Although buffers are among the simplest materials used in bioprocessing, they are critical to biopharmaceutical manufacturing success. Buffer preparation, storage, and handling can require significant investments in time, labor, equipment, and facility space. Jenny Dunker, MSc, and Alexander Troken, PhD (global product managers for customized bioprocess solutions and for process liquids and buffers, respectively, at Cytiva), delivered an ‚ÄúAsk the Expert‚ÄĚ presentation on 30 March 2021 to explore strategies for intensifying buffer management.
Biopharmaceutical manufacturers often prepare buffers manually. However, 2020 market analyses from Cytiva and BioPlan Associates show that drug companies now cite buffer management as a significant constraint on production capacity. A primary challenge is that buffer tanks occupy considerable facility space ‚ÄĒ and for much longer than other kinds of equipment. In-house preparation is time- and labor-intensive, with high potential for variation across batches. Such concerns ultimately compound the difficulties of scaling up production.
Dunker and Troken explained that drug manufacturers can stave off such problems by purchasing premade buffers, concentrates, and stock solutions from industry suppliers. Outsourcing can provide immediate capacity relief and decrease labor time significantly. Suppliers are equipped to minimize variability across batches, and often they can customize solutions for a specific process or facility. Outsourcing requires early collaboration between drug companies and suppliers to set specifications, qualify materials and processes, and address supply chain concerns. Users also should consider whether their buffer recipes require intellectual property (IP) protection.
BioPlan reports that 41% of surveyed biomanufacturing executives are considering hardware solutions to buffer bottlenecks. In-line dilution (ILD) systems add water for injection (WFI) to concentrated buffers. Such an approach greatly simplifies buffer preparation. Using concentrates also decreases requisite storage footprints. But ILD operators must be vigilant for dilution-related shifts in buffer pH. ILD skids also require greater capital expenditure than conventional setups.
In-line conditioning (IC) systems are gaining ground as alternatives to ILD units. Rather than diluting concentrates, IC units add WFI to stock solutions (i.e., an acid, base, and salt) to prepare buffers at the point of use. An advantage of IC is that many buffers can be prepared using the same stock solutions. IC units also enable dynamic control of process parameters such as conductivity and pH. However, they require considerable capital expenditure.
To compare the intensification potential of different buffer strategies, Dunker and Troken shared results from simulations of six buffer workflows for a three-step monoclonal antibody (MAb) production process. The simulations evaluated space, time, and cost as key performance indicators (KPIs) for
- conventional buffer preparation
- outsourcing of standard-concentration (1√ó) buffers
- ILD of in-process chemicals for internal preparation of buffer concentrates
- ILD of in-process buffer concentrates procured by outsourcing
- IC of in-process chemicals for internal preparation of single-component stock solutions
- IC of in-process single-component stock solutions procured by outsourcing.
The simulations assumed consumption of 12 buffers or 10 single-component stock solutions per workflow. Three production scales were considered: 400 L, 4,000 L, and 15,000 L of buffer per batch, representing 0.4-kg, 2-kg, and 10-kg MAb processes, respectively.
Saving Space: To show how production volumes influence facility space, Troken shared a simulation of linear scale-up to a 10-kg MAb process requiring 15,000 L of buffer. He observed that conventional workflows could be unfeasible at such volumes because the room needed for buffer kitchens and processing suites could occupy nearly all available floor space. In Cytiva‚Äôs simulation, ILD or IC of in-process chemicals required half as much space as conventional methods, and the IC option could be intensified further by preparing concentrates for multiple batches simultaneously. Outsourcing 1√ó buffers reduced the preparation footprint further still. Workflows for ILD and IC of outsourced concentrates or single-component stock solutions occupied the least and second least amount of space, respectively, with system size accounting for the differences in footprint.
Troken added that large-scale buffer workflows can present operational challenges as well as space constraints. For all six sample workflows, Cytiva estimated what volumes of liquids employees would need to handle from receipt of raw materials to application of 15,000 L of buffer in a processing suite. Assuming that outsourced materials are transferred directly from a warehouse to a processing suite, IC of outsourced stock solutions required the least liquid handling, followed by ILD of similar components.
Saving Time: As with space, outsourcing showed clear benefits for labor time. Dunker shared a simulation tallying how long buffer preparation takes per MAb batch. For 10 kg of MAb, conventional preparation of 15,000 L of buffer required ~400 hours for receipt of raw materials, primary and secondary preparations, primary and secondary holds, and final processing. By contrast, outsourcing 1√ó buffers, ILD of concentrates, and IC of stock solutions all required <50 hours. Companies seeking to prepare some solutions internally could benefit from IC of stock components, which required the least time among in-house strategies.
Dunker added that buffer-production and quality-control (QC) steps accounted for the largest labor-related costs in Cytiva‚Äôs simulations. If a company must prepare some materials manually, using an IC system could reduce those steps and their related costs significantly.
Reducing Costs: No single buffer- management strategy will make sense for all companies and processes. Which one to select can depend on manufacturing scale and other factors.
Dunker compared total operational costs per year for the six sample workflows at both 400-L and 15,000-L scales. She and Troken defined operational costs as expenses for hardware maintenance, process liquids and chemicals, consumables, buffer-related WFI, cleaning solutions, and buffer-related labor. Capital expenditure did not factor into that value.
Conventional preparation incurred high operational costs at both 400-L and 15,000-L scales. At 400 L, outsourcing 1√ó buffers incurred lower operational costs than most other options, making it a good choice for small-scale operations. At 15,000 L, ILD of outsourced concentrates and IC of outsourced stock solutions accrued the lowest operational costs. Overall, IC of internally prepared stock solutions proved to be cost-effective because it minimizes labor time and QC efforts.
Similar trends emerged in a cumulative cost comparison that accounted for initial investment costs and 10 years of operational expenses. Outsourcing 1√ó buffers was a viable strategy for small-scale operations, whereas ILD and IC approaches were most cost-effective for large scales. IC remained the best option for companies wanting to prepare some solutions internally. Cumulative comparison also revealed that all workflows achieved return on investment within two years.
Dunker emphasized the importance of flexibility in buffer operations. In that respect, IC systems might be more helpful than ILD technologies, enabling preparation of many buffers from the same stock materials. IC systems also feature more sophisticated process controls. Dunker cited experiments in which Cytiva scientists evaluated an IC system‚Äôs ability to compensate for known variations in stock concentrates. Cytiva‚Äôs skid enabled adjustment of flow, pH, and conductivity, such that buffers were produced at specification despite deviations in solution quality.
Troken explained that outsourcing can provide flexibility to early stage companies that cannot yet invest in hardware solutions. Purchasing 1√ó buffers enables easy incorporation of raw materials into a process. Using buffers from qualified suppliers also helps to minimize variability in processes that are not fully established. Whereas conventional preparation can require qualification of several materials, outsourcing would require qualification of a single supplier. Troken added that applying single-use technologies can eliminate some cleaning and validation activities, and ‚Äújust-in-time‚ÄĚ hydrated solutions can improve cycle times.
With so many buffer workflows available, drug companies must consider their needs carefully. Companies that have identified concerns with space, labor, and operational costs could benefit from hardware-based buffer solutions. Troken pointed out that some users remain uncertain about abandoning established preparation methods. Feeling comfortable with a process is important, but reaching commercial-scale manufacturing might influence a company‚Äôs priorities. Bioprocess suppliers such as Cytiva can assist with scale-up considerations.
Questions and Answers
When should a company inquire about custom buffer solutions? Such solutions are advisable when standard buffers are insufficient for a process ‚ÄĒ e.g., when an off-the-shelf buffer requires additional testing to ensure that it meets pH, conductivity, and osmolality targets. Drug companies also should speak with their suppliers about buffer stability and shelf life. Cytiva‚Äôs HyClone custom stability program, for instance, helps perform testing at specified time-frames and temperatures to determine storage requirements and expiry dates.
How quickly do drug companies tend to implement ILD and IC technologies? Companies often roll out ILD and IC systems incrementally to ensure that hardware-prepared buffers exhibit the same characteristics as those from manually prepared batches.
How complex is an IC skid? An IC unit operates much as a chromatography skid does and requires similar maintenance. If you understand the chemistry behind buffers, you also will understand how to choose between control modes. If you understand how pump specifications influence the in-line dilution factor and other such parameters, you will understand how stock solutions are mixed.
Is filtration required after ILD? Some drug companies filter ILD-generated buffers, as they do with manually prepared buffers. Other companies ensure that their concentrates have undergone filtration, then proceed with ILD. Because no single buffer- management strategy will serve every process, manufacturers should consider their needs and internal protocols carefully.