CIP Optimization: Hyde Engineering Overview

1/19/2017
CIP Optimization
Design, Implementation and Operation
John M. Hyde
Chairman and Founder
Hyde Engineering + Consulting
Boston Chapter Meeting
19 January 2017
HYDE ENGINEERING OVERVIEW
– Bioprocess and GMP Manufacturing Focus

• Process Engineering
• Commissioning/Qualification
• Cleaning/Process Validation
• Compliance Engineering
– Highly Experienced staff
– Client Focused
– Founded 1993
– 275+ Staff, Engineers & Scientists
– 12 Offices - 6 in US, Ireland (2), Belgium, India (2), Singapore
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Phases of CIP Implementation
• Concept Design
• Process/Facility Requirements and Constraints
• Cycle Requirements
• Detailed Design
• CIP Skids
• CIP Circuitry
• Commissioning/Cycle Development
• Skid Operations
• Circuit Flow Paths
• Cleaning Validation
• Initial Testing at Commercial Scale
• Ongoing Monitoring of Cleaning Performance
• Benefits of Efficient CIP Design
Connecting Pharmaceutical Knowledge ispe.org 3
CIP Concept Design
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CIP Concept Design
• Process Requirements
• Unit Operations
• Interconnecting Piping
• Containment/Contamination Control Requirements
• Bio-Safety Level
• Pre/Post Virus Removal
• Production Targets (e.g., Lots/Year, Changeovers, etc.)
• Facility Constraints
• PW and WFI Supply
• Drain Capacities and Waste Treatment Requirements
• CIP Skid Location and Space Requirements
• Skids Preferably Located at or Below Elevation of
Process Equipment Being Cleaned
CIP Concept Design
• CIP Cycle Requirements

• Water Only Versus Chemical Cleaning
• CIP Cycle Time Targets
• Typically 2 Hours for Full Chemical CIP and 45 Minutes for Water
Only Cycle
• Cleaning Efficiency Goals
• Minimization of Water (PW and WFI) Consumption
• Minimization of Cleaning Agent Consumption
• Minimization of Waste Streams
• Minimization of Number of Cleaning Cycles per Lot
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CIP Detailed Design
CIP Detailed Design
• CIP Skids
• Tankage Requirements
• Number of CIP Skid Vessels
• Size of CIP Skid Vessels
• Vessel Pressure Rating Requirements
• Wash Solution Make-Up Methodology
• Batching of Cleaning Solutions in the CIP Skid Tank
• Formulation of Cleaning Solutions in the Cleaning Circuit
• Control of Cleaning Critical Control Parameters
• Required for Effective Cleaning
• Required for Repeatable and Reliable Cleaning
• Required for Efficient Cleaning
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Typical CIP Skid P&ID
CIP Skid – Pre-Rinse and Drain
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CIP Skid – System Fill Vessels
CIP Skid – Recirc, Heat and Cleaning Agent Feed - Vessels
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CIP Skid – Recirc, Heat and Cleaning Agent Feed - Piping
CIP Detailed Design
• CIP Circuitry
• Cleaning of Vessels
• Cleaning of Interconnecting Piping
• Piping is Often Cleaned Independently from Vessels
• Results in Increase of Cycles Per Lot Requirement by Factor of 2
to 3
• Often Results in Significant Increase in Valves Required due to
Leak Protection
• Circuitry Layout Strategies
• Clean Vessels with Outlet Piping in Reverse Flow
• Clean Filter Housings Inline
• Ultimate goal is to Have no Circuits That are Just Piping
• Clean and Dirty Hold Time Considerations
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Process Vessels P&ID
Process Vessels – Process Transfer
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Process Vessels - CIP
CIP Commissioning and

Cycle Development
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Commissioning and Cycle Development
• Determination of Cleaning Critical Control

Parameters (CCCPs)
• Supply Flow Rate
• Supply Pressure
• High Range Conductivity
• Low Range Conductivity
• Cleaning Solution Temperature
• Establishment of Cycle Setpoints
• Rinse Durations
• Wash Durations
• Airblow/Drain Durations
Establishment of CCCPs at Lab Scale
• Test Plan
• Author an experimental test plan describing the approach
used to conduct bench scale cleaning process developmental
studies for post production residues
• Cleaning Agent Selection
• Test each residue using a designed experiment to
screen alkaline, neutral, and acidic post production
residues over a range of typical cleaning process
temperatures to determine an appropriate cleaning
agent for a particular post production residue
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1/19/2017
• Cleaning Process Design Space Exploration

• Using the appropriate cleaning agent, explore combinations
of temperature, turbulence, and concentration to assess the
response of removal rate over typical ranges of these
process variables via a DOE based study
• Worst Case Residue Evaluation
• Compare the removal rates of selected post production
residues to empirically determine which are worst case with
respect to the cleaning process
5 cm
~1 in2
5 cm
• Consistent soiling •Cleaning Process Control

• Amount of material
•PID Temperature Control
• Reproducible surface area
•Controlled Agitation
• Control “Dirty Hold Time”
•Precisely Formulated cleaning
solutions
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1/19/2017
Determining Reynolds Number
- density Agitated Immersion:

- viscosity
N – Impeller speed in revolutions per second
D – Impeller Diameter D 2 N
N Re  
NRe < 2100 Laminar
NRe > 3000 Turbulent
Example:
T=25ºC
D = 2” (0.0508 m)
 = 997 (kg/m3)
µ = 0.0089 poise 2”
N = 64 rpm (1.07 rps)
NRe = 3082
Connecting Pharmaceutical Knowledge ispe.org
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1/19/2017
Coupon Soiling
Representative Post-Production
Residue Applied to Coupon
Soiled Coupon Dried to Simulate
Post-Production Conditions
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1/19/2017
Coupon Testing
Gravimetric Assessment
Laboratory Microbalance
Accuracy ±0.00005 grams
Tare mass of coupons
Amount of residue spiked on
coupons
Amount of residue remaining after
cleaning assessment
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1/19/2017
Range Finding Results

Range Finding Tests
12.00
10.00
Water 25C
Water 65C
8.00
Rate of Removal [mg/sec]
COSA‐CIP‐92 25C
COSA‐CIP‐92 65C
COSA‐CIP‐72 25C
6.00
COSA‐CIP‐72 65C
COSA‐PUR‐80 25C
COSA‐PUR‐80 65C
4.00
2.00
0.00
0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240
Duration [sec]
Worst Case Residue Identification

% Removal vs. Time A B
100%
C D
90%
80% E F
70%
G H
% Residue Remaining
60%
I J
50%
K L
40%
30% Q M
20%
N O
10%
P
0%
0 2 4 6 8 10 12 14 16 18 20
Cleaning duration (seconds)
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1/19/2017
Surface Response Plot
Surface Plot of Rate vs Temp, pH
4
Rate
3
6
pH 60
9 50
40
12 30 Temp
Establishment of CIP Setpoints for Cleaning Vessels and Piping
Re ≥ 34,000
CIP Supply
High
Low Level
Variable Level
CIP (‐)
(+)
System
Concentration 1% 2%
CIP Return Temperature 25°C 65°C
Energy NRe 3,000 34,000
Re ≥ 3,000
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Commissioning and Cycle Development
• Protein Containing Residues

• Full CIP (Rinses, Alkaline Wash and Acid Wash)
• Buffer Containing Residues
• Typically Rinse Only
• Periodic Full CIP for Maintenance Purposes
• Cleaning Cycle Critical Parameters Grouped by
Residues
• Media, Buffer, Cell Culture and Harvest, and Purification
• Residue-Based CCCPs Provide for More Effective and
Economical Cleaning
• “One Cycle Fits All” Approach Very Inefficient and my
also be Ineffective
Cycle Development at Commercial Scale
• Input of Critical Cleaning Control Parameters

(CCCPs)
• Analysis of CIP Cycle Operational Sequence
• Input of CIP Cycle Parameters into Control System
Setpoint Format
• Hydraulic Balancing Equally Important to
Implementation of CCCP Values
• CIP Supply and Return Flow Rates Must be Equal
• Cleaning Efficacy Confirmed with Concurrent
Process Validation and Cleaning Validation Runs
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Bioreactor Example
• Not all components may be cleaned simultaneously
• Many components to be cleaned in this complex CIP Circuit
 Cleaning vessel with sprays
 Cleaning multiple lines to bioreactor
• CIP system can only provide a limited flow rate to the
bioreactor
• Bioreactor has limited drain rate
• Clean components in sets with toggle sequences:
• Toggle CIPS valves to clean sets
• Clean all sets of components sequentially
• Use short toggle times and repeat toggles to get required
contact time
• Base Exposure Times for Piping on Residue to be Removed
• Gas Lines Versus Product or Media Containing Lines
Bioreactor Example
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Cleaning Validation
37
Cleaning Validation Trends
• Utilization of FDA 2011 Process Validation Guidance

Approaches for Bases of Cleaning Validation Program
• Extensive Utilization of Risk Analysis and Management to
Establish Focus Areas for Cleaning Validation and
Ongoing Monitoring
• Development of Existing and New In-Process Material
Residue Matrix from Laboratory and Pilot Scale Cleaning
Data
• Usage of Residue Matrix Data for Determination of Extent
of Full Scale Cleaning Validation Testing (e.g., Utilization
of Laboratory Derived Data and Residue Matrices Rather
Than Three Full-Scale Runs for Validation of Cleaning for
New Products)
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Cleaning Validation Trends

• Generation of Product Inactivation Data to Justify
Analytical Methodologies and Residue Limits for Multi-
Product Facilities
• Residue Limits not Based Upon MAC Calculations Unless
Residues Contain Significant Levels of Active Drug
Product
• Usage of PAT Methodologies and Data for Basis of Initial
Cleaning Validation Studies and On-Going Monitoring for
Defining Re-Validation Requirements
Multi-Product Cleaning Validation Trends

• Re-Use of Elastomers Between Manufacturer of Different
Products
• Utilization of “Normal” Cleaning Cycles Between
Manufacturer of Different Products
• Limited Cleaning Verification Between Manufacturer of
Different Products if Justified by Existing Lab and Pilot
Scale Cleaning Data
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Benefits of Efficient
CIP Design
41
Case Study – Mab Facility
• CIP Systems
• Large CIP Vessels Sized to Batch CIP Solutions
• CIP-100 Only Cleaning Agent Used
• CIP Circuits
• Piping and Vessels Cleaned Separately
• Piping Circuits Cleaned “Once-Through”, e.g., CIP-100
Solution Not Recirculated
• Performed Optimization Study
• Analyzed CIP Parameters and Operational Sequences
• Combined Piping and Vessel Cleaning
• Eliminated Once-Through CIP-100 Washes
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1/19/2017
WFI Consumption
Operational Number of WFI Usage (L) Number of WFI Usage (L)
Mode Cycles Per Lot Per Lot Lots per Year per Year
Vessels and 70 816,000 120 100,368,000

Piping Cleaned
Separately
Vessels and 70 530,400 120 65,239,000
Piping Cleaned
Separately
Optimized
Vessels and 30 408,000 120 50,184,000
Piping Cleaned
Together
Vessels and 30 269,000 120 33,121,000
Piping Cleaned
Together
Optimized
WFI Consumption
Operational Number of Skid Usage Number of Skid Usage
Mode Cycles Per Lot (H) per Lot Lots per Year (H) per Year
Vessels and 70 408 120 50,190

Piping Cleaned
Separately
Vessels and 70 238 120 29,275
Piping Cleaned
Separately
Optimized
Vessels and 30 224 120 27,600
Piping Cleaned
Together
Vessels and 30 149 120 18,380
Piping Cleaned
Together
Optimized
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WFI Consumption
Operational Number of CIP-100 Usage Number of CIP-100 Usage
Mode Cycles Per Lot (L) Per Lot Lots per Year (L) per Year
Vessels and 70 5,900 120 736,000

Piping Cleaned
Separately
Vessels and 70 3,950 120 482,950
Piping Cleaned
Separately
Optimized
Vessels and 30 2,600 120 324,720
Piping Cleaned
Together
Vessels and 30 1,750 120 213,070
Piping Cleaned
Together
Optimized
Questions?
Please use the microphone indicated so
our recording includes audio of your
question
46
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1/19/2017
Contact Information
John M. Hyde, B.Sc., M.Sc.

Principal Consultant
Chairman and Founder
Hyde Engineering + Consulting, Inc.
john.hyde@hyde-ec.com
+1.303.641.5468
24

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1/19/2017

HYDE ENGINEERING OVERVIEW

– Bioprocess and GMP Manufacturing Focus

– Highly Experienced staff

– 275+ Staff, Engineers & Scientists

– 12 Offices - 6 in US, Ireland (2), Belgium, India (2), Singapore

Phases of CIP Implementation

Connecting Pharmaceutical Knowledge ispe.org 3

CIP Concept Design

CIP Concept Design

CIP Concept Design

• CIP Cycle Requirements

Connecting Pharmaceutical Knowledge ispe.org 6

CIP Detailed Design

CIP Detailed Design

Connecting Pharmaceutical Knowledge ispe.org 8

Typical CIP Skid P&ID

Connecting Pharmaceutical Knowledge ispe.org 9

CIP Skid – Pre-Rinse and Drain

Connecting Pharmaceutical Knowledge ispe.org 10

CIP Skid – System Fill Vessels

Connecting Pharmaceutical Knowledge ispe.org 11

CIP Skid – Recirc, Heat and Cleaning Agent Feed - Vessels

Connecting Pharmaceutical Knowledge ispe.org 12

CIP Skid – Recirc, Heat and Cleaning Agent Feed - Piping

Connecting Pharmaceutical Knowledge ispe.org 13

CIP Detailed Design

Connecting Pharmaceutical Knowledge ispe.org 14

Process Vessels P&ID

Connecting Pharmaceutical Knowledge ispe.org 15

Process Vessels – Process Transfer

Connecting Pharmaceutical Knowledge ispe.org 16

Process Vessels - CIP

Connecting Pharmaceutical Knowledge ispe.org 17

CIP Commissioning and

Commissioning and Cycle Development

• Determination of Cleaning Critical Control

Connecting Pharmaceutical Knowledge ispe.org 19

Establishment of CCCPs at Lab Scale

Connecting Pharmaceutical Knowledge ispe.org 20

Establishment of CCCPs at Lab Scale

• Cleaning Process Design Space Exploration

Connecting Pharmaceutical Knowledge ispe.org 21

Establishment of CCCPs at Lab Scale

• Consistent soiling •Cleaning Process Control

Connecting Pharmaceutical Knowledge ispe.org 22

Determining Reynolds Number

- density Agitated Immersion:

Connecting Pharmaceutical Knowledge ispe.org

Connecting Pharmaceutical Knowledge ispe.org

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Connecting Pharmaceutical Knowledge ispe.org 26

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Connecting Pharmaceutical Knowledge ispe.org

Range Finding Results

Connecting Pharmaceutical Knowledge ispe.org 29

Worst Case Residue Identification

Connecting Pharmaceutical Knowledge ispe.org

Surface Response Plot

Surface Plot of Rate vs Temp, pH

Connecting Pharmaceutical Knowledge ispe.org 31

Establishment of CIP Setpoints for Cleaning Vessels and Piping

Connecting Pharmaceutical Knowledge ispe.org