Designed for sterility assurance.

Aseptic filling processes for liquids are subject to strict conditions to prevent microbiological contamination during production. The patented Slim Design of the new VF 18 "liquid filler" by Romaco Macofar guarantees advanced aseptic processing conditions. Risky manual interventions are restricted to a minimum when the machine is running at medium-high speed; as such, according to Romaco Macofar's Nicola Magriotis, it's ideal for the filling of highly sensitive biotech pharmaceuticals.

Specialists are widely united regarding the growing significance of so-called red biotechnology. Almost half of the pharmaceuticals that are currently undergoing licensing procedures around the world are biotech products. It is conceivable that high-priced niche products will gradually conquer international markets and the age of agent innovations, sold in large quantities, appears to be history. Great advances in gene technology in recent years have formed the basis for this development, with biopharmaceuticals being obtained from the organic material of animals, plants and micro-organisms. They are used in the hope of a medical breakthrough in the treatment of life threatening illnesses such as cancer or in the diagnosis of rare inherited diseases. In addition, biotech medicines are used in the manufacture of vaccines and insulin preparations.

The majority of biotech products are injected into patients instead of being administered orally. The manufacture of these parenteral drugs is thus subject to the strict conditions of sterile production procedures. These obligatory standards are laid down in "Good Manufacturing Practices" (GMPs) that are issued by both the European Commission (EC) and the US Food and Drug Administration (FDA). And, despite variations in classification, the directives agree on one point: the particle content of the air during filling and closing operations has to be minimized as much as possible. Particles can contaminate a product as well as act as a vehicle for harmful micro-organisms. This makes critical area control essential. The limit values are defined according to product type, production mode and area. The FDA and EC thereby differentiate four clean room classes arranged from Grade A to Grade D (EC), and Class 100 to Class 100,000 (FDA). The zones of Grade A and Class 100 are subject to the most rigorous regulations. These standards must initially be taken into account during the design of a plant for the sterile filling of pharmaceutical liquids.

The VF 18 Slim Design Liquid Filler

During sterile filling, the main aim is to keep the concentration of harmful micro-organisms in the machine's processing area and in the ambient air as low as possible. This is achieved through the use of ventilation systems and filters, and the targeted control of temperature, air humidity and air pressure, amongst others. The technical design of the filling equipment also plays a vital role. The Romaco Macofar VF 18 aseptic filling machine is built extremely compactly: the distance between the filling nozzles and the front of the machine is less than 600 mm. The critical zone, the so called "white area," through which the open containers are passed, is very narrow to ensure the effective control of harmful microbes. The patented Slim Design of the machine supports the strict monitoring of the aseptic process and counteracts the formation of particles. The VF 18 can fill bottles and vials with diameters of 14-68 mm and heights of 35-140 mm. The fill volume is between a fraction of a millilitre and 250 mL. Moving at medium-high speed, the sterile filling machine has a maximum output of 18,000 vials per hour.

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In addition to processing pharmaceutical liquids, the plant is also used for handling freeze-dried products. There are three different filling systems available: a volumetric pump system, a mass flow filling system and peristaltic pumps. If required, the machine can be fully integrated into an aseptic line. In this case, the vials to be filled are initially fed to a washing machine before passing through a depyrogenation tunnel, where they are sterilized using hot air at up to 340 [degrees]C. After the aseptic filling and stoppering using rubber stoppers, the vials can optionally be freeze-dried before receiving a final seal using an aluminium cap.

Through-Wall Installation

Generally, aseptic filling processes must take place in their own clean rooms, set up specfically for the purpose and subject to particular conditions regarding hygiene and air quality. The maintenance and monitoring of these sterile areas is extremely laborious and costly, which is why small rooms are advantageous. The design of the VF 18 is ideal for through-wall installation, where the rear section of the machine is sealed off from the clean room. Maintenance work can thus be done at any time by factory technicians without having to comply with the special regulations for entering clean rooms. This not only saves the space and the costs involved in setting up sterile zones but also increases production security. The fewer people entering clean rooms, the lower the risk of microbial contamination. A study published by the "Parenteral Drug Association" (PDA) on "Top Contamination Sources in Cleanrooms" verified that the greatest risk of germ contamination comes from human beings. (1) In their current GMP report, the FDA supports this assumption: "As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases. To ensure the maintenance of product sterility, it is critical for operators involved in aseptic activities to use aseptic technique at all times." (2)

The respective GMPs therefore also contain precise rules for behaviour in white areas. These stipulate, for example, the regular training of personnel, and contain directions on clothing and details regarding how to deal with sterile instruments. Fast and frequent movements in clean rooms are to be avoided, as uncontrolled air circulation promotes the unwanted formation of particles. Only one person, who controls the machine through a touchscreen operator panel, is generally required to operate the Macofar VF 18. The vial filler is constructed so that the operator can comfortably reach all parts of the machine without having to make any large movements. In this way, the machine combines all the advantages of balcony and tabletop design machines: the high distance between the clean room floor and the machine bottom plate minimizes the surfaces to be cleaned and the high distance between the bottom plate of the machine and the open vials avoids air turbulence around the vials.

Air-Flow Regulation During Aseptic Processing

Production conditions for the sterile filling of pharmaceuticals have improved significantly in the last few decades. The development of HEPA filters in the mid-1950s was a breakthrough for modern aseptic processes. The introduction of gas-tight glove boxes, with glove access for manual operations was a further step towards product sterility assurance. Technical innovations in isolator technology are providing new opportunities as they move the conventional clean room into the machine process area. Isolators form physical barriers between the aseptic process and the operating environment of the plant. As direct human intervention is not possible here during production, this strict separation requires reliable work routines and a higher degree of automation in mechanical production. The alternative is "Restricted Access Barrier Systems," or RABS. This technology combines clean room and isolator technologies: RABS systems allow limited individual access into sterile production workflows, which is why they are more flexible than isolators--but slightly controversial regarding their product protection.

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Depending on the application, the VF 18 can optionally be equipped with isolators or RABS. Both procedures capitalize on the flow principles of modern air conditioning technology. Laminar flow systems can be installed in both the classic clean room environment and the interior of the machine. The cleaning effect is achieved with an air preparation facility, which steers sterile air from above into the critical zone. Owing to the prevailing pressure conditions, a vertical flow of air is generated, which protects the processing area. A unidirectional flow of air prevents turbulence in the open-vial area. Swirling air in the sterile zone must always be avoided, as it inhibits product protection. At the same time, turbulence cannot be completely eliminated because it is a physical consequence of any mechanical movement. The interior of the VF 18 is therefore designed so that the high distance between the machine bottom plate and the vials avoids turbulent air movements in the vials area; they spread out evenly in the lower section of the filling machine without approaching the open vials. To reduce the formation of particles further, linear mechanical movements between 'white' and 'grey' areas are converted as much as possible into rotating movements.

Particle Reduction Through Automation

Thanks to the use of brushless servomotors, the VF 18 provides a high level of automation that leads to operational accuracy as well as process reproducibility. Size parts changeover is almost automatic and can be done by recalling product recipes on the operator panel. Integrated weighing units check the weight of empty and full vials and automatically adjust the filling process. "Cleaning in Place" (CIP) and "Steaming in Place" (SIP) systems are optionally available and make the time-intensive cleaning procedures that are essential for product sterility assurance much easier and repeatable. The whole production schedule is documented and data can be viewed at any time. This increases the safety and transparency of the whole process.

Personnel interventions are therefore reduced to the greatest possible extent in the case of frequent product changes and/or small batch sizes. Biotech pharmaceuticals are frequently manufactured in very small quantities; they often represent very special/individual applications and/ or expensive niche products. The development of active pharmaceutical ingredients requires costly procedures and many years of research work. The risk of contamination by harmful micro-organisms should therefore be taken into account as a "constant" during processing. The aim of development work in the coming years will be to continually optimize equipment suitability for aseptic processing. The technology of the VF 18 vial filler is one of the ways of making this possible.

For more information

Nicola Magriotis

Romaco Macofar

Via Marzabotto 5, I-40067 Rastignano (BO), Italy.

T. [phone]

E. [e-mail]

www.romaco.com

References

(1.) J.P. Agalloco, et al. "Technical Report No. 36, Current Practices in the Validation of Aseptic Processing-2001," PDA J. Pharm. Sci. Technol. 56(3, Supplement) 2002.

(2.) US Department of Health and Human Services, Food and Drug Administration, "Guidance for Industry, Sterile Drug Products, Produced by Aseptic Processing--Current Good Manufacturing Practice," Pharmaceutical CGMPs (September 2004) pp 1-63.