From Orphan Drug to Blockbuster: Health and Safety Opportunities in Biopharmaceutical R&D and Production

1. From Orphan Drug to Blockbuster:Health and Safety Opportunities in Biopharmaceutical R&D and Production Bill Gaylord Director, R&D Environmental Health & Safety Allergan CIHC-- December 6, 2010

2. Overview • Pharmaceutical Industry Overview • Orphan Drugs • Allergan History, with BOTOX® • Health and Safety in Biopharmaceutical R&D and Production • Classic Industrial Hygiene approach to risk assessment and mitigation • Results of mitigation (examples) • and, ‘…oh by the way…’ LD50 in vertebrates is 2.1 nanogram/ kg 

3. Who We Are • Allergan is a multi-specialty health care company • that discovers, develops and commercializes • innovative pharmaceuticals, biologics and medical devices that enable people to live life to its greatest potential – to see more clearly, move more freely, express themselves more fully.

4. Headquarters in Irvine, California

5. Medical Dermatology AVAGE® AZELEX® BOTOX® for Hyperhidrosis FLUOROPLEX® TAZORAC®for Acne TAZORAC® for Psoriasis Neurosciences BOTOX® Therapeutic Imitrex® STATdose System Amerge® Products to Improve Patients’ Lives Eye Care REFRESH DRY EYE THERAPY® REFRESH DRY EYE THERAPY® Sensitive REFRESH® LACRI-LUBE® REFRESH LIQUIGEL® REFRESH PLUS® REFRESH P.M.® REFRESH REDNESS RELIEF™ REFRESH TEARS® RESTASIS® ZYMAR® ACULAR® ACULAR LS® ALOCRIL® ALPHAGAN® P ALPHAGAN® COMBIGAN® LUMIGAN® OPTIVE™ REFRESH® CELLUVISC® REFRESH® Classic REFRESH CONTACTS® Breast Aesthetics The NATRELLE™ Collection Tissue Expanders Facial Aesthetics BOTOX® Cosmetic CLINIQUE JUVÉDERM™ COSMODERM® and COSMOPLAST® HYLAFORM® ZYDERM® and ZYPLAST® PREVAGE® MD FORTE® VIVITE™ Urologics Health LAP-BAND® System BIB® System SANCTURA® SANCTURA XR™

6. 60 Years of Innovation • Founded 1950; an anti-allergy nasal drop named Allergan • 2009 Sales of nearly $4.5 Billion • Products marketed in more than 100 countries • More than 8,000 dedicated employees worldwide • Sales and Marketing Presence in More Than 100 Countries • More than 1,300 R&D personnel, more than 300 Ph.D. degrees • State-of-the-art R&D facilities and World-class of manufacturing

7. Pharmaceutical Industry • One Drug in Development • 12 years • $800,000 million (includes failures) • Pharmaceutical Sales Drivers (“Big Pharma” targets) • $100,000 million annual sales target (desired) • $500,000 million annual sales very good target (pleased) • $1 billion/ yr.- (arrived!) at the BlockBuster level • Pfizer’s Lipitor had 2009 sales WW sales of ~ $12.5 billion

8. Pharmaceutical Industry- Orphan Drug • Orphan Drug • Rare chronic, degenerative, and often life-threatening diseases • Fewer than 200,000 patients in the United States • ½ of the disease actually affecting 25,000 patients or less • 1983 fewer than 10 treatments commercialized • 2010 ~1,700 drugs • Pharma companies historically: • -little financial incentive to invest • -very low expectation of financial gains

9. History • Botox History • Allergan- 1950 to 1989- an ‘eyedrop’ company • A leader in contact lens solutions, sales of ‘salt water’–Lens Plus contact wetting and cleaning solutions • 1989- Co-Market Agreement for ‘Occulinum’ Orphan Drug, approved for the treatment of blephrospasm and strabismus • 1991- Purchased‘ Occulinum’ a company • And, ‘…oh by the way…’ LD50 in vertebrates is 2.1 nanogram/ kg

10. History

11. BOTOX® Indications

12. History

13. History

14. History

15. History

16. History

17. History

18. History • 2010 – October- US FDA Approval for Chronic Migraine Headache

19. Mechanism of Action

20. BOTOX® Indications • 2010 US Indications • BOTOX® (onabotulinumtoxinA), BOTOX® Cosmetic (onabotulinumtoxinA) and Vistabel® • Chronic Migraine • Upper Limb Spasticity • Cervical Dystonia • Blepharospasm and Strabismus • Primary Axillary Hyperhidrosis • Cosmetic (glabellar lines)

21. Regulations/ Regulatory Approach • FDA and worldwide regulatory agencies • they give ‘approval’ for manufacture, marketing and sales • US Centers for Disease Control (CDC) • they give ‘approval’ to possess, produce and transfer ‘Select Agents’ (bioterrorism agents) • Local regulatory agencies (water, air, fire, disposal, etc.)

22. Reality • and, ‘…oh by the way…’ • the LD50 in vertebrates is 2.1 nanogram/ kg

23. Approach: Classic Industrial Hygiene • Anticipation • Recognition • Evaluation • Prevention • Control • for those environmental factors or stresses arising in or from the workplace which may cause sickness, impaired health and well being, or significant discomfort among workers or among citizens of the community. • and, ‘…oh by the way…’ LD50 in vertebrates is 2.1 nanogram/ kg 

24. Biopharmaceutical Production of Botulinum Neurotoxin • Botulinum Neurotoxin • - culture • - fermentation • - purification • - testing • Engineering Controls • Administrative Controls • PPE

25. Biopharmaceutical Production of Botulinum Neurotoxin • Clostridium botulinum (organism) • Gram-positive • Spore-forming rod • Anaerobic • Forms potent neurotoxin • Spores are heat-resistant • Botulinum neurotoxin • LD50 2.1 ng/kg vertebrate • BOTOX® 100 units ~4 ng/ vial

26. Risk Assessment • Where it all starts • Route(s) of exposure • Injection • Ingestion • Dermal • Inhalation • Mechanism of action for botulinum toxin • at the NMJ(Neuromuscular Junction) • Allergan’s botulinum toxin in water solution

27. Work Activities and GroupsUsing Botulinum Toxin and Organism

28. Work Activities and Groups • GROUP I • Safety features described under CDC/NIH Biosafety for Microbiological and Biomedical Labs Level 3 (BSL-3) • Glove boxes where feasible (Class 3 Biosafety Cabinets) • Biosafety cabinets where feasible

29. Work Activities and Groups • Restricted access • Respiratory protective equipment (during fermentation, toxin purification and emergencies) • Protective clothing (as described in gowning SOPs) • Participation in the immunization program

30. Biopharmaceutical Drugs • Biopharmaceutical Drug • vs. ‘small molecule’ (MW ~max of 800 Daltons) • Biopharmaceutical (MW range 800 Da- 900 kilo Daltons) • Some properties of Biopharmaceutical Drugs • - difficult to deliver (injection vs. dermal or oral) • - ‘fragile’ • - easily decontaminated • (bleach, sodium hydroxide, heat)

31. Risk Assessment • Headcount History over the years

32. Risk Assessment • This is what it is all about • Beckman- Coulter Ultra Centrifuge • Potential for sample leaking from rotor with speed of 100,000 rpm, 800K g force • No bio-containment rotor head

33. Flow Sciences Custom Enclosure

34. Vented Balance Enclosure • Labconco (Top Mounted HEPA Filter • Housing) • Flow Sciences • (Canister and Top Mounted HEPA Filter Housing)

35. Flow Sciences Custom Enclosure • Mircro Fluidics • microfluidizer • - Risk • 30,000 psi • - Size • - Access

36. BioSafety Cabinet • Multiple Vendors, HEPA filtration • Class 2 B2 • Baker SteriChemGard

37. BioSafety Cabinet • Class 3 Biosafety Cabinet (or Isolator) • la Calhene Glove Box

38. la Calhene -Transfer • Rapid Transfer Port • Transfer of products between environments, • without breaking integrity • Alpha assembly, is mounted on the wall of the isolator • Beta assembly (the mobile part), is attached • and sealed to a rigid container

39. la Calhene –RTP

40. Beckman Coulter Biomek • Beckman Biomek • - Size • - Access • - Interlock

41. MainFrame, Inc. Custom Enclosure • MainFrame, Inc. • - Size • - Access • - Interlock

42. Custom Enclosure- Location • Cold Room Installation • - Airflow • - Temp • - Access

43. BSL-3 Lab/ Production • Lab with Anti-room, • Directional Airflow (inward) • +/- terminal HEPA exhaust airflow • Contained work • Minimize employee exposure

44. BSL-3 Lab/ Production Biosafety Level 3 Issues • Expensive • Long lead time to build • Training • PPE (including PAPR) • Containment of product and process • Engineering Control to assures no Environmental Impact

45. BSL-3 Lab/ Production • PPE • (including PAPR)

46. Future Roof HEPA Filters

47. Warning: Risk Assessment May Be HazardousClass 3 BSC’s (Isolators) • WE Plan • WE Conduct Factory Acceptance Testing (FAT) • WE Know the Containment Will Be Protective • And Yet: • WE Don’t Know when the Program Changes…….

48. Warning: Risk Assessment May Be HazardousClass 3 BSC’s (Isolators) are EXPENSIVE

49. Allergan and BOTOX® • A Short 20 year History From Orphan Drug • (Strabismus and Blephrospasm) • To BlockBuster Status • $1+ billion/ yr. • and, ‘…oh by the way…’ • the LD50 in vertebrates is 2.1 nanogram/ kg

50. Allergan and BOTOX®