Sterilization aqueous product

Sterile aqueous D-sorbitol solutions are fermented with y cetobacter subo >gichns in the presence of large amounts of air to complete the microbiological oxidation. The L-sorbose is isolated by crystallisation, filtration, and drying. Various methods for the fermentation of D-sorbitol have been reviewed (60). A.cetobacter suboyydans is the organism of choice as it gives L-sorbose in >90% yield (61). Large-scale fermentations can be carried out in either batch or continuous modes. In either case, stefihty is important to prevent contamination, with subsequent loss of product. 

Briefly stated, the production of chloramphenicol by the surface culture method involves inoculating a shallow layer, usually less than about 2 cm, of a sterile, aqueous nutrient medium with Streptomyces ver)ezuelae and incubating the mixture under aerobic conditions at a temperature between about 20° and 40°C, preferably at room temperature (about 25°C), for a period of about 10 to 15 days. The mycelium is then removed from the liquid and the culture liquid is then treated by methods described for Isolating therefrom tne desired chloramphenicol. 

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... 

Aseptic Crystallization and Dry Powder Filling. Aseptic crystallization is primarily used for manufacture of sterile aqueous suspensions. However, if the physical form of the drug is critical to quality of the final product, better control over physical form can be attained by aseptic crystallization because a large variety of organic solvents can be used to control the crystallization process. In aseptic crystallization, the drug is... 

Most ophthalmic products, however, cannot be heat sterilized. In general, the active principle is not particularly stable to heat, either physically or chemically. Moreover, to impart viscosity, aqueous products are generally formulated with the inclusion of high molecular weight polymers, which may, similarly, be affected adversely by heat. 

Aqueous products moist heat at 121°C/15 minutes then moist heat to achieve a F0 value of not less than 8 minutes to achieve a sterility assurance level of 10 6 then aseptic filtration and aseptic processing then the use of presterilized components and aseptic compounding and assembly... 

The toxoid is then prepared by treating the active toxin produced with formaldehyde. The product is normally sold as a sterile aqueous preparation. Tetanus vaccine production follows a similar approach. Clostridium tetani is cultured in appropriate media. The toxin is recovered and inactivated by formaldehyde treatment. Again, it is usually marketed as a sterile aqueous-based product. 

A suitable negative product control for an aqueous product could be distilled water in a similar container. A negative product control for testing an ointment could be a container of liquid paraffin or ointment base that has been sterilized by dry heat pouring the liquid paraffin from a container would be adequate to simulate squeezing of ointment from a tube. 

Category I la. Injections, other parenterals including emulsions, otic, sterile nasal products, and ophthalmic products made with aqueous bases or vehicles... 

Suspensions offer another dispersed platform for delivery of poorly water-soluble agents. As compared with solutions, suspensions afford higher loading. However, as with emulsions, the suspended particles must be stabilized with surfactants to prevent aggregation. A number of steroids have been available for years as suspensions for IM and intra-articular delivery. Examples include DEPO-MEDROL (Pfizer, Kalamazoo, Michigan, U.S.A.) Sterile Aqueous Suspension. The marketed product contains methylprednisolone acetate, a white, water-insoluble, crystalline... 

After sterilizing, and adjusting to pH 7.0, 100 ml of the medium was placed in each of several test tubes, 500 ml capacity, and sterilized. Streptomyc carzinostaticus var.neocarzinostaticus strain F-41 was inoculated therein, and fermented with agitation for 24 h at 27°C and then used as the stock culture. Next, an aqueous production culture medium was prepared containing (%) glucose 3.0, peptone 0.5, meat extract 0.5, sodium chloride 0.5, calcium carbonate 0.2. 

Although com can be adequately steeped in sterile, aqueous solutions of sulfur dioxide or sodium, magnesium or potassium bisulfite (hydrogen sulfite) in the laboratory,164-166 commercial steeping involves microorganisms. Raw com carries natural populations of bacteria, yeasts and molds which are capable of rapid multiplication in aqueous systems. Wet-millers learned early that com steeped at temperatures of 45-55°C was sweet, but that putrefaction and butyric acid or alcohol production... 

The science that underpins steam sterilization is well known and has been long established. It is the preferred method of sterilization in the pharmaceutical industry it is used for sterilization of aqueous products in a wide variety of presentations, for sterilization of equipment and porous materials required in aseptic manufacture, in microbiology laboratories for sterilizing media and other materials, and for sterilization of massive systems of vessels and pipework [steam-in-place (SIP) systems]. Numerous rules and guidelines have been published on the topic, yet steam sterilization and particularly bio-validation of steam sterilization is still a subject for controversy and debate. 

For pharmaceutical products and materials used in connection with aseptic manufacture, sterilization specifications apply to conditions of temperature and time, or Fq, or combinations of Fq, temperature and time to which the contaminating micro-organisms themselves must be exposed over the hold period of the sterilization process. In practice, this means actually within aqueous products, on the surfaces of rubber stoppers or metal machine parts, or within the folds of cartridge filters, etc. 

Air removal is particularly important in porous and equipment loads, but is usually of little importance in the sterilization of aqueous pharmaceutical products. Air removal can be important to the specification of new autoclaves—those which are to be designated only for aqueous product sterilization have no need for the pumps and ancillary equipment required to pull deep vacuums. 

For instance, if ampules of aqueous products were to be sterilized in a hot air oven, the mechanisms of microbial inactivation would still be by coagulation of intracellular proteins. However, heat transfer from hot air is much slower than heat transfer from steam, which is why this is not seen as a practical process. Microwave irradiation could be an alternative means of sterilizing aqueous pharmaceutical products utilizing the same antimicrobial mechanisms as steam certainly there is evidence that microwave killing patterns are mainly due to heat transfer with very little direct energy being absorbed from the microwaves. 

Hydrophilic and hydrophobic sterilization grade filters are used throughout the BFS process for the sterilization of product and air, respectively. Filters should be purchased from an approved supplier and should be certified as meeting the regulatory requirements for sterilizing grade filters. By definition this means that the filter will have full bacterial retention when subjected to an aqueous challenge of Brevundimonas diminuta (ATCC 19146) at a minimum concentration of 1 X 10 cfu/cm of filter surface area. 

Sterile aqueous solutions prepared with high purity ascorbic acid and pyrogen-free distilled water in glass-lined equipment under absolute sanitary operations and filled into ampules are necessary for injectable solutions for parenteral use in humans and animals. For all injectable products, it is important to select container, stopper, preservative, and other ingredients that are compatible. 

Fig. 19.1 Decision tree for sterilization choices for aqueous products (from CPMP/QWP/054/98).

Figure 19.2 gives the decision tree for sterilization choices for non-aqueous liquid, semi-solid or dry powder products. Intermediary decisions, based on radiation and not found with aqueous products, may be seen in the tree. 

All these recommendations are summarized in the Decision trees for the selection of sterilization methods, edited by the EMEA [23] (Fig. 1).Two cases are considered on one hand, the aqueous products and on the other hand, the non-aqueous liquid, semi-solid and dry powder products. Figure 1 shows the order of preference of the sterilization methods for the second group. The terminal ones are ranked in the first place. Among them, thermal sterilization is still referred as the best choice, radio-sterilization ranking right after. Since gas sterilization is excluded and non-terminal methods are listed as the last choice, radiosterilization now precedes all these methods. It is deemed as the recommended alternative method to thermal sterilization. 

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