Liquids filtration sterilization

Technical Report No, 26, Sterilization Filtration of Liquids, Parenterals Drug Association, Inc. 1998. 

Adsorption of t-PA to process equipment surfaces consisting of either stainless steel or glass was minimized by adding the detergent polyoxyethylene sorbitan monooleate (Tween 80) to the serum-free culture conditioned media at 0.01% (vol/vol). The equipment was also rinsed, before use, with phosphate buffered saline (PBS) containing 0.01% Tween 80. Hydrophilic, plastic equipment was used whenever possible. All buffers were sterile filtered. Sterile filtration of liquids and gases is usually carried out using 0.2 or 0.45 Jim filters. 

Filters for use in sterile gas filtration must conform to standards similar to those mandated for sterile liquid filtration. Nondestructive integrity tests may be applied. The tests are performed by wetting the filter with an appropriate solvent, commonly 60/40 isopropyl alcohol/water for hydrophobic membranes, and applying air or nitrogen gas at a preset pressure. 

Sterilizing Filtration of Liquids, technical report no. 26. Parenteral Drug Association (1998). 

Membrane polymeric materials for separation applications are made of polyamide, polypropylene, polyvinylidene fluoride, polysulfone, polyethersulfone, cellulose acetate, cellulose diacetate, polystyrene resins cross-linked with divinylbenzene, and others (see Section 2.9) [59-61], The use of polyamide membrane filters is suggested for particle-removing filtration of water, aqueous solutions and solvents, as well as for the sterile filtration of liquids. The polysulfone and polyethersulfone membranes are widely applied in the biotechnological and pharmaceutical industries for the purification of enzymes and peptides. Cellulose acetate membrane filters are hydrophilic, and consequently, are suitable as a filtering membrane for aqueous and alcoholic media. 

TR 11 Sterilization of Parenterals by Gamma Irradiation, 1988 TR 13 Fundamentals of an Environmental Monitoring Program, 2001 TR 22 Process Simulation Testing for Aseptically Filled Products, 1996 TR 26 Sterilizing Filtration of Liquids, 1998... 

Fig. 7 Manual bubble point test set-up. (Reprinted from Technical Report No. 26, Sterilizing Filtration of Liquids 1998 by PDA.)...

Sterile filtration of liquids and gases is now virtually always done using mem brane filters. The first U.S. patent for membrane filters was filed in 1922 and pertained to cellulose acetate membranes. A wide range of membrane filter media are now commercially available to suit various applications cellulose esters, polyvinylidinefluoride, polytetrafluoroethylene (PTFE), and polyhexam-ethyleneadipamide (nylon 66), separately or as laminates with polyethylene, polypropylene, and polyester for more robust phy.sicai characteristics. 

Technical Report No. 26 (2008) Sterilizing filtration of liquids. PDA J Pharm Sci Technol 62 S-5... 

A set volume of fuel is filtered through an appropriate sterile filtration unit. The filter can be evaluated for microbial contamination by directly placing it on agar media or suspending it in sterile liquid media to extract microorganisms and then plating the liquid media onto agar media (Institute of Petroleum, 1996). 

CiystaUization is the preferred method of forming many final prod-uc ts because veiy high purification is possible. High purity antibiotic ciystals can be produced from colored, rather impure solutions if the filter cake is uniform and amenable to good washingto remove the mother hquor. When a sterile pharmaceutical produc t is desired, ciystals are formed from liquid streams that have been sterihzed by filtration. 

Principles of the methods employed to sterilize pharmaceutical products are described in Chapter 20. The British Pharmacopoeia (1993) recommends autoclaving and filtration as suitable methods applicable to aqueous liquids, and dry heat for non-aqueous and dry sohd preparatiorrs. The choice is determined largely by the ability of the formulation and container to withstand the physical stresses apphed by moist heat... 

The USP also recommends the use of biological indicators, whenever possible, to monitor all sterilization methods except sterile filtration. Biological indicators are generally of two types. If a product to be sterilized is a liquid, microorganisms are added directly to carefully identified representative samples of the product. When this is not practical, as with solids or equipment to be sterilized, the culture is added to strips of filter paper. The organism chosen varies with the method of sterilization. 

The anhydrous petrolatum base may be made more miscible with water through the use of an anhydrous liquid lanolin derivative. Drugs can be incorporated into such a base in aqueous solution if desired. Poly-oxyl 40 stearate and polyethylene glycol 300 are used in an anti-infective ointment to solubilize the active principle in the base so that the ointment can be sterilized by aseptic filtration. The cosmetic-type bases, such as the oil-in-water (o/w) emulsion bases popular in dermatology, should not be used in the eye, nor should liquid emulsions, owing to the ocular irritation produced by the soaps and surfactants used to form the emulsion. 

Nonaqueous liquids, semi-solids, and dry powders dry heat at 160°C/120 minutes then dry heat under alternative conditions of time and temperature to achieve a sterility assurance level of 10 6 then an alternative to dry heat, e.g., ionizing radiation with a minimum absorbed dose of not less than 25 kGy then a validated alternative irradiation dose (according to ISO 11137) then aseptic filtration and aseptic processing and then the use of presterilized components and aseptic compounding or filling... 

Rebif is produced via recombinant DNA technology in a CHO cell line. It displays an identical amino acid sequence to that of native human IFN-P-la and, like the native product, is glycosylated. After cell culture the interferon is purified using a series of chromatographic steps (affinity, ion-exchange, gel-filtration and reverse-phase liquid chromatography). It is formulated as a sterile solution in pre-filled syringes and contains mannitol, HSA, sodium acetate, acetic acid and sodium hydroxide as excipients. It is administered subcutaneously three times weekly. 

Liquid product is fed to the BFS machine from a holding tank or vessel. The pathway is sterilized in place prior to receiving product, and product is sterilized by means of in-line sterilizing-grade filters. There is usually more than one stage of sterile filtration required on the product pathway. 

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