General Safety Considerations Sterility

Every ophthalmic product must be manufactured under conditions validated to render it sterile in its final container for the shelf life of the product (65,66). Sterility testing is conducted on each lot of ophthalmic product by suitable procedures, as set forth in the appropriate pharmacopoeia and validated in each manufacturer's laboratory. While the majority of topical ophthalmic preparations contain preservatives for multiple-dose use, sterile preparations in special containers for individual use on a single patient must also be made available and are more common in the European Union. This availability is especially critical for every hospital, office, or other installation where accidentally or surgically traumatized eyes are treated, as well as for patients intolerant to preservatives.

The USP recognizes six methods of achieving a sterile product: (i) steam sterilization, (ยป') dry-heat sterilization, (iii) gas sterilization, (iv) sterilization by ionizing radiation, (v) sterilization by filtration, and (vi) aseptic processing (67). For ophthalmic products packaged in plastic containers, typical for ophthalmic products, a combination of two or more of these six methods is routinely used. For example, for a sterile ophthalmic suspension, bottles, dropper tips, and caps may be sterilized by ethylene oxide or y-radiation; the suspended solid may be sterilized by dry heat, y-radiation, or ethylene oxide; and the aqueous portion of the composition may be sterilized by filtration. The compounding is completed under aseptic conditions.

One can see by the complexity of these types of manufacturing procedures that much care and attention to detail must be maintained by the manufacturer. This sterile manufacturing procedure must then be validated to prove that no more than three containers in a lot of 3000 containers (0.1%) are nonsterile. Ultimately, it is the manufacturer's responsibility to ensure the safety and efficacy of the manufacturing process and the absence of any adverse effect on the product, such as the possible formation of substances toxic to the eye, an ever-present possibility with gas sterilization or when using ionizing radiation. For ophthalmic products sterilized by terminal sterilization (sterilization in the final sealed container, e.g., steam under pressure), the sterilization cycle must be validated to ensure sterility at a probability of 106 or greater.

In addition to process controls the USP has specific product sterility testing criteria for solutions, suspensions, ointments, and parenteral products. The two other major global compendia the Japanese Pharmacopoeia and the European Pharmacopoeia have similar testing criteria to assure the sterility of ophthalmic products. Unfortunately, the three major global compendia are not harmonized (68,69).

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