Despite generic industry requests for FDA to allow flexibility in generic product design, the agency declined to make any major modifications to its draft guidance on the size, shape and other physical characteristics of generic tablets and capsules.

The Generic Pharmaceutical Association and Mylan Inc. had advised the agency that manufacturers make generic drugs larger than the brand to get around the brand’s design patents. They argued in separate comments that if adopted, the draft guidance would “create a new life cycle management tool for NDA sponsors to stifle or delay generic competition.”

FDA’s final guidance, “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules,” is virtually identical to the draft guidance the agency released in December 2013 ([A#14131210005]).

In a June 19 Federal Register notice announcing the availability of the document, FDA said it considered the comments it received and “made editorial changes primarily for clarification.” The agency did not address the submissions about the draft guidance.

The one significant change FDA made was to delete an attachment citing the standard sizes of two-piece capsules. Par Formulations Pvt. Ltd. and ACG Associated Capsules Pvt. Ltd., a manufacturer of empty capsules in India, had requested that the attachment be excluded. ACG said the dimensions provided in the attachment would restrict flexibility of drug manufacturers from using alternate capsule suppliers.

Requirements Should Apply To Brand Too, Mylan Says

Explaining the rationale for the guidance, FDA said it was concerned that differences in physical characteristics between the generic and reference listed drug may affect patient compliance and acceptability of medication regimens or could lead to medication errors. The agency stated that differences in size and shape could affect the transit of the product through the pharynx and esophagus and adherence to the esophagus and thus cause difficulty swallowing.

Mylan said that FDA’s document would not resolve these issues because it does not address size and shape requirements for branded as well as generic drugs. The company recommended that FDA determine what drug characteristics cause the problem, identify whether it is likely to be important in the context of a particular drug, and ensure that the branded or generic does not have the characteristic.

The guidance specifies that if the reference listed drug is less than 17 mm in its largest dimension, the generic product should be no more than 20% larger than the RLD in any single dimension and no more than 40% larger than the volume of the RLD. And if the RLD is equal to or greater than 17 mm in its largest dimension, the generic product should be no larger than the RLD in any single dimension and no larger than the volume of the RLD.

Mylan said these size requirements would “significantly limit generic manufacturers’ options to design non-infringing products.” In addition to patents, Mylan said that brand companies also may seek to protect the size, shape or other distinctive physical attributes of their products through trademarks and trade dress and thereby use the guidance to delay approval of a generic product.

Mylan and GPhA both noted that the sponsor of the reference listed drug valsartan (Novartis AG’s Diovan) has a patent that prevents a generic drug from having a similar percentage of active pharmaceutical ingredient in its tablet and thus generic versions must have a larger volume of excipient.

What Would Justify Deviation From RLD?

The guidance also states that when the RLD capsule is of size 2 or larger, an increase of one capsule size should be considered only when adequate justification can be shown for the size increase.

GPhA and Mylan said FDA provides no explanation of what information or research would qualify as “adequate justification” for such an increase.

FDA states that if a tablet or capsule intended to be swallowed intact differs from the criteria recommended in the guidance document, then the applicant should contact the Office of Generic Drugs “with supportive information and justification” before establishing the quality target product profile for their generic candidate.

Mylan said in a footnote in its comments that the guidance doesn’t establish any procedure for making contacts with OGD and that without a process for review and discussion generic manufacturers will be unable to achieve timely resolution of questions regarding necessary differences from FDA’s recommendations.

“Given the uncertainty as to how OGD would review, process, and approve deviations from the recommended criteria and how long it would take to do so, a brand-name company could create a potential lengthy delay for a generic manufacturer at the beginning of the development process,” Mylan stated.

GPhA Advocates Case-By-Case Approach

GPhA recommended that FDA formulate a policy and allow for case-by-case discretion with regard to physical attributes.

The association said there is no provision in the Hatch-Waxman Act allowing FDA to deny approval of an ANDA based on differences in physical attributes from the RLD. It said any FDA action related to physical characteristics of generic drugs must be tied to the safety of the drugs to avoid exceeding the agency’s statutory mandate.

The guidance says additional flexibility may be given for products that are 8 mm or smaller in their largest dimension.

Dr. Reddy's Laboratories Ltd. and Apotex Inc. asked FDA to elaborate on what additional flexibility may be given for these products. Apotex also questioned the applicability of the guidance recommendations to a modified release dosage form.

Prior to issuing the draft guidance, FDA had begun to reject ANDAs for generic tablets that are larger than their brand equivalent Also see "FDA Rejects Generic Tablets Larger Than Brand Citing Safety And Efficacy Concerns" - Pink Sheet, 9 January, 2012..

Wockhardt USA LLC is one company that seems to have embraced the draft guidance. Earlier this year, it introduced its over-the-counter fexofenadine antihistamine products with the equivalent color, size and shape of Sanofi’s Allegra Allergy ([A#14150107001]).

Generic Firms Fear 'New Lifecycle Management Tool' From FDA Pill Size Guidance

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