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8/12/2019 Bio Manufacturing
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So, What is Biomanufacturing?
*Bench Top to Bottle*Facilities in Biopharmaceutical ManufacturingCompetencies/Job and Career Opportunities
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Basisof the Bioeconomy
Central Dogma: DNA RNA Protein
Discovery Research (DNA Centric)
Process Development and Biomanufacturing
(Protein Centric)
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The Drug Discovery, Development and Approval Process
for Biopharmaceuticals (Biologics)
DISCOVERY DEVELOPMENT LAUNCH
Testing
Phase
Discovery /
Preclinical
Testing
Test
Population
Laboratoryand animals
studies
Purpose
Assesssafety
biologicalactivity andformulations
Success
Rate
5,000compounds
evaluated
Manufacturin
Activities
Cell lineconstruction,Cell banking
Years 6.5
ApproximateCost $350M
Clinical Trials
Phase I Phase II Phase III
20 to 100healthy
volunteers
100 to 500patient
volunteers
1,000 to 5,000patient volunteers
Determinesafety and
dosage
Evaluateeffectiveness, look for
side effects
Confirmeffectiveness,
monitor adversereactions from long-
term use
5 enter trials
Process development, assay development,
process optimization, scale-up, cGMPmanufacture
1.5 2 3.5
$70M $100M $200M
File
application
Reviewprocess /approval
1 approved
Commercialmanufacture
1.5
$80M
Phase IV
Additionalpost-
marketingtesting
required byFDA
=15
= $1B
F
ileNDA
atFDA
FileINDa
tFDA
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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 Scientist
Scientist II
Scientist I
Senior Research Associate
Research Associate
BioinformaticsScientist/Engineer
Analyst/Programmer
Molecular Modeler
Lab FacilitiesFacility Manager/Supervisor
(Animal Sciences)
Veterinarian
Lab Assistant/Glasswasher
Process/Product
Development
Director of Process/ProductDevelopment
Process Development Supervisor
Process Development Associate
Process Development Technician
Manufacturing
& ProductionManufacturing Supervisor
Manufacturing 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 Affairs
Regulatory Affairs Associate
Clinical Data Manager/Associate
FinanceChief Financial Advisor
Accounting Manager
Accounting Clerk
AdministrationDirector of Human Resources
Human Resources Representative
Safety Manager
Purchasing Agent/Buyer
Receptionist
Administrative Assistant
Business DevelopmentDirector of Business Development
LegalPatent / IP Attorney
Information SystemsManager of Information Systems
Systems Analyst
Analyst/Programmer
Facilities ManagementFacilities Manager
Facilities Technician
Shipper/Receiver
Career Opportunities in Biotechnology/Biomanufacturing
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Business of Biotechnology
Discovery Research (identifying, cutting out and pasting in various
genes to create an expression vector; expression vector via thecentral dogma creates RNA from the genetically engineered DNAof the expression vector and the protein(s) of interest from RNA;the proteins are the biopharmaceuticals.
Process Development (during which animal trial and clinical trial
materials are made) identifies and maximizes the efficiency of theequipment and processes used to culture the cells that make theprotein (upstream processing) and to purify it by centrifugation,filtration, and chromatography (downstream processing). Parallelto identifying equipment and processes for production, quality
control microbiology and quality control biochemistry tests aredeveloped for raw materials and the equipment and processesutilized to make the biopharmaceutical and the biopharmaceuticalitself using current Good Manufacturing Practices as spelled out bythe Code of Federal Regulations 21 CFR 210 and 211 that includes
following equipment and process SOPs and recording everything ina Batch Record (quality assurance).
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Business of Biotechnology Biomanufacturing
Commercial scale biomanufacturing involves the building of a facility to
produce the biopharmaceutical following upstream processing anddownstream processing equipment and process SOPs. Samples are testedin quality control microbiology and quality control biochemistrylaboratories to make sure the molecule has been produced correctly.cGMPs guide the process of manufacturing a biopharmaceutical andeverything is documented (If you didnt document it you didnt do it.) Anew protein requires a facility to be prepared for its production and 400 to600 individuals are hired, usually at least 50% are technicians. The largestbioreactor in such a facility is 25,000 liters.
Once constructed and commissioned, the facilitys equipment and processSOPs must undergo validation.
All instruments must be calibrated (instrumentation/calibration or
metrology often part of facilities) and the set up, maintenance and use ofeach piece of equipment is logged.
Environmental Health and Safety (EH&S) requirements are of centralimportance.
21 CFR Part 210 and 211 is highly enforced during the making of an FDAapproved protein for commercial production and widespread use(qualityassurance).
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Ten Technician Jobs Anchor
Ten Biomanufacturing 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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Pilot PlantOverall Flow Plan
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Facilitiesin Gray Space
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Production Clean RoomsCleanrooms are Maintained by
Facilities/Metrology Technicians to the
Following Specifications
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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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 beeasily 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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Facilities: HEPA Filters
http://people.deas.harvard.edu/~jones/lab_arch/nano_facilities/hepa.gif
High Efficiency Particulate Air
Minimum particle collection efficiency:99.97% for 0.3m diameter particles.
Disposable
Filter made of pleated borosilicate glass microfiber
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Biological Safety Cabinets
Class 100
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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 maintainedbetween the aseptic area and an adjacent room with
a different clean room classifications (doors open)
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http://news.thomasnet.com/images/large/451/451402.jpg
Facilities:
Airlocks
Permit the passage of objectsand people into a clean room.
Consists of two airtightdoorsin series which do not opensimultaneously.
Spray down materials with
70% IPA before placing in theairlock
http://en.wikipedia.org/wiki/Hermetic_sealhttp://en.wikipedia.org/wiki/Doorhttp://en.wikipedia.org/wiki/Doorhttp://en.wikipedia.org/wiki/Hermetic_seal8/12/2019 Bio Manufacturing
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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?
Why are aqueous solutions arepreferred?
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Gowning Certification
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INCORRECT
3
21
4
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Biopharmaceutical ManufacturingQC Microbiology
A significant portion of the cGMP regulations pertain to the quality control
laboratories including the QC Microbiology Unit which carries out
microbiological testing of the product and the microbiological control of site
utilities and environment. The principal functions of this unit are: Environmental
Monitoring, Microbiological Testing and ID, and the Cell Culture Collection.
Environmental Monitoring = Monitor non-viable and viable contamination(bioburden) throughout the facility using laser particle counter and
microbial air sampler.
Microbiological Testing and ID = Gowning certification, air sample processing,
production (raw materials, upstream and downstream processing, aseptic filland finish and storage) and other samples for microbiological contamination(bioburden); ID using Microbial ID System (Biolog, API Strips, PCR, othertests). Use LAL test for endotoxin in WFI water, raw materials and product. Testfor mycoplasma in cell cultures (PCR, other tests).
Cell Culture Collection = Testing and release of cell banks.
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Gowning Certification
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INCORRECT
3
21
4
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FOREHEAD
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ENVIRONMENTALMONITORING
In aseptic processing, one of the most
important laboratory controls is the
environmental monitoring program
Guidance for Industry: Sterile Drug Products Produced by Aseptic ProcessingCurrent Good Manufacturing Practice, FDA, September 2004
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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
http://www.millipore.com/images/large/867302-06%5B811-ALL%5D.jpg8/12/2019 Bio Manufacturing
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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
http://www.safety-epa.com/history_mold_air_sampling.htmhttp://www.safety-epa.com/history_mold_air_sampling.htmhttp://www.safety-epa.com/history_mold_air_sampling.htmhttp://www.safety-epa.com/history_mold_air_sampling.htm8/12/2019 Bio Manufacturing
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Production Clean Rooms
Cleanrooms are Maintained by
Facilities/Metrology Technicians to the
Following Specifications
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
Utiliti M d b F iliti /M t l T h i i
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Utilities Managed by Facilities/Metrology Technicians
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 C degrees. 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.
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Biopharmaceutical Manufacturing
Facilities/Metrology Competencies
http://www.biomanufacturing.org/gbc2/competencies/Competencies_Maintenance_Instrumentation_021209.pdf
http://www.biomanufacturing.org/gbc2/competencies/Competencies_Maintenance_Instrumentation_021209.pdfhttp://www.biomanufacturing.org/gbc2/competencies/Competencies_Maintenance_Instrumentation_021209.pdf8/12/2019 Bio Manufacturing
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Quality Assurance
If you didnt document it, you didnt do it.
Q alit Ass ran e
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Quality Assurance
21 CFR Parts 210-211 contain the
minimum current goodmanufacturing practice for
methods to be used in, and the
facilities or controls to be used for,
the manufacture, processing,packing, or holding of a drug to
assure that such drug meets the
requirements of the act as to
safety, and has the identity and
strength and meets the quality and
purity characteristics that it
purports or is represented to
possess.http://www.21cfrpart11.com/files/library/pred_rules/mcdowall_gmp_annotate.pdf
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QUALITY
ASSURANCE
APPROVES ALL
DOCUMENTS
andMAINTAINS
THE FILES
If you didnt document it, you didnt do it.
BIOMANUFACTURING
DOCUMENTATIONAssures the product reproducibly meets
predetermined specifications
TYPES f DOCUMENTS
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TYPES of DOCUMENTS
RAW MATERIAL SPECIFICATIONS
SOPsMASTER BATCH PRODUCTION RECORDS
PRODUCTION BATCH RECORDS
DEVIATION FORMS
NUMBERING SYSTEMVALIDATION RECORDS
EQUIPMENT USE and CLEANING LOG BOOKS
COMPONENT, CONTAINER and CLOSURE RECORDS
DISTRIBUTION RECORDS
COMPLAINT FILES
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Document
is written
Circulated
forreview
Approved and
signed by
QC, QA,
operations,
facilities
Effective date
assigned
allowing for time
to train personnel
QA distributesto authorized
Personnel.
Obsolete versions
destroyed.
Master copy retained
QA assigns a
documentnumber
DOCUMENT BECOMES EFFECTIVE
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SOP: Standard Operating Procedure
PurposeScope
Responsibilities
ReferencesDefinitions
Precautions
Materials/EquipmentProcedure
Attachments
History
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Describes why the SOP exists.Purpose
ScopeDefines to whom and to what the procedure
applies.
ResponsibilitiesThe person or people responsible for
performing and updating the SOP.
May also include the person responsible for
overseeing the activities of the SOP
Documents such as manufacturer manuals
and other SOPs that were consulted to write the
SOP and those that should be consulted to
perform the SOP.
References
Describes any words, phrases or abbreviations
specific to the SOP
Ex:Do not include pH, it is common terminology
Definitions
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PrecautionsDescribes any hazards associated with
the procedure or with materials used in performin
the procedure
Any and all materials and/or equipment that are
needed to execute the SOP.
A step by step description of theprocedure organized into subgroups
Lists attachments by name and number.
Attachments are all documents that are
necessary to perform the SOP. Typically
includes diagrams and drawings
Origin of document and revisions
Materials and
Equipment
Procedure
Attachments
History
Recommended