This invention relates to ceramic ultrafiltration and separating life sciences substances.
Asymmetric ceramic filters provide media for microfiltration and ultrafiltration separation processes. These ceramic filters today are becoming recognized for their excellent structural bonding and integrity and are rapidly extending the fields of filtration applications to separations processes performed under extreme conditions of pressure, temperature, and pH.
"New Ceramic Filter Media for Cross-Flow Microfiltration and Ultrafiltration" by J. Gillot et al of the Ceramic Membranes Department of SCT in Tarbes, France, as published in Filtra 1984 Conference, Oct. 2-4, 1984. (Apr., 1986) presents alumina membrane-on-support filter media composed of a macroporous support with ceramic membrane layered on multi-channels through the support over channel diameters of 4 or 6 mm. Microfiltration membranes are presented with average pore diameters ranging from 0.2 microns to 5 microns, and ultrafiltration membranes are presented with average pore diameters ranging from 40.ANG. to 1000.ANG.. The membranes on support elements are assembled in modules with filtration surface areas of 0.01 to 3.8 m.sup.2. The Gillot et al publication points out characteristics for a support composition of alpha-alumina and for microfiltration membranes composed of alpha-alumina and for ultrafiltration membranes of gamma-alumina.
Ultrafiltration membranes are used for separation processes over a range of filtration size exclusion of generally from about 10 to 20.ANG. to about 1000 to 2000.ANG.. In the context of filtration separations over an entire spectrum of small particle separation processes, reverse osmosis extends from about 1 to 10.ANG. to 20.ANG., ultrafiltration from about 10.ANG. to 2000.ANG., microfiltration from about 500.ANG. or 0.05 micron to about 2 microns, and particle filtration from about 1 to 2 microns and up.
Pyrogens are fever-inducing substances and are identified operationally as a substance which, when injected into rabbits in an amount of 10 ml of solution per kg of body weight, raises the body temperature of one rabbit 0.6.degree. C. or a total rise of more than 1.4.degree. C. for three rabbits (USD XIX). Endotoxins are high molecular weight complexes, e.g., molecular weights of about 10,000 up to 100,000 to 200,000 and by some reports up to 1 million, which derive from gram negative bacteria. Bacteria shed their outer membrane into the environment, similarly to a human shedding an outer layer of skin. It is well known that endotoxin causes fever in humans. It appears that the biological activity of endotoxin derives from the lipid portion of the molecule.
Pyrogens are not eliminated by autoclaving because the endotoxin, as represented by the lipopolysaccharide molecule, is resistant to thermal destruction. The lipopolysaccharide molecule is thermally stable, and destruction requires exposure to 250.degree. C. for one-half hour to an hour or more.
Pyrogens can be deactivated, as in depyrogenation, by removal or deactivation. The endotoxin can be treated with an acid or base to deactivate the endotoxin, and this is called depyrogenation by deactivation.
Endotoxins can be removed from a liquid by distillation which is the traditional method for depyrogenation of water and one of two approved methods for the manufacture of non-pyrogenic water, or water for injection. The endotoxin has a large molecular weight compared to the molecular weight of water, so that distillation is effective in rendering the source water non-pyrogenic through distillation processes. The other approved method for manufacture of non-pyrogenic water is reverse osmosis.
Endotoxins can be removed based on molecular size exclusion through reverse osmosis. Reverse osmosis membranes are exclusion membranes but require pressures and structures which make processing difficult because of the small pore size of the reverse osmosis membranes. Moreover, lower molecular weight substances such as salts are excluded by reverse osmosis and this becomes a drawback in forming non-pyrogenic parenteral solutions containing certain salts.
Certain drawbacks are associated with prior conventional processes for pyrogen removal, including distillation, reverse osmosis, and adsorption by asbestos or other media. Distillation processes are highly capital intensive and expensive to operate. Reverse osmosis offers a less expensive method of pyrogen removal but presents substantial problems of cleaning, depyrogenating, and maintaining a non-pyrogenic permeate over extended operational time periods. Distillation and reverse osmosis have the further drawback that neither can be used to depyrogenate parenteral solutions because distillation and reverse osmosis remove the solute with the pyrogen. Asbestos systems now are unacceptable, and other charge media are not sufficiently effective in pyrogen removal.
Ultrafiltration has been identified as a method for pyrogen removal from liquids, polymer structures with pore sizes larger than reverse osmosis membranes but smaller than the microporous filters.
Ultrafiltration membranes concentrate products which are either dissolved or particulate. Through concentration, the product is retained by the filter in a retentate while water and low molecular weight solutes including salts, alcohols, etc., pass through the membrane as a permeate. The concentration operation can be limited by a buildup of retained material at the skin membrane surface. The buildup is called concentration polarization and results in significant resistance to filtration flow.
Ultrafiltration can be an effective means of pyrogen removal because molecular weights of lipopolysaccharides can be on the order of 20,000, for example, and then a 10,000 molecular weight cut-off membrane generally is used to insure high removal efficiency.
However, life sciences applications typically produce a slime on the polymeric membrane, including a film layer which sets up in cross-flow ultrafiltration. Polymeric membranes are particularly susceptible to this buildup of slime because polymeric membranes are not easily cleanable. The polymeric membrane also is degraded by high temperatures or concentrated corrosive chemicals, e.g., such as acids or bases which otherwise would readily clean the membrane.
Polymeric membranes have this drawback not only in cleanability but also in initial sterilization or depyrogenation. To deliver pyrogen-free product, the filter must be pyrogen-free to begin. The membrane also should be sterilizable to eliminate colony-forming bacteria on the membrane structure, and the high thermal stability of lipopolysaccharides makes heat unavailable as the sterilizable, depyrogenating method of choice. Further, the polymeric materials typically cannot be depyrogenated with strong acid (to depyrogenate for initial cleanup). The same factors attributable to polymeric membranes as drawbacks for initial cleaning also apply to regeneration of the polymeric systems also.
It is an object of the present invention to provide a method for depyrogenating a liquid through a filter which can be chemically cleaned initially and on regeneration.
It is a further object of the present invention to provide a method for depyrogenating through a filter which can be acid depyrogenated initially and on regeneration.
It is a further object of the present invention to provide a filter for removing pyrogens from a liquid which can be used over a long period and through numerous regeneration cycles.
It is yet another object of the present invention to provide a method for removing pyrogens from a liquid through a filter having high flux and high permeability.
These and further objects of the present invention will become apparent from the detailed description which follows.
USPTO Backgrounds
USPTO Backgrounds