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

October 2022 (Rev. 1)

We will continue our series of looking at the growing list of FDA Guidance Documents related to the pharmaceutical industry and to compounding. This week, we will finish looking at a Guidance Document that applies only to manufacturing, but there may be some principles that we may want to be reminded of in compounding. This week, we will look at the "RECOMMENDATIONS" section.

OUTLINE

1. INTRODUCTION
2. BACKGROUND
   1. Differences in Size and Shape of Tablets and Capsules between a Reference Listed Drug and a Drug Product Subject to an Abbreviated New Drug Application
      1. Size
      2. Shape
      3. Patient Factors
   2. Other Physical Attribute Considerations
3. RECOMMENDATIONS
   1. Size
   2. Shape
   3. Other Physical Attributes
   4. Biowaivers

III. RECOMMENDATIONS

The recommendations in this guidance are based on published literature regarding patient experiences swallowing tablets and capsules and Agency experience with NDAs and ANDAs submitted for oral tablets and capsules. If a tablet or capsule intended to be swallowed intact differs from the criteria recommended in this guidance document, then the applicant should contact OGD with supportive information and justification before establishing the QTPP.

1. Size
   
   For comparable ease of swallowing as well as patient acceptance and compliance with treatment regimens, the Agency recommends that generic oral tablets and capsules intended to be swallowed intact should be of a similar size to the corresponding RLD. The Agency recommends limiting size differences between therapeutically equivalent tablets as follows:
   
   
   • If the RLD is less than 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 single dimension of the generic should not exceed 17 mm).
     • No more than 40 percent larger than the volume of the RLD.
   • 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.
     • No larger than the volume of the RLD.
   • 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.

   Additional flexibility may be given for products that are 8 mm or smaller in their largest dimension, but efforts should be made to develop tablets and capsules that are of a similar size and shape to the RLD.

   Under the standard capsule size convention, the allowances described above 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.

   The Agency recognizes that two drug products may have different recommended upper size limits, but size should be considered as part of a single product risk/benefit profile. When establishing therapeutic equivalence, the applicant should compare their generic product only to the RLD.

2. Shape

   In addition to the size recommendations described above, we recommend 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. Evaluating and comparing the largest cross sectional areas of the RLD and generic product is one strategy to quantify changes in shape. Tablets and capsules that have a larger cross sectional area (e.g., tablets that are rounder) would generally be more difficult to swallow than tablets or capsules of the same volume but with smaller cross sectional areas.

   The largest dimension refers to the length of oval or capsule shaped tablets or the diameter of round tablets.

   For the purposes of this guidance, volume refers to the volume occupied by the tablet or capsule.

   An internationally accepted numbering system for capsule sizes is used in approved U.S. drug products. For the purpose of this guidance, a liquid fill capsule is considered a capsule.

   For the purposes of this guidance, the largest cross sectional area is defined by the largest cross sectional area of the tablet that lies in a plane perpendicular to the longest axis of the tablet. If the shape of tablet is unconventional (e.g., pentagon, triangle, diamond, heart), then the largest cross sectional area will be defined as the area of the smallest circle, oval, or ellipse that would completely enclose this largest cross sectional shape.

   There are a variety of techniques that may be used to determine the volume measurements of a tablet or capsule, including use of pycnometers, or calculations based on physical measurements of the tablet or the die used to produce the tablet. For the purpose of this guidance, spatial imaging and/or the use of computer models is recommended, because they are more accurate and applicable to a variety of shapes, although other appropriately validated methods may be used if properly justified.

   The size of a tablet or capsule should be provided in the common technical document (CTD) format section 3.2.P.1, Description and Composition of the Drug Product of the ANDA. Any studies and/or related information should be provided in the CTD section, 5.3.1.2, Comparative Bioavailability and Bioequivalence Study Reports. The Agency may request samples for evaluation of the physical attributes of a tablet or capsule.

3. Other Physical Attributes

   Other 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.

   Description of these physical characteristics should be provided in the CTD section 3.2.P.1, Description and Composition of the Drug Product of the ANDA. A summary of any studies to support sizes outside the recommendation provided in this guidance should be provided in the CTD section 3.2.P.2, Pharmaceutical Development or CTD section 3.2.P.5.6, Justification of Specifications.

4. Biowaivers

   A biowaiver (i.e., the waiver of in vivo bioequivalence data) for additional strengths of a solid oral dosage form is generally granted if it meets one of the criteria set forth in the regulations, one of which is proportional similarity between strengths in active and inactive ingredients. Compositional proportionality may be particularly relevant when considering tablet size and tablet formulation for other strengths (both lower and higher) of the same dosage form to be considered for a waiver of the in vivo bioequivalence study requirement. Although compositional proportionality may exist when all active and inactive ingredients are in the same proportion between different strengths, other methods of achieving compositional proportionality may be more amenable to maintaining appropriate tablet sizes for generic products when compared with the RLD. A detailed description of how the Agency defines proportional similarity can be found in the Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations.

   See ICH guidance for industry M4Q: The CTD - Quality. It is available on the Internet at http://www.fda.gov/​Drugs/​Guidance​Compliance​Regulatory​Information/​Guidances/​default.htm under International Conference on Harmonisation - Quality.

   See 21 CFR 320.22(d).
   This guidance is available on the Internet at http://www.fda.gov/​Drugs/​Guidance​Compliance​Regulatory​Information/​Guidances/​default.htm under Biopharmaceutics.

   FDA recommends that applicants consider Agency published guidance, product specific 223 guidance, and relevant regulations on the waiver process when designing and formulating other strengths of the same dosage form that will be studied with bioequivalence studies. For specific questions related to biowaivers, you should contact the appropriate review division within OGD.