Demands on process analytical tools in Biomanufacturing

							                                                                                      Products of
                                                                                      Biomanufacturing

                                                                          •   Proteins and peptides
                                                                          •   Metabolites
      Demands on process analytical tools                                 •   High value biologicals
      in Biomanufacturing                                                 •   API’s
                                                                          •   Biochemical transformation products
                              Gunnar Hörnsten
                                                                          •   Bulk chemicals
                            Manager of NbiNet                             •   Treatment of industrial side-streams
             SIK The Swedish Institute for Food and Biotechnology              – Refined raw materials to other processes
                                                                               – Degradation products that become ‘A product’

                          Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                      Gunnar Hörnsten SIK, Analysdagarna 2006-06-13




                 Differences among                                                   NbiNet
                 Biomanufacturing                                                    Nordic Biomanufacturing
                 Industries                                                          Network
• The optimal Biomanufacturing process                                    NbiNet aims at becoming the best known and most
   – regulatory systems lead to different demands and results
                                                                          respected organisation in the Nordic region in the fields
   – product value sets boundaries
• Improved production economy                                             of Biomanufacturing and Bioprocesses
   – reasons for investments differ between industries
• Understanding of the process
                                                                          • 40 members
   – benefits with acquiring knowledge differ between industries
   – measurements ‘for the purpose of documentation’ or for action
                                                                          • www.sik.se/nbinet
A take home message:
• Lots to learn through networking within Biomanufacturing


                          Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                      Gunnar Hörnsten SIK, Analysdagarna 2006-06-13
            Outline                                                         PAT as Regulatory concept

• PAT as Regulatory concept
                                                                  • PAT: Process Analytical Technologies implemented
• Pharma: PAT develops new measurement strategies                   within production of Pharmaceuticals
• Hypothesis: FDA and EMEA means business
   – Consequences for Biopharmaceuticals production               • PAT changes the way Pharmaceuticals industry
   – Spin-Off: New knowledge on Biomanufacturing                    should work
• Conclusions




                  Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                       Gunnar Hörnsten SIK, Analysdagarna 2006-06-13




            The goal of PAT                                                    FDA - Definition of PAT


•     understand and control the
    is to
                                                                  • “PAT is a system for:
                                                                     – designing, analysing, and controlling manufacturing
    manufacturing process                                              through
                                                                     – timely measurements (i.e., during processing) of critical
                                                                       quality and performance attributes of
• quality cannot be tested into products; it should be               – raw and in-process materials and processes with the
                                                                       goal of
  built-in or should be by design                                    – ensuring final product quality.”



                  Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                       Gunnar Hörnsten SIK, Analysdagarna 2006-06-13
               Meaning of ’Analytical’ in                                             PAT gives focus to new
               PAT                                                                    tools that:

‘analytical’ is viewed broadly to include                                • “enable scientific, risk-managed pharmaceutical
• chemical,                                                                development, manufacture, and quality assurance”
• physical,                                                              • “constitutes effective and efficient means for acquiring
• microbiological,                                                         information to facilitate process understanding, develop
• mathematical and                                                         risk-mitigation strategies, achieve continuous
• risk analysis                                                            improvement, and share information and knowledge”
All conducted in an integrated manner

Consequence: PAT is an arena for experts within different disciplines.


                        Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                         Gunnar Hörnsten SIK, Analysdagarna 2006-06-13




               Process Analytical                                                     Regulatory PAT is useful also
               Technology tools                                                       to Non-Pharma industries

                                                                         • Chemometrics already in use
• Multivariate data acquisition and analysis tools                       • Automation and LIMS in place
• Modern process analysers or process analytical                         • Multifaceted Control Strategies
  chemistry tools                                                           – Adaptive Control Strategies already in use
• Process and endpoint monitoring and control tools
• Continuous improvement and knowledge management                        • Wider use of existing tools across a larger product value regime
  tools                                                                  • More knowledge will be generated with roots in needs within
                                                                           Pharma Quality Control
                                                                            – Novel tools for Non-Pharma companies




                        Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                         Gunnar Hörnsten SIK, Analysdagarna 2006-06-13
               The FDA and EMEA                                                   Pharma Manufacturing in
               means business with PAT                                            2001 (PriceWaterhouseCoopers)

• FDA CDER PAT teams gives weight to the process                      •   Utilisation levels: 15% or less
   – Key representatives of the FDA spreads the                       •   Scrap and rework: often 5 - 10%
     message in person at different meetings;
                                                                      •   Time to effectiveness: Takes years
       • see http://www.fda.gov/cder/OPS/PAT.htm for
         downloadable presentations                                   •   Costs of Quality: In excess of 20% …
   – Guidance for Industry, September 2004 available
     for download as .pdf or at
     http://www.fda.gov/cder/guidance/6419fnl.htm
• EMEA PAT Over-view
  http://www.emea.eu.int/Inspections/PAThome


                      Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                      Gunnar Hörnsten SIK, Analysdagarna 2006-06-13




                                                                                  Pharma: PAT develops new
               Strategy basis                                                     measurement strategies

• Critical and Quality process parameters                             • measurements for the purpose of testing and
   – Proven acceptable range (PAR)                                      documentation
   – Normal operating range (NOR)
   – Implications of a critical measurement
                                                                      • measurements for adaptive control and active
       • Quality: Design, Validation, Maintenance, Batch release        prognostic use of measurement data
   – Risk analysis
       • Optimal cost for measurements
                                                                      Incentive
   – Failure
       • Acceptable cost for a failure                                • Investing in PAT for improved process economy
• Robust technologies                                                 • Shorten the distribution time to market
• ‘Steady-state’ controllers keeping within the boundaries of NOR


                      Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                      Gunnar Hörnsten SIK, Analysdagarna 2006-06-13
               What makes
                                                                                         Ex demands on PAT tools
               measurements difficult?

                                                                          • Robust, uncomplicated to use In-, At- or On-line
• High complexity and variability in Bioprocesses                         • Easy operator interface, simple routines understood by
• Complex matrix (contains hundreds of components)                          operators, supporting “hands on” and “decision making”
                                                                          • Low cost
• Large dynamic range (levels span a million-fold                         • Large flexibility in dynamic range
  range)                                                                  • Flexibility to changes in matrix conditions
• Flexibility (different cultivation conditions)                          • Fouling and CIP
• Response time varies                                                    • Functional contamination barrier
                                                                          • Sensitivity protein product < 0.1 mg/ml
• Scalable process                                                        • Accuracy < 10%
• Problem with fouling                                                    • Reproducibility < 20% RSD
• Aseptic conditions                                                      • Following Standards e.g. CFR part 11, port sizes etc


                        Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                            Gunnar Hörnsten SIK, Analysdagarna 2006-06-13




                                                                                         PAT: Inoculums and cell
               Operational issues
                                                                                         bank

•   Inoculums and cell bank                                             • Medium, nutrients and batch variation (Everything OK?)
•   Biomanufacturing step / cultivation                                 • Master cells, Cell line, productivity, stability, trends (Everything OK?)
•   Cell separation                                                        – PAT: ‘A go ahead to production scale’ decision
•   Capture, purification and polishing
•   Final steps of production e.g. filtration, freeze drying            Tools
                                                                        • Transcriptomics and Proteomics
                                                                        • NIR/IR
More info:
                                                                        • Fluorescence spectroscopy / flow cytometry
PDA Technical report No 42:
                                                                        • Chemical imaging of substrates and blending
”Process Validation of Protein Manufacturing”, Sept/Oct 2005
                                                                        • Chemometrics
http://www.pda.org/science/FinalTechRpts.html                           • Trend analysis

                        Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                            Gunnar Hörnsten SIK, Analysdagarna 2006-06-13
           PAT: Biomanufacturing                                               PAT: Biomanufacturing
           step / cultivation                                                  step / cultivation

• Biomass                                                         Tools
                                                                  • Gas analysis (optical, electrochemical, GC/MS etc)
   – Consumption and productivity rates                           • pH/Temp/Capacitance
   – Viability and Cell death                                     • Fluorescence spectroscopy
                                                                  • Flow cytometry
   – Metabolic activities                                         • Bio- and Chemical sensors
   – Infections                                                   • Optical absorbance
                                                                  • On-line / At-line protein analysis LC/CE/Groton ARS + GPA
• Critical parameters (often process specific)                      1000/GyrolabTM
• Optimal point for harvest                                       • PCR, Fingerprinting, transcriptomics
                                                                  • Multivariate analysis of production data
• Fingerprinting methods for ‘Golden batches’                     • Smart sensors


                  Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                       Gunnar Hörnsten SIK, Analysdagarna 2006-06-13




                                                                               PAT: Capture, purification
           PAT: Cell separation
                                                                               and final steps

• Optimal flow of cell mass to centrifuge                         •   Gradient Control and Monitoring
  – Monitoring - Aiming for reproducible and high yield           •   Product monitoring: Quality and Concentration
    product recovery                                              •   Aggregates
                                                                  •   Viruses
Tools                                                             •   Process contaminants
• Spectroscopy                                                         – e.g. Toxins, Metabolites, Protein and DNA
• Fluorescence methods                                                 – Rinse until end-point



                  Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                       Gunnar Hörnsten SIK, Analysdagarna 2006-06-13
               PAT: Capture, purification                                            Consequences of this
               and final steps                                                       view on PAT

Tools                                                                  • The understanding to be used in PAT-tools                I wish …
• UV/VIS and Fluorescence spectroscopy                                    – grows out of a rigorous process development
• Nephelometry and Light Scattering (aggregation)                         – grows out of analysis of production statistics
• On-line LC/CE
                                                                          – grows out of mental preparedness to change a process
• Conductivity
                                                                       • Financial return on investment through improved production
• pH
                                                                         results
• Biosensors
                                                                          – Quality control using real time prognostic tools is not in
• SPR
                                                                            conflict with QC to confirm quality off-line
• MS (Molecular variants of Product)
                                                                               • Adaptation to actual conditions. “Less need to fix the
• Automatic monitoring of toxins and microbial contaminants (product             Steering wheel, when in heavy traffic!”
   and WFI)
                                                                       • PAT affects the mind setting and the work organisation

                       Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                          Gunnar Hörnsten SIK, Analysdagarna 2006-06-13




                                                                                  Consequences for
               Consequences of this
                                                                                  Biopharmaceuticals
               view on PAT
                                                                                  production
• The understanding to be used in PAT-tools                I wish …    PAT leads to:
   – grows out of a rigorous process development                       • understanding what the actual measurement means in terms of
   – grows out of analysis of production statistics                      final product quality
   – grows out of mental preparedness to change a process              • prognostic tools
• Financial return on investment through improved production           • corrective measures
  results                                                              • shorter production times
   – Quality control using real time prognostic tools is not in        • more rapid distribution of products
     conflict with QC to confirm quality off-line
        • Adaptation to actual conditions. “Less need to fix the       • FDA and EMEA aim at lowered prices of pharmaceutical
          Steering wheel, when in heavy traffic!”
                                                                         products
• PAT affects the mind setting and the work organisation

                       Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                          Gunnar Hörnsten SIK, Analysdagarna 2006-06-13
             Spin-Off: New knowledge                                                     Getting a PAT
             on Biomanufacturing                                                         infrastructure in place

• Pharmaceuticals development will finance generation               •   Industry:
  of process understanding / QA (PAR and Failure)                        – Process and technology validations. Implementation of improved
                                                                            understanding and Novel solutions.
• Non-pharmaceuticals Biomanufacturing draws                        •
                                                                         – Products from Biotech Supply Companies and Expert consultants
                                                                        Industrial R&D Institutes:
  conclusions from data mining of historical production                  – Concept validation and Benchmarking of Novel solutions and understanding
  data (PAR and Failure)                                                 – Knowledge dissemination
                                                                    •   Academy:
• Tools to validate Raw materials and quality of                         – Improved understanding and Novel solutions/principles
                                                                         – Education and Knowledge dissemination
  production (PAR and Failure)                                      •   Regulatory bodies:
                                                                         – Communication, education, setting examples and adaptation
                                                                    •   Networking:
                                                                         – EUFEPS European PAT Sciences Network, ISPE, NbiNet, local networks …
                                                                         – Building centers with critical mass to deal with this job!!!
                                                                         – Site visits and work at other’s labs: Industry-Institutes-Centers-Academy

                    Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                                Gunnar Hörnsten SIK, Analysdagarna 2006-06-13




             Conclusions                                                                Acknowledgements

•   PAT is here to stay!                                                • All NbiNet members have contributed in different
•   PAT will change the work organisation                                 ways
•   PAT will lead to increased co-operation
•   PAT will lead to prognostic tools                                   Special thanks to:
•   PAT will lead to adaptation to real time situations                 Anders Hagman, AstraZeneca
•   PAT will affect the path to market                                  Helene Sundström, KTH
•   PAT will not prolong the time to market
                                                                        Christian Cimander, Novozymes Biopharma
•   PAT will lead to more efficient production
                                                                        Jan Peter Axelsson, Pfizer
•   PAT will change the way regulatory bodies work

                    Gunnar Hörnsten SIK, Analysdagarna 2006-06-13                                Gunnar Hörnsten SIK, Analysdagarna 2006-06-13