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Manufacturing drug products aseptically requires the utmost care to ensure that safe and effective products can make it to patients. It starts with the facility design and construction and is immediately followed by the manufacturing equipment selection, installation, and implementation. When choosing the correct equipment and systems for manufacturing, process scientists, process engineers, microbiologists, and manufacturing experts start by defining the requirements. The user (manufacturing operations and manufacturing sciences) defines what is needed in the equipment, based on the manufacturing process. Each step is mapped out, from the start of the manufacturing sequence of operations through the transfer of the product to storage. Mapping of the process defines the points where critical steps occur and the factors that must be addressed by the equipment design and functionality. Once defined, the user requirements give the project team the basis for what the equipment must do and how it is expected to perform manufacturing the product.
In advanced sterile processing, the most critical phase is the sterile filling of products into vials, ampules, syringes, or cartridges. Aseptic filling can be performed using systems of varying complexity and a range of technology. The filling equipment can be installed in an open aseptic processing room through installation in fully automated, containment or barrier isolator technology. As technology has advanced, the protection of the product during sterile filling has been enhanced with barrier systems that shield the product from the environment and from the operators that are performing the manufacturing activities. Adding barrier technology to the processes reduces the risk to the product from environmental and human contamination. The first type of barrier technology was RABS (Restricted Access Barrier Systems) which limited but did not prevent human access to the filling process. A later and more popular type of barrier technology is the positive pressure glovebox isolator. Isolator technology allows strict control of the environment immediately around the product filling activities while the glove box design allows for operator manipulation during the process. There is still some introduced risk due to the use of polymer gloves on the isolator that are fragile and can become damaged during a batch, putting product at risk. As robotic and automation technology advances are made, some filler and isolator technology is fully automated, with no glove ports to access the interior of the filling isolator during processing. These systems are typically compact and are expected to run, fully automated, without human intervention. The elimination of human interaction with the process reduces the potential for product contamination, serving to de-risk the aseptic processing activities.
After the filling suite configuration is identified, the other pieces of the process have to be assembled, like a puzzle where each piece is integral to the safety and efficacy of the product. The design of the sterile filling process starts at the holding vessel and its connections to the sterile filtration apparatus. The holding vessel can range from small, single-use bags to large, stainless steel process vessels and the design of this vessel is important to successful sterile processing. The process vessel is connected, through properly designed connections, to the sterilizing filter and the product makes its transition to the filling system where each unit is filled under sterile conditions. All of the connections in the flow path are considered when designing robust and clean systems in parenteral manufacturing. Once filled and closed, the risk to the product drops dramatically. At this point, the filled units can be transported for their next step in the process, 100% visual inspection.
