7 out of 10 downstream equipment with longest occupancy duration are buffer related

How are buffers usually prepared?
Traditionally, each buffer is prepared manually by mixing powder and water at specific concentrations and formulations. The buffers are stored before use. Manual buffer preparation consumes a significant amount of labor, time, and resources and requires a large portion of the facility footprint.

In fact, seven out of the ten downstream equipment types with the longest occupancy duration are buffer related.

What is the best buffer preparation strategy?
Buffer preparation is one of the most resource-intensive activities in biomanufacturing due to the large number and overall volume of buffers and process liquids used in a typical bioprocess workflow. As a result, buffer preparation can create bottlenecks in the manufacturing process.

There are different approaches to take care of buffer preparation, including outsourcing buffer preparation, using technologies for automated buffer preparation, including inline conditioning (IC) and inline dilution (ILD) and manual buffer preparation.

The preferred buffer management plan depends on the size and scale of the biomanufacturing process.

What equipment, resources, and functions are involved in buffer preparation in a controlled environment?
The equipment, resources, and functions for buffer preparation used in a typical bioprocess workflow vary depending on lot size, numbers of buffers used, and scale of the process. However, many requirements are similar, such as sourcing materials from qualified suppliers, selecting the grade of the required raw material(s), associated resource planning, and management of inventory, space, and logistics of consumables.

The quality control group validates that the buffer quality parameters are fulfilled for every manufactured batch of buffers. Batch records are generated and reviewed prior to a release for use in commercial manufacturing.

Manually manufactured buffers, usually prepared in advance, require additional planning around timing (when to use the buffers) and appropriate storage until use, as the large liquid volumes require considerable storage space within one’s facility.  This can be alleviated when considering outsourcing buffer preparation.

If automated buffer preparation technologies are being used, such as inline dilution (ILD) or inline conditioning (IC), the equipment needs to be qualified, and the chosen processes validated. The equipment requires long-term maintenance and calibration to ensure minimal variability between the different volumes and characteristics of buffers.

What options do I have for commercial/industrial scale buffer preparation?
There are different approaches to take care of buffer manufacturing: manual buffer preparation, outsourcing buffer preparation, or using automated buffer preparation technologies such as IC or ILD.

The preferred buffer management plan depends on the size and scale of the biomanufacturing process.

How can I increase my buffer preparation throughput?
Maximizing throughput in your buffer manufacturing is determined by many factors, such as available staff, equipment, and space. Furthermore, investments to either strategically build out capacity, potentially using automated buffer management solutions, or outsourcing buffers, using an established logistics model, play a large component. 

Internally, lean procedures and continuous improvement approaches often support just-in-time buffer preparation to minimize facility footprint.  Lastly, refining your bioprocessing workflow as new technologies and products become available are often supportive of reducing volumes of buffers needed at large-scale.

How do inline dilution (ILD) and inline conditioning (IC) help solve capacity constraints in biomanufacturing?
In ILD and IC buffers are prepared inline from buffer concentrates or from highly concentrated, low-volume, single-component stock solutions.

This way, buffer preparation can be directly integrated with the chromatography or filtration step, eliminating the need for intermediate storage in buffer bags or holding tanks.

In addition to reducing facility footprint, automating the buffer preparation process also ensures the quality of the final formulation. Integrated inline buffer preparation supports the industry’s need to streamline processes, increase productivity, and utilize facilities more efficiently.

By implementing techniques such as ILD and IC, buffer production remains an in-house activity, but the labor and space required for buffer preparation and associated handling are reduced by automating the preparation process and using concentrates to reduce buffer volumes.

Buffer manufacturing can be intensified even further by outsourcing your buffer concentrates for inline dilution or single-component stock solutions for inline conditioning. This will save significant amounts of time and space.

How does inline conditioning (IC) work?
Unlike ILD, IC does not use a concentrated buffer. Instead, you split the buffer into its individual components — acid, base and salt — and mix at the point of use with water.

The system uses different control modes to adjust the amount of each component during mixing. This allows it to meet the acceptance criteria of the target buffer. The same set of stock solutions can be used to prepare a range of different buffers.

What are the benefits of inline conditioning?
With an IC system you can create a range of buffers using the same set of stock solutions, just by adjusting the flow of the individual components. Compared with using buffer concentrates, volumes are significantly reduced, allowing the use of smaller tanks or disposable bags.

The system can fine-tune the final buffer using feedback from pH and conductivity sensors, together with flow feedback. This level of control ensures buffer specifications are met, even if there are variations in temperature or in the stock solutions.

The IC system can also be used for diluting concentrated solutions to their final concentration.

What are the drawbacks of inline conditioning (IC)?
System investment cost can be perceived as high, and training is required.

How does inline dilution (ILD) work?
ILD uses well-defined, multi-component buffer concentrates that are diluted with water.

With an ILD system, you need to make every buffer as a concentrate. For example, if you are making six buffers, you still need to prepare six different buffers with the right characteristics, but in a concentrated form. This means the same amount work is required to prepare the buffers, but the volumes are smaller compared to manual buffer preparation when the buffers are being produced in tanks.

Since diluting a concentrated buffer solution might cause a pH shift in the solution, you must account for this shift when preparing the concentrated solution in order to meet the specifications of the final buffer. The ILD system will perform the dilution, but it will not adjust for shifts in pH of the final buffer.

What are the benefits of inline dilution (ILD)?
With ILD significant reductions in floor space and tank volumes can be achieved.

What are the drawbacks of inline dilution (ILD)?
pH shifts due to dilution must be considered, it is sensitive to least soluble component, and it is affected by common ion effect (CIE).

What are the benefits of outsourced buffers?
Outsourcing buffer preparation is a simple and fast way to gain extra capacity. It is still relatively rare in the industry, but a recent report shows that it is becoming more prevalent for biomanufacturers and it has become a key area of interest (1). There is a growing market for outsourcing, particularly among new single-use facilities and continuous chromatography unit processes.

These generally “downsized” facilities are prime candidates for adopting the outsourcing strategy. Also, it is likely that the increasing number of new retrofitted facilities will adopt buffer fluid outsourcing, perceiving this as being advantageous for speed-to-market and flexibility.

Thus, outsourcing buffers can be a good solution especially for biomanufacturers either operating at smaller scales or producing a large array of buffers for different processes and products. In addition to enabling a smaller facility footprint, the ability of a supplier to handle quality assurance (QA) and quality control (QC) can further lessen the burden on the manufacturer (2).

What are the long-term product availability considerations for outsourced buffer production?

When it comes to ensuring uninterrupted supply in the biomanufacturing industry, it is critical that the supplier has invested in security of supply and has robust business continuity management and supply risk management processes and programs in place.

All Cytiva’s BioProcess manufacturing sites have been certified according to ISO 22301 Business Continuity Management (BCM), and we are able to produce buffers at multiple manufacturing sites. All buffers undergo rigorous quality control as all procedures are validated and conducted on qualified equipment.

Also, collaborative demand and supply planning with our customers is critical for a secure supply to ensure more precise forecast accuracy.

What are the drawbacks of outsourced buffers?
Buffer outsourcing requires some initial efforts upfront such as qualifying the supplier and setting specifications. Additional logistics considerations are required to order, receive, and use buffers as needed.

Ready to learn more about inline conditioning? Find answers to your technical questions here

References

1 Report and survey of biopharmaceutical manufacturing capacity and production, BioPlan (2019)

2 Bioprocessing buffers and related fluids: market opportunities and analysis, Bioplan, commissioned by GE Healthcare Life Sciences (2017)