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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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 (PHARMI)
Objective: To Describe and Capture the Opportunity to Improve
Pharmaceutical Manufacturing Performance
MIT Pharmaceutical Manufacturing Initiative
Research Development Manufacturing Marketing
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
ACTIVE FORMULN FILL/FINISH PACKAGE
ACTIVE FORMULN FILL/FINISH PACKAGE
ACTIVE FORMULN FILL/FINISH PACKAGE
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing Performance
COST
QUALITY
TIME
SAFETY
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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 (PHARMI)
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing Performance
Blending
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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 (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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 (PHARMI)
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing Performance
Which Products?High VolumeComplexLiquid
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing Performance
Which Products?High VolumeComplexLiquid
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing Performance
Which Products?High VolumeComplexLiquid
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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.
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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 (PHARMI)
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing Performance
COST
QUALITY
TIME
SAFETY
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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 (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
• 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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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 (PHARMI)
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing Performance
Which Products?High VolumeComplexLiquid
BlendingDryingGranulation
FlowTabletingTransport
AssayFermentation
Rapid MicrobialDetection
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Pharmaceutial Manufacturing Performance
Which Products?High VolumeComplexLiquid
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
Period of Flow, Seconds
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
Period of Flow, Seconds
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%
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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..
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
ACKNOWLEDGEMENTS
• Consortium for the Advancement of Manufacturing of Pharmaceuticals (CAMP)
• Professor Charles Cooney (MIT)
• Professor Stephen Byrn (Purdue)
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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