MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PHARMACEUTICAL MANUFACTURING: NEW TECHNOLOGY...

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


Objective: To Describe and Capture the Opportunity to Improve

Pharmaceutical Manufacturing Performance

MIT Pharmaceutical Manufacturing Initiative

Research Development Manufacturing Marketing


Pharmaceutical Manufacturing:Context of Experiences..

FDAFood & Drug

Administration

MIT:MIT Pharma Mfg Initiative

(PHARMI)

G.K. Raju, Ph.D.

Purdue Univ:Dept of Industrial & Physical Pharmacy

CAMPConsortium

For The Advancement Of

Manufacturing ForPharmaceuticals


ACTIVE FORMULN FILL/FINISH PACKAGE



RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE

Pharmaceutial Manufacturing


ACTIVE FORMULN FILL PACK



RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE

Pharmaceutial Manufacturing Performance

COST

QUALITY

TIME

SAFETY


OUTLINE









RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE


Blending


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


OUTLINE






PROCESS D: BLENDING PROCESS DEVELOPMENT

CHEMICAL WEIGHING

GRANULATION

Processing

STEP

BLEND 1: BLEND 2: PRE- BLEND

FINALBLEND

FILMCOATING

COMPRESS BOTTLEPACKAGING

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


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


On-Line Blend Uniformity Opportunity in Process Development

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

• Large variability reduction in blend process development time

• Independence of organization/product -> predictability

SUMMARY


OUTLINE









RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE


Which Products?High VolumeComplexLiquid


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 D WITH QC TESTS

CHEMICAL WEIGHING

GRANULATION

Processing

STEP

BLEND 1: BLEND 2: PRE- BLEND

FINALBLEND

FILMCOATING

COMPRESS BOTTLEPACKAGING

• API • Particle Size• LOD

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

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

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

• 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





RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE




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





RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE




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


OVERALL CYCLE TIMES:QC TESTING TIMES ARE SIGNIFICANT

0

5

10

15

20

25

TIME (Days)

A B C D E F

PROCESS CASE STUDY

Overall Cycle Time Components

Process Times

QC Testing Times


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, Data Analysis, etc.


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


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

SPACE


COST

QUALITY

TIME

SAFETY


PHARMACEUTICAL MANUFACTURING:LOOKING BEYOND THE “AVERAGE”

0 100 200 300 400 500 600 700 800

LOT NUMBER

OV

ER

AL

L C

YC

LE

TIM

ES

Lots without Exceptions

Lots with Exceptions

NEED FOR FUNDAMENTAL TECHNOLOGY


OUTLINE






OVERALL CYCLE TIMES:QC TESTING TIMES ARE SIGNIFICANT

0

5

10

15

20

25

TIME (Days)

A B C D E F

PROCESS CASE STUDY

Overall Cycle Time Components

Process Times

QC Testing Times


• 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

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

NEED FOR FUNDAMENTAL TECHNOLOGY


OUTLINE




• Pharmaceutical Manufacturing: • The New Technology Opportunity..





RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE



BlendingDryingGranulation

FlowTabletingTransport

AssayFermentation

Rapid MicrobialDetection





RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE



BlendingDryingGranulation

FlowTabletingTransport

AssayFermentation

Rapid MicrobialDetection

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

PM

T S

ign

al, v

olt

s

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 10 20 30 40 50

Number of Rotations

LIF

Sig

na

l U

nit

s

A: 4.75% T/L

B: 4.75% T/L

C: 4.75% T/L

Excitation @ 460 nm & PMT @ 305 volts bias

Mixing State

Steady State

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 10 20 30 40 50

Number of Rotations

LIF

Sig

na

l U

nit

s

A: 4.75% T/L

B: 4.75% T/L

C: 4.75% T/L

Excitation @ 460 nm & PMT @ 305 volts bias

Mixing State

Steady State

0

500

1000

1500

2000

2500

3000

3500

0 10 20 30 40

Period of Flow, Seconds

LIF

lactose

Add 0.1%

Add 1.0%

Add 5.0%

Add 10.0%

Flow Rate @ 176g/min Linear Flow Rate @ 55 cm/min

0

500

1000

1500

2000

2500

3000

3500

0 10 20 30 40


LIF

lactose

Add 0.1%

Add 1.0%

Add 5.0%

Add 10.0%

0

500

1000

1500

2000

2500

3000

3500

0 10 20 30 40


LIF

lactose

Add 0.1%

Add 1.0%

Add 5.0%

Add 10.0%

lactose

Add 0.1%

Add 1.0%

Add 5.0%

Add 10.0%

Flow Rate @ 176g/min Linear Flow Rate @ 55 cm/min

0

5

10

15

20

25

30

35

0 50 100 150 200

Number of Readings @ 0.375 s/reading

Sig

na

l, v

olt

s

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 & Drug

Administration

MIT:MIT Pharma Mfg Initiative

(PHARMI)

G.K. Raju, Ph.D.

Purdue Univ:Dept of Industrial & Physical Pharmacy

CAMPConsortium

For The Advancement Of

Manufacturing ForPharmaceuticals


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

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) PHARMACEUTICAL MANUFACTURING: NEW TECHNOLOGY...

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