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Scalability

Ensure that what you do in the lab can be scaled up. The most common cause of delays and failures is to neglect this consideration.

Chromatography Media Selection
Chromatography media to be included in the scouting have to be reduced to a reasonable number to cut down on time and effort spent at the initial phase of method development. Only those media supporting the issues of scalability, validatability and process robustness should be considered useful candidates.

Most important issues are:

chemical stability
physical rigidity
bead size
large scale column packing
column lifetime
regulatory support
technical support

Robustness
Because variations is the rule in producing biological products, the design of a process to manufacture products with consistent quality poses special challenges. The design must allow for a certain level of variability in critical processing parameters (conductivity, pH, temperature etc.), incoming materials (water, buffer components, chromatography media, feed material etc.), equipment, personnel, holding times and working routines.

The reason for most scale up failures is that the scope of process development has not been broad enough to carefully characterize these different sources of variation. Safety margins have to be built into the process control parameters, based on challenge tests performed at upper and lower limits of "normal" variations.

Compliance
Process design must ensure compliance with both manufacturing and regulatory requirements. Therefore, the final anticipated production scale must be defined as a scale-up model already at the research stage. The evaluation of the scale-up model must include early involvement of production experienced personnel.

This approach is necessary in order to avoid the design-in of equipment and unit operations that are difficult, or impossible, to operate on a large scale. When necessary corrections have been made to the scale-up model, it is scaled down to the proper size for completion of the process development work.