pat initiative – pilot project api production gerhard korb...

PAT Initiative – Pilot Project API Production

G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt

Gerhard Korb

Sanofi-Aventis Deutschland GmbH

Process Development Chemistry

Chemical & Particle Engineering

Frankfurt



Summary

• Tools - Definition

• Example

• Additional PAT Elements

• Resources/Infrastructure

• Cooperation with the FDA (POV)

• PAT Comparability Protocol

• Learning experience



Sanofi-Aventis PAT Tools

Sensors

Data

Analysis

Design for Quality

ProcessControl

Inferential•pH, pressure, tempDirect•NIR, Raman, NMR

•Feed-Forward•Feedback•Multivariate Control•Continuous Processes

•DOE•FMEA•Qualification•Validation

•Univariate•Multivariate•Real-Time•On Location



Overview – Definition: PAT System

Current Test• off-line

Alternate Test*• at-line• same specs• same sample size• near real-time

control• backed-up by lab

test• etc.

PAT PAT MeasurementMeasurement System*System*•• onon--line or inline or in--lineline•• differentdifferent acceptance criteriaacceptance criteria•• differentdifferent sample sizesample size•• realreal--time releasetime release•• feed back / forwardfeed back / forward•• increased increased 'knowledge''knowledge'•• PAT submissionPAT submission•• etc.etc.PA

T-Ap

proa

ch

like-for-likeapproach

PAT SystemApproach

Like-for-like can mean: using modern sensor technology not integrated in a PAT system.

PAT SystemApproach



Options to implement PAT

A. Currently marketed “robust” products. PAT to improve efficiency (minimalimprovement in quality assurance)*

B. Currently marketed products that needimprovement. Step-wise PAT approach -First improve quality and then improveefficiency

C. New products. PAT utilized throughoutdevelopment and scale-up. Lab basedtests to ensure shelf-life and/or forestablishing “public standards”.

IO Pilot

R & D



Project overview – API production and DP manufacturing

DP1

Wet Granulationacitve

Excipients

DP2

Drying

CompendialTesting

processparameters

Control

process parameters

Control

LOD

DP4

Blending/Lubrication

processparameters

Control

Powder Fineness

DP5

Compression

processparameters

Control

WeightHardnessThickness

DP6

Film Coating

processparameters

Final Product

Avg Tablet WeightBulk Physical Defects

Control

Bulk Physical DefectsFriability

Spec TestingID

AssayWaterCU

DegradentsDissolution

PAC

PAC

PAC PAC

PAC

proposedPAT System

IP 6

API Hydrate

API

API (milled)

NIR (reagentcontent)

NIR (Processcontrol)

Laser Diffraction(Process Control)

RM IP 1

IP 3

IP 2

SM IP 5

IP 4NIR

NIR(distillation)

NIR(turnover)

NIR

GC (off-line)GC (off-line)

IR (off-line)

HPLC (off-line)

Base titration (off-line)

Water contentKarl Fischer (off-line)

Particle Size andSSA (off-line)

Current Analytical Method



Projekt API production - Overview

proposedPAT System

IP 6

API Hydrate

API

API (milled)

NIR (reagentcontent)

NIR (Processcontrol)Laser Diffraction

(Process Control)

RM IP 1

IP 3

IP 2

SM IP 5

IP 4NIR

NIR(distillation)

NIR(turnover)

NIR

GC (off-line)GC (off-line)

IR (off-line)HPLC (off-line)

Base titration (off-line)

Water contentKarl Fischer (off-line)

Particle Size andSSA (off-line)

Current Analytical Method



Example – Intermediate: Overview ReactionSide reaction

A + B CA + D E

100%

Example

50%

5%0%

Sampling

Conversion

ContentA

Reaction90 – 120 °C/3 bar

In-line NIR

On-lineReaction timeOff-line sampling(HPLC)



Example – Intermediate: Situation without PAT

Parameter-Nitrogen flow-Heating-Dosage B Off-line Test

-Main product-Hydrolysis by product

IntermediatePre step Next step



Example – Intermediate: PAT Approach

IP 6

API Hydrate

API

API (milled)

RM IP 1

IP 3

IP 2

SM IP 5

IP 4

Optimal conversionAvoiding hydrolysis

Minimaziationdecomposition

Reduction of variability ofRelated substance

Minimaziation E

Minimaziation F

Minimaziation G



Example – Intermediate: PAT Approach

NIR In-line-Content Water

-Content A-Nitrogen flow-Heating-Dosage B

IntermediatePre step Post step



Example – Intermediate: Information from NIR spectra

Water content

Content A



Example – Intermediate: Scale Up/Scale Down

Dosage B

NIR



Example – Intermediate: Scale Down/Scale Up

NIR Sensor

Nitrogenflow Hydrodynamic!



Example – Intermediate: Implementation

To PCS Non Ex Zone Ex Zone



Generell Procedure for implementation of PAT tools

Scale Down

Feasibility

Model Validation

Implementation

Laboratoryconditions

Conditions inProduction plant

T, p, ..... constant T, p, .....variabel

Process Monitoring

Process Control



0

20

40

60

80

100

120

19.0

8.20

04 2

1:00

:00

19.0

8.20

04 2

1:38

:15

19.0

8.20

04 2

2:16

:30

19.0

8.20

04 2

2:54

:45

19.0

8.20

04 2

3:33

:00

20.0

8.20

04 0

0:11

:15

20.0

8.20

04 0

0:49

:30

20.0

8.20

04 0

1:27

:45

20.0

8.20

04 0

2:06

:00

20.0

8.20

04 0

2:44

:15

20.0

8.20

04 0

3:22

:30

20.0

8.20

04 0

4:00

:45

20.0

8.20

04 0

4:39

:00

20.0

8.20

04 0

5:17

:15

20.0

8.20

04 0

5:55

:30

20.0

8.20

04 0

6:33

:45

20.0

8.20

04 0

7:12

:00

20.0

8.20

04 0

7:50

:15

20.0

8.20

04 0

8:28

:30

20.0

8.20

04 0

9:06

:45

20.0

8.20

04 0

9:45

:00

20.0

8.20

04 1

0:23

:15

20.0

8.20

04 1

1:01

:30

20.0

8.20

04 1

1:39

:45

20.0

8.20

04 1

2:18

:00

20.0

8.20

04 1

2:56

:15

20.0

8.20

04 1

3:34

:30

20.0

8.20

04 1

4:12

:45

20.0

8.20

04 1

4:51

:00

20.0

8.20

04 1

5:29

:15

0

2

4

6

8

10

12

Content Water ppm (NIR)Content p-CPKE coarse modelTemperature reactorHCl mass (kg)Content p-CPKE release modelpressure (bar)

Water (NIR)

Content A Release model (NIR, Model validated

Mass B

Content A Coarse model (NIR)

Temperature

Pressure

Example – Intermediate: Data integration



Example – Intermediate: Variability Content A Control chart: batches produced in 2004 (without PAT)

HP

LC: c

onte

nt p

-CP

KE

(%)

CTR = 0,76UCL = 2,31

LCL = -0,78D

0692

D07

03

D07

14

D07

25

D07

36

D07

47

D07

58

D07

69

D07

80

-0,8

0,2

1,2

2,2

3,2

4,2

Control chart: batches produced in 2004 (with PAT)

HP

LC: c

onte

nt p

-CP

KE

(%)

CTR = 0,46UCL = 1,09

LCL = -0,16

D 0

790

D 0

801

D 0

812

D 0

823

-0,8

0,2

1,2

2,2

3,2

4,2

Control chart: batches produced in 2004 (with PAT)

NIR

: con

tent

p-C

PK

E (%

)

CTR = 0,49UCL = 1,11

LCL = -0,13

D 0

790

D 0

801

D 0

812

D 0

824

-0,8

0,2

1,2

2,2

3,2

4,2

Batches 2004 without NIR

Monitoring Final ImplementationHPLC NIR



Example – Intermediate: Variability G in API

Fexofenadin gemahlen (Gehalt Isopropyl-Analog)

Geh

alt (

%)

CTR = 0,01

UCL = 0,02

LCL = 0,01

Spezifikation: <= 0,15 %L7

32L7

53L7

74L7

95L8

16L8

37L8

58L8

79L9

00L9

21L9

42D

963

D98

4D

007

D02

8D

049

D07

0D

091

00,010,020,030,040,050,060,070,080,09

0,10,110,120,130,140,15

Content related substance in API



Example – Intermediate: Results

• Measurement of differnet substances

(Water + A) with one sensor Reduction von Investitment

• Optimal reaction conditions Yield improvement

• Monitoring of Water and conversion Minimaziation of by products

• Batch release by operators Cycle time reduction

• Reduction of variability Quality improvement/Risk minimaziation

• Avoiding of sampling Improvement of operators safety

Return On Investment? Payback



Additional PAT Elements: System Performance (NIR)SPEKTROMETER COMPUTER EXTERNE SYSTEME

Control Module

Start / StopMeasurement

4 ... 20 mA,

ProfiBus

Industry-PCOPUS-Software-Modules

Data

SENSOR

FO

Conection box

Light source Spectra

File Server

PCS



Additional PAT Elements: Model generation/Validation NIR

Model generation and Model validation

Sensor calibration

System CalibrationMethod Transfer/Monitoring

Long term satability

NIR-Water content-Content A

Method PAT Laboratory Plant

Spectral Information Model Chemometry Test/Validation

Documentation

Transfer



Additional elements: Risik analysis

Measurement

PeopleMachine

Variability (Water, pCPKE) NIR

Method

Automation

Material

Piping

P-CPKE

Sensor design/location

Length

NIR

Humidity (Heptan)

Reactor

Agitator

Temperature/Pressure settings

Volumetric rate

Material of construction

Calibration

Maintenance

Performance

Operatop‘s error

No Training

Carelessness

No process understanding

Nitrogen blowing

Nitrogen volumetric rate

Calibration/Maintenance

Controler settings HCl cylinder

Agitator speed

Toluene

Sampling System

Process/System p-CKE Area Affected: p-CKE production IC14 Prepared ByPAT TeamResponsible Team: PAT Team Product: Fexofenadine HCl FMEA Date (20. Aug 04

Other Areas InvoProduction, Engineering, Quality Quality Control NA FMEA Date (Draft; 26. Aug. 2004

PROCESS FUNCTION

POTENTIAL FAILURE

MODE

POTENTIAL FAILURE EFFECT

POTENTIAL FAILURE CAUSE

Current Controls in

Place

Current Detection Method

Recommended

Action(s)

Area/Individual

Responsible for Action

and

Action Results

Action(s) Taken

SEV

OC

C

QQQQQ

QQQ

Potential Failure Mode and Effects Analysis

Effect Severity

Occurence of C

ause

Detectability

RPN

Effect Type Q S B

Gehalt A

• Fishbone• FMEA• FTA• ...........



Resources for PAT Project:• Programmer

• Database Expert

• Material Characterization Scientist

• Statistician

• Manufacturing Leader

• Operators

• Regulatory specialist

• PAT Project Leader

• Analytical Development Scientist

• Chemometrician

• Spectroscopist

• Process Engineer

• Process Control Engineer

• Quality Leader



Infrastructure for PAT Project

Dioden Array NIR

Dioden Array UV/VIS

Turbitidy

Reactor control

Computer FT-NIR

FT-NIR withMultiplexer

Sensor

10 l HC4 Reactor

PCS



Cooperation with the FDA: Chronologie

• Mai 2003 Presentation of the project (Rockville, MD)

• Nov 2003 – Juli 2004 Discussion of CP drafts with PATRIOT

• Aug 2004 FDA Pre Operational Visits (KC, FFM)

• Okt 2004 PAT CP (Comparability Protocol) Submission

• Dez 2004 PAT CP Approval



Cooperation with the FDA: Pre Operational Visits (POV)

DP manufacturing and API production

•Technologies und scientific approach-Measurement systems, Data models, Development reports.......

•Industrialisation-Vendor selection, Data architecture.......

•Process-Prozess understanding, Risik analysis........

•Methodology-Calibration, Qualification, Documentation, Training.........



Learning experience from PAT Pilot Project

• Use of New Technologies in lab and production

• Generation of Models for Prediction of properties, .......

• Data Analysing/Risk Analysis

• Calibration/Qualification/Validation of In-/On-line measurements

• Transfer of Analytical Methods from Laboratory to Plant

• Working in Multidisciplinary Teams

• To cooperate with regulatory bodies like FDA



Take Home Message:Multidisciplinary Team Approach necessary

to have success

pat initiative – pilot project api production gerhard korb...

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