Recent developments in vial and syringe filling lines have been primarily evolutionary rather than revolutionary, with a few exceptions. Most of the new vendor offerings have focused on improving the flexibility, reliability, or efficiency of the filling and associated processes; on reducing product contamination risk; or on minimizing personnel exposure to potent compounds. Innovations introduced by one vendor have quickly been followed by similar offerings from its competitors.
Trends which have been identified through an evaluation of recent machine offerings, as well as discussions with key equipment suppliers, fall within the following categories:
* Flexible lines with more rapid changeover
* Improved filling techniques and process control
* Reduced customization
* Integrated and compact lines
* Enhanced integration with barrier isolators or RABS
* Higher grade vial capping
* Integration of external vial washing
Flexible Lines with More Rapid Changeover
According to Jeff Jackson, PHL Sales Director for Bosch Packaging Technology North America, and John Erdner, Director of Sales and Marketing for IMA North America, there has been a move towards filling of smaller batches of higher value drugs, requiring more accurate fills and faster line changeovers.
Pharmaceutical companies are driving vendors toward single use, disposable dosing systems in which the entire product path is discarded; for example, peristaltic pump systems which are further detailed below. Lengthy CIP/SIP of filling pumps and transfer piping (along with the required cleaning validation for each product) is replaced by simple mounting of a new presterilized tubing set and product tank. In addition, disposable product vessels, such as Stedim bags, are being combined with the dosing system for even greater disposability1.
Some vendors have improved their designs so that only one change part is needed for a vial diameter change, and others have designed vial carriers suitable for a wider range of diameters than ever before. This reduces spare parts cost and improves line efficiency by speeding changeover.
Several clients are now specifying fillers with more than one dosing system, to provide flexibility for filling a variety of products. Vendors have responded by supplying interchangeable, cart-based stations, and are looking into building a dual dosing system capability in a single station. The desired dosing system is then selected by the operator on the HMI.
Rapid changeover has now become more important than machine speed for many pharmaceutical companies. However, a number of clients still have high-volume products which demand a high-speed line. Varying customer demands have resulted in a wide range of machine offerings, from semi-automatic 1500/hr vial fillers to a fully automatic 48,000/hr vial line just introduced by Groninger. Vendors including Bausch & Stroebel and Optima (Inova) have recently gone from a 10-head nested syringe filler to a 16-head, raising processing rates of 1 ml long and 0.5 ml syringes to up to 60,000/hr.
Improved Filling Techniques and Process Control
Rotary piston pumps (volumetric): Still the most commonly used filling mechanism, this requires matched sets of piston and cylinder due to the tight clearances between the two, plus manual disassembly and cleaning after each use. While suitable for liquids of a wide range of viscosities and temperatures, use with shear- sensitive liquids and suspensions can be an issue. According to Matthias Poslovski, Director of Technical Sales at Optima Group Pharma GmbH, suspensions of particle size <10mcg may become trapped between the piston and cylinder, blocking it from cycling. Hard suspensions can degrade the surfaces of stainless steel pumps. CIP/SIP of rotary pumps can also be problematic.
Rolling diaphragm pumps: This is essentially a variant of a piston pump with a membrane joined to the piston and body to prevent product leakage. While typically fabricated of stainless steel, a new development from Bosch is a disposable system consisting of polycarbonate pump and needle bodies, with stainless steel retained for the needle tips in order to achieve the required tolerances.
Peristaltic pump systems: These systems were originally used for fluid transfer rather than high speed, accurate dosing. To improve their accuracy, machine suppliers have replaced the stepper motor controls with servo-drive controls, with the ability to control the motion and position of the rollers, and have integrated a feedback loop from a checkweighing sytem. Mechanical setup has been made more repeatable by changing the dynamics of how the elastomeric tubing is pinched on the unit. As noted above, this type of filling offers complete disposability, with virtually no chance of product cross-contamination, plus fill weight is temperature-independent. Disadvantages include a limited product viscosity range and a filling precision somewhat less than that of rotary pumps.
Time/pressure: These systems, incorporating a pressurized product tank and pinch valves to open and close silicone tubing between the tank and filling needles, have now become as accurate or in some cases more accurate than pump systems, due to improvements in tank headspace pressure control and process feedback control.
Other reasons for their increasing popularity include very low product shear and compatibility with CIP/SIP. Time/pressure systems do take more time to tune in at the start of a fill, and require control and/or compensation for product temperature as this affects product flow properties.
Mass-flow: This mass rather than volume-based technique utilizes the Coriolis effect created when fluid passes through a vibrating sensor pipe to control the opening and closing of a valve surrounding silicone tubing. The viscosity range is limited and fill accuracy at the lower end of the scale (of interest for injectables) is inferior to the other methods, so its use is currently limited to products such as ophthalmics.
Integrated Process Control (IPC) for vial fillers: Checkweighing with feedback for automatic adjustment of the metered quantity is especially valuable in that it reduces the overfill of expensive products and compensates for any fill weight drift over time. 100% checking can be supplied for low to intermediate output fillers, or can be used for the beginning and end of fill for high output machines, with a lower sampling rate employed throughout the rest of the fill. Weigh cells are isolated on a freestanding base to eliminate effects of machine vibration. While IPC systems have been available for several years on vial lines, the control algorithms have grown more sophisticated, and mechanical design has improved to the point that some new machines are capable of doing 100% testing at rates of up to 375/minute. Larger and larger proportions of fill lines are being purchased with these systems, with increasing sampling rates, notes Jorg Bengelsdorf, Director of Pharmaceutical Projects for Groninger USA.
IPC for nested syringe fillers: Syringe fillers have lacked an automated checkweighing feature until the last three to five years. As noted by Andreas Plank, Technical Sales Manager/Project Management for Bausch & Stroebel, the increasing number of products being prefilled in syringes and the high value of a subset of these, biotech products, have been an incentive for minimizing overfills. Furthermore, the double handling of syringes in and out of nests for tare weighing and then reweighing after filling require more complex design and space than for vials which are freestanding, taking more time to develop.
Non-contact checkweighing: Since BOC Edwards’ 2005 integration of an NMR-based, in-line, noncontact check-weighing (NCCW) system on a filling line, only a couple of lines have been built with such a feature. The elegance of this approach is that it is rapid and does not require contact with or removal of the vial from the transport system, permitting 100% weighing at high speed, avoiding the introduction of cosmetic defects on the container, and simplifying mechanical design of the filler. Downsides limiting more widespread adoption include high cost and the need to calibrate or “train” the system for each product to be run on the line.
Faced with smaller internal engineering and validation staff handling multiple projects at multiple sites, and having had negative experiences in the past with highly customized equipment, a majority of pharmaceutical clients have adopted the mantra of wanting “standard” machines. Standardization has included the selection of vendors, machine models, PLC controls, HMIs, component transfer systems, filling method, and design of RABS or isolator enclosure. Recognized benefits have included faster line fabrication, shorter FATs, and reduced risk associated with startup, SAT, IQ, OQ, and PQ. Test protocols can be reused for several machines with only minor modification. Easier maintenance and a reduced spare parts requirement are added advantages.
Integrated and Compact Lines
Pharmaceutical firms are moving towards single-sourced, integrated lines, making one vendor responsible for functioning of the complete line. This has influenced several recent acquisitions and consolidations, including IMA’s purchase of the BOC Edwards lyophilizer and loading systems business and Optima’s similar purchase of the Klee business.
Requiring a single vendor to integrate and pre-test the entire line in a facility (and in some cases supply all pieces of the line) reduces risk during the official factory acceptance test, startup and overall line qualification. This is a key benefit considering the more and more limited internal engineering/validation staffs available at many clients and the importance of timely product launches.
The cost of building aseptic processing facilities has skyrocketed in recent years, as well as labor costs and the expense of product recalls and lawsuits. For low to intermediate production volumes, some vendors have been developing compact lines, including IMA’s Modular Aseptic Compact System (MAC), a fully integrated line which replaces a separate vial washer, depyrogenation oven, and filler. Operator handling of components between process steps is eliminated, reducing the likelihood of introducing microbiological contamination and making the entire process more efficient. The floorspace required is also minimized, reducing facility capital investment and ongoing operating costs.
Enhanced Integration with Barrier Isolators or RABS
To optimize airflow, vaporized hydrogen peroxide (VHP) distribution, the ergonomics of gloveport access to all workstations for loading components, removing waste, and clearing jams, vendors have designed increasingly streamlined machines. This usually takes the form of a linear filler with a narrow profile. For example, the new IMA XTREMA F2000 filler has a width just larger than a standard HEPA filter.
Clients purchasing RABS-type fillers are tending to specify HEPA filters mounted directly on the guarding of the machine, as with an isolator design, rather than relying upon ceiling-mounted filters, thereby ensuring better airflow control at the point of filling.
For isolator-based fillers, vial transport systems have been improved to allow complete exposure to VHP, and features such as inflatable gasket seals have been added to depyrogenation tunnels to make them VHP-sterilizable.
Electron beam tunnels are now available from at least four different suppliers to carry out surface sterilization of tubs of presterilized syringes directly feeding a syringe filler, at rates of 6 tubs/minute and higher. Automated bag opening has been integrated upstream of these tunnels and automated tub lid removal downstream to provide greater separation of operators from the process and to minimize the opportunity for microbial contamination of the product.
Addressing the issue of limited reach in an isolator using gloveports, two-piece ergonomically designed pumps have been developed which can be assembled with a single hand through a gloveport, simplifying setup.
Higher Grade Vial Capping
Three general approaches have been taken to crimp caps: a spinning head with wheels, a fixed rail, and an idle roller. The latter two systems are preferred because they produce less particulate, but no system is without particulate generation issues. The latest trend, driven in part by the new EU GMP Annex 1 Guidelines2 calling for a Grade A air supply over capping, is to move from full HEPA coverage to providing a true RABS enclosure around the capper, targeting unidirectional downward airflow over the capping head, sorting bowl, and chute. Going forward, vendors are considering placing additional guarding between the main crimping operation and the bowl/chute assembly, as the sorting and feeding operations are now often the main sources of particulate.
In cases where capping and filling are installed on the same machine base, a vertical wall is often installed between the filler and capper with a small “mousehole” opening connecting the two to keep particles from entering the fill area.
Integration of External Vial Washing
To minimize personnel exposure to potent compounds and antibiotics, clients are purchasing external vial washers for the end of their filling lines, such as that manufactured by Seidenader Maschinenbau GmbH. Vials can be sprayed with warm water, followed by an active-neutralizing or detergent solution, and then a water rinse, or simply with multiple water rinses. The water nozzles are directed to keep the caps from getting wet. Non-heated, or in some cases heated, compressed air is used to blow the vials dry. Removal of external contaminants has the added advantage of decreasing cosmetic reject rates at downstream vision inspection.
In the last few years substantial progress has been made in the accuracy and control of filling processes, combined with increasingly flexible lines allowing for rapid changeover in an effort to be responsive to changing product demands. Lines have become more integrated to improve efficiency and pass greater responsibility to the equipment suppliers. Moreover, steady improvement has been made in suitability for barrier isolation, particulate control, and limiting product exposure in order to enhance sterility assurance and safety.
1 “Disposable Technologies for Aseptic Filling,” J.E. Zandbergen and M. Monge, BioProcess International, 4(6):S48-S51 (June 2006).
2 Revision to EU GMP Annex 1, “Manufacture of Sterile Medicinal Products,” (November 2008). Provisions on capping of vials expected to be implemented by March 1, 2010.
About the AuthorPeter Heyman is a Senior Manager of Pharmaceutical Manufacturing Technology at CH2M HILL Lockwood Greene. He is responsible for providing engineering services to pharmaceutical clients in process flow design and facility layout, as well as the specification and design of fill/finish manufacturing equipment. He joined CH2M HILL Lockwood Greene in 2006 after 21 years on the client side, working for Genentech, Merck, and Becton Dickinson. He holds an M.S. degree in Biomedical Engineering from the University of Utah and a B.S. degree in the same field from the University of Pennsylvania. He can be contacted by telephone: 732-868-2253 or by email at [email protected]