PharmTech: How is industry using excipients today compared with 10 years ago?
Busch: The biggest change has been the improved understanding of the role excipients play in the final performance of the
API. Excipients have been defined as an inactive substance used as a carrier for the active ingredients of a medication. This
is, in fact, the first sentence when one looks up 'excipient' in Wikipedia (May 21, 2010). IPEC defines excipients as any
substance other than the active drug or product that is included in the manufacturing process or is contained in a finished
pharmaceutical dosage form. Today, it is well understood that excipients provide a range of functionality—from process aids
for lubricity, flowability, and compressibility to finished dosage-form functionality aids, which may improve the availability
or control the dissolution rate of an API. The US Pharmacopeia-National Formulary (USP-NF) includes extensive categorizations of excipients.
FDA's Rosa Motta. (PHOTO: COURTESY EXCIPIENTFEST)
With the advent of FDA's QbD initiative, drug manufacturers are being asked to provide proof of their understanding of the
role each excipient plays in their finished formulation. This requires the drug manufacturer to run a design of experiments
(DOE) to understand the role that each ingredient in the formulation plays in the final dosage-form functionality. In the
ideal case, the manufacturer can develop a design space to predict the finished dosage-form performance based on properties
of the individual formulation components. Because there is inherent variability in any raw material, the key challenge is
to develop robust formulations that will be able to use the excipient within its variability. Can a manufacturer use any excipient
that meets its specification limits? If so, the manufacturer has a robust formulation.
Excipient variability is compounded, however, when purchasing material from different suppliers, who may use different processes
and unit operations to produce the excipient. Two excipients may not be interchangeable, and thus, it is important to understand
the differences and how they affect processing and final dosage form.
To correct for inherent variability, both formulation flexibility and process flexibility are needed, the degree of flexibility
being dependent upon limits determined during the design space development. Excipient variability is compounded when purchasing
material from different suppliers, who may use different processes and unit operations to produce the excipient. Two excipients
may not be interchangeable, and thus, an understanding of the differences and how they affect the processing and final dosage
form must be achieved.
PharmTech: Why is industry's understanding and control of excipients important to FDA?
Motta: Excipients generally comprise a significant portion of a dosage form and can potentially compromise drug product quality
if their quality is not adequately controlled. A single batch of an excipient can be used to manufacture many batches of drug
products. Thus, an excipient manufactured or held under subpar conditions can cause a large number of drugs to be adulterated,
potentially putting patients at risk or resulting in a shortage of a medically necessary drug. Although excipients are not
pharmacologically active, many excipients play a key role in drug bioavailability. Even excipients that are less prominent
in their functionality have quality attributes that, if not adequately controlled, might compromise the quality, stability,
or performance of the drug product. In the worst case—demonstrated by recurring events in which diethylene glycol (DEG) was
added to an excipient to increase its market value—when excipients are not controlled, the result can be a widespread outbreak
of serious adverse events.