applying batch data principles to continuous manufacturing aiche final

Applying Batch Data Principles to Continuous Manufacturing for the Purposes of Data Management, Batch Reporting, Analytics and Traceability

Paul BrodbeckChief TechnologistQbD Process Technologies, Inc.

Bob EngelVice PresidentInformetric Systems Inc.

Ravendra SinghChemical and Biochemical Engineering Department, Rutgers University

2 QbD Process TechnologiesContinuousPlant™ Software Suite

Background• Many pharmaceutical processes that have been implemented using traditional batch

techniques are now evolving towards continuous manufacturing in order to improve manufacturing efficiency and product uniformity

• There is intense research and development associated with applying continuous process technology to drug manufacturing that was previously batch oriented

• Since there is not discrete separation of materials at various stages of the process, it can be difficult or impossible to link incoming raw and intermediate materials to final product

• The regulatory and traceability considerations are particularly critical in this area• Residence Time Distribution (RTD) models represent a possible solution for product

traceability that is required with respect to regulatory and safety guidelines, as well as Current Good Manufacturing Practice (cGMP)

• RTD models enable batch reporting, analysis and material traceability of continuous processes


Continuous Plant for OSDRutgers

Engineering Research Center for Structured Organic Particulate Systems (ERC-SOPS)

Singh, R., Boukouvala, F., Jayjock, E., Ramachandran, R. Ierapetritou, M., Muzzio, F. (2012). Flexible Multipurpose Continuous Processing. PharmPro Magazine, 28 June, 2012,


Experimental Setup and Instrumentation

• NIR sensor has been integrated with process for real time monitoring and feedback control

• Chemometric tools have been used for real time NIR spectrum analysis in order to acquire a concentration input

• OPC communication protocol has been used to communicate the data across different software tools

• Control loops have been implemented in distributed process control system

• Controller outputs have been sent to the actuators through fieldbus devices


Residence Time Distribution (RTD)• Models relationship between input and

output concentrations• Input pulse dissipates through unit

operation as function of time

Time

Out

let C

onc.

τ

Time

Inle

t con

c.

t0

0

( )(t)

( )

out

out

C tE

C t dt

0

( )MRT t E t dt

Mean residence time

RTD

• Output concentration is characterized by Mean Residence Time (MRT) and distribution

• Maximum output concentration amplitude represents maximum possible response to input disturbance


Continuous Plant / RTD Models

Feed Frame &Tablet Press

Loss-in-Weight Feeders

Comil

Mixer

M

M

EXM

M

API

M

M

MgSt

Loss-in-Weight Feeders

Comil/Mixer

Mixer

Feed Frame &Tablet Press

Flowsheet Continuous Line

RTD Models

(… N …)

Full line RTD can be achieved by integrating the individual unit RTDs


Residence Time Distribution (RTD)

Feeder1

Feeder2

Feeder5

Feeder4

Feeder3 BLENDERCOMIL

TABLETPRESS

TABLET

E(t) – Probability Ratio of Drum IDFor example 10/90kg Refill Strategy 90% Drumn 9% Drumn-1 .9% Drumn-2 .09% Drumn-3.009% Drumn- 4

E(t)d1

DrumDrum

DrumDrumDrum

Barcode

E(t)d5

E(t)d4

E(t)d3

E(t)d2

E(t)dn E(t)dc E(t)dbBlend Uniformity RSD

API %

E(t)dp

tdc tdb tdp

Probability Convolution FormulasE(t)tablet,drum = E(t)dn + tdc + E(t)dc + tdb + E(t)db + tdp + E(t)dp + ttab

E(t)tablet,RSD = tdp + E(t)dp + ttab

E(t)tablet,API = tdp + E(t)dp + ttab

ttab

Direct Compression RSD FormulasIdeal CSTR has an exponential residence time distribution: )

Residence Time (tc)

E(t) = 1/tc * (e-t/tc)


RTD Modeling for Material Tracing

Lot A

Raw Material Drums

FeederRTD

MillRTD

BlenderRTD

TabletPressRTD

TabletDrums

E(tF) E(tM) E(tB) E(tTP)tDF tDTtDTPtDBtDMt0 tF+ + + + + + ++ + =

RTD: E(t) = 1/tc * (e-t/tc)Deadtime: tD

t1

t2

t3

t4

t5

t6

t7

t8

t9

t10

t1

t2

t3

t4

t5

t6

t7

t8

t9

t10

t11

t12

TRACEBACK

TRACEFORWARD

Material Tracing in DeltaV

RAWMATL

DRUMS

TABLETDRUMS

Lot B

Lot C


Reporting Architecture


Reporting Stages• Data Collection

– Report server collects raw data from disparate data sources according to specified context model

• Aggregation– Report server aligns data– Report server performs intermediate calculations

• Rendering– Report server renders formatted report


Contextualization• Traditional Batch

– S88 Procedural Model (recipe driven)

• Continuous– RTD Model Driven

Material Tracing

Model based


Example Report – Tablet API Tracing


Summary• The evolution of traditionally batch oriented processes to continuous manufacturing

introduces challenges related to product traceability• Residence Time Distribution (RTD) models enable the application of traditional batch

reporting and analysis techniques to continuous manufacturing processes• Contact Information:

– Paul Brodbeck, QbD Process Technologies, Inc., [email protected]

– Bob Engel, Informetric Systems Inc., [email protected]– Ravendra Singh, Rutgers University, [email protected]– References:

• “Modeling of Residence Time Distribution in Continuous Solid Oral Dose Pharmaceutical Manufacturing Processes”. AIChE Annual Meeting. M. Sebastian Escotet-Espinoza, Amanda Rogers, Fernando J. Muzzio and Marianthi Ierapetritou. Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ

mailto:[email protected]



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