Continuous Quality Verification: G.K.Raju, PH.D

CONTINUOUS QUALITY
VERIFICATION
(CQV)
G.K.Raju, Ph.D.
Pharmaceutical Manufacturing Initiative (PHARMI),

MIT Program on the Pharmaceutical Industry,
Massachusetts Institute of Technology
July 2001
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
MIT Pharmaceutical Manufacturing Initiative

Objective: To Describe the Opportunity to Improve
Pharmaceutical Manufacturing Performance
Research
Development
Manufacturing
Marketing
Pharmaceutical Manufacturing
Research
Inbound
Logistics
Bulk
Active
Development Manufacturing
Bulk
Formulation
Filling &
Finish
Marketing
Packaging
Outbound
Logistics
STUDYING PHARMACEUTICAL MFG:

VERTICAL VS. HORIZONTAL APPROACH
VERTICAL
APPROACH
Plant A
Bulk
Active
Plant A
Bulk
Formulation
Filling/
Tableting
Packaging/
Finishing
Plant B
Bulk
Active
HORIZONTAL
APPROACH
Bulk
Active
Bulk
Filling/
Formulation Tableting
Packaging/
Finishing
Bulk
Filling/
Formulation Tableting
Packaging/
Finishing
Plant B
Bulk
Formulation
Filling/
Tableting
Packaging/
Finishing
Bulk
Active
PHARMACEUTICAL MANUFACTURING
THE HORIZONTAL APPROACH
Company A
Bulk
Active
Bulk
Formulation
Filling/
Tableting/
etc.
Packaging/
Finishing
Bulk
Active
Bulk
Formulation
Filling/
Tableting/
etc.
Packaging/
Finishing
Bulk
Active
Bulk
Formulation
Filling/
Tableting/
etc.
Packaging/
Finishing
Company B
Company C
CONTINUOUS QUALITY VERIFICATION (CQV)
DESCRIBING THE OPPORTUNITY

IN
ROUTINE MANUFACTURING
PROCESS CYCLE TIMES
WHICH PROCESSES?
In Process
Development
Biggest Impact Here?

Time-to-market
Enabling
Potent Products
In Routine
Manufacturing
Place for Validation?

Potent Products
Difficult Processes
High Volume Products
Products with Tough QC Tests
PROCESS A WITH QC TESTS
DRY MIX
WEIGHING
QC1
API
MICRO
STEP
WET
GRANULATION
FB DRY
STEP
BLEND
SIEVE
QC2
QC3
ENCAPSULATE
QC4
LOD Particle Size Description

ID
Assay
CU
Impurity
Dissolution
MICRO
PROCESS A WITH CYCLE TIMES

< 3 DAYS
DRY
ProcessingFB DRY BLEND
MIX
WEIGH WETSTEP
GRANULN
7 DAYS
QC2
QC1
API
MICRO
LOD
SIEVE
ENCAPSULATE
QC3
Particle
Size
13 DAYS
QC4
Description
ID
Assay
CU
Impurity
Dissolution
MICRO
PROCESS B WITH QC TESTS
CHEMICAL
WEIGHING
QC1
API
OVI
BLEND
FILL CAPSULES
BOTTLE
PACKAGING
QC2
Description
ID
Assay
CU
Impurity
Dissolution
PROCESS B WITH CYCLE TIMES

17 DAYS
CHEMICAL
WEIGHING
14 DAYS
BOTTLE
BLEND FILL
CAPSULES PACKAGING
7 DAYS
QC1
QC2
API
OVI
Description
ID
Assay
CU
Impurity
Dissolution
PROCESS C WITH QC TESTS
GRANULATION
WEIGHING
QC1
API
FB DRY
COMPRESS
STEP
FILM
BOTTLE
COATING PACKAGING
BLEND
QC2
Particle Size
LOD
QC2
Description
ID
Assay
CU
Impurity
Dissolution
PROCESS C WITH CYCLE TIMES

21 DAYS
GRANULATION
6 DAYS
WEIGHING
QC1
API
FB DRY
STEP
COMPRESS
BLEND
BOTTLE
PACKAGING
FILM
COATING
14 DAYS
QC2
Description
ID
Assay
CU
Impurity
Dissolution
PROCESS D WITH QC TESTS
GRANULATION
CHEMICAL
WEIGHING
QC1
API
Processing
FILM
COATING
STEP
BLEND 1: BLEND 2: FINAL COMPRESS

PREBLEND
BLEND
QC2
Particle Size
LOD
BOTTLE
PACKAGING
QC3
Description
ID
Assay
CU
Impurity
Dissolution
PROCESS D WITH CYCLE TIMES
20 DAYS
15 DAYS
BLEND 2:
PRE-BLEND
FILM
COATING
GRANULATION STEP
CHEMICAL
WEIGHING
PROCESSING
BLEND 1:
FINAL
BLEND
COMPRESS
BOTTLE
PACKAGING
10 DAYS
QC1
API
15 DAYS
QC2
QC3
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
COATING
GRANULATION
STEP
CHEMICAL
BLEND 1: FINAL COMPRESS BOTTLE
WEIGHING
PROCESSING
PACKAGING
BLEND
10 DAYS
QC1
21-90 DAYS
15 DAYS
QC2
QC3
60 DAYS
PROCESS D WITH QC TESTS
Cycle Times
20
15
Actual
10
Target
Potential
5
0
QC1
PFD
QC3
20 DAYS
Release
15 DAYS
BLEND 2:
PRE-BLEND
FILM
COATING
GRANULATION STEP
CHEMICAL
WEIGHING
PROCESSING
BLEND 1:
FINAL
BLEND
COMPRESS
10 DAYS
QC1
BOTTLE
PACKAGING
15 DAYS
QC2
60 DAYS
QC3
WHAT DRIVES THE

QC TESTING TIMES?
20
15
Actual
10
Target
Potential
5
0
QC1
PFD
QC3
Release
2%
Sampling
Batching
Other Products
Waiting
Coordinating
TEST
Other Products
Other Paperwork
Waiting
Coordinating
PROCESS CYCLE TIMES
WHICH PROCESSES?
In Process
Development

Time-to-market
Enabling
Potent Products
In Routine
Manufacturing

Potent Products
Difficult Processes
PROCESS E WITH QC TEST POINTS

ACTIVE
INITIAL GRANULATION STAGE
LOD
MILL
WEIGH
DRY MIX
SECOND GRANULATION STAGE
QC1 WET GRANULN
WET
GRANULN
LOD
DRY
MIX
QC2 SIFT
BLEND
MIX
COATING STAGE
LOD
MILL
SIFT&BLEND STAGE
SIFT
MILL
COAT
MILL
WET GRAN
FL BED DRY
STORE
LOD
GRANUL
DRY
STORE
MIX
MIX
QC3
DRY
QC4
STORE
BLEND&FILL STAGE
BLEND
BLEND
BLEND
STORE
BOTTLE FILL
MILL
EXCEPIENT PREPARATION STAGE
PROCESS E WITH QC TEST TIMES
7 days
QC1
3 days
QC2
7 days
QC3
7 days
QC4
ACTIVE
<1 <1
day day
FIRST SECOND
GRAN GRAN
1-2 < 1
days day
COAT SIFT&
BLEND
<1
day
<1
day
BLEND
FILL
TOWARDS PARAMETRIC RELEASE
WHICH PROCESSES?
In Process
Development

Time-to-market
Enabling
Potent Products
In Routine
Manufacturing

Potent Products
Difficult Processes
PROCESS F: LIQUID LINE

ENVIRO. MONITORING
WFI TESTING
Endotoxin
TOC
QC Check
WASH AUTOCLAVE
WFI
STOPPERS
WEIGH
QC Check
QC Check
WASH DEPYROGEN
BUFFER
SEALS
VIALS
WEIGH
ID
pH ADJ COMPOUND
WEIGH
ID
TERMINAL
FILL STOPPER CAP STERILIZATION
FILTER
pH
BIOBURDEN
LABEL/PKG
Wt Check
Visual Check Appearance

ID
Assay
Impurity
Fill Vol, Osmolarity, Partic.
Endotoxin
STERILITY TESTING
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
PERCEIVED PROCESS CYCLE TIMES:

SUMMARY
Process
Flow
A
B
C
D
E
F
Process MICRO Optimized Process

QC QC:Process
Type Test? Process? Cycle Time Cycle Time Time
High Vol. Y
Y
3
20
6.7
High Vol. N
N
17
21
1.2
High Vol. N
N
21
20
1.0
High Vol. N
N
20
25
1.3
Variable N
Y
7
24
3.4
Parentals Y
N
3
20
6.7
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
Inventory Hold
Primarily Manual Operation

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
Inventory Hold
Primarily Manual Operation

Actual test
On-line LIF, NIR, Pattern Recognition, etc.

CQV OPPORTUNITY IN ROUTINE MANUFACTURING
SUMMARY
Quality Monitoring is Discontinuous

QC testing times are approximately = 1 month
Factor of 20-25 opportunity in cycle time: Process
Factor of 20-25 opportunity in cycle time: QC
QC Cycle Times >= Process Cycle Times
Time is driven by off-line nature of test
Exception is MICRO test
DESCRIBING THE OPPORTUNITY

IN PROCESS DEVELOPMENT
THE VERTICAL APPROACH

Company A
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Company B
Company C
Flow
Rapid
Fermentation Blending
Drying
Tableting Microbial
Granulation Transport Detection
VERTICAL ANALYSIS I:
BLENDING UNIT OPERATION

Company A
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Company B
Company C
Eg. Blending
PROCESS CYCLE TIMES
WHICH PROCESSES?
In Process
Development

Time-to-market
Enabling
Potent Products
In Routine
Manufacturing

Potent Products
Difficult Processes
MIT Pharmaceutical Manufacturing Initiative
FOCUS
Explore the Potential Impact of On-line
Monitoring Technology on Blending
Process Development
Blending Operation Model
Undermixed
mix-longer
Raw material load
Mixing
Active
Excipients
ingredient
Homogeneous
Blender
cleaning
Sampling
Next batch
Discarded
Next batch
Homogeneity test
OK?
Results & Decision

Making
Analysis
Transporting
PHARMACEUTICAL MANUFACTURING:
LIF FOR ON-LINE MONITORING OF BLENDING
LIGHT INDUCED FLUORESCENCE SYSTEM

FOR THE DETERMINATION OF THE
HOMOGENEITY OF DRY POWDER BLENDING
4500
LIF Signal Units
4000
3500
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
End Point Determination
6
LIF % Triamterene A
LIF % Triamterene B
Thief Assay A
Thief Assay B
5
4
3
2
1
0
4.75%
3.22%
1.64%
Run Batch
PROCESS D:
BLENDING PROCESS DEVELOPMENT
CHEMICAL
WEIGHING
Processing
FILM
COATING
STEP
BLEND 1: BLEND 2: FINAL COMPRESS

PREBLEND
BLEND
BOTTLE
PACKAGING
OFF LINE QC TEST

Mixing Of 1:10 Triamterene-Lactose
@ 70% Fill & 27.4 RPM
ON LINE SENSOR
PMT Signals, Volts
GRANULATION
40
35
30
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
OFF LINE
Raw Materials
Process
knowledge
Blending
Sampling
Transport
Analysis
Results &
Decision making
Waiting Stock
Information Flow
R/D/W
Materials Flow
a- Process Development
ON LINE
Reprocessed
Raw Materials
Discarded
Well Blended
Blending
Analysis &
Decision making
b- manufacturing
Well Blended
Discarded
On-line
Information Feedback
Blending Data Collected from CAMP Companies
Operation Characteristics
Low
Medium
High
Cleaning time (min)
20
250
480
Loading time (min)
10
35
60
Discharge time (min)
18
30
Sampling time (min)
60
90
120
Transport time (min)
30
60
QC Testing time (min)
20
250
480
QC Holding time (min)
25
48
Results
Blending Performance
Process Development and Validation
6% no wait between blends
Time (days)
1 Blend
Best
2.32 0.36
Med.
13.19 1.31
Worst
25.82 2.57
2 Blends
4.96
3 Blends
0.68
8.45
1.07
23.45 1.93
30.65
2.41
43.40 3.56
56.17
4.46
Blending Performance
Process Development and Validation
Impact of the number of blends on total
process time
60
Time (days)
50
40
30.65
30
20
23.45
13.19
10
2.41
1.93
1.31
0
1
Number of blends
Avg Off line
Avg On line
APPROACH TO LEARNING:
Consequences on Process Development & Commercial Production
Current Approach
Process Development
Proposed Approach
1a
2a
x
x
xxxxxxxxx
xxx
x
xx
xxxx
x
x xx xx
x x
x
x x x
x
Commercial Production
1b
x
x
xxxxxxxxx
xxx
x
2b
xxxxx
xxx
CQV Opportunity in Process Development

SUMMARY
Process development can be on the critical path

Factor of 10-15 reduction in cycle time in blend
process development (maybe more..)
Variability reduction in blend process dev. time
independence of organization/product -> predictability
Benefits not restricted to use of new on-line sensors
improvement data analysis of existing sensor data
use of this for experimental design
WHAT ARE THE

IMPLICATIONS?
Consortium for the Advancement of

Manufacturing in Pharmaceuticals (CAMP)
Pharmaceutical Companies
Abbott
Hoffmann-La Roche
Aventis
Glaxo SmithKline
Bristol-Myers Squibb Wyeth-Ayerst
FDA
Johnson & Johnson
Vendors
CAMP
Purdue
MIT
PROCESS A WITH CURRENT QC TESTS

AND NEW POSSIBILITIES
DRY MIX
WEIGHING
QC1
API
MICRO
STEP
WET
GRANULATION
FB DRY
STEP
BLEND
SIEVE
QC2
ENCAPSULATE
QC3
LOD
Particle Size
QC4
Description
ID
Assay
CU
Impurity
Dissolution
MICRO
Need to Focus on Both

Material Flow and Information Flow
INFORMATION FLOW
Sensor1 (or QC test1)
Bulk
Active
t1
Y1
Bulk
Formulation
t2
Y2
Sensor3 (or QC test3) Sensor4 (or QC test4)
Filling/
Tableting/
etc.
Y3
t3
Packaging/
Finishing
Y
Y4
t4
MATERIAL FLOW
Manufacturing Information Management:

Has Hardware and Software Components
Fast Response
On-Line
Real-Time
Accurate
Robust
Rapid Rate of Learning

Short Cycle Times
Benchmarking
Modeling
Continuous Problem Solving
20
Mixing Of 1:10 Triamterene-Lactone @ 85%
10.00
5.00
y = 1.9757x + 0.4886
0.0
2.0
4.0
6.0
8.0
10.0
10
5
0
0
R = 0.9983
0.00
30
25
20
15
50
100
150
200
250
Number of Rotations
300
Fluorescence Signals, volts
Signals, volts
PMTSignal, volts
15.00
30
16
40
35
20.00
35
18
Fill (10g) And 27.4 RPM
14
12
10
15
1%
0.5%
0.1%
4
1:10 powder flow
50
100
150
200
50
100
150
200
Number of Readings @ 0.375 s/reading
1:20
0
250
Readings @ 0.375 seconds
% of Triamterene
5%
20
10
12.0
10%
25
Signal, volts
25.00
Bulk
Active
Y1
Bulk
Formulation
Y2
Filling/
Tableting/
etc.
Y3
Packaging/
Finishing
Y
Y4
HORIZONTAL AND VERTICAL APPROACHES

Company A
High Vol
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Bulk
Active
Bulk
Formulation
Filling &
Finish
Packaging
Company B
Variable
Company C
Liquids
Flow
Rapid
Fermentation Blending
Drying
Tableting Microbial
Granulation Transport Detection
CQV: BENEFITS
Data Mining of Process Data

Data -> Information -> Knowledge
Rationale for New Sensors
Variable Categorization: PCCPs, etc.
Basis for Specifications, Batch Record Design
Basis for Experimental Design, Etc.
Learning Curve: Cycle Times

Accelerated Learning Curve Facilitated By
Continuous Quality Verification
Total cycle time
days
1000
100
10
0
50
100 150 200 250 300 350 400 450 500 550 600 650 700
batch #
CQV: SO WHAT?
On-line sensors doing the same thing will have
only incremental impact
This impact will still be only incremental
even if there is an MES/EBR system
Data Warehousing focused on exceptions can
have a large impact
On-line sensors + EBR + Data Warehousing
can fundamentally change pharma. mfg.
PRODUCT LIFE CYCLE: OPPORTUNITIES

1: NET INCOME
1:
2: NET INCOME
3: NET INCOME
370.88
2
1
Reduction of
manufacturing cost
3
Reduction of
time-to-market
1:
114.92
3
2
1:
-141.04
1.00
8.25
15.50
Net Income (Untitled Graph)
Years
22.75
30.00
7:15 AM Tue, Mar 02, 1999
Pharmaceutical Manufacturing:
Opportunity Areas
Manufacturing:
Cost --> Profit
Organizational focus: Functional --> Process
Optimization:
Local --> Supply chain
Inventory Management: JIC --> JIT
Cost of Quality: Inspection --> Prevention
KEY TECHNOLOGY OPPORTUNITY:

On-line Sensors+EBR+Data Warehousing!
ACKNOWLEDGEMENTS
Professor Charles Cooney (MIT)

Professor Stephen Byrn (Purdue)
CAMP
NOTE ON CONTEXT
This presentation does not necessarily represent

the views of MIT, Purdue or CAMP
Some data have been disguised for reasons of
sensitivity and confidentiality

Continuous Quality Verification: G.K.Raju, PH.D

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CONTINUOUS QUALITY

Pharmaceutical Manufacturing Initiative (PHARMI),

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MIT Pharmaceutical Manufacturing Initiative

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

STUDYING PHARMACEUTICAL MFG:

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

CONTINUOUS QUALITY VERIFICATION (CQV)

DESCRIBING THE OPPORTUNITY

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PROCESS CYCLE TIMES

Biggest Impact Here?

Place for Validation?

PROCESS A WITH QC TESTS

LOD Particle Size Description

PROCESS A WITH CYCLE TIMES

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PROCESS B WITH QC TESTS

PROCESS B WITH CYCLE TIMES

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PROCESS C WITH QC TESTS

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PROCESS C WITH CYCLE TIMES

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PROCESS D WITH QC TESTS

BLEND 1: BLEND 2: FINAL COMPRESS

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PROCESS D WITH CYCLE TIMES

Particle Size Description

PROCESS D WITH QC TESTS:

Cycle Times including BULK ACTIVE

PROCESS D WITH QC TESTS

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

WHAT DRIVES THE

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PROCESS CYCLE TIMES

Biggest Impact Here?

Place for Validation?

PROCESS E WITH QC TEST POINTS

INITIAL GRANULATION STAGE

SECOND GRANULATION STAGE

QC1 WET GRANULN

EXCEPIENT PREPARATION STAGE

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PROCESS E WITH QC TEST TIMES

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

TOWARDS PARAMETRIC RELEASE

Biggest Impact Here?

Place for Validation?

PROCESS F: LIQUID LINE

Visual Check Appearance

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

PERCEIVED PROCESS CYCLE TIMES:

Process MICRO Optimized Process

CYCLE TIME COMPONENTS

Primarily Manual Operation

ON-LINE TECHNOLOGY IMPACTS

Primarily Manual Operation

On-line LIF, NIR, Pattern Recognition, etc.

CQV OPPORTUNITY IN ROUTINE MANUFACTURING