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

Table 1. Depth Filters Used in the Screening Study
We evaluated filter performance by a constant flow experiment (Pmax study).2 The study's screening criteria were filter capacity, filtrate quality determined by filtrate turbidity, target protein mass balance, and robustness regarding variation in feed characteristics such as % solids and feed turbidity. Depth filters were first flushed with sufficient buffer to wet filter media thoroughly and remove extractables. Then the feed, which was agitated and maintained cold (2 to 8C), was pumped through the filters at a constant flow rate (manufacturers' recommended rates are given in Table 2) until reaching a differential pressure of 25 to 30 psi. We plotted the differential pressure versus normalized throughput at different time intervals. Throughput at 50% of maximum differential pressure for all the filters is summarized in Table 3. While most filters exhibited good capacity with feed containing 0% solids, filter capacity declined significantly when using feed containing 0.7% solids. The only exceptions to this observation were the performance of the Millistak+A1HC and B1HC, which have open diatomaceous earth (DE) media, tighter DE media, as well as 0.1 mm cellulosic membrane. Both filters provided adequate capacity for both feeds. The recovery across the filters was measured by a product specific assay and was found to be 80 to 95%. Instant filtrate turbidity and filtrate pool turbidity were measured by a Hach turbidity meter. There was no turbidity increase, and the filtrate pool turbidity with feed containing 0.7% solids was about 3 Nephelometric Turbidity Units (NTU) for all the filters. For feed containing 0% solids, an appreciable turbidity breakthrough was observed, and the pool turbidity was 10 to 15 NTU for most filters, 8 NTU for the Millistak+ A1HC, and 11.3 NTU for the Millistak+B1HC.

Filter screening results indicated that pressure breakthrough is the primary limitation for this application, and the Millistak A1HC and B1HC appeared to be the most suitable filters due to their high capacity with respect to variation in feedstock characteristics.

Table 2. Recommended Flow Rate for Pmax Study
COMPARISON OF THE MILLISTAK+A1HC AND B1HC Table 3 presents data from experiments with different filters and feeds with different proportions of solids. We chose the feed (0% versus 0.7% solids) based on the manufacturer's recommendation for each filter. In most cases, if the filter performed poorly with feed containing 0.7% solids, we did not test it with the 0% solids feed. As seen in Table 3, the A1HC filter has a higher capacity than the B1HC filter with 0% solids feed, but a lower capacity with 0.7% solids feed. We believe this is due to the different particle size distribution of the two feeds; the 0% solids feed contains more smaller particles that lead to a faster plugging of the B1HC filter, which is structurally more open in comparison to the A1HC. We compared the Millistak+A1HC and B1HC further, using a different lot of feed (Figure 1). For this lot, the A1HC demonstrated higher capacity than the B1HC for both low- and high-solids content feed. Also, while there was no turbidity breakthrough with 1% solids feed, with the 0% solids feed, breakthrough occurred earlier with the B1HC filter than with the A1HC. Based on these results, Millistak+A1HC was chosen due to its superior filter capacity.

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