ISPE Biopharmaceutical Baseline Guide
Presented by: Jeff Biskup, CRB
At
Omaha, Nebraska
April 14, 2005
Biopharm Baseline Guide
Presentation Overview
Jeff Biskup, CRB – Background,
Intro/Overview and Process Utilities
„ Mark VonStwolinski, CRB – Facilities
Issues
„ Pat Hamell, Pfizer – Process Equipment
& Manufacturing Issues and Real Life
Applications
„
First Some Background
Biopharmaceutical Industry
Evolution
„
Biopharmaceutical Industry is Evolving
– Transitioning from
» R&D focus to commercial manufacturing
» Small entrepreneurial companies becoming big
businesses
„
Biopharmaceutical Baseline Guide will
significantly impact industry.
Where has it Been?
Primarily in R&D, most recently heavy in
Development
„ Mostly technology based
entrepreneurial operations
„ Mostly located in R&D centers
„ Staffing predominantly PhD’s and highly
creative developers
„
Where is it Now?
„
Transitioning to commercial production for
blockbusters
– Learning how to produce GMP products
– Moving to industrial regions
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Building MEGA plants for large scale
production
Building clinical production operations
Matching up business partners
Recognizing the importance of being in
manufacturing regions
Where is it Going?
„
There will be:
– More companies manufacturing GMP
biotech product & many larger companies
– Multi-product producers with many small
products
„
Companies will need to learn to produce
cost competitive products for smaller
patient markets
Some Key Challenges Resulting
from the Evolution
„
Needed Resources:
– Efficient production facilities
» Few licensed facilities
– Experienced workers
» Development
» Construction
» Production
» Support services
Some Key Challenges Resulting
from the Evolution
„
What is wrong with existing biotech
staff?
– Not enough of them
– Few are experienced in large scale GMP
production
Some Key Challenges Resulting
from the Evolution
„
Challenges converting existing pharma
company staff for biotech
– Processes significantly different
» More vulnerable to bioburden issues
» Not accustomed to processing conditions
conducive to developing biological
contamination
» New or evolving product lines and processes
pose challenges
And then came the
Biopharmaceutical Baseline Guide
How will the Biopharmaceutical Baseline Guide help to
resolve these challenges?
As a Training Tool
„
The Guide provides fundamental
information regarding bioprocess
operations
– Describes general principles of bioprocess
operations
– Identifies process operations where
product is vulnerable
– Highlights differences with conventional
pharmaceutical operations
Helping Harmonize Pharmaceutical
Regulators Worldwide
„
ISPE Baseline Guides focus on
fundamental principles of GMP
– What is critical to producing quality
products consistently and reliably?
„
Fundamentals help unify regulators and
minimize focus on special/regional
interests
Providing Background for Evolving
Manufacturing Operations
„
Guide presents substantial information
relative to:
– Multi-product manufacturing
» Cleaning operations
» Product segregation strategies
– Various production scales
And Now
The Guide
Goals & Objectives of the
Biopharmaceutical Baseline Guide
„
„
Balance capital, risk, and operating cost
Get CBER, CDER and field buy-in
– Understand Team Biologics
„
Consistency in best practices
Clarify and document common industry issues
Reduce ambiguity in requirements
Address multi-product manufacture
Reduce start-up and qualification efforts
„
Baseline of critical regulatory issues, not a textbook
„
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AND to
Promote the BASELINE Philosophy
„
Focus investment on facility issues that
effect our goal to produce quality
pharmaceutical products and
devices reliably and consistently.
„
Avoid unnecessary spending on facility
features that do not contribute to that
goal.
The Steering Team
„
Co-Chairmen
– Richard Priester
– Mel Crichton
– Jan Gustafsson - Novo
„
FDA
– Kip Priesmeyer
„
Team
–
–
–
–
–
–
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–
–
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Geoff Attenborough - Amgen
Gary Bird - Lilly
Jeff Biskup - CRB
Ken Jacobson - CRB
Tom Keuer - Baxter
Steve Miller – Wyeth Biopharma
Noshir Mistry – BristolMyers Squibb
Mark vonStwolinski – Dowler Gruman
Jeff Sarvis – Fluor
Patricia Turney - Amgen
John Ward – Biogen
Depak Agarwal – Jacobs
Jeff Odum – CRB
Additional Participants in the
Biopharmaceutical Baseline Guide
„
Steering Committee = Writers
– Industry + Engineers + FDA contact
Chapter Teams = primary review
„ Industry review:
„
– Focus Groups
– Presentations
– Industry Reviewers
„
FDA Reviewers
– Content locked in after FDA comment
Industry Reviewers
„
Over 100 people
– Discussion Team
– Writers
– Reviewers
„
Representation
–
–
–
–
–
Pharma
Biotech
Engineering Consultants
Contract Manufacturers
Equipment Manufacturers
FDA Reviewers Supporting Kip
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Tom Arista - National Expert, Team Biologics - Dallas
Janice Brown - CBER reviewer (licensing) - Rockville
Mark Brunswick, PhD - CBER Reviewer (prod spec) - Bethesda
Earl Dye PhD - CBER Reviewer (prod spec) - Bethesda
Jay Eltermann - CBER
John Finkbohner PhD - CBER reviewer (licensing) - Rockville
Rick Friedman - CDER Office of Compliance - Rockville
Jim Giefer - Drug Specialist - St Louis
Dennis Guilfoyle, Ph.D. - regional micro lab
Mariza Jafary - Team Biologics - Los Angeles
Kevin Kallander - Sterility Specialist - Denver
Steve Kilker - Investigator - Cincinnati
Joe McGinnis, Drug Specialist, North Brunswick, NJ to the FDA
Rick Thornton - Team Biologics - Buffalo
Chapters of the
Biopharmaceutical Guide
1: Introduction
2: Concepts & Regulatory Philosophy
3: Manufacturing Activities / Operations
4: Process & Equipment Considerations
5: Process Support
6: Facility Integration
7: Process Controls & Automation
8: Commissioning & Qualification
9: Glossary
10: (Appendix) European Aspects
Chapters 1 & 2
Introduction & Regulatory Concepts
„
Provides broad introduction to Guide
and perspective on Regulatory
Concepts
– Principles of Product Protection
– Controlled bioburden processing versus
aseptic processing
– Open versus closed processing
– Multi-product issues
Chapters 1 & 2
Introduction & Regulatory Concepts
„
Introduce concepts like
– Segregation
– Biohazard containment
– Cleanability
– Area cleanliness classification
Chapter 3
Manufacturing Operations
„
Procedural and Operational Controls
– Open vs. closed process
Bioburden-controlled processing
„ Viral clearance/inactivation
„ Segregation methods
„ Multiple product operations
„ CT materials manufacture
„
Chapter 4
Process and Equipment
„
Organization
– PFDs for Typical Biopharmaceutical
Processes
– Critical Process Parameters
– General Considerations for Equipment
Design
– Specific Equipment Design Considerations
Chapter 4
Process and Equipment
„
General Considerations
– Integration of equipment design with facility
– Process Closure
– Materials on Construction
– Biohazards
– Cleaning
– Modular Equipment
Chapter 4
Process and Equipment
„
Specific Equipment Design
Considerations
– Raw Material Storage/Handling/Dispensing
– Media/Buffer/Component Prep/Hold
– Inoculum Prep
– Fermentation/Cell Culture
– Recovery/Harvest
– Purification
BioProcess Equipment Design
Consdierations
Figure 4.1 - Design Considerations
Solution Preparation:
Media
Buffer
C
C
Cell Culture
Microbial Fermentation
Recovery:
Centrifugation
Cell Disruption
Microfiltration
Depth Filtration
Extraction
Refold
Expanded Bed Chromatography
Purification:
Ion Exchange Chromatography
Affinity Chromatography
Hydrophobic Interaction Chromatography
Size Exclusion Chromatography
High Pressure Liquid Chromatography
Precipitation
Chemical Treatment
Ultrafiltration / Diafiltration
Nanofiltration
C
C
Bulk Formulation / Bulk Fill
Sterilize-in-Place
Clean-in-Place
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
N
C
C
C
C
C
C
C
C
N
N
N
N
C
C
N
C
C
C
N
N
N
N
N
C
C
N
N
C
C
N
N
C
C
C
N
N
N
C
C
C
C
C
C
N
C
N
N
N
Vis
co
sit y
Om
sm
o la
li ty
Co
nd
uc
tivi
Ste
ty
rilit
y
Bio
Bu
rde
n
Gr
ow
th
R
a te
Ce
ll C
on
ce
Pro
n tr
du
ati
ct
on
Co
Ce
nc
ll C
en
ult
t ra
ure
tio
Ot
n
By
he
rB
-pr
od
y-p
Yie
u
rod
ct
ld
Pr
uc
ot e
ts
ins
Sta
bili
ty
Pro
du
ct
Ide
Pu
nti
ri ty
ty
En
do
tox
in
Vir
al
Cle
ara
Co
nc
mp
e
os
iti o
no
fP
Process Steps & Unit Operations
Ho
mo
ge
ne
Sh
i ty
ea
/U
r
nifo
Te
rm
mp
i ty
e ra
t
u
pH
re
CRITICAL PROCESS VARIABLES
C
C
C
C
N
N
C
C
C
N
C
C
C
C
C
C
N
N
C
C
N
N
C
C
C
C
C
C
C
C
C
C
C
C
C
N
C
C
C
C
C
C
C
N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
N
N
N
N
N
C
C
C
C
N
C
N
N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
LEGEND:
C
Typically a critical variable
N
A design consideration, but not usually a critical variable
Usually not a design consideration
Rev. St. Louis - April 2003
Chapter 5
Process Support
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Pharmaceutical Water Systems
Cleaning, Sterilization and Depyrogenation
Systems
Process & Utility Gases
Process Temperature Control Systems
Bio-waste & Process Waste Handling
Seal Support Systems
Plumbing & Piping Systems
Emergency Power
Chapter 5
Process Support
„
„
Assess GMP impact of each system
Methods to minimize product contamination
risk
– Minimize need to access the process area
– System Layout and Routing
„
„
Potential contamination sources and cures
Key concepts for biopharmaceutical water &
cleaning systems
System Layout and Routing
Centralized vs Decentralized Services
„
Centralized Services
– Advantages
» May reduce capital cost
» May improve
maintainability and
operability
» Easier to provide
redundancy
– Disadvantages
» May increase cross
contamination risks
• May increase
operational complexity
„
Decentralized Services
– Advantages
» Better product
segregation
» May simplify operations
– Disadvantages
» May increase cost
» Duplicated systems and
operations
» Redundancy is
expensive
System Layout and Routing
Use of Unclassified Manufacturing Space
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Minimizes need to access to classified
area
Reduce gowning time and costs
Reduces product exposure potential
Creates heightened awareness in critical
areas
Pharmaceutical Water Systems
„
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„
Reference Baseline
Guide to
Pharmaceutical
Water & Steam
Focus on issues
unique to Biopharma
Nutrient water feed
covered as process
step
Pharmaceutical Water Systems
Importance of delivery temperature
„ Methods to achieve low or ambient
temp at POU
„ Impact of these issues on design
„
Chapter 5
Process Support
ƒIncludes discussion of water cooling approaches not in
the ISPE Water/Steam Baseline Guide
Restriction
Orifice (mount
in vertical)
Hot Loop
Hot Loop
Coolant
Coolant
T
Point
Of Use
Point Of Use Installed in Subloop
Relative Advantages of Water Cooling Alternatives
Table 5.1
.
DESCRIPTION
Water Guide Fig. 8-10
Single Point of Use
Steamed
ADVANTAGES
DISADVANTAGES
COMMENTS
Simple connections &
operations.
Reliable performance
once properly flushed
and tested.
Superior microbial
control for intermittent
use points. HX is
continuously sanitized
except when in use.
Potentially many HX
installations with potentially
significant water consumed for
flushing. Difficult to control
flushing & mirror
Higher pressure drop in
distribution piping system.
See Note A.
Most advantageous
when few low
temperature users.
Water Guide Fig. 8-12
Point of Use HX with
Multiple Branched
Users
Water Guide Fig. 8-11
(Modified)
Multiple Branched
Users
Cooling by Process
Vessel
See Note B
Extensive start-up flushing
required to sanitize multiple
points of use.
See Note B
Superior microbial
control for intermittent
use points. HX is
continuously sanitized
except when in use.
Utilizes heat exchanger
required by process in
lieu of dedicated.
Pressure drop in distribution
piping from HX’s in series.
Most advantageous
when a few units
can serve most low
temp users.
Added time to cool down may
not effectively utilize installed
equipment.
May require oversizing of tank
cooling systems.
Most advantageous
when cool down
time is available.
May not be
optimum utilization
of critical and
expensive process
components.
Ambient or Cold
Distribution
Generally lowest cost
for operation and
installation.
May require relatively frequent
sanitization and associated
time when only high
temperature water is
available.
May require that high temp
water be occasionally
available through CIP circuit.
Most advantageous
when 4 hr. period
at high temp
operation is
possible.
Water Guide Fig. 8-11
Single Point of Use
Installed in Sub-Loop
Table 5.1 Notes:
A.
B.
Heat exchanger and associated piping and traps consume critical clean room space.
Relatively fewer but larger heat exchangers.
Most advantageous
with few low temp
users and relatively
short distribution
runs.
Conclussion
„
Publication of ISPE’s Baseline
Pharmaceuticals Guide will be a great
tool for the evolving bioprocess industry
Thank You
Any Questions???