Qualification of Pat Based Control Strategies For Batch and Continuous Manufacturing Presentation PDF - Watermarked and Locked PDF

ED
RV
SE
RE
Qualification of PAT Based S
Control Strategies for H T
Batch and Continuous IG
Manufacturing R
L L
A
–
Webinar Presented by the ISPE PAT & LCS
Communities of Practice
P E
IS
Speakers: Line Lundsberg-Nielsen, Lorenz Liesum &
Martin Warman
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24 September 2019
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©
Moderator/Speaker ED
RV
Line Lundsberg-Nielsen, PhD
SE
Managing Consultant
RE
S
NNE
H T
I G
Line is a physicist working as a Managing Consultant at NNE. She holds a
R
Ph.D. in NIR spectroscopy. Her background is pharmaceutical manufacturing
L L
and development. She works as a consultant focusing on Science & Risk
based approaches in terms of QbD, PAT, Control Strategy, Process Validation,
A
Qualification and Pharma 4.0. Line has been a member of ISPE for +15 years
–
and has served many roles. She is currently the chair of the global PAT &
LCS CoP.
P E
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© Connecting Pharmaceutical Knowledge ISPE.org 2
ED
RV
SE
RE
T S
Introduction H
I G
Line Lundsberg-Nielsen, NNE R
L L
A
–
P E
IS
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©
Agenda ED
RV
• Introduction (Line Lundsberg-Nielsen) SE
•
RE
Commissioning and Qualification (C&Q) for PAT Systems (Lorenz Liesum)
• S
Science and Risk Based Approach to PAT qualification (Martin Warman)
T
• Q&A H
I G
R
L L
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–
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Introduction ED
RV
• For both batch and continuous manufacturing,
SE
on- and in-line analysers are used in the
framework of PAT (Process Analytical RE
Technology) for controlling and monitoring unit
T S
operations in pharmaceutical operations
H
I G
• R
To utilise this technology in a GMP production
L L
environment the instruments, their interfaces
A
and the related Control Strategy must be
–
commissioned and qualified before
analytical method P E
proceeding to the validation of the PAT based
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Qualification of a PAT Based Control System ED
R V
• Often a very complex system
S E
• A hybrid of a stand-alone analytical lab
instrument, a manufacturing equipment and an
R E
S
automation system
• Include elements such as:
• An analytical instrument with PC based control
H T
• Physical interface between a probe and the
I G
R
manufacturing equipment
• Data interfaces to the process control system,
historians, MES, LIMS etc
L L
A
• Feedback and feedforward automated control
loops
–
• Reporting and storage functionalities
• How to qualify these PAT basedE
P control systems?
IS
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What Are You Going to Hear During This E D
Webinar?
R V
Share practical examples, S E
R E
highlighting different approaches on
how to commission, qualify and verify T S
H
PAT systems designated for I G
sophisticated control strategies R
L L
in the most efficient and A
resource-saving way –
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Questions to Be Discussed During the Webinar ED
R V
• Is qualification always required when bringing PAT into
S E
manufacturing?
• What is the instrument vendor covering during C&Q in R
E
relation to the PAT system? S
• How is the PAT qualification task linked to method T
H
validation ?
I G
R
• What is a science & risk-based approach to qualification
of PAT systems?
• What are important points to consider L
L
A
when defining the
URS for a PAT based control system?
–
E
• How should the integration and automation be managed
during qualification?
S P
• What is expected in terms
I control strategy?
of cost and resources for
9
qualification of a PAT based
1
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Qualification Approaches ED
RV
Classical Science & Risk based
SE
• Equipment commissioning & qualification E
• Verification of the control strategy
R
S
• FAT, SAT, DQ, IQ, OQ, PQ • Based on CQA, CPP, Critical Aspects
• V model T
• QRM from CQAs to URS & Qualification plan
H
I G
R
L L
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–
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Two ways to reach the same destinationED
V
- a qualified PAT system ready in manufacturing
R
SE
RE
T S
The classical H
G
The science & risk based
qualification approach:
Applying the V-model
R I approach:
Applying Science & Risk
Lorenz
L L
A Martin
–
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Poll 1 ED
RV
Have You Ever Qualified SE
a PAT System? RE
T S
1. Yes, for use in operation in a GH
GMP environment R I
2. Yes for use in development L L
A
–
3. No, PAT is only used for
creating supportive E
data
P
IS PAT so far
4. No experience with
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ED
RV
SE
Commissioning and R E
Qualification (C&Q) for T S
PAT Systems H
Lorenz Liesum, Novartis
IG R
L L
A
–
P E
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©
Speaker ED
RV
Lorenz Liesum, PhD
SE
Novartis Technical Operation RE
Global PAT Head, Manufacturing Science and Technology
T S
H
Lorenz studied Chemistry and Mathematics and holds a Ph.D. in Physical
I G
Chemistry from ETH Zurich. He started his industrial career as an analytical
R
scientist in chemical and pharmaceutical development at Roche and Novartis.
L L
Since more than 10 years he is working in the field of Process Analytical
A
Technology and was involved in regulatory QbD filings.
–
He is leading the Statistics and PAT group within global Manufacturing Science
P E
and Technology in Novartis Technical Operation supporting the production
sites globally for all statistical relevant topics and managing PAT and QbD
IS
implementation with a strong focus on advanced control strategies based on
9
NIR spectroscopy and multivariate statistical process control.
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Agenda ED
RV
• Introduction S E
• What is so special about the qualification R
E
of a PAT systems?
• The “classical” qualification approachT S
H
• Lesson learned from case examples IG R
L L
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–
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What is a PAT System? ED
R V
“A system for analysing and controlling manufacture through timely measurement
of critical quality and performance attribute” (PAT definition according to PAT, ICH and EMA Guidances)
S E
R E
T S
H
G
PCS
Manufacturing
Equipment
R I
L
Process Control
A L
–
Probe
P E PAT Control
IS
PAT Sensor CoA
PC
1 9 Process Monitoring/
Release
2 0
PCS: Process Control System, CoA: Certificate of Analysis

When and Why Do We Need a Qualified PAT System? E D
R V
• Qualification is the collection of documented evidence that S E
an instrument performs
R E
suitably for its intended purpose and is a perquisite for method validation
• Qualification is not needed for PAT systems used
in the framework of process development and scale T S up
H
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R
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Focus of this
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webinar
© 2 Connecting Pharmaceutical Knowledge ISPE.org 16

The «Classical» Approach ED
RV
Reference:
SE
E
 FDA guidance for Industry on Process Validation (January 2011)
R
 ISPE Baseline Pharmaceutical Engineering Guide, volume 5
T S
• Qualification is the demonstration of suitability for intended use which has
been formally documented and approved by the Quality Unit
H
I G
• Commissioning is a well planned, documented and managed engineering
approach following Good Engineering Practice (GEP)
R
L L
• Equipment qualification and method/process validation are decoupled
A
–
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Why Is the Qualification of a Pat System Not That E D
Straight Forward? R V
S E
It is neither fish nor fowlR
E
T S
H
I G and a manufacturing equipment
• It is a hybrid between an analytical instrument
• It is a mixture between COTS (spectrometer)R and custom-built elements
(automation, probes)
L L
• PAT systems are not dedicated forAone specific process
–
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Why to Bother about Qualification? ED
RV
SE
• It is a costly and long process, whereas the cost can exceed the spectrometer
price by a multiple
RE
T S
• The value of the qualification exercise in comparison to the method
development/validation is limited and very much compliant driven
H
G
• There are more complex systems (Pharma 4.0/AI/CM) to come in the future which
I
all will requite a sound qualification process
R
L L
A
–
Consequently, there is a strong interest for a more lean and cost-effective
qualification process
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Qualification of Analytical Equipment E D
R V
Analytical devices are not custom built, they are commercialS offEthe shelf (COTS)
As a consequence:
R E
 IQ und OQ scripts are written by the vendor T S
 Functional and design specification are supplier responsibility
H
 There is no «real» PQ needed
I G
R
The scope of the qualification encompasses “only”:
 URS
L L
A
 High level risk assessment (including audit risk assessment)
 Qualification plan
–
P E
 IQ/OQ plans and reports with contributions of the vendor
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Qualification of Manufacturing Equipment ED
R V
Manufacturing equipment is custom built S E
As a consequence:
R E
 Functional risk and impact assessment T S
 Full V-model has to be applied including functional and design specification
H
 Traceability matrix referring to the URS
I G solution applied
R
 GAMP assessment of the software and automation
 Tailor-made IQ, OQ and PQ protocols
L
 Stringent change and discrepancy managementL under QA oversight
A
–
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Qualification of a PAT Installation ED
R V
Mechanical:
S E Automation:
Design/P&IDs
Piping/cabling
R E Data transfer and
PCS
Manufacturing interfaces
S
Fittings Equipment Data
T
Safety (ATEX) storage/integrity
H Control logic
G
Involvement: P
URS,DQ,IQ,
OQ,PQ
r
o
b
R I Involvement:
URS,
e
L L FS,HDS,SDS,IQ,
A
OQ, PQ
PAT Sensor PAT Control
– PC
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PAT Expert:
Selection of sensor, probe design, method development and validation
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Involvement: URS, IQ, OQ, method validation and PQ
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©
22 Connecting Pharmaceutical Knowledge ISPE.org 22
Scope of Qualification ED
R V
S E
Spectroscopic performance,
E
e.g. resolution, wavelength
R
accuracy
Per USP 1119, Phar. Eur. 2.9.40
Off the shelf
SpectrometerTS
H
HSE, Ports and CIPs
I G Data integrity,
R
21 CFR Part 11
L L
A
–
E
Data storage,
Customized Mechanics Automation
P
Transfer
IS
Feedback
control loops
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Development of the User Requirement Specification E D
R V
Spectroscopic requirements
S E
 Resolution, mode of measurement , wavelength range
 Meeting Pharmacopeia requirements, e.g. (USP <1119> and Phar. R E
Eur. 2.2.40 for NIR instruments)
Mechanical requirements
 Interface with manufacturing equipment, e.g. size of port T
S
H
 Cleaning procedures
I G
R
 Length of optical cable
ATEX requirements
Automation requirements L L
 Data interfaces to other data bases, e.g.A
OPC
–
 Data integrity requirements, e.g. 21 CFR part 11
 Control loops
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Optional: Method specific requirements
 Method accuracy and precision
 LOD/LOQ
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Open Question for the URS ED
RV
Should product & process specific requirements be incl in the URS? SE
RE
Example: Measurement of water with LOQ
T S
of 1% and bias to the reference of 0.3%
H
+ Allows for a risk based approach
I G
- The instrument will be used for many R
products and on different machines
L L
A
- For completion of the qualification a
–
validated method would be needed to
P E
verify these requirements in a PQ
- Any changes would fall under change
IS
management process under QA
oversight
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Case Examples ED
RV
On-line NIR system for an API drying process measuring two solvents SE
• Tailor made probe with flushing system
RE
• Automated control of process based on NIR signal
T S
H
• Quantitative model for solvent concentration with defined performance
specification
I G
R
L L
A
–
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IQ/OQ, Method Valdiation and PQ ED
R V
S E
R E
IQ OQ of PAT Method
T S Performance
H
qualification and
sensor and development and process
G
automation validation
I
validation
R
Qualification of the
L L
Method developed
PQ with the
Project Scope
NIR instrument, data
Aon the qualified
validated method
–
interface to PCS stopping the drying
URS system and
and the port to the process
E
validated
dryer automatically
P
IS
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Lessons Learned from a Small Molecule Example E D
R V
S E
• Long and costly exercise with a need to educate the involved team members, in
particular QA
R E
process aspects T S
• Changes can be tedious when URS is comprising equipment, product and
H can be very cumbersome, i.e.

G
• The coordination between the involved vendors
I
machine and PAT vendor
R
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Poll 2 ED
RV
Do you think the qualification of SE
an automated control system,
RE
including PAT, is?
T S
H
1. A straight forward, standard I G
procedure which is well under R
control L L
2. A tedious, time and cost –
A
intensive
exercise
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3. I have made no experience so far
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ED
RV
SE
Science and Risk Based R E
Approach to PAT T S
qualification H
IG R
Martin Warman, Martin Warman Consultancy Ltd
L L
A
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©
Speaker ED
R V
Martin Warman
SE
Director
RE
Martin Warman Consultancy Ltd and a Professor of Practice at University of
Strathclyde
T S
H
I G
Martin spent 7 years at Vertex, developing the Vertex continuous manufacturing (CM)
R
platform, on which the first approved CM products are manufactured.
L L
He has over 25 years’ experience in the field having previously led the Global PAT
A
Development Team, Pfizer Global Manufacturing. Martin is on the Exec Committee of
– committee and chairs the UK Affiliate PAT CoP.

ASTM E55, chairing ASTM E55.01 PAT, is on the ISPE PAT Community of Practice
(CoP) global steering
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Part of this role at University of Strathclyde includes supporting the Centre for
ResearchIS
Process Analytics and Control Technology (CPACT) and CMAC Future Manufacturing
Hub as well as being on Technical Advisory Committee (TAC) for the new
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Medicines Manufacturing Innovation Centre (MMIC) being built in Renfrewshire,
1
0
Scotland.
©2 Connecting Pharmaceutical Knowledge ISPE.org 31

PAT Installations are Complex ED
RV
S
• They include specification and qualification of instrument hardware E
R E
• To ensure they are capable of executing the validated PAT method
• Connection of the hardware to external systems
• To allow them to run under recipe control T S
H
• To allow control decisions to be made
I G
R
• For control actions to me taken
• For product disposition
L L
• They are also not all the same– A
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How are PAT Methods Different? ED
R V
• All PAT methods have their own •
S E
PAT methods have risk loadings
• Specifications for PAT hardware
•
R E
PAT method acquiring data but not making a
control decision
• Data collection/ ‘sampling’
•
•
T S ‘low risk’
Making a control decision which is
H confirmed/checked downstream
• Installations can range from I G • ‘medium risk’
R • Making a control decision that is the final
L
• ‘Non-configured’ decision around product disposition
• Configured
A L •
• ‘high risk’
PAT methods can have multiple data sources
• Custom
– • E.g. speed of powder flow is used as an input
P E •
for a spectroscopic model
More complex
IS • Data from in multiple locations, and mass flow
9
models are used to ‘track’ the material as it flows
1
through the process
2 0
Why Do We Need a Science and Risk Based Approach? E D
R V
• A traditional approach assumes…. S E
E
type, method risk and data source complexity R
• ‘Worst case’ PAT hardware qualification, but also data frequency, integration
S
• Qualification of many functions/complexitiesTwhich do not apply
H
• More importantly only qualifies a ‘snapGshot’ (set of frozen capabilities) of
time of qualification R I
L L
• There is no verification if that functionality has changed
A
• Vendors develop ‘one-off’ functionality for clients (custom code), but then
– off-the shelf (COTS) offering – reduces risk
incorporate into their commercial
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Science and Risk Approach – Bottom Driven ED (1)
R V
• Determine the attributes to be S E
measured
R E
 Drives the requirements of the
instrument hardware T S
H
 URS should reflect application need,
I G
 Separates the qualification to collectR
not instrument capability
data (low impact) in a GMP area L Lfor

development, from where theAPAT is
– decisions
(medium/high impact) E
being used to provide control
P
IS
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Science and Risk Approach – Bottom Driven ED (2)
R V
• Determine sample size and sampling S E
interval
R E Equipment
Spectrometer
Failure (Multiple spectrometers)
Spectrometer non qualified
Warmup-time
Control, experimental Low or high
or noise
Experimental
NA
risk priority
High
NA
Measurement
Detector channel number
Spectra not typical
Measurement trigger ???
Control, experimental Low or high risk
or noise priority Environment
Light
Temperature
Humidity
Clogging of the line
Control, experimental Low or high
or noise
Noise
Noise
risk priority
Low
High
Low
Method
Performance verification not performed

Performance verification failure
Control, experimental Low or high risk
or noise priority
S
Probe PC-login-blocked (previous used no operator equipment set-up error (boot-up order)
 Ensure the PAT interface does not impact

logout)
Failure (Multiple probes) Experimental High Start time for collecting data
Light source aging Presence of air in the environment Noise Low
T
of the probe
Position Control Low Product accumulation on probe Noise High Back-up procedure for data (model)
process dynamics, or is impacted by

window (Cleaning failure)
PC Humidity gradient within PK To be evaluated Maintenance/qualification documentation
during
H
feasibility study
Failure ? ?
process dynamics
Software version NA NA
Software not validated NA NA Data collection parameters
Memory shortage (disk full) NA Low Probe pathlength Control
G
Fiber Spectral resolution Experimental
I
• For example PAT installed in a tablet feed
Failure ? ? Gain Experimental
Position/bending Noise Low Number of averaged scans (one measurement) Experimental
Length probe window size ??? Control
Type
R
frame, assumes the powder moves in front of
SIPAT Consistency of NIR data and sample to be measured with reference technique + Sample
representativity of PK
Failure Location of sampler Control To be evaluated
during feasibility
study
the mixing paddles, BUT!

L
Clock synchronization Sampling time Experimental To be evaluated
during feasibility
study
Connection issue w/ spectrometer Storage of samples to be analysed with reference Experimental To be evaluated
L
method during feasibility
o The movement of the paddles creates a pressure

study
PDV
Wrong regulation of granules flow rate Experimental or Noise High Outlier detection method
A
Insufficient quantity of retained granules Noise Low
wave (compacting powder) in front of the paddle Raw materials Feeding Statistical analysis (DOE: # experiments Control NA
Not trained to method
Not trained to hardware
o The bulk density of the powder bed fluctuates as

–
& repetitions) ??? Design of calibration
and validationd data sets
API batch (physical properties, impurities...) Experimental High Powder feed rate (PFR) Experimental Number of spectra (replicated Control NA Wrong set up of collection parameters Control Low
measurements corresponding to a
the powder moves, changing the mass of powder

single reference result)
Excipients batches Experimental Wavenumbers (selection of spectral Control NA Procedure not followed
E
variables)
contributing to the spectra

Water content of raw materials Noise Data preprocessing Control NA Loading incorrect method/model NA Low
Granules Twin screw granulation Rank (Number of latent variables) Control NA
residual solvents NA NA L/S ratio Experimental High
P
PSD Experimental High Screw speed Experimental LCM (predictive and corrective
maintenance of model) : Update of data
 Highlights importance of using Risk

sets, ajustment of regression
parameters,…
Porosity High Screw configuration Control
ISqualification through
Density High Line rate Experimental RMSEP criteria (vs ref. anal. technique &
vs. process) ???
Assessments
Stability Fluid bed drying PLS1/PLS2
Barrel temperature test set / cross validation
Air flow rate End point setting (DCS)
Loading time
Miscellaneous
9
Attrition of granules within piping NA NA
 That cover equipment

Segregation of granules in holding
vessel at the top of GCU
1
Materials Control, experimental Low or high Process Control, experimental Low or high risk Model Control, experimental Low or high People Control, experimental Low or high risk
to method validation
or noise risk priority or noise priority or noise risk priority or noise priority
2 0
Science and Risk Approach - Bottom Driven ED (3)
R V
• What are the control actions? S E
 What is the control strategy complexity?
R E
• 3 levels of control strategy
T S
 Recipe control – level 3
H
 Pharmaceutical control – level 2 I G
R
 Engineering control – level 1
L L
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–
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Qualification Approach ED
R V
• Still follow classical validation V model S E
RE
• The difference is the application is described in terms of what we need for the
method
T S
•
H
Instrument range, resolution, precision, accuracy, drift etc determined considering process
dynamics, attribute to be measured
I G
•
R
Hardware qualified to be fit for purpose to acquire data
•
L
Methods built and validated dependent on risk
L
•
A
Appropriate quality audit checks vendor systems (script and bench testing)
•
–
Configured modules tested by type testing and then testing a representative sub set of configured
E
modules
•
P
Custom modules kept to a minimum
 IS in the validation master plan
Everything managed/traced
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Example Process Control System Overview ED
R V
CTL Automation Control System (ACS) S E
+
R E
PAT Data Management System (PMS)
T S
H
= Overall Process Control System (PCS) I G
R
L L
A
–
P E
IS
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Structured Testing – No Custom Code (CM Example) ED
R V
S E
E
Overall PCS limited modular testing
R
T S ACS non-configured testing
H
I G
R
L L
PMS configured module testing
A
–
P E
IS
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40© Connecting Pharmaceutical Knowledge ISPE.org 40
Structured Testing – Incl. Custom Elements (Batch) E D
R V
Existing New
S E
Center location
R E New Manufacturing site
• Application specific hardware
S qualification
SentroPAT BU SentroPAT BU
Bruker
Matrix-F
H T
Embedded PC
Operator
PC
Embedded PC
Operator
PC
• PMS configured module testing
• Running the instrument
I G File
Addition to existing File
R
Server Server
• PMS custom module testing
L L
PAT Data Management System
• Pulling historical data from file
server
A
CITRIX
User PC • Analyzing data to determine if
–
Server
Corporate Network correct end point had been
E
User PC reached
(Advanced user)
P
• Comparison of primary and
Model file User PC
IS
(Common user) Instruments
LEGEND
Instrument control
parallel decision to confirm
Unscrambler/ PMS infrastructure Data flow primary performance
Corporate Network
9
Model flow
Matlab IT infrastructure User access
01
© 2 Connecting Pharmaceutical Knowledge ISPE.org 41
Considerations for Science and Risk Approach E D
R V
• Qualification is a ‘snap shot’ showing current capability SE
R E
• If the application needs change = URS changes and qualification needs updating
• Validation Master Plan is linked to CPV to ensure Sobserved trends in the method
H
and process performance are not outside qualifiedT status
I G
• Any new application/method requires verification that the new method is within
qualified status R
L L
A
–
• This is a risk management
P E activity not simply a risk
avoidance activity IS and needs to be managed!
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Lessons Learned ED
RV
• Pharmacopeial requirements are not based on applications S E
• Need to justify why you are not following USP/EP chapters,E
doing is of a higher standard. R or rather why what you are
• Advantageous to avoid ‘custom’ code T S

• Work with vendors to get functionality included into H their COTS packages
•
I G
Either as non-configured or configured functionality
R
 Often beneficial to wait until a function is part of a COTS product and covered by vendors
quality systems L
L traditional approach, the coordination
• One common lessons shared withAthe
between the involved vendors – can be very cumbersome
• Equipment vendors startingEto offer ‘PAT ready’ systems, not providing final solution but
P
IS systems
expecting to add a PAT method for control so including physical locations but also
triggers/inputs from PMS
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Poll 3 ED
RV
What do you see as the main
SE
challenges applying a science & risk
based approach to qualifying a PAT
RE
based control strategy?
T S
1. Regulatory accept, will the inspectors H
accept the approach
I G
2. Internal acceptance a cross the
R
organisation (manufacturing, QA,
regulatory affairs)
L L
A
3. The control strategy and the PAT systems
–
are not clearly defined, so we are not sure
what needs to be qualified
P E
4. It is straight forward to use the science &
IS
risk based approach
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Q&A ED
Contact Information Upcoming Webinars R V
Line Lundsberg
SE
NNE, Managing Consultant
Email: llun@nne.com
•
RE
16 Oct 2019 - The ISPE Pharma 4.0
Operating Model Introduction – Basis
S
for the ICH Holistic Control Strategy
T
H
Lorenz Liesum, PhD
• 21 Nov 2019 – Overview of the New
Novartis, Global PAT Head, Manufacturing Science
and Technology
I G Critical Utilities Water and Steam
Email: lorenz.liesum@novartis.com R Baseline Guide
L L
Martin Warman
A • 11 Dec 2019 - Data Science Tools for
Martin Warman Consultancy, Director
– Successful Technology Transfer
E
Email: martin@martinwarmanconsultancy.co.uk
P
IS Topic Ideas or Feedback?
1 9 Send to ispeak@ispe.org
2 0

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Qualification of Pat Based Control Strategies For Batch and Continuous Manufacturing Presentation PDF - Watermarked and Locked PDF

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ED

© Connecting Pharmaceutical Knowledge ISPE.org 15

© 2 Connecting Pharmaceutical Knowledge ISPE.org 16

H can be very cumbersome, i.e.

– committee and chairs the UK Affiliate PAT CoP.

©2 Connecting Pharmaceutical Knowledge ISPE.org 31

• Installations can range from I G • ‘medium risk’

R • Making a control decision that is the final

IS • Data from in multiple locations, and mass flow

data (low impact) in a GMP area L Lfor

Performance verification not performed

 Ensure the PAT interface does not impact

process dynamics, or is impacted by

the mixing paddles, BUT!

o The movement of the paddles creates a pressure

o The bulk density of the powder bed fluctuates as

the powder moves, changing the mass of powder

contributing to the spectra

 Highlights importance of using Risk

 That cover equipment

• Advantageous to avoid ‘custom’ code T S

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