1. Orally Inhaled and Nasal Drug Products (OINDP) Subcommittee Report to the Advisory Committee for Pharmaceutical Sciences Rockville, Maryland November 15, 2000 Dose Content Uniformity Issues Guirag Poochikian, Ph.D. Chemistry Team Leader Division of Pulmonary and Allergy Drug products Center For Drug Evaluation and Research Food and Drug Administration

2. Outline Background Questions Summary of Comments

3. Published OINDP Draft CMC Guidances (Under Revision) Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug products Chemistry, Manufacturing, and Controls Documentation Nasal Spray and Inhalation Solution, Suspension, and Spray Drug products Chemistry, Manufacturing, and Controls Documentation http://www.fda.gov/cder/guidance/index.htm

4. Activities Since Publication of the OINDP Draft Guidances Public Comments on MDI and DPI Drug Products Guidance (March 1999) AAPS/FDA/USP Workshop (June 3-4, 1999) Public Comments on Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products Guidance (September 1999) OINDP Expert Panel (November 1999) OINDP Subcommittee Meeting (April 2000) OPS Advisory Committee (November 2000)

5. Dose Content Uniformity Dose uniformity among units within a batch (Inter-unit/Intra-batch) Dose-to-Dose uniformity within a unit/container (Intra-unit)

6. Questions to Subcommittee A.Should there be a single content uniformity standard for all orally inhaled and nasal drug products (OINDPs)? B.Should the FDA continue development of the proposed statistical approach to evaluating content uniformity?

7. Summary of Comments on Question A Data are needed before the question can be answered. A single C.U. standard would be desirable. Last decade D.P.s AP under FDA guidance criteria. Multiple standards may be the best approach. Existing D.P.s may be grandfathered until phase-out. C.U. considered in context of in vitro/in vivo assessments. Lack of standardization unfair to clinicians and public.

8. Questions to Subcommittee A.Should there be a single content uniformity standard for all orally inhaled and nasal drug products (OINDPs)? B.Should FDA continue development of the proposed statistical approach to evaluating content uniformity?

9. Summary of Comments on Question B Yes. FDA should continue development of the proposed statistical approach by Dr. Hauck. Data from existing products would enable the parametric statistical approach to move forward. Other statistical approaches may be considered. With Dr. Hauck’s statistical approach, the Agency sets the allowable consumer risk, and the producer determines its own risk. One approach would be to use the properties of reference products to help determine criteria.