Continuous Manufacturing &

Automation Solutions
2017 Engineering, GMP & Validation Forum

Anand Sunit Kulkarni

Life Sciences Industry Leader_ Asia Pacific
Emerson Automation Solutions
Agenda

Continuous Manufacturing: The Path Ahead

Pharma Manufacturing: Batch Vs Continuous

Dynamics of Continuous Manufacturing

Automation Management and Control Strategies

Closing

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 Pharmaceutical Manufacturing: The Path Ahead..

“ 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 favour of cleaner, flexible, more efficient
continuous manufacturing.”

Dr.Janet Woodcock, AAPS Annual meeting, October 2011

Pharmaceuticals Need to Change

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Continuous Production is Coming

• Example of a modular manufacturing capable of supporting process development, clinical, or full

commercialized production.

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Strong Financial Incentives to Change

Operational Flexibility Improved Quality Capital Savings

Scales based on time
Low residence time
and parallelization vs Vertex facility is only
size 4,000 sq. ft. vs 100,000
Real-Time
monitoring, PAT, sq. ft in a traditional
Portability on site deployment 1
& Advanced Control 2
Use across stages 2

Higher Throughput Cost Savings

Shorter production times
New facility
makes 100,000 Waste reduction / don’t
tablets / hour discard entire batch
vs >4 weeks at
a batch plant 1 >30% operating cost
reduction—Novartis / MIT 1

1 WSJ Feb. 8, 2015 Drug Making Breaks Away from It’s Old Ways
Emerson Confidential 2 Biotechnology and Bioengineering Vol. 112, Issue 4, April 2015, Pages 648-651 5
Pharmaceutical Manufacturing (Synthetic Drugs)

• Different sites and large equipment

• Larger Supply Chain management
• Collectively for Months

• Single Site Operations

• Modular Equipment/Shorter Supply Chain
• Shortened to Days

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 Pharmaceutical Manufacturing (Biotech / Biosimilars)
Batch
Buffer / Feb Batch Drug
Media Cell Harvest Capture Chromatograph Filtratio Substance
Prep Culture y n
• Product transfers between each unit
operation in batches
• Finished product is tested at off-line
laboratories
• Actual processing time = days to
weeks

Continuous

Continuous
Buffer / Media Perfusion Continuous Capture Chromatography Drug Substance
Prep Cell Culture (Chrome 1) (Chrome 2 and 3) Filtration

• Product flows between each unit

operation
Continuous • Product is adjusted based upon in-
process measurements
• Actual processing time = hours to days

Konstantinov and Cooney, Journal of Pharmaceutical Sciences 104:813-820, 2015

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Secondary Manufacturing – Batch to Continuous
Batch Continuous

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Dynamics of Continuous Manufacturing

Residence Time Distribution

• Variation in material attributes and process parameters

• Optimization of the Equipment Design
• Tracking of material and disturbances

Real Time Release Testing and Process Control

• On-line / In-line / At-line Measurements

• Process Control and Multivariate Models
• Adequate Models and Validation

Production Capacity
• Demonstrate manufacturability within expected range
• Equipment performance and Process Dynamics
• Uniformity of Quality

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Comprehensive Control Solutions Required

• Continuous Regulatory Control for minimum

Real-time Optimization (RTO) Variability
– PID Control is the workhorse
• Advanced Control for Constraint Optimization
– Multivariable Control
Target tracking MPC Layer – Control of Difficult Dynamics
– Inferential Control
– Optimization Objectives
• Statistical Process Control
Regulatory PID Layer – Multivariate
• Principle Component Analysis
• Partial Least Squares

Process

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Continuous Automation Implementation Challenges

Automation Management Strategies Control Strategies

• Understand the unit operation(s) / how far • Basic PID Control

does “continuous manufacturing” extend?
• Modular automation design
• Data integrity from source through use
• Equipment states
• Start- Up and shutdown activities
• Unit Operation Modeling
• Advanced Process Control
• Batch / Lot definition
• Batch context

Automation is Crucial for Continuous Manufacturing

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 Automation Management Strategy :Modular Automation Designs
• Standardized, modular automation • Units need to be autonomous
• Support a complete scope of solutions for
Compliance
optimized unit production
Requirements Paperwork – Measurement with integrity
Recipe
– Local control
Data

Unique ID in System

Characterization Data – Start-up / shutdown / product change-over

sequencing for on-the-fly transitions
Local Control Sequences – Process characterization to determine optimized
Service
GMP
Time end result
Advanced
Control
Status
Hours Run
– On-line analyzers are critical in many cases
– Alarm Management
PID Control Running
Data – Process History
Local
Alarms Dynamic
Characteristics

Trips Temperature
Process
Capabilities
Pressure
Integrity
Status
Flow Rate

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Control Strategy: Start with “Basic” PID Control
• Temperature profile, T(t), is main design
Real-time Optimization (RTO) variable for cooling crystallization
– Cannot set T(t) directly; T(t) specified from valve
positions of cold and hot water streams
Solution
Target tracking MPC Layer xc (t ) Jacket energy
Tc Fc (t )
balance, Tj
Jacket
Cooling Water
Regulatory PID Layer xh (t )

Th Fh (t ) Crystallizer
energy
Hot Water
Process Physical balance, T
actuation
Flow-valve
relationship, F=f(x)
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Control Strategy: Then Add on Optimization
• There are two main classes of models used in Multivariate Process Control (MPC) formulations

• Objective: Optimizes economics

Real-time Optimization (RTO) • Strategy: Steady state optimization

• Objective: Drive system to target setpoints

Target tracking MPC Layer • Strategy: Dynamic constrained optimization
Can improve by combining
these two layers
Regulatory PID Layer
Drawbacks of layered approach
• RTO targets may not be reachable
• True optimal situation may not be
Process achieved at a constant setpoint

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Automation Approach Combining Regulatory and Optimization
Feeders
M

M API M M

M M
Data Integrity is critical for
M

M
mill Cross-check pharmaceutical quality
Content/Density measurements and becomes
Blend Uniformity Content
Blender (check) even more important with
Feed forward NIR, Raman
continuous for Real Time
control Release and Continuous
Force Process Verification.
Compression
Gap LT US NIR
Tablet Press
Thickness
Weight
Density
Hardness Dissolution
Emerson Confidential (check)
Doug Hausner, Ph.D., Associate Director, ERC SOPS, Rutgers University
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Emerson Exchange Life Science Forum Oct. 2016
Key FDA Issues for Continuous Manufacturing
“Lots”
21 CFR 210.3
• Lot – a batch, or a specific identified portion
of a batch, having uniform character and
quality within specified limits; or, in the case
of a drug product produced by a
continuous process, it is a specific
identified amount produced in a unit of
time or quantity in a manner that assures
its having uniform character and quality
within specified limits.
Need to track Lots
Regulatory Definitions – Applicable to continuous processes
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“Batch”
21 CFR 210.3
• Batch – a specific quantity of a drug or
other material that is intended to have
uniform character and quality, within
specified limits, and is produced according
to a single manufacturing order during the
same cycle of manufacture.
• Batch refers to the quantity of material
and does not specify the mode of
manufacture
Need to track Batches
MIT-CMAC International Symposium on Continuous Manufacturing of Pharmaceuticals, May 20, 2014
Janet Woodcock, M.D. Center for Drug Evaluation and Research, FDA
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Managing Batch / Lots:
Residence Time Distribution (RTD)
Diagnostic tool used to determine the time (mean and distribution) a particle stays in a unit operation

[Tracer]
Inlet
Pulse of Tracer
(i.e., API)

t0 Time

[Tracer]
Outlet

Detector
(i.e., PAT tools) Time
τ
C (t )
E (t)  
RTD models are used to determine:
C out (t )dt
1. Disturbance dissipation 0

2. Raw material traceability MRT     t  E (t )dt
3. Mixing patterns in unit operations 0

Doug Hausner, Ph.D., Associate Director, ERC SOPS, Rutgers University

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Managing Batch / Lots:
Residence Time Distribution (RTD)
Integration of RTDs in Continuous Direct Compression
Given the relationship of batch API and continuous drug product manufacturing, multiple lots
of API will inherently need to be mixed in order to make product

Regulatory question: How can we determine the API lot composition of the drug product?

Case Study Using RTD

API API
Lot A M EX
M

Lot B M

M
MgSt
M
M

How much of AB?

Overlap of the curves represents
Lot AB
the mixing of the lots
Doug Hausner, Ph.D., Associate Director, ERC SOPS, Rutgers University
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Unlocking the Value of Continuous Manufacturing Requires Planning
Continuous
Manufacturing in Life
Science is progressing.
Assess people,
processes and
technologies within
your organization to
determine how to get the
benefits
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The number of approvals is growing
The technology barriers are being addressed
Secondary manufacturing is moving the fastest
but primary is also progressing
Approach requires re-thinking your
manufacturing approach
Requires people with a combination of process
and automation / data technology skills
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 Back Up Slides

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New Data Integrity Requirements

Data Integrity
• Completeness, consistency, and accuracy of data.

• Attributable ALCOA +
• Legible • Enduring
• Contemporaneous • Complete
• Original (or true copy) • Consistent
• Accurate • Retrievable
Managing Data Integrity and Change Control
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It Starts with the Sensor:
Data with Status / Unit Operations Using Status

Rich Tools Equipment

In Use
Advisory State Model
Inactivate In-Use /
Tools Equipment Complete
PERFORMANCE HEALTH ENERGY Inactivated Unavailable
Applications No
Standalone Yes
CIP’d Clean Calibrate Calibrated
Insight
Tools Out of
Service In-Use
Out of Service Available / Start

Traditional Data Pathways IIoT Application Gateways

Secure
Security First Mile

Single Use Single Use Radar Analyzers Electrical Steam Vibration Valve Position Single Use
Pressure pH Level Monitoring Traps Monitor Pinch Valve
Pervasive
Data
Sensing

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Procedural Automation for Continuous Process (ISA 106) Growing in Importance
Process State Operational States
Not Ready (Out
Not Ready
of Service

Preparing Preparing

Ready (Idle) Ready

Filling Start-up

Heating

Running Running

Abnormal
(Off Spec)

Shutting
Shutting Down Down ISA-TR106.00.01-2013 Procedure Automation for Continuous Process Operations
Manufacturing Savings via Procedural Automation
Faster Startup • Dow is a major contributor to
Faster Shutdown development of the ISA106
Shorter Maintenance standard.
– State Based Control has been applied in
around 200 Dow plants globally
– 75% of Dow Assets are run using state
based control*
• In one recent example, Dow
reported the reduction in shutdown
time achieved by automating
cleaning procedures resulted in a
16% increase in plant profit.

Procedural Automation State Based Control, Yahya Nazer, Janette Brightwell, ARC Forum, 2015

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Account for Likely Sources of Disturbances
Temperature Pressure
fluctuations drop
xc (t )

Tc Fc (t )

Cooling Water
xh (t ) Heat of
crystallization +
Th Fh (t ) other non-idealities

Hot Water

Mitigate disturbances by
design of regulatory
control layer
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Design of Regulatory Layer: Cascade Control
Pc Tc Th

Fc, SP xc Fc Tj
PID PID CW Valve Jacket

Ph
T j , SP Fh, SP xh Fh
PID PID HW Valve

Tj
TSP T
PID Crystallizer
Crystallizer
temperature

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When Combined, There Are Two Main Approaches
• There are two main classes of models used in MPC formulations

1. Empirical / black-box models

• Based completely on process data
• Majority of methods generate linear models

2. First principles models

• Derived from physics of problem (mass/energy
balances, kinetic rate expressions, thermodynamics)

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Empirical vs. First Principles
Characteristics Empirical Model
Model derivation Only from process data
Number of parameters Usually high due to black-box nature
Identification Must perturb process for relatively
long time for each manipulated
variable
Accuracy Only around a steady state, where
experiment conducted
Capability Mostly target tracking to keep model
accuracy reasonable
Versatility Hard to deal with unmeasured states
Resultant optimization in MPC LP or QP: typically fast to solve
online
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First Principles Model
Based on physics; need some
modeling expertise
Smaller; based on physical
parameters
Smaller perturbations (if past data is
informative, no experiments needed)
Accurate in wider range than a
steady state
General objectives (e.g., profit,
energy usage)
Can handle unmeasured states and
disturbances explicitly
NLP: need more sophisticated
solvers and expertise to speed up for
real time usage
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First Principles Models are Accurate over Larger State-space Region

x2
Accuracy region for first endpoint
principles model

Only guaranteed Ex: State trajectory for startup

to be valid locally!
Steady-state where
step response model
was developed
x1

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Add on Modeling per Unit Operation Requirements:
Modeling Dissolution
• When C < Csat, crystals will dissolve in solution

C  Csat (T )
or crystals dissolve
completely…

• Dissolution can be modeled as a first-order process

in terms of relative supersaturation
k g S g , S  0 Need to calculate rate of crystal loss
G (equivalent B for dissolution in μ0 ODE)
 kd S , S  0 Moment equations same for j > 0

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Usually large  fast dynamics 31
More Research / Proofs Exist in Secondary Process Modeling
Flowsheet model

Feedforward
Feedback control
control

Doug Hausner, Ph.D., Associate Director, ERC SOPS, Rutgers University

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Process Modeling for Control Development:
Basic Regulatory
FEEDERS:
Model: Delay Differential
Equation, Transfer Function

rpm
d50,ρ d50,ρ
Fset Fout

CO-MILL:
Model: RTD model, Mass
balance equation
rpm
d50,ρ d50,ρ
Fin,Ci, Fout, Ci,

MIXER:
Model: Population TABLET PRESS:
Balance model, RTD Model: Kawakita equation and
model, surrogate model feed frame RTD model
rpm
d50,ρi d50,ρ P, rpm
Fin,Ci d50,ρ ε, σ,
Fout, Ci,
Fin,Ci, Ci, Fout

Doug Hausner, Ph.D., Associate Director, ERC SOPS, Rutgers University

Emerson Confidential Emerson Exchange Life Science Forum Oct. 2016 33
 Process Modeling for Control Development:
Add in Optimization for the Unit
Flowrate

Flowrate
Feeder Fill level

Mass Hold-up Co-mill

Flowrate

Blender Mass Hold-up

Doug Hausner, Ph.D., Associate Director, ERC SOPS, Rutgers University

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