Bio Manufacturing

8/12/2019 Bio Manufacturing

1/37

So, What is Biomanufacturing?

*Bench Top to Bottle*Facilities in Biopharmaceutical ManufacturingCompetencies/Job and Career Opportunities


2/37

Basisof the Bioeconomy

Central Dogma: DNA RNA Protein

Discovery Research (DNA Centric)

Process Development and Biomanufacturing

(Protein Centric)


3/37

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


4/37

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


5/37

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).


6/37

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).


7/37

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


8/37

Pilot PlantOverall Flow Plan


9/37

Facilitiesin Gray Space


10/37

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


11/37

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


12/37

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


13/37

Biological Safety Cabinets

Class 100


14/37

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)


15/37

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_seal


16/37

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?


17/37

Gowning Certification


18/37

INCORRECT

3

21

4


19/37

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.


20/37

Gowning Certification


21/37

INCORRECT

3

21

4


22/37

FOREHEAD


23/37

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


24/37

QC Microbiology

Environmental Monitoring

Laser Particle Counter

Air Samplers


25/37

Environmental (Air) Monitoring

Particles Viable Microbes (Bioburden)

Microbial Air Sampler

http://www.millipore.com/images/large/867302-06%5B811-ALL%5D.jpg


26/37

Environmental (Air) Monitoring


(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.htm


27/37

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


28/37

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.


29/37

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.pdf


30/37

Quality Assurance

If you didnt document it, you didnt do it.

Q alit Ass ran e


31/37

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


32/37

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


33/37

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


34/37

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


35/37

SOP: Standard Operating Procedure

PurposeScope

Responsibilities

ReferencesDefinitions

Precautions

Materials/EquipmentProcedure

Attachments

History


36/37

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


37/37

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