PHARMACEUTICAL MANUFACTURING...MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Blending...

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PHARMACEUTICAL MANUFACTURING:NEW TECHNOLOGY OPPORTUNITIES..

G.K.Raju, Ph.D.Executive Director,

Pharmaceutical Manufacturing Initiative (PHARMI),MIT Program on the Pharmaceutical Industry,

Massachusetts Institute of Technology

November 16th 2001


OUTLINE

• MIT Pharmaceutical Manufacturing Initiative • Process Development

• Blending: On-line blend uniformity• So what?

• Routine Manufacturing• Where is the time spent “on average”?• Looking beyond the “average”• So what?

• Pharmaceutical Manufacturing: • The New Technology Opportunity


MIT Pharmaceutical Manufacturing Initiative

Objective: To Describe and Capture the Opportunity to Improve Pharmaceutical Manufacturing Performance

Development Manufacturing MarketingResearch


Pharmaceutical Manufacturing:Context of Experiences..

FDAFood & DrugAdministration

MIT:MIT Pharma Mfg Initiative

(PHARMI)

G.K. Raju, Ph.D.

CAMPConsortium

For The Advancement Of

Manufacturing ForPharmaceuticals

Purdue Univ:Dept of Industrial & Physical Pharmacy


Pharmaceutial Manufacturing

ACTIVE FORMULN FILL/FINISH PACKAGE



RESEARCH

DEVELOPMENT

MANUFACTURING

SPACE

TIME


Pharmaceutial Manufacturing Performance

ACTIVE FORMULN FILL PACK



RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACECOST

QUALITY

TIME

SAFETY


OUTLINE







SPACE

ACTIVE FORMULN

ACTIVE FORMULN FILL


RESEARCH

DEVELOPMENT

MANUFACTURING

PACK

FILL PACK

TIMEBlending


Blending Operation Model

8

Mixing

Active ingredient

Excipients

Raw material load8 8

Sampling

Transporting

Homogeneity test

OK?

Results & Decision Making

Analysis

Undermixedmix-longer

Homogeneous

Next batch

Blendercleaning

Discarded

Next batch


PHARMACEUTICAL MANUFACTURING:LIF FOR ON-LINE MONITORING OF BLENDING

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

Sign

al U

nits

A: 5% T/LB: 5% T/LC: 5% T/L


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

End

Poin

t Det

erm

inat

ion

LIF % Triamterene ALIF % Triamterene BThief Assay AThief Assay B


OUTLINE






STEP

BLEND 1: BLEND 2:PRE-BLEND

FINALBLEND

COMPRESS

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

05

10152025303540

0 50 100 150 200 250 300

Number of RotationsPM

T Si

gnal

s, V

olts

• OFF LINE QC TEST

• ON LINE SENSOR

PROCESS D: BLENDING PROCESS DEVELOPMENT

CHEMICAL WEIGHING

GRANULATION

Processing

FILMCOATING

BOTTLEPACKAGING


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

Raw Materials Sampling Transport Analysis

Results &Decision making

Reprocessed Discarded Well Blended

Information FlowMaterials FlowR/D/W

Process knowledge

Waiting Stock

Blending

a- Process Developmentb- manufacturing

OFF

LIN

EO

N L

INE

On-lineInformation Feedback

Well Blended

Discarded

Analysis &Decision making

BlendingRaw Materials


Blending PerformanceProcess Development and Validation

Impact of the number of blends on total process time

1.31 1.9313.19

30.6523.45

2.410

10

20

30

40

50

60

1 2 3Number of blends

Tim

e (d

ays)

Avg Off line Avg On line


On-Line Blend Uniformity Opportunity in Process Development

SUMMARY

• Large (Factor of 10-15) reduction in cycle timein blend process development

• Large variability reduction in blend process development time

• Independence of organization/product -> predictability


OUTLINE










RESEARCH

DEVELOPMENT

MANUFACTURING

SPACE

Which Products?High VolumeComplexLiquid

TIME


PROCESS A WITH QC TESTS

WEIGHING

QC1

WETGRANULATION

STEP FB DRY

STEP

BLEND

ENCAPSULATESIEVE

QC3

DRY MIX

• API• MICRO

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

QC4QC2

• LOD


PROCESS A WITH CYCLE TIMES

< 3 DAYS

WEIGH WETGRANULN

STEP ENCAPSULATESIEVE

• Particle Size

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

QC1

QC3QC4

QC2

• LOD

7 DAYS

ProcessingFB DRYBLENDDRY MIX

13 DAYS

• API• MICRO


PROCESS D WITH QC TESTS

CHEMICAL WEIGHING

QC1

GRANULATION

Processing

STEP

BLEND 1: BLEND 2: BOTTLEPACKAGING

QC2 QC3

FILMCOATING

PRE-BLEND

FINAL COMPRESSBLEND

• API • Particle Size• LOD

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


PROCESS D WITH CYCLE TIMES

QC1

CHEMICAL WEIGHING PROCESSING BLEND 1: FINAL

BLENDCOMPRESS

FILMCOATING

BOTTLEACKAGING

QC2 QC3

10 DAYS

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

• Particle Size• LOD

BLEND 2:PRE-BLEND

GRANULATION STEP

P

15 DAYS

20 DAYS 15 DAYS

• API

60 DAYS


PROCESS D WITH QC TESTS:Cycle Times including BULK ACTIVE

CHEMICAL WEIGHING BLEND 1:FINAL

BLENDCOMPRESS

FILMCOATING

BOTTLEPACKAGING

QC2

15 DAYS10 DAYSPROCESSING

QC1

BLEND 2:PRE-BLEND

GRANULATIONSTEP

QC3

20 DAYS 15 DAYS

60 DAYS21-90 DAYS






RESEARCH

DEVELOPMENT

MANUFACTURING Which Products?High VolumeComplexLiquid

SPACE

TIME


PROCESS E WITH QC TEST TIMES

ACTIVE

FIRST GRAN

SECONDGRAN

QC1

7 days

COAT SIFT&BLEND

BLEND

QC4QC3QC2

FILL

3 days 7 days 7 days

< 1 < 1 day day

1-2days day

< 1 < 1 day

< 1 day






RESEARCH

DEVELOPMENT

MANUFACTURING Which Products?High VolumeComplexLiquid

SPACE

TIME


PROCESS F: LIQUID LINE WITH CYCLE TIMES

7 days• ENVIRONMENTAL MONITORING

10 days

3-4 days

• WFI TESTING

3-4 months

• STERILITY TESTING

17-20 days

7 days

• BIOBURDEN TESTING


OVERALL CYCLE TIMES:QC TESTING TIMES ARE SIGNIFICANT

0

5

10

15

20

25

TIME (Days)

A B C D E FPROCESS CASE STUDY

Overall Cycle Time Components

Process TimesQC Testing Times


CYCLE TIME COMPONENTS

STEPS IN THE PROCESS/PLANT IN QC/QAProcess/Unit operationInterruption of the processSecuring of sample from processHolding of sample in plantDocumentation and verification of samplingTransferring of samples to QC labBatching of samples in QCPreparation of test samplesActual test - separationActual test - measurementTest data collection and processingDocumentation and verification of testingTransferring of results for reviewDecision 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/QAProcess/Unit operationInterruption of the processSecuring of sample from processHolding of sample in plantDocumentation and verification of samplingTransferring of samples to QC labBatching of samples in QCPreparation of test samplesActual test - separationActual test - measurementTest data collection and processingDocumentation and verification of testingTransferring of results for reviewDecision regarding impact on process

Process/Process Step Primarily Manual OperationInventory Hold Actual test

On-line LIF, NIR, Data Analysis, etc.


WHAT DRIVES THE QC TESTING TIMES?

0

5

10

15

20

QC1 PFD QC3 Release

ActualTargetPotential

2%

• Sampling• Batching• Other Products• Waiting• Coordinating

• Other Products• Other Paperwork• Waiting• Coordinating

TEST


CONTINUOUS QUALITY VERIFICATION IN ROUTINE MANUFACTURING

• Quality testing is Discontinuous• QC testing times are large • QC Cycle Times > Process Cycle Times• OFF-LINE NATURE of test drive time

ON-LINE QC TESTING CAN GREATLY IMPACT OVERALL CYCLE TIMES


OUTLINE










RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACECOST

QUALITY

TIME

SAFETY


PHARMACEUTICAL MANUFACTURING:LOOKING BEYOND THE “AVERAGE”

OVE

RA

LL C

YCLE

TIM

ES

NEED FOR FUNDAMENTAL TECHNOLOGY

Lots with Exceptions

Lots without Exceptions

0 100 200 300 400 500 600 700 800

LOT NUMBER


OUTLINE






OVERALL CYCLE TIMES:QC TESTING TIMES ARE SIGNIFICANT

0

5

10

15

20

25

TIME (Days)

A B C D E FPROCESS CASE STUDY

Overall Cycle Time Components

Process TimesQC Testing Times


Pharmaceutical Manufacturing:Impact of Exceptions(Detailed Analysis of 2 Products)

• Average Cycle time 95 days• Std dev(Cycle time) > 100 days• Exceptions increase cycle time by > 50 %• Exceptions increase variability by > 100%• Capacity Utilization of “System” LOW

PERFORMANCE MEASURE VALUE

NEED FOR FUNDAMENTAL TECHNOLOGY


OUTLINE




• Pharmaceutical Manufacturing: • The New Technology Opportunity..






RESEARCH

DEVELOPMENT

MANUFACTURING

TIME


BlendingDryingGranulation

FlowTabletingTransport

AssayFermentation

Rapid MicrobialDetection

SPACE






RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE


BlendingDryingGranulation

FlowTabletingTransport

AssayFermentation

Rapid MicrobialDetection

y = 1.9757x + 0.4886R 2 = 0.9983

0.00

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 Triamterene0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 10 20 30 40 50

Num be r of Rota tions

LIF

Sign

al U

nits

A : 4.75% T/LB : 4.75% T/LC: 4.75% T/L

E xc ita tion @ 460 nm & P M T @ 305 vo lts b ias

M ix ing S ta te

S teady S ta te

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 10 20 30 40 50

Num be r of Rota tions

LIF

Sign

al U

nits

A : 4.75% T/LB : 4.75% T/LC: 4.75% T/L

E xc ita tion @ 460 nm & P M T @ 305 vo lts b ias

M ix ing S ta te

S teady S ta te

0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

3 0 0 0

3 5 0 0

0 1 0 2 0 3 0 4 0

P e r io d o f F lo w , S e c o n d s

LIF

l a c t o s e

A d d 0 . 1 %

A d d 1 . 0 %

A d d 5 . 0 %

A d d 1 0 . 0 %

F l o w R a t e @ 1 7 6 g / m i n L i n e a r F l o w R a t e @ 5 5 c m / m i n

0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

3 0 0 0

3 5 0 0

0 1 0 2 0 3 0 4 0


LIF

l a c t o s e

A d d 0 . 1 %

A d d 1 . 0 %

A d d 5 . 0 %

A d d 1 0 . 0 %

0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

3 0 0 0

3 5 0 0

0 1 0 2 0 3 0 4 0


LIF

l a c t o s e

A d d 0 . 1 %

A d d 1 . 0 %

A d d 5 . 0 %

A d d 1 0 . 0 %

la c t o s e

A d d 0 . 1 %

A d d 1 . 0 %

A d d 5 . 0 %

A d d 1 0 . 0 %

F l o w R a t e @ 1 7 6 g / m i n L i n e a r F l o w R a t e @ 5 5 c m / m i n

0

5

10

15

20

25

30

35

0 50 100 150 200

Number of Readings @ 0.375 s/reading

10%5%

1%0.5%0.1%


PHARMACEUTICAL MANUFACTURING:The New Technology Opportunity..

• New Technology Can Be A Huge Win For:• INDUSTRY• FDA• SOCIETY

• But We Can Only Capture Its Potential If We Work Together In a “Win-Win” Mode

• If We Don’t We All Lose..• Lets Find A Way To All Win..


Pharmaceutical Manufacturing:Context of Experiences..

FDAFood & DrugAdministration

MIT:MIT Pharma Mfg Initiative

(PHARMI)

G.K. Raju, Ph.D.

CAMPConsortium

For The Advancement Of

Manufacturing ForPharmaceuticals

Purdue Univ:Dept of Industrial & Physical Pharmacy


ACKNOWLEDGEMENTS

• Consortium for the Advancement of Manufacturing of Pharmaceuticals (CAMP)

• Professor Charles Cooney (MIT)• Professor Stephen Byrn (Purdue)


NOTE ON CONTEXT

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

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

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