ISPE Biopharmaceutical Baseline Guide Presented by: Jeff Biskup, CRB - - PowerPoint PPT Presentation
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
ISPE Biopharmaceutical Baseline Guide
Presented by: Jeff Biskup, CRB
At
Omaha, Nebraska April 14, 2005
Jeff Biskup, CRB – Background,
Mark VonStwolinski, CRB – Facilities
Pat Hamell, Pfizer – Process Equipment
Biopharmaceutical Industry is Evolving
– Transitioning from
» R&D focus to commercial manufacturing » Small entrepreneurial companies becoming big businesses Biopharmaceutical Baseline Guide will
Primarily in R&D, most recently heavy in
Mostly technology based
Mostly located in R&D centers Staffing predominantly PhD’s and highly
Transitioning to commercial production for
blockbusters
– Learning how to produce GMP products – Moving to industrial regions
Building MEGA plants for large scale
production
Building clinical production operations Matching up business partners Recognizing the importance of being in
manufacturing regions
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
Needed Resources:
– Efficient production facilities
» Few licensed facilities
– Experienced workers
» Development » Construction » Production » Support services
What is wrong with existing biotech
– Not enough of them – Few are experienced in large scale GMP production
Challenges converting existing pharma
– 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
How will the Biopharmaceutical Baseline Guide help to resolve these challenges?
The Guide provides fundamental
– Describes general principles of bioprocess
– Identifies process operations where product is vulnerable – Highlights differences with conventional pharmaceutical operations
ISPE Baseline Guides focus on
– What is critical to producing quality products consistently and reliably?
Fundamentals help unify regulators and
Guide presents substantial information
– Multi-product manufacturing
» Cleaning operations » Product segregation strategies
– Various production scales
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
Focus investment on facility issues that
Avoid unnecessary spending on facility
Co-Chairmen
– Richard Priester – Mel Crichton – Jan Gustafsson - Novo
FDA
– Kip Priesmeyer
Team – 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
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
Over 100 people
– Discussion Team – Writers – Reviewers
Representation
– Pharma – Biotech – Engineering Consultants – Contract Manufacturers – Equipment Manufacturers
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
Provides broad introduction to Guide
– Principles of Product Protection – Controlled bioburden processing versus aseptic processing – Open versus closed processing – Multi-product issues
Introduce concepts like
– Segregation – Biohazard containment – Cleanability – Area cleanliness classification
Procedural and Operational Controls
– Open vs. closed process
Bioburden-controlled processing Viral clearance/inactivation Segregation methods Multiple product operations CT materials manufacture
Organization
– PFDs for Typical Biopharmaceutical Processes – Critical Process Parameters – General Considerations for Equipment Design – Specific Equipment Design Considerations
General Considerations
– Integration of equipment design with facility – Process Closure – Materials on Construction – Biohazards – Cleaning – Modular Equipment
Specific Equipment Design
– Raw Material Storage/Handling/Dispensing – Media/Buffer/Component Prep/Hold – Inoculum Prep – Fermentation/Cell Culture – Recovery/Harvest – Purification
Figure 4.1 - Design Considerations
CRITICAL PROCESS VARIABLES Process Steps & Unit Operations
Homogeneity / Uniformity Shear Temperature pH Viscosity Omsmolality Conductivity Sterility BioBurden Growth Rate Cell Concentration Product Concentration Cell Culture By-product Proteins Other By-products Yield Stability Product Identity Purity Endotoxin Viral Clearance Composition of P Solution Preparation: Media C N C C C C C C C C Buffer C N C C C C C C C C Cell Culture C C C C N C C C C C C C C C C Microbial Fermentation C C C N C C C C C C C C C Recovery: Centrifugation C N C C C C C C C Cell Disruption C N N N C N C C C Microfiltration C C N N C C C C C C C Depth Filtration N C N C N Extraction C C C C C C C C C C Refold C C C C C C C C C C C C Expanded Bed Chromatography C N C C C N C C C C C C C N C Purification: Ion Exchange Chromatography C N C C C C C C C C C C N C Affinity Chromatography C N C C C C C C C C C C C N C Hydrophobic Interaction Chromatography C N N C C C C C C C C C N C Size Exclusion Chromatography C N N C C C C C C C N C High Pressure Liquid Chromatography C N C N C C C C C C C C C C N C Precipitation C C C C N C C C C C C C C C N C Chemical Treatment C N C C C C C C C C C C C C Ultrafiltration / Diafiltration C C N N N C C C C C C C C C C Nanofiltration C N N N N C C C C C C C C C C Bulk Formulation / Bulk Fill C N C C C C C C C C C C C C C Sterilize-in-Place C C C C N Clean-in-Place C C N C C N N C
LEGEND:C
Typically a critical variableN
A design consideration, but not usually a critical variable Usually not a design consideration 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
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
» Easier to provide redundancy
– Disadvantages
» May increase cross contamination risks
Decentralized Services
– Advantages
» Better product segregation » May simplify operations
– Disadvantages
» May increase cost » Duplicated systems and
» Redundancy is expensive
System Layout and Routing
Use of Unclassified Manufacturing Space
Minimizes need to access to classified
area
Reduce gowning time and costs Reduces product exposure potential Creates heightened awareness in critical
areas
Reference Baseline
Guide to Pharmaceutical Water & Steam
Focus on issues
unique to Biopharma
Nutrient water feed
covered as process step
Importance of delivery temperature Methods to achieve low or ambient
Impact of these issues on design
Includes discussion of water cooling approaches not in the ISPE Water/Steam Baseline Guide
Point Of Use Installed in Subloop
Hot Loop Hot Loop Coolant Coolant Point Of Use Restriction Orifice (mount in vertical)
T
Relative Advantages of Water Cooling Alternatives
Table 5.1
. DESCRIPTION ADVANTAGES DISADVANTAGES COMMENTS Water Guide Fig. 8-10 Single Point of Use Steamed
Simple connections &
Reliable performance
and tested. Potentially many HX installations with potentially significant water consumed for
flushing & mirror See Note A. Most advantageous when few low temperature users.
Water Guide Fig. 8-11 Single Point of Use Installed in Sub-Loop
Superior microbial control for intermittent use points. HX is continuously sanitized except when in use. Higher pressure drop in distribution piping system. Most advantageous with few low temp users and relatively short distribution runs.
Water Guide Fig. 8-12 Point of Use HX with Multiple Branched Users
See Note B Extensive start-up flushing required to sanitize multiple points of use.
Water Guide Fig. 8-11 (Modified) Multiple Branched Users
See Note B Superior microbial control for intermittent use points. HX is continuously sanitized except when in use. Pressure drop in distribution piping from HX’s in series. Most advantageous when a few units can serve most low temp users.
Cooling by Process Vessel
Utilizes heat exchanger required by process in lieu of dedicated. 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
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
possible.
Table 5.1 Notes:
A. Heat exchanger and associated piping and traps consume critical clean room space. B. Relatively fewer but larger heat exchangers.
Publication of ISPE’s Baseline