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By Rakesh P. Patel, Gayatri C. Patel, Nikunjana A. Patel, Dr. Madhabhai M. Patel and Rishad Jivani, S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Gujarat, India
Today, a growing number of pharmaceutical manufacturers are using advanced aseptic processing technologies to minimize operator intervention and contamination risk in the filling and packaging of liquid parenteral drugs. One of these technologies is form-fill-seal (FFS), in which a polymeric material is formed and sealed inline to a container of choice, while the container is being filled.
FFS offers cost savings over conventional aseptic processing in glass. Traditional parenteral filling and packaging requires 23 steps and individual machines for filling, stoppering and capping. In contrast, FFS requires one piece of automated machinery, and takes place in six seconds or less.
The entire FFS process is performed under a class-100 laminar flow, preventing external contamination. The fully automatic, computer-controlled technology allows for filling and packaging of up to 40,000 bottles of IV fluid per day. Nitrogen purging options are available for sensitive formulations such as amino acids.
Sterilization is achieved through an automatic, microprocessor controlled, circulating water-shower. The water becomes sterile during the process without any hazard to the product. The pressure/temperature link controls the whole process. The system uses a nylon filter medium to remove colloidal silica, pyrogens, mycoplasma, viruses and other contaminants.
A typical FFS process works as follows.
When used for aseptic manufacturing, the cycle is conducted automatically within the machine’s own internal sterile air flushed environment (or air shower). The range, accuracy, reproducibility and response time of all controlling and recording instruments associated with the FFS machine and all supporting equipment, must be adequate to ensure that defined process conditions will be consistent during routine production. All instruments must be calibrated before any meaningful operational qualification can be performed. Written calibration procedures should specify the methods to be used for each instrument. Recalibration should be carried out after any maintenance, and all records maintained. New machine specs should state requirements for:
• Materials of construction for all components, particularly all contact parts, such as machine pipe work; internal components of purchased fittings like automatic valves including elastomeric and mechanical seals; pipeline joint seals; welding materials; filters and filter housings including casing and substrate layers of cartridges, as well as the main medium and all elastomeric seals; and polymer extrusion equipment.
• Pipe work configuration, with attention to sterile fluid pathways — for example, the elimination of “deadlegs”; position of thermocouples (“as installed” configuration, verified against the original design configuration and confirmed by temperature mapping is typically part of the validation protocol); and filter housing design.
• Porosity of the product and air filters. The validation data from the filter manufacturers should be available.
• Mold design, considering fill volume range, wall thickness, opening characteristics and ease of use, shape and other aesthetic considerations.
If FFS machines are used for the manufacture of non-sterile products, FDA’s current Good Manufacturing Practices (cGMP) requirements should be followed. When used to manufacture products intended for subsequent sterilization, these machines may be installed within an environment that would normally be considered appropriate for the manufacture and filling of terminally sterilized products. If the machines are to be used for the aseptic filling of sterile products they are usually provided with a localized environment at the point of fill with Grade A air.
The Installation Qualification process for any FFS system should confirm and certify that the room conforms to the specified Environmental Standard. A new cleanroom installation should include: room air filter integrity tests; determination of air velocity at the face of each air inlet filter; room air change rate; air particle counts, both viable and non-viable, in the rest condition; room pressure differentials; and lighting, heating and humidity readings.
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