Sterile suspensions preparation

Many dry solid parenteral products, such as the cephalosporins, are prepared by sterile crystallization techniques. Control of the crystallization process to obtain a consistent and uniform crystal form, habit, density, and size distribution is particularly critical for drug substances to be utilized in sterile suspensions. For example, when the crystallization process for sterile ceftazidime pentahydrate was modified to increase the density and reduce the volume of the fill dose, the rate of dissolution increased significantly. 

An example of the second method of parenteral suspension preparation is testosterone suspension. Here, the vehicle is prepared and sterile-filtered. The testosterone is dissolved separately in acetone and sterile-filtered. The testosterone-acetone solution is aseptically added to the sterile vehicle, causing the testosterone to crystallize. The resulting suspension is then diluted with sterile vehicle, mixed, the crystals allowed to settle, and the supernatant solution siphoned off. This procedure is repeated several times until all the acetone has been removed. The suspension is then brought to volume and filled in the normal manner. 

System (1) has been adopted by the USP [71] for the assay of cortisone acetate and its official pharmaceutical formulations (either sterile suspension or tablets). The standard is prepared by transferring about 12 mg of cortisone acetate RS, accurately weighed, into a glass-stoppered 50-mL conical flask. 25.0 mL of internal standard solution is added, and the solution sonicated for 5 minutes. Approximately 1 mL of this solution is combined with 3 mL of mobile phase to obtain the standard preparation. The column is any 25 cm x 4.6 mm column that contains packing L3. The... 

For seeding, each unit requires 21 of diluted cell suspension, prepared in a sterile 2-1 Erlenmeyer flask equipped with a No. 10 rubber stopper, air filter and silicone tubing (Figure 5.7.2). 

Injectable preparations are usually either sterile suspensions or solutions of a drug in water or in a suitable vegetable oil. Solutions act faster than drugs in suspensions with an aqueous vehicle, providing faster action than an oleaginous vehicle. Drug absorption occurs... 

Ophthalmic preparations (solutions and suspensions) are sterile aqueous preparations with other qualities essential to the safety and comfort of the patient. Ophthalmic ointments must be sterile and free from grittiness. 

Class 10,000 areas are suitable to prepare solutions that shall be sterile but cannot be sterilized in their final containers (referring to that sterile filtration is needed before filling) to prepare solutions of large volume parenterals that can be sterilized in their final containers to prepare, filter, fill and seal solutions of small volume parenterals fc50ml) and eye drops to prepare, filter, fill and seal oral solutions that can not be sterilized by steam sterilization to prepare, fill and seal ointments, creams, suspensions, emulsions that can not be sterilized in their final containers and to purify, dry, and package bulk pharmaceuticals for preparing injections. 

Ophthalmic Dosage Forms. Ophthalmic preparations can be solutions, eg, eye drops, eyewashes, ointments, or aqueous suspensions (30). They must be sterile and any suspended dmg particles must be of a very fine particle size. Solutions must be particle free and isotonic with tears. Thus, the osmotic pressure must equal that of normal saline (0.9% sodium chloride) solution. Hypotonic solutions are adjusted to be isotonic by addition of calculated amounts of tonicity adjusters, eg, sodium chloride, boric acid, or sodium nitrate. 

A 100 ml aliquot of this medium is placed In a 500 ml Erlenmeyer flask and sterilized by autoclaving for 20 minutes under 15 psi pressure. Spores of mutant strain S. aureofaciens S1308 (ATCC No. 12,748) are washed from an agar slant Into the flask with sterile distilled water to form a suspension containing approximately 10 spores per milliliter. A 1.0 ml portion of this suspension is used to inoculate the fermentation media in the example which follows. A fermentation medium consisting of the following ingredients was prepared. 

The pH of the medium thus prepared is about 6.8. An 8 ml portion Is measured into an 8 inch 8rewer tube and sterilized at 120°C for 20 minutes. The sterilized medium is than inoculated with 0.5 ml of an aqueous spore suspension of a strain of S. aureofaciens capable of producing chlorodemethyltetracycline, such as S-604, containing approximately 40-60 million spores per milliliter. The inoculated medium is incubated for 24 hours at 28°C on a reciprocating shaker operated at 110 cycles per minute. 

The spores from an inclined culture of Fusarium lateritium Wr, CSB 119.63 on a gelose medium are extracted with sterilized distilled water to obtain a suspension containing about 600,000 spores per ml. This suspension is then used to seed the medium prepared as earlier described. The contents of the flask are left to incubate at 27°C. Sterile air is injected into the liquid to effect thorough agitation and uniform supply of oxygen into the medium. 

For parenteral use, the antibiotic is packed in sterile vials as a powder (reconstituted before use) or suspension. For oral use it is prepared in any of the standard presentations, such as film-coated tablets. Searching tests are carried out on an appreciable number of random samples of the finished product to ensure that it satisfies the stringent quahty control requirements for potency, purity, freedom horn pyrogens and sterility. 

Biological indicators (Bis) for use in thermal, chemical or radiation sterilization processes consist of standardized bacterial spore preparations which are usually in the form either of suspensions in water or culture medium or of spores dried on paper, aluminium or plastic carriers. As with chentical indicators, they are usually placed in dummy packs located at strategic sites in the sterilizer. Alternatively, for gaseous sterihzation these may also be placed within a tubular hehx (Line-Pickerill) device. After the sterilization process, the aqueous suspensions or spores on carriers are aseptically transferred to an appropriate nutrient medium which is then incubated and periodically examined for signs of growth. Spores of Bacillus stearothermophilus in sealed ampoules of cultrrre medium are used for steam sterilization morritoring, and these may be incubated directly at 55°C this eliminates the need for an aseptic transfer. 

In contrast, parenteral suspensions have relatively low solids contents, usually between 0.5 and 5%, with the exception of insoluble forms of penicillin in which concentrations of the antibiotic may exceed 30%. These sterile preparations are designed for intramuscular, intradermal, intralesional, intraarticular, or subcutaneous injection. Syringeability is an important factor to be taken into consideration with injectable dosage forms. The viscosity of a parenteral suspension should be sufficiently low to facilitate injection. Common suspending vehicles include preserved isotonic saline solution or a parenterally acceptable vegetable oil. Ophthalmic and optic suspensions that are instilled into the eye/ear must also be prepared in a sterile manner. The vehicles are essentially isotonic and aqueous in composition. The reader should refer to Chapter 12 for further discussion on parenteral products. 

Two basic methods are used to prepare parenteral suspensions (a) sterile vehicle and powder are combined aseptically, or (b) sterile solutions are combined and the crystals formed in situ. Examples of these procedures may be illustrated using Penicillin G Procaine Injectable Suspension USP and Sterile Testosterone Injectable Suspension USP. 

Aqueous suspensions are prepared in much the same manner, except that before bringing the batch to final volume with additional sterile water, the solid that is to be suspended is previously rendered sterile by heat, by exposure to ethylene oxide or ionizing radiation (gamma or electrons), or by dissolution in an appropriate solvent, sterile filtration, and aseptic crystallization. The sterile solid is then added to the batch, either directly or by first dispersing the solid in a small portion of the batch. After adequate dispersion, the batch is brought to final volume with sterile water. Because the eye is... 

Ophthalmic, nasal, and oral inhalation preparations Appearance, color, consistency, pH, clarity (solutions), particle size and resuspendibility (suspensions, ointments), strength, and sterility... 

A spore suspension was prepared by resuspending the spores from the agar plate in 15 mL physiological aqueous solution (8.5 g NaCl, 1 g peptone, and 1 g Tween 80 in 1 L distilled water, sterilized at 121 °C for 20 min) with a Drigalski spatula. The spore suspension was diluted to a concentration of approximately 2.5 x lO spores/mL and stored in a 50 mL Falcon tube at 4 °C. 

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