A Hard Pill to Swallow? In Transit for a Couple of Years, FDA Finally Coughs Up Draft Guidance on Physical Attributes of Generic Tablets and Capsules

By Kurt R. Karst –    

Last week, FDA announced the issuance of a long-anticipated draft guidance document, titled “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules,” providing details on acceptable physical attribute differences between generic drugs and their NDA Reference Listed Drug (“RLD) counterparts.  Issuance of a draft guidance on this topic is contemplated as a Regulatory Science Plan goal the Agency agreed to under the 2012 Generic Drug User Fee Amendments, and as reflected in the Generic Drug User Fee Act Program Performance Goals and Procedures for Fiscal Year 2013:

Topic 10: Evaluation of drug product physical attributes on patient acceptability
Impact: Laboratory and human studies on physical attributes such as tablet size, shape, coating, odor perception (residual solvents), score configuration, taste masking or color on the ability of patient to use (for example swallow) or perceive quality (for example smell) will allow OGD to provide better guidance to applicants on how these physical attributes should be controlled and compared to the RLD.

The issue of generic drug physical attributes and how they compare to their RLD counterparts is not new; however, there seems to be increasing focus on the issue by FDA.  As we reported nearly two years ago, FDA has refused to approve various ANDAs because of size issues, and has issued various documents on topics such as bead size and tablet scoring.  (Size issues have even found their way into ANDA 180-day exclusivity decisions – see here and here.)  And although not the topic of FDA’s draft guidance, we note that physical attribute issues are not just cropping up where tablets and capsules are concerned.  They come up in other contexts as well.  For example, in drug-device combination products.  We’ve seen instances in which FDA has advised potential applicants that their device component should be “interchangeable in patient hands” vis-à-vis the RLD device component.  FDA has even gone so far as to recommend that “the color scheme be similar to the RLD . . . . because patients associate color schemes with the product and strength.”

The problem, of course, is that the more FDA requires a generic drug product to look and feel the same as the RLD product, the greater the likelihood that a generic will run smack dab into intellectual property protections on the brand-name drug, such as patents and trademarks.  Indeed, with tight restrictions on physical attribute differences, some companies may now more than ever be incentivized to seek the issuance of patents with claims broad enough to cature the physical attribute variations identified by FDA as permissible.  What physical attribute variations you ask?  Well, before we go there, let’s start with the “why”? 

The gist of FDA’s draft guidance is that generic drug manufacturers should consider physical attributes when they develop Quality Target Product Profiles (“QTPPs”) for their generic product candidates because it is in the interest of patient safety.  As FDA states:

[A] variety of factors may affect the ability of a patient to swallow a tablet or capsule.  Although not all patient factors can be addressed through pharmaceutical design and manufacture, the physical characteristics of a product can be.  These characteristics influence the ability of certain patients to swallow the product, particularly in vulnerable populations.  We believe that tablets and capsules can be effectively developed and manufactured to minimize swallowing difficulties, which can encourage and improve patient compliance with medication regimens. 

With that in mind, and after a whole lot of citation to published literature, FDA states its draft recommendations.  Insofar as tablet size is concerned, FDA recommends limiting size differences between therapeutically equivalent tablets as follows:

• 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.

For products that are 8 mm or smaller in their largest dimension, FDA comments that “[a]dditional flexibility may be given,” but also reemphasizes that “efforts should be made to develop tablets and capsules that are of a similar size and shape to the RLD.”

Insofar as capsule size is concerned, FDA references the standard capsule size convention (provided below) and says that it will:

generally allow an increase of one capsule size, when the RLD capsule is of size 3 or smaller.  When the RLD capsule is of size 2 or larger, an increase of one capsule size should only be considered when adequate justification can be provided for the size increase.  These recommendations would allow an increase of one capsule size when the capsule size is less than capsule size 00. . . .  

Moving on to shape, FDA recommends “manufacturing tablets and capsules that have a similar shape or have a shape that has been found to be easier to swallow compared with the shape of the RLD.”  Earlier in the guidance, FDA notes that “[i]n vitro studies suggest that flat tablets have greater adherence to the esophagus than capsule-shaped tablets,” and that “[s]tudies in humans have also suggested that oval tablets may be easier to swallow and have faster esophageal transit times than round tablets of the same weight.”

Finally, in a catch-all “other physical attributes” bucket, FDA merely notes that “[o]ther physical attributes of tablets and capsules should be considered in the context of their effect on ease of swallowing.  For example, tablet coating, weight, surface area, disintegration time, and propensity for swelling should be considered when developing a QTPP for generic tablets.” 

Generic drug manufacturers clearly have a lot to consider these days as FDA tightens the screws on them – whether in product pysical attributes or labeling changes for that matter (see our previous post here).