Sterliization Continuous Manufacturing
Continuous manufacturing has been described as a manufacturing breakthrough and as the method of the future by Konstatine
Konstantinov, vice-president of commercial process development at Genzyme (now part of Sanofi), and Robert Bradway, chairman
and CEO of Amgen (1, 2). The trend toward using this method is increasing as manufacturers of bio/pharmaceuticals strive to
meet growing demand, reduce floor space, improve manufacturing flexibility and capacity, and reduce costs.
The adoption of continuous manufacturing for biopharmaceuticals emphasizes the need to inactivate microorganisms continuously
at rates consistent with these new processes. The adoption of HTST and UHT continuous processing and surrounding technologies
is a natural fit. Early adopters in the biotechnology and biopharmaceutical industries have begun to deploy these processes.
The question remains, however, what are the reasons to adopt HTST and UHT in these industries? Are their benefits simply a
function of the continuous process or are there additional benefits that make HTST and UHT even more desirable?
Benefits ofF HTST and UHT
Figure 1: Flow diagram for continuous-flow thermal processes. (ALL FIGURES COURTESY OF AUTHOR)
The benefits of HTST and UHT processes result from their continuous flow nature and their use of different and more highly
refined time and temperature conditions. To understand their benefits, it is useful to consider an example process like that
shown in Figure 1. The product is pumped continuously through the process at constant flow and is heated to the process temperature under steady-state
conditions. It flows through the hold tube, which is of sufficient length to ensure that the product is hot for the time needed
for the required lethality, before it is cooled as it exits the system. The result is that the product experiences a controlled,
well-defined time–temperature exposure. This time–temperature history (TTH), conceptually shown in Figure 2, is usually less than two minutes from start to finish. Although there are relatively few rules linking the terms "pasteurization"
or "sterilization" to specific temperatures, for the sake of this discussion, pasteurization is usually conducted at hold-tube
temperatures between 70 °C and 121 °C. Sterilization hold temperatures range from 128 °C to 150 °C. Hold times most commonly
range from 2 to 30 seconds.
Because HTST and UHT continuous-flow processes are closed systems that operate at steady state, the impact of the thermal
process on product quality and lethality is uniform and independent of batch and container size. In contrast, the thermal
exposures delivered to liquids being pasteurized or sterilized in large-scale fermenters or vessels in autoclaves/retort are
not as uniform because the heat exposure varies with the container size and location. In comparison, it becomes apparent that,
in the continuous process, several major sources of variation and potential points of failure have been eliminated and overprocessing
has been greatly reduced.
Figure 2: Conceptual plot of product time–temperature history.
As thermal processes, HTST and UHT processes are effective against viral contamination. These processes are especially useful
for emulsions and suspensions that are not compatible with filtration. They provide real-time monitoring and record-keeping
of processing conditions. They are precise, and the actual process time and temperature conditions can be adjusted to optimize
the retention of key components and the delivered lethality. This precision can be important to maximize retention of key
media components being fed into a fermentation process or of a desired active agent resulting from a different step of manufacture.
Unlike scale-up of batch operations, scale-up of HTST and UHT processes is often unnecessary because processing more material
is linked only to the processing time, not the vessel size. Larger volumes of product are processed by simply running the
equipment longer. Thus, multiple systems may not be needed for different batch sizes. When scale-up is necessary within the
same general style of HTST or UHT equipment, it is a matter of duplicating the TTH. If a different style system is used, the
detailed matching of the TTH may require more powerful mathematical and modeling tools for thermal process evaluation.
In the food industry, these processes are used to make many high quality products that would not be viable using longer-time
and lower-temperature methods, such as autoclaving, because of poor quality. These examples demonstrate the potential to pasteurize
or sterilize many bio/pharmaceutical materials that are also not well-suited to autoclaving. In simpler terms, these are enabling