Scaleup and Validation

One of the principal biochemical engineering considerations associated with affinity separations is to transform a successful laboratory separation procedure into a viable industrial unit operation. Packed bed separation procedures can be successfully scaled up to almost any extent provided certain rules are maintained and scale-up of affinity separations can also be achieved in a rational manner without dificulty. A suggested approach is:

• Ensure that the same adsorbent (including the chosen particle size) is used in both laboratory and large-scale procedures.

• Conduct investigations to determine the approximate dynamic capacity of the affinity adsorbent for the desired product and estimate the volume of the bed that will be needed to process the scaled-up batch size.

• Select a bed height of adsorbent that is compatible with the above volume. This will depend to a large extent on the diameters of commercially available columns, paying due regard to manufacturers' recommendations concerning minimum bed height to diameter ratios to achieve satisfactory flow distribution across the bed and maximum bed heights recommended to avoid excessive pressure drops and resultant bed compression.

• Optimize all stages of the separation in laboratory experiments using narrow columns of the same height as chosen for the full sized bed.

• Maintain the linear flow velocities and durations of each stage of the optimized laboratory process in the scaled-up procedure.

Adherence to these procedures should ensure that the characteristics of the separation and cycle time of the separation are maintained.

Before any downstream purification process can be used in the production of therapeutic agents it must be validated as part of the procedure to ensure compliance with GMP. For affinity separations, the issues are similar to those pertaining to any adsorption or chromatographic procedure. However, quality assurance issues associated with the source and origin of the affinity ligands may be of additional importance especially if these are molecules isolated from natural sources. Issues such as installation qualification and operational qualification and the associated documentation are dealt with in depth by Sofer and Hagel (see Further Reading).

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