From the Editor: Excipients: Out of Sight, Not Out of Mind

Questions of QbD, supply chain management, anticounterfeiting and adverse reactions cannot end with the formulation or active ingredient. PAT will be essential

By Agnes Shanley, Editor in Chief

Think of any wonder drug and one immediately thinks of the active pharmaceutical ingredient (API).  Who ever remembers the humble excipient?  After all, aren’t these “inert” rather than “active,” mere fillers that allow the final drug to be formed and carried within the patient’s body?

However, these supporting actors play a crucial role in the final drug formulation and in ensuring patient safety. Regulators and manufacturers are paying a whole lot more attention to excipient issues.

The wrong excipient can interact with an active ingredient, hurting patients, while a contaminated or fake one can lead to adverse patient responses, or worse. Last month in Korea, a number of patients died after taking drugs made with asbestos-laden talc from you-know-where.

Excipients are much more complex than the term “inert” would imply, and this complexity makes different batches of them very distinct.  The end result?  Variability in final product quality. 

Consider natural products----starch processed from corn grown during a dry season may bear little resemblance, when its physical properties are measured, to starch made from corn grown from a rainy season.  Lactose made from the milk of cows who have feasted on winter sileage will differ dramatically from that made from the milk of grass-fed cows.

Yet, in both cases, the materials are considered “the same” when formulating.

The human factor adds further complexity. A material that is in short supply or becoming more expensive may be vulnerable to counterfeiting.  Contamination is also a risk, and has been a culprit in many recent industry tragedies.

It was only in the 1980s that physicians began to explore the whole topic of excipients’ role in adverse patient responses.  In a 1994 article in the Canadian Medical Association Journal, Dr. Edward Napke analyzed the issue and turned the phrase “out of sight, out of mind” on its head. He argued for full disclosure of all ingredients, active and inactive in any drug formulation, something that we now take for granted.

But merely noting and listing inactives won’t protect patients from the potential impact of excipient variability. Controlling raw material specs closely could be a solution, except that excipients are cheap commodities.  Tight specs would push production costs through the roof.  Meanwhile, pharma is far from being the biggest consumer of excipients;  large suppliers would switch off and focus on cheaper, easier markets.

Many of these issues were explored last month at ExcipientFest, a conference sponsored by the Drug Chemicals and Associated Technologies Association (DCAT), with participation and support of IPEC, a group dedicated to providing guidance  on use of excipients.  They have made all the presentations available on the Internet. ( We’ve posted several on PharmaQbD, but you’ll find the entire lineup here.)

A key message was the need for manufacturers to work much closer with suppliers, as automakers did with suppliers via QS9000.

Dr. Brian Carlin from FMC Polymer discussed drug-excipient interactions at the event; Janeen Skutnik, chair of IPEC, discussed new IPEC initiatives, but also QbD as it impacts excipients.  Industry is focused on applying QbD to active ingredients, Skutnik says, suggesting that the scope should be broadened, particularly since regulators are paying far more attention to excipient variability. 

As she later commented, controlling raw material properties based on functionality-related characteristics may not the best way to conquer variability, since a material property that works well in one formulation won’t work at all in another.

One must accept excipient variability as a fact of life, she said, but “cancel it out” with greater process controls, presumably developed as part of the process design space.

Consultant Paul Vogel discussed the use of third party inspections, and a recent EMEA/FDA joint inspection of an API facility.  Dave Schoneker, director of regulatory affairs at Colorcon, discussed qualifying suppliers. One problem is the fact that the pharma quality departments often aren’t involved when sourcing decisions are made, with disastrous possibilities for commercialization.

IPEA offers a third-party vendor certification program, and IPEC plans, among other things, to get involved in Rx360, a new anticounterfeit drug group that will hold its first meeting in June.  (For more information, visit IPEC).

Whether you’re a tiny generics supplier or a huge brand name company, you can’t afford to ignore excipient variability.  PAT, and closer involvement with suppliers, appears to be the key to avoiding liability down the line.   PAT’s too expensive you say?  Consider the costs of a product recall, FDA Warning letter or worse.

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