Robots bring a smooth touch to cell culture

Automation of cell culture and drug discovery programmes is increasing as companies realise the advantages of using multi-axis robots to bring precise control and consistent performance to complex and delicate processes

The medical and pharmaceutical sectors are responding to the increasing demand for vaccines, drugs and all types of medical equipment and devices by automating both the production processes and many laboratory techniques traditionally carried out manually.Manufacturers and research companies alike are discovering that the use of multi axis robots results in a high precision but flexible solution to their automation requirements and provides a reliable process base from which production volumes can be scaled up as demand increases.

high precision

Stäubli Unimation, specialist manufacturer of multi axis robots, produces a range of robots that are ideal for these challenging applications. Its RX robots provide high precision, a compact footprint and conform fully to Class 1 cleanroom standards (many are performing to Sub-Class 1 cleanliness ratings in selected applications). They are currently used right across the medical and pharmaceutical sectors for a wide range of applications, from assisting the surgeon in the operating theatre with hip replacements to the processing and handling of blood plasma containers.

A significant number of the processes applied in pharmaceutical laboratories, while complex and requiring extremely careful handling, are essentially repetitive in nature and therefore very suitable for automation, provided the close control and intricate manipulative skills of the human operator can be faithfully replicated.

The use of multi-axis robots to automate such processes also brings additional advantages. Batch to batch variation is reduced dramatically and contamination of the product is effectively eliminated; a contamination frequency level of 1 in 50m is regularly achieved by automated systems compared with typically just 1 in 20 with manual handling. Automation also permits the scaling up of production volumes to be achieved without the problems normally encountered in moving to bulk manufacturing from a manual bench top system.

integrated solutions

One company that has specialised in the design, development, manufacture and integration of automation solutions for the life science industries is The Automation Partnership (TAP) of Royston in Hertfordshire, UK. TAP was formed in 1988 as the automation division of The Technology Partnership, a start-up venture drawing on the resources of nearby Cambridge University. In 1995 TAP became an

independent company specialising in automation solutions for sample management and handling, liquid handling, high throughput screening and cell culture systems.

Its involvement in cell culture started when an existing customer wanted to automate a manual laboratory-based process for the production of hormones. TAP devised a solution, built around a Stäubli RX60 six-axis robot that replicated the smoothness of handling and dexterity of movement of the human arm. Richard Archer, TAP's ceo, little thought at the time that this would be the start of a new ongoing activity for the company. 'Our customer was very specific on the performance criteria of this automated system; we regarded our solution as being uniquely suited to these requirements and doubted that there could be a market for this type of dedicated automation.'

automated cell growth

The system proved so successful that the customer installed four manufacturing lines. Word of the success of this automated cell growth system spread across the scientific sector and soon TAP was receiving interest from other drug manufacturers.

One of the first enquiries was from leading US pharmaceutical company Merck & Co. Merck wanted to automate the manufacture of its new Varicella (chicken pox) vaccine and scale up production volumes in response to rapidly growing demand. Traditionally, scaling up meant transferring the process from small culture vessels into large bioreactors - a technically difficult and time-consuming development with no guarantee of success. TAP believed that it would be possible to automate the bench-scale process, avoiding the need for risky technical changes while achieving the required increase in production rate and consistent level of quality. The end result was the robot-based automated cell culture system now branded Cellmate.

Positioned at the centre of each Cellmate system, in a clean (class 100) laminar flow cabinet, a Stäubli RX 60GR cleanroom robot replicates precisely every step of the previously manual process, mimicking each movement just as it would be performed by the operator at the lab bench. The system automates all operations e.g. cell seeding, media changes, bottle gassing and cell sheet rinsing, and requires the operator only to load the infeed conveyor and unload the bottles or flasks after processing. It can handle cells in both roller bottles and T-flasks up to volumes of 1,000 bottles per day.

Smoothness of movement is a vital factor when dealing with the fragile cells, as any jerking or slightly rough handling can cause cell damage and halt the cell growth process. TAP chose the Stäubli RX range of six axis robots as being the most suitable to meet the demanding requirement of being able to replicate exactly the operator's movements. The unique JGS gear reduction system of the RX Robots provides zero backlash and precise torque control, allowing power to be applied gradually to each joint as required.

The cleanroom characteristics of the robot fall well within the specified class 100 range required and actually achieve class 1 cleanroom levels. The smooth wipeable outer sealed surface of the robot is a distinct benefit when cleaning the system between the processing of different cell types.

Together TAP and Stäubli defined the sequence and speed of the robot movements and developed the PG interface and control systems required. The PC controlled RX60 arm can be easily reprogrammed or modified to suit any specific cell line or process. Multiple protocols can be stored on the PC, alongside all process variables such as volumes, temperatures and timings as well as the specific robot movements. Staeubli and TAP have jointly developed the simple control interface, which allows users to alter parameters after the minimum of training.

smooth operation

Cellmate is simple to operate: the operator selects the required protocol from an on-screen menu, moves through the start-up menus, which give precise set-up instructions, confirms or amends variable parameters such as the volume of cell seed stock required, and then starts the process. Once running, the operator simply loads bottles or flasks onto the infeed conveyor, then removes them from the outfeed conveyor when processed. One junior technician can run two Cellmates simultaneously.

All process liquids are held outside the cabinet and delivered via peristaltic pumps. The robot arm picks up the vessel and moves smoothly to a succession of workstations within the cabinet in accordance with the processing instructions selected on the PC. On completion the vessel is placed on the output conveyor.

The Cellmate system was developed from design to a fully operational system in nine months. Merck has now installed 11 systems and there are currently Cellmate systems operating in 65 locations around the world.

Demand for Cellmate looks set to rise further as a result of advances in genetic engineering that call for precise and reliable automated cell production.

Building on the success of Cellmate, TAP has launched a system that extends the benefits of automation into the drug discovery sector.

The system, being marketed as SelecT, is a fully automated system capable of processing small batches of up to 40 different cell lines in parallel to provide overnight assay plates ready for immediate analysis. The idea stemmed from a consortium of existing TAP Cellmate customers who had experienced the benefits of cell culture automation techniques and wanted to achieve similar benefits in their drug discovery activities.

SelecT is constructed around a horizontally mounted Stäubli RX60L robot that performs all the handling, incubating and sampling movements on up to 160 T-flasks, all of which are held in the machine. The robot can handle both flasks and pipettes and is capable of media exchange and cell sheet rinsing as well as cell splitting to harvest, pool and seed cells into new flasks. It can prepare up to 300 assay-ready microtitre plates and can operate unattended.

The benefit of having a batch of plates ready for analysis on a Monday morning is particularly attractive.

The PC-controlled SelecT system incorporates an easy-to-use graphic interface, which is used to programme the robot's movements in accordance with the material being processed.

On completion the vessel is replaced back into the integral store, held in the temperature-controlled incubator or discarded as specified. Batches of assay plates are assembled ready for analysis either manually or on one of TAP's automated HTS systems. This new system meets the growing demand for cell-based assays and increases the security of the cell culture lines, providing a complete audit trail using bar code tracking.

The first installations of SelecT systems, which are being constructed at TAP's Royston factory, began in the second quarter of 2002 and installations will continue through 2003.

The discovery of the human genome sequence will place increasing demands on life sciences companies to produce in larger volumes. In addition, higher throughput and more efficient techniques for evaluation and testing of the new drug compounds will be required.

Stäubli's RX range of multi-axis robots aims to provide the first choice solution for these varied and demanding automation applications.