Peer Reviewed: Aseptic Processing www.ivtnetwork.com ABSTRACT Ophthalmic preparations are sterile liquid, semi-solid, or solid preparations intended for application to the conjunc- tiva, the conjunctival sac, or the eyelids. Sterility is a key issue in manufacture and use of ophthalmic products. Preservative selection is a critical activity in product design. Other important aspects requiring assessment in the manufacture of ophthal- mic products include sterility, tonicity, pH, buffering, drug toxicity, solubility, stabili- ty, viscosity, aseptic filling, packaging and storage. Microbial content or bioburden of the raw materials, in-process intermedi- ates, and drug substance or active product ingredient are potential sources of con- tamination and require incoming testing of ingredients. Most ophthalmic products are sterilized by aseptic filtration through a 0.22-μm filter. Preservatives in the oph- thalmic solution will, to varying degrees, bind or be adsorbed onto many common membrane filter materials. Most commer- cial liquid ophthalmic products are pack- aged in plastic containers fitted with noz- zles for drop wise administration. Plastic containers are generally sterilized by gam- ma irradiation or ethylene oxide. Facilities used to prepare ophthalmic preparations are required to operate within a controlled environment using HEPA filtration to min- imize contact of airborne contamination with critical sites such as open product prior to application of closures, injection ports, and vial septa. Aseptic filling oph- thalmic medications is typically achieved through the use of blow-fill-seal (BFS) technology in which product containers are formed from plastic granules on-line and then filled with drug solution and sealed in one operation. Blow-fill-seal-technology has a theoretically lower risk of microbial contamination compared with convention- al aseptic filling. Quality control of these products includes traditional tests such as identification, potency, purity, impurities, sterility, and particulate matter and per- formance tests such as dissolution or drug release. Physical or chemical instability will be demonstrated by noticeable changes in the dosage form such as changes in color, consistency, agglomerates, grittiness, emul- sion breakdown, crystal growth, shrinking due to evaporation of water, or evidence of microbial growth. e finished product must also be subject to the sterility test and endotoxin tests. INTRODUCTION Ophthalmic preparations (eye prepara- tions) are sterile liquid, semi-solid, or solid preparations that may contain one or more active pharmaceutical ingredients. Oph- thalmic products are intended for appli- cation to the conjunctiva, the conjunctival sac, or the eyelids. e course of treatment may extend during several days. Although eye preparations contain a preservative, there is a probability of microbial contam- ination aſter the package sterility seal has been broken during the period of use. ese forms of medication must be ad- ministered directly to the eye because many of the ingredients such as peptides, pro- teins, and chemotherapeutic agents would be inactivated in the gastrointestinal tract if they were taken orally. e issue of over- riding importance in relation to the prepa- ration of all ophthalmic dosage forms is that they are sterile. is paper considers the key elements relating to the manufacture of ophthalmic products from the perspective of microbi- al contamination control. Its focus is upon the aseptic dispensing of the products and environmental and technological require- ments including blow-fill-seal filling and container sealing systems. PRESERVATIVE SELECTION e first contamination-related consid- eration is with the selection of the preserva- tive and its efficacy. An ideal preservative is a rapidly effective and topically non-irritat- ing. It may be a single antimicrobial agent or a mixture of such agents. Preservatives are designed to prevent the growth or to destroy microorganisms accidentally intro- duced into the product when the container is opened during use. Preservatives are a necessary additive. ere are several critical considerations in selecting a preservative for inclusion in the dosage form. ese include preserva- tive stability, chemical compatibility with the other components of the formulation, compatibility with packaging materials, and concentration. Preservative agents must to be effective throughout the entire shelf life of the product (1). Common pre- servatives used with ophthalmics include benzalkonium chloride (BAK), parabens, potassium sorbate, chlorhexidine acetate, chloroscresol, and polyhexamine gluconate (2). A preservative will only provide pro- tection from microbial growth for a short Sterile Ophthalmic Preparations and Contamination Control Tim Sandle