Chewable Tablets: Companies Seek Clarity on FDA Draft Guidance

Regulatory NewsRegulatory News | 19 August 2016 |  By 

Pfizer, AstraZeneca, Bayer, Genentech and Shire, among others, are seeking more clarity from the US Food and Drug Administration (FDA) on draft guidance covering the critical quality attributes drugmakers should consider when developing chewable tablets.

The draft guidance, released in June, comes as FDA has warned that for “numerous approved” chewable tablets, companies have not evaluated critical quality attributes such as hardness, disintegration and dissolution "as may have been warranted.”

And even companies with already-approved chewable tablets should reevaluate their products' critical quality attributes as the agency will take "appropriate action … to alleviate the risk to public health" posed by any tablets that do not meet FDA's quality expectations.


The New York-based pharmaceutical company said in comments dated in late July that FDA in some cases, provides a level of detail that “is too prescriptive, while lacking some clarity.”

Specifically, Pfizer says, “It is unclear what, if any, of the recommendations need to be applied to currently marketed products (NDA, ANDA and OTC). In addition, for currently marketed products that do not include all of the recommendations in the guidance, it is unclear if there is any expectation from the FDA that the company will have to provide justification why they have deviated from the guidance.”

As an example of where the company seeks more information on critical quality attributes, Pfizer notes that chewable dosage forms may be made by extrusion, rather than powder compression, which results in a compressible gum, so “the concept of hardness has no meaning.”

In addition, Pfizer says FDA’s recommendation to collect whether the tablet was chewed, swallowed whole, with water or without, during pivotal studies, may be difficult and place an additional burden on the study sponsor unless the pivotal study is a bioequivalence study in healthy volunteers, and not a Phase 3 study in patients.

“This is particularly relevant to pediatric patients. It may be more reasonable to collect this information in a Phase 1 study,” the comment adds.


New Jersey-based Bayer called on FDA to expand the guidance to address quality attributes for all chewable dosage forms.

“Such an expansion in scope should include the appropriate adjustments for tests for the specific chewable dosage form,” Todd Paporello, VP and head of North American regulatory affairs, wrote.

He also noted that the calculation for chewing difficulty index “is based specifically on flat round tablets and without acceptable validated ranges seems to offer no utility over tablet hardness, especially for tablets that are not flat and round. Additionally, adding this into the specifications would lead to unnecessary quality control testing on the chewing difficulty index, where hardness would be sufficient.”


Eileen McBride, team manager of global operations at AstraZeneca, also raised concerns that the draft does not have any text related to tablet hardness or chewing difficulty on stability.

“Tablets may harden over time or can turn into a moist gritty mass as superdisintegrants can pick up moisture and soften the tablets. Both situations are undesirable,” she wrote.

And the company with Maryland roots also questioned if there will be a recommendation from FDA “to assess the attributes (e.g., taste, mouth feeling and aftertaste) ahead of the pivotal clinical study by qualitative evaluation of taste on the basis of analytical method e.g. dissolution 1-2 min in artificial saliva and particle size to assess mouthfeel?”


In its comment dated last Wednesday, the San Francisco-based Roche subsidiary pointed out that in general, the guidance statement for dissolution applies only to immediate release (IR) chewable tablets, but not to modified release chewable tablets.

“Product may not be designed as IR and for poorly soluble API or for microparticulates with functional coatings dissolution under four media conditions is not relevant,” Genentech's Kin Tang wrote. “Furthermore, the guidance advises to use at least four different media to characterize the product during development” though also says testing should follow the principles of IR tablets from FDA guidance on dissolution testing of IR products, “which does not advise testing in at least four media.”


The Pennsylvania-based drugmaker points to a section of the draft referring to an in vitro 30-second exposure using simulated salivary fluid.

“It is not clear how the exposure to the fluid is performed in the laboratory in order to ensure consistent results. For example, what type of vessel should be used, how is the tablet exposed to and removed from the fluid, after removal what amount of time elapses before the tablet is tested for hardness, is the tablet blotted and/or allowed to dry prior to the hardness testing, and so forth. Please consider providing more detail on the test methods to ensure consistency between analysts and laboratories,” Wendy Severs wrote in a comment dated last Wednesday.

Comments on Draft Guidance


© 2022 Regulatory Affairs Professionals Society.

Discover more of what matters to you

No taxonomy