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

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

ATTRIBUTES OF AN EFFECTIVE VIRAL CLEARANCE METHOD An ideal viral clearance method should embody several key characteristics, including: a well-defined mode of action, high viral titer reduction, and high product recovery. Also, it should not interfere with the biological integrity and reactivity of the product; it should not contaminate the product; it should have no additional stabilizers or other additives; and it should be scaleable, possible to validate, and applicable to a wide range of products.4-7 The characteristics of a product dictate the suitability of a particular viral clearance method. The size of the protein, its conformation, and its lability to heat or other inactivation methods are important considerations. Likewise, viral size, lability, and the presence or absence of particular macromolecules should be evaluated as characteristics of potential viral contaminants. Process evaluation techniques also guide the suitability of a particular viral clearance method. Understanding how the chosen viral clearance method affects other variables in the process is a critical component of the elimination and it should be documented as part of a viral clearance strategy.


Figure 2. Impact of Lot to Lot Variation on Performance of Millistak + A1HC - Feed 1 vs. Feed 2, both 0% solids. Pressure drop curves show data from duplicate experiments for each set of conditions.
FILTRATION FOR VIRAL CLEARANCE Of the available viral clearance (inactivation and removal) strategies, size exclusion filtration is preferred because it is less dependent on product or process conditions and, therefore, more robust. Membrane surface chemistry and interactive forces between contaminants and the membrane can affect the retention efficiency and capacity of membrane filters. Adsorptive retention by a membrane is subject to pore surface chemistry and resultant electrokinetic or hydrophobic interactions between viral particles and the membrane surface. Virus retentive membrane filters typically rely primarily on size exclusion with minimal adsorptive properties. Ion exchange chromatography membranes, however, feature significantly larger, non-size-retentive pores with active membrane surfaces able to adsorb viruses from process fluids.

VIRUS FILTER RATINGS Users should understand the basis of a filter's rating. In general, virus filters can be classified into two groups, higher rating filters (nominally 35 to 80 nm) providing ≥4 log titer reduction (LTR) for ≥40 to 50 nm viruses (for example, retroviruses, SV40, and BVDV) and lower rating filters (nominally 15 to 25 nm) providing ≥3 LTR for 18 to 25 nm viruses (that is, parvoviruses and hepatitis A. Where a specific virus size, LTR, and test condition are required, typical virus retention for a specific filter generally can be predicted through a combination of the manufacturer's validation data — often generated with bacterial viruses (bacteriophage) of known size in model fluids — and published data on retention of various mammalian viruses in process fluids. Manufacturers' ratings are useful in membrane selection for further performance evaluation under product and process-specific conditions.


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