The role of Process Control in Process Analytical Technology (PAT)

1. The role of Process Controlin Process Analytical Technology (PAT) Arne Koggersbøl, NNE A/S, Denmark APACT 05 Birmingham, April 20-22

2. About NNE • Consultancy and engineering to the international pharmaceutical and biotechnological industry • More than 70 customers round the world.Brazil, China, Denmark, France, Ireland, Japan, Sweden, Switzerland, USA • Project volumes: 3,000 – 300,000,000 € • PAT / Process Analysis and Control. • Conceptual designs and strategy consultancy. • Construction projects: Building, mechanical, automation, etc. • Fast track projects.14½ month from green-field to insulin purification plant. • Worlds largest insulin production plant (in 2003). www.nne.biz

3. Why is PAT interesting? • North American pharmaceutical market (in 2003) 200 Billion € 49% of the world market • Heavily regulated by Food and Drug Administration (FDA) • And … www.nne.biz

4. PAT is FDA’s offerto ease the regulatory burden Heavyregulatoryburden PAT www.nne.biz

5. What burden? • Todays definition of a drug product: • procedure • equipment • conditions • certain end-product properties • Burden: Provide evidence! (validation) • Validation is establishment of documented evidence that the process to a high degree of certainty will perform consistently according to specifications. www.nne.biz

6. Effect of burden Pharmaceutical industry is behind • Innovation is slow Not World Class performing like other industries • flight • electronics • food • chemicals • petrochemicals www.nne.biz

7. Effect of burden • Industry Perspective: • Utilisation levels - 15% or less • Scrap and rework - plan for 5-10% • Time to effectiveness - takes years • Hesitant to innovate • Public Health Perspective • Increasing trend toward manufacturing-related problems • Recalls: 176 in 1998354 in 2002 Dr. Janet Woodcock,FDA Science Board www.nne.biz

8. What’s PAT • Future definition of a drug product: • critical quality attributes • Prerequisites: • risc based approach • measure or analyse • active control • design quality control into process • Mantra: • Process understanding • Design, analysis and control • System www.nne.biz

9. PAT versus PAC • Is PAT what we’ve been doing for years and called PAC? • PAT is more: • PAT is a new approach to process validationin relation to FDA and to EMEA • PAT is not necessarily closed-loop control • Strong focus on final product quality • Process understanding is essential • The methods of PAC may be seen as PAT-tools: • Analysis tools • Control tools • A PAC application may be developed into a PAT application. www.nne.biz

10. PAT Typical tasks of the control engineer Process understanding Design Analysis Control Model Diff. equations Data driven XX X XX Controllability study Equipment modifica. X X X Control strategy development X X Prediction and observers X Signal processing X - a PAT-interpretation Process Control www.nne.biz

11. SPC Process Control - in a PAT framework Engineering Process Control • subject to continuous improvement • focus on final product quality Product quality • inversely proportional to variance • subject to statistical analysis EPC Process Identifycause If out of control EPC = Engineering Process Control SPC = Statistical Process Control www.nne.biz

12. Process www.nne.biz

13. OutputConcernInput Process review Sterile andnutritiousThermal degradation- Particle free product solution.High YieldFoulingInput as clear as possible Stable biomass and productconcentrationMetabolismSterile and nutritious feed Clear supernatantThrough-putStable inlet concentration of dry-matter www.nne.biz

14. Step 1: 5 filters in parallel Feed Step 2: 2 filters in parallel Water Product Waste Micro filtration • Step 1: • Flow control on permeate and retentateto obtain required separation • Step 2: • Balancing retentate flows to avoid fouling run-away • Control permeate flows to obtain required yield • Control up-stream pressure (feed pressure) www.nne.biz

15. Micro filtrationSolutions Pressure-flow model for valves and filters Adaptive:K-factors are estimated continuously Anti-fouling control: Yield control: Pressure control indirectly byperturbing the flow control algorithm: Step 2:2 filters in parallel Feed Waste Product www.nne.biz

16. Micro filtrationBenefits Process understanding: Valve and filter models. • Valve and filter characteristics estimated continuously. • Monitoring changes in characteristics used for maintenance purposes. • Adaptive control of pressure and flowrobust towards: • Changing valve characteristics. • Filter fouling. • Change of filter characteristics.Case: Unproblematic introduction of new filter type. www.nne.biz

17. Micro filtrationPAT perspective • Flows are critical (pressures are important) • These are measured • Process understanding • Basis for the control solution • Enhanced while producing the solution • Analysis on-line based on process model • All above is used for control • Consistent production based on flow requirements • Product not defined in terms of e.g. specific micro filter material • Future • Detection of leakage through membranes • Optimisation of yield using analyser www.nne.biz

18. Centrifugation • Objective: Clear supernatant • Concern: Optimise through-put • Optimum is feed-flow dependent www.nne.biz

19. CentrifugationSolution • Continuous optimisation of feed/flocculant ratio using • pertubation of the ratio signal. • signal processing, noise handling. www.nne.biz

20. CentrifugationBenefits Feed flow Low sludge High sludge Time www.nne.biz

21. CentrifugationPAT perspective • Clearness is critical • This is measured • Process understanding • is the basis for the solution • Analysis on-line based on pertubations • All above is used for control • Consistent production based on clearness requirement • Product not defined in terms of e.g. use of a specific centrifuge with a specific flocculant and a specific feed/flocculant ratio. www.nne.biz

22. Fermentation • Objective: Stable biomass and product concentration • Concern: Optimise production avoid metabolism change avoid metabolism overflow. • Complex medium • Carbon • Protein • Salts, vitamins, trace metals, etc. www.nne.biz

23. FermentationSolutions • Change from 1 to 2 feed streams • Carbon hydrate medium (Speed)Feedback control • Complex medium (Product/impurity) • On-line off-gas analysis used to determinestate of metabolism (respiration/fermentation). www.nne.biz

24. FermentationBenefits • Improved monitoring of metabolism • helps keep process on a high-yield metabolic path • Metabolism overflow avoided • controlling dissolved oxygen using carbon hydrate flowrate • Begin using standardised media www.nne.biz

25. FermentationPAT-perspective • State of metabolism is critical • This is analysed and controlled for profit, not quality • Process understanding enhanced for profit, not quality • Carbon hydrate source may not be indifferent to cells • Complex feed composition is essential Typically not used for feed-back quality control • Product is defined in terms of • physical conditions (temperature, pressure, pH, aeration, agitation and time) , and • geometry of certain equipment.The link to product quality is usually not well understood. www.nne.biz

26. FermentationFuture PAT • Enhancement of process understanding for product quality control • Further decoupling of media effects • Tighter metabolism control based on analysis of metabolites • Impurity monitoring and control • Important for downstream processing • Infection monitoring. www.nne.biz

27. Continuous sterilisation • Objective: Sterile and nutritious product. • Concern: Thermal degradation of nutrientsHow to handle disturbances diminishing lethality (F0) www.nne.biz

28. Continuous sterilisation • Individual control of flow and temperature to obtain F0-target. • F0-target set high to take into account simultaneous disturbances in temperature and flow. • This results in undesired thermal degradation of nutrients. www.nne.biz

29. Continuous sterilisationSolution • F0-estimator based on mathematical model • enables tight control • F0-target can be set close to the minimum www.nne.biz

30. Continuous sterilisationBenefits • Improved quality of product • Less degradation of nutrients • More confidence in product quality • Monitoring has been enabled. www.nne.biz

31. Continuous sterilisationPAT-perspective • Sterility is critical ……………………… Not measured • Lethality is not critical ……………… Analysed and controlled • Thermal degradation is critical … Not measured • Probably consistent production based on lethality requirement • Consistent lethality  consistent degradation ? • Product is defined in terms of fixed conditions:Exposing the medium to a certain lethal effect regardless of initial amount of life. • Future PAT • Measure live biomass at points in the process • Measure non-degraded nutrients www.nne.biz

32. Points • PAT is a potential revolution for the pharmaceutical industry • Be alert (there are jobs here) • Process control engineers have significant roles to play • Similar mindsets • PAT-solutions are likely to start as PAC-solutions • When doing PAC in pharmaceutical production, think: • “process understanding” • “design, analysis & control” • “continuous improvement” • “risk based” www.nne.biz

33. Further information Arne Koggersbøl akog@nne.dk +45 3079 7579 www.nne.biz