1. Particulate Matter - Visual Detection to Identification Scott Aldrich PDA Visual Inspection, October 19-20, 2009

6. Visible Sub-visible Sub-micrometer Size Domains 1µm 25µm 10µm 150µm Increasing Probability of Detection What size domain matters for the product stability? Visible Gray zone

13. Particle Count by Light Obscuration – First Tier Groves, 1993 CONSTITUTES KEY FILING DATA

19. Capillary Removal and Transfer

22. Inspection at Microscopy Bench Tools of the Trade The Particle Atlas

27. Membrane Method for ID Isolation

28. PLM Spectroscopy Hotstage Schemes for Material Ultramicroanalysis (Light Obscuration) Membrane Isolate Picking Direct SEM-EDS Optical Count PLM-Spectroscopy Direct SEM-EDS ID Quant

32. Thanks for Your Attention Questions?

33. Membrane Microscopic Count is Key Bio: Scott Aldrich is a long-standing member of American Chemical Society, AAPS, State Microscopical Society of Illinois, PDA and Microscopy Society of America. He is a member of the United States Pharmacopeia (USP) Parenteral Products – Industrial Expert Committee for the current (2005-2010) term. He is a 38 year veteran of the pharmaceutical industry, through employment at Upjohn, Pharmacia, and Pfizer. Scott is President of Ultramikro, LLC an independent consulting firm specializing in microscopy training and particulate matter control programs.

34. Parenteral and Ophthalmic Limits – A Comparison

36. FDA Review of Recent PM Data 295 Drug Applications (SVP’s, by LO)* * Nath, et al. Particulate Contaminants of Intravenous Medication and the Limits set by USP General Chapter <788>, 2005 Pharm. Forum n/a n/a 151 1504 Mean + 3SD 13 (27)/mL 59 (89)/mL 15 (43)/pkg 219 (415)/pkg Mean (± 1SD) 1983 data (19 LVP products by membrane) ALL – 406 lots (354 in glass vials) 10 (24)/pkg 82/pkg 154 (289)/pkg 1021/pkg 17 (45)/pkg 153/pkg 245 (438)/pkg 1560/pkg Mean (± 1SD) Mean + 3SD 600 ≥25  m 6000 ≥10  m 600 ≥25  m 6000 ≥10  m USP <788> Limits 112 294 # Batches TERMINAL STERILE PROCESS ASEPTIC PROCESS