1. ITFG/IPAC Collaboration CMC Specifications Technical Team ITFG/IPAC TECHNICAL TEAM: CMC SPECIFICATIONS Presented by: Bo Olsson, PhD 26 April 2000 Rockville, MD

2. ITFG/IPAC Collaboration CMC Specifications Technical Team CMC SPECIFICATIONS TECHNICAL TEAM Focus on Dose Content Uniformity (DCU) Particle Size Distribution (PSD)

3. ITFG/IPAC Collaboration CMC Specifications Technical Team ICH: HARMONISATION OINDP are amenable to the principles set forth by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The ICH Harmonised Tripartite Guideline on "Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances" (Q6A) provides a process for establishing specifications.

4. ITFG/IPAC Collaboration CMC Specifications Technical Team ICH Q6A: SPECIFICATIONS “ The justification [of specifications] should refer to relevant development data, pharmacopoeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long term stability studies, as appropriate. Additionally, a reasonable range of expected analytical and manufacturing variability should be considered. It is important to consider all of this information.” (62 Fed Reg 62892)

5. ITFG/IPAC Collaboration CMC Specifications Technical Team DCU Hypothesis: The current state of OINDP technology may not allow general compliance with the DCU specifications in the draft FDA CMC Guidances. To date, more than 12 companies have initiated the process to collect a world-wide blinded database of more than 45 products to examine actual DCU capability of OINDP Initial assessment by July 31

6. ITFG/IPAC Collaboration CMC Specifications Technical Team DCU ITFG/IPAC position: The specifications in the draft Guidances should be based upon sound statistical practices such that they can be translated into a quality requirements. Investigate, using database, alternate DCU specifications ICH Q4 (Pharmacopoeial Harmonisation) draft proposal Dr. Walter Hauck's Approach ISO 2859-1 Approach Other Approaches

7. ITFG/IPAC Collaboration CMC Specifications Technical Team PSD To date, more than 12 companies have initiated a process to collect a world-wide blinded database of more than 40 products to examine actual PSD capability of OINDP Initial assessment by July 31 Purpose of PSD survey Examine the relevancy of the mass balance requirement as a product specification versus system suitability requirement. Investigate if fewer than 3-4 stage groupings can provide equivalent control.