PHARMACEUTICAL MANUFACTURING...MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI) Blending...
Transcript of 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
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)
MIT Pharmaceutical Manufacturing Initiative
Objective: To Describe and Capture the Opportunity to Improve Pharmaceutical Manufacturing Performance
Development Manufacturing MarketingResearch
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
Pharmaceutial Manufacturing
ACTIVE FORMULN FILL/FINISH PACKAGE
ACTIVE FORMULN FILL/FINISH PACKAGE
ACTIVE FORMULN FILL/FINISH PACKAGE
RESEARCH
DEVELOPMENT
MANUFACTURING
SPACE
TIME
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
Pharmaceutial Manufacturing Performance
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACECOST
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)
Pharmaceutial Manufacturing Performance
SPACE
ACTIVE FORMULN
ACTIVE FORMULN FILL
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
PACK
FILL PACK
TIMEBlending
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
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
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4
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4.75% 3.22% 1.64%
Run Batch
End
Poin
t Det
erm
inat
ion
LIF % Triamterene ALIF % Triamterene BThief Assay AThief 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)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
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40
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60
1 2 3Number of blends
Tim
e (d
ays)
Avg Off line Avg On line
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
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)
Pharmaceutial Manufacturing Performance
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
SPACE
Which Products?High VolumeComplexLiquid
TIME
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
Pharmaceutial Manufacturing Performance
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING Which Products?High VolumeComplexLiquid
SPACE
TIME
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
Pharmaceutial Manufacturing Performance
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING Which Products?High VolumeComplexLiquid
SPACE
TIME
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
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 FPROCESS CASE STUDY
Overall Cycle Time Components
Process TimesQC Testing Times
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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.
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
WHAT DRIVES THE QC TESTING TIMES?
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5
10
15
20
QC1 PFD QC3 Release
ActualTargetPotential
2%
• Sampling• Batching• Other Products• Waiting• Coordinating
• Other Products• Other Paperwork• Waiting• Coordinating
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)
Pharmaceutial Manufacturing Performance
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACECOST
QUALITY
TIME
SAFETY
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
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 FPROCESS CASE STUDY
Overall Cycle Time Components
Process TimesQC Testing Times
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
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
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)
Pharmaceutial Manufacturing Performance
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
Which Products?High VolumeComplexLiquid
BlendingDryingGranulation
FlowTabletingTransport
AssayFermentation
Rapid MicrobialDetection
SPACE
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
Pharmaceutial Manufacturing Performance
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
Which Products?High VolumeComplexLiquid
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
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 %
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 %
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%
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 & 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
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