September 10, 2019

Can you trust a machine for downstream bioprocess buffer preparation?

By Enrique Carredano, Applications Specialist

There is a limit to how many stainless-steel tanks you can squeeze into a biomanufacturing facility. Is automated buffer preparation a solution to the dilemma of balancing increased production capacity against limited footprint expansion alternatives?

Did you know that seven out of ten downstream equipment types with longest occupancy duration are buffer related? In other words, buffer management is definitely worth exploring when looking for ways to intensify your process.

The majority of downstream bioprocess equipment with the longest occupancy duration are buffer related.

Traditionally, buffer management has received little focus in process intensification even though it can be very labor-, space-, time-, and material-intensive. Tank farms seem to be ever growing in biomanufacturing facilities, but there are available alternatives that can intensify buffer preparation.

You can reduce the size and number of tanks by introducing automated just-in-time (JIT) at point-of-use (POU) solutions. Examples of such solutions are inline buffer dilution (ILD) and inline conditioning (IC). But can you trust a machine to deliver the same results as more manual buffer preparation methods?

Schematic flow diagram of an inline conditioning system for bioprocessing.

Schematic flow diagram of an inline conditioning system for bioprocessing.

Going from manual to automated buffer preparation

When adapting a new technology to a GMP environment, it is essential to demonstrate its benefits compared to existing methodology. In this case, compared to manual buffer preparation. New processes must also be accepted as equivalent to the existing practices to satisfy quality and regulatory requirements.

To do this, it is important to identify the critical operating parameters for buffers that make the comparison possible, revealing the potential variability. In buffer preparation, these parameters are pH and conductivity.

How does inline conditioning compare to manual buffer management?

In a recent publication, Tsai et al evaluated JIT and POU buffer delivery using solution concentrates and inline conditioning. In that study, an acetate buffer system was used in a set of experiments based on a cubic centered face (CCF) design with three factors: pH (3.7 to 5.7), buffer concentration (20 to 100 mM) and salt concentration (0 to 250 mM).

The impact of control mode was also explored. Two sets of experiments were conducted using different control modes: Recipe and Flow and pH-Flow. Recipe and Flow is a flow feedback with a calculated recipe and is essentially equivalent to ILD. pH-Flow is one of the main control modes of IC. It is a combination of flow and pH feedback, where the former is used to maintain the buffer and salt concentration.

Buffer capacity and pump flow rate are critical operating parameters

Buffer capacity and pump flow rate were identified as the critical operating parameters in controlling buffer pH when using IC. Robustness was maximized when making a buffer with high buffer capacity while operating the pumps within the flow rate specifications.

These results are aligned with the wider industry understanding that buffer preparation is dependent on how well a solution is designed around the pKa of the buffer system and on accurate measurement and delivery of individual components by the system pumps.

The control mode comparison also showed that both control modes gave similar results (within ±0.1 pH units from target with one exception [0.15]). However, the pH-Flow control mode was closer to the target (within ±0.05 pH units), indicating that if the release specification is tighter, pH-Flow feedback control would be required when using IC.

Reliable buffer conductivity prediction

Conductivity data was analyzed with respect to a typical release specification showing that when operating within the pump specification limits, each prepared buffer met the ±10% of target requirements consistently regardless of the control mode. The chemical equilibria framework predicts buffer conductivity with good agreement with actual conductivity measurements.

Can you switch to automated buffer preparation?

The study results show that automated buffer management solutions like inline conditioning can be implemented in a biomanufacturing process if the critical operating parameters are kept under control.

Manual buffer preparation still dominates the biomanufacturing industry, but major advantages can be achieved within facility use and labor requirements by marrying hardware, software algorithms, and chemistry for automated buffer preparation.

Explore available solutions for automated large-scale bioprocess buffer management.