Particle Size and Polymorph of Drug Substance Summary Slides

Polymorph

Screening for Polymorph Diversity in approaches –Focus on DS manufacturing process solvents –Investigate beyond solvents in DS manufacturing process and impact on DP process Data should be discussed at the EOP2 meeting Reviewers want assurance of “due diligence”

Polymorph Acceptance Criteria Qualitative test may be adequate when only one of multiple polymorphs is consistently produced –“Sunset” or “Skip” testing might be an option after demonstration of control More complicated situations may need bioavailability data to resolve –compare polymorph performance of mixtures and pure forms

Complicated Situations DS polymorph changes throughout a manufacturing process or during stability Drug product containing DS with multiple polymorphs having different bioavailabilty

Things to Consider How close is solution dosage form to saturation solubility for least soluble polymorph If an amorphous DS is considered for development an EOP2 meeting is important to discuss data. Decision tree 4 in polymorphism –How different is “different” –“Change” includes DP manufacture and stability

Common Thoughts Do we need more dialog to enable FDA and industry to understand what is needed to establish tests and acceptance criteria? –Case studies –From joint Industry/Agency group Is there negative impact from providing additional data and rationale the FDA seems to be asking of Industry?