Process Analytical Technology (PAT) For Continuous ......Process Analytical Technology (PAT) For...
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Process Analytical Technology (PAT) For Continuous Bioprocessing Edita Botonjic-Sehic, Sr. Principal R&D Scientist, PAT/Automation; Steven Harris, Sceintist II, PAT/Automation, Pall Life Sciences, 20 Walkup Drive, Westborough MA 01581 What to expect in the next 25 years? “Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today. It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing.” Janet Woodckock, Director CDER, FDA (AAPS meeting, 2011) Pall Life Sciences is assessing the needs process analytical technology (PAT) as an overall capability upgrade to be used in conjunction with our existing and planned continuous bioprocessing toolbox to enable on-line and at-line real time continuous monitoring and automation of the continuous products. PAT paves the way of continuous maufacturing with the adoption of innovative technologies to perform timely measurements on critical quality attributes (CQAs) of raw and in-process materials, allowing better process understanding and control. What is Continuous Bioprocessing? Figure 1a Current: Batch BioProcess* (individual unit operations) Figure 1b Future: Continuous BioProcess* (one piece flow) To implement a strategy in a continuous process, it is crucial to understand and minimize: incoming material variation, critical quality attributes (CQA) and critical process parameter (CPP) variations, perform timely in-process measurements, define representative sampling, develop chemometric models and set appropriate acceptance criteria, and characterize the propagation of changes and disturbances through the system. In contrast to batch processing, in which local control of each piece of equipment is in many occasions considered sufficient, in continuous manufacturing not only is local control mandatory, but also the entire process flow must be coordinated and equipped with second-level control systems that supervise and align the work of individual unit operations. The selection of appropriate PAT tools is a crucial step toward setting efficient monitoring and control strategies in continuous processes. easy-to-use instrumentation, measuring frequencies, ability to monitor multiple process parameters, directly measure CQAs, capturing the real-time process state, and eliminate traditional off-line techniques and increase efficiency. An example of data obtained using off-line analytics; however this could be trended in real-time via PAT tools in the future. Key critical quality attributes that could be measured on-line and/or at line are: Bioburden Product concentration Host cell protein (HCP) Aggregates Glycosylation profiles Metabolites, etc… Figure 2 Percent aggregation by size-exclusion HPLC* Figure 3 Protein concentration (mg/mL)* Figure 4 Host Cell Protein per mg of mAb* In order to ensure product quality, mAb concentration monitoring is one of the CQA’s Figure 5 The ideal continuous controls platform combines automation, analytics and process control strategy; empowering users to execute advanced processes with excellence in quality, yield, and ROI True continuous tools (sensors, PAT, new data processing approaches) Data Management, Data Analysis, Data Insight and Automation Fill in the gaps using established platforms to meet new continuous requirements Value of PAT implementation Ensure consistent product quality and increase robust overall manufacturing performance reducing heterogeneity Enable end-to-end continuous process by implementing lean, flexible and portable biomanufacturing Advanced computational tools enhance continuous monoclonal antibody production Integration of process analytical tools for monoclonal antibody toxicology measurement can be achieved Process time and cost savings can be achieved through automation and continuous integration in existing facilities INTRODUCTION USING PAT TO SET MONITORING AND CONTROL STRATEGIES CHEMOMETRIC MODELS FOR CONTINUOUS BIOPROCESSING: CONCENTRATION MONITORING THROUGHOUT THE CONTINUOUS PROCESS IMPORTANT CQAs FOR CONTINUOUS OPERATIONS OUTLOOK Efficiency, Simplicity, Flexibility, Quality, Cost, Smaller Facility Footprint Continuous 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 Acoustc Wave Separation In-line Concentration (ILC) Protein A Capture Virus Inactivation Depth Sterile Filtration Anion Exchange Mixed Mode Cation Exchange Pegasus ™ Prime (VF) In-line Diafiltration (ILDF) Final ILC 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 MAB CONC (G/L) 21 hour continuous production of mAb © 2017 Pall Corporation. Pall and are trademarks of Pall Corporation. ® indicates a trademark registered in the USA and TM indicates a common law trademark. 3/17, 17.1002 Phone: +800.717.7255 (USA) • +41 (0)26 350 53 00 (Europe) • Email: [email protected] • Web: www.pall.com/biopharm 2.3% 3.0% 3.0% 3.0% 2.3% 1.7% 1.9% 2.2% 0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5% Pro-A VI D/S MQ CMM SSV ILDF ILC Percent Aggregation by Size-Exclusion HPLC 0 10 20 30 40 50 60 12:00 14:24 16:48 19:12 21:36 00:00 02:24 04:48 07:12 Protein Conc (mg/mL) Time of Day Pro-A VI D/S MQ CMM SSV ILDF ILC 1 10 100 1,000 10,000 100,000 1,000,000 09:36 12:00 14:24 16:48 19:12 21:36 00:00 02:24 04:48 07:12 ng HCP per mg mAb Time of Day AWS Feed Pro-A VI D/S MQ CMM SSV ILDF ILC *Note Abreviations: AWS (Acoustic Wave Separation), VI (Virus Iactivation), D/S (Depth and Sterile Filtration), MQ (Anion Exchange), CMM (Mixed Mode Cation Exchange), SSV (Pegasus™ Prime VF), ILDF (In-line diafiltration), ILC (In-line Concentration)
Transcript of Process Analytical Technology (PAT) For Continuous ......Process Analytical Technology (PAT) For...
Process Analytical Technology (PAT) For Continuous Bioprocessing Edita Botonjic-Sehic, Sr. Principal R&D Scientist, PAT/Automation; Steven Harris, Sceintist II, PAT/Automation, Pall Life Sciences, 20 Walkup Drive, Westborough MA 01581
What to expect in the next 25 years?
“Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today. It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing.” Janet Woodckock, Director CDER, FDA (AAPS meeting, 2011)
Pall Life Sciences is assessing the needs process analytical technology (PAT) as an overall capability upgrade to be used in conjunction with our existing and planned continuous bioprocessing toolbox to enable on-line and at-line real time continuous monitoring and automation of the continuous products.
PAT paves the way of continuous maufacturing with the adoption of innovative technologies to perform timely measurements on critical quality attributes (CQAs) of raw and in-process materials, allowing better process understanding and control.
What is Continuous Bioprocessing?
Figure 1aCurrent: Batch BioProcess* (individual unit operations)
Figure 1bFuture: Continuous BioProcess* (one piece flow)
To implement a strategy in a continuous process, it is crucial to understand and minimize:
incoming material variation,
critical quality attributes (CQA) and critical process parameter (CPP) variations,
perform timely in-process measurements,
define representative sampling,
develop chemometric models and set appropriate acceptance criteria, and
characterize the propagation of changes and disturbances through the system.
In contrast to batch processing, in which local control of each piece of equipment is in many occasions considered sufficient, in continuous manufacturing not only is local control mandatory, but also the entire process flow must be coordinated and equipped with second-level control systems that supervise and align the work of individual unit operations.
The selection of appropriate PAT tools is a crucial step toward setting efficient monitoring and control strategies in continuous processes.
easy-to-use instrumentation,
measuring frequencies,
ability to monitor multiple process parameters,
directly measure CQAs,
capturing the real-time process state, and
eliminate traditional off-line techniques and increase efficiency.
An example of data obtained using off-line analytics; however this could be trended in real-time via PAT tools in the future.Key critical quality attributes that could be measured on-line and/or at line are: Bioburden
Product concentration
Host cell protein (HCP)
Aggregates
Glycosylation profiles
Metabolites, etc…
Figure 2 Percent aggregation by size-exclusion HPLC*
Figure 3Protein concentration (mg/mL)*
Figure 4Host Cell Protein per mg of mAb*
In order to ensure product quality, mAb concentration monitoring is one of the CQA’s
Figure 5
The ideal continuous controls platform combines automation, analytics and process control strategy; empowering users to execute advanced processes with excellence in quality, yield, and ROI
True continuous tools
(sensors, PAT, new data processing approaches)
Data Management, Data Analysis, Data Insight and Automation
Fill in the gaps using established platforms to meet new continuous requirements
Value of PAT implementation
Ensure consistent product quality and increase robust overall manufacturing performance reducing heterogeneity
Enable end-to-end continuous process by implementing lean, flexible and portable biomanufacturing
Advanced computational tools enhance continuous monoclonal antibody production
Integration of process analytical tools for monoclonal antibody toxicology measurement can be achieved
Process time and cost savings can be achieved through automation and continuous integration in existing facilities
INTRODUCTION
USING PAT TO SET MONITORING AND CONTROL STRATEGIES
CHEMOMETRIC MODELS FOR CONTINUOUS BIOPROCESSING: CONCENTRATION MONITORING THROUGHOUT THE CONTINUOUS PROCESSIMPORTANT CQAs FOR CONTINUOUS OPERATIONS
OUTLOOK
Ef�ciency, Simplicity, Flexibility, Quality, Cost, Smaller Facility Footprint
Continuous
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
Acoustc Wave Separation
In-line Concentration (ILC)
Protein A Capture Virus
Inactivation Depth Sterile Filtration
Anion Exchange Mixed Mode Cation Exchange
Pegasus™ Prime (VF)
In-line Diafiltration (ILDF)
Final ILC
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
MA
B C
ON
C (G
/L)
21 hour continuous production of mAb
© 2017 Pall Corporation. Pall and are trademarks of Pall Corporation. ® indicates a trademark registered in the USA and TM indicates a common law trademark. 3/17, 17.1002Phone: +800.717.7255 (USA) • +41 (0)26 350 53 00 (Europe) • Email: [email protected] • Web: www.pall.com/biopharm
2.3% 3.0% 3.0% 3.0%
2.3% 1.7%
1.9% 2.2%
0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5%
Pro-A VI
D/S MQ
CMM SSV ILDF ILC
Percent Aggregation by Size-Exclusion HPLC
0
10
20
30
40
50
60
12:00 14:24 16:48 19:12 21:36 00:00 02:24 04:48 07:12
Pro
tein
Con
c (m
g/m
L)
Time of Day
Pro-A VI D/S MQ CMM SSV ILDF ILC
1 10
100 1,000
10,000 100,000
1,000,000
09:36 12:00 14:24 16:48 19:12 21:36 00:00 02:24 04:48 07:12
ng H
CP
per m
g m
Ab
Time of Day
AWS Feed Pro-A VI D/S MQ CMM SSV ILDF ILC
*Note Abreviations: AWS (Acoustic Wave Separation), VI (Virus Iactivation), D/S (Depth and Sterile Filtration), MQ (Anion Exchange), CMM (Mixed Mode Cation Exchange), SSV (Pegasus™ Prime VF), ILDF (In-line diafiltration), ILC (In-line Concentration)
