This document discusses regulatory and monetary drivers for implementing real-time analytics in biotech processes. Regulatory drivers include enabling quality by design approaches through continuous process monitoring and improvement. Real-time data collection allows for better design space definition and linking of critical process parameters to critical quality attributes. Monetary benefits include fewer lost batches through higher quality, faster processing times, and potential transition to continuous manufacturing with higher facility utilization.

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Regulatory and Monetary
Drivers for Real Time
Analytics
Barry Rosenblatt, PhD
SMEbiotech1@comcast.net

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Outline
 Introduction: Defining Real Time Analytics
 In-Process vs Quality Attributes
 Regulatory Drivers
 QBD
 Continuous Process Improvement
 Real Time vs Batch Release
 Monetary Drivers
 Facility Utilization
 Continuous Processing
 Process Improvements/optimization

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Defining Real-Time Analytics
The FDA Guidance on Process Analytical Technology
Describes Real-Time Analytics as:
Nondestructive measurements that contain information
related to biological, physical, and chemical attributes
of the materials being processed. These measurements
can be:
 at-line: Measurement where the sample is removed,
isolated from, and analyzed in close proximity to the
process stream.
 on-line: Measurement where the sample is diverted from
the manufacturing process, and may be returned to the
process stream.
 in-line: Measurement where the sample is not removed
from the process stream and can be invasive or
noninvasive

4. Defining Real-Time Analytics
 Use of RTAs
 Defining/developing design space
 Operating parameters
 CPP vs pCPP vs nCPP
 In-process checks
 Critical quality attributes
 Process and Product
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5. Defining/Developing Design
Space
Current Paradigm (Off line analysis)
 Early development
 Define “edge of Failure”
 Platform approach
 Usually “built for Speed”
 Mid development
 Narrow operating parameter
 Gain full scale experience
 Late Development/PQ
 FEMA analysis
 DOE
 Set Specifications
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Current Paradigm
Phase 0 Phase 1 Phase 2 Phase 3
Develop
Apply
Analyze
Specs?
Comparability?Comparability?
PQ
FEMA
DOE

7. Current Paradigm
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Bioreactor
Harvest
Capture
Inputs/Ops
Polishing
Combination of “at Line”
“On-line and “In-Line”
Seeding, pH, Temp, dO2
Agitation
“at Line” testing
VCD, Titer, Gly, PTM,
Structure, Micro, AVA
Outputs/OpS
BDS
Flow rate/TMP
Volume, Mass
Titer, Volume
Flow Rate, Mass
pH, Cond
Titer, Vol, Turbidity, Filt Int. Micro
Titer, Volume, Mass, pH, Cond, PTM/structure
Purity, Micro
Titer, Volume
Flow Rate, Mass
pH, Cond
Titer, Volume, Mass, pH, Cond, PTM/structure,
Purity, Micro
Flow rate/TMP
Volume, Mass
BDS Release

8. Relationship of Operating
Parameters to CQA
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CQA

9. Design Space Studies: DOE
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Adapted from “A Mab: a Case Study
in Bioprocess Development”
CMC Biotech Working Group

10. “Quality By Design”
“… the desired state of pharmaceutical
manufacturing and regulation may be
characterized as follows:
 Product quality and performance are ensured
through the design of effective and efficient
manufacturing processes
 Product and process specifications are based on a
mechanistic understanding of how formulation
and process factors affect product performance
 Continuous real time quality assurance”
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11. QBD Paradigm
Early Development
o Define Design space
o DOE
o Linkage of CPP to CQA
Mid Development/Late Development
o Continuous Process Improvement
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12. QBD Paradigm
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Bioreactor
Harvest
Capture
Inputs/Ops
Polishing
Combination of “On-line
and “In-Line”
Seeding, pH, Temp, dO2
Agitation
“Combination of “On Line”
and “In Line” testing
VCD, Titer, Gly, PTM,
Structure, Micro, AVA
Outputs/OpS
BDS
Flow rate/TMP
Volume, Mass
Titer, Volume
Flow Rate, Mass
pH, Cond
Titer, Vol, Turbidity, Filt Int. Micro
Titer, Volume, Mass, pH, Cond, PTM/structure
Purity, Micro
Titer, Volume
Flow Rate, Mass
pH, Cond
Titer, Volume, Mass, pH, Cond, PTM/structure,
Purity, Micro
Flow rate/TMP
Volume, Mass
BDS Release
X
CQA testing
“In line

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QBD Paradigm
Phase 0 Phase 1 Phase 2 Phase 3
Develop
Apply
Analyze
Specs?
Continuous PQ
FEMA
DOE

14. Monetary Drivers
 Better definition of “Platform”
processes
 Fewer lost lots (Higher quality)
 Shortened Processing
 Quicker TAT of analytics
 Lot release is “instantaneous”
 Possible transition to “continuous”
Processing
 Higher utilization of plant
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15. Reference Documents
 ICH Q8
 ICH Q9
 ICH Q10
 ICH Q11
 Guidance for Industry: PAT- A Framework for Innovative
Pharmaceutical Development, Manufacturing, and Quality
Assurance 2004
 Questions and Answers on Design Space Verification (Joint FDA/EMA)24
October 2013 EMA/603905/2013
o A Mab: a Case Study in Bioprocess Development” CMC Biotech
Working Group Ver2 Oct 2009
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Questions?
SMEbiotech1@comcast.net
linkedin.com/in/rosenblattbarry