STRATEGIES FOR CLEANING

AND CLEANING VALIDATION

THAT MINIMIZE DOWNTIME

FOR PRODUCT CHANGEOVERS

JOHN HYDE

HYDE ENGINEERING + CONSULTING

PRESENTATION OUTLINE

• Importance of Cleaning Process Development at Lab and Pilot Scale for Transfer to Commercial Scale Equipment to Support Effective and Efficient Cleaning Operations

• Commercial Scale Cleaning Cycle Development Strategies that Enable Expeditious Cleaning of Process Equipment for Product Changeover

• Cleaning Circuit Configurations that Minimized the Number of Cleaning Cycles per Lot of Product Manufactured

• FDA Process Validation Guidance Three Stages of Validation• Importance of Cleaning Cycle Development

– Lab and Pilot Scale Methodologies• Commercial Scale Testing Strategies• Ongoing Monitoring

– Statistical Analytical Methodologies– Application of PAT to CIP Operations

CLEANING AND QUALIFICATION OBJECTIVES

• Primary Operational Concerns– Product and Patient Safety

– Cleaning Consistency

– Cleaning Quality

– Cost Effectiveness

• Bases of Assessment of Cleaning Validation– Acceptance Criteria Based Upon Well Understood Design

Space

– Scientifically Proven Operating Ranges

– Testing Scale – Lab, Pilot Plant, Commercial Plant

– Risk Bases of Cycle Development, Full Scale Testing and Ongoing Monitoring

TRADITIONAL APPROACH TO VALIDATION

• Established, Highly Controlled Procedure• Three Consecutive, Successful Commercial Runs• Confidence Placed in the Consistent Performance of

the Controlled Procedure Every Time• Some Late Stage Cleaning Cycle Development Often

Occurs During Validation • At The Time Of Commercial Manufacture

Excursions/Deviations Are Evaluated and Compared to Historical Norms

RISK BASED APPROACH TO VALIDATION

• Focused on Cleaning Cycle Development– Validation Studies Design and Execution Based Upon

Risk Analysis and Management• Buffer Prep and Holding Versus Final Filling

– Established Process Design Space Provides Identification of Critical Control Parameters and Boundary Conditions for Effective and Tight Process Controls

– Ongoing Monitoring of Critical Cleaning Parameters Provides Bases of Risk Review and Management With Ongoing Real Time Confirmation of Process Operation Within Validated Design Space• Monitoring Sampling Plan Based Upon Risk

NEW APPROACHES TO CLEANING

QUALIFICATION AND MONITORING

• 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)

NEW APPROACHES TO CLEANING

QUALIFICATION AND MONITORING

• 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

NEW CLEANING PRACTICES FOR CLEANING

OF MULTIPRODUCT PROCESS EQUIPMENT

• 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

CLEANING CIRCUIT DESIGN OPTIMIZATION

• CIP circuits are configured such that each vessel, its inlet piping and its outlet piping are cleaned as separate CIP circuits– This results in 2 to 3 times as many cleaning cycles per lot

than if the vessels and inlet and outlet piping are cleaned together in one circuit

• Cleaning circuit system flow path sequencing used to clean interconnecting piping attached to vessels and piping branches in piping circuits– Cleaning flow paths grouped to optimize flow rates or

downstream pressure drops

– Cleaning flow path groupings optimized based upon post production residue contact

9

2011 GUIDANCE-BASED PRACTICES

• New guidance describes process validation activities in three stages– Stage 1: Process design

– Stage 2: Process qualification

– Stage 3: Continued process verification

• Stated another way, process validation may be defined as:– Process Validation = Lab Studies + Development

History + Commercial Scale Manufacturing @ Target Values + Ongoing Monitoring

STAGE 1 – CLEANING DESIGN

• 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.

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 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

TESTING METHODOLOGY

• Consistent soiling• Amount of material

• Reproducible surface area

• Control “Dirty Hold Time”

• Cleaning Process Control• PID Temperature Control

• Controlled Agitation

• Precisely Formulated cleaning solutions

5 cm

5 cm

~1 in2

DETERMINING REYNOLDS NUMBER

- density

- viscosity

N – Impeller speed in revolutions per second

D – Impeller Diameter

NRe < 2100 Laminar

NRe > 3000 Turbulent

Agitated Immersion:

NDN

2

Re

Example:

T=25ºC

D = 2” (0.0508 m)

= 997 (kg/m3)

µ = 0.0089 poise

N = 64 rpm (1.07 rps)

NRe = 3082

2”

COUPON SOILING

• Representative Post-Production Residue Applied to Coupon

• Soiled Coupon Dried to Simulate Post-Production Conditions

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

RANGE FINDING RESULTS

0.00

2.00

4.00

6.00

8.00

10.00

12.00

0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240

Rate

of

Rem

oval

[m

g/se

c]

Duration [sec]

Range Finding Tests

Water 25C

Water 65C

COSA-CIP-92 25C

COSA-CIP-92 65C

COSA-CIP-72 25C

COSA-CIP-72 65C

COSA-PUR-80 25C

COSA-PUR-80 65C

WORST CASE RESIDUE IDENTIFICATION

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20

% R

esi

du

e R

em

ain

ing

Cleaning duration (seconds)

% Removal vs. Time A B

C D

E F

G H

I J

K L

Q M

N O

P

EFFECTS OF PH AND TEMPERATURE

0

1

2

3

4

5

6

7

COSA

-CIP

-72

[pH

2]

COSA

-CIP

-72

[pH

2]

COSA

-CIP

-72

[pH

2]

Dis

tille

d W

ater

[pH

7]

Dis

tille

d W

ater

[pH

7]

Dis

tille

d W

ater

[pH

7]

COSA

-PU

R-8

0 [p

H7]

COSA

-PU

R-8

0 [p

H7]

COSA

-PU

R-8

0 [p

H7]

COSA

-CIP

-92

[pH

12]

CO

SA-C

IP-9

2 [p

H1

2]

COSA

-CIP

-92

[pH

12]

25 45 65 25 45 65 25 45 65 25 45 65

Ave

rage

Rem

oval

Rat

e [m

g/se

c]

1% Detergent and Temperature [ C]

Average Removal Rate [mg/sec]

SURFACE RESPONSE PLOT

2

3

6

9

12

6

4

6

6050

4030

Rate

pH

Temp

Surface Plot of Rate vs Temp, pH

TURBULENCE ASSESSMENT AND SCALE-UP

CIP System

CIP Supply

CIP Return

Re ≥ 34,000

Re ≥ 3,000

VariableLow Level

(-)

High

Level

(+)

Concentration 1% 2%

Temperature 25°C 65°C

Energy NRe 3,000 34,000

TECH TRANSFER TO COMMERCIAL SCALE

• 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 Ineffient and my

also be Ineffective

TECH TRANSFER TO COMMERCIAL SCALE

• Input of Critical Cleaning Control Parameters (CCCPs)– Analysis of CIP Cycle Operational Sequence

– Input of CIP Cycle into Control System SetpointFormat

• Hydraulic Balancing Equally Important to Implementation of CCCP Values

• Cleaning Efficacy Confirmed with Concurrent Process Validation and Cleaning Validation Runs

PRODUCT FRAGMENTATION/INACTIVATION

• Conduct Studies to Show Fragmentation / Inactivation of Active Molecule by Cleaning Process– Expose Formulated Bulk Product to Cleaning Solutions

at Use Strength and Temperature

– Analyze Residues with SDS-Page and Western Blot to Prove Fragmentation / Inactivation

• Favorable Results Justify Non-Product Specific Residue Testing Methods, Re-Use of Elastomersand Utilization of Normal CIP Cycles Between Manufacture of Different Products

STAGE 2 – CLEANING QUALIFICATION

• During this stage, the cleaning cycle design is confirmed as being capable of effective and reproducible at commercial manufacturing scale

– Cleaning cycles challenged with typical post-production residues

– Dirty and clean hold times also assessed

• Qualification of the facility, utilities and equipment is required

– Cleaning systems, clean and plant utilities and process equipment systems are of primary interest

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

• May require additional testing to ‘prove’ the process

– Qualification testing typically requires the analyses of more 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

CIP CYCLE, PHASE AND STEP HIERARCHY

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

Pre-RinseAlk.

Wash

Post

Rinse

Air

Blow

&

Drain

WashSupply

Air BlowRInse

Final

Rinse

Supply

Air Blow

Final

Drain

Full CIP Cycle

4 Delay to Conductivity

3

2

1

Air Blow

Fill Water Tank

Check Interlocks

# Example Step Description

CIP Phases

4

3

2

1

#

Final Rinse

Alkaline Wash

Post Rinse

Rinse Phase

Example Phase Description

4

3

2

1

#

Acid Wash

Rinse Cycle

Drain Cycle

Full CIP

Example Cycle Description

CIP Steps

STAGE 3 – CONTINUED CLEANING VERIFICATION

• Ongoing assurance that cleaning is in control• Monitor, collect information, assess, continuous

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”

• Study trends, OOS/OOT to make improvements

• Feedback into design stage for significant process shifts or changes

CONFIRMATION OF CCCPS IN REAL TIME

• Essential for Control and Ongoing Monitoring of Cleaning Parameters

• Factors Affecting Cleaning Efficiency Measured via:– Supply/Return Temperature

– Supply Flow Rate

– Supply Pressure

– Supply/Return Conductivity

TRADITIONAL VS. QBD APPROACHES

Aspects Traditional QbD

Cleaning Development Empirical; typically single

variable experiments

Systematic; multi variable

experiments

Cleaning Process Fixed Adjustable within design

space; opportunities for

innovation (PAT)

Cleaning Control Annual re-validation; very

risky because of product

quality implication of test

failures

PAT utilized for feedback

and feed forward at real

time and ongoing

monitoring

Cleaning Specification Primary means of quality

control; based on cycle

completion w/o errors

Part of the overall quality

control strategy; based on

operation within design

space

Control Strategy Black-box; Validated cycles

are relied upon as basis of

cleaning success

Data-based; monitoring

and analysis of critical

parameters

Lifecycle Management Reactive to problems and

OOS; improvements driven

by CAPAs and remediations

Continual improvement

enabled within design

space

SUMMARY

• Risk Based Approach to Validation Results in More Comprehensive and Effective Result

• FDA Process Validation Guidance Three Stages of Validation Provides Excellent Basis to Cleaning Validation Study Design

• Importance of Cleaning Cycle Development Studies Crucial to Commercial Scale Success

• Ongoing Monitoring Provides Real-Time Assurance of Cleaning Efficacy

CONTACT INFO

John M. Hyde, B.Sc., M.Sc.Principal Consultant

Chairman and FounderHyde Engineering + Consulting, Inc.

john.hyde@hyde-ec.com+1.303.641.5468