30 Years of Innovation

Hamilton Company was founded by Clark Hamilton in his California garage with the goal of improving the precision measurements of laboratory analytics by inventing the microliter syringe. As demand for these syringes grew, Hamilton found himself in need of a European distribution base. He had been considering the Netherlands until a hiking trip brought him to Bonaduz, Switzerland, a small picturesque town in the Swiss Alps.

pH sensors required the same expertise in glass work and precision measurements that made Hamilton the most trusted brand of glass syringes.

In 1966 he began Hamilton Company’s Swiss operation in a former military barracks with two employees. The first managing director, Max Wälchli, led the small team in syringe production, and by the 1970s it had grown to around 30 employees. Further still — and perhaps invigorated by the fresh, mountain air of Bonaduz — the growing team leveraged the Hamilton entrepreneurial spirit to find other ways to extend the application of their glass expertise beyond syringes. It was then that Wälchli realized that pH sensors required the same expertise in glass work and precision measurements that made Hamilton the most trusted brand of glass syringes.

pH sensors are more than just precision glass handling — they require an extensive knowledge of electrochemical measurements. To build this knowledge, Hamilton formed a special research team in 1989, thereby creating Hamilton PA.

Hannes Bühler led the operation, himself an expert in electrochemistry with both industrial and academic experience. Hannes and three colleagues were recruited from the prestigious technical university ETH Zürich by Peter Locher, responsible for new products.

Other figures critical to the initial success of Hamilton PA were Hans Camenisch, head of research and development in Bonaduz, and glass expert Arthur Vuille, who took charge of electrode production.

The team’s initial breakthrough was the invention of “single pore” electrodes. Taking inspiration from the precision bores needed for the company’s microliter syringes, Hamilton developed a single, very narrow, glass channel that prevents the sensor electrolytes from mixing, while resisting clogging better than traditional porous separators or diaphragms.

The first pH electrodes launched in 1991 and received immediate interest and sales. But rather than maintaining a sole focus on pH measurement, the PA team sought to find other measurement parameters in which they could innovate.

As the quickly modernizing biopharmaceutical industry continued to look for ways to control critical process parameters (CPPs), Hamilton looked to expand into measurement technology for oxidation-reduction potential (ORP or redox), conductivity, and dissolved oxygen (DO) measurement, which can all be measured using electrochemical techniques similar to those used for pH. Hamilton developed robust and accurate sensors to address these needs in rapid succession with ORP coming to market in 1993, conductivity in 1996, and DO in 1997. These sensors provided strong benefits to biopharmaceutical processes and are still major components in the PA line.

ABOVE: Getting ready to sell – the product proposal for the production of the first pH sensor is approved!

While innovation is a hallmark of Hamilton’s culture, the company does not seek to innovate for its own sake. Rather, Hamilton’s vision from the beginning has been to approach sensor technology from the perspective of the customer — in other words, what can Hamilton do to help customers optimize their processes and reach new levels of productivity and efficiency? This approach has resulted in many new technological advancements, including the revolutionary optical dissolved oxygen sensor.

The electrochemical sensors developed by Hannes Bühler and his team in the 1990s are robust probes that are still widely used in many applications. However, customers using these sensors in a bioreactor experienced several issues related to limitations of the hardware design. For instance, the time and materials required for polarization time, anode/cathode repair, and other maintenance activities add a significant amount of complexity and labor cost. Electrochemical sensors are also susceptible to drift in the presence of CO₂.

In response, Hamilton explored a wide range of alternatives to electrochemical (or polarographic) probes, eventually focusing on the potential of optical measurement technology. The resulting VisiFerm series of sensors leverage a blue LED in the sensor shaft and an oxygen-sensitive dye (luminophore) fixed to a glass window in a replaceable sensor cap. The blue light excites the luminophore and then a photodetector in the sensor shaft senses the red light that is returned from the luminophore. A microprocessor in the sensor correlates the emitted blue light and the measured red light to partial pressure of oxygen. This measurement can then be output as a simulated nA signal, 4 – 20 mA, or digital protocol.

The use of this technology nearly eliminates sensor maintenance and inaccuracies. The “Visi” family of sensors was then adapted in numerous other ways to meet the needs of other markets like brewing, water treatment, and food and beverage.

To a bioprocessing company whose business is growing cells, control of pH and DO are key. These parameters are ubiquitously measured for their indication of cell health and straightforward control strategies, but they cannot give direct information about the cells themselves. The health and viability of the cells in a bioreactor directly impact final product yield and quality, and thus should be evaluated as directly as possible.

For as long as scientists have been growing cells to produce pharmaceuticals, they have used offline techniques to understand cell viability. This generally involves taking samples at defined intervals and measuring them in a lab away from the production line. This process of offline measurement is labor-intensive, prone to error and contamination, and time consuming. Moreover, offline sampling can also miss capturing data for key process events that occur between sample periods.

Driven again by a focus on improving customer processes, Hamilton invested in a project in 2014 to find an in-line (or in-situ) measurement for total and viable cell density. Acquiring the baseline technologies of another company, Hamilton leveraged its experience with optical sensors to optimize a new turbidity-based sensor for bioreactors for correlation to total cell density, named Dencytee®. Next, the electronics expertise was utilized toward the optimization of a capacitance-based probe for viable cell density, named Incyte.

These new probes enabled users to understand cell production in unprecedented ways. In-line measurements provide data in real time, so process events are never missed and can be responded to immediately. This increase in data immediacy and accuracy has enabled many users to increase process yield, reduce waste, and precisely control process actions.

After 15 years working with biopharma companies to improve measurement across a variety of critical process parameters, Hamilton PA pivoted to ask a question that affected its entire sensor portfolio: what is an overall limitation of sensor measurement loops (including sensors, cables, transmitters, process control systems) that can unlock a whole new level of capabilities and efficiency for customers? What they discovered led to a whole new way to approach measurement and sensor management.

Until that time, every Hamilton sensor (and almost all analytical sensors) relied on separate transmitters to communicate a usable sensor signal to the process control system. The output from most sensors was a very small electrical signal, too fragile to transmit over long distances, so the transmitter converted this to a robust signal more resistant to interference.

PA pivoted to ask: what is an overall limitation of sensor measurement loops that can unlock a whole new level of capabilities and efficiency for customers? What they discovered led to a whole new way to approach measurement and sensor management.

Transmitters play a clear role, but they also add complexity and cost to sensor management. When installing new sensors in a bioprocess, the probes must first be calibrated. Thus, a technician has to grab the sensor from storage and take it out to the transmitter at the line along with all the materials needed for calibration. Occasionally, errors would be found during this calibration and troubleshooting would be needed. If the troubleshooting did not work, then the technician would need to start again with a different sensor. All during this process, the technician would need to remember to take adequate notes for future use.

Then Hamilton asked: But what if the transmitter could be integrated directly into the sensor? For starters, that would mean that sensors could be calibrated in a controlled lab setting where technicians could better control and optimize the calibration process. Secondly, sensors could begin to store calibration information and quality metrics that could be used for troubleshooting and documentation. Just like automobiles now keep track of their own mileage and recent oil changes, sensors with integrated transmitters can assist in diagnostics and electronic data logging.

In 2009, Hamilton introduced the “Arc” line of sensors, which successfully miniaturized transmitter electronics and integrated them directly into sensors for a variety of parameters. Not only do the sensors connect directly to process control systems, they also connect via Bluetooth® to computers and mobile devices running the ArcAir application, offering full access to all the new data stored within the sensor.

While its sensors have been adopted in a variety of industries, Hamilton PA has always maintained a special focus on biopharmaceutical manufacturing. And with more regulation coming to that industry, biopharma companies increasingly need a trusted partner like Hamilton to help them keep up.

According to Philipp Arquint, Hamilton’s current head of innovation, process sensor management was historically handled in-house with internal expertise. “Pharma companies had highly trained experts who specialized in pH measurements,” Arquint says. “Now many of them don’t have this expertise themselves and they rely heavily on equipment suppliers. Customer expectations are much higher.”

This situation was exacerbated in the early 2000s when regulatory bodies such as the U.S. Food and Drug Administration (FDA) issued strong guidances, such as “PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance” (2004). PAT pushed the industry to capture and as much in-situ data as possible to use for analysis and optimization. It set a high bar for companies, and it requires a significant leap forward in terms of bioreactor sensor technology.

Fortunately, this is the direction Hamilton PA had been going all along: developing intelligent, robust, in-line sensors to measure a variety of critical process parameters. Now Hamilton has dedicated itself to PAT solutions for biopharma that enable quality-by-design (QbD) processes.