1. Does CVM follow CDER’s Guidance for Industry Tablet Scoring: Nomenclature, Labeling and Data for Evaluation?
Yes, in general CVM does follow CDER’s Guidance, however, there may be exceptions due to the differences in human and animal dosing practices.
2. When are split tablet studies required?
Split tablet studies may be required for scored solid oral dosage forms under the following circumstances:
- New animal drug application
- Generic animal drug application
- The addition of a tablet score
- A new tablet strength
- Major change in formulation or major change in manufacturing process, likely to affect the physical characteristics of the tablet
- A change in tablet shape
This is not meant to be an all-inclusive list of when split tablet studies would be required. Contact the Division of Manufacturing Technologies with any additional questions.
3. Does CVM allow a non-functioning score?
CVM does not typically allow a non-functional score on a tablet.
4. How should the length of time for the split tablet stability study be determined?
The length of the split-tablet study should be based on the anticipated routine storage by the end-user (veterinarian, owner, etc.). The length of the study should be the worst-case scenario based on the tablet dosing section of the labeling and the number of tablets per container in which split tablets will be stored (marketed container, prescription bottle, etc.). This may be more or less than 90 days and the justification, based on veterinary practices, should be provided.
The container closure system should also be addressed in the justification of the length and conditions used in the split tablet stability study. If there are 1000 tablets marketed in a bottle, but it is only sold to veterinary clinics where they dispense smaller quantities of tablets per prescription, then a split tablet stability study for the 1000-tablet bottle size may not be necessary. However, split tablet stability studies for the smaller quantity dispensed would be required. Additionally, if the scored tablets are stored in a blister pack, then there is no container closure for the split tablet to be stored in and different stability conditions may be required. The length and conditions of the split tablet study should depend on how sensitive the drug product is to light, moisture, and oxidation, and how long the split portion of the tablet is stored before use.
The tablet dosing section of the labeling may dictate if a split tablet stability study is needed. For example, if the drug product label states “throw away half tablets” or “dispense the second half the next day”, then a split tablet stability study would not be necessary.
All portions of the tablet can be used for the stability studies.
5. Should splitability (loss of mass and friability) and dissolution of the split portions be tested at both ends of the hardness range? Does it matter what hardness value is used for the study?
Splitability (loss of mass and friability) should be demonstrated at both the low and the high ends of the hardness range, which should have been previously validated. Dissolution does not need to be demonstrated at both ends of the hardness range for immediate release solid oral dosage forms. For modified release dosage solid oral dosage forms, dissolution should be demonstrated at both ends of the hardness range. The evaluated hardness values should be reasonably close to the low and high ends of the proposed hardness range. These studies may be performed on bench scale sized batches (e.g., 50 tablets) and all segments from a single tablet may be used. If you have multiple strengths from a common blend that have different hardness ranges, contact the Division of Manufacturing Technologies to discuss how you may approach testing the different strength tablets across the proposed hardness ranges.
6. Can USP <705> Quality Attributes of Tablets Labeled as Having A Functional Score be used in place of the CDER Guidance testing recommendation?
No, testing proposed in the CDER's guidance “Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation” should be performed or an appropriate justification should be provided if you believe specific expectations listed in CDER's guidance are unnecessary for the purposes of your proposed tablet. Additional testing per USP <705> may also be performed along with the CDER Guidance testing recommendations.
7. What testing is required for each score mark?
Split tablet portions should meet the same finished-product testing requirements as for a whole-tablet product with equivalent strength. For Uniformity of Dosage Unit tests, only a single segment from each tablet should be used. For an oblong tablet, an even ratio of end and center segments should be evaluated rather than exclusively end or center segments. For all other tests described in question 5 (i.e., Loss of Mass and Friability), all segments from a single tablet may be used.
8. Can scoring be different on a generic product vs. the reference listed new animal drug (RLNAD)? For example, if the RLNAD is single-scored, can the generic version be scored in quarters?
CVM recognizes the need for consistent scoring between a generic product and its RLNAD. In addition, consistent scoring ensures that neither the generic product nor the RLNAD has an advantage in the marketplace because one is scored and one is not. However, you may submit a suitability petition (SP) requesting fewer scores on the generic product than are present on the RLNAD as long as all labeled doses can be obtained in a manner that does not increase the risk of mis-dosing. If the SP is granted, this would allow for the generic product to have reduced scoring as compared to the RLNAD. Outside of the SP process, there is no viable path forward for proposed generic products with scoring differences.
9. How should tablets be split for these studies?
Tablets should typically be split both by hand and mechanically in parallel studies. Hand splitting is the worst-case scenario and this study should always be included; however, mechanical splitting may be omitted, if appropriate justification is provided.