Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
Learnings from other industries
See What is Possible
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Speaker Introduction
• Consultant with Emerson Process Management, Systems & Solutions Division
• 38 Years experience with Process Control across all of the Process Industries
• Specialist in advanced regulatory control and multivariable model-predictive control (APC)
• Joined Emerson in 1984
• Previous employer: Olin Corp (1978-1984)
• Education: BSChE from MIT (1978)
E-mail: [email protected]
Lou
Heavner
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Agenda
• Process Flow• Continuous vs batch• Refinery description• Quality Parameters
• Crude Comp/Qualities – Material Attributes
• Crude Frac – Critical Process Parameters (CPP)
• Product Comp/Qualities – Critical Quality Attributes (CQA)
• Economic Opportunity• Adaptability to Spot Crudes - Flexibility• Crack Spread Example
• Energy
• Emissions
• Seasonal – Summer gas vs Winter Diesel
• Process Capability – Show me the data (% rejects & why they were rejected)• Analyticals – Reliability of method
• Just because you can measure it…
• Batch vs Continuous Blending• Batch loading vs continuous pipeline
• Enablers
• Control Strategy – MVs, DVs, etc (explain) (Proc Ins vs Proc Outs)
• Summary
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Continuous vs Batch
• Continuous• Smaller Capital Investment
• Usually less Working Capital
• Process upset results in small loss of on-spec product• On-the-fly Grade Transitions
• Transition material may not be saleable
• Focus on Regulatory Control (APC)
• Batch• Entire Batch Subject to Rejection
• Each batch has defined recipe
• Focus on Batch Sequence Control (Golden Batch)
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Comparative Analysis
Characteristic Refining Pharmaceutical
Process Continuous Batch, Continuous growing interest
Throughput High volume Low volume
Feed Quality Variable, mixture High purity
Product Quality Complex Set of Properties, tight specifications
High purity, consistent
Number of products Few to Many 1 to few per campaign, many formulations
Challenges Variable feedstock, Variable seasonal demand
Regulatory requirements, fit for consumption
Reactor Catalytic Various processes, classical organic chemistry as well as powder processing
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Refining Process Flow
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Petrochemicals
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Quality Parameters
• Feedstock – Crude Qualities (Material Attributes)• Wide Specifications Typical
• Allows Flexibility of Operation
• Fractionator Process – KPIs (Critical Process Parameters)• Continuously Monitored and Controlled
• Economic - Operating (including Optimization)• Regulatory
• Safety
• Environmental
• Products – Product Qualities (Critical Quality Attributes)• Tight and Seasonal Specifications
• Regulatory are achieved in Processing• Economic are achieved in Blending
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Typical Gasoline Specification
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Agenda
• Process Flow• Continuous vs batch• Refinery description• Quality Parameters
• Crude Comp/Qualities – Material Attributes
• Crude Frac – Critical Process Parameters (CPP)
• Product Comp/Qualities – Critical Quality Attributes (CQA)
• Economic Opportunity• Adaptability to Spot Crudes - Flexibility• Crack Spread Example
• Energy
• Emissions
• Seasonal – Summer gas vs Winter Diesel
• Process Capability – Show me the data (% rejects & why they were rejected)• Analyticals – Reliability of method
• Just because you can measure it…
• Batch vs Continuous Blending• Batch loading vs continuous pipeline
• Enablers
• Control Strategy – MVs, DVs, etc (explain) (Proc Ins vs Proc Outs)
• Summary
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Economic Margins
Crack Spread is basis for profitability• BBL of Crude• BOE of Products• Utility Cost• Environmental Limits
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Factors of Profitability
• Crudes• Heavy vs Light
• Sulfur• Wax
• Disadvantaged
• Products• Reformulated (Geographic Demand)• Low Sulfur• Gasoline vs Heating Oil (Seasonal Demand)
• Utilities and “By-products”
• Planning & Scheduling (Optimization)
• Process Capability• Refinery Size• Refinery Complexity• Refinery Location
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Opportunity
• Create the greatest spread between crude and products with the capability of the Refinery• Lowest priced crude that can be refined
• Highest value mix of products
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Agenda
• Process Flow• Continuous vs batch• Refinery description• Quality Parameters
• Crude Comp/Qualities – Material Attributes
• Crude Frac – Critical Process Parameters (CPP)
• Product Comp/Qualities – Critical Quality Attributes (CQA)
• Economic Opportunity• Adaptability to Spot Crudes - Flexibility• Crack Spread Example
• Energy
• Emissions
• Seasonal – Summer gas vs Winter Diesel
• Process Capability – Show me the data (% rejects & why they were rejected)• Analyticals – Reliability of method
• Just because you can measure it…
• Batch vs Continuous Blending• Batch loading vs continuous pipeline
• Enablers
• Control Strategy – MVs, DVs, etc (explain) (Proc Ins vs Proc Outs)
• Summary
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Product Qualities
• On-line vs Off-line analyzers• Reliability
• Sampling Systems
• Validation/Verification
• Inferentials• First Principles vs Empirical
• Validation/Verification
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Sequential Vs. Ratio Blending
• Sequential Blending (Batch)• One Component at a time• Economical Method
• Larger piping offset by less instrumentation
• Quality Check at end of blend (Off-line)
• Line Flush required for proper product quality
• Blend Accuracy assured only for completed batches• Off spec Blends can be difficult and
costly to patch
• High Working Inventory (Working Capital)
• In-Line Parallel Metering (Continuous)• In-line or All at same time
• Requires meter and valve for each stream• Smaller diameter Pipes and instruments
• Fewer tanks
• Online Blend Analyzer Required
• Precise control of blending• Instantaneous alarms on blend available
• Blend quality assured on aborted blends
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Traceability
• Critical requirement in Pharmaceutical, not so much in other industries• Can be done by Time Segments
• Used for Pipeline Transportation• Multiple Products
• Multiple Producers
• Regulatory Approval requirements will require discussion
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Agenda
• Process Flow• Continuous vs batch• Refinery description• Quality Parameters
• Crude Comp/Qualities – Material Attributes
• Crude Frac – Critical Process Parameters (CPP)
• Product Comp/Qualities – Critical Quality Attributes (CQA)
• Economic Opportunity• Adaptability to Spot Crudes - Flexibility• Crack Spread Example
• Energy
• Emissions
• Seasonal – Summer gas vs Winter Diesel
• Process Capability – Show me the data (% rejects & why they were rejected)• Analyticals – Reliability of method
• Just because you can measure it…
• Batch vs Continuous Blending• Batch loading vs continuous pipeline
• Enablers
• Control Strategy – MVs, DVs, etc (explain) (Proc Ins vs Proc Outs)
• Summary
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Automation - Key Enabler
• Continuous Regulatory Control for minimum Variability• PID Control is the workhorse• On-the-fly grade transitions• On-line analyzers are critical in some cases
• Some but less reliance on QA
• Alarm Management• Process History
• Advanced Control for Constraint Optimization• Multivariable Control• Control of Difficult Dynamics• Inferential Control• Typical Optimization Objectives
• Maximize Production• Maximize Yield• Minimize Utilities
• Statistical Process Control• Multivariate – PCA & PLS
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Single Loop Variability
11 10.5 10.70333
11 10.6 10.70333
11 10.8 10.70333
11 10.7 10.70333
11 10.9 10.70333
11 10.8 10.70333
11 10.6 10.70333
11 10.8 10.70333
11 10.6 10.70333
11 10.5 10.70333
11 10.7 10.70333
11 10.6 10.70333
11 10.8 10.70333
11 10.9 10.70333
0
1234
5678
1 4 7 10 13 16 19 22 25 28 31
INCREASED PRODUCTION OR
EFFICIENCY
TIME
TYPICAL CONTROL
CONSTRAINT
PV AVERAGE
11 10.6 10.70333
0
1234
5678
1 4 7 10 13 16 19 22 25 28 31
INCREASED PRODUCTION OR
EFFICIENCY
TIME
TARGET SHIFTED
CONSTRAINT
PVAVERAGE
11 10.9 10.70333
11 10.7 10.70333
11 10.5 10.70333
11 10.7 10.70333
11 10.6 10.70333
11 10.7 10.70333
11 10.8 10.70333
11 10.9 10.70333
11 10.7 10.70333
11 10.9 10.70333
11 10.7 10.70333
11 10.5 10.70333
11 10.7 10.70333
11 10.6 10.70333
11 10.9 10.70333
0
1234
5678
1 4 7 10 13 16 19 22 25 28 31
INCREASED PRODUCTION OR
EFFICIENCY
TIME
IMPROVED CONTROL
CONSTRAINT
PV AVERAGE
0
2
4
6
8
10
12
1 4 7 10 13 16 19 22 25 28 31
INCREASED PRODUCTION OR
EFFICIENCY
TIME
CONSTRAINT SHIFTEDCONSTRAINT
PV AVERAGE
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Crude Unit Issues
T-7
Naphtha Stabilizer
Light Naphth
aAtmosTower
T-1
RefluxDrum
Pump-arounds
Naphtha
LGO
HGO
LP Steam Injection
Atmospheric Residue To Vacuum
Column
T-6
T-5
T-4
T-3
T-2
AID86 95%
AIFlash Pt. Density
AI
Cloud Pt. D86 5%
AI
Cloud Pt.
AI
Color
Heavy Naphth
aJet FuelKero
Diesel
HeavyGas Oil
IntermediateGas Oil
Heater
Desalter
Crude OilStripper Columns
Preheat
Preheat
Largest
Unit Energy
Consumption
in Refinery
Frequent
Changes in
Crude Feed
Sets Basic Yield Pattern In The Refinery
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Multivariable Problem
• Scope• Process Inputs (Independent)
• Manipulated Variables
• Disturbance Variables (Feed Forward)
• Process Observations (Dependent)• Control Variables
• Constraint Variables
• Challenge• Variable Interaction
• Difficult Dynamics
• Multiple Control Objectives
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Control Objectives for Maximum Profit• Maximize throughput when desired
• Minimize off-spec product and lost production on crude switches
• Maximize heater outlet temp when desired• Increases distillation yields• Minimize pass outlet temperature difference
• Maximize high value product yields• Operate at max end point (or initial point) specs• Minimum overflash required to meet GO color
• Minimum pressure• Improves relative volatility• Limited by tower flooding, condenser limit, overhead system valve positions
• Minimize heater excess air• Limited by minimum stack O2 or max CO
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Benefit Calculation Example
• Basis:• 23kBPD Crude unit• 10kBPD Vacuum unit
• 2% increase in throughput worth $ 1million annually (if production limited)
• 0.5% increase in distillate yield is worth $0.4 million annually
• 3% energy saving is worth $0.3 million annually
Economic Assumptions
• $ 6/Bbl Refinery incremental throughput margin
• $ 10/Bbl differential between vac resid and HVGO
• Energy – Fuel $5/ mBTU; Steam $10 mBTU
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
100% position
0% position
0%
po
siti
on
10
0%
po
siti
on
Maximized ThroughputMaximized ProfitMinimized Energy
Constraint Optimization
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Example – Cruise Control
• Consider the standard cruise control for an automobile• Control Variable = Speed
• Manipulated Variable – Accelerator pedal
• Enhanced Cruise Control• Control Variable = Speed
• Constraint variable = Fuel Economy (mpg)
• Manipulated Variable – Accelerator
• Manipulated Variable – Brake
• Disturbance Variable – Forward looking slope detection
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Example – Cruise Control
• Enhanced Cruise Control w/ Constraint Optimization• Objective 1 – Minimize Operating Cost
• Maximize Control Variable = Speed (up to the target since we don’t want to get a ticket)• Maximize Constraint variable = Fuel Economy (mpg, km/l, etc)• Manipulated Variable – Accelerator• Minimize Manipulated Variable – Brake• Disturbance Variable – Forward looking slope detection
• Objective 2 – Minimize Deviation from Speed Target• Maximize Control Variable = Speed• Constraint variable = Fuel Economy (mpg)• Manipulated Variable – Accelerator• Manipulated Variable – Brake• Disturbance Variable – Forward looking slope detection
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Agenda
• Process Flow• Continuous vs batch• Refinery description• Quality Parameters
• Crude Comp/Qualities – Material Attributes
• Crude Frac – Critical Process Parameters (CPP)
• Product Comp/Qualities – Critical Quality Attributes (CQA)
• Economic Opportunity• Adaptability to Spot Crudes - Flexibility• Crack Spread Example
• Energy
• Emissions
• Seasonal – Summer gas vs Winter Diesel
• Process Capability – Show me the data (% rejects & why they were rejected)• Analyticals – Reliability of method
• Just because you can measure it…
• Batch vs Continuous Blending• Batch loading vs continuous pipeline
• Enablers
• Control Strategy – MVs, DVs, etc (explain) (Proc Ins vs Proc Outs)
• Summary
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Summary
• Parallels between Continuous Industries and Pharmaceuticals• Regulatory Pressure
• Economic Pressure
• Advantages of Continuous Manufacturing• Manufacturing Equipment Cost
• Disturbances Handled on-the-fly
• Challenges of Continuous Manufacturing• Small-scale Production Lots
• Traceability
2nd International Symposium on Continuous Manufacturing of PharmaceuticalsImplementation, Technology & Regulatory
September 26-27, 2016
Questions?