Applying Continuous-Flow Pasteurization and Sterilization Processes - Pharmaceutical Technology

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Applying Continuous-Flow Pasteurization and Sterilization Processes
High-temperature, short-time (HTST) pasteurization and ultra-high temperature (UHT) sterilization have potential use for continuous manufacturing of bio/pharmaceuticals.

Pharmaceutical Technology
Volume 37, Issue 5, pp. s28-s31

Figure 2: Conceptual plot of product time–temperature history.
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.

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 technologies.

Basis of HTST and UHT’s effectiveness

The effectiveness of HTST and UHT processing can be explained by thermal-process reaction kinetics. The exposure time and temperature in these processes exploit the differences between the reaction kinetics of the inactivation of microorganisms and of the reactions that define product quality. Quality can be broadly defined by components ranging from nutrient content to enzyme activity, but the overall relationship remains.

Table I: Equations for determining reaction kinetics, t = time, T = Temperature.
The Bigelow and Ball method or Arrhenius kinetics can be used to describe the reaction kinetics supporting these processes, as shown in Table I. Microbial inactivation and the loss of quality both follow first-order kinetics. The decimal reduction time (D value) is the time needed to reduce a microbial population by one log cycle at one temperature. Both the D value and the reaction rate (k) change exponentially with temperature. This temperature sensitivity is described by the z-value and the activation energy (Ea).

The important point is that the reactions for inactivating microorganisms accelerate exponentially more than those defining quality, regardless of the mathematical model. The z values are smaller for microbial inactivation than for the destruction of most qualitative components. Correspondingly, the Eas are larger for microbial inactivation than for the destruction of most qualitative components.

Figure 3: Plot of the log of process time (t) vs. 1/T or (Tr-T) showing optimization region of quality and process lethality, T = temperature, Tr- = reference temperature.
This gap provides the opportunity to select conditions that optimize product safety and quality. Consider pasteurization or sterilization where the target organism and the microbial reduction (calcuated by log (N0/N) in which N0 is the initial microbial count and N is the microbial count), reference temperature (Tr), D-value at Tr (Dr), and z are all known. Using either Bigelow and Ball or Arrhenius kinetics, the resulting equation yields a constant or iso-process line representing all the time and temperature combinations that provide the microbial reduction for pasteurization. Each pair of time and temperature conditions on the line delivers the same microbial kill. More than that, they define a boundary, which is shown in Figure 3. Treatments higher in temperature or longer in time (i.e., those left or above the microbial log reduction line in Figure 3) have higher microbial kill and higher assurance levels. All other treatments do not have sufficient lethality.

Similarly, the iso-process line for a qualitative factor (e.g., nutrient retention) can be calculated. As shown in Figure 3, this line has a different slope because the reactions inactivating nutrients do not have the same sensitivity to temperature change as those inactivating microorganisms. All the points below and right of this line (i.e., lower temperature and time) retain more nutrients.

Figure 3 demonstrates why HTST and UHT processes retain quality and deliver proper lethality. Tracing the pasteurization/sterilization line toward higher nutrient retention leads to higher-temperature and shorter-time processing conditions. The higher- temperature and shorter-time processes retain more nutrients than the longer-time and lower-temperature processes, such as autoclaving. In addition, a treatment combination between the lines that increases both microbial inactivation and nutrient retention can be selected.

The significance of these relationships and this analysis are considerable. Having the reaction-kinetic parameters for the target organism and the qualitative factor (in this case, nutrient retention) enables the selection of optimal processing time and temperature conditions. Taken another way, determining the thermal-destruction kinetics of qualitative materials allows them to be screened for suitability to preselected conditions. Either way, determining the thermal reaction kinetics for the target organism and the materials that are to be retained in the actual product is valuable because it allows prediction of their performance under a wide range of conditions using simple math and avoids problems at the production level.


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