ensuring repeatable and robust results in terms of cell growth, yield, and product quality. As the industry looks for ways to continuously optimize the development and production of biopharmaceuticals, introducing automation to address the shortfalls of hydrating dry powder is a logical step to pursue.

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