Ophthalmic preparations that are intended for sterile topical application in the eyes require a rigorously controlled quality standard. Quality assurance requires validation, and since these products are susceptible to contamination, constant validation becomes important for maintaining quality and standard. This chapter gives a comprehensive description of the valve, process valve, and cleaning validation in sterile ophthalmic formulation. Process validation focuses on the desire to provide sufficient evidence that a process capable of producing a product that meets the standards set will indeed deliver such a product. In the context of sterile ophthalmic formulations, process validation means media fill simulation for assessing aseptic processing techniques, sterility for ensuring microbial-free product, and environmental control to check manufacturing environment freedom. Through these validation studies, the manufacturers can get confirmation of their processes’ stability and performance. Equipment validation means confirming the suitability of equipment that is used during the manufacturing of sterile ophthalmic products to perform its intended operations. That is design qualification, installation qualification, operational qualification, and performance qualification. Design qualification ensures that an item of equipment has been designed to provide requisite performance and function satisfactorily. Installation qualification ensures that an equipment is installed properly and harmonizes with the other manufacturing procedures. Operational qualification decides the competence of the equipment to perform at predetermined level. Performance qualification shows that the equipment continuously generates quality-related products. A particular emphasis is made to the specifics of ophthalmic devices and the discussion discovers the difficulties that appear during the use of sterile ophthalmic products due to the sensitivity of the ocular surface and the risk of microbial invasion. This chapter thus discusses various validation methods that are carried out in order to ensure aseptic processing. They include media fill simulations, sterility test, and environmental monitoring.