Using Automated Inline Dilution to Ease Bottlenecking

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Higher titer yields in upstream processing have necessitated the need for better buffer management in downstream processing. A significant innovation has been the implementation of automated inline dilution systems, which offer a solution for de-bottlenecking the demand for greater volumes of buffer as a result of these higher titer yields.

Higher yields necessitate larger buffer volumes downstream, making buffers increasingly difficult to manage, particularly if they are manually mixed and/or formulated, says Chris Rombach, vice-president, Sales and Marketing, Asahi Kasei Bioprocess America. Automated inline dilution allows for more efficient, quicker, on-demand processing. “If a system is sized/designed appropriately, an entire campaign of buffers can be made in a matter of hours with little to no manual intervention,” Rombach states.

“The ability to prepare different buffers in quick succession with the same machine provides an unprecedented opportunity to optimize large-scale processes for contract manufacturing organizations (CMOs) and traditional biologics operations,” Rombach explains.

Single-use inline dilution can simplify the process of managing and the delivery of downstream processing buffers for chromatography and diafiltration operations, says Timothy Korwan, director of New Product Introduction at Avantor. Inline dilution of a concentrated chemical on-demand and eliminates the need to store large volumes of buffers and other downstream products in large storage tanks, which reduces capital and operational costs by eliminating the need for these tanks, he adds.

“Inline dilution of buffers can simplify scheduling of production runs for different drugs,” adds Pranav Vengsarkar, process development manager at Avantor. “Normally, large volumes of buffers need to be produced and stored days or weeks ahead of time to be ready when a new drug is scheduled to be run. This means multiple hold tanks will be needed, and all the documentation associated with this prep and storage has to be done ahead of time including QC (quality control) release. Inline dilution greatly reduces this requirement through on-demand creation and delivery of buffers,” he says.

“Existing facilities with fixed buffer preparation suites often cannot meet the requirements for increased buffer demand, and automated buffer dilution can resolve these challenges,” adds Darren Verlenden, head of BioProcessing, MilliporeSigma.

Inline dilution also offers the advantage of a smaller facility footprint because it reduces the cost and complexity of downstream buffer make-up and delivery, not only in pilot plants but also in clinical trial processing and startup processing, notes Jurgen Dijkstra, manager of Technical Services & Operations, Avantor. “Pilot production systems typically have smaller footprints and are producing smaller titers in their upstream stages, although a sizable amount of material still needs to be produced. That, in turn, means that a corresponding amount of buffers need to be prepared for a pilot run,” Dijkstra explains.

“Another advantage of automated inline buffer dilution systems is that they can be designed using single-use technology, allowing for one system to be used to deliver different buffers. Standard stainless-steel buffer delivery systems are often dedicated to one buffer or material in order to avoid the risk of cross-contamination or inefficiencies associated with thoroughly cleaning stainless steel storage tanks when changing out the buffers they hold,” Dijkstra says.

“With intensified buffer preparation, capital expenditure and labor are reduced by greater than 50% compared to fixed buffer preparation,” chimes in Verlenden. “With the automated dilution system and configured buffer concentrates, the buffers are made just-in-time for the process they are supplying. Depending on the size of the facility and the overall process run rate, this can reduce the cost per liter of buffer by up to 16%. Furthermore, with the lower labor requirements, highly skilled operators can be re-deployed to more value-added activities.”

Integrating inline dilution

Some challenges can cause hesitation in implementing an automated inline dilution system. For one, the industry is already comfortable with traditional-made in-house buffer preparation methods, whereas outsourcing buffer concentrates and using automated dilution can be perceived as posing additional risks, Verlenden observes. “For now, we have found that manufacturers are most comfortable with centralized buffer preparation with typical quality control release. Our buffer delivery platform (BioContinuum), for example, allows for high precision, rapid, and automated buffer preparation that allows for testing and release of the buffers prior to use in a process. Inline dilution that directly feeds a unit operation may be gradually adopted as the perceived risk of intensified buffer preparation decreases,” he says.

Having a seamless integration into operations is also a challenge to implementation, Rombach adds. “When a customer is used to manually making buffers, they sometimes don’t know how inline dilution should fit operationally, since it’s usually their first implementation. Who writes recipes and how to manage ‘buffer campaigns’? Do they fill tanks, bags, direct to another system like a HPLC [high-performance liquid chromatography]? What concentrates should they use? Does that effect their existing supply chain? How do we get our operators trained on new processes/technology?” Rombach explains.

Dijkstra adds that a continuous challenge with inline dilution is assuring the purity of the concentrates being used. “The shelf life of the materials needs to be properly tested, validated, and ultimately managed with good supply chain practices to ensure that those concentrates are unaltered when finally used,” he says.

Innovations provide control

Technology and equipment innovations are at the core of making inline dilution manageable and offer a comfortable transition for users more familiar with manual manipulation. Verlenden sees two components as being particularly important for making inline dilution technology successful. He describes a combination of highly accurate volumetric flow dilution with pre-titrated buffer concentrates. This combination provides prescribed ready-to-use buffers.

“With our experience in buffer manufacturing and the high precision of the buffer dilution system, buffer concentrates can be prepared at up to 50x concentration at our sites, shipped to the end-user facility, and accurately and reliability diluted for use in the bioprocess,” Verlenden adds.

In Korwan’s experience, the introduction of single-use sensors and technology, such as pH and conductivity probes and highly accurate single-use flow meters, are important in enabling the creation of single-use inline dilution systems that can correctly and accurately control the amount of concentrates and water combined to create a buffer mixture that meets a biomanufacturer’s specification. “Since each downstream process will have a unique buffer requirement, controlling the dilution factor for the buffer being processed, precision is essential. It has made it possible for these single-use systems to provide a more efficient, less time-consuming, and cost-effective way to provide buffers to the downstream processing,” he states.

Rombach, meanwhile, points to several elements that have significantly contributed to inline dilution’s ability to resolve debottlenecking issues, including low-volume shear blending, generous pump turndown ratios, and reliable analytic sensors. “In addition, instruments and programmable logic controllers (PLCs) with rapid refresh rate also enable tighter in-spec control of inline buffer dilution,” he states.

Further improvements needed involve educating the systems integrators, plant operators, and decision makers on the benefits of inline buffer dilution, Rombach continues. This education is the key to making automated inline dilution technology mainstream, he stresses.

“On the technology front, integration of artificial intelligence algorithms and predictive analytics further enhances the utility and reliability of the technology to resolve bottlenecking issues in bioprocessing. Integrating the use of automated inline dilution equipment with other processes, such as chromatography, will further capitalize on the benefits of this technology,” Rombach says. Other improvements needed include having standardized concentrates, shifting more toward formulation instead of dilution, and “smart” recipe generation (i.e., telling the software what you want to make, what concentrates are being used, and push start), he adds.

“One of the biggest improvements would be a continued technology investment in innovating these systems by adding additional capabilities to increase the portfolio of buffers that can be produced and delivered. This includes improving the ability to add variations to the system (such as different streams of buffers being easily mixed in precise proportion to produce the final solution) and being able to fine-tune pH and conductivity inline factors to make it easier to create variations of buffer mixtures using the controls technology,” Vengsarkar says.

About the author

Feliza Mirasol is the science editor for BioPharm International.

Article Details

BioPharm International
Vol. 33, No. 12
December 2020
Pages: 36–37, 50

Citation

When referring to this article, please cite it as F. Mirasol, “Using Automated Inline Dilution to Ease Bottlenecking,” BioPharm International 33 (12) 2020.