Introduction
Process liquids and buffers are necessary tools for biotherapeutic manufacturing. In small-scale process development scales, these liquids are often overlooked as the focus is usually on the molecule, technology, or process at hand. However, as processes scale up for commercialization, liquid volumes can quickly reach tens of thousands of liters for a single production batch (Figure 1). Direct, manual scale-up of buffers for a large-scale facility tends to become resource-intensive with raw materials and tanks causing space constraints, and labor requirements impacting the facility’s throughput.1 As cGMP requirements are implemented, the combination of these demands from liquid production and handling consequently causes bottlenecks, which in turn, drive higher costs.
Figure 1. As scales increase, hardware, as well as the consumables and buffers needed to serve them, increase as well.
There are different approaches to alleviate these bottlenecks, and their implementation could be dependent on, or influenced by, a variety of factors that arise from product phase, stage of scale-up, supply chain strategies, the facility’s age, or the desire to adopt new technologies, among others.
Outsourcing buffer manufacturing
When buffer needs fluctuate due to variability in a plant’s throughput or if additional capacity is required but sufficient space for expanding onsite buffer production is lacking, a straightforward approach is to outsource production. This approach would be most effective using an established supplier that has a demonstrated capability to deliver large volumes of bulk fluids or pre-blended powders.
In outsourcing buffer production, upfront tasks—such as supplier qualification, setting raw material and container specifications, and validating components in single-use systems—are generally required. These tasks, however, are offset by significant long-term benefits. Some of these benefits include access to the supplier’s manufacturing infrastructure, established supply chains, logistics expertise, and dedicated QA/QC teams. Once vendor validation is complete, biomanufacturers can streamline operations by reducing time spent on buffer preparation, quality control testing, and QA documentation.
Hardware-based approaches
For companies that prefer to produce large-scale buffer volumes in-house but still want time, cost, or space savings, hardware-based approaches such as inline dilution (ILD)2,3 and inline conditioning (IC)4–6 can be implemented.
ILD is a buffer management strategy that dilutes a buffer concentrate before use, while IC is an advanced buffer management strategy that enables real-time buffer formulation from single-component concentrates directly within the manufacturing processes.
The input in ILD is a concentrated version of a well-defined buffer that is diluted prior to application. In preparation for a production run, ILD can help achieve space savings, as the concentrated buffer requires less space in a warehouse as compared to the 1X needs. It does not necessarily reduce the labor need compared to traditional buffer preparation, as the same number of individual concentrate batches needs to be manufactured. Because there is no dynamic control of pH or conductivity in ILD, one must be cognizant of shifts in these parameters and respectively, account for them as the concentrate is diluted.
IC is an advanced buffer management strategy that enables real-time buffer formulation directly within manufacturing processes. The following explores this strategy’s technology, system design, benefits, and implementation, along with its role in continuous validation and regulatory compliance.
How IC works
At its core, IC uses a large water pump to dilute concentrated stock solutions of acids, bases, and salts. This setup enables precise control over multiple buffer properties simultaneously, allowing for flexible and accurate buffer formulation directly within the process.
IC systems can be applied in several ways. When integrated into a chromatography system, IC can drastically reduce the need for buffer holdup tanks. Alternatively, the system can function in a “buffer kitchen” mode, preparing buffers for storage in bags or bins. IC can also supply buffers directly to filtration skids.
A typical IC system includes up to five pumps, each paired with a flow meter in a feedback loop. These pumps draw from multiple inlets connected to different stock solutions. After each mixing point, sensors monitor and control critical parameters such as pH and conductivity. A second set of sensors provides independent monitoring before the buffer is released to the process, ensuring quality and consistency.
Flexible buffer formulation
IC allows for the production of a wide variety of buffers from the same stock solutions. For example, using 2 M acetic acid and 2 M sodium acetate, a 50 mM acetate buffer at pH 4.0 can be formulated by mixing 2.1% acid, 0.4% base, and 97.5% water. Adjusting these proportions enables the creation of other buffers, such as 75 mM acetate at pH 4.5 or 100 mM sodium acetate at pH 5.0. Buffers with added salt can also be formulated by including the appropriate salt stock solution. Simple inline dilutions, such as preparing 0.5 M sodium hydroxide from a 3 M stock, are also straightforward.
Key benefits of IC
IC offers numerous advantages when buffers are delivered directly to the process. It reduces capital and operating costs by minimizing the time and labor required for buffer preparation, transport, and cleaning. The system also reduces the facility footprint by enabling the use of smaller tanks or disposable bags.
Operational simplicity is another benefit. IC reduces manual preparation and allows the same stock solutions to be used for multiple buffer formulations. Additionally, the technology can enhance accuracy and robustness by compensating for variability in stock solution concentrations in real time.
Drivers and challenges for adoption
The adoption of IC is driven by the need to increase capacity without expanding facilities, to intensify processes by eliminating non-value-adding steps, and to improve reproducibility and robustness. However, implementation challenges include demonstrating equivalence to traditional methods, shifting responsibilities across teams, and upgrading infrastructure to support IC.
IC systems offer multiple feedback control modes to ensure buffers meet their Critical Process Parameters (CPPs), such as pH, conductivity, and concentration. These modes include flow feedback, pH and flow feedback, and pH and conductivity feedback. Each mode is suited to different levels of variability in temperature and stock solution concentration, ensuring consistent buffer quality.
IC supports a continuous validation approach aligned with Quality by Design (QbD) principles. This includes defining the Target Product Profile, identifying Critical Quality Attributes, and establishing a control strategy. Thus, IC enables real-time monitoring and control of buffer quality, allowing inline release and reducing separate quality control steps.
Case study: real-world implementation
Between 2017 and 2020, a pharmaceutical company invested €300 million in a new manufacturing suite and implemented IC as part of the expansion. Feasibility and validation studies confirmed the technology’s robustness, leading to regulatory approval. The facility required 170,000 liters of buffer, and IC reduced storage capacity requirements by 80%, cut plastic waste by 50%, and saved the company €1.25 million annually as compared to an alternative traditional approach with buffer tanks. The implementation also accelerated time-to-market. The new suite earned recognition as a World Economic Forum Global Sustainability Lighthouse.
Some or all … next steps
Bottlenecks caused by buffer-related manufacturing can have a strongly negative impact on the throughput, space, and labor force of a facility. These bottlenecks can be costly.
Each of the listed approaches in Figure 2 has its own inherent advantages and disadvantages when applied at certain timeframes and circumstances. Combining them can extract further value, depending on facility needs and requirements. For example, outsourcing the needed concentrates for ILD or IC can also mitigate bottlenecks in labor and space.
Figure 2: Considerations in choosing large-scale buffer management strategies.
IC is a transformative approach to buffer management in biopharmaceutical manufacturing, particularly for large-scale buffer needs using a condensed set of concentrated stock solutions. With proven benefits in cost, efficiency, and sustainability, IC is a powerful solution for meeting the evolving demands of biologics production.
There is no single, universal approach for buffer management as each manufacturer and facility has its own set of challenges based on scale, volume needs, and facility constraints. But setting a long-term strategy early can reduce potential pitfalls related to buffer-related complications.
References
BioPlan Associates. 22nd annual report and survey of biopharmaceutical manufacturing capacity and production. BioPlan Associates, Inc; 2025.
Matthews T, Bean B, Mulherkar P, Wolk B. An integrated approach to buffer dilution and storage. Pharma Manufacturing (online only). 2009.
Malone T, Li M. PAT-based in-line buffer dilution—serving the paradigm of quality by design. BioProcess Int. 2010;8(1):40-49
Tsai AM, Carredano E, Busson K. Deploying automated buffer production for cGMP use: points to consider. BioProcess J. 2019;18. doi.org/10.12665/J18OA-Tsai
Carredano E, et al. Simplification of buffer formulation and improvement of buffer control with in-line conditioning (IC). In: Biopharmaceutical Processing: Development, Design and Implementation of Manufacturing Processes. Amsterdam, Netherlands: Elsevier Ltd. 2018;513-525.
Busson K, Kamperveen R, Carredano E. Demonstrating the equivalence of traditional versus automated buffer preparation methods using in-line conditioning control modes to manage incoming stock solution variability. Bioprocess J. 2021;20. doi.org/10.12665/J20OA.Busson
Enrique Carredano, PhD, is Senior Application Specialist, Karolina Busson, MSc, is Application Specialist, Alexander Troken, PhD, is Senior Global Product Manager at Cytiva.
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