The US Food and Drug Administration (FDA) on Thursday issued new draft guidance covering the quality attributes drugmakers should consider when developing chewable tablets.
The guidance also includes recommendations for what information drugmakers should include when submitting developmental, manufacturing and labeling information to FDA.
FDA says the new guidance is needed, as "numerous approved drug product applications for chewable tablets revealed that in certain cases critical quality attributes such as hardness, disintegration, and dissolution were not given as much consideration as may have been warranted."
Specifically, the agency says that some applications contained insufficient data on quality attributes or used "widely ranging values that were not justified as acceptance criteria."
While the guidance is mostly targeted at new drug applications (NDAs), abbreviated new drug applications (ANDAs) and some chemistry, manufacturing and controls (CMC) supplements, FDA says some of its recommendations also apply to investigational new drug applications (INDs) as well.
FDA says the quality attributes and information discussed in the draft guidance apply to both types of chewable tablets recognized by the United States Pharmacopoeia (USP): "those that may be chewed for ease of administration, and those that must be chewed or crushed before swallowing to avoid choking and/or to ensure the release of the active ingredient."
According to FDA, a chewable tablet should have the following four characteristics:
- Easy to chew
- Palatable (taste masked or of acceptable taste)
- Of appropriate size and shape
- Able to disintegrate readily to maximize aspiration and facilitation of dissolution
"Critical quality attributes for chewable tablets should include hardness, disintegration, and dissolution, as well as all factors that may influence drug bioavailability and bioequivalence. In addition, careful attention should be given to tablet size, thickness, and friability, as well as taste, which may impact the ability or willingness of a patient to chew the chewable tablet," FDA writes.
As such, FDA says that reliance on a single quality characteristic is insufficient, and calls on companies to ensure they have a proper balance of quality attributes.
For NDAs specifically, FDA says that sponsors should be able to answer the following questions:
- Were the chewable tablets swallowed intact (i.e., without breaking) or after being thoroughly chewed?
- If swallowed intact, does the shape and size of the chewable table pose a choking or bowel obstruction risk?
- If water was used to aid swallowing, what was the volume?
- What was the subject's sensory experience (e.g., taste, mouth feel, and aftertaste?
And for ANDAs, the agency says sponsors should focus on sensory experience, such as taste and mouthfeel, and ease of swallowing when conducting bioequivalence studies.
Additionally, FDA says that companies with already-approved products in chewable tablet form should reevaluate their products' critical quality attributes, and warns that 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.
|Critical Quality Attributes|
|Hardness||The hardness of chewable tablets should be such that they withstand the rigors of manufacturing, packaging, shipping, and distribution, as well as be easily chewed by the intended patient population. Hardness is generally measured as the force needed to break the tablet in a specific plane. Tablet hardness may be measured and expressed in a variety of units. Applications submitted to FDA should use the same unit of measure in reporting results and specifications. including: kilopond (kp), kilogram-force (kgf), Newton (N), and Strong-Cobb Units(scu). 1 kp = 93 1 kgf = 9.8 N = 1.4 scu. Public standards also exist to ensure consistent measurement of the tablet hardness (Tablet Breaking Force).|
|Disintegration||The time required for a tablet to break up into small particles is its disintegration time. For chewable tablets, disintegration time should be short enough to prevent GI obstruction in the event a tablet is not completely chewed by the patient. Usually, the presence of the correct type and amount of a disintegrant facilitates rapid disintegration of the tablet. In vitro disintegration testing should be conducted using intact tablets in suitable medium using established disintegration equipment (such as USP Disintegration Apparatus) and methods.|
|Dissolution||Drug absorption from chewable tablets depends on the release of the drug substance(s) from the intact or the chewed tablets; therefore, in vitro dissolution testing of chewable tablets should follow the principles of dissolution testing of conventional IR tablets. That is, the active pharmaceutical ingredient(s) of the chewable tablets should adequately dissolve out of the tablet with or without chewing. For product characterization during development in vitro dissolution testing should be conducted on intact tablets in at least four media, such as water, aqueous media at pH 1.2, buffer pH 4.5, and buffer pH 6.8, with established dissolution methods using equipment such as USP Apparatus 1 (basket), USP Apparatus 2 (paddle), or USP Apparatus 3 (reciprocating cylinder).|
|Performance in Simulated Physiological Media||Chewable tablets should also be evaluated using dissolution media such as simulated fasted and fed state gastric and intestinal fluids with enzymes (biorelevant dissolution media). Hardness should also be tested after brief (30-120 s) exposures to small quantities (1-2 mL) of human or simulated saliva. Such studies may provide a better understanding of in vivo performance of the chewable tablets. In vitro testing in physiological media, consistent with the targeted patient population characteristics may support further characterization of the drug product and its critical quality attributes.|
|Biowaiver and Postapproval Considerations||The solubility and permeability characteristics of the drug substance may be used to determine where the drug fits within the Biopharmaceutics Classification System (BCS). Depending on the BCS classification of the drug substance, proposals for waiver of bioequivalence (BE) studies may be considered for chewable tablets. Changes in the chemistry, manufacturing and controls after approval of the chewable tablets should be made in conformance with the principles outlined in the Scale-up and Post-Approval Changes Immediate Release (SUPAC IR) guidance.|