Manufacturing Techniques

In general, aqueous ophthalmic solutions are manufactured by methods that call for the dissolution of the active ingredient and all or a portion of the excipients into all or a portion of the water, and the sterilization of this solution by heat or by sterilizing filtration through sterile depth or membrane filter media into a sterile receptacle. If incomplete at this point, then this sterile solution is mixed with the additional required sterile components, such as previously sterilized solutions of viscosity-imparting agents, preservatives, and so on, and the batch is brought to final volume with additional sterile water.

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 (y 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 (329). Because the eye is sensitive to particles larger than 25 |im in diameter, proper raw material specifications for particle size of any dispersed solids must be established and verified on each lot of raw material and final product. The control of particle size of the final suspended material is very important, not only for comfort of the product but also for improving physical stability and resuspendability of the suspension throughout the shelf life and the in-use life by patients.

When an ophthalmic ointment is manufactured, all raw material components must be rendered sterile before compounding unless the ointment contains an aqueous fraction that can be sterilized by heat, filtration, or ionizing radiation. The ointment base is sterilized by heat, and appropriately filtered while molten to remove extraneous foreign particulate matter. It is then placed into a sterile steam-jacketed kettle to maintain the ointment in a molten state under aseptic conditions, and the previously sterilized active ingredient(s) and excipients are added aseptically. While still molten, the entire ointment may be passed through a previously sterilized colloid mill for adequate dispersion of the insoluble components.

After the product is compounded in an aseptic manner, it is filled into previously sterilized containers. Commonly employed methods of sterilization of packaging components include exposure to heat, ethylene oxide gas, and ^Co (y) irradiation. When a product is to be used in conjunction with ophthalmic surgical procedures and must enter the aseptic operating area, the exterior of the primary container must be rendered sterile by the manufacturer and maintained sterile with appropriate packaging. This may be accomplished by aseptic packaging or by exposure of the completely packaged product to ethylene oxide gas, ionizing radiation, or heat. Whenever ethylene oxide is used as a sterilant for either the raw material or packaging components, strict processing controls and validated aeration cycles are required to assure lower residual limits permitted by the regulatory agencies.

With the need of, and the preference for, unpreserved formulations of active drug(s) by ophthalmologists and patients, the blow/fill/seal concept, also termed the "form/fill/ seal method," has gained acceptance for manufacture of unpreserved ophthalmic products, especially for artificial tear products. In this process, the first step is to extrude polyethylene resin, at high temperature and pressure, and to form the container by blowing the resin into a mold with compressed air. The product is filled as air is vented out, and finally the container is sealed on the top. There are several published articles describing and validating this technology (330-335). Automatic Liquid Packaging, Incorporated, located in Woodstock, Illinois, U.S., designs and fabricates bow/fill/seal machines as well as provides contract manufacture in the U.S. Hollopack (BottlePack-6) and similar equipment in Europe.

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