Three Key Considerations in Chromatography Process Development: Engineering, Cost Control, and Supply Chain Security

The ultimate goal of meticulously developed laboratory-scale processes is their seamless transfer to production. With this in mind, this article will analyze chromatography process development from three perspectives—engineering, cost control strategies, and supply chain security—aiming to introduce new insights and approaches to the development process.

Engineering Considerations: Focusing on Details to Pave the Way for Scale-Up Production

In addition to the conventional process parameters listed in Table 1, which directly impact product quality and efficiency, engineering challenges arising from production scale-up can also indirectly affect these critical factors. Engineering considerations refer to proactively addressing potential scale-up issues during the IND (Investigational New Drug) phase of small-scale process development, even before process transfer.

While process optimization and design space studies are conducted during Phase I-III clinical trials and process characterization, these efforts are based on the foundation established during IND-stage process development. By incorporating engineering foresight early in process development, subsequent stages—including process optimization, characterization, transfer, and scale-up—can be executed more efficiently, reducing project costs and mitigating risks.

Table 1: Potential Impact of Downstream Processes on Quality Attributes

(Data Source: A-Mab: A Case Study in Bioprocess Development)

Engineering Considerations in Process Development During IND Phase: Balancing Speed and Scalability. To achieve rapid IND approval while ensuring future manufacturability, it is recommended to embed engineering foresight early in platform process development. This approach allows subsequent projects built on this platform to meet regulatory timelines while preemptively addressing scale-up challenges. Key engineering focus areas include:

● Preserving pH and Conductivity Accuracy in Critical Solution Preparation Steps

When preparing small batches of solutions, it's easy to control the pH and conductivity of small solutions, for example, to within ±0.05 for pH and ±0.5 mS/cm for Cond. However, when scaling up the process to production scale, such as preparing a 5000 L solution, despite having a solution preparation SOP, factors such as personnel, equipment, materials, methods, and the environment make it very difficult to consistently maintain pH and conductivity accuracies within ±0.05 for pH and ±0.5 mS/cm for Cond. Typically, experiments are conducted with the most critical and challenging solutions, using different personnel, environments, and pH and conductivity testing equipment. The system error is calculated to confirm that the process requirements are met within this system error. Therefore, avoid overly stringent processes during early process development to reduce operational complexity for production personnel during the production phase, thereby minimizing the risk of project failure and overall costs.

● Column efficiency setting pitfalls

During pilot testing, column packing is relatively easy due to the small scale of the column. Furthermore, to adapt the process to a wider range of upstream sample qualities, the column efficiency is often set high. However, during scale-up, such high column efficiency is often not achieved, or repeated column packing is required to achieve high column efficiency. Production-scale column packing has high requirements and takes longer. For example, packing a 1000/500 mm column, including efficiency testing, can take three people two days to complete. Furthermore, if the column efficiency at production scale drops below the process requirement, repacking is necessary. Setting a very high column efficiency process during production significantly increases the frequency of column packing, impacting the workshop's annual production batches. It is recommended to strike a balance between process and workload when setting column efficiency parameters.

● Flow Rate Setting Considerations

Sample quality may vary significantly between the pilot process development and production stages. This can necessitate a reduced flow rate during some production steps due to overpressure. Setting a fixed flow rate in these situations can lead to process deviations. It is recommended to set the flow rate within a range for some processes, such as the CIP stage, which is prone to overpressure.

● Minimize dilution, pH adjustment, and conductivity adjustment between process steps.

During the pilot process development phase, sample dilution, pH adjustment, conductivity adjustment, and filtration are relatively easy to perform due to the small scale. However, at production scale, these steps require additional equipment such as pumps, tubing, pressure gauges, disposable sample bags, and mixing. This also adds numerous validation steps, all of which increase workload and production costs. By optimizing the process during development, these steps can be minimized.

● Column Size Selection for Process Development

Considering data comparisons with the process characterization phase and column wall effects, columns with excessively large or small inner diameters should not be selected during the IND process development phase. Columns with an inner diameter of approximately 1 cm are generally suitable. Columns with an inner diameter of less than 6 mm exhibit significantly increased wall effects. Columns with an inner diameter greater than 1 cm consume a significant amount of sample during later process optimization and characterization. However, considering the requirements for virus removal process validation, the column inner diameter requires comprehensive consideration.

● Column Bed Height

During process development, the recommended column bed height is generally within a certain range. First, the filler is in a suspended state, and the final column packing height may vary from one run to the next. Second, standard chromatography columns have a limited number of inner diameters. To accommodate a specific amount of filler, in addition to adjusting the inner diameter for the packing volume, the packing height can also be adjusted within a limited range.

● Temperature ramping and cooling

Laboratory processes easily ramp up and down temperatures for small samples. However, when scaling up to production scale, rapidly and accurately ramping and cooling large quantities of samples is challenging. Secondly, due to the principle of thermal expansion and contraction, higher requirements are placed on the equipment's ability to maintain pressure at varying temperatures and pressures. Thirdly, temperature fluctuations can affect the conductivity of some solutions, such as those containing Tris buffer, reducing process stability. All of these requirements only increase equipment procurement costs, so during process development at the IND stage, we strive to avoid process routes requiring ramping and cooling.

● Process Scale-Up Consistency

Chromatographic process scale-up is similar to linear scale-up. However, differences in dead volume/flow path volume, column wall effects, system flow path design, control software, and detection components can lead to variations in peak position, peak height, and resolution during scale-up. Therefore, when selecting equipment, it is important to prioritize equipment with the same or similar design principles, flow path design, and control software. This facilitates subsequent process transfer and scale-up, reduces the risk of failure, and minimizes process validation workload.

Cost Control: Calculate Costs Carefully to Enhance Market Competitiveness

Companies produce goods and ultimately need to consider their market competitiveness. Cost is a crucial factor. We should consciously consider process economics during the process development phase to reduce production costs from the source:

1. Simplify Process Steps: During process development, we must consider not only the explicit costs of equipment, consumables, and labor during subsequent scale-up, but also the hidden costs associated with different processes, such as the required GMP workshop space and staffing schedules, as well as increased operating and management costs.

2. Diversify Supplier Strategies: We should have alternative suppliers for key consumables to avoid exclusive use of products and ensure the stability of the future production supply chain. Strong competition among suppliers will result in reasonable prices and excellent service.

Supply Chain Security: Plan ahead to ensure production continuity.

1. Establish a multi-source supplier system: When screening platform processes, should you source two or three suppliers for key processes? While long-term supply agreements are in place, uncertainties in the external environment can lead to future supply instability. For example, during the COVID-19 pandemic, many key bioprocess equipment and consumables were in short supply. Due to a lack of alternative suppliers, companies had to make temporary process changes, leading to production halts.

2. Promote localization: Amid global trade protectionism and geopolitical tensions, some products supplied by overseas suppliers may face the risk of extended lead times, increased tariffs, or even supply disruptions. Actively seeking partnerships with high-quality domestic suppliers is the current priority.

In short, during platform process development and IND-stage process development, it is crucial to balance time efficiency with overall costs across the entire lifecycle, effectively reducing development and production costs, making products more competitive in the market, ensuring market supply, and benefiting patients.

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