Particulate products, aseptic processing

The purpose of open unidirectional airflow benches is to protect products from particulate contaminants by creating a controlled environment. These benches are used, for example, in electronic, biological, pharmaceutical, and food industries. It should be mentioned that within pharmaceutical production, aseptic sterile processes must be carried out in a Class 100 environment (U.S. Federal Standard 209 E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones). To avoid particle contamination in the bench, horizontal or vertical airflow with high-efficiency particulate air (HEPA)-filtered air is used. The air velocity is normally 0.4-0.5 ra s". Some examples of typical arrangements of open unidirectional airflow benches are shown in Fig. 10.51. 

The concepts of aseptic processing for pharmachemical processing to assure the sterility of the product is no different than classical parental drug production. A sterile facility has a number of fundamental characteristics the first is complete separation and isolation from all other operations. This dictates that people, materials, and even the ventilation be independent of all other activities at the site. First, the HVAC system must be totally independent of the main system, it providing only filtered air, generally through HEPA filters that remove essentially all particulate matter larger than 0.21 pm. 

To reduce risks of microbial contamination, aseptic processing is executed in a controlled environment, in which the air supply, facility, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels [3]. Contact between product and environment should be minimised, sterile equipment should be used, and there should be two consecutive filtration processes through sterile 0.2 pm filters. The first filter will minimise the microbial challenge to the second filter, which should be just before the sterile final container. The shelf-life of the product is often restricted and it may be stored in the refrigerator to further reduce the risks of microbial growth. 

While blending times and tablet press parameters may not be fully established for early phase clinical supply manufacturing of solid oral dosages, those variables have a much lower potential to directly affect product safety than sterility, endotoxin contamination, or objectionable types and levels of particulates do for sterile, parenteral clinical supplies. Because clinical supplies can be incompletely characterized, and are usually given to patients already in weakened conditions, those processes and their related validation data necessary to guarantee patient and product safety (e.g., sterilization and aseptic fill) are expected to be in place as early as Phase I clinical supply manufacture. ... 

A suitably sized solution preparation system similar to that mentioned under the previous sections can be used to provide material for bulk freeze drying. (Since product solutions can be sterile-filtered directly into the final container, microbial and particulate exposure will be minimized.) The sterile solution is subdivided into trays and placed into a sterilized freeze dryer. Aseptic transfer of sterile product in trays to the freeze dryer must be validated. After tray drying, the sterile product is aseptically transferred through a mill into suitably designed sterile containers. The preparation of sterile bulk material is usually reserved for those cases where the product cannot be isolated by more common and relatively less expensive crystallization methods. Due to recent advances in this field, a freeze drying process should be considered as a viable option. ... 

Small stocks of substances that have to be measured or weighed during the production process (e.g., buffers) may be kept in the production area, provided that they are not returned to the general stocks. Otherwise, dry materials used to formulate buffers, culture media, etc. should be weighed and put into solution in a contained area outside the purification and aseptic areas in order to minimize particulate contamination of the product. 

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