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ERT 420BIOPHARMACEUTICAL
ENGINEERING
Semester 1 Academic Session 2012/2013
HUZAIRY HASSANSchool Of Bioprocess Engineering
Universiti Malaysia Perlis
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BIOPHARMACEUTICAL FACILITIES
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The Drug Discovery, Development and Approval Processfor Biopharmaceuticals (Biologics)
DISCOVERY DEVELOPMENT LAUNCH
Testing Phase
Discovery / Preclinical
Testing
Test Population
Laboratory and animals
studies
Purpose
Assess safety
biological activity and formulations
Success Rate
5,000 compounds evaluated
ManufacturinActivities
Cell line construction, Cell banking
Years 6.5
Approximate Cost $350M
Clinical Trials
Phase I Phase II Phase III
20 to 100 healthy
volunteers
100 to 500 patient
volunteers
1,000 to 5,000 patient volunteers
Determine safety and
dosage
Evaluate effectiveness, look for side
effects
Confirm effectiveness,
monitor adverse reactions from long-
term use
5 enter trials
Process development, assay development, process optimization, scale-up, cGMP
manufacture
1.5 2 3.5
$70M $100M $200M
File application
Review process / approval
1 approved
Commercial manufacture
1.5
$80M
Phase IV
Additional post-
marketing testing
required by FDA
=15
= $1B
Fil
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Research & Development (Pre-Clinical):
Discovery Research, Bioinformatics,
Lab Safety
Quality:Quality Control
& Assurance
Operations:Process/Product,
Development,Manufacturing & Production
Clinical Research:Clinical Research,Regulatory Affairs
Finance & Administration:
Finance,Business Development,
Administration,Information Systems,
Legal, Facilities Management
VP of Research/Development VP of Operations Direction of Quality Medical Director VP of Finance & Administration
Discovery ResearchScientific Director
Associate Scientific DirectorPrincipal Scientist
Senior ScientistScientist IIScientist I
Senior Research AssociateResearch Associate
BioinformaticsScientist/Engineer
Analyst/ProgrammerMolecular Modeler
Lab FacilitiesFacility Manager/Supervisor
(Animal Sciences)Veterinarian
Lab Assistant/Glasswasher
Process/ProductDevelopment
Director of Process/ProductDevelopment
Process Development SupervisorProcess Development Associate
Process Development Technician
Manufacturing& Production
Manufacturing SupervisorManufacturing Associate
Manufacturing Technician (Operator)
Manufacturing Instrumentation/Calibration Technician
Quality Control (QC)
ChemistryQC Analyst
QC Technician
MicrobiologyQC Analyst
QC Technician
Quality Assurance(QA)
QA Manager/SupervisorQA Documentation Specialist
QA Documentation Coordinator
Clinical ResearchClinical Research
Manager
Regulatory AffairsManager of Regulatory AffairsRegulatory Affairs Associate
Clinical Data Manager/Associate
FinanceChief Financial AdvisorAccounting Manager
Accounting Clerk
AdministrationDirector of Human Resources
Human Resources RepresentativeSafety Manager
Purchasing Agent/BuyerReceptionist
Administrative Assistant
Business DevelopmentDirector of Business Development
LegalPatent / IP Attorney
Information SystemsManager of Information Systems
Systems AnalystAnalyst/Programmer
Facilities ManagementFacilities Manager
Facilities TechnicianShipper/Receiver
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Biomanufacturing• Commercial scale biomanufacturing involves the building of a facility to
produce the biopharmaceutical following upstream processing and downstream processing equipment and process SOPs. Samples are tested in quality control microbiology and quality control biochemistry laboratories to make sure the molecule has been produced correctly. cGMPs guide the process of manufacturing a biopharmaceutical and everything is documented.
• For ex: A new protein requires a facility to be prepared for its production and 400 to 600 individuals are hired, usually at least 50% are technicians. The largest bioreactor in such a facility is 25,000 liters.
• Once constructed and commissioned, the facility’s equipment and process SOPs must undergo validation.
• All instruments must be calibrated (instrumentation/calibration or metrology often part of facilities) and the set up, maintenance and use of each piece of equipment is logged.
• Environmental Health and Safety (EH&S) requirements are of central importance.
• 21 CFR Part 210 and 211 is highly enforced during the making of an FDA approved protein for commercial production and widespread use (quality assurance).
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Biopharmaceutical Manufacturing Departments
• Facilities/Metrology• Validation• Environmental Health and
Safety (EH&S)• QA• Upstream Processing• Downstream Processing• QC Microbiology• QC Biochemistry• Process Development
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Facilities in Gray Space
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Facilities General Cleanroom Design
• HEPA filters in ceiling• Exhaust vents on floor• Seamless and rounded floor to wall junctions• Readily accessible corners• Floors, walls, and ceilings constructed of smooth hard surfaces that can be
easily cleaned• Limited equipment, fixtures and personnel• Layout of equipment to optimize comfort and movement of operators• Pressure Differentials between rooms• Airlocks to control air balance
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FacilitiesProduction Clean Rooms
FS209 Cleanroom
classification
ISO 14644-1 Cleanroom
classification≥0.5um
particles/m3
Viable Microbes(cfu/m3)
Ave Airflow Velocity
(fpm)Air
changes/hr
100,000 8 3,520,000 100 5-10 5-48
10,000 7 352,000 10 10-15 60-90
1000 6 35,200 7 25-40 150-240
100 5 3,520 1 40-80 240-480
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FacilitiesHEPA Filters
High Efficiency Particulate Air
Minimum particle collection efficiency: 99.97% for 0.3µm diameter particles.
Disposable
Filter made of pleated borosilicate glass microfiber
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Biological Safety CabinetsClass 100
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A microbiologist performing influenza research within a biosafety cabinet
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FacilitiesPressure Differentials
• Used to maintain airflow in the direction of higher cleanliness to adjacent less clean areas
• A minimum of 10-15 Pascals should be maintained between the aseptic area and an adjacent room with a different clean room classifications (doors open)
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Facilities Airlocks
Permit the passage of objects and people into a clean room.
Consists of two airtight doors in series which do not open simultaneously.
Spray down materials with 70% IPA before placing in the airlock
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ISOPROPYL ALCOHOL Powerful disinfectant and antiseptic
Mode of action: denatures proteins, dissolves lipids and can lead to cell membrane disintegration
Effectively kills bacteria and fungi
What is not killed by IPA? So, use what?
Why are aqueous solutions are preferred?
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Gowning Certification
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QC Microbiology –Environmental Monitoring
Laser Particle Counter
Air Samplers
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Environmental (Air) Monitoring
Particles Viable Microbes (Bioburden)
Microbial Air Sampler
Laser Particle Counter
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Environmental (Air) MonitoringLaser Particle Counter(particles/cubic meter)
Microbial Air Sampler (colony forming units/cubic meter)
www.safety-epa.com/history_mold_air_sampling.htm
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Utilities
Water*: 200,000 to 300,000 liters of water are used per day in a commercial biopharmaceutical manufacturing facility.
• WFI: sand, diatomaceous earth, charcoal filter, water softener, RO, uv treatment, distillation, and constant circulate in a loop at 80 ⁰C. WFI piped to production equipment for CIP and SIP processes and for making media and buffers for production.
• DI and USP water used in QC labs (less pure); chilled potable water used for cooling.
Gasses: • Air, oxygen, and carbon dioxide to keep cells happy, nitrogen,
and helium (to check for leaks in equipment).
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HVAC: Heating, ventilation, and air conditioning in clean rooms and gray spaces.
Waste*:• Cells (sludge) - heat to very high temperatures and to
sewer; liquids (media and buffers) treat with base and acid in a series of (three) tanks until neutral pH and to sewer. *Piped with 316L stainless dairy piping, triclover clamps,
and valves.
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Services for Drug Development
• Cell Banking and Characterization• Product Characterization• Process Characterization (Residual Testing)• Vaccines and Cell Therapy• Viral Clearance • Stability Testing• In Vivo Biosafety• In Vivo and In Vitro Potency Testing• Biosimilar Testing• Discovery and Development• Polyclonal Antisera Production• Consulting and Project Management
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VALIDATION PARAMETERSThe following are validation parameters for key utilities and
services
GMP autoclaves. Overkill cycle, 60 minutes at 121°C at 15 psi. No survival of Bacillus stearothermophilus spores at a
population of 106
Pure steam generator. Condensed pure steam meets USP WFI specifications. Endotoxin <0.125 EU/ml, and microbial
content <1 Cfu/100 mL.
Depyrogenation oven. 60 min. cycle at 250°C. <100 0.5 μm particles/ per ft3 of 0.5 μm size. Minimum of 3 log endotoxin
reduction. No survival of Bacillus subtilus at a population of 106.
Ultra high quality water. <10 ppb of metals (such as Ni, Cu, and CO), <10 PPB of organics; <0.03 EU/mL of endotoxin; and <1Cfu/100mL. Resistivity 15-18 megohm. Meets and exceeds
USP specifications for water for injection (WFI).
HVAC and environmental baseline. Controlled areas except wash and microbial production (10,000 particles/ft3/min) and
wash room and microbial production (100,000 particles/ft3/min). < 25 viable organisms/10 ft3 of air; temperature 23±3°C; and
humidity 40-60%.
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• Bench scale vs pilot For batch processes, in the pharmaceutical
industry for example, bench scale is typically conducted on samples 1–20 kg or less, whereas pilot scale testing is performed with samples of 20–100 kg.
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Pilot Plant – Overall Flow Plan
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Biopharmaceutical Pilot plant
General facility layout for a flexible, biopharmaceutical pilot facility with a 30,000-ft2 area. AL = airlock; EN = entry airlock; EX = exit airlock;O = GMP depyrogenation oven; A = GMP autoclave; Utilities = UHQ water, pure steam, plant steam; Entry Corr = entry corridor to cell culture facility; Exit Corr = exit corridor from cell culture facility; QC = quality control; Mol Biol = molecular biology laboratory; RE = research laboratory entry/exit; PE = production facility entry/exit; PG = pregowning room; Jan = janitorial supply room; DR = dark room; PG = pregown room.
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THANK YOU
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Reference
• http://people.deas.harvard.edu/~jones/lab_arch/nano_facilities/hepa.gif
• http://news.thomasnet.com/images/large/451/451402.jpg
• www.bio-link.org
• Koichi, K., et al. Biopharmaceutical Manufacturing Facilities (2009). IHI Engineering Review, Vol 42, No. 2.
• http://www.bioasset.in/biopharmaceutical-service.html