ERT 420BIOPHARMACEUTICAL

ENGINEERING

Semester 1 Academic Session 2012/2013

HUZAIRY HASSANSchool Of Bioprocess Engineering

Universiti Malaysia Perlis

BIOPHARMACEUTICAL FACILITIES

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

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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

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).

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

• 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

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

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

Biological Safety CabinetsClass 100

A microbiologist performing influenza research within a biosafety cabinet

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)

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) MonitoringLaser 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 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%.

• 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

• 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