One should consider the risk analysis, which needs to include factors that may affect product performance outcomes (e.g.,
critical tablet properties such as dissolution rate and stability) and product processing ability (e.g., the ability to perform
high-speed compaction). As an example of the former, we know from work in our laboratory that the right combination of DC
filler-binder and disintegrant is vital to maintain stability of disintegration, and thus, dissolution. Dibasic calcium phosphate
dihydrate has the potential to dehydrate under accelerated stability conditions with consequent changes in disintegration.
It is essential that the right disintegrant is selected in formulations containing high levels of this filler to prevent adverse
stability findings. Excipient companies can help by providing formulators with enough information about the criticality of
excipient interactions to enable formulators to make a well-informed risk analysis and to construct the best design space.
In your experience, how has using a QbD approach improved process understanding? What are the advantages and disadvantages
of applying QbD to solid dosage formulations?
In addition to the answer provided to the first question, in general, QbD is a concept that requires a pharmaceutical manufacturer
to design a product on the basis of employing tools (e.g., statistical DoE) that provide a scientifically valid framework
for identifying all key process and formulation parameters, and thus facilitate effective process optimization. That process,
coupled with the implementation of an effective risk-assessment strategy ensures that factors that impact product quality
(in its broadest sense) are clearly identified. When conducted effectively, such an approach will provide levels of understanding
of the process that were never possible before, especially given that the critical information is developed using tools that
are more scientifically valid than the empirical approaches (often based on personal bias) used in the past.
If used effectively, the implementation of QbD will ensure that every batch of manufactured product conforms to specification.
In addition, the need to rework or recall batches as a result of failure to meet specification will potentially become a thing
of the past.
In terms of disadvantages of QbD implementation, certainly, upstream costs such as those associated with formulation and process
development, are likely to increase, but these increases are likely to be more than offset by downstream savings because rejected
batches and analysis of cause of failure, can be eliminated. The timeframe for product development is likely to increase as
well, which may be somewhat problematic for generic-drug manufacturers who are already working under severe time constraints.
The implementation of QbD could also complicate matters when product development is outsourced. In these instances, those
responsible for product and process development are farther removed from those ultimately responsible for product manufacture.
The biggest lesson to be learned is that studies can find the points at which a formulation will fail, and a prudent formulator
will place his product well away from the edge-of-failure. I have two examples.
The first instance involved a desire to minimize the amount of magnesium stearate in a formulation because of the well-known
risk of overlubrication. The lubricant level selected from development trials was insufficient to prevent the slow build-up
of a film on the punches during long tableting runs, thereby, resulting in sticking. We learned to assess the lubricant level
in an experimental design and to use an amount well above the level that appears to prevent sticking in small-scale trials.
This approach provides assurance against scale-up problems.
A second example focused on minimizing the coating time for an enteric-coated tablet by applying the thinnest coat consistent
with enteric protection. Periodic failures occurred during production, and the sampling size for disintegration testing, based
on sampling by attributes, had to be increased enormously with consequent loss of yield. We had to reprocess several batches.
The net result was that the coating process was worse than it would have been if the product had originally been placed away
from the edge-of-failure with a slightly thicker coat.
It's hard to identify the disadvantages of applying QbD to oral solid dosage forms in principle. For innovative companies,
however, it is possible that new drug availability constraints can limit the extent of experimental trials that can be performed.