Optimization, scale-up, and validation issues in Filtration of Biopharmaceuticals, Part 1 - - BioPharm International


Optimization, scale-up, and validation issues in Filtration of Biopharmaceuticals, Part 1

CHARACTERIZATION OF THE MILLISTAK+A1HC FILTER To ensure robust operation at large scale, we evaluated the effect of key operating parameters on the performance of this unit. These parameters included % solids in the feed, lot-to-lot variation in feed, batch-to-batch variation in filters, filtration flow rate, and temperature. Figure 2 illustrates the performance of the Milistak+A1HC filter using two different lots of feed material. While both feeds contained 0% solids, the turbidity was 58 NTU and 129 NTU, respectively. Lot-to-lot variation in feed resulted in earlier pressure and turbidity breakthrough in one case, indicating the need for a safety factor during scale up.

Table 3. Throughput Comparison (L/m2 at 15 psi)
Further, the effect of the percentage of solids on filter capacity was evaluated (Table 4). As expected, the required filter area increases significantly with the increase in percentage of solids in the feed. Based on this data, we decided that specifying the percentage of solids for the preceding centrifugation step is necessary for a consistent and validatable process.

Figure 1. Comparison of A1HC with B1HC Using Different Feeds
SCALE-UP OF THE DEPTH FILTRATION STEP To test the feasibility of large-scale operation of the depth filtration step, we used an 8 cell 16 in. A1HC filter with 1.8 m2 surface area to filter 300 L of fermentation broth. We evaluated filtrate turbidity and the pressure drop generated at this scale and compared the results to those at bench scale. As seen in Figure 3, under the conditions investigated, data from the two scales compare favorably, demonstrating robust performance and scaleability of this step. Product recovery across the step was 95%, same as that seen in the small-scale experiments.

Table 4. Millistak+A1HC Capacity vs. % Solids
SUMMARY We found the Millistak+A1HC to be the most effective depth filter for harvest of this protein expressed in Pichia pastoris. It was observed that pressure breakthrough is the dominant factor while processing high % solids feed (>0%). Turbidity breakthrough was only observed while processing lower percentage solids feed (~0%). We found the characteristics of feedstock significantly impacted filter performance.

Jerold M. Martin, Pall Life Sciences

Validation of Viral Clearance by Direct Flow Membrane Filtration The use of cell culture and plasma-derived proteins to treat a wide range of disorders continues to expand. Coupled with these developments is the need to ensure the safety of newly developed and established biopharmaceutical drugs. While biological raw materials contaminated with infectious or cytopathogenic viruses are preferably excluded from use in biopharmaceutical manufacturing, a variety of circumstances can result in viral contamination of final products. The use of appropriate viral clearance methods can significantly reduce the risk of accidental viral transmission and thus enhance safety.

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