Sterile Filtration

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Chapter: Pharmaceutical Engineering: Sterilization

Several filter geometries are available to perform sterile filtration.


STERILE FILTRATION

Several filter geometries are available to perform sterile filtration. These consist of flat membranes in a stainless steel press (<0.293 m), pleated membranes housed in stainless steel cartridges, and stacked plates in the form of flat seg-ments of membrane filters.

Matrix filters consist of fibers with pores having a depth of up to 1.2 x 10-4 m. Cellulose nitrate may be dissolved in the highly volatile solvents amyl acetate, ether, and dioxane. A gel-forming solvent, acetone, ethanol, or propanol, may be added. The mixture is poured on a flat plate and placed in a controlled-temperature environment to dry. Pore size is dependent on the gel-forming solvent concentration. A number of other substances may be used as filter material. These include other cellulose esters, acetate and butyrate; polyamides (nylon); polysulfones; fluorocarbons (Durapore membranes), poly-vinylidenedifluoride (hydrophobic) or surface modified with organic amides (hydrophilic); acrylic polymers; and polyvinyl chloride. To make some mem-branes hydrophilic, surfactants may be added including Tween 80, Triton X-100, hydroxypropyl cellulose, and glycerol. Sieve filters are made of polycarbonate (nucleopore 10 5 m thick). Collimated uranium fission products form nucleation tracks in film. Etching chemical exposure determines pore size.


Adsorption and Screening

Most membrane filters, when wetted, have negative charge. Bacteria have a similar negative charge and do not necessarily remain on the filter. Filters with other characteristics can be selected under these circumstances. Positively charged (AMF Zeta Plus Membrane) or protein- and peptide-adsorbing (Pall Posidyne Nylon 66) filters can be selected.

Ionic strength, pH, pressure, and flow rate all effect adsorption of particles. The flow rate through a filter is described in equation (1).


where Ci is the inherent resistance of the filter to flow (a function of void volumes), A is the surface area, P is the pressure, and V is the viscosity.

Filters are related according to nominal pore size and absolute pore size (the largest pore in the filter). This recognizes that a pore size distribution exists.


Filter Integrity

The filter integrity can be evaluated by a number of techniques. The destructive test involves filtering a suspension of bacterial cells (Pseudomonas diminuta, 0.3 x 10-6 m) through a 2 x 10-7 m filter. Six liters of suspension containing 1 x 1010 org/L grow up on an agar plate. Downstream of a 10-6-m filter, there should be nothing and an 8-log reduction would have occurred. The bubble point test assumes that pores can be characterized as capillaries. When totally wetted, all the capillaries should be full of water or solution. The pore length is generally much greater than the diameter. Pressure is applied to the wetted filter. The bubble point pressure (P) may be described as follows:


where γ is the surface tension (7.2 N/m2), θ is the contact angle, and D is the diameter of capillary.

The bubble point test is performed before and after sterile filtration.


Product Development Considerations

A specified area of filter must be soaked in a specified volume of product for a designated time. The accelerated stability of a product in the presence of a filter can be performed at 313 to 333 K for 60 days. The extent of damage, nature and quantity of extractables, and potency of active ingredients must be evaluated prior to selection of a filter for a particular process.

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