Multidose sterile formulations

Preservatives are necessary when developing multidose parenteral formulations that involve more than one extraction from the same container. Their primary function is to inhibit microbial growth and ensure product sterility throughout the shelf life or duration of use of the drug product. Commonly used preservatives include benzyl alcohol, phenol, and m-cresol. Although preservatives have a long history of use with small-molecule parenterals, the development of protein formulations that include... 

For multidose sterile products, the preservative must be capable of reestablishing sterility between each use, whereas for a non-sterile topical cosmetic the function of the preservative might simply be to prevent growth. The associated toxicity of preservatives often limits the concentrations at which they can be employed thus, lower concentrations are generally employed for opthal-mic products and injectables. In choosing a preservative the likely capacity required, the rate of killing desired, and the ingredients and pH of the formulation must be borne in mind. 

Commercial kits contain the freeze-dried, sterile formulation in a multidose vial, sealed under a nitrogen atmosphere. The lyophilized preparation is readily soluble in Tc-pertechnetate injection and in saline. For labeling, the vial is placed into a lead-shielded container. Aseptically sterile Tc-pertechnetate shonld be injected into the vial in a volume of 1-8 ml, with an activity up to 2.22 GBq (60 mCi). Before removing the syringe, 2-5 ml of gas should be withdrawn from the space above the solution to normalize the pressure inside the vial. The shielded vial should be agitated gently to dissolve the lyophilized material. The reaction should proceed at room temperature for about 20 min, with occasional agitation. 

Dosage form Epogen is formulated as a sterile, buffered solution in single-dose, preservative-free vials. Each ml of solution contains 2000,3000,4000, or 10,000 units of epoetin alfa. A single-dose vial containing a more concentrated solution, 40,000 units per ml, is also available, as are multidose, preserved vials. 

Preservatives In addition to those processing controls mentioned above (Section 3.1.4.3), the sterility of a product may be maintained through the addition of antimicrobial preservatives. Preservation against microbial growth is an important aspect of multidose parenteral preparations as well as other formulations that require preservatives to minimize the risk of patient infection upon administration, such as infusion products [52], Aqueous liquid products are prone to microbial contamination because water in combination with excipients derived from natural sources (e.g., polypeptides, carbohydrates) and proteinaceous active ingredients may serve as excellent media for the growth [57], The major criteria for the selection of an appropriate preservative include efficiency against a wide spectrum of micro-... 

Benzyl alcohol is commonly used as a preservative in multidose injectable pharmaceutical formulations. For this purpose, concentrations in the range of 0.5-2.0% are used and the whole amount of benzyl alcohol injected is generally very well tolerated. Concentrations of 0.9% are used in Bacteriostatic Sodium Chlorine (USP), which is often used in the management of critically ill patients to flush intravascular catheters after the addition of medications or the withdrawal of blood, and in Sterile... 

Unit-dose systems offer the easiest technical solution to this problem, but have the disadvantages of higher cost of manufacture and of not being as compact as a multidose product containing equivalent doses. Unit-dose products are usually made of low-density polyethylene (LDPE), with the formulated sterile solution being without a preservative, and sealed using the form-fill-seal process. 

Ophthalmic products have to be manufactured sterile and be free from micro-organisms. Once opened, the sterility of a multidose product must be maintained during its period of use. This is usually required for at least 4 weeks, after which the product is discarded. If the drug itself does not possess antimicrobial properties, then an antimicrobial preservative must be included in the formulation to ensure that any micro-organisms accidentally introduced during use are destroyed. 

Sterile Epinephrine Ophthalmic Solution USP takes us out of the realm of sterile parenteral products into ophthalmics. The manner of presentation of ophthalmics (i.e., as drops or ointments) is likely to be quite familiar. For the most part (but not exclusively) they are in multidose presentations. As such, most formulations include some form of preservative to control proliferation of any microorganisms that may by chance contaminate the product on one or other of the occasions when it is open, or during the time when it is left standing on the bathroom shelf. The inclusion of preservatives in a multidose formulation of an ophthalmic (or parenteral) is not a primary part of the process of achieving sterility. It has quite a separate purpose. 

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