Best Practices for Manufacturing Biologicals

1
Best Practices for Manufacturing Biologicals

• Dr. Peter Clarke
• VP Production and Technical Processes
• Introgen Therapeutics, Inc.

2
Best Practices for Manufacturing Biologicals
Discovery
Process Development
Pilot Production
Pre-clinical Studies
Clinical Production
Clinical Studies
Phase I
Phase II
Phase III
Consistency Series Production
Commercial Manufacture
Product Launch
10 15 Years
3
Best Practices for Manufacturing Biologicals

• Start Up Companies Have
• Innovation/Science
• Vision
• Finance
• Start Up Companies Dont Have
• Means of Executing Vision
• CGMP Manufacturing
• Clinical Research Organization

4
Best Practices for Manufacturing Biologicals

• Requirements of Biologicals Manufacturing
• 1 Facilities and Engineering
• Facility Design
• Construction Management
• Facility Equipment Commissioning
• Facility Equipment Validation
• Facility Equipment Maintenance
• Instrument Calibration
• ISPE Baseline Guides

5
Best Practices for Manufacturing Biologicals

• Requirements of Biologicals Manufacturing
• 2 Manufacturing Technology
• Process Scale-up
• Increased demand as clinical trials proceed
• Economies of scale for commercialization
• Process Industrialization
• Increased Robustness
• Intensification
• Different engineering solutions at different
  scales
• - ISPE Baseline Guides

6
Best Practices for Manufacturing Biologicals

• Requirements of Biologicals Manufacturing
• 3 Materials Management
• Purchasing
• Warehousing
• Inventory Control
• Shipment Logistics
• APICS

7
Best Practices for Manufacturing Biologicals

• Requirements of Biologicals Manufacturing
• 4 Compliance
• FDA (Title 21 CFR 210)
• EU Directives (Orange Guide)
• GAMP
• GLP
• (IND/IRB/GCP)
• EPA
• NIH/RAC
• Local Laws

8
Best Practices for Manufacturing Biologicals

• Barriers to Commercialization
• Time
• Money
• Expertise
• Solution
• Contract Manufacturing Organizations
• Contract Testing Laboratories
• (Clinical Research Organizations)

9
Best Practices for Manufacturing Biologicals

• What to Invest in
• In-House Expertise
• QA dept. separate
• Compliance (FDA)/QSA/Lot Release/Due Diligence
• Manufacturing Professional
• Compliance (EPA/NIH)/Technology/PD/Due Diligence
• Contracts/Program Manager
• IP/MSA/CDA/MTA/Integration
• (Reg Affairs Professional)

10
Best Practices for Manufacturing Biologicals

• Introgens Experience
• Stayed virtual until deal with RPR agreed.
• First clinical materials produced by CMO with
  most release tests done at contract labs.
• Dissatisfied with CMO performance.
• No one would aseptically fill our products
• First in Class, Live Virus, Gene Therapy
• Decision to build facility in 1997

11
Best Practices for Manufacturing Biologicals

• Introgens Experience
• Decision successful because
• Clinical trial requirements could be satisfied
  with PD scale lots.
• Manufacturing technologies selected reduced
  capital investments.
• Became expert in the production of these types of
  Biologics (selected by ARMWG and FDA to produce
  world reference material).
• Captured Manufacturing Process IP

12
Best Practices for Manufacturing Biologicals

• Introgens Experience
• Currently operate 2 facilities
• Holcombe (2 buildings 45,000 sq ft total)
• 4000 sq ft clean rooms
• 5000 sq ft laboratories
• El Rio
• 1000 sq ft clean rooms (1 building 8,000 sq ft)

13
Best Practices for Manufacturing Biologicals

• Initial Process
• Roller Bottle (Adherent cell) culture
• Serum containing medium
• CsCl centrifuge gradient purification
• 1014 viral particles per batch
• -80 degC storage

14
Best Practices for Manufacturing Biologicals

• Improved Process
• CellCube (Adherent cell) culture
• Serum containing medium
• Chromatographic purification
• 1015 viral particles per batch
• -80 degC storage

15
Best Practices for Manufacturing Biologicals

• Current Process
• WAVE200 (suspension cell) culture
• Protein-free medium (animal component free
  process)
• Chromatographic purification
• 1016 viral particles per batch
• Refrigerated storage formulation

16
Best Practices for Manufacturing Biologicals

• Future Process
• WAVE1000 (suspension cell) culture
• Protein-free medium (animal component free
  process)
• Chromatographic purification
• 1017 viral particles per batch
• Room temperature formulation

17
Best Practices for Manufacturing Biologicals

• Timing of Process/Facility Change Implementation
• Sooner the better/cheaper
• Definitely before pivotal trials (usually Phase
  3)
• Dont sweat it. Change is expected and science
  (data) can persuade CBER

18
Best Practices for Manufacturing Biologicals

• How NOT too Scale Up
• Hot results gt Program acceleration
• Bench Scale 5ml dialysis of intermediate in 1L
  buffer.
• Phase 3 clinical materials required dialysis of
  3L of product in 600L buffer.
• Solution 3 x 1M3 stainless steel fully
  instrumented tanks with full SIP/CIP under Grade
  B environment.

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Best Practices for Manufacturing Biologicals

• How NOT too Industrialize
• Compliance Zeal gt No process variation
• 1L scale process always controlled at a pH 8.20
  (range 8.19 8.21)
• No validatable instrument can report that
  accurately.
• Required further (late stage) PD to match process
  requirements with equipment capabilities.

20
Best Practices for Manufacturing Biologicals

• How NOT too Design
• Science jargon ? Engineering jargon
• Buffers made up at Litre scale from solids
  would cause solids handling problems at 10M3
  scale.
• Engineering solution Mix liquid concentrates.
• Issue 1M NaCl, pH 7.3 7.7 is not a buffer and
  cannot be made by mixing concentrated HCl and
  NaOH.

21
Best Practices for Manufacturing Biologicals

• How NOT too Design
• Enthusiasm is no substitute for expertise
• Clinical Manufacturing facility designed, built
  and commissioned in 15 months by Scientitsts
  (with help from World Renowned Contract
  Engineering Company)
• No advice from Reg. Agencies sought before 12MM
  invested
• First audit found problems totaling 8MM to put
  right