Manufacturing Environment

Aside from drug safety, stability, and efficacy and shelf life considerations associated with tonicity, pH, and buffer capacity, the major design criteria of an ophthalmic pharmaceutical product are the additional safety criteria of sterility, preservative efficacy, and freedom from extraneous foreign particulate matter. Current U.S. standards for Good Manufacturing Practices (GMPs) (322) provide for the use of specially designed environmentally controlled areas for the manufacture of sterile large- and small-volume injections for terminal sterilization. These environmentally controlled areas must meet the requirements of class 100,000 space in all areas where open containers and closures are not exposed, or where product-filling and -capping operations are not taking place. The latter areas must meet the requirements of class 100 space (323). As defined in Federal Standard 209E, classes 100,000 and 100 spaces contain not more than 100,000 or 100 particles, respectively, per cubic foot of air of a diameter of 0.5 |im or larger. The readers are also referred to the British Standard 5295: 1989 for classification of clean room environments. Often these design criteria are coupled with laminar airflow concepts (324,325). This specification deals with total particle counts and does not differentiate between viable and nonviable particles. Federal Standard 209 was promulgated as a "hardware" or mechanical specification for the aerospace industry and has found applications in the pharmaceutical industry as a tool for the design of aseptic and particle-free environments. Class 100,000 conditions can be achieved in the conventionally designed clean room where proper filtration of air supply and adequate turnover rates are provided. Class 100 conditions over open containers can be achieved with properly sized high-efficiency particulate air (HEPA)-filtered laminar airflow sources. Depending on the product need and funds available, some aseptic pharmaceutical environments have been designed to class 100 laminar-flow specifications throughout the manufacturing area. However, during actual product manufacture the generation of particulate matter by equipment, product, and (most importantly) people may cause these environments to demonstrate particulate matter levels two or more orders of magnitude greater than design. It is for this reason that specialists in the design of pharmaceutical manufacturing and hospital operating room environments are beginning to view these environments not only from the standpoint of total particles per cubic foot of space alone but also from that of the types of particles, for example, the ratio of disease-transmitting biocontaminants to inert particulates (326).

Such environmental concepts as mass air transfer may lead to meaningful specifications for the space in which a nonterminally sterilized product can be manufactured with a high level of confidence (327).

When dealing with the environment in which a sterile product is manufactured, the materials used for construction of the facility, as well as personnel attire, training, conduct in the space; the entrance and egress of personnel, equipment, and packaging; and the product, all bear heavily on the assurance of product sterility and minimization of extraneous particulate matter.

The importance of personnel training and behavior cannot be overemphasized in the maintenance of an acceptable environment for the manufacture of sterile ophthalmic products or sterile pharmaceutical agents in general. Personnel must be trained in the proper mode of gowning with sterile, nonshedding garments and also in the proper techniques and conduct for aseptic manufacturing. The Parenteral Drug Association can be contacted at their offices in Bethesda, Maryland, for a listing of training films on this subject. To maximize personnel comfort and to minimize sloughing of epidermal cells and hair, a cool working environment should be maintained, with relative humidity controlled to between 40% and 60%. Additional guidelines on pharmaceutical clean room classifications—which became effective on January 1, 1997, for Europe—are contained in a "Revision of the Annexes to the EU Guide to Good Manufacturing Practice— Manufacture of Sterile Medicinal Products" (328).

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