1. Pharmaceutical Nomenclature Issues and challenges Moheb M. Nasr, Ph.D. Acting Director Office of New Drug Chemistry (ONDC) OPS, CDER, FDA Advisory Committee for Pharmaceutical Sciences (ACPS) October 22, 2003

2. ACPS, October 22, 2003 2 Pharmaceutical Nomenclature Issues and challenges FDA Perspective Orally Disintegrating Tablets (ODT) Topical Dosage Form Classification - an Update Committee Discussions Dan Boring, R.Ph.,Ph.D. Frank Holcombe, Jr., Ph.D. Lucinda Buhse, Ph.D.

3. ACPS, October 22, 2003 3 Issues and challenges z Impact on regulatory decisions, marketing, drug development, and the public z Nomenclature development (scientific and regulatory challenges) y How to do it right the first time? y Is a new dosage form needed or is it just a minor modification in an existing dosage form that can be handled by labeling? y How to establish definitions and criteria for new dosage forms? y Do we need to have that many dosage forms?

4. ACPS, October 22, 2003 4 Issues and challenges z Coordination with different organizations and stakeholders z Definitions (descriptive and quantifiable attributes) z Refinement and/or replacement of older dosage forms z Pharmaceutical equivalence issues

5. ACPS, October 22, 2003 5 Questions for ACPS 1.What are the factors that the Agency should consider in determining (a) whether a new dosage form name is warranted and (b) how such a dosage form should be defined? 2. Is it reasonable or useful to include a quantifiable attribute when defining a dosage form or distinguishing between closely related dosage forms where appropriate? Can such an approach be viewed as too arbitrary in some cases and too rigid in other cases?

6. ACPS, October 22, 2003 6 Questions for ACPS 3. Is the proposed criterion, i.e., an in vitro disintegration time of less than 60 seconds, reasonable for defining an orally disintegrating tablet? 4. Has the update on topical dosage forms presented today addressed the questions/comments raised by the ACPS at the March 2003 meeting?

7. FDA Perspective on Dosage Form Nomenclature Dr. Dan Boring, R.Ph., Ph.D. Review Chemist; Labeling Expert ONDC, OPS

8. ACPS, October 22, 2003 8 Nomenclature of Pharmaceutical Dosage Forms z Issues and challenges y Scientific y Regulatory y Marketing y Legal y Healthcare provider y Patient

9. ACPS, October 22, 2003 9 What is an Established Name? z The FD&C Act states “drug” only z Drug substance and/or drug product? z At CDER, an established name for both drug substance and drug product z In general, an established name for a drug product is: [(drug substance) (release characteristic) (route of administration) (dosage form)] z Today’s focus is on dosage form

10. ACPS, October 22, 2003 10 Definition of a Pharmaceutical Drug Product z Drug Product is defined as a finished dosage form such as tablet, capsule or solution z What is a dosage form? z A dosage form could be defined as the physical form of a drug product at the point that it is introduced into the body, or, where final preparation is required before introduction into the body, the physical form of the drug product in the package that bears instructions for final preparation (private communication) z Dosage forms are non-proprietary

11. ACPS, October 22, 2003 11 Stakeholders z Innovators y Research, development, marketing, legal z FDA y OND, ONDC, ODS, COS, NSC z USP y Expert Comm on Nomenclature and Labeling z Healthcare providers and patients y Not direct participants

12. ACPS, October 22, 2003 12 FDA Nomenclature Issues z New drugs y No USP monograph exists y Is a new name necessary? y Is it nomenclature or labeling? z Generic drugs y Compliance with USP monograph? y Is a compendial name being developed? y Will name allow proper product selection for substitution? y Name definition should not allow generic manufacturers to substitute a new dosage form for a RLD z OTC drugs y Product selection by patient

13. ACPS, October 22, 2003 13 Nomenclature Assessment Factors z Name must clearly identify the product z Name promotes accurate recognition without risk of medication errors z Name meets database, indexing and listing needs z Name consistent with precedents (i.e., systems) z Name should not provide an advantage through exclusive proprietary technology

14. ACPS, October 22, 2003 14 Challenges z Will a new name serve long-term needs? z Is an older term still accurate? z Is a developing new term appropriate? z Can objective standards be developed to define a new dosage form? z How should name development be coordinated (innovator, FDA, USP)? z Global harmonization? z Implementation?

15. ACPS, October 22, 2003 15 New Dosage Forms and Drug Delivery Systems z Orally disintegrating tablets z Tablets for suspension z Liposomes z Microspheres z Films? z Iontophoretic systems?

16. Defining Orally Disintegrating Tablets Frank Holcombe, Jr. Ph.D. Associate Director for Chemistry Office of Generic Drugs, OPS

17. ACPS, October 22, 2003 17 Current Definitions of ODT z FDA definition “A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue” z USP Stimuli proposal “A solid oral dosage form that disintegrates rapidly in the mouth”

18. ACPS, October 22, 2003 18 Desired Characteristics and Benefits of ODT z Oral disintegration z Rapid disintegration z No chewing or liquids necessary z Provides improved route of administration and increased compliance for certain patient populations

19. ACPS, October 22, 2003 19 Issues Concerning ODT z Limited experience – similarity of all initial products z Expansion in product variations due to changes in y Technologies y Formulations y Additional drug products y Target market population

20. ACPS, October 22, 2003 20 Issues Concerning ODT z Format of suitable definition y Should address both the desired characteristics and control of extent of product range y Must address: x Method of administration x Objective criteria (limits for disintegration time)

21. ACPS, October 22, 2003 21 Issues Concerning ODT z Disintegration evaluation y In-vivo testing (subjective, objective) y In-vitro testing (objective) x Variety of methods x Results may be method dependent

22. ACPS, October 22, 2003 22 In-vitro Testing Methods z Applicant in-house methods (proprietary) z FDA laboratory method (static) z USP Chapter Disintegration (dynamic)

23. ACPS, October 22, 2003 23 In-vitro Testing Results z Static: 1-78 sec z Dynamic: 1-69 sec z Most products in 1 to 30 sec range z No data correlating in-vivo and in-vitro disintegration times

24. ACPS, October 22, 2003 24 In-vitro Testing Results

25. ACPS, October 22, 2003 25 FDA Proposal z A revision of the ODT definition to include in-vitro disintegration method and acceptance criteria (USP, < 60 sec) Objective: To provide criteria (based on original expectations) for distinguishing orally disintegrating tablets from other tablet forms

26. Topical Dosage Form Classification – an Update Lucinda Buhse, Ph.D. Acting Director Division of Pharmaceutical Analysis Office of Testing and Research, OPS

27. ACPS, October 22, 2003 27

28. ACPS, October 22, 2003 28 Advisory Committee Input z No need to include appearance and feel (e.g., greasy, non- greasy) z Definitions should be based on the vehicle z Ointments and suspensions could be classified as lotions (an overused term) z Do not make cream a default definition and do not separate creams using hydrophilic-vs-hydrophobic z Use detailed rheological evaluation (e.g., yield values) to distinguish gels and/or lotions from creams z Reconsider criteria used to classify gels

29. ACPS, October 22, 2003 29 CDER Activities z Evaluation of ACPS input z Consultations with Dr. Arthur Kibbe z Analysis of liquid/semi-solid borderline products based on more extensive rheological evaluation z Examination of optical properties and compositions of gels

30. ACPS, October 22, 2003 30 Rheological Evaluation Sample Yield Value (D/cm 2 ) 1 50 29 90 62125 61160 36195 50200 51525 4600 32660 Conforms to container Does not conform to container

31. ACPS, October 22, 2003 31

32. ACPS, October 22, 2003 32 Questions for ACPS 1.What are the factors that the Agency should consider in determining (a) whether a new dosage form name is warranted and (b) how such a dosage form should be defined? 2. Is it reasonable or useful to include a quantifiable attribute when defining a dosage form or distinguishing between closely related dosage forms where appropriate? Can such an approach be viewed as too arbitrary in some cases and too rigid in other cases?

33. ACPS, October 22, 2003 33 Questions for ACPS 3. Is the proposed criterion, i.e., an in vitro disintegration time of less than 60 seconds, reasonable for defining an orally disintegrating tablet? 4. Has the update on topical dosage forms presented today addressed the questions/comments raised by the ACPS at the March 2003 meeting?