When a generic drug seeks approval from the US Food and Drug Administration (FDA) under Section 505(j) of the Federal Food, Drug and Cosmetic Act (FD&C Act), the majority of FDA's review time is spent assessing whether the drug is chemically equivalent to its reference listed drug (RLD).

Background

But, as FDA notes in a newly released draft guidance document, physical attributes can have a meaningful impact on safety and efficacy as well, and manufacturers need to take those attributes into account when developing new generic drugs.

FDA's guidance, Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules, comes after years of skirmishes between branded and generic pharmaceutical companies over the physical attributes of their products. The scoring of tablets-literally the lines indicating where a tablet can be split-had been a frequent point of contention between companies. Some companies maintained that the scoring lines of a generic needed to be identical in order to be marketed, and sometimes used the tactic to delay market entrants, who needed to file amended applications every time the branded company obtained approval for a new scoring configuration.

FDA ultimately clamped down on the practice in 2012, when it excoriated a Citizen Petition filed by Warner Chilcott (now Actavis) that sought to compel generic pharmaceutical manufacturer Mylan to comply with a two-score configuration of Doryx. FDA said it believed there was "very little chance" of the difference confusing patients. In March 2013, the agency released a final guidance on the scoring of tablets, indicating the standards by which companies would need to evaluate scored products. It was further recommended-but not required-that the scoring marks be identical to that of the RLD.

New Guidance

But as FDA's new guidance indicates, scoring is but a fringe issue compared to the more fundamental physical qualities of a drug, including a tablet's size and shape. Whereas only a small number of people split their tablets, everyone has some level of interaction with a drug's physical qualities.

Take, for example, the size of a drug capsule. If the RLD is a small and easy-to-swallow capsule, but the generic drug is a large and cumbersome tablet, the end user may be unable to take the drug or even choke on it.

"[We] are concerned that differences in physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient compliance and acceptability of medication regimens or could lead to medication errors," FDA wrote in its guidance. "We believe these patient safety concerns are important, and we are recommending that generic drug manufacturers consider physical attributes when they develop quality target product profiles (QTPPs) for their generic product candidates," FDA added.

While the guidance doesn't apply to generic drugs already on the market, it will apply to new ones.

General Considerations

And, as FDA's guidance explains, companies will have plenty of factors to consider when designing the physical attributes of their drugs. For example, a target audience's age may influence their ability to take a medication (such as the very young or the very old), as might their underlying disease (muscular dystrophy, Parkinson's) or the position in which they take the drug (like a hospital- and bed-bound individual).

"The Agency recognizes that a variety of factors may affect the ability of a patient to swallow a tablet or capsule," FDA conceded. "Although not all patient factors can be addressed through pharmaceutical design and manufacture, the physical characteristics of a product can be."

Secondary factors, such as film coatings, taste-enhancing excipients and the improved smell of products can all increase the ease with which patients take a tablet.

Specific Recommendations

FDA's guidance goes on to make a number of recommendations, including:

• If the RLD is less than or equal to 17 mm in its largest dimension, the generic product should be no more than 20 percent larger than the RLD in any single dimension (the resulting dimension 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 in volume.
• We recommend that the largest dimension of a tablet or capsule should not exceed 22 mm and that capsules should not exceed a standard 00 size (per a size reference attachment to the guidance).
• Efforts should be made to develop tablets and capsules that are of a similar size and shape to the RLD if they are 8mm or smaller in their largest dimension.
• Products should have a similar shape to the RLD, and changes should be quantified through computer modeling or other validated methods.
• All other physical attributes of the drug-coatings, weight, surface area, disintegration time, swelling-should be considered.

Comments on the guidance are due to FDA in 90 days.

Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules

Federal Register