Page/Steiner: In the past, quality control techniques have tended to consider and record only binary attribute data such as pass or fail/good
or bad. This approach is often rooted in old-fashioned concepts of quality control by inspection of the final product. But
if only pass/fail attributes are recorded, a lot of useful information about the parameter being measured is lost. By determining
and recording actual measurements it is possible to apply simple statistical process control techniques that can characterise
the capability of the process and give warnings of unpredicted variability long before the process reaches a specification
limit. For example, measurement of shrinkage within an acceptable range may be a useful indicator that the process is moving
closer to a point where an unacceptable level of collapse may occur.
Pikal: I would like to think there are actual examples of industry implementing this advice and finding enthusiastic endorsement
from the FDA. However, I have no direct knowledge of such examples. I do know, however, that many processes are run far from
the optimal. If these were optimised, or at least improved using existing good freeze-drying practice, it would result in
shorter processes with absolutely no increase in the risk of loss of product quality attributes. Indeed, in some cases, risk
of loss of product quality attributes would be less in the redesigned process. In the formulation area, we know now how to
formulate at least some proteins in such a way as to obtain far superior stability, with the amount of aggregation developing
at room temperature storage for two years being far less than the aggregation that develops during two years at refrigerated
storage. However, I have not seen any examples of a company reformulating to reduce the level of aggregates, as long as the
"current formulation" meets the minimum product requirements.
Q. What analytical tools and techniques are essential for monitoring an enhanced approach to a lyophilised product?
Gieseler: An innovative PAT approach for freeze-drying would requires a PAT tool that allows the determination of a critical product
parameter, such as product interface temperature and product resistance, for the batch as a whole (batch method). Ideally,
the technology should be applicable in all scales of equipment. As a compromise, two different technologies (one applied in
the laboratory, one in production) can be used, but they must provide a reliable and comparable measure of the same parameter
without inherent scale factor.
In addition to the batch method, a complementary single-vial technology is also necessary that allows a noninvasive measurement
(no contact with the product) of a critical process or product parameter in a single vial. The reason for such a combination
is simple. A batch method draws a global, average picture of the product drying performance, while the single vial method
determines specific product drying performance at a given spot in the freeze dryer. This would help to delineate drying heterogeneity
between vials (edge effects, hot or cold spots on the freeze dryer shelf) which is always present in a freeze dryer in whatever
scale and which might even change over time in a given unit.
Mayeresse: One of the current weak points for freeze-drying is the absence of direct measurement during the process. In the past, product
probes where used to monitor the freeze-drying cycle, but they were not really reliable. There are many reasons for this,
but mainly they are invasive because as you modify the freezing of that vial (metallic wire), it creates some void around
the wire that allow vapour to escape more quickly. Today, automatic loading systems mean that these probes cannot be used
at all anymore. However, new PAT tools are appearing on the market.
Nail: As indicated above, we use TDLAS as the main PAT for design space development. It isn't essential, but it greatly decreases
the time and effort required to construct a design space. We have found TDLAS to give accurate mass flow rates on laboratory
scale equipment, usually within about 3% as compared with gravimetric determination. We do this by weighing the filled vials
and stoppers before and after freeze-drying. However, TDLAS on production-scale equipment is considerably less accurate because
of complexities in the dynamics of water vapour flow from the chamber to the condenser in large-scale freeze-drying equipment.
Steven Nail (Baxter Pharmaceutical Solutions)