Beyond the impeller: a different approach to mixing sensitive bioproducts

By the time a protein or peptide drug substance reaches formulation, it has already done extensive upstream production and downstream purification. Formulation may involve relatively few unit operations, but these steps remain critical. The drug substance must be brought to the desired concentration and composition, thoroughly mixed, held, and filled without compromising product quality.

The challenge is to mix the product thoroughly enough to maintain uniformity while handling the molecule gently enough to avoid compromising its quality. For insulin and other injectable products, each vial must deliver a precise dose, so the bulk must be homogeneous before filling begins. Conventional agitation can provide the mixing needed for homogeneity, but the mechanical and interfacial stresses associated with agitation can also promote protein aggregation and, in susceptible molecules such as insulin, fibrillation. Product that has absorbed the entire cost of upstream processing can be lost at the last step before it becomes a dose.

One way to reduce the mechanical stress associated with agitation is to run the impeller more gently and accept a longer mixing time. As a result, the product remains exposed to the mechanical forces generated by the rotating impeller for a longer period, potentially increasing the overall risk of product damage for sensitive molecules.

Rather than using a rotating impeller, the FUNDAMIX® Vibro-Mixer generates mixing through an oscillating perforated plate. An electromagnetic drive moves the plate vertically at high frequency and small amplitude. Conical bores in the plate accelerate the fluid through the openings, generating axial circulation throughout the entire liquid volume rather than the tangential flow produced by a rotating impeller. Reversing the orientation of the plate reverses the direction of flow.

Three things follow from removing the rotating impeller:

• No dynamic seal. Nothing rotates inside the vessel, eliminating the need for a dynamic seal that must be monitored, cleaned, and maintained.
• No vortex. Because the FUNDAMIX® generates axial rather than tangential flow, it does not require baffles or vortex breakers to prevent vortex formation, which can simplify the vessel design.
• Effective mixing at low fill levels. The perforated plate can sit within centimeters of the vessel floor, allowing for effective mixing even at low fill volumes and minimizing the unmixable heel. Minimizing heel volume reduces product loss.

Published studies provide examples of Vibro-Mixer technology being used successfully in biopharmaceutical production. In one study, tetanus vaccine was produced in a 500 liter Vibro-Mixer fermenter and reached optimal antigenic purity in five to six days, compared with eight days using a stationary pot culture. In another study, recombinant human erythropoietin was produced in a 100 liter suspension culture over six weeks with no measured cell damage or significant cell clumping. Growth rates and product formation were comparable to those observed with a conventional paddle stirrer.

Insulin preparation, buffer and media preparation, plasma fractionation, and albumin production are all established industrial application areas for the FUNDAMIX®. DrM, the Swiss manufacturer behind it, has delivered more than 600 units to 41 countries since reintroducing the current generation in 2012, mostly into pharmaceutical and biopharmaceutical production. Systems are CIP and SIP compatible and scale from laboratory units to 12,000 liters.

For modular, multiproduct, or biologics facilities, FUNDAMIX® SU incorporates the same oscillating plate inside a pre-sterilized, fully enclosed disposable bag, in working volumes up to 500 liters. All product contact surfaces are contained inside the bag, eliminating cleaning and sterilization steps. The same mixing principle is used in both the stainless-steel and single-use systems, providing consistency when transitioning between formats.

By the time a product reaches formulation, most of its value has already been created. How it is mixed at that point is a question of mechanism, not only of how carefully a rotating impeller is operated.

1. Biffa internal savings data, average saving (January - August 2023)
2. Nisbets internal savings data, average saving (January – September 2023)
3. Compliance365 internal data, average  savings
4. HEINEKEN UK data, Calculations based on SmartDispense® active accounts each year since 2015 with 10 lines
5. Independent test results based on subterranean and ground floor pub cellars of varying sizes
6. Independent test results based on subterranean and ground floor pub cellars of varying sizes