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

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From Orphan Drug to BlockbusterHealth and
Safety Opportunities in Biopharmaceutical RD and
Production

• Bill Gaylord
• Director, RD
• Environmental Health Safety
• Allergan
• CIHC-- December 6, 2010

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Overview

• Pharmaceutical Industry Overview
• Orphan Drugs
• Allergan History, with BOTOX
• Health and Safety in Biopharmaceutical RD 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 

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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.
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Headquarters in Irvine, California
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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 ZY
DERM and ZYPLAST PREVAGE MD FORTE VIVITE
Urologics
Health LAP-BAND System BIB System
SANCTURA SANCTURA XR
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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 RD personnel, more than 300
  Ph.D. degrees
• State-of-the-art RD facilities and World-class
  of manufacturing

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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
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• Pfizers Lipitor had 2009 sales WW sales of
  12.5 billion

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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

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History

• Botox History
• Allergan- 1950 to 1989- an eyedrop company
• A leader in contact lens solutions, sales of
  salt waterLens 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

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History
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BOTOX Indications
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History
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History
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History
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History
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History
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History
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History

• 2010 October- US FDA Approval for Chronic
  Migraine Headache

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Mechanism of Action
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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)

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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.)

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Reality

• and, oh by the way
• the LD50 in vertebrates is 2.1 nanogram/ kg

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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 

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Biopharmaceutical Production of Botulinum
Neurotoxin

• Botulinum Neurotoxin
• - culture
• - fermentation
• - purification
• - testing
• Engineering Controls
• Administrative Controls
• PPE

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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

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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)
• Allergans botulinum toxin in water solution

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Work Activities and GroupsUsing Botulinum Toxin
and Organism
Work Activities Group I Group II Group III
If ANY of the following conditions apply If ANY of the following apply If ALL of the following conditions apply
Organism Allowed No organism used No Organism used
Sharps Allowed Sharps NOT Allowed -Sharps Use Allowed
Potential for activities which produce aerosols conducted in work area May be conducted outside Biosafety Cabinet or on benchtop All potential for aerosols-- must conducted in BSC Class II, Type B2 cabinet or fully contained system Bench top work allowed
Use of toxin containing pressurized lines Use of pressurized lines No use of pressurized lines -N/A
Concentration (mouse units per container) Greater than 1,000 Greater than 1,000 Less than 1,000
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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

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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

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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)

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Risk Assessment

• Headcount History over the years

1993 2010
RD 6 100
Manufacturing 3 110
EHS (Full Time Equivalent) 1 4
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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

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Flow Sciences Custom Enclosure
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Vented Balance Enclosure

• Labconco (Top Mounted HEPA Filter
• Housing)
• Flow Sciences
• (Canister and Top Mounted HEPA Filter Housing)

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Flow Sciences Custom Enclosure

• Mircro Fluidics
• microfluidizer
• - Risk
• 30,000 psi
• - Size
• - Access

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BioSafety Cabinet

• Multiple Vendors, HEPA filtration
• Class 2 B2
• Baker SteriChem Gard

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BioSafety Cabinet

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

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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

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la Calhene RTP
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Beckman Coulter Biomek

• Beckman Biomek
• - Size
• - Access
• - Interlock

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MainFrame, Inc. Custom Enclosure

• MainFrame, Inc.
• - Size
• - Access
• - Interlock

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Custom Enclosure- Location

• Cold Room Installation
• - Airflow
• - Temp
• - Access

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BSL-3 Lab/ Production

• Lab with Anti-room,
• Directional Airflow (inward)
• /- terminal HEPA exhaust airflow
• Contained work
• Minimize employee exposure

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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

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BSL-3 Lab/ Production

• PPE
• (including PAPR)

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Future Roof HEPA Filters
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Warning Risk Assessment May Be HazardousClass 3
BSCs (Isolators)

• WE Plan
• WE Conduct Factory Acceptance Testing (FAT)
• WE Know the Containment Will Be Protective
• And Yet
• WE Dont Know when the Program Changes.

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Warning Risk Assessment May Be HazardousClass 3
BSCs (Isolators) are EXPENSIVE
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Allergan and BOTOX

• A Short 20 year History From Orphan Drug
• (Strabismus and Blephrospasm)
•  
• To BlockBuster Status
• 1 billion/ yr.
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• and, oh by the way
• the LD50 in vertebrates is 2.1 nanogram/ kg

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Allergan and BOTOX
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Thank You