LIFECYCLE

C C APPROACH
O C
TO CLEANING VALIDATION

Paul L. Pluta, PhD

Validation Week EU, 2013

1
 MANUAL CLEANING -- Do you really know what is happening?

Q to operator: Why is there so much foam in the tub?

A: I put in extra soap because the equipment was really dirty.

Q to operator: Why is there powder on the (clean) equipment?

A: No
No problem -- We
Wellll get the residue when we set up
up.

Q to operator: Why
Why don
dontt you follow the cleaning procedure?
procedure?
A: The cleaning procedure really doesnt work.

ABOVE NOT ACCEPTABLE TRAINING NEEDED

2
 MANUAL CLEANING -- Do you really know what is happening?
Q to operator:
p Why
y is there p
powder on the clean equipment?
q p
A: Its clean enough.
Q to QA (equipment inspection person): Did you approve that the equipment
is clean?
A: Its clean enough.
Q to management: Do you know that your equipment is not clean?
A: Its clean enough.

Q to operator: You cleaned the gasket with pure soap this is not the
procedure? Also it is dangerous these are corrosive chemicals.
A: That is the only way to get it clean.
Q: So why dont you tell someone to change the procedure?
A: We dont have time.

ABOVE NOT ACCEPTABLE TRAINING NEEDED

3
 MANUAL CLEANING -- Do you really know what is happening?

Q to management: Did you finish cleaning the equipment? We are

here to swab for cleaning validation.
A (very
( proudly):
dl ) W
We cleaned
l d th
the equipment
i t th
three ti
times so th
thatt we
wont have any problems.

Q to validation person: Did you know that the manufacturing people

always clean the equipment multiple times before it is swabbed?
A: Sure, we knew.
Q: Why didnt you stop this?
A: These people are our friends. We have to work with these people.

ABOVE NOT ACCEPTABLE TRAINING NEEDED

4
 OUTLINE

Lifecycle Approach Applied to Cleaning Validation

Stage 1 Activities
Cleaning Method Development
Analytical Method Development
Site equipment
Stage 2 Activities
Cleaning documentation
Validation conformance lots
Stage 3 Activities
Maintaining Validation
Change Control
Management review

5
 OBJECTIVES
1. Application of lifecycle approach to cleaning
validation
2. Cleaning lifecycle stage details
Process development and understanding
Process qualification
Maintaining
g the validated state
3. Cleaning validation problems
Global experiences

6
 Lifecycle Approach to Cleaning Validation
Value? Does this make sense?
Cleaning is a process

Validation lifecycle concepts being applied to equipment,

facilities, utilities, computers, etc., by validation and
technical experts
p

Who can argue with understanding, performing, and

maintaining
g the validated state?

Consistent with QbD and ICH approaches

Lifecycle approach (i.e., understanding, performing,

maintaining) vs. traditional approach Which would
you rather present to an auditor?
7
 WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification (PPQ)
A t
Automated
t d CIP System
S t

Process steps Qualification

1. Residue on equipment Equipment
2. Water procedure Purified Water
3 Cleaning agent procedure
3. Computer / software
4. Water procedure Compressed air
5. Purified Water procedure Conductivity analysis
6. Dryy TOC analysis
y

Equipment is clean -- Process is validated

Process parameters Quality attributes

8
 WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification (PPQ)
M
Manuall Cleaning
Cl i

Process steps Qualification

1. Residue on equipment Personnel
2. Water rinse Purified Water
3 S
3. Scrubb with
ith cleaning
l i agentt C
Compressed d air
i
4. Water rinse
5. Scrub
6. Water rinse
7. Purified Water rinse
8 Dry
8.
Equipment is clean -- Process is validated

Process parameters Quality attributes

9
 CLEANING VALIDATION OVERVIEW
1990 present
1990s t

1. Defined cleaning
gp procedure ((SOP)) basis?
2. Product A batch does not contaminate subsequent
Product B batch
3. Acceptance limit calculated
4. Assume uniform contamination of all equipment
5 Three conformance lots = Validated cleaning procedure
5.
6. Validated analytical method (original API)
7 Worst
7. Worst-case
case matrix approach

One-time event

10
 FDA PROCESS VALIDATION GUIDANCE
LIFECYCLE APPROACH TRANSITION
APPPLICATION TO CLEANING VALIDATION

Pre Lifecycle

Cleaning development (?) PQ change control

________________________

Lif
Lifecycle
l Approach
A h
Development PQ Maintenance
EXPANDED SCOPE OF VALIDATION
INCREASED SPECIFIC STAGE REQUIREMENTS
11
 LIFECYCLE APPROACH TO CLEANING VALIDATION
Scientific and technical approach
Design and development
Residue + cleaning agent + cleaning procedure Clean equipment
Performance demonstration
Monitoring and maintenance
Rationale, responsibility, and accountability
Future process improvements
Not the following:
Standard
St d d site it method
th d (no
( basis
b i or rationale)
ti l )
Personnel driven (no control)
Do whatever it takes (high variation)
SOP (no accountability)
Validation (?) One-time event.

12
 STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)
APPLICATION TO CLEANING
FDA Guidance Topics
1. Building and capturing process knowledge and understanding.
2. Establishing a strategy for process control.

Application to Cleaning
Understand residue chemistry (solubility, stability)
Determine cleaning agent based on residue chemistry
Determine cleaning process
Identify sources of variability
Establish methods to control variability
Process Analytical Technology

Rational analytical
y method and supporting
pp g work
Characterization of equipment to be cleaned and supporting work
Trained sampling personnel

DOCUMENT ALL OF THE ABOVE

13
 DEVELOPMENT (STAGE 1)
CLEANING PROCESS DEVELOPMENT
Physical and chemical properties of the residue is basis for cleaning
process
Considerations for determination of most difficult-to-clean residue
Residue solubility and stability in determining worst-case soils
Residue chemistry critical for analytical method
Cleaning agent chemistry consistent with residue chemistry
Cleaning process chemistry and engineering and consistent with
residue and cleaning agent.

RESIDUE CHEMISTRY
BASIS FOR CLEANING PROGRAM
BASIS FOR ANALYICAL METHOD

14
 RESIDUE PROPERTIES -- BASIS FOR CLEANING PROCESS

Case study: Antibiotic suspension containing insoluble API (base)

Original cleaning method: Water, PurW, dry
No documented cleaning validation for many years
Unknown peaks on original cleaning validation attempts
API insoluble

Second method: Alkaline soap wash

wash, water
water, PurW,
PurW dry
Unknown peaks again
API insoluble

Finall method:
Fi th d Acid
A id wash,
h alkaline
lk li soap wash,
h water,
t PurW,
P W dry
d
No residues
Unknown peaks determined to be degradants and flavors.
API dissolves
di l (acid-base
( id b neutralization)
t li ti )

Consider active drug and other residue chemistry in development

of cleaning process
15
 DETERMINATION OF
MOST DIFFICULT TO CLEAN RESIDUE
BASIS FOR CLEANING PROGRAM

Water solubility USP Tables

Is this adequate? NO!
pH effect API with ionizable groups?
Solubility in cleaning agent?

Determine solubility at range pH 1-12

Understand solubility at pH of cleaning liquid
Understand solubility in cleaning agent liquid

16
 pH SOLUBILITY
p SO U PROFILE,
O , pH
p 1-12

Solubility
mg/ml

Drug A

Drug B

pH 1 7 12

17
 RESIDUE SOLUBILITY AND STABILITY FOR
DETERMINING WORST
WORST-CASE
CASE SOILS
Solubility considerations
Hydrophilic and hydrophobic molecules
Ionization Effect of pH
Effect
Eff t off temperature
t t
Surface active molecules
Liquid and semisolid product vehicle polarity

Stability considerations
Hydrolysis,
Hydrolysis oxidation
oxidation, photolysis
photolysis, physical changes

What residue is really present?

Consider chemistry of residues
18
 CLEANING MATRIX
Determine Worst-Case Soil
SOLUBILITY (mg / ml)
pH
H1 W t
Water pH
H 12 Alkaline
Alk li
Cleaning Agent
Drug A 25 25 25 25

Drug B 15 15 15 15

Drug C 5 5 150 250

Drug D 150 10 10 50

Drug E 125 10 100 250

Consider acid cleaning agent for drugs D and E

19
 WORST CASE CLEANING

Determination of worst-case cleaning based

on API toxicity, worst-case
worst case dose, etc.
Standard calculation
Cleaning procedure may be based on
excipients having greatest effect on
cleaning
Hydrophilic polymers
Dyes
D
Hydrophobic vehicles

20
 BIOTECH CLEANING CHEMISTRY -- API
Protein molecules degrade in alkaline conditions
Degradation
g rate is milder in acidic conditions
Degradation rate increases with temperature
API residues typically consist of protein fragments and
aggregates
Analytical method: Non-specific analysis

Reference: Kendrick, Canhuto, and Kreuze. Analysis of

Degradation
g Products of Biopharmaceutical
p API Caused
by Cleaning Agents and Temperature. Journal of
Validation Technology, V15, #3, Summer 2009.

21
BIOTECH CLEANING CHEMISTRY GROWTH MEDIUM

Medium Composition
Acids or bases
Monovalent salts
Polyvalent salts
Amino acids
Proteins (polypeptides)
Carbohydrates
Aqueous
q soluble organics
g
Non-aqueous soluble organics

Consider medium composition at end of cycle.

Reference: Azadan and Canhoto. A Scientific Approach to the Selection of

Cleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing.
Cleaning and Cleaning Validation, Volume 1. 2011.

22
 CLEANING CHEMISTRY MECHANISMS
Wetting
Emulsification
Dispersion
Solubilityy
Chelation
Oxidation
Hydrolysis

23
 CLEANING AGENT OPTIONS
Water
Commodityy alkalis and acids
Organic solvents
Surfactants
Anionic
Cationic
Amphoteric
Nonionic
Formulated detergents

24
 COMPONENTS OF FORMULATED DETERGENTS
Surfactants
Alkalis
Acids
Sequestrants / chelants
Dispersants / anti-redeposition agents
Corrosion inhibitors
Oxidizing agents
Enzymes
Buffers / builders
Preservatives

MUST HAVE CONTROL OF CLEANING AGENT

HAVE CONFIDENTIALITY AGREEMENT WITH SUPPLIER

25
 CLEANING ENGINEERING
Factors affecting cleaning
Soil residue
Soil levels, soil condition, hold times, soil mixing,
water quality and residue,
Cleaner and parameters (TACT)
Time, Action, Concentration, Temperature
Others
Surface and equipment design

26
 CLEANING PROCESS
SOURCES OF VARIATION

Cleaning agent preparation must be exact

Automated cleaning vs. manual cleaning
Manual cleaning process variation
Human physical strength variation
g between same-product
Cleaning p batches in
campaign residue level build-up
Campaign length residue level build-up
Time to initiate cleaning (dirty hold time)
Residue chemical and p physical
y changes
g
27
 EQUIPMENT TO BE CLEANED
Cleaning-related qualification
Product-contact materials
Compatibility with cleaning agents
Surface areas need for residue calculations
E i
Equipment t equivalence
i l
Most-difficult-to-clean locations on equipment -- Highest
risk locations for sampling
Non-uniform contamination equipment
Non-uniform contamination sampling g locations
Sampling methods (swab / rinse)
Part of IQ/OQ/PQ for manufacturing equipment

28
 PROCEDURE TO DETERMINE SAMPLING
LOCATIONS

Specific documented procedure recommended

Equipment technical evaluation
Observation of equipment after processing
Equipment disassembly review
Cleaning procedure review
Equipment evaluation review
Operator interviews
SOP describing above
Documentation of above for equipment sampling
29
 TIME TO INITIATE CLEANING
DIRTY
DIRTY HOLD TIME
TIME
1. Make Product A
2 Cl
2. Clean
3. Make Product B
How long between end of #1 and start #2?
Is residue same? Does residue change?
Wh can h
What happen to the
h residue?
id ?
Wet and dry processes

Chemical changes (hydrolysis, oxidation,

oxidation etc
etc.))

Physical changes

30
 CAMPAIGN LENGTH

How many lots in manufacturing campaign before

cleaning must be done?

What about cleaning

cleaning between batches?
Equipment should be visually clean
Terminology: Between
Between lot procedure
procedure
How much residue build-up?

DO NOT IDENTIFY AS BETWEEN LOT CLEANING

31
 MANUAL CLEANING
Manual cleaning procedures should be
monitored and maintained with increased
scrutiny compared to non-manual procedures
More frequent training of cleaning personnel
Increased supervision
Periodic (annual?) revalidation batches

Manual cleaning is high risk

32
 ANALYTICAL METHOD DEVELOPMENT
Early stage 1 (development) analysis
validation not required but must be sound
Validated method when used for Stage 2
cleaning validation and post
post-validation
validation
testing (change control)

All methods and data (including stage 1) subject to

regulatory audit

33
 ANALYTICAL METHOD DEVELOPMENT
Analytical method must measure actual residue
what residue is actually present on equipment
surfaces?
Small molecules
API
API degraded specific or non-specific method
Biotech
Bi t h molecules
l l
API degraded non-specific method

UNDERSTAND RESIDUE CHEMISTRY

34
 ANALYTICAL METHOD DEVELOPMENT

Cleaning agent residue

Analytical method to determine residual cleaning
agent.
Information from cleaning agent vendor

35
 ANALYTICAL METHOD DEVELOPMENT
Recovery studies
R t di
Can sampling procedure adequately recover residue
from equipment surfaces?
Product contact materials
High % of total surface area
Obtain representative coupons from equipment
fabricators
High
Hi h ((e.g., >80%)
80%) acceptance
t criteria
it i
Factor may be used in calculation
Multiple approaches
Factor every calculation?

All sampled surfaces must have recovery data

36
 SAMPLING
Sampling methods
Sampling (swab) critical activity
Training program
Trained sampling personnel
Demonstrated acceptable performance
Documented training and retraining
Worst case compounds / procedures in training
Volatile solvents (importance of rapid technique)
Worst case sampling equipment
Extension poles
Retraining considerations
Who does sampling? Personnel skills

37
 SAMPLING TRAINING

Sampling is extremely critical to cleaning

validation program
Inadequate sampling = false negative
Insufficient pressure on surface
Swab solvent evaporation
Insufficient
I ffi i t area sampled
l d

Auditors routinely ask for sampling program training

methods and training records

38
 STAGE 2, PROCESS QUALIFICATION
(VALIDATION PERFORMANCE)
APPLICATION TO CLEANING
1. Design of a facility and qualification of utilities and equipment
2. Process performance qualification
3. PPQ protocol
4
4. PPQ protocol
t l execution
ti andd reportt
Qualification of equipment, utilities, facilities
Cleaning equipment (CIP)

Process Performance Qualification (PPQ) commercial scale

Conclusion that process consistently produces clean equipment
Conformance batches
All support systems, documents, training, personnel, etc. in place
Target / nominal operating parameters within design space
Additional testing (swab / rinse)
Decision to release
release cleaning process
process for routine commercial use
Post validation monitoring plan Based on risk
Drug residue properties
Manual or CIP

39
 CLEANING EQUIPMENT

CIP system must be qualified (IQ/OQ/PQ or ASTM

E2500)
Riboflavin ((or other)) coverage
g testing
g
Temperature controls
Flow rates,
rates etc
etc.
PAT inline systems
Drug
g disappearance
pp spectrophotometry,
p p y other methods
Cleaning agent rinse -- conductivity

40
 CLEANING PROCEDURE DOCUMENTATION
(Cl
(Cleaning
i B Batch
t hRRecord)
d)
SOP
Fill tank
t k half
h lf full
f ll
Add half scoop of soap
Scrub as needed
Rinse until clean
Re-scrub and re-rinse if needed

CLEANING PROCEDURE RECORD

Fill tank with 500 L water. Sign/date __________
Add 20.0 kg cleaning agent. Sign/date __________
Disassemble Part A. Steps 1,2,3,4,5
Scrub for 20 minutes. Sign/date __________
Disassemble Part B. Steps 1,2,3,4,5
Soak Part B in cleaning liquid for 10 minutes. Sign/date __________
Rinse Part A and Part B with 50 L water. Sign/date __________
Rinse with 50 L Purified Water. Sign/date __________
Dryy with compressed
p air

41
 CLEANING PROCEDURE RECORD
Fill tank with 500 L water. Sign/date __________
Add 20.0 kg cleaning agent. Sign/date __________
Disassemble Part A. Steps p 1,2,3,4,5
Scrub for 20 minutes. Sign/date __________
Disassemble Part B. Steps 1,2,3,4,5
Soak Part B in cleaningg liquid
q for 10 minutes. Sign/date
g __________
Rinse Part A and Part B with 50 L water. Sign/date __________
Rinse with 50 L Purified Water. Sign/date __________
Dryy with compressed
p air

KEY POINTS
Exact concentration of cleaning agent liquid
Signature on quantitative steps
Grouping non-quantitative steps (e.g., disassembly)

42
 VALIDATION REQUEST / PLAN
Initiates cleaning validation
New cleaning validation or change control process
i
improvements t
Strategy and approach
Scientific and technical basis
Specify required protocols and other work to accomplish
validation
Risk-based
References: Stage 1 Design / development reports

43
 VALIDATION PROTOCOL
Cleaning validation protocols and other work
as specified in Validation Plan
Risk based
Include sampling pages indicating worst
case sampling locations.
S
Specify
if acceptance
t criteria
it i

44
 VALIDATION RESULTS / REPORT

Test results as required in validation protocol.

Discussion.
Discussion Consistency with Stage 1
development work.
Clear statement the cleaning process is (or is
not) validated.
Recommendations for Stage 3 monitoring and
maintenance.
Additional limited testing based on data and risk
Routine monitoring based on risk

45
 STAGE 3, CONTINUED PROCESS VERIFICATION
(VALIDATION MONITORING AND MAINTENANCE)
APPLICATION TO CLEANING
Activities to assure process remains in validated state
Changeg control -- evaluate impact
p of change
g and validate ((test)) as
necessary
Trend and assess data
PAT rinse times
Conductivity data
Study OOS and OOT (Out of Trend) data
Improve process
Improve control to detect and reduce variability
Cleaning non-conformances and deviations
Re-validation definition: Actual batch or paper
Is re-testing necessary?
When should re-testing be considered?
Periodic Management Review
Documentation reviewed by management
Documented
D d review
i
46
POST-VALIDATION MONITORING AND MAINTENANCE

1. Stage 2 specific requirements

Additional testing based on actual data
Ex: One location has high (acceptable result)
2. Routine monitoring and maintenance
Risk based
3 Change control program
3.

CHANGE CONTROL MOST IMPORTANT AND

DIFFICULT TO ADMINISTER
PERSONNEL MUST RECOGNIZE CHANGE
CHANGE
47
POST-VALIDATION MONITORING AND MAINTENANCE

Residue toxicity risk

Residue that can be visually seen
Room lighting must be adequate
Provide additional lighting if necessary

Residue that cannot be visually

y seen
Swab after each batch?

CONSIDER PATIENT RISK AND COMPANY RISK

48
 CHANGE CONTROL
All associated personnel must be aware of
change
h control
t l
Change control system developed
Process improvements expected based on
ongoing experience
Process
P improvements
i t should
h ld b be evaluated
l t db by
technical people (i.e., Stage 1)
Stage
St 2 PPQ conducted
d t d whenh appropriate
i t
based on Stage 1 technical evaluation.

49
 POST-VALIDATION MONITORING

Periodic review of cleaning performance

Deviations
Non-conformances (dirty equipment)
Re-cleaning
R l i
Change control
Other
O h monitoring
i i (CIP d data))
Product APR data
Statistical Process Control data treatment
Management review -- documented

50
 CLEANING DOCUMENTATION
High level documents
Specific cleaning validation documents
Design/Development, performance, monitoring/maintenance
Specific cleaning validation support documents (equipment
qualifications)
Cleaningg validation approach
pp documents ((Worst case matrix,,
calculations, sampling locations, etc.)
Production documents (Cleaning Procedure Records)
Production cleaning
gppolicies
Management review documents
Associated documents
Personnel training in direct and associated areas
HR records

51
 CLEANING DOCUMENTATION
High level documents
Corporate policy
VMP (Cleaning VMP)
Stage 1 documents
Cleaning
Cl i process d
development
l t reportt
Analytical method development report
Supporting equipment documents (materials, surface areas, equivalent equipment,
sampling,
p g, etc.))
Stage 2 documents
Validation PPQ request, protocol, results
Cleaning equipment qualification
Cleaning procedure record
Stage 3 documents
Change control documents
Process monitoring
Management review

CONSISTENT LIFECYCLE STRATEGY AND APPROACH

52
 SUMMARY
STAGE 1 -- DESIGN AND DEVELOPMENT
INCLUDING COMMON PROBLEMS

Understanding cleaning process

Residue properties
Residue degradation
Rational cleaning process based on residue
Scientific and technical cleaning matrix
U d t d and
Understand d control
t l sources off variation
i ti
Dirty hold time
Campaigns
Rational analytical method based on residue properties
Equipment to be cleaned characterized
Worst case sampling

53
 SUMMARY EQUIPMENT TO BE CLEANED
INCLUDING COMMON PROBLEMS

Equipment characterization
Residue calculations
Materials of product contact
Surface areas
W t
Worst-case areas for
f sampling
li b
based
d on risk
i k
Non-uniform contamination
Equivalent equipment

54
 SUMMARY ANALYTICAL
INCLUDING COMMON PROBLEMS

Understand residue
Solubility and stability
Validated analytical method for actual residue
Specific or non-specific analytical methods
API and cleaning agent residue
Recovery studies from product contact materials
API and cleaning agent
Swab / rinse testing on equipment
Most difficult to clean sampling sites
Use of auxiliary sampling equipment (extension pole)
Swab / rinse training of sampling personnel

55
 SUMMARY
STAGE 2 PERFORMANCE
INCLUDING COMMON PROBLEMS

Cleaning Process Conformance Lots

Cleaning equipment qualified
Cleaning procedure specified (Not SOP)
Cleaning documentation
Request
Protocol
Results / Report

Manual cleaning high risk

56
 SUMMARY
STAGE 3 -- MAINTAINING VALIDATION

Change control -- evaluate impact of change

and validate (test) as necessary
Improve process
Improve control to detect and reduce
variability
y
Cleaning non-conformances and deviations
g
Periodic Management Review

57
CLEANING AND CLEANING VALIDATION
For the Pharmaceutical and Medical Device
I d ti
Industries

V1. Basics,
V1 Basics Expectations
Expectations, and Principles
V2. Applications of Basics and Principles
V3 Lifecycle Approach to Cleaning Validation
V3.
(Expected end 2013)

Paul L. Pluta, PhD, editor

58
PAUL L.
L PLUTA,
PLUTA PhD
Editor-in-Chief
Journal
Jo rnal of Validation Technolog
Technology
Journal of GXP Compliance
Advanstar Communications

Adjunct Associate Professor

University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA

Pharmaceutical industry
y experience
p

Contact: paul.pluta@comcast.net

59
 EQUIPMENT SAMPLING INSTRUCTIONS FOR CLEANING VALIDATION

EQUIPMENT: MIXING TANKS

X SAMPLED
ASSET# EQUIPMENT NAME LOCATION
EQUIPMENT
Equipment #XXX Mixing Tank #XXX Room XXX
Equipment #XXX Mixing Tank #XXX Room XXX
Equipment #XXX Mixing Tank #XXX Room XXX
Equipment #XXX Mixing Tank #XXX Room XXX
Equipment #XXX Mixing Tank #XXX Room XXX

PRODUCT CONTACT
EQUIPMENTSAMPLING LOCATION SAMPLE TYPE RATIONALE
MATERIAL
1. Tank surface just above liquid-air Maximum residue
Stainless Steel Swab
interface accumulation.
Representative of tank surface.
2. Tank surface below manway and
Stainless Steel Swab Maximum residue
below liquid level
accumulation.
3. Discharge valve Stainless Steel Swab Maximum product contact.
4. Baffle (if present on tank and if
Stainless Steel Swab Maximum product contact.
accessible)

LIQUID
LEVEL

TYPICAL
4 BAFFLE 3
LOCATION

Pictures are representative of all mixing tanks.

SAMPLED BY: _________________________________ DATE: __________

VERIFIED BY: _________________________________ DATE: __________