Real Time Release Testing
Line Lundsberg-Nielsen, NNE Pharmaplan
PAT seminar , 6 October 2010
Outline
• What is Real Time Release Testing (RTRT)
• How QbD provides the opportunity for real-time release
testing in lieu of end-product testing: QbD, PAT & RTRT
• Minimal versus Enhanced Control strategy
• How to develop a control strategy facilitating RTRT:
Linking CQAs, CPPs, DS, CS
• Implementation of RTRT, practical issues
• Examples of cost reduction – benefits by introducing
RTRT
• Organisational aspects of changing to RTRT
• Conclusion
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Real Time Release Testing, NNE Pharmaplan 2010
What is real Time Release testing
What is Real Time Release Testing?
• Real Time Release Testing (RTRT) is defined in ICH Q8(2):
– The ability to evaluate and ensure the quality of in-process
and/or final product based on process data, which typically
include a valid combination of measured material attributes
and process controls
• Real time release testing can replace end product testing, but does not
replace the review and quality control steps called for under GMP to
release the batch.
• Real time release testing is “moving the QC lab into the process” and
“measure the CQAs where they are generated”
• Parametric Release: One type of RTRT. Parametric release is based
on process data (e.g. temperature, pressure, time for terminal
sterilization) rather than the testing of a sample for a specific attribute
(ICH Q8 Q&A).
• Batch release: Approved RTRT may form a basis but more aspects
needs to be taken into account in the decision of a Qualified Person to
release a batch. These aspects could include batch results of testing for
an attribute not subject to RTR T as well as specific GMP requirements.
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Real Time Release Testing, NNE Pharmaplan 2010
Controlling CQAs and CPPs
• The QbD approach helps to identify what is
critical for the product quality incl what to
control, where and how
• Focuses on what matters – and not
controlling every thing
• Reduced risk of failure of important controls
• Critical Quality Attributes can be measured
in real-time during manufacturing
• Quality decisions can be made using
these measurements to
– Control and adjust the process
as needed
– Make go/no-go decisions
– Replace IPC or add more value to IPC
– Real time release testing to
replace end product testing
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Real Time Release Testing, NNE Pharmaplan 2010
End product testing
INPUTS
FIXED
PROCESS
OUTPUT
Disturbance
Several days
later...
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Real Time Release Testing, NNE Pharmaplan 2010
QC end
product
test result
Real Time Release Testing
ARMA filter
Finding denoised
Gradient
SattLine
NIR interface
SIGN function
Zero Crossing + Matched Detector filter
Process analyzers used to measure the
process parameters and adjust the process
Y
3,0
2,8
2,6
2,4
2,2
2,0
1,8
1,6
1,4
INPUTS
ADJUSTABLE
PROCESS
OUTPUT
Disturbance
Immediately!
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Real Time Release Testing, NNE Pharmaplan 2010
Example:
API purity – controlling reaction by NIR
• Reaction developed and understood during
development – typical tools are IR, NIR and Raman
• At commercial scale NIR is used to control the
reaction
• Stop the reaction at Maximal API Concentration
• Stopping time differs from Batch to Batch
• Real time release measurement of the API assay and
bi-product (impurity)
• No sampling for in-process control or end-product
testing for this CQA
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Real Time Release Testing, NNE Pharmaplan 2010
Benefits by introducing Real Time Release Testing
•
•
•
•
•
•
•
•
•
The outcome of a high level of process understanding
Controlling the process
Adjust for variability in raw and in-process materials
Increase yield, reduce waste, scrap
Reduce the risk of losing a batch
Reduced QC test
Increased control activity on the manufacturing shop floor
Reduced cycle time
Real time monitoring of CPPs and CQAs for free (must also be included in
continuous process verification and Annual Product Review)
• Quality of the finished product can be measured during manufacturing –
no surprises!
• Regulators might be more interested in the beginning but this will fade as
process understanding has been demonstrated – reduced inspection
frequency
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Real Time Release Testing, NNE Pharmaplan 2010
Challenges by introducing Real Time Release Testing
• New – not familiar to many
• PAT tools in place (in-line analysers, PAT data management, multivariate
data analysis, process control)
• Require new skills and reorganisation of work
• Risk associated with implementing PAT
– Installation of probes, representative sampling, failure of instrument,
failure of multivariate models, failure in feed forward & backward
controls, etc
• Backup strategy must be in place
• Models needs frequent update
• If RTRT fails it cannot be replaced by end-product testing
• Regulators might be very interested in the beginning...
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Real Time Release Testing, NNE Pharmaplan 2010
Quality by Design (QbD),
Process Analytical Technology (PAT) &
Real Time Release Testing (RTRT)
What is QbD really about?
The patient.....
QbD and PAT links
the patient,
product and process
• Understanding what the patient needs
• Designing and developing a product meeting these needs
• Designing and developing a manufacturing process
capable of delivering the product that meets these needs
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Real Time Release Testing, NNE Pharmaplan 2010
Process
Understanding
Quality by Design, QbD
Definition:
A systematic approach to development that begins with predefined
objectives and emphasizes product and process understanding
and process control, based on sound science and quality
risk management
Control Strategy
(PAT, RTRT)
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Real Time Release Testing, NNE Pharmaplan 2010
ICH Q8(R2)
PAT and Real Time Release Analysis
CQAs and
CPPs
In-line & on-line
analysers
Process Analytical Technology is:
A system for designing, analyzing, and
controlling manufacturing through timely
measurements (i.e., during processing)
of critical quality and performance
attributes of raw and in-process materials
and processes with the goal
of ensuring final product quality
Predictive
ICH Q8
models
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Real Time Release Testing, NNE Pharmaplan 2010
Real Time
Release Testing
QbD in One Page – small molecule
Quality Target
Product Profile
Id
Id
CQAs
CQAs
Quality
target
Product
profile
(QTPP)
Critical Quality
Attributes
What is
critical
to the
Patient
PAT
QRM
Critical Process
Parameters
Id
Id
CPP
CPP
andMaterial
Material
and
attributes
attributes
Material
Attributes
Design Space
Design Space
•5
•4
•3
•2
•1
•0
••1
••2
••3
••4
••5
••6
••7
••1•0•1•2•3•4•5•6•7•8•9•1
•0•1
•1•1
•2•1
•3•1
Control Strategy
SOP
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Control Strategy
PAT
PAT, RTRT
Real Time Release Testing, NNE Pharmaplan 2010
PAT
PAT,
RTRT
SOP
QbD in One Page – large molecule
Quality Target Product Profile
R&D
Quality
Risk
Assessment
Design
Space
Upstream
Downstream
Formulation,
Fill & Finish
Control
Strategy
Production
Implemented
Control
Strategy
Based on ISPE/PQLI 2009 A-Mab Case Study
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Real Time Release Testing, NNE Pharmaplan 2010
Control Strategy
Control Strategy
• A planned set of controls, derived from current product and
process understanding, that assures process performance and
product quality.
• The controls can include parameters and attributes related to
drug substance and drug product materials and components,
facility and equipment operating conditions, in-process controls,
finished product specifications, and the associated methods and
frequency of monitoring and control. (ICH Q10)
Manual
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Simple
Real Time Release Testing, NNE Pharmaplan 2010
Advanced, automated
Control Strategy
Every product MUST have a control strategy
Minimal
• Drug product quality controlled
primarily by intermediates (inprocess materials) and end
product testing
Enhanced
• Drug product quality ensured
by risk-based control strategy
for well understood product and
process
• Quality controls shifted
upstream, with the possibility of
real-time release testing or
reduced end-product testing
ICH Q8
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Real Time Release Testing, NNE Pharmaplan 2010
Laying out the control strategy
1.
2.
3.
4.
5.
•
•
•
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Identify CQAs
Identify related CPPs and Material Attributes (MAs)
Develop the design space for the CPPs and MAs
Develop the control strategy ensuring the CPPs and MAS are
always within the design space
Based on risk-assessment plan how the control strategy can
be implemented
This process starts in development
It is a lifecycle activity and
The Control Strategy can be updated as new knowledge has
been gained
Real Time Release Testing, NNE Pharmaplan 2010
Linking it all together
CQAs, CPPs, Design Space,
Control Strategy
Oral solid dosage, API synthesis and dry granulation roller
compaction process
Based on PQLI CS work
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Real Time Release Testing, NNE Pharmaplan 2010
Oral solid dosage
•
•
•
•
Content Uniformity (CU) has been identified as CQA
API Particle Size Distribution (PSD) has an impact on CU
Design Space has been developed for the API PSD
Unit Operations having an impact on the CU is:
– Drug Substance
• Reaction – impact on PSD
• Crystallisation – impact on PSD
• Drying – impact on PSD
– Drug Product
• Dispensing – API PSD
• Blending - homogeneity
PSD: 80-160 μm
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Real Time Release Testing, NNE Pharmaplan 2010
PSD: 6-20 μm
Defining the Control Strategy
1
2
3
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Real Time Release Testing, NNE Pharmaplan 2010
Control Strategy Challenge:
API - link between CQAs and Controls
Input
Materials
Ethanol
Reaction
Crystallisation
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Real Time Release Testing, NNE Pharmaplan 2010
Drying
Based on PQLI CS work
Control Strategy Challenge:
Drug Product - link between CQAs and Controls
Raw
Materials
Blend
Blend
Mill
Mg Stearate
RC/Mill
Final
Blend
Compress
Film Coat
Packaging
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Real Time Release Testing, NNE Pharmaplan 2010
Based on PQLI CS work
Summary: Control Strategy for CU – RTRT
API Control Strategy
CQA
Content
Uniformity
CPP or MA
Unit
Operation
Controls
Reaction
PSD: Ratio of EtOH/API
On-line NIR
Concentration
(feedback control)
Crystallization
PSD Specification
FBRM PSD, determination
Cooling Rate
Automated process
control
Drying
Drug Product Control Strategy
CQA
Content
Uniformity
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Unit Operation
CPP or MA
Controls
Dispensing
API PSD
Obtained from API CoA
Final blend
API Blend uniformity
On-line NIR
Real Time Release Testing, NNE Pharmaplan 2010
Implementation of
Real Time Release Testing
Practical issues related to implementing the RTRT
• The Pharmaceutical Quality System must support the operation of the control strategy
• Make a Risk Assessment focusing on the potential failure mode of operating the Control Strategy and
RTRT
– What if the RTRT fails?
• Examples of additional elements to the Pharmaceutical Quality System:
– Responsibilities – Q involvement
– How to control the process – automation, feedback, feed-forward, manual
– Alarms
– Sampling
– Data trending
– OOS definition
– Batch release strategy
– Equipment mal-function strategy
– Updating and validation of multivariate models
– Training
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Real Time Release Testing, NNE Pharmaplan 2010
Examples
Conventional testing versus
Real-time release testing
Assay (HPLC)
Purity, related
impurities, ((HPLC)
Residual solvent (GC)
Moisture content (KF)
Heavy Metals
Etc…
Dispensing
NIR, at-line (id raw materials)
Reaction
NIR, on-line (reaction id)
Purification
IR, on-line (purity, assay)
Crystallisation
FBRM, on-line (PSD)
Drying
NIR, on-line (Moisture, purity
LAB
ID, Assay, CU (HPLC)
Purity, ((HPLC)
Dissolution,
Appearance
Moisture content (KF)
Etc…
Dispensing
NIR, at-line (id raw materials)
Blending
NIR, on-line, blend homogeneity
Compression
NIR, on-line (assay, CU, ID)
Coating
Vision, on-line (appearance)
LAB
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Real Time Release Testing, NNE Pharmaplan 2010
CQA: CU, dissolution, ...
Crystal size during formation - PSD
• Focuses beam reflectance
measurements can be used to
measure PSD
• Measure crystal diameter
• Probe inserted into reactor
Ref: Figure Pfizer
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Real Time Release Testing, NNE Pharmaplan 2010
RTRT of PSD
• FBRM used to
define the best
cooling ramp
• FBRM used to
measure PSD inline
• RTRT of PSD
• No sampling and
QC test
Ref: Figure Pfizer
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Real Time Release Testing, NNE Pharmaplan 2010
Design Space for drying
Effect of inlet temperature and air flow on degradation and generation of fines
Inlet temperature
Inlet temperature
Inlet temperature
Degradation and fines
Fines
Degradation
+
Air flow
=
Air flow
Air flow
Ref: Mock P2
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Real Time Release Testing, NNE Pharmaplan 2010
Design Space
and Control Strategy for drying process
18.5%
17.5%
Regions of uncertainty
Known edge of failure due to fines
%
H2O
Known edge of failure due to degradation
Trajectories describing the
boundaries of the design space
where product quality is assured
2.0%
1.5%
Drying time
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Real Time Release Testing, NNE Pharmaplan 2010
Example, Mock P2, picture: Pfizer
Fluid bed drying - NIR
Ref S. Hammond, Pfizer
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Real Time Release Testing, NNE Pharmaplan 2010
RTRT of moisture content by NIR
Fluid bed drying
R5D2DP.DAT
Pfizer Ltd. / Aspect Plus V1.52
Filter cleaning
Dry
-1.2
-1.4
-1.6
FBD2R2D2.DAT
Peak Height
Decreasing With Drying
0.8
-1.8
Pfizer Ltd. / Aspect Plus V1.62
-2.0
40
80
120
160
Wet
200
Product
0.4
sec
[10E-4]
SECT: RUN5D2.DAT / 1409.2nm
Sep.21.2000/11:51:25AM
-0.0
•
•
•
•
RTRT of moisture content
No sampling
No waiting for LoD results
Reduced risk of processing
poor quality material
-0.4
-0.8
Real Time Release Testing, NNE Pharmaplan 2010
Water
1410
1430
nm
[10E-4]
1
37
Peak Height
Increasing With
1450Drying 1470
2
Sample values
3
4
May.11.2001/11:46AM
5
6
7
8
9
10
Ref S. Hammond, Pfizer
Tablet dissolution, real time release
Material
FBRM
attributes PSD
Process
Process
Process
Parameters Parameters Parameters
100
90
6
70
Dry Mix = 62µm
1.5 min = 75µm
3 min = 79µm
4.5 min = 86µm
6 min = 95µm
7.5 min = 105µm
9 min = 120µm
10.5 min= 150µm
12 min = 180µm
Equivalent Vol%
5
4
3
Dissolution, predicted
80
At-line FBRMMeasurement in Acetone
60
50
Multivariate
calibration
2
5m in
40
10m in
30
15m in
20
30m in
20m in
45m in
10
1
60m in
0
0
0
10
100
1000
20
40
60
Dissolution, ref
80
100
Chord Length (µm)
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Real Time Release Testing, NNE Pharmaplan 2010
Based on case by Higgins, MSD, 2009
Cost savings, example from AstraZeneca
•
•
•
•
•
First batch released October 18th 2007
4 days from start of manufacture to release
Batch packed on Friday October 19th 2007
Batch on the market Monday October 22nd 2007
Substantial cost savings on stockholding and QC
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Real Time Release Testing, NNE Pharmaplan 2010
Thanks to Rob Hughes – AZ
Organisational Aspects
RTRT versus traditional QC lab
RTRT :
the end of
traditional QC labs ?
Or
The start of
A more cost effective business model
facilitating “Right first Time” and
continuous improvement
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Real Time Release Testing, NNE Pharmaplan 2010
Organisational impact
• Fewer people in the QC doing traditional end-product testing but more people
involved in updating, maintaining and validating PAT applications (multivariate
models)
• Fewer people in manufacturing due to less scrap & shorter lead time
• More people in manufacturing to execute the control strategy
• More training and new skills – empowering of people
• More cross-functional team work upfront
– Risk Assessments
– Establishing the business processes
• Different approach to Quality
– Cross functional approach
– Quality decisions
– Role of QP
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Real Time Release Testing, NNE Pharmaplan 2010
?
Conclusion
•
•
•
•
Real Time Release Testing is a QbD option – not a requirement
RTRT requires the application of PAT and PAT data management
RTRT approved by health authorities
Huge savings reported by Big Pharma
• When the challenge of implementing a new way of working has
been addressed, huge benefits
• Can be applied to new and marketed products
• The Generic Industry is also very interested in RTRT – help to
reduce cost
• Ties perfectly with continuous manufacturing
• Will be a competitive advantage – if not already so!
• Good luck!
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Real Time Release Testing, NNE Pharmaplan 2010
Thank you for your attention!
llun@nnepharmaplan.com
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Real Time Release Testing, NNE Pharmaplan 2010
Is RTRT like
the beautiful
woman or the
old witch?