Critical process parameters
What CPPs are affected by the choice of the excipient and the interaction of the excipient in the formulation for a solid
CPPs may well vary from process to process and product to product. Thus, what a CPP is for one product may not be for another
product. In addition, what may be deemed to be CPPs for the manufacture of an oral dosage form that is presented as an immediate-release
powder-filled capsule product is likely to be entirely different when manufacturing a film-coated, sustained-release matrix
tablet. If the criteria for excipient selection are scientifically valid, then the choice of a particular excipient may have
no impact on CPPs. Under other circumstances, selection of a particular excipient may affect several CPPs.
There are some very obvious examples. Of course, one should always use excipients designed for direct compression (DC) in
a DC process. One example we experienced regarding what can go wrong when two excipients interact in a process is the failure
of a DC formulation to compress on scale-up. The root cause in this instance was found to be unintentional over-mixing of
the lubricant (magnesium stearate) with sieved lactose in the rotary feed-frame of a tablet machine. An open feed-frame had
been used in development.
In terms of material specification, we have examples of differing disintegration time of tablets when different sources of
croscarmellose sodium were used. The croscarmellose had a different particle-size distribution that was not noted on the CoA.
What should be taken into consideration when devising the design space for a solid dosage formulation?
Dow believes there are two key considerations when thinking about design space. The second one is what most folks think of
when they hear the words 'design space,' which we define as 'process design space.' What are the potential interactions between
the various unit operations in the drug manufacturer's process and the drug dosage formulation that control the final product
efficacy? This thinking assumes that the formulation is fixed and that the only way to handle formulation variability, which
may occur via any of the formulation components (e.g., the API or excipients), is through process changes that are well understood and
documented to 'correct' for formulation variability.
For example, when using a formulation with polyethylene oxide as a hydrophilic matrix-tablet rate controlling polymer, if
changes in molecular weight occur between one lot and the next, one may have the flexibility in the process to change the
compression force during the tableting operation to attempt to compensate for excipient variability. However, Dow believes
that another, and in fact the first, important aspect of design space is the formulation design space, which is the understanding
of potential interactions between the formulation components, and how individual component variability affects the finished
If one understands the function of the formulation components, it may be possible to reduce or minimize finished product variability
by making slight changes to the formulation. Using the example above, with a well-documented design space, if polyethylene
oxide is being used to control the dissolution profile of the API and if a lot of polyethylene oxide with a lower molecular
weight is being used compared to the previous lot which had a higher molecular weight, one may have the ability to increase
the percentage of the polyethylene oxide in the finished tablet to compensate for the lower-molecular-weight material being
A second method might involve using a blend of two grades of polyethylene oxide to achieve a given functionality. If one of
the grades shifts in molecular weight, then its percentage in the formulation could be changed to compensate for this shift,
thus resulting in a formulation with consistent efficacy but inconsistent composition. The benefit of formulation flexibility
is that it does not force the drug manufacturer to rely solely on the process to smooth out the variability inherent in the
formulation. Slight changes in formulation and process can work together to minimize the variability inherent in the formulation
(1). A second example is colored-tablet coating formulations, where slight variations may be made in the formulation to achieve
a consistent finished tablet color due to variability in the various color components used to make the master batch.