An idea for a more convenient dosage form for an existing drug product often presents an opportunity for a commercial advantage. Fortuitously, it also presents the possibility for using the 505(b)(2) regulatory pathway to product approval, which is often faster and less expensive than the 505(b)(1) route.
Recently, FDA issued a brief draft guidance describing the important quality characteristics of a seldom used alternate dosage form: Quality Attribute Considerations for Chewable Tablets-Guidance for Industry (CDER, June 2016). The guidance suggests that chewable tablets could be an attractive method of oral drug delivery “…in a diverse patient population, pediatric, adult or elderly patients who are unable or unwilling to swallow intact tablets due to the size of the tablet or with difficulty swallowing.” The draft guidance is designed to assist the drug development of chewable tablet products, focusing on the requisite quality attributes needed for a successful NDA or ANDA application.
FDA’s guidance defines a “chewable tablet” as “…an immediate release (IR) oral dosage form intended to be chewed and then swallowed by the patient rather than swallowed whole.” Citing the USP, FDA notes that there are two different types of chewable tablets: 1) those that may be chewed for of administration and 2) those that must be chewed or crushed before swallowing to avoid choking and/or ensure the release of the active ingredient. The guidance focuses on fur characteristics considered important for the “…ideal chewable tablet…”:
- Easy to chew (FDA discusses at some length a “Chewing Difficulty Index”)
- Palatable (taste masked or of acceptable taste)
- Of appropriate size and shape
- Able to disintegrate readily to minimize aspiration and facilitate dissolution
The guidance correspondingly notes the adverse events most likely associated with a chewable tablet not developed with adequate attention to the aforementioned characteristics: gastrointestinal obstruction resulting from patients swallowing whole or incompletely chewed tablets, tooth damage and denture breakage from excessive tablet hardness, as well as esophageal irritation from the chewable tablet.
The guidance provides further specifics on the primary measures to be employed in achieving the desired drug quality attributes: hardness, disintegration, and dissolution. Also included are some specifics on measuring each.
Several pages of recommendations (Section IV) are provided for consideration during drug development. In summary, the recommendations are:
- Use of a disintegrant(s) to facilitate release of the active ingredient
- Use of sweeteners and flavoring agents for palatability and/or taste masking
- Investigation into possible interaction between excipients and/or the active ingredient
- Elements to be included in the (A)NDA
- During pivotal clinical studies, were chewable tablets swallowed intact or after being thoroughly chewed?
- If swallowed intact, does the does the size/shape pose a risk of choking or bowel obstruction?
- If water was used to aid swallowing, what volume?
- What were subjects sensory experience, e.g., taste, mouthfeel, aftertaste
- Potential for buccal absorption and stability in the buccal environment (assessable in vitro)
The recommendations expand on the specified measures useful in achieving the desired quality attributes:
The guidance recommends that hardness be kept low (<12 KP) while allowing for higher hardness in the presence of significant disintegration in the presence of significant in the presence of saliva before chewing, OR the demonstration of the absence of damage to teeth, dentures or other problems in the use of higher hardness.
Disintegration and Dissolution
Disintegration and dissolution should meet the same specification as IR tablets. The guidance points to the use of in vitro testing, but cautions against unquestioning acceptance because of the probability of variability of “chewing patterns” in patients. Additional assessments “…may be needed on a case-by-case basis.”
The guidance provides information on some labeling considerations for chewable tablets, again distinguishing between tablets that MAY be chewed versus tablets that MUST be chewed and/or, not swallowed.
Finally, two Appendices are provided, one providing a detailed method for the determination of a product’s “Chewing Difficulty Index” and a second which lists a formulation for simulated salivary fluid.
So, FDA has provided a fairly useful blueprint for a robust product development program for chewable tablets. Using the guidance in concert with all the other components of a successful product development plan could yield an approved new dosage form with a substantial commercial advantage over existing ones, especially those which, for whatever reason, are large solid oral dosage forms. Premier Consulting has an experienced CMC staff, adept at formulation and analytical development, available to assist if needed. Contact us for more information.
William Stoltman, JD
Senior Director of Quality Assurance / Compliance