Process Analytical Technology
Examples & Business Case Development
Jonathan Roy
Presenter
• Chemical Engineering (Northeastern University)
• Career History
• Wyeth
• NNE Pharmaplan
• Focus
• ASTM E2500, PAT & QbD, project management,
commissioning and qualification
This presentation
•
Part 1
• Broad overview of QbD & PAT
• Different types of PAT and implementation model
• Examples with simple ROI
• Business impact of PAT
•
Part 2
• Why have a business case
• Different financial models
• Soft factors
• Visualization for decision making
Part 1
QbD and PAT
Benefits of submission
•
PAT & QbD can be used much more powerfully – a new way of submitting to
the authorities (Q8, Q9 and Q10 guidances)
Development
Facility
x
x
xx x xxx
x
•Low process knowledge
•Difficult scale up
Submission
x 10000
•Long ramp up
•Mass validation
•Huge resource use
•Huge paper exercise
•Process fixed using
3 validation batches
•Process fixed
•Scrap 5-10%
•Capacity 30%
•Limited continuous
improvement
Submission
Operations
Traditional approach
Development
Operations
Facility
x 100
•Smart experiments
•High process knowledge
•Ease of scale up
PAT & QbD approach
•Short ramp up
•Risk based verification
•Efficient resource
•Paper ‘lite’ submission
•Demonstrates
scientific knowledge
•Gives regulatory relief
•Robust & adjustable
process
•Scrap < 1%
•Capacity > 70%
•Full continuous
improvement
•Continuous processing?
QbD & PAT
• Process Development
• Process monitoring to develop mechanistic
understanding
• Model building and correlations to enhance
process understanding
• Establishment of design space
• Manufacturing
• Process control to ensure robust and
reproducible operations
• Flexible operation through process controls
• Real-time release
• Continual improvement
• Historical data tracking and trending
• Statistical process control for early identification
of potential problems
Or more simply
• QbD and PAT are extremely close allies – they are
typically used in combination
• QbD helps design the process playing field
• PAT is used in manufacturing* for financial gain
Analytical Measurements
•
•
Current manufacturing requires that tens of thousands of
analytical measurements are required at a manufacturing
facility annually
These typically take place for several reasons
•
•
•
•
QC testing for batch release
In process testing to reduce risk
Raw material acceptance testing
Analytical Development
•
•
Develop tests to be finally used in the facility
Support drug development process
General analysis times
Off-line
Analysis performed
in Laboratory
Days
At-line
Analysis performed
on factory floor
Minutes
On-line
Automated sampling
and analysis
Seconds
In-line
No sampling –
instrument in
process
< 1 second
Time
delay
Frequency
of
sampling
Detailed Comparison
Release specifications for drug product
Specification (CQA)
Traditional test
Time frame
No. of samples per analyst per 8h
Dissolution
Disintegration
Assay
Hardness
Content uniformity
Impurity
Appearance
Identification
Water
Microbiology
Dissolution test
Physical test
HPLC
Physical test
HPLC
HPLC
Appearance
IR/UV
Karl-Fischer
Biological test
2 days
2 days
2 days
2 days
4 days
3 days
2 days
2 days
2 days
7-14 days
8
24
24
24
3
24
48
12
24
12
Specification (CQA)
21st century testing
Time frame
No. of samples per analyst per 8h
Dissolution
Disintegration
Assay
Hardness
Content uniformity
Impurity
Appearance
Identification
Water
Microbiology
NIR
NIR
NIR/NMR
NIR
NIR
On-line HPLC/HPLC
Colorimetry/NIR
NIR
NIR/NMR/TE
RMM
1s
1s
1s
1s
1s
10 minutes
1s
1s
1s
12h – 14 days
No analyst (> 1 million samples
No analyst (> 1 million samples
No analyst (> 1 million samples
No analyst (> 1 million samples
No analyst (> 1 million samples
24 (off-line) – 24 (on-line)
300
300
No analyst (> 1 million samples
24
per
per
per
per
per
day)
day)
day)
day)
day)
per day)
Use of process Analysers
Secondary Manufacturing Process
Spec
Identity
Water
content &
particle
size
Granulate
size (end
point)
Water
content &
fines (end
point)
Blend
homogeneity
(end point)
Assay &
physical
properties
Correct
label &
pack
PAT
NIR
NIR
Passive
acoustics
NIR
Thermal
effusivity
NIR
Video
capture
Real time
release
Benefit
Release
time ➪
99%
Cycle
times ➪
10%
Cycle time
➪ 30% (+
➪ 40%
with CIP)
Cycle time ➪
40% (+ ➪
40% with
CIP)
Cycle times
➪ 70% (+
➪ 40% with
CIP)
Scrap &
rework ➪
2%
Scrap &
rework ➪
2%
Release
time ➪
99%
Scrap &
rework ➪
2%
Scrap &
rework ➪
2%
NIR
Cycle time
➪ 30%
Perform HPLC for impurity release here
NIR
TE
NIR
PA
VC
NIR
UV
API & raw
materials
Weighing/ Granulation
Dispensing
UV
UV
Fluid Bed
Drying
Blending
Compression
Packaging Finished product
CIP linked with PAT to reduce cycle times 40% and release 90%
Process Analyzers
Spectroscopic
Toolbox
Alternative
Toolbox
Hyphenated
Toolbox
IR (Infra-red)
TE (Thermal effusivity)
GC (Gas Chromatography)
NIR (Near Infra-red)
Conductance/Resistance
IC (Ion Chromatography)
Raman
Passive Acoustics
UV/Vis (Ultraviolet/visible)
TOC (Total Organic Carbon)
HPLC (High Performance
Liquid Chromatography)
Active acoustics
Vision/Imaging
NMR (Nuclear
Magnetic Resonance)
RMM (Rapid
Microbiological Methods)
EPR (Electro
Paramagetic Resonance)
Colorimetry
Fluorescence
MS (Mass Spectrometry)
XRF (X-ray
Fluorescence)
FIA (Flow
Injection Analysis)
Process analysis and control
How to effectively implement
• Implementation of process analysis
Analyser
Selection
•
Project
Management
Analytical
Development
Quality
Systems
Process &
Mechanical
tools for control requires a project
team containing multiple skills
It is crucial to have all of these
functions working in harmony in
order to achieve:
• Effective analysis (select the right
•
•
IT
&
Automation
•
tool, supplier, sampling and analysis
model)
Control and understanding (control
is essential to realise financial
rewards)
Quality (without commitment here
compliance issues will occur)
Project management (effective coordination and pit-stop working
mean full implementation in a few
months rather than several years)
At-line analysis
Sampling
• At-line analysis requires getting a
sample from the process and analysing
it manually at the process line
• Various sampling systems are
available to not disturb production and
provide safety
• A key element of at-line analysis is
ease of operation of equipment for
unskilled operators
Sampling technology example
At-line Analysis: Near Infra-red (NIR)
NIR for Identity
•
•
•
•
•
•
•
Requirement to test every bag
of API entering site
Each batch arriving contains
600 bags
Each batch creates enough
work to keep an analyst busy
for 2/3 months with
sampling/testing
API was potent with health risks
associated with sampling
NIR method developed to
identify API through plastic bag
Test performed by trained
warehouse operators
Can analyse a full batch in a
day
ROI – 6 months
At-line Analysis: Raman spectroscopy
Raman for Identity
•
•
•
•
•
•
Requirement to test all raw
materials arriving at site
Testing outsourced at a cost of
over 200,000 USD per year
Sampling and organizing
samples a huge task keeping 1
FTE busy
Lead time of 2 weeks for results
Use of Raman simply replaced
all need for outsourced testing
Lead time reduced from 2
weeks to 30 seconds
ROI < 3 months
At-line Analysis: X-Ray Florescence
(XRF)
Rapid assay for real-time release
•
•
•
•
•
This particular consumer
healthcare product had specific
functional chemistry making rapid
detection simple
On-line analysis may have been
possible but it was much cheaper
to provide an at-line solution
Results turnaround reduced from 2
days to 2 minutes
Real-time release based on XRF
technology (used widely in oil and
mining industries)
Savings of over 140k USD per year
compared to 28k USD investment
ROI < 3 months
On-line analysis - sampling
• Samples are removed from the
process using some form of flow
• This is typically a sampling loop
where process material is
returned to the process
On-line Analysis: Microwave
Microwave for water content
•
•
•
Microwave technology is
cheap, robust and widely
used in oil and associated
industries
A fast sample loop system
was used to present the
sample to a standard pipe
diameter with the microwave
technology embedded
Instant readings for water
content in slurries (also
potential in oil/water mixes
etc)
On-line Analysis: UV
UV for CIP
•
•
•
•
A process at a top 10
Pharma required
significant CIP time
resulting in reduced
capacity
Cytotoxic nature of
compound and risk of
cross-contamination
meant lack of
commitment to reduce
this CIP cycle time
UV was used to guarantee
safety and effect of crosscontamination
CIP cycles reduced by
40%
ROI < 2 months
In-line analysis - sampling
• Here some sort of sampling
probe may be necessary
which is actually placed in the
process vessel permanently
• These probes have sapphire
coated windows and can be
incorporated with a CIP
system to prevent fouling
• Some special analysers don’t
even need to be in the
reaction vessel (acoustics)
In-line Analysis: NIR
Fluid bed drying - NIR
ROI - 12 months
Facilities operating with PAT
•
This manufacturer
applied risk based
approaches, PAT and
common sense to move
away from a lab based
QC system to one that
was predominantly
performed on the
factory floor by process
operators
Specification
(CQA)
Traditional
test
Time frame
Assay
HPLC
2 days
Viscosity
Viscometer
1 day
Impurity
HPLC
2 days
Appearance
Appearance
2 days
Identification
IR/UV
2 days
Microbiology
Biological test
7-14 days
Specification
(CQA)
PAT test
Time frame
Assay
XRF
2 minutes
Viscosity
Viscometer
10 minutes
Impurity
Removed
based on QRM
-
Appearance
Appearance
2 minutes
Identification
NIR
2 minutes
Microbiology
RMM
12 hours
Today
Example – 21st century concept
Future
Less area
need
Multifunctional
development
centre
(formulation,
chemistry,
process,
analytical and
physical)
Shared function (logistics, storage etc etc)
QC
QC
Administration/
QA/regulatory
QC
QC
Production area
QC
QC
QC
QC
QC
Specialist
support (NMR)
Less area
need
Less area
need
Less area
need
Less area
need
Note: “QC” in the production area is the integration between analytical and engineering control
Filename:
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Order no.:
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Init.: NGu
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Date: 2007/06/06
Operational costs
Western facility
33%
Manning
Investment,
depreciation
and cost of
capital
33%
33%
Materials
Developing world facility
17%
22%
Investment,
depreciation
and cost of
capital
Manning
33%
Materials
What will PAT mean?
More
• Data available for
continuous improvement
• Less scrap
• Shorter cycle times
• Higher quality
• Factory floor QC
• PAT replaces lab QC
tests
• Advanced process
control models (SPC and
MSPC)
• Real time release
Less
• Routine analysis
• End-product testing
• Stability testing
• Re-testing
• OOS
• Regulatory involvement
Conclusions
• Process analysers take many forms – select whatever is
suitable for objective reasons, not scientific satisfaction
• It can be estimated that the use of at-line, on-line and inline alone could save the life science industry significant
money (and result in significant job reassignment from
AD and QC)
• PAT can improve the profitability of a manufacturing
business and actually lower investment costs
Part 2
Why have a financial business
case?
•
One of the major reasons that projects do not go ahead is financial constraints
(resources and time are effectively financial)
•
There are people (or committees) in organisations who control funding – they
make decisions based on:
•
•
•
•
•
•
How much the project will cost
Timeline
What the project will provide in financial benefit
What the risks of the project are
How it fits into the big strategy and what impacts the project may have
They (mostly) do not make decisions on (even though they may be
interested):
•
•
•
•
Being at the forefront of technology
Implementing innovative science
Vague benefits (but it will improve process understanding!)
Vague costs and timelines (such as knowing how much an instrument costs but not
knowing what it takes to implement one)
In other words
Scientific case
• Increases process understanding
• Will allow process monitoring in real
time
• Will reduce cycle times
• Will reduce scrap
• Will improve quality
• The equipment costs $150k
Financial business case
• Average of 3 batch failures per year at
cost of $80k each which can be
prevented
• Cycle time reduction of 25% - results in
capacity increase of 10% for this step –
can reduce additional shift work
resulting in savings of $60k per year
• Quality improvement resulting in 20
less OOS and deviation reporting per
year – this equates to a saving of 800
man hours ($75k)
• Total annual savings of $375k
• Project costs:
• The equipment costs $150k
• Development and Validation $60k
• Regulatory changes $50k
• Procedure and control system $100k
• Project management $60k
• Project time line of 6 months
• ROI – under 14 months (excl CoC)
Building a financial model
•
This may seem obvious but calculating the true financial cost of implementing
a PAT solution is typically an essential requirement from management
•
Costs fall into several categories
•
•
•
•
Investment costs (buying and validating the equipment)
Operational costs (consumables, cost of capital, increased training)
Hidden or other costs (eg contacting regulatory authorities to let them know of
change)
Likewise; for financial benefits:
•
•
•
Investment benefits (may not need to build additional line)
Operational benefit (increased yield, less routine analysis, ease of technical transfer)
Hidden benefits (improved staff satisfaction, perceived added value to product)
Engineering is
always difficult to
predict – normal to
build in a 10% buffer
Estimating costs
•
•
•
•
•
Costs are always more than the
equipment – typically the
equipment is only a minor
percentage of the implementation
costs
Use friends and colleagues to
help with estimates (or form a
team)
Unless the intention is to play
with the PAT solution it is wise to
consider the wider costs of
implementation (especially
control – without control there is
less financial benefit – see later)
Optionally – consider full costs;
this includes converting internal
time spend on the project to a
financial cost
There are also operational costs
to consider!
Consider internal
costs and convert to
financial numbers
Estimate
Alternative 1
Purchase and installation
NIR Analyser
Model building
Engineering
Validation
Integration into control system
System validation
Sub total, Purchase and installation
Contingency etc
Contingency
Inflation, 2007 to 2008
Sub-total
Estimate
100.000
30.000
30.000
30.000
100.000
100.000
390.000
10%
3%
39000
12870
441.870
Alternative 1
Internal costs
Feasibility and selection
Operational time
Materials and consumables
Project Management
Order of Magnitude Estimate:
5.000
30.000
5.000
80.000
120.000
Estimating financial benefits
•
A lot of factors can be distilled to finance
• Resource
• Time
Knowing the value
• Productivity
of the batch (or
similar) is crucial to
translate operational
benefit into financial
data
Estimate
Alternative 1
Yields
Typical yield
Improved yield
Number of batches per year
Typical batch value
Internal COGS
Value added
Estimate
Reducing scrap will add value
Alternative 1
Cycle times
69,5%
73,0%
90
100.000
40%
189.000
Alternative 1
Reduced scrap
Preventable batches scrapped
Typical batch value
Manufacturing value at time of scrap
Value added
Estimate
Gaining extra
capacity from the
facility may be of
benefit
Cycle times (batch to batch)
Improved cycle time
Number of batches per year
Typical batch value
Internal COGS
Value added
Estimate
72
68
90
100.000
40%
300.000
Alternative 1
Analytical testing
2
100000
70%
140.000
Number of analysts for assay
Company cost of analyst
Value added
Reducing personnel costs in an
obvious advantage
2
60000
120.000
Estimating the financial
cost/benefit
• Several models can be used
• ROI (Return on Investment)
• NPV (Net Present Value)
• FMC (Full Manufacturing Cost)
•
There are advantages and flaws with each
• Most small & short term PAT projects would fall into an ROI analysis
• If the projects are large and/or long term it may be worth considering a
NPV or FMC analysis
•
There may be an organisationally favourite way of presenting business
cases
• Find out which one it is and use it if relevant
ROI
• Return on Investment simply
•
•
•
•
compares the cost of the project
against it’s financial benefit
This is then translated into how
long it will take to repay the
initial investment
This simple model does not take
into account cost of capital or
project timings
Is useful for smaller, quick
turnaround projects
What is a ‘good’ ROI??
• Depends which organisation
you are in
• Size of project
• Many other factors
ROI in months
Values in USD
Income and/or savings
Yields
Cycle times
Reduced scrap
Analytical testing
Costs
Investment:
Purchase and installation
Internal costs
2008
599.000
189.000
150.000
140.000
120.000
631.870
561.870
441.870
120.000
Operational costs:
70.000
Analyst (50%)
60.000
10.000
Service
ROI
months
13
Discount factor (can be No savings until
changed depending on implementation
investment factors)
NPV
Discounting factor: 8%
USD
No utilisation
savings after 2010
due to capacity
change
Analysts can’t be
reassigned until
2011
Value of money 10 years
from now at todays value
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
0
100%
1
93%
2
86%
3
79%
4
74%
5
68%
6
63%
7
58%
8
54%
9
50%
479.000
189.000
150.000
140.000
479.000
189.000
150.000
140.000
449.000
189.000
449.000
189.000
449.000
189.000
449.000
189.000
449.000
189.000
449.000
189.000
449.000
189.000
140.000
120.000
140.000
120.000
140.000
120.000
140.000
120.000
140.000
120.000
140.000
120.000
140.000
120.000
350.935
280.935
220.935
60.000
360.935
280.935
220.935
60.000
80.000
0
80.000
0
80.000
0
330.000
250.000
190.000
60.000
80.000
0
80.000
0
80.000
0
80.000
0
Operational costs:
70.000
80.000
80.000
80.000
80.000
80.000
80.000
80.000
80.000
80.000
Analyst (50%)
60.000
10.000
60.000
20.000
60.000
20.000
60.000
20.000
60.000
20.000
60.000
20.000
60.000
20.000
60.000
20.000
60.000
20.000
60.000
20.000
Year number:
Discounting:
Income and/or savings
0
Yields
Cycle times
Reduced scrap
Analytical testing
Costs
Investment:
Purchase and installation
Internal costs
Service
Total
USD
Cash flow:
-350.935 118.065 399.000 369.000 369.000 119.000 369.000 369.000 369.000 369.000
NPV:
1.577.394 -350.935 109.319 342.078 292.924 271.226
80.989 232.533 215.308 199.359 184.592
Net Present Value of
project over 10
years
Analytical specialist
needed from project
start
Investment costs
spread over 2 years
Further investment
needed in 2013
Total cost per kg of
product (traditional)
FMC
Raw materials costs
Wages, Salaries and Other Employee
Consumables & Other Expenses
FMC07
Wages, Salaries and Other Employee
Depreciation
FMC09
Cost of Capital
FMC12
Primary input data:
kg per year
1) Raw materials cost
2) Number of employees, FMC07 related
Additional FMC09 related (Total plant)
Average Salary etc. per FTE
3) Calculated as percentage of Wages etc.
Very inexact !
4) Investment - Building
Investment - Production Equipment
Depreciation - Years - Building
Depreciation - Years - Equipment
5) Cost of Capital
Calculation 1
Total per year
FMC
USD
USD per kg
4.125.000
55,00
2.520.000
33,60
2.394.000
31,92
120,52
900.000
12,00
2.280.000
30,40
162,92
1.840.000
24,53
187,45
Calculation 1
75.000
55 USD per kg
42 FTE
15 FTE
60.000 per FTE
8%
Calculation 2 (PAT)
Total per year
FMC
USD
USD per kg
3.750.000
50,00
1.800.000
24,00
1.764.000
23,52
97,52
720.000
9,60
2.075.000
27,67
134,79
1.600.000
21,33
156,12
Primary input data:
kg per year
Calculation 2 (PAT)
75.000
1) Raw materials cost
50 USD per kg
2) Number of employees, FMC07 related
Additional FMC09 related (Total plant)
Average Salary etc. per FTE
3) Calculated as percentage of Wages etc.
Very inexact !
70%
7
16
25
8
Raw materials costs
Wages, Salaries and Other Employee
Consumables & Other Expenses
FMC07
Wages, Salaries and Other Employee
Depreciation
FMC09
Cost of Capital
FMC12
Total cost per kg of
product (PAT)
Million USD
Million USD
Years
Years
4) Investment - Building
Investment - Production Equipment
Investment - PAT
Depreciation - Years - Building
Depreciation - Years - Equipment
5) Cost of Capital
30 FTE
12 FTE
60.000 per FTE
70%
5
11
4
25
8
Million USD
Million USD
Million USD
Years
Years
8%
Less staff needed in PAT facility
Less invesment in building and process
Additional investment
in PAT
Soft factors & Risk
• We live in a complex world so it is not always possible to put a
financial value on everything
• It is also vital to consider business risk to the investment or
benefits
• This may be the possibility of the project costing more or taking longer
• The risk of the project actually failing
• Benefits not being realised
• Soft factors and risk can be listed - but more convincing is to try
and attribute semi-quantitative values to them so decisions can be
made
• Adding values to soft factors and risk is a good way to try and
select the right projects to start with from many competing projects
Soft factors & Risk
Criteria (non financial)
Separate PAT projects
Weight
PAT 1
PAT 2
PAT 3
PAT 4
PAT 5
PAT 6
PAT 7
PAT 8
PAT 9
PTS
45%
1,8
2,8
3,7
2,3
2,4
3,0
3,5
1,2
2,3
Technology
Process
Automation
70%
25%
5%
1,5
2,5
1,5
3,0
2,5
2,0
3,5
4,0
4,0
2,0
3,0
2,5
2,0
3,5
2,5
3,0
3,0
3,0
3,5
3,5
3,5
1,0
1,5
2,0
2,0
3,0
3,0
People
20%
2,4
2,1
3,2
2,0
2,2
2,6
3,3
1,6
2,2
Training
Strike action
Morale
20%
40%
40%
2,0
2,5
2,5
1,5
2,0
2,5
3,0
3,0
3,5
2,0
2,0
2,0
2,0
2,5
2,0
3,0
3,0
2,0
3,5
3,5
3,0
1,0
2,0
1,5
2,0
2,5
2,0
Quality
15%
2,3
2,3
3,7
2,3
2,4
3,0
3,5
1,8
3,0
FDA delay in acceptance
Inspection issues
Internal quality issues
40%
40%
20%
2,0
2,0
3,5
2,5
2,0
2,5
4,0
3,5
3,5
2,0
2,0
3,5
3,0
2,0
2,0
3,0
3,0
3,0
3,5
3,5
3,5
2,0
1,5
2,0
3,0
3,0
3,0
Strategic fit
10%
2,2
2,6
2,3
2,0
3,1
2,6
2,5
1,9
1,8
Future expansion
Influence and relations
Fast regulatory approval
20%
30%
50%
2,5
1,5
2,5
3,5
2,0
2,5
2,0
2,0
2,5
2,0
2,0
2,0
3,0
4,0
2,5
2,5
2,0
3,0
2,0
2,0
3,0
3,0
1,0
2,0
2,5
1,0
2,0
Partners and outsourcing
10%
2,0
3,0
4,0
3,0
2,3
3,0
3,7
1,7
3,7
Inability to deal with change
More effort to educate
30%
70%
2,0
2,0
3,0
3,0
4,0
4,0
4,0
2,5
3,0
2,0
3,0
3,0
4,0
3,5
2,0
1,5
4,0
3,5
100%
2,0
2,6
3,5
2,3
2,4
2,9
3,4
1,5
2,5
8
4
1
7
6
3
2
9
5
Total
Rank according to
implementation:
Weighting to define
importance of factors
Total soft factor score
Project rank – soft factor only
Using finance and soft factors
• To help make decisions on which projects should go forward
• Compare soft factors against financial factors
• Visualise for most impact
• Care need to be taken to categorise projects
• Care needs to be taken in comparing major (eg 5 million USD) and
•
•
small (eg 500k USD) projects
Both may have the same ROI (but will have radically different NPVs or
FMCs)
Compare like projects
Visualisation
NPV vs soft factors
Financial
attractiveness
NPV, Index
(on costs only)
Financial
attractiveness
NPV, Index
(on costs only)
PAT
2
3 mil.
15 mil.
PAT
9
PAT
1
PAT
3
2 mil
PAT
8
PAT
4
PAT
5
10 mil
PAT
7
PAT
6
5 mil
1 mil
1
2
Soft Factor Score
1= low, 4= high
3
4
1
2
3
Soft Factor Score
1= low, 4= high
4
Business Case Success
• Projects are always in competition with each other
• If a project is good it needs to be translated into benefits (preferably
financial)
• Calculating costs and benefits is an estimation game
• Use similar tools to what is typically used in the organisation
• Present the case in the best possible financial light to win project
funding