Biopharmaceutical production depends on buffers. Making sure the right buffer solutions are available, in the right place on the manufacturing line, at the right time, and in the right quantity, is a considerable challenge.
“The nomenclature differs depending on the stage of the process in which buffers are being used,” says Chor Sing Tan, Senior Upstream Bioprocessing Applications Leader at GE Healthcare Life Sciences. “Solutions used upstream are typically referred to as media, and those used downstream are typically referred to as buﬀers. Chemists would deﬁne a buﬀer as a solution which maintains its pH over a wide range of concentrations.”
“Most solutions used in downstream meet these criteria, but the term buﬀers is generally used as a catch-all for all solutions used in the downstream section of a facility,” he adds. “Buffers downstream are used widely in purification, diafiltration, and formulation steps. Buffers are used to equilibrate and condition, and to wash and elute chromatography columns.”
“As a result, multiple buffers are needed for each process,” according to David Jones, Business Development Leader—Buffers and Process Liquids at GE Healthcare Life Sciences, who cites purification as an example.
“Companies will need 10–15 different buffer formulations for efficient purification of their therapeutic. Although most purification steps utilize the same few biocompatible buffer systems, the buffer strength, pH, and ionic strength are usually optimized for each purification,” Jones says.
In addition, the buffer volumes can be considerable. According to Tan, making a monoclonal antibody can use hundreds of liters of buﬀers and media per process/run/batch.
He told us, “Typical large-scale production bioreactor volumes for such processes are in the range 10,000 L to 30,000 L,” he points out. “Each batch may use in the region of 20–40 diﬀerent buﬀers.”
The key questions are how best to make or source these buffers and how to store and use them at the manufacturing site.
Many companies make buffers in-house. While this strategy provides control over raw materials, formulation, and quality, it requires an investment in capacity.
“Ensuring capacity is available when needed is complex,” Jones says, “particularly when drugs are being scaled-up from the development lab.
“The biggest challenge in buffer management is planning through the scale-up process as therapeutics move from processes development at bench-top scale to large-scale GMP. This scale-up can put a strain on buffer manufacturing capacity,” he explains.
Jones explains that in-house preparation is material, labor, time, and space intensive.
“For example, in downstream operations, 7 out of 10 downstream equipment types with the longest occupancy duration are buffer related,” he says.
“Outsourcing buffer production is another option. The major advantage of the approach is that it minimizes investment,” according to Jones.
“Investing capital into liquid manufacturing capacity when that capacity will be underutilized is costly. Outsourcing buffer manufacturing, in this case, is a way to add flex capacity without capital investment.
In addition, buying premade buffers, single component concentrates, or stock solutions from a contract supplier minimizes preparation time.
But outsourcing cedes oversight of quality control to the contractor.
It also requires that the developer finds a way of ensuring supplies are available in the long term.”
Deciding whether to make buffers in-house or outsource is complex, according to Jones. Questions that companies must ask and answer include: Where are we going to produce the various process liquids to manufacture and purify this new therapeutic?
Do we need to add a water for injection (WFI) system and additional buffer kitchen space to facilitate production?
Making the correct choice is critical for small biotech companies, who may not be able to absorb infrastructure costs as easily as their larger counterparts.
“The biggest difference lies in larger companies’ ability to either leverage existing liquid manufacturing capacity or invest in new capacity with lower risk of underutilization,” Jones notes.
This view is shared by Tan. He says that large drug facilities usually have a high degree of automation, which enables facilitates to have better quality control. “Large biotech companies have extensive raw material control and pricing advantage on buffer salts through agreement with suppliers,” he details.
In-house production may be too costly for small biotech companies.
Instead, Tan says, they should invest in expertise, both internal and through partnership, rather than capacity. “For reduction of CAPEX, single-use mixing technology may be preferable for small biotech companies,” he suggests. “In this scenario, manual intervention and prior knowledge are needed to ensure quality buffer management.”
On-site preparation and logistics are the other major considerations to keep in mind when developing a buffer management strategy. The standard approach is to store the buffers centrally. It is also commonplace for waste buffer to be stored at the plant prior to disposal.
But on-site storage can be a problem, according to Jenny Dunker, Global Product Manager of Customized BioProcess Solutions at GE Healthcare Life Sciences, who says many plants lack the dedicated capacity.
“Often when you walk around a facility, there are tanks, bins, and bags everywhere because there is nowhere to store buffers,” Dunker points out, adding that, “the desire for higher throughput and larger production volumes is exacerbating the situation.”
These storage challenges have prompted some to alternative solutions. One method to emerge was inline dilution (ILD). In this strategy, buffer concentrates are diluted with water. The key benefit is concentrates require less floor space than prediluted buffers.
In recent years, inline conditioning (IC) has started to attract attention. Like inline dilution, inline conditioning involves the preparation of concentrates followed by direct introduction into the line.
The difference is the concentrates in inline conditioning contain only a single component of the buffer. These concentrates can be combined to prepare multiple buffers that can then be delivered directly to the process.
Dunker told us: “Inline conditioning enables a reduction of the number of solutions needed, as different buffers are formulated from the same set of single-component-concentrates, thus lowering investments, and running costs as well as cleaning and maintenance,” explains Dunker.
In addition, because the concentrates used in inline conditioning are stored in smaller tanks and disposable bags, storage-specific requirements are reduced.
Dunker told us, “Using inline conditioning, for a typical three-step monoclonal antibody (mAb) purification process from a 2000-L culture feed with a mAb titer of 3 g/L a 79% reduction in buffer volumes which translates into a 33% footprint reduction, can be achieved. In this example,” she adds, “we went from 11 buffer formulations to 8 single-component solutions.”
She cited a second case study in which a customer, with GE Healthcare’s assistance, reduced the proportion of manufacturing space used for storage by incorporating inline conditioning into facility design.
“Our input helped them design a facility to make the most of inline conditioning in this case. In the end, they had an overall production footprint of 61% and went from 26 buffers to 11 stock solution. So there were a lot of savings.”
Quality and precision
Automation is what makes inline conditioning possible. In this approach, concentrates are mixed in response to feedback provided by monitoring systems, reducing the risk of errors.
This is a huge plus from a quality standpoint, according to Dunker, who insists that precise formulation is vital:
“If you use an incorrect buffer formulation, you will not obtain the desired protein. That is why it’s critical to produce a buffer that meets specifications, so you end up with the right product coming out of the manufacturing process.”
Uptake of new technology takes time in a conservative industry
“Although the potential advantages are clear, there will likely be a learning curve required for the adoption of alternatives, such as inline conditioning to current in-house methods,” Tan suggests.
Dunker adds, “The industry is very conservative, so adoption of new technologies will take time. However, in the past year or two, we have seen an increase of customers coming back to us who we’ve talked with before saying, ‘we need to do something’ and ‘there are buffers everywhere.’”