MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CONTINUOUS QUALITY VERIFICATION (CQV) G.K.Raju,...

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

CONTINUOUS QUALITY VERIFICATION

(CQV)

G.K.Raju, Ph.D.Pharmaceutical Manufacturing Initiative (PHARMI),

MIT Program on the Pharmaceutical Industry,Massachusetts Institute of Technology

July 2001


Objective: To Describe the Opportunity to Improve

Pharmaceutical Manufacturing Performance

MIT Pharmaceutical Manufacturing Initiative

Research Development Manufacturing Marketing


Pharmaceutical Manufacturing

Research Development Manufacturing Marketing

BulkActive

BulkFormulation

Filling &Finish

PackagingInboundLogistics

OutboundLogistics


HORIZONTAL APPROACH

STUDYING PHARMACEUTICAL MFG:VERTICAL VS. HORIZONTAL APPROACH

BulkActive

BulkFormulation

Filling/Tableting

Packaging/Finishing

BulkActive

BulkFormulation

Filling/Tableting

Packaging/Finishing

Plant A

BulkActive

BulkFormulation

Filling/Tableting

Packaging/Finishing

BulkActive

BulkFormulation

Filling/Tableting

Packaging/Finishing

Plant B

Plant A

Plant B

VERTICAL APPROACH


BulkActive

BulkFormulation

Filling/Tableting/ etc.

Packaging/Finishing

BulkActive

BulkFormulation


Packaging/Finishing

Company A

Company B

Company CBulkActive

BulkFormulation


Packaging/Finishing

THE HORIZONTAL APPROACH

PHARMACEUTICAL MANUFACTURING


DESCRIBING THE OPPORTUNITYIN

ROUTINE MANUFACTURING

CONTINUOUS QUALITY VERIFICATION (CQV)


WHICH PROCESSES?

PROCESS CYCLE TIMES

In Process Development

In Routine Manufacturing

Biggest Impact Here?Time-to-marketEnablingPotent Products

Place for Validation?Potent ProductsDifficult ProcessesHigh Volume ProductsProducts with Tough QC TestsGeneric Competition


PROCESS A WITH QC TESTS

WEIGHING WETGRANULATION

STEP FB DRY

STEP

BLEND

ENCAPSULATESIEVE

• API• MICRO

• Particle Size • Description• ID• Assay• CU• Impurity• Dissolution• MICRO

QC1 QC3 QC4

DRY MIX

QC2

• LOD


PROCESS A WITH CYCLE TIMES

WEIGH WETGRANULN

ProcessingFB DRY

STEP

BLEND

ENCAPSULATESIEVE

• API• MICRO

• Particle Size

• Description• ID• Assay• CU• Impurity• Dissolution• MICRO

QC1

QC3

QC4

DRY MIX

QC2

• LOD

7 DAYS 13 DAYS

< 3 DAYS


PROCESS B WITH QC TESTS

CHEMICAL WEIGHING

BLEND FILL CAPSULES BOTTLEPACKAGING

• API• OVI

• Description• ID• Assay• CU• Impurity• Dissolution

QC1 QC2


PROCESS B WITH CYCLE TIMES

CHEMICAL WEIGHING

BLEND FILL CAPSULES

BOTTLEPACKAGING

• API• OVI


QC1 QC2

7 DAYS14 DAYS

17 DAYS


PROCESS C WITH QC TESTS

WEIGHING

GRANULATION

FB DRY

STEP

BLEND

FILMCOATING

COMPRESS BOTTLEPACKAGING

• API • Particle Size• LOD


QC1 QC2 QC2


PROCESS C WITH CYCLE TIMES

WEIGHING

GRANULATION

FB DRY

STEP

BLEND FILMCOATING


• API • Description• ID• Assay• CU• Impurity• Dissolution

QC1 QC2

21 DAYS

6 DAYS 14 DAYS


PROCESS D WITH QC TESTS

CHEMICAL WEIGHING

GRANULATION

Processing

STEP

BLEND 1: BLEND 2: PRE- BLEND

FINALBLEND

FILMCOATING


• API • Particle Size• LOD


QC1 QC2 QC3


PROCESS D WITH CYCLE TIMES

QC1

BLEND 2: PRE-BLEND

CHEMICAL WEIGHING

GRANULATION

PROCESSING

STEP

BLEND 1: FINALBLEND

COMPRESS

FILMCOATING

BOTTLEPACKAGING

QC2 QC3

15 DAYS10 DAYS

20 DAYS 15 DAYS

60 DAYS


• Particle Size• LOD

• API


PROCESS D WITH QC TESTS:Cycle Times including BULK ACTIVE

QC1

BLEND 2: PRE-BLEND

CHEMICAL WEIGHING

GRANULATIONSTEP

BLEND 1:FINALBLEND

COMPRESS

FILMCOATING

BOTTLEPACKAGING

QC2QC3

15 DAYS10 DAYS

20 DAYS 15 DAYS

60 DAYS 21-90 DAYS

PROCESSING


PROCESS D WITH QC TESTSCycle Times

QC1

BLEND 2: PRE-BLEND

CHEMICAL WEIGHING

GRANULATION

PROCESSING

STEP

BLEND 1: FINALBLEND

COMPRESS

FILMCOATING

BOTTLEPACKAGING

QC2QC3

15 DAYS10 DAYS

20 DAYS 15 DAYS

60 DAYS

0

5

10

15

20

QC1 PFD QC3 Release

Actual

Target

Potential


WHAT DRIVES THE QC TESTING TIMES?

0

5

10

15

20

QC1 PFD QC3 Release

Actual

Target

Potential

• Sampling• Batching• Other Products• Waiting• Coordinating

• Other Products• Other Paperwork• Waiting• Coordinating

2%

TEST


WHICH PROCESSES?

PROCESS CYCLE TIMES






PROCESS E WITH QC TEST POINTS

WEIGH DRY MIX WET GRANULN

WET GRANULN FL BED DRY MILL

MILL

STOREDRY SIFT WET GRAN MIX MIX

COAT

STORE

MILL

SIFT

STORE

BLEND BLEND BLEND BLEND STORE BOTTLE FILL

DRY

MIX MIX GRANUL DRY MILL

MILL

ACTIVE INITIAL GRANULATION STAGE

SECOND GRANULATION STAGE COATING STAGE

EXCEPIENT PREPARATION STAGE

SIFT&BLEND STAGE BLEND&FILL STAGE

QC4QC3QC2

QC1

LOD

LOD LOD

LOD


PROCESS E WITH QC TEST TIMES

ACTIVE

FIRST GRAN

SECOND GRAN

QC1

7 days

COAT SIFT&BLEND

BLEND

QC4QC3QC2

FILL

7 days7 days3 days

< 1 day

< 1 day

1-2 days

< 1 day

< 1 day

< 1 day


WHICH PROCESSES?

TOWARDS PARAMETRIC RELEASE






PROCESS F: LIQUID LINE

WEIGH

pH ADJ COMPOUND

FILTER

FILL STOPPER CAP

LABEL/PKG

TERMINALSTERILIZATION

WEIGH

WEIGH

VIALS

STOPPERSWFI

BUFFER

WASH

WASH AUTOCLAVE

DEPYROGEN

SEALS

• Appearance• ID• Assay • Impurity• Fill Vol, Osmolarity, Partic.• Endotoxin• STERILITY TESTING

• ENVIRO. MONITORING

• BIOBURDEN

• WFI TESTING• Endotoxin• TOC

• ID

• ID

• pH • Visual Check• Wt Check

• QC Check

• QC Check• QC Check


PROCESS F: LIQUID LINE WITH CYCLE TIMES

10 days

7 days• ENVIRONMENTAL MONITORING

• BIOBURDEN TESTING

17-20 days

7 days

3-4 days

• STERILITY TESTING

• WFI TESTING

3-4 months


PERCEIVED PROCESS CYCLE TIMES:SUMMARY

Process Process MICRO Optimized Process QC QC:ProcessFlow Type Test? Process? Cycle Time Cycle Time Time

A High Vol. Y Y 3 20 6.7B High Vol. N N 17 21 1.2C High Vol. N N 21 20 1.0D High Vol. N N 20 25 1.3E Variable N Y 7 24 3.4F Parentals Y N 3 20 6.7


CYCLE TIME COMPONENTS

STEPS IN THE PROCESS/PLANT IN QC/QAProcess/Unit operation

Interruption of the process

Securing of sample from process

Holding of sample in plant

Documentation and verification of sampling

Transferring of samples to QC lab

Batching of samples in QC

Preparation of test samples

Actual test - separation

Actual test - measurement

Test data collection and processing

Documentation and verification of testing

Transferring of results for review

Decision regarding impact on process

Process/Process Step Primarily Manual OperationInventory Hold Actual test


ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES

STEPS IN THE PROCESS/PLANT IN QC/QA

Process/Unit operation

Interruption of the process

Securing of sample from process

Holding of sample in plant

Documentation and verification of sampling

Transferring of samples to QC lab

Batching of samples in QC

Preparation of test samples

Actual test - separation

Actual test - measurement

Test data collection and processing

Documentation and verification of testing

Transferring of results for review

Decision regarding impact on process

Process/Process Step Primarily Manual OperationInventory Hold Actual test

On-line LIF, NIR, Pattern Recognition, etc.


CQV OPPORTUNITY IN ROUTINE MANUFACTURING

• Quality Monitoring is Discontinuous• QC testing times are approximately = 1 month• Factor of 20-25 opportunity in cycle time: Process• Factor of 20-25 opportunity in cycle time: QC• QC Cycle Times >= Process Cycle Times• Time is driven by off-line nature of test• Exception is MICRO test

SUMMARY


DESCRIBING THE OPPORTUNITYIN PROCESS DEVELOPMENT



BulkActive

BulkFormulation

Filling &Finish Packaging

BulkActive

BulkFormulation


BulkActive

BulkFormulation


Company A

Company B

Company C

THE VERTICAL APPROACH

BlendingDryingGranulation

Fermentation Rapid MicrobialDetection

FlowTabletingTransport


BulkActive

BulkFormulation


BulkActive

BulkFormulation


BulkActive

BulkFormulation


Company A

Company B

Company C

VERTICAL ANALYSIS I:BLENDING UNIT OPERATION

Eg. Blending


WHICH PROCESSES?

PROCESS CYCLE TIMES






FOCUS

Explore the Potential Impact of On-line Monitoring Technology on Blending

Process Development

MIT Pharmaceutical Manufacturing Initiative


Blending Operation Model

Blender cleaning

8

Mixing

Active ingredient

Excipients

Raw material load8 8

Sampling

Transporting

Homogeneity test

OK?

Results & Decision Making

Undermixedmix-longer

Homogeneous

Next batch

Discarded

Next batch

Analysis


LIGHT INDUCED FLUORESCENCE SYSTEMFOR THE DETERMINATION OF THE

HOMOGENEITY OF DRY POWDER BLENDING

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 10 20 30 40 50

Number of Rotations

LIF

Sig

na

l Un

its

A: 5% T/L

B: 5% T/L

C: 5% T/L

PHARMACEUTICAL MANUFACTURING:LIF FOR ON-LINE MONITORING OF BLENDING


LIF VERIFICATION STUDIES

Established a correlation between LIF assessment of homogeneity and thief-sampling with off-line analysis

0

1

2

3

4

5

6

4.75% 3.22% 1.64%

Run Batch

En

d P

oin

t D

ete

rmin

ati

on

LIF % Triamterene A

LIF % Triamterene B

Thief Assay A

Thief Assay B


PROCESS D: BLENDING PROCESS DEVELOPMENT

CHEMICAL WEIGHING

GRANULATION

Processing

STEP

BLEND 1: BLEND 2: PRE- BLEND

FINALBLEND

FILMCOATING


Mixing Of 1:10 Triamterene-Lactose @ 70% Fill & 27.4 RPM

05

10152025303540

0 50 100 150 200 250 300

Number of RotationsP

MT

Sig

nal

s, V

olt

s

• OFF LINE QC TEST

• ON LINE SENSOR


Raw Materials Sampling Transport Analysis

Results &Decision making

Reprocessed Discarded Well Blended

Information Flow

Materials FlowR/D/W

Process knowledge

Waiting Stock

Blending

a- Process Development

b- manufacturing

Blending Operation: Two Technologies, Two ApproachesProcess Development, Validation and Manufacturing

On-lineInformation Feedback

Well Blended

Discarded

Analysis &Decision making

Blending

Raw Materials

OF

F L

INE

ON

LIN

E


Blending Data Collected from CAMP Companies

Operation Characteristics

Low Medium High

Cleaning time (min) 20

10

6

250

35

18

480

60

30

60 90 120

6

20

2

30

250

25

60

480

48

Loading time (min)

Discharge time (min)

Sampling time (min)

Transport time (min)

QC Testing time (min)

QC Holding time (min)


Results

Blending PerformanceProcess Development and Validation

6% no wait between blends

1 Blend 2 Blends 3 Blends

Best

Med.

Worst

2.32

13.19

25.82

0.36

1.31

2.57

4.96

23.45

43.40

0.68

1.93

3.56

8.45

30.65

56.17

1.07

2.41

4.46Tim

e (d

ays)


Impact of the number of blends on total process time

1.31 1.93

13.19

30.6523.45

2.41

0

10

20

30

40

50

60

1 2 3

Number of blends

Tim

e (d

ays)

Avg Off line Avg On line

Blending PerformanceProcess Development and Validation


APPROACH TO LEARNING:

Current Approach Proposed Approach

xx x

x

x

x

x

x

x

x

x

x

xx

xxxx

x

x

xxx

x

xxxxxx

xxxxxxxxxxxx

x

xxxxxxxxx

xxxxxxxxxx

xxxxxxxxxxxx

xx

x

Process Development

Commercial Production

1a

1b

2a

2b

Consequences on Process Development & Commercial Production


CQV Opportunity in Process Development

• Process development can be on the critical path• Factor of 10-15 reduction in cycle time in blend

process development (maybe more..)• Variability reduction in blend process dev. time

• independence of organization/product -> predictability…

• Benefits not restricted to use of new on-line sensors• improvement data analysis of existing sensor data• use of this for experimental design

SUMMARY


WHAT ARE THE IMPLICATIONS?



FDA

Pharmaceutical Companies

CAMP

Purdue MIT

• Abbott

• Aventis

• Bristol-Myers Squibb

• Johnson & Johnson

• Hoffmann-La Roche

• Glaxo SmithKline

• Wyeth-Ayerst

Consortium for the Advancement of Manufacturing in Pharmaceuticals (CAMP)

Vendors


PROCESS A WITH CURRENT QC TESTS AND NEW POSSIBILITIES

WEIGHING WETGRANULATION

STEP FB DRY

STEP

BLEND

ENCAPSULATESIEVE

• API• MICRO

• Particle Size • Description• ID• Assay• CU• Impurity• Dissolution• MICRO

QC1 QC3 QC4

DRY MIX

QC2

• LOD


Need to Focus on Both Material Flow and Information Flow

BulkActive

BulkFormulation


Packaging/Finishing

Sensor1 (or QC test1)

YXY1 Y2 Y3

t 1 t 2 t 3 t 4

Y4

t

Sensor2 (or QC test2) Sensor3 (or QC test3) Sensor4 (or QC test4)

INFORMATION FLOW

MATERIAL FLOW


Manufacturing Information Management: Has Hardware and Software Components

BulkActive

BulkFormulation


Packaging/Finishing

Sensor1 (or QC test1)

YXY1 Y2 Y3

t 1 t 2 t 3 t 4

Y4

t

Sensor2 (or QC test2) Sensor3 (or QC test3) Sensor4 (or QC test4)

0

2

4

6

8

10

12

14

16

18

20

0 50 100 150 200 250

Readings @ 0.375 seconds

Flu

ore

scen

ce S

ign

als,

vo

lts

1:10 powder flow

1:20

y = 1.9757x + 0.4886

R2 = 0.99830.00

5.00

10.00

15.00

20.00

25.00

0.0 2.0 4.0 6.0 8.0 10.0 12.0

% of Triamterene

PMT

Sign

al, v

olts

Mixing Of 1:10 Triamterene-Lactone @ 85%

Fill (10g) And 27.4 RPM

0

5

10

15

20

25

30

35

40

0 50 100 150 200 250 300

Number of Rotations

Sig

nal

s, v

olt

s

0

5

10

15

20

25

30

35

0 50 100 150 200

Number of Readings @ 0.375 s/reading

Sig

nal

, vo

lts

10%

5%

1%

0.5%0.1%

• Fast Response• On-Line• Real-Time• Accurate• Robust

• Rapid Rate of Learning• Short Cycle Times• Benchmarking• Modeling• Continuous Problem Solving


BulkActive

BulkFormulation


BulkActive

BulkFormulation


BulkActive

BulkFormulation


Company A

Company B

Company C

HORIZONTAL AND VERTICAL APPROACHES

BlendingDryingGranulation

Fermentation Rapid MicrobialDetection

FlowTabletingTransport

High Vol

Variable

Liquids


CQV: BENEFITS

• Data Mining of Process Data

• Data -> Information -> Knowledge

• Rationale for New Sensors

• Variable Categorization: PCCPs, etc.

• Basis for Specifications, Batch Record Design

• Basis for Experimental Design, Etc. …


Learning Curve: Cycle Times

Total cycle time

10

100

1000

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700

batch #

days

Accelerated Learning Curve Facilitated ByContinuous Quality Verification


CQV: SO WHAT?

• On-line sensors doing the same thing will have only incremental impact

• This impact will still be only incremental even if there is an MES/EBR system

• Data Warehousing focused on exceptions canhave a large impact

• On-line sensors + EBR + Data Warehousing can fundamentally change pharma. mfg.


PRODUCT LIFE CYCLE: OPPORTUNITIES

7:15 AM Tue, Mar 02, 1999

1.00 8.25 15.50 22.75 30.00

Years

1:

1:

1:

-141.04

114.92

370.88

1: NET INCOME 2: NET INCOME 3: NET INCOME

1

1

1

2

2

2

2

3

3

3

3

Net Income (Untitled Graph)

Reduction of time-to-market

Reduction ofmanufacturing cost


Pharmaceutical Manufacturing:Opportunity Areas

• Manufacturing: Cost --> Profit

• Organizational focus: Functional --> Process

• Optimization: Local --> Supply chain

• Inventory Management: JIC --> JIT

• Cost of Quality: Inspection --> Prevention

KEY TECHNOLOGY OPPORTUNITY: On-line Sensors+EBR+Data Warehousing!


ACKNOWLEDGEMENTS

• Professor Charles Cooney (MIT)

• Professor Stephen Byrn (Purdue)

• CAMP


NOTE ON CONTEXT

• This presentation does not necessarily represent the views of MIT, Purdue or CAMP

• Some data have been disguised for reasons of sensitivity and confidentiality

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) CONTINUOUS QUALITY VERIFICATION (CQV) G.K.Raju,...

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