applications in kilo lab flow chemistry and scale-up. edel hughes

Global Process Development Center, Kilo Technology Lab

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Global Process Development Center

DynoChem User’s Meeting 2011Title: Applications in Kilo Lab Flow Chemistry and Scale-up

Presenter: Edel Hughes


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Pfizer in Ireland

• With almost 5,000 employees, Pfizer is one of Ireland’s leading employers and the largest pharmaceutical sector investor in the state

• 10 locations across Cork, Dublin, Kildare, and Limerick.

• $7 billion capital investment in Ireland


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Agenda

1. Kilo Technology Lab (KTL) facility overview

2. KTL static mixer characterisation

3. Centrifugation case study

4. KTL future plans for DynoChem


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KTL FACILTY OVERVIEW


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1. Facility Overview

Kilo Technology Lab (KTL):

Facility run by the Process Development Centre (PDC).

Scale-up facility

• Kg to commercial

Process development facility

New Technology Facility

Filing variations to Approved Drug Applications (future)

Kilo Technology Laboratory Facility, Ringaskiddy API Plant, Cork Ireland (Water tower in background)


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1. Facility Overview cont..

Process Modules* Module 1: Batch Reactor Module 2: Static Mixer Reactor Module 3: Horizontal Thin Film Evaporator Module 4: Vertical Thin Film Evaporator Module 5: Crystalliser / CSTR Module 6: Filter Dryer Module 7: Centrifuge (future)

Sub-modules* Feed vessels Heat exchangers Pumps CINC centrifugal separators

KTL Static Mixer Module

*Modules are ‘plug ‘n play’, flexible, can operate as single unit operation or as equipment train


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KTL Static Mixer Characterisation


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Aim: Physically characterise KTL

static mixer reactor

In addition… Compare with the plant static

mixer reactor Use reaction with known kinetics

to make sense of the characterisation

Verify accuracy of the characterisation

Demonstrate the importance of heat transfer

2. KTL Static Mixer Characterisation

KTL Static Mixer Module


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Figure 2: Plug flow vs Laminar flow

Components have varying residence

times

Components have equal residence

times

What is a static mixer reactor?

ProductReagents



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KTL Static Mixer

• Manufacturer A• 4 x 1m length• 10mm diameter

Plant Static Mixer

• Manufacturer B• 5 x 3m length • 100mm diameter

Comparison of KTL and Plant Static Mixers



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KTL Static Mixer

Mass Transfer• kLa

Homogeneity (in pre-mixer)• CoVr = 0.02

Heat Transfer• A/V = 450m2/m3

• U = 209 W/m2K• U (unmixed) = 38 W/m2K

Plant Static Mixer

Mass Transfer• kLa

Homogeneity (in pre-mixer)• CoVr = 0.27

Heat Transfer• A/V = 40m2/m3

• U = 62 W/m2K• U (unmixed) = 16 W/m2K

For CoV = 0.02: pre-mixer plus 1.5m

reactor required.

Batch reactor A/V = 2-6m2/m3

CoVr < 0.05 ensures homogeneity for most applications

Good quality of mixing achieved in

pre-mixer

Using Dynochem to ‘Characterise’



12 Predicted % Rxn Completion =76% Actual % Rxn Completion = 82%

Using Dynochem Model to ‘Predict’

• KTL Static Mixer (U = 209 W/m2K)

• 10 min residence time

• Co-current jacket

• Inlet temp = 118oC

• Jacket temp = 130oC

The kinetic data for this continuous reaction were regressed from batch experiments that were not carried out in the KTL.



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Predicted % Rxn Completion = 82%

Reagents pre-heated so reactor heat transfer not as critical

Actual % Rxn Completion = 85%

Degree of rxn completion without mixers?


• KTL Static Mixer with no mixers (U = 38 W/m2K)

• 12.5 min residence time

• Co-current jacket

• Inlet temp = 118oC

• Jacket temp = 130oC


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No Preheating and reactor U = 209 W/m2K

% Rxn Completion = 72%

Pre-heating becomes very important if reactor heat transfer is inadequate

No Preheating and reactor U = 38 W/m2K


Is reactor heat transfer critical if no reagent preheating?




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How important is pre-heating at plant scale?

Plant reactor (U = 62 W/m2K) and pre-heat to 118oC.

% Rxn Completion = 63% % Rxn Completion = 91%

Plant reactor (U = 62 W/m2K) and pre-heat to 130oC.

Pre-heating becomes very important if reactor heat transfer is inadequate



U = 209 W/m2K)


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Conclusions

• Dynochem is an excellent way to enhance our process and equipment knowledge to lead to better more efficient processes

• A good model can actually avoid some experimentation

• Dynochem can be used to determine critical process parameters

• Batch reactions in the lab can be adequately used to determine reaction kinetics for a continuous reaction.

• Now that the KTL static mixer reactor is fully characterised and verified reactions with known kinetics can be interrogated and optimised ever before running the process in the equipment.



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Centrifugation Case Study


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3. Centrifugation Case Study

Aim: Model the KTL rental centrifuge for Product A

Regress Product A cake characteristics using:

• Lab experimental data

• DynoChem simple model for cake filtration.

Predict how this cake would form on our rental pilot scale centrifuge using:

• Cake characteristics from former model

• Centrifuge physical dimensions

• DynoChem’s centrifuge model.

This model was later verified using lab experiments.

Rental pilot scale centrifuge used in the KTL


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Aim: Model the KTL rental centrifuge for Product A

Cake characteristics of Product A determined using lab experimental data and regressing using the DynoChem simple model for cake filtration.

Component Product A

Compressibility Index (-) 1

Cake Resistance Constant (m/kg) 3.08 x 1010

Media Resistance (1/m) 1.1 x 1010

Resistances Evaluated Using DynoChem

ά = ά0 (ΔP)s Rm = kRmΔP+Rm,0

Considered highly compressible



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0

1

2

3

4

0

0.5

1

1.5

2

2.5

3

3.5

4

0 50 100 150 200 250 300

Mas

s in

Rec

ieve

r (kg

)

Time (s)

Product A Validation Trial Dec '10

Lab Data

Dynochem Model

Good prediction of lab data till the latter end of the experiment.

Unable to accurately maintain feed flow rate especially when feed vessel was almost empty because feeding by gravity.

Feed rate is the dominating factor for centrifuging cakes with high compressibility and hence any change in feed rate has a marked effect on deliquoring rates.

DynoChem model stops when the liquor reaches the top of the cake.

Conclusion – DynoChemcentrifuge model verified for pilot centrifuge – but be aware of limitations.



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Conclusions In the past, the KTL used a custom made spreadsheet to determine cake

characteristics. KTL no longer use custom made spreadsheet.

Benefit of using DynoChem’s simple filtration model over the custom made spreadsheet (as per document in knowledge base section on DynoChemresources):

• Has numerical integration

• Better user interface

• More flexible

• Can fit cake properties simultaneously

• Better long term solution

Results from the simple filtration model can be fed directly into the centrifuge model.

DynoChem’s simple filtration model plus centrifuge model together are a good way to enhance your process knowledge and allows you to confidently troubleshoot and optimise your filtration / centrifugation.

3. Centrifugation Case Studies


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Future Plans for DynoChem


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4. Future Plans for DynoChem Physically characterise remaining equipment in the KTL.

Equipment characterised so far:

• All batch reactors / crystallisers / CSTRs

• Static Mixer reactor

Future characterisation

• CINC centrifuges

• Plate filter dryer

• Thin film evaporators

As a scale-up facility, it important to know the capabilities of all equipment to ensure that equipment is being operated at physical rates that are achievable by the plant equipment.

The KTL have put together a plan to file variations to Approved Drug Applications. The KTL will typically operate at less than 10% of the final commercial scale. Dynochemwill play an important role in assuring the regulatory authorities that 10% of scale isn’t essential if the ‘Science of Scale’ is well understood.


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Acknowledgements• Dynochem Support Team

• James Robinson (UCD)

• PDC / KTL Team

• Other Pfizer colleagues:• Elango Shanmugam• Janarthanan Narayanasamy• Pawel Dudzinski• George Routhier• David Erdman• Robert Jackson

• Donald Knoechel• Bill Perrault• Sarah Mancini• Wilfried Hoffmann• Flavien Susanne• Jason Mustakis

applications in kilo lab flow chemistry and scale-up. edel hughes

Documents

ktl static mixer reactor

ktl static mixer u

static mixer reactor

mpremixer reactor

technology lab pfizer

technology lab agenda1

premixer covr

process modules