On December 9, 2013, FDA issued a new draft guidance: Size, Shape, and Other Physical Attributes of Generic Tablets and Capules. FDA said that it issued the guidance because it is concerned that patients perceive differences in the physical characteristics (e.g., size and shape of a tablet of capsule) of generic drugs in relation to its referenced listed drug ("RLD") counterpart. FDA believes that these perceived differences are "important" and "may affect patient compliance and acceptability of medication regimens or could lead to medication errors." FDA does not plan for the Guidance to apply to generic drugs that are already on the market, unless there are safety issues, or other oral dosage forms.
According to the Guidance, many individuals have difficulty swallowing tablets and capsules, perhaps as many as 40 percent of Americans. Of these individuals, most blamed the dosage form size as an issue. In some instances, the larger tablets or capsules have been "shown to prolong esophageal transit time," which may lead to disintegration of the product in the esophagus or cause injury to the esophagus, or more general adverse events such as pain, gagging, choking, and aspiration. In the industry, these larger tablets or capsules have been called "horse pills." Some tablet and capsule shapes are known to be easier to swallow and have faster esophageal transit times than similar dosage forms with the same weight, e.g., oval sizes are easier to swallow than round. In turn, patient compliance may be affected by the size and shape of a tablet or capsule. Other physical attributes that affect ease of swallowing include coatings, weight of the tablet or capsule, and surface area of the dosage form.
As a result, FDA recommends that as part of its quality initiatives for generic drug products, generic oral tablets and capsules should be of a similar size to their corresponding RLD. In particular:
- If the RLD is less than or equal to 17 mm in it largest dimension, the generic product should be no more than 20 percent larger than the RLD in any single dimension (resulting dimention not to exceed 17 mm) and no more than 40 percent larger than the RLD in volume.
- If the RLD is greater than 17 mm in its largest dimension, the generic product should be no larger than the RLD in any single dimension or volume.
- We recommend the largest dimension of a tablet or capsule should not exceed 22 mm and that capsules should not exceed a standard 00 size
.FDA said that it may provide additional flexibility for products that are 8 mm or smaller in their largest dimension but still wanted the dosage form to be of a similar size and shape as the RLD. In terms of other physical attributes, FDA said that physical attributes that could affect the ease of swallowing should be considered, e.g., tablet coating, weight, surface area, , disintegration time, and propensity for swallowing with studies to support sizes (and perhaps any physically-relevant differences) outside the recommendations in the Guidance. Prior to developing quality target product profiles ("QTTPs") for generic drug products, FDA suggested that sponsors contact OGD if their proposed tablet or capsule swallowed intact differed from the criteria in the Guidance.
What the Guidance did not explain was why generic drug sponsors may alter the size, shape, or physical attributes from their RLD counterparts. Following initial patents on active pharmaceutical ingredients, many innovator companies file patents concerning specific formulations (including inactive ingredients and their relative percentages to the dosage form), as well as other physical characteristics of the final approved dosage form. One way generic drug companies may asset noninfringement includes developing generic drug products that fall outside the scope of these physical characteristics. So as FDA leans on generic drug sponsors to more closely mirror their RLD counterparts, generic drug companies may force a difficult choice: eliminate potential noninfringement arguments to speed approval, or keep the arguments with the potential need for additional studies to support similar swallowing attributes.