Cleaning and Cleaning
Validation Strategies for
Multiproduct Manufacturing
Facilities
John M. Hyde
Chairman and Founder
Hyde Engineering + Consulting, Inc.
Hyde
y Engineering
g
g + Consulting
g Europe
p Limited
22 May 2014
Presentation Outline
• Drivers of Multiproduct Manufacturing
Drivers of Multiproduct Manufacturing
– Demographic Factors, Tariffs and Trade Restrictions, • New Approaches to Cleaning Qualification and Monitoring
• FDA Process Validation Guidance Three Stages of Validation
• Importance of Cleaning Cycle Development
– Lab and Pilot Scale Methodologies
Lab and Pilot Scale Methodologies
• Commercial Scale Testing Strategies
• Ongoing Monitoring
– Statistical Analytical Methodologies
S i i lA l i lM h d l i
– Application of PAT to CIP Operations
Demographic Factors
g p
• Life Expectancy
Lif E
t
– Average Life Expectancy has Increased by More Than 50% in BRIC Countries Since 1940
50% in BRIC Countries Since 1940
– Increased Rates of Chronic Disease Conditions
• Age Related
g
• Genetic Predispositions
• Increasing Incomes and Growing Middle Classes
– Growing Developing World Middle Class Income Translates Into Growing Demand for Biopharmaceutical Products
Biopharmaceutical Products
– By 2035, More Than 50% of Middle Class Households will be in India and China
International Trade Issues
• Tariffs
– Many Developing World Governments Impose Heavy Tariffs on Imported Goods Including Pharma Products
– Pharma Products Manufacturing in Developing Countries are Often Given Preferred Tax Treatment, E
Especially for Exports
i ll f E
• Special Economic Zones (SEZs)
• Other Trade Restrictions
– Indonesia has Erected Import Barriers, Through Withholding Regulatory Approval, for Pharma Products Imports
Developing World Biopharma Manufacturing Incentives
• Domestic Demand
– Growing Incomes and Middle Classes
• Export to Developed Countries
– Supply of Low Cost Bio‐Similars
• Demand to Support International Vaccination Initiatives
– Growing Demand for Low Cost Per Dose Products
• Lower Production Costs
– Labor and Equipment Cost Advantages
– Shorter Timelines to Bring Facilities Online
Factors Impacting Future Bio‐Manufacturing
• Higher Titers
– Less Cell Culture Capacity Required
L
C ll C lt
C
it R
i d
• Therapeutic Competition
– Often Several Therapies for the Same Disease Condition
Often Several Therapies for the Same Disease Condition
• Rheumatoid Arthritis •
•
•
•
•
•
Growth in Vaccine Demand
Biosimilars
COGS
Geographics ‐ Global Health
Green – CO2 reduction
Most were not driving forces 10 years ago
Cleaning and Qualification Objectives
Cleaning and Qualification Objectives
• Primary Operational Concerns
Pi
O
i
lC
–
–
–
–
Cleaning Consistency
Cleaning Quality
Cleaning Safety
Cost Effective Operations
• Bases of Assessment of Validation Studies
– Acceptance Criteria Based Upon Well Understood Design Space
– Scientifically Proven Operating Ranges
– Testing Scale – Lab, Pilot Plant, Commercial Plant
New Approaches to Cleaning Qualification and Monitoring
lf
d
• Extensive Utilization of Risk Analysis and Management to Establish Focus Areas for Cleaning Validation and O
Ongoing Monitoring
i M it i
• Development of Existing and New In‐Process Material Residue Matrix from Laboratory and Pilot Scale Cleaning
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 M ti
Matrices Rather Than Three Full‐Scale Runs for Validation R th Th Th
F ll S l R
f V lid ti
of Cleaning for New Products)
New Approaches to Cleaning Qualification and Monitoring
lf
d
• Generation of Product Inactivation Data to Justify Analytical Methodologies for Multi‐Product Facilities
• Residue Limits not
Residue Limits not Based Upon MAC Calculations Based Upon MAC Calculations
Unless Residues Contain Significant Levels of Active Drug Product
g
• Usage of PAT Methodologies and Data for Basis of Initial Cleaning Validation Studies and On‐Going Monitoring f D fi i R V lid i R
for Defining Re‐Validation Requirements
i
• Utilization of FDA 2011 Process Validation Guidance Approaches for Bases of Cleaning Validation Program
Approaches for Bases of Cleaning Validation Program
New Cleaning Practices for Cleaning of Multiproduct Process Equipment
l
d
• 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
Traditional Approach To Validation
pp
• Established,
Established, Highly Controlled Procedure
Highly Controlled Procedure
• Three Consecutive, Successful Commercial Runs
• Confidence Placed in the Consistent Performance of Confidence Placed in the Consistent Performance of
the Controlled Procedure Every Time
• Some Late Stage Cleaning Cycle Development Often g
g y
p
Occurs During Validation • At The Time Of Commercial Manufacture E
Excursions/Deviations Are Evaluated and Compared i /D i ti
A E l t d dC
d
to Historical Norms
Risk Based Approach To Validation
Risk Based Approach To Validation
• Focused on Cleaning Cycle Development
– Validation Studies Design and Execution Based Upon Risk Analysis and Management
– Established Process Design Space Provides Identification of Critical Control Parameters and
Identification of Critical Control Parameters and Boundary Conditions for Effective and Tight Process Controls
– Ongoing Monitoring of Critical Process Parameters Ongoing Monitoring of Critical Process Parameters
Provides Bases of Risk Review and Management With Ongoing Real Time Confirmation of Process Operation Withi V lid t d D i S
Within Validated Design Space
2011 Guidance‐Based
2011 Guidance
Based Practices
Practices
• New guidance characterizes process validation d
h
ld
as a lifecycle rather than a discrete event, as implied in the definition in the 1987 guidance
• New guidance goes on to say that “process g
g
y
p
validation involves a series of activities taking p
place over the lifecycle of the product and y
p
process”
2011 Guidance Based Practices
2011 Guidance‐Based Practices
• N
New guidance describes process validation id
d
ib
lid ti
activities in three stages
– Stage 1: Process design
– Stage 2: Process qualification
– Stage 3: Continued process verification
• Stated
Stated another way, process validation may be another way, process validation may be
defined as:
– Process Validation = Lab Studies + Development Process Validation = Lab Studies + Development
History + Commercial Scale Manufacturing @ Target Values + Ongoing Monitoring
Target Values Ongoing Monitoring
Stage 1 Cleaning Design
Stage 1 –
Cleaning Design
• Test Plan
l
– Author an experimental test plan describing the approach used to conduct bench scale cleaning h
dt
d tb h
l l
i
process developmental studies for post production residues.
residues
• Cleaning Agent Selection
– Test
Test each residue using a designed experiment to each residue using a designed experiment to
screen alkaline, neutral, and acidic post production residues over a range of typical cleaning process g
yp
gp
temperatures to determine an appropriate cleaning agent for a particular post production residue.
Stage 1 Cleaning Design
Stage 1 ‐
Cleaning Design
• 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.
• Worst Case Residue Evaluation
– Compare the removal rates of selected post p
production residues to empirically determine which p
y
are worst case with respect to the cleaning process.
Essential Cleaning Parameters
Essential Cleaning Parameters
• Critical Cleaning Control Parameters (CCCPs)
C i i l Cl
i C
lP
(CCCP )
– An input cleaning parameter that should be controlled within a meaningful narrow operating range to ensure that cleaning quality attributes meet their specifications. (Out of range results may lead to cleaning failures.)
• Key Cleaning Control Parameters (KCCPs)
Key Cleaning Control Parameters (KCCPs)
– An input cleaning parameter that should be carefully controlled within a narrow range and is essential for cleaning performance. Does not affect cleaning cycle efficacy but may affect the efficiency (utility usage time
cleaning cycle efficacy, but may affect the efficiency (utility usage, time, etc.)
• Critical Cleaning Quality Attributes (CCQAs)
– An output variable that cannot be directly controlled but is an indicator of cleaning performance and cleaning efficacy.
CCCPs and CCQAs for Cleaning
CCCPs and CCQAs for Cleaning
• Cleaning Process Inputs:
– Demonstration of Consistent and Real Time Demonstration of Consistent and Real Time
Control of Cleaning Parameters, Flow Rate, Temperature, Contact Time, Conductivity, etc.
• Cleaning Process Outputs:
Cl
i P
O t t
– Demonstration of Ability to Consistently Meet Specifications for Cleaning Quality Attributes
Specifications for Cleaning Quality Attributes, e.g., TOC, Conductivity, Bioburden, Endotoxin, etc.
T i l CIP S t
Typical CIP System Analog Instrumentation
A l I t
t ti
• Essential for Control and Ongoing Monitoring of Cleaning Parameters
Cleaning Parameters
• Factors Affecting Cleaning Efficiency Measured via:
–
–
–
–
Supply/Return Temperature
Supply Flow Rate
Supply Flow Rate
Supply Pressure
Supply/Return Conductivity
Supply/Return Conductivity
Testing Methodology
Testing Methodology
5 cm
~1 in2
5 cm
• Consistent soiling
• Amount of material
• Reproducible surface area
• Control “Dirty Hold Time”
C t l “Di t H ld Ti ”
• Cleaning Process Control
• PID Temperature Control
• Controlled Agitation
• Precisely Formulated cleaning solutions
cleaning solutions
Determining Reynolds Number
Determining Reynolds Number
ρ- density
μ- viscosity
N – Impeller speed in revolutions per second
D – Impeller Diameter
NRe < 2100
Laminar
NRe > 3000
Turbulent
Agitated Immersion:
N
Re
=
D 2 Nρ
Example:
T=25ºC
D = 2”
2 (0.0508 m)
ρ = 997 (kg/m3)
µ = 0.0089 poise
N = 64 rpm (1.07
(1 07 rps)
NRe = 3082
2”
μ
Coupon Soiling
Coupon Soiling
• Representative Post‐
Production Residue Applied to Coupon
• Soiled Coupon Dried to Simulate Post‐
Production Conditions
Coupon Testing
Coupon Testing
Gravimetric Assessment
Gravimetric Assessment
• Laboratory Microbalance – Accuracy ±0.00005 grams
– Tare mass of coupons
– Amount of residue spiked on coupons
– Amount of residue remaining after cleaning f
assessment
Range Finding Results
Range Finding Results
Range Finding Tests
Range Finding Tests
12.00
10 00
10.00
Rate oof Removal [mg/seec]
Water 25C
Water 65C
8.00
COSA‐CIP‐92 25C
COSA‐CIP‐92 65C
COSA‐CIP‐72 25C
6.00
COSA‐CIP‐72 65C
COSA‐PUR‐80
COSA
PUR 80 25C
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]
COSA‐CIP‐72 [pH2]
COSA‐CIP‐72 [pH2]
Water [pH7]
Distilled W
COSA‐PU
UR‐80 [pH7]
COSA‐CIPP‐92 [pH12]
COSA‐CIPP‐92 [pH12]
COSA‐CIPP‐92 [pH12]
25
45
65
25
45
65
25
45
65
1% Detergent and Temperature [°C]
25
45
65
COSA‐PU
UR‐80 [pH7]
COSA‐PU
UR‐80 [pH7]
Distilled W
Water [pH7]
Distilled W
Water [pH7]
COSA‐CIP‐72 [pH2]
Average Rem
moval Rate [mgg/sec]
Effects of pH and Temperature
Effects of pH and Temperature
Average Removal Rate [mg/sec]
Average Removal Rate [mg/sec]
7
6
5
4
3
2
1
0
Surface Response Plot
Surface Response Plot
Surface Plot of Rate vs Temp, pH
6
Rate
4
2
3
6
pH
9
12
30
40
50
Temp
60
Box Plot Representation
Box Plot Representation
Boxplot of Rate
6
Rate
5
4
3
2
Temp
pH
25
45
2
65
25
45
7
65
25
45
12
65
Contour Plot Representation
Contour Plot Representation
Contour Plot of Rate vs Temp, pH
65
Rate
< 2
2 – 3
3 – 4
4 – 5
5 – 6
> 6
60
55
T
Temp
50
45
40
35
30
25
2
4
6
8
pH
10
12
Product Fragmentation/Inactivation
Product Fragmentation/Inactivation
• Conduct
Conduct Studies to Show Fragmentation / Studies to Show Fragmentation /
Inactivation of Active Molecule by Cleaning Process
– Expose Formulated Bulk Product to Cleaning Solutions at Use Strength and Temperature
g
p
– Analyze Residues with SDS‐Page and Western Blot to Prove Fragmentation / Inactivation
• Favorable Results Justify Non‐Product Specific Residue Testing Methods, Re‐Use of Elastomers
g
,
and Utilization of Normal CIP Cycles Between Manufacture of Different Products
Stage 2 Cleaning Qualification
Stage 2 –
Cleaning Qualification
• During this stage, the cleaning cycle design is confirmed as being capable of effective and reproducible at commercial manufacturing scale
i l
f t i
l
– Cleaning cycles challenged with typical post‐production residues
– Dirty and clean hold times also assessed
Di t
d l
h ld ti
l
d
• Qualification of the facility, utilities and equipment is required
– Cleaning systems, clean and plant utilities and process equipment systems are of primary interest
equipment systems are of primary interest
Stage 2 Cleaning Qualification
Stage 2 –
Cleaning Qualification
• Usually run at operating parameter set points within proven acceptable range or design space
– Boundary condition testing is not typically performed at this stage as it has been assessed in Stage 1
• Requires additional QC testing to Requires additional QC testing to ‘prove’
prove the process
the process
– Qualification testing requires the analyses of many more samples than for ongoing monitoring of cleaning
samples than for ongoing monitoring of cleaning
• Risk analysis used to determine extent of testing requirements
– Equipment and residue groupings used to determine testing requirements
P i t t C id f Cl
Points to Consider for Cleaning Qualification
i Q lifi ti
•
•
•
•
•
Analytical Methods Selection
Sampling Methods
Visual Inspection
Residue Limits
Residue Limits
Role of Risk Assessment in Determination of Extent of Cleaning Q alification Testing
of Cleaning Qualification Testing
Sampling Requirements
• Are Swab and Rinse Samples Needed?
S b d i
S
l
d d?
– Some Firms Combine Rinse Samples With Rigorous Vi l I
Visual Inspection Only
i O l
– What is the Objective of Each Sample Type?
• How are “Worst Case” Sample Sites Identified and Justified?
– For Rinse Samples, Points of Maximum Cleaning Solution Contact
– For Swab Samples, Difficult to Clean Areas Due to Physical Constraints or Areas of Residue Accumulation
Sampling Requirements
• Requirements for Rinse Samples
– Residues Include USP Criteria and What Else?
– Specific API Residue, Total Protein, Bioburden, Endotoxin?
• Requirements for Swab Samples
R
i
t f S bS
l
– Residues Include Specific or Non‐Specific Testing (e.g. TOC Total Protein or Specific Assays)?
TOC, Total Protein or Specific Assays)?
– Swabbing Method Validation
• Including LOD and LOQ!
g
– Recovery Study
Visual Inspection
Visual Inspection
• Determine Visual Residue Limit (VRL)
• Establish Critical Parameters
Establish Critical Parameters
– Viewing Distance
– Light Intensity
Li h I
i
– Viewing Angle
– Lighting Angle
• Inspector
Inspector Qualification and Training are Qualification and Training are
Crucial
Acceptance Criteria
Acceptance Criteria
• How Clean is Clean Enough?
H Cl
i Cl
E
h?
– Maximum Allowable Carryover (MAC) Calculations
– Toxicity or Alergenicity Data
– LOQ for Analytical Method
LOQ for Analytical Method
– Cleaning System Performance
– Role of Product Fragmentation from Exposure to f
f
Cleaning Cycle
– Scientific Rationale Behind Decision?
Typical BioPharma Acceptance Criteria
Typical BioPharma
Acceptance Criteria
Visual
•
No residue present. No pooling or standing WFI. Vessel is visibly clean and dry
and dry.
Rinse Water Samples
•
•
•
•
Rinse Water Conductivity : 1 – 10 µS/cm
Rinse Water TOC : <0.5 ppm
Bioburden: < 10 CFU/100mL to 1000 CFU/100mL
Endotoxin:<0.25 EU/mL
/
Surface Samples
•
2 Swabbed Surface Swabs : <1 –
f
b
2 ppm TOC in 40 mL Diluent
l
f
for 100 cm
bb d
Area
Risk Analysis and Management
Risk Analysis and Management
• Risk
Risk Analysis and Management is at the Core of the Analysis and Management is at the Core of the
Primary Objectives of Validation
– Risk
Risk Analyses Provides the Bases for the Focus of the Analyses Provides the Bases for the Focus of the
Process and Cleaning Validation Programs
– Risk Management Provides the Means for Ongoing g
g g
Assurance of Consumer Safety and Product Efficacy
– Process Analytical Technologies (PAT) Can Provide Risk R d ti Th
Reduction Through Enhanced Process Understanding hE h
dP
U d t di
and Real‐Time Failure Detection
Document The Risk Assessment
Document The Risk Assessment
Stage 3 – Continued Cleaning Verification
Stage 3 –
Continued Cleaning Verification
• O
Ongoing assurance that cleaning is in control
i
th t l
i i i
t l
• Monitor, collect information, assess, continuous verification cleaning process improvements
verification, cleaning process improvements
• No longer “revalidation”, instead ongoing periodic evaluation
– 21 CFR 211. 180(e) – “Annual review to determine whether changes in specifications or manufacturing or control procedures are needed”
procedures are needed
• Study trends, OOS/OOT to make improvements
• Feedback into design stage for significant process shifts or changes
Monitoring Consistency Process Capability Index
Monitoring Consistency ‐
Process Capability Index
• Capability
Capability index is the total specification range divided by index is the total specification range divided by
the process operating variability, 6σ spread.
Cp = total specification/ 6σ
l
f
/
= (USL‐LSL)/6σ
• Measures
Measures how close the process parameter operates to the how close the process parameter operates to the
specification
• Cp
Cp = 1.33 indicates the process variability consumes only 1 33 indicates the process variability consumes only
75% of the specification
– The specification is 1.33 times the process variability spread
• Typical Cp goals are 1.33 – 2.0
Capability Index
Capability Index
Amount within
Specification
Process Monitoring – Control Chart Analysis
• Nelson Rules
– Lloyd S Nelson, 1984
Lloyd S Nelson 1984
• Western Electric Rules
• Tests for Out of Control Patterns on Control Charts
How Can PAT Apply To Cleaning?
How Can PAT Apply To Cleaning?
• Control of Cleaning CCPs
– Critical for Assurance of Repeatable p
Cleaning Operations
– Assurance of Cleaning Operation Within g p
Well Defined Design and Operating Spaces
• Real Time Adjustment of CCPs for Input j
p
Variability
• Provides Bases for Cleaning Process Provides Bases for Cleaning Process
Improvements
PAT: On Line TOC for Cleaning Verification
PAT: On‐Line TOC for Cleaning Verification
Final Rinse
Machine with valves
End rinse
Provides a ‘finger print’ of process
performance
Avoid cleaning
g failure
Avoid excess water use
Final Rinse
Tank
Summary
• Many
Many Significant Drivers Resulting in Extensive Significant Drivers Resulting in Extensive
Multiproduct Manufacturing
• New FDA Process Validation Guidance Provides a Very Good Framework for Effective Cleaning Validation
• Cleaning Process Development is a Crucial Element
Cleaning Process Development is a Crucial Element
• Risk Assessment and Management are Key Elements of Program
• New Approach Results in More Effective Cleaning Qualification and Ongoing Assurance of Cleaning Efficacy
• PAT Applied to CIP Systems Can Result in Improved and More Reliable Cleaning Operations
Contact Info
John M. Hyde, B.Sc., M.Sc.
P i i lC
Principal Consultant
l
Chairman and Founder
H d E i
Hyde Engineering + Consulting, Inc.
i +C
lti
I
john.hyde@hyde‐ec.com
john
hyde@hyde‐ec com
+1.303.641.5468