An Engineer Dive in the Bio and Medical Devices World

1. An Engineer Dive in the Bio and Medical Devices World Presentation by: Amer El-Hage 11/20/2006 Beeston Engineering Consulting

2. Outline • A bit about myself, Beeston Engineering and this industry • What my Engineering education missed! • What is Art, Science and what is Engineering? • Common Engineering issues • Project management! • Summary Beeston Engineering Consulting

3. My Qualifications • 25 years in scientific instrument development at Beckman, Varian, LJL Biosystems and Molecular Devices • Over 30 product development programs experience. Several products carried from concept to full production • Directed product development projects in meeting their specification, budget and schedule goals • Involved in several instrument designs (fifteen issued patents), product validation and risk assessment programs • Developed at Varian, LJL and MDC their product development process • ASME Silicon Valley volunteer for over five years, chair 2006 • U.C. Berkeley M.S. 1980, Mechanical Engineering- Design and Automation Beeston Engineering Consulting

4. Beeston Engineering Consulting • Independent evaluation of product or devices at any stage in the development cycle • Identify necessary technical skills and tools to execute a product development project successfully • Program Management: Develop tasks, budget, and resources • Develop plans to validate prototypes to relevant standards and regulatory systems • Draft engineering, quality and processes to efficiently transfer or release your product to manufacturing Beeston Engineering Consulting

5. California and Bay area Bio-SpaceSome Statistics and Graphs Beeston Engineering Consulting

6. Defining the Industry The Biotech & Biomedical (Life-science)Industry in California is comprised of many sectors, with employment today exceeding 250,000. Employment breaks down as follows: • Biopharmaceuticals (34%) • Medical devices, instruments and diagnostics (33%) • Academic research (18%) • Laboratory services (12%) • Other (3%) Source: CHI, California’sBiomedical Industry, 2004 Beeston Engineering Consulting

7. A Few Figures for California • Total biomedical companies: 2,600 (90% founded since 1980 and 80% privately owned) • Total world-wide revenues: $32.3 billion • Total employment: 230,100 (This exceeds the number employed by the computer industry in the same time frame!) • Total wages and salaries paid: $14 billion • These companies serve as powerful economic drivers in the 7 regional clusters in which they are located. Source: CHI, California’sBiomedical Industry, 2004 Beeston Engineering Consulting

8. Biomedical Industry Wages in CA Beeston Engineering Consulting Source: CHI, California’sBiomedical Industry, 2004

9. Employment Growth 23% growth from 1990 to 2002 Source: CHI, California’sBiomedical Industry, 2004 Beeston Engineering Consulting

10. Some of my Instrumentations and Medical Devices Experience • Chemical and Immunodiagnostics – Design audit, Project planning and transfer to manufacturing • Combinatorial Chemistry systems • DNA, HIV and other detection systems • Biology and cell based assays • Pulmonary drug delivery device – Plastic molding • Glaucoma, Bone density - Technical reviews and project development for medical devices measurement, Insulin inhaling device • Catheters and Stents – SLA models, and coating processes • Quality Engineering, Design Control and process validation Beeston Engineering Consulting

11. A Typical Automated Laboratory Setting Automated Liquid Handler “Dispensers” Microplate Hotel or Storage Microplate Reader Robot Arm Other Mechanical Laboratory Gizmos Beeston Engineering Consulting

12. Microtubes Moved Into 96 Well Microplates Beeston Engineering Consulting

13. Beeston Engineering Consulting

14. Time and Dollars scale It usually takes 8 -10 years to get a pharmaceutical product or drug to market and $500-900M investment Medical Devices require 4 - 6 years and $40-100M to develop Scientific Instruments require 3-4 years and ONLY $5 - 10M to develop! Beeston Engineering Consulting

15. What about the Bay Area? • 750+ companies * • 86,000+ employees • 30+ academic and research institutions • The Bay Area has the largest concentration of medical device start-ups in the U.S.,and the largest concentration of companies bought out by medical device giants. * Excludes the 98 companies and 5,000 employees in the Sacramento area Source: CHI, California’sBiomedical Industry, 2004 Beeston Engineering Consulting

16. Example of some Scientific and medical Devices companies Beeston Engineering Consulting

17. BD BiosciencesDivision of Becton Dickinson Company • Medical Device company - Regulated industry • Parent company well established > 100 yrs • IVD products • Research products • Approximately 15,000 employees (1,000 BA) • Revenue of $4B ($300-400M) per year Figures in (parenthesis) are my estimates Beeston Engineering Consulting

18. A BD Diagnostic Instrument Made Possible by “Engineers” Beeston Engineering Consulting

19. Molecular Devices Corp. • Scientific and Bio-analytical solution company – Non Regulated (yet!) • Company well established > 20 yrs • Drug discovery tools, includes reagents • Research, and Analytical instruments • Approximately 600 employees • Revenue of $160-200M per year • Wide portfolio, steady growth mostly by acquisitions • Operate several independent companies worldwide Beeston Engineering Consulting

20. Microplate Reader Beeston Engineering Consulting

21. Inside a Microplate Reader Beeston Engineering Consulting

22. Predicant Biosciences • Medical Device company- will have to be FDA regulated • Startup - about 3 yrs old • IVD products • System that analyzes protein patterns in blood to correlate with disease state. • Approximately 40 employees • No revenue…yet Beeston Engineering Consulting

23. A “Mechanical” Medical Device Beeston Engineering Consulting

24. Areas that I learned something about after graduation… • Program and Project management • Instruments, device design – Mechanical, fluidics, and opto-mechanical • Plastics, labware and consumables – Co-chair SBS/ANSI Microplate Standards • Quality, Audit, QMS and Regulatory (CE and ISO, too) • MEMS and special processes – Member on SEMI Fluid Interface Task force Beeston Engineering Consulting

25. What my Berkeley Education missed! • All data is NOT created EQUAL! • How to design “in-tolerance”… and promote probabilities • The problems with diversity and dependencies, DOE • Freedom of choice is great… ” as long as it is my choice!” • Write your processes or you’re Left with regulators • Do not create every design… buy the wheel! • Talking and making friends with business Beeston Engineering Consulting

26. What is Art and What is Science? • This stuff is organic… and it really stinks! • What’s the matter with this material?Polymers and the slippery, sticky, and non-linear stuff… • Give Precision to the Scientist, and leave the Accuracy to the Gods... • Lab-On-A-Chip, Microfluids, MEMS, and the uncharted murky nano-waters • Time, Temperature, and Temperof Biological entities large and small. Beeston Engineering Consulting

27. Errors !!! • Random or Systematic • Deviation from the mean (DFM) is used to define or distinguish the type • False Negatives: Appearance of a negative value or “No result” when a positive or some value is expected. • False Positives: Appearance of a positive value or result when a negative value is expected. Beeston Engineering Consulting

28. Accuracy & Precision • Accuracy is a measure of the result in comparison to the intended or ideal value. Expressed usually as a percentage bias or measure of deviation from the absolute or ideal. Inaccuracy (%) = [(Va-Vm )/ Vm ] x 100 • Precision is a measure of the variability or variance. Usually expressed as percent deviation from the mean, or a % coefficient of variation of the data. Precision (%CV) = [Standard Deviation /(mean)] x100 * Beeston Engineering Consulting

29. What’s Art and What’s Engineering • Rules of Thumb(ROT)and fundamentals are always helpful, but watch the unexpected in MEMS and living entities • Tiny Mechanical gadgets .. that can do (work) on nothing • Optics Galore – Not just Snell your Beer’s law? • Fluidics… Reynolds and the Junk • There will be always a bubble or a leak • Carryover, cross contamination… How do you clean this Atto-mole junk? • CAD-CAM, SLA, RPT and other fine acronyms Beeston Engineering Consulting

30. Common Engineering Issues • Fluid dynamics (not what you learned at your Alta Mater) • Material properties (not only Stainless) • Galvanic (ions are everywhere) • Polymers • Adhesives • Surface Chemistry ( especially when things get smaller and need to be sensitive) • Manufacturing and cost issues • Packaging and Sterility Beeston Engineering Consulting

31. Schedules and Projects from Hell ! • Get the requirements first, the specs (speck-less) and agreed on early! • Typical project equation = 2t x 2$<spec/2 • Watch for Creeping Elegance • The many distinct Phases of Product Development - Three times (min.) is a charm… Beeston Engineering Consulting

32. Responsibilities and Contributors • Phase 0 - R&D and Business Development • Phase 1 – R&D, Marketing, and QA • Phase 2 - Engineering, Marketing and R&D • Phase 3 - Engineering, Marketing, QA and Manufacturing • Phase 4 - Manufacturing, QA/QC, service and sales support • Phase 5 – Operation, QC and Production Beeston Engineering Consulting

33. Product Development Steps Beeston Engineering Consulting

34. Summary High Level Areas • Interactionwith Biological matrix and the nature of small and “large living species” • QSR regulatory and FDA – QA is part of Development • Management types: Optimistic (marketing driven) or conservative and inefficient (Scientific and technical driven) • Collaborations, Finance, VC, IP and legal issues • Discipline and focus Beeston Engineering Consulting

35. Conclusions • Biomedical Device Engineering is a true multidisciplinary activity • It is the best “continuous learning” career • Creativity is not bounded by the laws of Physics, but by the laws of Business! • Driven by desire to do products for industry, society’s health and its patients (self interest) Beeston Engineering Consulting

36. Q&A Contact: amerhaj@Netzero.net Beeston Engineering Consulting

37. Supporting slides Beeston Engineering Consulting

38. Choices Beeston Engineering Consulting

39. Target Selection Lead Identification Lead Optimization Discovery Development Drug Discovery Process and its functional elements Target ID (e.g. Protein families as drug targets from Genomics and Proteomics research) Assay Development Lead Generation and Target Validation (Using small molecules or antibodies from combinatorial synthesis, natural extracts as drug candidates) Assay Screening Medicinal Chemistry In Vivo cell Biology and Animal Medicinal Pharmacology Clinical Trials Commercialization Beeston Engineering Consulting

40. SBS and the Microplate Standards History • First annual meeting held in Philadelphia, Sept. 1995 • Working Groups formed to address variety of issues relevant to its members • A group was to address issues where standardization would improve performance of automation • Top on the list of issues was standardizing the 96 well microplate • In 1998, SBS Board re-opened the standard • Email ListServ started in March 1998 • First meeting held in Boston in August 1998 • The Microplate Standards Development Committee Became an Accredited ANSI Standards Developer in July, 2002 • 4 Standards submitted and approved by ANSI in Jan 2004 Beeston Engineering Consulting