Pharmaceutical Manufacturing:: New Technology Opportunities.

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

Pharmaceutical Manufacturing:
Context of Experiences..
MIT:
MIT Pharma Mfg Initiative
(PHARMI)
CAMP
FDA Consortium
Food & Drug G.K. Raju, Ph.D.
For The
Administration Advancement Of
Manufacturing For
Pharmaceuticals
Purdue Univ:
Dept of Industrial &
Physical Pharmacy

Pharmaceutial Manufacturing
SPACE
RESEARCH
ACTIVE FORMULN FILL/FINISH PACKAGE
DEVELOPMENT
MANUFACTURING
TIME
Pharmaceutial Manufacturing Performance
SPACE
RESEARCH
ACTIVE FORMULN FILL PACK
COST
DEVELOPMENT QUALITY
TIME
MANUFACTURING
SAFETY
TIME

OUTLINE

• So what?
• So what?

SPACE
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
Blending
Blending Operation Model
Undermixed
mix-longer
Blender Homogeneous
cleaning
Next batch
8
Active
Excipients
ingredient
Raw material load Mixing Sampling Discarded
Next batch
Homogeneity test
OK?
Results & Decision Analysis Transporting

Making

LIF FOR ON-LINE MONITORING OF BLENDING
LIGHT INDUCED FLUORESCENCE SYSTEM

FOR THE DETERMINATION OF THE
HOMOGENEITY OF DRY POWDER BLENDING
4500
4000
3500
LIF Signal Units

3000
2500
2000
1500 A: 5% T/L
1000 B: 5% T/L
500 C: 5% T/L
0
0 10 20 30 40 50
Number of Rotations

LIF VERIFICATION STUDIES
Established a correlation between LIF assessment of

homogeneity and thief-sampling with off-line analysis
6
LIF % Triamterene A
5 LIF % Triamterene B
End Point Determination
Thief Assay A
4 Thief Assay B
0
4.75% 3.22% 1.64%
Run Batch

OUTLINE

• So what?
• So what?

PROCESS D:
BLENDING PROCESS DEVELOPMENT
FILM
GRANULATION STEP COATING
CHEMICAL Processing BLEND 1: BLEND 2: FINAL COMPRESS BOTTLE

WEIGHING PRE- BLEND PACKAGING
BLEND
• OFF LINE QC TEST
Mixing Of 1:10 Triamterene-Lactose

@ 70% Fill & 27.4 RPM
40
35
PMT Signals, Volts

30
• ON LINE SENSOR 25
20
15
10
5
0
0 50 100 150 200 250 300
Number of Rotations

Blending Operation: Two Technologies, Two Approaches
Process Development, Validation and Manufacturing
Raw Materials Blending Sampling Transport Analysis

OFF LINE
Process
knowledge Results &
Decision making
Waiting Stock
Information Flow
R/D/W Materials Flow
a- Process Development
b- manufacturing
Reprocessed Discarded Well Blended
ON LINE
Blending Well Blended

Raw Materials Analysis &
Decision making
Discarded
On-line
Information Feedback
Blending Performance
Process Development and Validation
Impact of the number of blends on total

process time
60
50
Time (days)
40
30.65
30
23.45
20
13.19
10 2.41
1.31 1.93
0
1 2 3
Number of blends
Avg Off line Avg On line
On-Line Blend Uniformity
Opportunity in Process Development
SUMMARY
• 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

OUTLINE

• So what?
• So what?

SPACE
RESEARCH
DEVELOPMENT
MANUFACTURING Which Products?

ACTIVE FORMULN FILL PACK High Volume
Complex
Liquid
TIME

PROCESS A WITH QC TESTS
DRY MIX STEP FB DRY BLEND
WEIGHING WET STEP SIEVE ENCAPSULATE

GRANULATION
QC1 QC2 QC3 QC4
• LOD • Particle Size

• API • Description
• MICRO • ID
• Assay
• CU
• Impurity
• Dissolution
• MICRO
PROCESS A WITH CYCLE TIMES
< 3 DAYS
DRY
ProcessingFB DRY BLEND
MIX
SIEVE
WEIGH WETSTEP ENCAPSULATE
GRANULN
7 DAYS QC2 13 DAYS

QC3
QC1 • LOD • Particle
Size
QC4
• API • Description
• MICRO • ID
• Assay
• CU
• Impurity
• Dissolution
• MICRO

PROCESS D WITH QC TESTS
FILM
CHEMICAL Processing BLEND 1: BLEND 2: FINAL COMPRESS BOTTLE

WEIGHING PRE- BLEND PACKAGING
BLEND
QC1 QC2 QC3
• API • Particle Size • Description

• LOD • ID
• Assay
• CU
• Impurity
• Dissolution

PROCESS D WITH CYCLE TIMES
20 DAYS 15 DAYS
BLEND 2:
PRE-BLEND
FILM
CHEMICAL
WEIGHING PROCESSING BLEND 1: FINAL COMPRESS BOTTLE
BLEND PACKAGING
10 DAYS 15 DAYS
QC1 QC2 QC3
• API • Particle Size • Description
• LOD • ID
• Assay
• CU
• Impurity
• Dissolution
60 DAYS
PROCESS D WITH QC TESTS:
Cycle Times including BULK ACTIVE
20 DAYS 15 DAYS
BLEND 2:
PRE-BLEND
FILM
GRANULATION
STEP COATING
CHEMICAL
WEIGHING BLEND 1: FINAL COMPRESS BOTTLE
PROCESSING BLEND PACKAGING
10 DAYS 15 DAYS
QC1 QC2 QC3
21-90 DAYS 60 DAYS

SPACE
RESEARCH
DEVELOPMENT

Complex
Liquid
TIME

PROCESS E WITH QC TEST TIMES
7 days 3 days 7 days 7 days
QC1 QC2 QC3 QC4
ACTIVE
<1 <1 1-2 < 1 <1 <1

day day days day day day
FIRST SECOND COAT SIFT& BLEND FILL
GRAN GRAN BLEND

SPACE
RESEARCH
DEVELOPMENT

Complex
Liquid
TIME

PROCESS F:
LIQUID LINE WITH CYCLE TIMES
• ENVIRONMENTAL MONITORING
7 days
10 days
• WFI TESTING
3-4 days
3-4 months
• STERILITY TESTING
17-20 days
7 days
• BIOBURDEN TESTING

OVERALL CYCLE TIMES:
QC TESTING TIMES ARE SIGNIFICANT
Overall Cycle Time Components
25
20
TIME 15
(Days) 10 Process Times
QC Testing Times
5
0
A B C D E F
PROCESS CASE STUDY

CYCLE TIME COMPONENTS
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 Operation
Inventory Hold Actual test

ON-LINE TECHNOLOGY IMPACTS
DOMINANT 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 Operation
Inventory Hold Actual test
On-line LIF, NIR, Data Analysis, etc.

WHAT DRIVES THE
QC TESTING TIMES?
20
15
Actual
10 Target
Potential
5
0
QC1 PFD QC3 Release
2%
• Sampling TEST • Other Products
• Batching • Other Paperwork
• Other Products • Waiting
• Waiting • Coordinating
• Coordinating

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

• So what?
• So what?

SPACE
RESEARCH
COST
DEVELOPMENT QUALITY
TIME
MANUFACTURING
SAFETY
TIME

LOOKING BEYOND THE “AVERAGE”
Lots with Exceptions
Lots without Exceptions

OVERALL CYCLE TIMES
0 100 200 300 400 500 600 700 800

LOT NUMBER
NEED FOR FUNDAMENTAL TECHNOLOGY

OUTLINE

• So what?
• So what?

OVERALL CYCLE TIMES:
QC TESTING TIMES ARE SIGNIFICANT
Overall Cycle Time Components
25
20
TIME 15
(Days) 10 Process Times
QC Testing Times
5
0
A B C D E F
PROCESS CASE STUDY

Impact of Exceptions
(Detailed Analysis of 2 Products)
PERFORMANCE MEASURE VALUE

• 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
NEED FOR FUNDAMENTAL TECHNOLOGY

OUTLINE

• So what?
• So what?
• The New Technology Opportunity..

SPACE
RESEARCH
DEVELOPMENT
MANUFACTURING
Which Products?
High Volume
Complex
Liquid
TIMEAssay Blending Flow Rapid
Fermentation Drying Tableting Microbial
Granulation Transport Detection
35
25.00 Excitation @ 460 nm & PMT @ 305 volts bias 3500
4500 30
10%
Add 10.0%
P M T S ig n a l, v o lts
20.00 4000 3000
L IF S ig n a l Un its
Sig n a l, v o lts
Steady State Add 5.0% 25
15.00
3500 2500
20
5%
3000 Add 1.0%
L IF
2000
2500 15
10.00 Add 0.1%
2000 1500
10
Mixing State A: 4.75% T/L
5.00
y = 1.9757x + 0.4886
1500 1000
Flow Rate @ 176g/min 5
1%
B: 4.75% T/L
2
R = 0.9983
1000
500 Linear Flow Rate @ 55 cm/min 0.5%
0.00 500 C: 4.75% T/L
0
lactose 0 0.1%
0.0 2.0 4.0 6.0 8.0 10.0 12.0 0 0 50 100 150 200
0 10 20 30 40 50 0 10 20 30 40 Number of Readings @ 0.375 s/reading
% of Triamterene
Number of Rotations Period of Flow, Seconds
SPACE
RESEARCH
DEVELOPMENT
MANUFACTURING
Which Products?
High Volume
Complex
Liquid
TIMEAssay Blending Flow Rapid
Fermentation Drying Tableting Microbial
Granulation Transport Detection
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..

Context of Experiences..
MIT:
MIT Pharma Mfg Initiative
(PHARMI)
CAMP
FDA Consortium
Food & Drug G.K. Raju, Ph.D.
For The
Administration Advancement Of
Manufacturing For
Pharmaceuticals
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

Pharmaceutical Manufacturing:: New Technology Opportunities.

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PHARMACEUTICAL MANUFACTURING:

NEW TECHNOLOGY OPPORTUNITIES..

November 16th 2001

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

• MIT Pharmaceutical Manufacturing Initiative

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

Research Development Manufacturing Marketing

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

• MIT Pharmaceutical Manufacturing Initiative

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

Results & Decision Analysis Transporting

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

LIGHT INDUCED FLUORESCENCE SYSTEM

LIF Signal Units

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

Established a correlation between LIF assessment of

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

• MIT Pharmaceutical Manufacturing Initiative

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

CHEMICAL Processing BLEND 1: BLEND 2: FINAL COMPRESS BOTTLE

• OFF LINE QC TEST

Mixing Of 1:10 Triamterene-Lactose

PMT Signals, Volts

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

Raw Materials Blending Sampling Transport Analysis

Blending Well Blended

Impact of the number of blends on total

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

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

• MIT Pharmaceutical Manufacturing Initiative

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MANUFACTURING Which Products?

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

DRY MIX STEP FB DRY BLEND

WEIGHING WET STEP SIEVE ENCAPSULATE

QC1 QC2 QC3 QC4

• LOD • Particle Size

7 DAYS QC2 13 DAYS

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

CHEMICAL Processing BLEND 1: BLEND 2: FINAL COMPRESS BOTTLE

• API • Particle Size • Description

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

21-90 DAYS 60 DAYS

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MANUFACTURING Which Products?

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

7 days 3 days 7 days 7 days

QC1 QC2 QC3 QC4

<1 <1 1-2 < 1 <1 <1

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MANUFACTURING Which Products?

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

STEPS IN THE PROCESS/PLANT IN QC/QA

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

STEPS IN THE PROCESS/PLANT IN QC/QA

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

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

• Quality testing is Discontinuous

• MIT Pharmaceutical Manufacturing Initiative