The role of process control in process analytical technology pat
1 / 33

The role of Process Control in Process Analytical Technology (PAT) - PowerPoint PPT Presentation

  • Uploaded on
  • Presentation posted in: General

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

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about 'The role of Process Control in Process Analytical Technology (PAT) ' - dakota

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
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


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).

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 …

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



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.

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

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

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

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.

Process control


Typical tasks of the control engineer

Process understanding




ModelDiff. equationsData driven




Controllability study

Equipment modifica.




Control strategy development



Prediction and observers


Signal processing


- a PAT-interpretation

Process Control

Process control1


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




If out of control

EPC = Engineering Process Control

SPC = Statistical Process Control


Process review


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

Micro filtration

Step 1: 5 filters in parallel


Step 2: 2 filters in parallel




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)

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




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.


    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


    • Objective:Clear supernatant

    • Concern:Optimise through-put

    • Optimum is feed-flow dependent

    Centrifugation solution

    • Continuous optimisation of feed/flocculant ratio using

      • pertubation of the ratio signal.

      • signal processing, noise handling.

    Centrifugation benefits

    Feed flow

    Low sludge

    High sludge


    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.


    • Objective:Stable biomass and product concentration

    • Concern:Optimise production avoid metabolism changeavoid metabolism overflow.

    • Complex medium

      • Carbon

      • Protein

      • Salts, vitamins, trace metals, etc.

    Fermentation solutions

    • 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).

    Fermentation benefits

    • 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

    Fermentation pat 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.

    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.

    Continuous sterilisation
    Continuous sterilisation

    • Objective: Sterile and nutritious product.

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

    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.

    Continuous sterilisation solution
    Continuous sterilisationSolution

    • F0-estimator based on mathematical model

      • enables tight control

      • F0-target can be set close to the minimum

    Continuous sterilisation benefits
    Continuous sterilisationBenefits

    • Improved quality of product

      • Less degradation of nutrients

    • More confidence in product quality

      • Monitoring has been enabled.

    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

    Point s

    • 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”

    Further information
    Further information

    Arne Koggersbøl

    +45 3079 7579

  • Login