The pharmaceutical industry has embraced the concept of single-use systems. Offering higher levels of sterility, lower capital costs and virtually no cleaning requirements, the disposable alternatives to traditional stainless steel are now used across numerous applications in both upstream and downstream processing. A driver for this recent growth is the availability of reliable and comparatively inexpensive disposable sensors.
Back in the Day …
Automation in tangential flow filtration (TFF) units is vital to ensure product consistency, according to Karl Schick, vice president of R&D at SciLog Inc. Schick remembers a time when TFF units relied on a lot of human interaction and less than ideal instrumentation.
“In a manual TFF system, you usually have three diaphragm valves to work with. Using an analog readout, the needle would jump back and forth because of the peristaltic pump, and the operator would have an estimate — but not an accurate output — of what the pressure was. A judgement call was necessary to adjust the back pressure to get the driving force for the filtration.
“Now, with pressure, conductivity and temperature sensors, and a digitally controlled peristaltic pump, we can optimize the process,” explains Schick.
|Dr. Karl Schick, SciLog Inc.'s vice president of R&D, and Dean Pighin, BioProcess Automation Engineering Manager at SciLog, stand with the company's SciFlex TFF single-use system. The white tubing makes up part of the disposable flow manifold.|
Pre-Calibration is Key
In order to transfer the benefits of automation to a single-use TFF system, Schick set out to develop a single-use flow manifold that incorporates disposable pressure, conductivity and temperature sensors. The sensors had to withstand the gamma-irradiation used to sterilize the manifold, be relatively inexpensive and remain stable during extended storage periods.
“The idea is to avoid the in-field calibration, as it compromises the whole single-use approach. To do that, the sensors need to be calibrated before they are inserted into a manifold and sterilized. So it is very important that the sensors are pre-calibrated, and that the calibration data survives the gamma radiation and storage period,” says Schick.
A memory device inside the sensor stores the sensor’s identification number and associated calibration factor, and is designed to withstand gamma-irradiation, steam sterilization, under pressure and high concentrations of NaOH. The stored value can then be used to reliably calculate the pressure, conductivity or temperature in relevant units.
Under Pressure to Yield & Change
Schick’s single-use fluid manifold and disposable sensors were incorporated into SciLog’s SciFlex TFF and normal flow filtration (NFF) units, with the later using system software used to monitor, control and maximize the product yield. As the NFF unit’s filter becomes covered by filter cake and the application-defined pressure limit is reached, the liquid handling system switches from constant output rate mode to constant pressure mode.
This automated process safely continues the NFF process until a predetermined filtrate cut off rate is reached. The filtrate collected after the pressure limit is reached contributes to 30–35 percent of the total filtrate yield.
Compared to the days or even weeks it takes to clean and validate a stainless steel filtration system, Schick estimates that “to change over a tubeset and filter would take about half an hour to 45 minutes, depending upon the time it would take to sanitize. To switch from one product to another could probably be done in less than an hour.”
Living the Dream — Upstream
Single-use technologies are arguably more prevalent in upstream processing, where disposable bioreactors are armed with dissolved oxygen and pH sensors, amongst others. Like SciLog’s flow manifold, disposable bioreactors and their associated sensors are usually combined and gamma irradiated prior to use.
Finesse Solutions is one of the companies producing single-use sensors for upstream processes. Finesse CTO Dr. Mark Selker believes that his company’s sensors are set apart by the fact that they don’t use fiber optics.
“By not using fiber optics, you mostly avoid sensitivity to physical movement and you basically eliminate photodegredation as an issue,” explains Selker.
That said, how do they compare to traditional sensors in terms of reliability?
“I will stack our dissolved oxygen sensor against any electrochemical sensor, in terms of repeatability, precision, accuracy, drift, sensitivity to bubbles and the ability to maintain sterility. People who say that a single-use dissolved oxygen sensor isn’t as reliable as traditional sensors haven’t used one before,” states Selker.
He adds, “I will concede that the pH range is limited,” due to the nature of measuring ion concentration in a liquid.
Mix and Match?
While some companies promote the combination of single-use and stainless steel components, also known as hybrid systems, Finesse CEO Dr. Barbara Paldus prefers to keep her company’s focus on “pure” single-use systems.
“We do hear that hybrid systems have a lot of problems, and we think people are better off sticking with either pure stainless or pure single-use. There are now complete upstream single-use systems where you can go from a three-liter plastic vessel to a 50-liter wave rocker for seed innoculant to a 50-liter bag bioreactor — so you can do your entire mixing, buffer preparation, media preparation and growth in single-uses systems today.
“Downstream is where things become more complicated, and that’s where people tend to use hybrid systems because there are certain parts of the downstream process where the invention has not caught up with the process — there just aren’t always single-use solutions” says Paldus.