High-temperature, short-time (HTST) pasteurization and ultra-high temperature (UHT) sterilization are continuous-flow thermal
processes that have been established and highly refined in other industries for many years. Their precision and minimal impact
enable the manufacture of products that cannot be made using batch technologies. HTST and UHT are traditionally used for heat-sensitive
products. As continuous-flow processes, they are effective against vegetative cells, viruses, and heat-stable endospores.
These characteristics and their continuous-flow nature make them potentially useful as part of the trend toward methods of
continuous manufacturing of bio/pharmaceuticals.
Technologies frequently evolve separately, often independently, in unrelated industries and transfer between them. This transfer
is often how industries and technologies advance and take significant steps forward. Identifying a technology that is proven,
highly refined, and fully supported industrially and regulatorily, however, is less common. This is the case for high-temperature,
short-time (HTST) pasteurization and ultra-high temperature (UHT) sterilization. HTST and UHT are continuous flow, thermal
processes that have been used to pasteurize and sterilize liquids (e.g., foods) for more than 60 years. The processes have
been developed as tightly controlled systems and refined to reliably produce high quality products at low cost. HTST and UHT
have been optimized to reach high assurance levels for inactivation of vegetative cells, viruses, and heat-stable endospores,
all while retaining quality that could not be maintained using batch processes, such as autoclaving.
HTST and UHT in the food industry
It seems somehow concerning to use a process that has evolved for food products, such as milk and juices, and use it for highly
refined pharmaceuticals, but let’s consider the fundamentals. The chemical-reaction kinetics that describe how and why these
processes inactivate bacteria but retain the quality in a biological fluid (e.g., milk) are the same as in any other biological
fluid. Commercially, these processes are well established and used for products ranging from juices to baby food and even
products as sensitive as liquid whole egg. These processes have annual capacities measured in hundreds of billions of packages
per year. Commercial equipment for HTST and UHT processes commonly operate at flow rates ranging from roughly 5 gallons to
more than 100 gallons per minute. Commercial capacities, however, do not lend themselves to the batch sizes and rapid cycles
of research and development. The need to conduct thorough research and to optimize treatments (e.g., hold time, temperature,
and heat transfer) for different products has triggered the development of miniaturized research equipment and experimental
methods for this purpose. These tools have enabled R&D professionals to address potential manufacturing issues early and avoid
losses and costly problems while also helping these processes to become better understood. Optimization of these processes
has led to development of a wide assortment of time and temperature treatments as well as highly refined tools to test products
and deliver these treatments. As a consequence, small-capacity systems have been developed for lower flow rates, bringing
the benefits of HTST pasteurization and UHT sterilization to the high-value, low-volume materials of pharmaceuticals.
Sterilization in 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 of HTST and UHT
Figure 1: Flow diagram for continuous-flow thermal processes.
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.