PharmTech: The ICH Q8R2 Pharmaceutical Development guideline states, "Changes in formulation and manufacturing processes during development and life-cycle management should
be looked upon as opportunities to gain additional knowledge and further support establishment of the design space."How can
this principle be applied to development of a lyophilization process?
Gieseler (University of Erlangen-Nuremberg):
One of the best methods of gaining additional knowledge about the product and process is to implement robustness testing
protocols during cycle development in the laboratory. Here, one would use the desired final formulation composition and desired
(optimized) freeze-drying recipe and then develop protocols that challenge the cycle and the formulation. The shelf temperature
is elevated in predefined steps to obtain higher product temperatures during primary drying. The same principle can be applied
to the chamber pressure set point. After the cycle, the product-quality attributes are inspected and correlated to the observed
process-performance attributes, such as mass flow rates, product temperature profiles and product resistance. This way, it
is possible to simulate, for example, the impact of a loss of pressure control situation in the drying chamber and its impact
on product appearance, moisture content, and other relevant factors. A loss of pressure control in the chamber will result
in increasing product temperatures that, in turn, can cause cosmetic or other defects.
The same robustness testing concept may be applied to the formulation stage. A change in excipient concentration or even exchange
of single excipients typically results in a significant change of the formulation performance, and thus design space. The
use of statistical methods, such as DoE, helps during formulation development to identify relevant factors. In general, DoEs
are much more helpful during the formulation stage than during process development because of the number of experiments required.
Overall, a gain of additional knowledge is certainly a desire for most formulation scientists or process engineers, but stringent
timelines in the routine day-to-day work don't usually provide enough time to look deeper into the science.
Mayeresse (GSK Biologicals):
The role of stabilizers such as sugar, buffer, polymers and surfactant are now better understood. Nevertheless, depending
on the complexity of the molecules, some surprises can occur during development that will need to be corrected. The knowledge
gleamed from this will be remembered when developing new molecules. It is necessary to detect all the specificities of the
molecule during the early stage of the development because at this stage it can easily be corrected without impacting results
of clinical studies. Formulation changes in the late stage of a project can be a major concern.
Nail (Baxter Pharmaceutical Solutions):
We don't consider changes in the formulation in the context of life-cycle management; that is, once the formulation is established,
we don't make changes. However, during product development, making systematic changes in composition is part of the development
of the formulation design space. This might be a plot of Tg' versus pH, for example. The idea is to get a good sense of how
changes in composition affect the behaviour of the product. For examining stability, we generally rely on shortterm testing
under stressed conditions.
Page/Steiner (GEA Pharma Systems):
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 (University of Connecticut):
I would like to think there are actual examples of industry implementing this advice and finding enthusiastic endorsement
from 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 optimized, 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.