Quality & Regulatory Issues in Biopharmaceutical Facility Design A Perspective from Industry Trends Paul Smock, Biotechnology Quality & Technical Consultant Meridian BioGroup LLC The opinions and views of the speaker presented are not necessarily those of Meridian BioGroup or AstraZeneca
Flexible Facilities - Business Drivers Enablers for Innovation and Design Quality and Regulatory Considerations Open vs Closed Systems and Layout Closed/Functionally Closed - Overview & Challenge References and Acknowledgements
Facilities need to be flexible, multi-product clinical and commercial Build to encompass shifting pipeline and demand scenarios Mixed volumes Smaller markets, personalized medicines, multiple indications Higher titers Campaigned production Segregation is based on time Short changeovers Cleaning validation & clearance between products Concurrent production Segregation by Engineering controls closed systems & space Closed systems allow for concurrent, side-by-side, multi-product
Objective Rationale Higher value for the patient Reduced CoGs Reduced time-to-market Higher product quality Lower potential for contamination Conditions can be carefully controlled Lower facility capital costs Simpler floor plan Less HVAC Shorter facility construction and qualification times Reduced area classifications Reduced facility complexity Lower facility operating costs Reduced energy Reduced gowning Reduced EMO Greater operational flexibility Ballroom, disposables and alternative design concepts Process equipment more accessible Process is easier to monitor, troubleshoot, and improve
Process design and understanding Simplified/platform design Robust understanding of critical steps and controls Closed Systems Flexible organizations Mindset and skills Communication and KM Advanced controls and testing Automation Reduced testing Data acquisition/analysis Facility & System Design Modularization System design options Multi-product manufacturing Area classification and layout
All Stainless Steel Pros Proven technology Possible to integrity test Cons Capital intensive Limited flexibility CIP/SIP adds complexity Hybrid Systems Pros Ability to operate at high pressures Lower operating costs Cons Functionally-closed systems. Connection points must be sanitized. All Single-Use Pros Lower capital costs No cleaning validation Cons Potential breaches Integrity testing problematic Leachables and extractables
Pictures: Saint Gobain, Wave Biotech, Bayer, Gemü, Sartorius, GE Health Care, Millipore, Central States Industrial Equipment and Service, Inc.
Points to Consider Facility Design and Operation
Concurrent multi-product process: A facility where different products of the same or different class are manufactured at the same time in parallel More challenging than a campaign scenario where production has been sequenced to allow temporal segregation with effective cleaning and changeover Application of Quality and Scientific Risk Management approaches Special considerations for product class, product compatibility and requirement for product containment Assumptions Shared media/buffer prep, bioreactor, harvest and purification process operations Some use of single use components Validated/Verified cleaning for product contact equipment/parts Enhanced controls for some operations (inoc. prep, final DS filtration) Compatible products requiring no special handling
Bioburden Control Strategy Facility Design Room Classifications, Cascades and Flows (QRM based) Functionally Closed Systems, Briefly Exposed Operation, Limited use of Open, Aseptic Operations (Axenic monoculture) Cleaning/Sanitization/Sterilization Engineering and Maintenance Controls Process Monitoring Bioburden/Endotoxin Environmental Monitoring Viral Control Strategy BSE/TSE Controls MCB/WCB/EPCB Preparation/Testing/Specifications EOP Testing/Specifications Viral Clearance Validation Facility Pre/Post Viral Segregation
Regulatory Drivers: Bioburden Controlled Biologic Bulk Substance Manufacture US FDA CFRs (GXP) and Guidance documents ISO 14644 Eudralex Volume 4, Part II ICH Q9 Annex 2 guided by Annex 1 through application of QRM Principles ICH Q10 PIC/S
Application of QRM principles for Product Protection and Cross-Contamination Control (Product Protection Control Strategy) Design and construction to facilitate cleaning, maintenance and operations Minimization of potential cross-contamination and limitation of exposure to (objectionable) microbial contaminants Use and justification of open versus closed processing Containment requirements & controls (GLSP/BL1/BL2) Use of Primary (Physical) vs Secondary (Procedural / Temporal) segregation (See EU Annex 2 (latest revision), Premises and Equipment for detail)
Weigh/Dispense, Buffer, Media Prep Segregation Personnel Flow Material Flow Animal vs Non-Animal derived material handling Filtration Point of Preparation or Use Cleanliness Levels, Adjacencies, Cascades ISO or EU Classification assignment/controls DeltaP and directional airflow HVAC supply/return design; use of HVAC sinks between zones Grey space use and flows Process Requirements for Unit Operations Upstream (Host Cell Containing) Harvest (Host Cell removing) Downstream (Non-Host Cell containing) Host cell Type (Mammalian, Bacterial, Other) Low Controlled Bioburden versus Sterile
GRADE ISO CLASS EUROPE/ USA FDA (approx.) IN OPERATION MAX # PARTICLES 0.5 µ & LARGER / M 3 MAX # OF VIABLE MICROORGANISMS (CFUs) / M 3 A 5 3500 <1 N/A 6 35000 7 B 7 350000 10 C 8 3500000 100 D "9" 3500000 (at rest) 200
Layout Considerations
Inoc CC Harv P1 P2 BF Line 1 Open Closed Closed Closed Closed Closed Line 2 Open Closed Closed Closed Closed Closed Individual room
Inoc CC Harv P1 P2 BF Line 1 Open Closed Closed Closed Closed Closed Line 2 Open Closed Closed Closed Closed Closed Individual room PIC/S Item 12. Processing steps after harvesting may be carried out in the same production area provided that adequate precautions are taken to prevent cross contamination.
Notes: 1. Common harvest filtration and storage equipment assumed. This could be feasible with single-use filters and storage bags. Change over cleaning for stainless steel equipment (e.g. pumps) Cleaning would have to be carefully planned and validated. 2. For basal media. By using a storage bin for this, the media preparation and bioreactor preparation activates can be decoupled. This allows implementation of a variable-volume inoculation scheme for the full scale bioreactor 3. Growth media can be stored in stacked bins. Typical Single Use Bags / Container s Typical Bio-Reactor SS or Single Use Flow Transition Spaces, separate or combined, as appropriate to facility Cell Culture Line 1 Chromatography Line 1 Matls. Matls. Matls. Matls. Final Purification Line 1 Matls. Flow Transition Spaces, separate or combined, as appropriate to facility Materials Note 1 Note 2 Note 3 Materials Personnel Personnel Assumptions: Inoculum transfer takes place as part of the material transfer into the Main Hall. Equipment Waste Common Media Prep. Matls. Matls. Matls. Matls. Matls. Common Buffer Prep Matls. Matls. Equipment Waste CNC Room environment in Main Hall and final Purification Areas. Closed Processes Shared equipment: Buffer Prep, Media Prep, Centrifuge, Harvest, & Clarification Cell Culture Line 2 Chromatography Line 2 Final Purification Line 2 Multiple Concurrent Processing
Why, What and How & The Big Challenge
Consider More Focus On Designing processes that are closed Verifying that processes are integral Demonstrating effectiveness of sanitization methods to achieve closure Less Focus On Designing and operating highly classified cleanroom environments Monitoring to demonstrate environments meet classification claims Complex gowning and procedures Airlocks Personnel, material, and waste flows that companies should focus on mitigating measures that are most effective and bring the highest value to the patient.
Closed System Scheme OUTPUT - Gas Phase exhaust air, vent lines INPUT - Gas Phase Air, CO2, N2, O2, etc. OUTPUT - Gas Phase exhaust air, vent lines Gas Filter Gas Filter INPUT - Liquid Phase media, buffer, ph adj. Liquid Filter Closed System Battery Limits Internal Fittings Closed System INPUT - Liquid Phase pre-sterilized media, pre-filtrated buffer, WFI INPUT - Vapor Phase CIP, Clean Steam INPUT - Liquid Phase Product Equipment Assembly XXX Sample port Instrumentation OUTPUT - Liquid Phase Product OUTPUT - Liquid Phase liquid waste OUTPUT - Liquid Phase steam condensate Closed System Legend Equipment Assembly Streams Connectors or Disconnectors.
More complex design Vessel and transfer line can be steamed and sanitized without opening Integrity testing possible Precedent for CNC manufacturing Operations segregation may be diminshed or eliminated May not be flexible!
Γ-sterilized Γ-sterilized Γ-sterilized Γ-sterilized Sterile tubing fuser or aseptic connector Design complexity borne by the vendor but end user must qualify. Possibility of leaks (integrity test may not be possible) Bag seams Tubing engagements Peristaltic pump tubing wear or misalignment Flexible; other Quality Issues e.g. E/L
NEED PROOF! Functionally-Closed Connection in CNC Open Connection in Grade C What could be in a the environment? Bacteria, mold, virus Cell culture material (from spill) In-Process API from another process Sanitization measures need to be validated
ISPE Biopharm Process Guide 2013 ISPE Biopharm Baseline Guide Volume 6, 2004 ISPE Biopharm Facility Guide 2013 ISPE Biopharm Single Use Guide 2014
Chalk, S., et.al.; Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of bulk Drug Substances, BioPharm. Intl., August, 2011 Chalk, S., et.al.; New Challenges to the Cleanroom Paradigm for Multi-Product Facilities, BioPharm Intl., May 2013
Simon Chalk, BioPhorum Operations Group Scott Probst, Bayer Technology Services David Estape, M+W Group, GmbH Ken Green, Pfizer Manufacturing Services Marc Pelletier, CRB Engineers Steve Miller, AstraZeneca- Global Engineering Alison Demarest, Meridian BioGroup