Shannon Ryan, senior director of application services at Avantor, describes why traditional buffer preparation models are increasingly strained at large scale.
Avantor
As biomanufacturing processes evolve to meet higher titers, tighter timelines, and more complex production demands, long-standing practices are being reassessed. Buffer preparation is a critical aspect of production and yet, has largely remained unchanged in recent years, despite its impact on labour, the production floor footprint, and manufacturing readiness.
Buffer preparation rarely gets the spotlight in biomanufacturing and yet can be a major constraint, especially at large scales. Why is that?
Buffer preparation has traditionally been treated as background infrastructure, and for decades, that approach was sufficient. But biomanufacturing continues to evolve, and buffer preparation has not kept pace.
If you look at the trajectory of upstream productivity, the shift is dramatic. Titers have increased from micrograms per litre to eight to ten grams per litre in modern processes. While productivity has increased in downstream unit operations as well, they have not matched upstream improvements. This capacity gain mismatch results in increased chromatography cycles, longer campaigns, and significantly more buffer consumption.
In existing facilities, the result is that there is a misalignment between their initial design criteria and current requirements. For example, a plant built for 2 g/L production may now be running at 5 g/L or higher, requiring two to three times more buffer than originally planned. That increase doesn’t just affect tank capacity, it impacts cleanroom footprint, labour allocation, scheduling, and campaign readiness. In many facilities, buffer preparation and staging occupy roughly one-third of available cleanroom space.
What’s striking is that buffer prep is often a final gate before downstream processing can begin. You can have your material harvested, your column packed, your operators scheduled, but if buffers aren’t released and ready at the right time, everything stops. That’s why buffer preparation has quietly become one of the most significant constraints in modern biomanufacturing.
Is this a breaking point for traditional buffer preparation models?
I believe we are at an inflection point. The traditional buffer prep model consists of manual dispensing of dry powders, followed by mixing, testing, and staging. While scaling out these methods can be successful, they do not align with the speed, flexibility, and efficiency that biomanufacturers require.
In addition to larger volumes, there is greater operational complexity. Facilities are increasingly multiproduct and changeovers are more frequent. Buffer preparation, which relies heavily on manual labour and fixed infrastructure, doesn’t adapt easily to that environment.
The industry has started to recognise this mismatch. Similar to the early days of single-use adoption, there’s a growing realisation that modernising buffer management, and leveraging outsourced solutions, can deliver increased efficiency. Just as drug manufacturers historically completed cleaning and validation, they are now comfortable receiving gamma-sterilised materials from suppliers of single-use systems, we’re now seeing a similar shift in mindset around buffer preparation and management.
What does “intensifying buffer preparation” really mean in practical terms?
At its core, intensification is about doing more with less, such as less space, less labour, less time, and less risk, while improving consistency and control. There are several ways to achieve that.
One approach is optimising the existing dry powder raw material workflow. This includes rethinking packaging, dispensing, and quality release. Pre-weighed, direct dispense formats reduce manual handling and improve powder flowability, while reliance on supplier quality systems, as outlined in ICH Q7, can significantly shorten the time from receipt to release. These changes may seem incremental, but together they can remove days or even weeks from raw material receipt to utilisation, streamlining manufacturing.
More transformative approaches involve preparation of solutions starting from buffer stocks and is accomplished either through inline dilution, using concentrated buffers that are diluted with water to reach final specifications at the point of use, or inline conditioning, which is the combination of multiple concentrates while adjusting pH inline to generate a wide range of buffers on demand.
What makes these approaches so powerful is that they offer an opportunity to fundamentally change the role of buffer prep. Instead of being a batch activity that happens days in advance, buffer generation becomes dynamic and just-in-time. This shift dramatically reduces staging requirements, simplifies scheduling, and allows facilities to operate with far greater agility.
How should manufacturers decide which buffer preparation strategies make sense for their operations?
Many existing studies focus on a single method of buffer preparation across an entire organisation, but in reality, most facilities benefit from a hybrid approach.
High-volume, buffer-intensive operations, such as chromatography and TFF, are often the best candidates for inline dilution or conditioning because they offer the greatest return on investment. Lower-volume or higher-risk buffers, such as formulation buffers, may remain internally prepared or sourced as ready-to-use solutions.
Therapeutic modality also plays an important role. Cell and gene therapy manufacturers often prioritise speed and many lack water-for-injection (WFI) infrastructure. For them, ready-to-use or concentrated solutions can eliminate significant operational complexity and deliver on speed. Larger, multi-therapeutic biologics facilities may instead favour inline systems that offer flexibility across multiple processes.
The key is being strategic and intentional, identifying where the real bottlenecks are, and applying the right solution to each use case rather than forcing a single model everywhere.
Beyond efficiency, what strategic advantages come from rethinking buffer preparation?
Efficiency gains are nearly universal, but they’re only part of the story. One of the most important benefits is risk reduction. Buffer preparation failures, whether due to incomplete dissolution, incorrect composition, or out-of-spec parameters, can be quite common. Each failure introduces delays, rework, and uncertainty.
Intensified buffer preparation also has meaningful workforce and ergonomic benefits. Handling large volumes of hygroscopic powders is physically demanding; reducing manual handling improves safety and frees skilled staff to focus on higher-value activities.
From a strategic perspective, buffer preparation is not the core competency of most drug manufacturers. Shifting buffer prep toward more specialised partners or intensified approaches allows companies to reduce non-core infrastructure while improving reliability and scalability.