1. 1 Advisory Committee for Pharmaceutical Science and Clinical Pharmacology July 22 -23, 2008 Classification of Orally Disintegrating Tablets Frank O. Holcombe, Jr., Ph.D. Associate Director for Chemistry Office of Generic Drugs July 23, 2008

2. 2 Classification of Orally Disintegrating Tablets Issue Orally Disintegrating Tablets are considered a distinct dosage form by the Food and Drug Administration. The dosage form definition describes expected functionality – i.e., disintegration. Because of the general nature of the definition, questions remain about variations and scope of the dosage form. The development of effective guidance is important for characterization and evaluation, but has been impeded by difficulty in determining meaningful criteria for this dosage form.

3. 3 Classification of Orally Disintegrating Tablets Initial Products Produced by lyophilization Formed in blister packaging cavity Cake-like Porous/Glassy state Fragile Low weight Designed to dissolve/disintegrate on contact with saliva

4. 4 Classification of Orally Disintegrating Tablets Initial Products Intended as a treatment advantage for target populations Trouble swallowing (pediatric, geriatric, dysphagia) General compliance issues Convenience

5. 5 Classification of Orally Disintegrating Tablets Initial Products Considered to be a new and distinct dosage form Physical form Manufacturing technology Administration and use

6. 6 Classification of Orally Disintegrating Tablets Initial Products Defined as: Tablet, Orally Disintegrating A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue.

7. 7 Classification of Orally Disintegrating Tablets Other Tablet Forms Based on Method of Use Tablet, Chewable Tablet, Dispersible Tablet, Effervescent Tablet, for Solution Tablet, for Suspension Tablet, Orally Disintegrating, Delayed Release Tablet, Soluble

8. 8 Classification of Orally Disintegrating Tablets Technology Development Manufacturing process shift from lyophilization to direct compression Simpler process Less time consuming Less expensive Avoids patented technology

9. 9 Classification of Orally Disintegrating Tablets Technology Development Direct compression tablet Allowed use of common tablet excipients Larger tablet than lyophilized product More robust product

10. 10 Classification of Orally Disintegrating Tablets Technology Development Tablet disintegration aided by Soluble binders Effervescence Superdisintegrants

11. 11 Classification of Orally Disintegrating Tablets Challenges “Orally Disintegrating Tablet” should represent a dosage form easily distinguishable from other tablets Definition includes “disintegrates rapidly, usually in … seconds”

12. 12 Classification of Orally Disintegrating Tablets Challenges Trend to Compressed Tablets Larger tablets Longer disintegration times

13. 13 Classification of Orally Disintegrating Tablets Challenges Question of When is a tablet no longer an ODT? Important issue in product labelling Critical issue for 505(j) products (ANDAs) because of requirement to be same dosage form as the reference NDA product

14. 14 Classification of Orally Disintegrating Tablets Guidance Development Early Considerations included Disintegration times of less than 60 seconds Labelling description of product characteristics

15. 15 Classification of Orally Disintegrating Tablets Guidance Development Current Draft Guidance General discussion of intention of dosage form Should disintegrate or dissolve rapidly on contact with saliva, eliminating need for chewing or swallowing intact tablet, or taking tablet with additional liquids.

16. 16 Classification of Orally Disintegrating Tablets Guidance Development Current Draft Guidance General discussion of expectations for dosage form General product development considerations Recommendation for in-vitro disintegration time of no more than 30 seconds Recommendation for use of USP disintegration test method Suggested tablet weight limitation of 500 mg

17. 17 Classification of Orally Disintegrating Tablets Public Comments on Draft Guidance Tablet Weight – Several OTC products larger than 500 mg - Would restrict use for high dose drugs - Issues can be addressed by formulation Disintegration Time – Should not be 60 seconds (can be higher or lower) - USP not an appropriate method - in-vivo/in-vitro correlations not good

18. 18 Classification of Orally Disintegrating Tablets Public Comments on Draft Guidance Disintegration Time – in-vitro criteria not relevant to successful use of product In-vivo Evaluation – should be required, including sensory evaluation and palatability

19. 19 Classification of Orally Disintegrating Tablets Questions 1.What properties (in-vivo or in-vitro) do you consider critical to this dosage form? 2. Should physical properties (e.g., size, formulation, and disintegration times) be a primary factor in determining conformance to this dosage form? (Yes/No/Abstain) a.If so, how specific or restrictive should the criteria be? 3. Can labeling (i.e., instructions for use) be considered sufficient to define the dosage form? (Yes/No/Abstain) a.If so, should labeling describe/include differences between/among NDA and ANDA products? 4. What, if any, special issues should be considered (e.g. Patient compliance, target populations/conditions)?