ERT 420
BIOPHARMACEUTICAL
ENGINEERING
Semester 1
Academic Session 2012/2013
HUZAIRY HASSAN
School Of Bioprocess Engineering
Universiti Malaysia Perlis
BIOPHARMACEUTICAL
FACILITIES
The Drug Discovery, Development and Approval Process
for Biopharmaceuticals (Biologics)
DISCOVERY
DEVELOPMENT
Clinical Trials
Phase I
Phase II
Phase III
Test
Population
Laboratory
and animals
studies
20 to 100
healthy
volunteers
100 to 500
patient
volunteers
1,000 to 5,000
patient volunteers
Purpose
Assess
safety
biological
activity and
formulations
Success
Rate
5,000
compounds
evaluated
Activities
Cell line
construction,
Cell banking
Determine
safety and
dosage
Evaluate
effectiveness,
look for side
effects
Confirm
effectiveness,
monitor adverse
reactions from longterm use
5 enter trials
Process development, assay development,
process optimization, scale-up, cGMP
manufacture
File
application
File NDA at FDA
Discovery /
Preclinical
Testing
File IND at FDA
Testing
Phase
Manufacturin
LAUNCH
Review
process /
approval
Phase IV
Additional
postmarketing
testing
required by
FDA
1 approved
Commercial
manufacture
Years
6.5
1.5
2
3.5
1.5
=15
Approximate
Cost
$350M
$70M
$100M
$200M
$80M
= $1B
Research & Development
(Pre-Clinical):
Discovery Research,
Bioinformatics,
Lab Safety
Operations:
Process/Product,
Development,
Manufacturing
& Production
Finance &
Administration:
Quality:
Clinical Research:
Quality Control
& Assurance
Clinical Research,
Regulatory Affairs
Finance,
Business Development,
Administration,
Information Systems,
Legal, Facilities Management
VP of Research/Development
VP of Operations
Discovery Research
Process/Product
Development
Scientific Director
Associate Scientific Director
Principal Scientist
Senior Scientist
Scientist II
Scientist I
Senior Research Associate
Research Associate
Bioinformatics
Scientist/Engineer
Analyst/Programmer
Molecular Modeler
Lab Facilities
Facility Manager/Supervisor
(Animal Sciences)
Veterinarian
Lab Assistant/Glasswasher
Director of Process/Product
Development
Process Development Supervisor
Process Development Associate
Process Development Technician
Direction of Quality
Medical Director
Quality Control
(QC)
Clinical Research
Chemistry
QC Analyst
QC Technician
Microbiology
Manufacturing
& Production
Manufacturing Supervisor
Manufacturing Associate
Manufacturing Technician
(Operator)
Manufacturing Instrumentation/
Calibration Technician
Clinical Research
Manager
QC Analyst
QC Technician
Quality Assurance
(QA)
QA Manager/Supervisor
QA Documentation Specialist
QA Documentation Coordinator
Regulatory Affairs
Manager of Regulatory Affairs
Regulatory Affairs Associate
Clinical Data Manager/Associate
VP of Finance & Administration
Finance
Chief Financial Advisor
Accounting Manager
Accounting Clerk
Business Development
Director of Business Development
Administration
Director of Human Resources
Human Resources Representative
Safety Manager
Purchasing Agent/Buyer
Receptionist
Administrative Assistant
Information Systems
Manager of Information Systems
Systems Analyst
Analyst/Programmer
Legal
Patent / IP Attorney
Facilities Management
Facilities Manager
Facilities Technician
Shipper/Receiver
Biomanufacturing
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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).
Biopharmaceutical Manufacturing
Departments
• Facilities/Metrology
• Validation
• Environmental Health and
Safety (EH&S)
• QA
• Upstream Processing
• Downstream Processing
• QC Microbiology
• QC Biochemistry
• Process Development
Facilities in Gray Space
Facilities
General Cleanroom Design
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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
Facilities
Production Clean Rooms
FS209
ISO 14644-1
Cleanroom
Cleanroom
classification 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
Facilities
HEPA Filters
High Efficiency Particulate Air
Minimum particle collection efficiency:
99.97% for 0.3µm diameter particles.
Disposable
Filter made of pleated borosilicate glass microfiber
Biological Safety Cabinets
Class 100
A microbiologist
performing influenza
research within a
biosafety cabinet
Facilities
Pressure 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)
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
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?
Gowning Certification
QC Microbiology –
Environmental Monitoring
Laser Particle Counter
Air Samplers
Environmental (Air) Monitoring
Particles
Viable Microbes (Bioburden)
Microbial Air Sampler
Laser Particle Counter
Environmental (Air) Monitoring
Laser Particle Counter
(particles/cubic meter)
Microbial Air Sampler
(colony forming units/
cubic meter)
www.safety-epa.com/history_mold_air_sampling.htm
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).
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.
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
VALIDATION PARAMETERS
The 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%.
• 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.
Pilot Plant – Overall Flow Plan
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.
THANK YOU
Reference
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http://people.deas.harvard.edu/~jones/lab_arch/nano_facilities/hepa.gif
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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