FDA Issues Draft Guidance On Quality Attributes to Consider When Developing Chewable Tablets, Part Two: FDA’s Recommendations

Additional information on FDA’s draft guidance is available in our preceding FDA News article, entitled “FDA Issues Draft Guidance On Quality Attributes to Consider When Developing Chewable Tablets, Part One: Introduction & Overview.”

FDA Issues Draft Guidance on Quality Attributes to Consider When Developing Chewable Tablets

Late last week, the FDA released a draft guidance providing manufacturers of chewable tablets with recommendations regarding critical quality attributes that should be assessed during the development of these products.  The draft guidance, entitled “Quality Attribute Considerations for Chewable Tablets,” outlines the quality attributes that should be considered during the development of chewable tablets.  In the document, FDA states that these criteria should be used as “appropriate and meaningful indicators of product performance throughout the shelf life of the product.”

In its draft guidance the FDA offers a number of recommendations, advising manufacturers to consider disintegrant(s) to facilitate release of the active ingredient, and sweeteners and flavoring agents for taste-masking when designing and developing potential products.  In addition, FDA notes that “the possibility of the interaction of excipients with each other and/or the drug substance(s), and their likely impact on the manufacturing process, should be explored.”

When conducting pivotal clinical studies, manufacturers should take the following questions into consideration and the answers should be included in the subsequent new drug application (NDA):

  1. “Were the chewable tablets swallowed intact (i.e., without breaking) or after being thoroughly chewed?”
  2. “If swallowed intact, does the shape and size of chewable tablet pose a choking or bowel obstruction risk?”
  3. “If water was used to aid swallowing, what was the volume?”
  4. “What was the subject’s sensory experience (e.g., taste, mouth feel, and aftertaste)?”

“For ANDA applications, general information such as subject’s sensory experience (acceptability of taste, mouthfeel, and aftertaste) and ease of swallowing – in case of tablets swallowed intact – can be collected during the conduct of bioequivalence studies and reported in the subsequent ANDA submissions.”

Critical Quality Attributes

FDA recommends establishing the hardness, dissolution, and disintegration of the chewable tablet early in the product’s development.  The Agency recommends that manufacturers study multiple attributes in order to address the tablet’s overall performance and incorporate it into the product specification.  As such, dependence on only one attribute should be avoided.

If the product requires the submission of an application to the FDA, all information pertaining to the product’s development should be provided in section 3.2.P.2 (Pharmaceutical Development) of a common technical document (CTD) formatted submission.  “The information on tablet hardness and chewing difficulty index (see Appendix I) should be provided in section 3.2.P.3.4 (Control of Critical Steps and Intermediates) or section 3.2.P.5.1 (Specification) of a CTD formatted application.”

In the guidance, FDA offers a number of specific recommendations pertaining to the hardness, disintegration and dissolution, as well as other critical quality attributes to consider.  For additional information, view the Agency’s full draft guidance.

Nomenclature & Labeling

The United States Pharmacopeia (USP) recognizes and distinguishes between the following types of chewable tablets:

  1. “The format ‘[DRUG] Tablets’ will be used for tablets that MAY be chewed or swallowed in their entirety. The labels and labeling for these products will also include a labeling statement indicating that the tablets MAY be chewed.”
  2. “The format “[DRUG] Chewable Tablets” will be used for tablets that MUST be chewed and for which there is no alternative route of administration. The labels and labeling for these products will also include a labeling statement indicating that the tablets MUST be chewed.”

In order to prevent patients from swallowing “[DRUG] Chewable Tablets” whole, FDA strongly advises manufacturers to include the following statement on the principle display panel of the container label as well as the carton labeling:

“Chew or crush tablets completely before swallowing.”

If space allows, the draft guidance also states that the labeling should include the following statement he with lesser prominence to reinforce the importance of chewing the tablets:

“Do not swallow tablets whole.”

Additionally, it is recommended that manufacturers include language similar to the above mentioned statements in the professional labeling as well as any accompanying patient information or Medication Guide (as necessary).

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