Along with the specified parameters, it is important to also consider both unspecified parameters as well as nonroutine parameters.
The variability of unspecified or unreported parameters, could impact drug-product performance depending upon its design and
intended use. Although unreported, these properties may be measured by the manufacturer as part of its control strategy. In
addition, excipients can vary in what is termed nonroutine parameters (e.g., residual reactants and residual catalysts). Variation
of these parameters may not be commonly measured by the manufacturer.
So in the majority of cases, robust drug products are successfully developed and manufactured to manage such excipient variability.
Failure, however, to understand and control excipient variability has indeed led to some serious quality issues.
FDA, for example, has spoken publicly about excipient variability and its relation to drug-product recalls from the market.
It is clear that some existing development and manufacturing practices can fail to ensure that medicines of the appropriate
quality standards that are routinely produced. Furthermore, demonstrating quality by testing does not prevent these substandard
drug products from entering the market. Obviously, quality failures, including those related to excipient variability, can
have serious consequences to the manufacturer in terms of financial and reputational damage. Ultimately, the end user, the
patient, is put at risk.
Substandard drug products reaching the patient can impact safety and efficacy. And even those that are captured and rejected
by quality control or those recalled from the market can lead to drug shortages. This, again, impacts the patient. So, with
increasing public focus upon the pharmaceutical industry and regulators alike, it is clear that managing excipient variability
will be an area of increasing industry importance.
It is critical, therefore, for excipient manufacturers and vendors to closely collaborate with the developer to better reduce
the risks of quality failures. This is important from early on in the drug product's development, whereby knowledge and experience
of the excipient can proactively support robust formulation design and efficient manufacturing control. Failure to account
for normal excipient variability can lead to the design and development of nonrobust formulations. Unfortunately, this can
necessitate tighter excipient-specification test limits, batch selection, or even custom manufacture to control the performance
of the finished drug product.
It must be recognized that, in some instances, the ability of the excipient manufacturer to meet such requirements may not
be easily achieved, if achievable at all. This, therefore, presents additional risk and cost to the overall product.
It also is important to consider the interplay of all variables including those of the API and the manufacturing process.
The use of risk assessment is helpful to identify those primary variables that may affect the drug product's critical quality
So, the ability of the developer to determine the effects and interactions of excipient material attributes, along with API
and processing parameters, using approaches such as design of experiments, can provide valuable insight into their true criticality
upon drug-product quality.
Using QbD, therefore, presents an opportunity to ensure quality is built in by design. Early collaboration by all stakeholders
can better ensure that the potential risks of normal excipient variability can be efficiently designed out by our prior knowledge
and available tools.