LIFECYCLE

C C
APPROACH
O C
TO CLEANING VALIDATION
Paul L. Pluta, PhD

Validation Week EU, 2013

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

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

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

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

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

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
1. Residue on equipment
2. Water procedure
3 Cleaning agent procedure
3.
4. Water procedure
5. Purified Water procedure
6. Dryy

Qualification
Equipment
Purified Water
Computer / software
Compressed air
Conductivity analysis
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
Manual
l Cleaning
Cl
i
Process steps
1. Residue on equipment
2. Water rinse
3 S
3.
Scrub
b with
ith cleaning
l
i agentt
4. Water rinse
5. Scrub
6. Water rinse
7. Purified Water rinse
8 Dry
8.

Qualification
Personnel
Purified Water
C
Compressed
d air
i

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

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

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
g
Products of Biopharmaceutical
p
API Caused
Degradation
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
p
batches in
Cleaning
campaign residue level build-up
Campaign length residue level build-up
Time to initiate cleaning (dirty hold time)
physical
y
changes
g
Residue chemical and p
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.
2.
3.
4
4.

Design of a facility and qualification of utilities and equipment

Process performance qualification
PPQ protocol
PPQ protocol
t
l execution
ti and
d 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 hR
Record)
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 __________

y with compressed
p
air

Dry
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
g liquid
q
for 10 minutes. Sign/date
g
__________
Soak Part B in cleaning
Rinse Part A and Part B with 50 L water. Sign/date __________
Rinse with 50 L Purified Water. Sign/date __________
y with compressed
p
air
Dry

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
g control -- evaluate impact
p
of change
g and validate ((test)) as
Change
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 when
h 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)
Cleaning
g validation approach
pp
documents ((Worst case matrix,,
calculations, sampling locations, etc.)
Production documents (Cleaning Procedure Records)
Production cleaning
gp
policies

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
Review
Periodic Management

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: [email protected]
59

EQUIPMENT SAMPLING INSTRUCTIONS FOR CLEANING VALIDATION

EQUIPMENT: MIXING TANKS
X SAMPLED
EQUIPMENT

ASSET#

EQUIPMENT NAME

LOCATION

Equipment #XXX
Equipment #XXX
Equipment #XXX
Equipment #XXX
Equipment #XXX

Mixing Tank #XXX

Mixing Tank #XXX
Mixing Tank #XXX
Mixing Tank #XXX
Mixing Tank #XXX

Room XXX
Room XXX
Room XXX
Room XXX
Room XXX

EQUIPMENTSAMPLING LOCATION

PRODUCT CONTACT
MATERIAL

SAMPLE TYPE

1. Tank surface just above liquid-air

interface

Stainless Steel

Swab

2. Tank surface below manway and

below liquid level

Stainless Steel

Swab

3. Discharge valve

Stainless Steel

Swab

Maximum product contact.

4. Baffle (if present on tank and if

accessible)

Stainless Steel

Swab

Maximum product contact.

Maximum residue
accumulation.
Representative of tank surface.
Maximum residue
accumulation.

1
LIQUID
LEVEL

TYPICAL
BAFFLE
LOCATION

RATIONALE

Pictures are representative of all mixing tanks.

SAMPLED BY: _________________________________

DATE: __________

VERIFIED BY: _________________________________

DATE: __________