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The role of Process Control in Process Analytical Technology (PAT). Arne Koggersbøl, NNE A/S, Denmark APACT 05 Birmingham, April 20-22. About NNE. Consultancy and engineering to the international pharmaceutical and biotechnological industry

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The role of process control in process analytical technology pat

The role of Process Controlin Process Analytical Technology (PAT)

Arne Koggersbøl, NNE A/S, Denmark

APACT 05

Birmingham, April 20-22


About nne
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).

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Why is pat interesting
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 …

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Pat is fda s offer to ease the regulatory burden
PAT is FDA’s offerto ease the regulatory burden

Heavyregulatoryburden

PAT

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What burden
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.

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Effect of burden
Effect of burden

Pharmaceutical industry is behind

  • Innovation is slow

    Not World Class performing like other industries

    • flight

    • electronics

    • food

    • chemicals

    • petrochemicals

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The role of process control in process analytical technology pat

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

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What s pat
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

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Pat versus pac
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.

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Process control

PAT

Typical tasks of the control engineer

Process understanding

Design

Analysis

Control

ModelDiff. equationsData 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

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Process control1

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

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Process
Process

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Process review

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

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Micro filtration

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)

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Micro filtration solutions
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

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Micro filtration benefits
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.

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    Micro filtration pat perspective
    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

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    Centrifugation
    Centrifugation

    • Objective:Clear supernatant

    • Concern:Optimise through-put

    • Optimum is feed-flow dependent

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    Centrifugation solution
    CentrifugationSolution

    • Continuous optimisation of feed/flocculant ratio using

      • pertubation of the ratio signal.

      • signal processing, noise handling.

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    Centrifugation benefits
    CentrifugationBenefits

    Feed flow

    Low sludge

    High sludge

    Time

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    Centrifugation pat perspective
    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.

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    Fermentation
    Fermentation

    • Objective:Stable biomass and product concentration

    • Concern:Optimise production avoid metabolism changeavoid metabolism overflow.

    • Complex medium

      • Carbon

      • Protein

      • Salts, vitamins, trace metals, etc.

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    Fermentation solutions
    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).

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    Fermentation benefits
    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

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    Fermentation pat perspective
    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.

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    Fermentation future pat
    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.

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    Continuous sterilisation
    Continuous sterilisation

    • Objective: Sterile and nutritious product.

    • Concern:Thermal degradation of nutrientsHow to handle disturbances diminishing lethality (F0)

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    Continuous sterilisation1
    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.

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    Continuous sterilisation solution
    Continuous sterilisationSolution

    • F0-estimator based on mathematical model

      • enables tight control

      • F0-target can be set close to the minimum

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    Continuous sterilisation benefits
    Continuous sterilisationBenefits

    • Improved quality of product

      • Less degradation of nutrients

    • More confidence in product quality

      • Monitoring has been enabled.

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    Continuous sterilisation pat perspective
    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

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    Point s
    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”

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    Further information
    Further information

    Arne Koggersbøl

    akog@nne.dk

    +45 3079 7579

    www.nne.biz


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