1. Ajaz S. Hussain, Ph.D. Office of Pharmaceutical Sciences CDER, FDA October 21, 2003 Dose Content Uniformity: Parametric Tolerance Interval Approach

2. Issues and Next Steps International Pharmaceutical Aerosol Consortium on Regulation and Science (PAC- RS) Proposal –Proposal discussed and refined for about three years –Resolution challenges OPS Executive decision –Need to resolve the remaining issues in next six months –If not resolved, step back to reevaluate options and approach Merge this with the Quality by Design approach

4. The Test One of several end product test “..designed to demonstrate the uniformity of medication per actuation or dose, consistent with the label claim, discharged from the mouthpiece of a sample of an appropriate number of containers from a batch (n=10 is recommended) “Providing an overall performance evaluation of a batch, assessing the formulation, the manufacturing process, the valve, and the actuator” (MDA/DPI draft Guidance)

6. Acceptance Criteria (draft Guidance) N=10; not outside 80-120% of label claim for more than 1 of 10 containers; none outside 75-125; and the mean is not outside 85- 115% If 2 or 3 of 10 is outside 80-120%, none outside 75-125%, and the mean is not outside 85-115%, an additional 20 containers can be sampled. No more that 3 of all 30 determinations is outside 80-120%; none of the 30 is outside 75-125%, and the mean is within 85-115%

8. Today: Framing Issues Dr. Adams (FDA) IPAC-PS presentations ACPS discussion –We seek your input on a process to resolve remaining issues in the next six months –In your deliberations please consider Clinical relevance and specifications tailored for intended use Hypothesis testing for every batch – is this consistent with “Quality by Design” –Hypothesis testing at the “process validation stage”; quality assurance and verification for routine production operations Complexity of PTIT with respect to explaining its meaning to the customers