Can you elaborate on that knowledge and related tools and solutions.
As I mentioned previously, formulation design is critical to ensuring robust product performance. And to illustrate this
point, I would really like to show an example of how normal excipient variability of a rate-controlling polymer, hypromellose
(METHOCEL K15M CR) was determined for drug release from a hydrophilic extended-release matrix. The study examined the importance
of METHOCEL concentration in regard to managing variation of particle size, viscosity, and percent hydroxylpropoxyl (HP) substitution
or percent HP material attributes. And the ranges studied were at the extremes and center point of the cell-specification
So using propranolol hydrochloride as the model drug, it could be seen that drug release was slower when one increased the
METHOCEL concentration from 15% to 30% (w/w), and this, of course, may be expected. The drug release was generally consistent
across the extremes of viscosity and percent hydroxylpropoxyl irrespective of drug concentration. Therefore, the formulation
was robust to the normal variation of these two material attributes.
Interestingly, however, for particle size it was clearly shown that lower METHOCEL concentration, 15% (w/w) resulted not only
in a difference of release rate, as seen previously, but also increased tablet variability. Here, faster and more variable
drug release was shown for the formulation containing the core subparticles of METHOCEL K15M CR polymer. At 30% METHOCEL concentration,
however, this variation was not observed. So robust dissolution performance was shown irrespective of the particle size.
These examples show that it is prudent to determine if such material attributes are a potential risk to drug-product quality
attributes during early formulation development. Clearly, in this stage, it is generally easier to adjust the formulation
and/or the process to manage such effects rather than implementation of changes during the latter stages of drug product development.
The impact of normal excipient variability, however, can also be managed in other ways. Certainly, QbD supports approaches
to develop formulation flexibility or formulation design space. Adjustment of the quantitative composition of the drug-product
batch can be justified to manage the variability of the ingoing excipient material attribute. As discussed in ICH guidelines,
enhanced knowledge of material attributes is needed to develop and justify such an approach. Nevertheless, it does provide
an opportunity for both the developer and the excipient vendor to further collaborate and ensure that the necessary physicochemical
properties of the excipient can be evaluated to develop such approaches.
Furthermore, it also is important not to view the excipient sales specification as the endpoint for control of excipient variation.
Excipient sales specifications and test limits can, of course, be variable. Therefore, these may not be representative of
the excipient manufacturer's control capability. And I think this is an important point, particularly for risk assessment.
Enhanced knowledge here can reduce the perceived risk of excipient property variability upon the drug-product quality attributes.
And, indeed, excipient manufacturers may be able to provide prior knowledge of their capability, for example, demonstration
of process capability, representative material-attribute trend data, or even descriptive statistics illustrating the control
for the individual manufacturing approach.
In the propranolol matrix case study, another tool available to the developer is that of the excipient material attribute
sample. These may be available to assist the developer in proactively testing the effect of normal excipient variability upon
its particular formulation. It may not always, however, be useful to study all of the excipient material attributes, particularly
if the manufacturer's control is tight and if variability lot-to-lot is insignificant. Such approaches, however, may be valuable
to support experimental design and subsequent development of design space.