Barriers for success

There is a trend in the pharmaceutical industry to use isolator technology with automatic filling systems to minimise direct human contact.

The resultant improved product handling reduces the risk of microbiological and particulate contamination, enhancing product sterility. It also gives the operator more protection from toxic or hazardous compounds. Two definitions will help understand the process better: containment is necessary to achieve a validated level of control of a potent substance to provide protection for people and the environment (level of exposure); isolation is necessary to protect the product from contamination from the environment by particulates, chemicals and micro-organisms. From an engineering point of view, containment is the application of design solutions to prevent uncontrolled escapes of highly potent or toxic compounds from a defined area, while isolation can be defined as the application of engineering solutions to prevent contamination or degradation of clean or aseptic materials and processes.

Specific machine designs According to what sort of safety needs to be achieved, the manufacturer will use a specific type of machine design. Sometimes, however, the task is more complicated. For cytotoxic products, the goal is to achieve both protection of the environment and protection of the product. This is also true when handling particularly high value products. There is, however, a conflict in the goals, since containment systems generally run under a negative atmosphere (pressure) while isolation is generally run under a slight positive one. In this case, the use of barrier technology along with particular engineering and manufacturing details can be considered as the key factor. As pharmaceutical companies look to reduce the "time to market" of new pharmaceutical compounds, toxicological and engineering issues must be multi-tasked. Co-operation between customer and manufacturer of the filling equipment is of paramount importance to ensure the containment technology is effective. As with all new working methods and procedures, barrier technology also brings with it advantages and disadvantages over the traditional solution – so what is the correct solution for the pharmaceutical industry and how can a machinery manufacturer deal with this requirement? The answer is complex. There are three possible mechanical interfaces that can be used to integrate a filling machine with an isolator. The most economic is to arrange the machine to accept the attachment of an isolator enclosure, keeping the standard machine base (Fig 1). This solution implies a simple design and construction phase since machine and isolator are two separate sections. In this case, the interface is located under the processing area. Another possibility is to design the machine baseplate to allow a mechanical connection and seals above the machine base itself (Fig 2). This makes cleaning and draining the system much easier.

Most complete solution The most complete solution is to have a so-called "six-walls isolator" (Fig 3), which is more complex since a customised design is required. This is the optimum choice in terms of cleanliness, draining and protection against leaks, but obviously involves more precise, accurate and complex design and construction concepts, which have to be considered at the assembly stage. From IMA's experience, the best compromise is the semi-integrated solution, both in terms of technology, construction time, costs and operational flexibility. In addition, there are a number of engineering design criteria that are common for all equipment to work under an isolator independently if it is a liquid or powder filling machine or even a tablet press. Further design features are implemented according to the specific product form: • Equipment is designed from the outset to be integrated with an isolator enclosure • Integrated teamwork must be in place throughout the supply chain – among the barrier, filling and sterilising system manufacturers • A dynamic pressure barrier can be installed between the different isolators in the line to avoid cross-contamination • The control of all physical parameters involved, such as particulates, humidity, pressure and temperature, during all phases of operation, must be a primary issue • Preference must be given for a compact machine with reduced footprint to reduce isolator volume and ease manual operator access and maintenance. To achieve this, ergonomic studies are carried out with the isolator supplier to define exact positioning of glove ports and RTP (rapid transfer ports) • "Air-smoothed", rounded shapes of all mechanical parts inside the machine is a must to assure a correct LAF at a defined and constant speed – especially at the filling location • All parts must be designed to ease uni-directional air flow and sterilant gas distribution inside the machine. • Vial transport systems, star-wheels and all size change parts must be specially designed to allow quick changeover, low maintenance and ease of transfer from the external environment. The size and weight of the parts is particularly important. • The machine bedplate sealing is another important issue. The choice of gaskets and seals must be accurate to ensure such items have the same mechanical and thermal properties. For example, parts in contact with the product or which cannot be sterilised in place must be able to withstand autoclave sterilising cycles. Parts must also be able to operate without lubricants in the aseptic processing area and in a dusty environment, with minimal release of particulates • The machine must be totally air-tight to prevent leaks or communication points between sterile and grey areas • From the initial design stage it must be ensured that all construction materials are compatible with the sterilising agents. Materials commonly used in isolators are AISI 304 L or 316 L stainless steel, high density polyethylene, glass, silicone rubber, Viton and ceramic (for liquid dosing units)

Reducing manual intervention To further reduce the operator's manual intervention, the filling machine must be equipped with a series of "improving systems" which should be proposed and provided by the manufacturer, such as: • CIP/SIP systems of the filling circuit for automatic product change • IPC check-weighing system. The availability of systems to check 100% of production is a further step towards total assurance of product quality • Automatic filling volume adjustment to ensure a higher filling accuracy with feed-back system from IPC One of the most critical aspects of working in aseptic conditions and under an isolator is the cleaning procedure that follows. IMA has several applications in the US market for filling both liquid and powder forms with semi-automatic cleaning of the white area. The technology allows cleaning of the sterile area while protecting the operator from product contamination, especially vital in the case of powder or hazardous liquids. The system works with an isolator without sealing and a surface roughness finish of the mechanical parts of around µRa0.8 and µRa1.6. The filling machine baseplate has a minimum inclined surface of roughly 2%. The finish and subsequent treatment of exposed surfaces, as well as the reduction of "dead areas" around gaskets and seals, are also critical to ensure thorough cleaning and to avoid cross contamination. The cleaning operation is divided into phases: some are manual wiping operations, while others are automatic. The operator manually washes the upper machine base and the isolator walls using gloves; the filling nozzles can be either dismantled and cleaned separately or cleaned in place (CIP). It is preferable that the dosing units are also washed and sterilised in place to reduce transfer and manual activities between grey and sterile areas, which would increase the chances of contamination. Demineralised water is used to wash the system. To ensure the system has a long life, it is necessary to guarantee that all stainless steel surfaces are treated with electro polishing or passivation. After the manual cleaning the operator positions the nozzles to allow the automatic cleaning of the transport system with the machine in motion. This function is set on the MMI of the machine and carried out automatically. At the end of the cycle, once the machine is not running, the operator can dry the isolator walls and machine base with a compressed air gun. The ultimate drying phase is carried out automatically. The isolator re-circulates hot air at 35°C for two hours. The semi-automatic washing and cleaning system of an isolator offers undeniable advantages over traditional cleaning processes of a sterile room. It is part of the manufacturer's role to advise the final system user about these advantages. Dedicated solutions can be adopted, depending on the specific nature of the contamination.

Sterilisation of the system Chemical sterilisation of the system is carried out by introducing the sterilising agent in the vapour or gaseous phase by means of the air handling units or nozzles placed inside the isolator itself. Vapour phase hydrogen peroxide is typically used nowadays to sterilise the processing area. During the sterilisation phase the machine can run at a reduced speed to allow the sanitising agent to reach all hidden parts, such as belt conveyors, silicon bellows and gaskets. Round shapes and no shaded areas are a must, which is far more stringent than usual in cleanroom design. The reduction of manual intervention also requires a highly advanced level of engineering accuracy and automation, especially when maintenance and operational activities are concerned. The use of this kind of technology clearly involves a deeper involvement and commitment by the filling machine manufacturer than in traditional cleanroom operations.