Streamlining Buffer Management To Enable Facility Flexibility

By Jeffrey Johnson, New Technology Lead, Merck & Co., Inc., Kenilworth, NJ, USA and Andrew Carass, Associate Director, Technology Management, MilliporeSigma

The last decade in biopharmaceutical manufacturing has brought a considerable amount of change to how drugs are developed and manufactured. Advances in science and technology have resulted in more diversified pipelines with increasingly complex molecules. Seeking faster ways to bring novel drugs to market while meeting stringent product quality requirements, biomanufacturers have become progressively more focused on process intensification. Innovation in areas such as process analytical technology (PAT), single-use technology, and R&D has led to improved productivity and efficiency, resulting in higher titers from the bioreactor and ultimately transforming the future of biopharmaceutical development and manufacturing.

As the industry drives toward increased throughput from modernized facilities, challenges are growing utilizing the legacy systems and processes traditionally used to produce therapeutic proteins. One area specifically is the preparation and delivery of buffers, which are necessary to control pH and stabilize the product of interest during the downstream purification. As titers increase, there is a corresponding increase in buffer volumes needed for downstream purification. The current methods for buffer preparation and management require production of buffers in large stainless steel tanks in a buffer preparation area. This puts a strain on capital expenditures as well as classified facility space, as biomanufacturers must dedicate a sizeable portion of a facility and a large amount of equipment to buffer preparation.

In addition, a dedicated team with multiple operators works several shifts a day to meet this increased buffer demand, making conventional buffer preparation a highly laborious operation. This team is responsible for weighing the raw materials used to create the buffers, mixing the solution, filtering it, and then transferring the final buffer to a storage vessel, often a single-use bag. These bags must then be kept in an area where the quality of the buffer can be maintained until it is used, increasing the need for large sections of a facility dedicated to buffer storage. These and other bottlenecks related to buffer preparation must be addressed if biomanufacturers want to keep pace with the evolution of today’s industry.

Alternative Approaches To Buffer Preparation

In 2017, the cross-industry collaboration Biophorum (formerly known as the Biophorum Operations Group, or BPOG) outlined its technology road map, which is intended to accelerate innovation in biopharma by focusing on challenges and potential solutions with existing processes and technologies.¹ One deliverable in this road map was to develop specifications for buffer systems that reduced the buffer preparation footprint as well as buffer labor, costs, and preparation time. While some companies are still comfortable with utilizing legacy buffer preparation techniques, despite the bottlenecks, there are a number of other strategies available now that could help drive the industry’s future vision for buffer management.

For example, buffer dilution uses multi-component buffer concentrates that are simply diluted with water for injection (WFI) at point of use, typically between five and 20 times, with one buffer concentrate required per final downstream buffer.

With buffer concentrates, a concentrated form of the buffer is stored in much smaller tanks or single-use bags, significantly decreasing the footprint required for buffer storage. This approach also gives biomanufacturers the option to outsource buffer preparation altogether, reducing or even eliminating the need for a buffer preparation area and allowing for reallocation of resources to more value-added tasks.

Another alternative method of intensified buffer delivery is buffer stock blending.

Buffer stock blending uses single-component stock solutions of acid, base, salt, and WFI to prepare buffers. Because a buffer blending approach uses single-component solutions, concentration factors of 10 to 50 times are possible. In addition, one stock solution each of acid, base, and salt can be used to produce several different downstream buffers. Typically, a chromatography step uses many different buffers with various ratios of the same salt matrix, requiring a buffer concentrate for each of those buffers. However, with buffer stock blending, the salts and ratios can be changed simply by modifying the recipe, allowing for a lower overall inventory of buffer stock than needed with buffer concentrate. This creates an opportunity for suppliers to provide standardized stock solutions rather than make them to order, reducing the lead time for buffers as well as the associated costs.

Buffer stock blending also eliminates the need for mixing or large storage tanks or manual intervention, as the system prepares the buffers within the necessary specifications for that product. By using PAT online sensors and monitoring, it can automatically detect any deviations, divert out of specification solution to drain, and notify the operators. Biophorum recently formed a collaboration with the technology group NIIMBL to design and develop a skid to further the concept of buffer blending. According to the Biophorum site, the Buffer Prep Team is leveraging $1 million in funding for $150,000 cash/in-kind contribution from 15 companies, among which are Merck & Co., Inc., Kenilworth, NJ, USA, and MilliporeSigma, to construct a prototype of the design to be built and tested at the University of Delaware.²  

Achieving Cultural Readiness For The Future

The biopharmaceutical industry is commonly known as a conservative one, due to the risks and expenses associated with failures in drug development and manufacturing. Nevertheless, major technological achievements and new therapeutic modalities have biomanufacturers at a crossroads, where innovation is driving them to seek processes and business strategies that will help them deliver drugs to the market in a reduced time period and a more cost-effective manner. Focusing on the science is exciting, and applying process intensification can improve security, yield, and process economy, but it is the infrastructure supporting these efforts that will support the push toward a more holistic approach to modernizing how drugs are produced.

Therefore, while improving efficiency in buffer delivery may seem like an inconsequential piece of the puzzle, it is actually an important part of meeting the goals of Biophorum’s road map for the future, which could be a critical strategy in increasing productivity and decreasing costs. Additionally, as companies explore what buffer preparation approach works best for them, sharing the data and the experience can help lower the barrier to entry and encourage acceptance where there is skepticism. And in the end, collaboration and communication have always been key factors in driving change, which is a primary goal for companies that want to expedite the path toward higher drug quality, lower costs, and overall better patient care.

1. Biophorum. (2017). Process Technologies. Technology Road Map. Retrieved from https://www.biophorum.com/process-technologies/ (Registration required)
2. Biophorum. Buffer Preparation. Retrieved from https://www.biophorum.com/buffer-preparation/