CLEANING VALIDATION PROBLEMS

GLOBAL PERSPECTIVE

Paul L
L. Pluta,
Pluta PhD
Journal of Validation Technology and Journal of GXP Compliance
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA

1
 OUTLINE
OVERVIEW OF IDENTIFIED PROBLEMS
PRODUCT PROBLEMS
Residue chemistry as basis for cleaning
Solubility in worst
worst-case
case residue determination
Cleanability in worst case residue determination

EQUIPMENT-RELATED PROBLEMS
Non-uniform contamination transfer
Most difficult-to-clean locations

CLEANING PROCESS PROBLEMS

Manual cleaning qualification
Cleaning procedure documentation
Dirty hold time (time to initiate cleaning)

LABORATORY PROBLEMS
Residue stability in cleaning residue analysis
Residue recovery studies
Swab sampling technique, reliability, and training

2
 OVERVIEW
CLEANING VALDIATION PROBLEMS

Problems or deficiencies identified by questions and

discussions with cleaning professionals at domestic and
international pharma cleaning meetings. Confirmation
by multiple experts

Four groupings of problems / deficiencies identified

Product residue problems
Equipment problems
Cleaning process problems
Laboratory problems

3
 AUDIT QUESTIONS
Is residue chemistry considered in developing cleaning procedure?
Is pH-solubility profile considered in worst-case matrix analysis?
Is residue cleanabilityy considered in worst-case residue
determination?
Is non-uniform contamination considered in residue calculations?
Are most difficult
difficult-to-clean
to clean equipment locations proceduralized?
Are manual cleaning personnel qualified and requalified?
Are cleaning procedures quantitative and documented?
A di
Are dirty
t hhold
ld ti
times controlled?
t ll d?
Is residue stability considered in cleaning residue analytical?
Have analytical recovery studies been conducted? On
representative materials?
Are swab sampling personnel trained / qualified?

4
 LIFECYCLE APPROACH TO CLEANING VALIDATION
FDA identified three stages of process validation
1. Process design and development (understanding)
2 Process
2. P qualification
lifi ti ((performance)
f )
3. Continued process verification (maintenance)

Problems discussed indicate most cleaning deficiencies in

Stage 1 process understanding, i.e., pre-work for
traditional validation.
Three problems are identified for Stage 2 processing.
Problems in Stage 3 validation not identified.
Almost no companies have a stage 3 program other
than change control.

5
 LIFECYCLE APPROACH TO PROCESS VALDIATION
KEY CONCEPTS

Stage approach
Design and development
General approaches
Specific cleaning methods
Process demonstration
Continued process verification
Scientific and technical basis
Risk
Variation identification and control

6
 1. PRODUCT RESIDUE PROBLEMS

Physical and chemical properties of residue as a basis for

cleaning
Residue chemistry, cleaning agent chemistry, and process must be
consistent. Would you clean an acid with a base or with another
acid?
Residue solubility in most-difficult-to-clean matrix
Determination of the true worst-case residue is critical for the
cleaning
g matrix. The consequences
q of incorrect identification of
worst-case products are disastrous.

Cleanability in determining the most-difficult-to-clean residue

Solubility and toxicity not only considerations for determination of
worst-case compounds

7
 PHYSICAL AND CHEMICAL PROPERTIES OF
RESIDUE AS BASIS FOR CLEANING

PROBLEM: No basis for cleaning procedure

Arbitrarily chosen
Best method at site
Methods used for years for all products
g soap
Bought p at local store sale p
price

8
 PHYSICAL AND CHEMICAL PROPERTIES OF RESIDUE
BASIS FOR CLEANING PROCEDURE

Case study #1: 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, water, PurW, dry

Unknown peaks again
API insoluble
i l bl

Final method: Acid wash, alkaline soap wash, water, PurW, dry
Significant improvement
No residues. Unknown peaks determined to be flavors.
API dissolves (acid-base neutralization)

Consider active drug and other residue chemistry in

development of9 cleaning process
 CLEANING METHOD
1. Three lots with new cleaning procedure
Acid cleaning liquid, drain Significant improvement in process
Alkaline cleaning liquid
liquid, drain
Water rinse
Purified water rinse
Dry
2. Swab sampling in worst case locations
3 No detectable residue
3. residue, no unknown peaks
4. Unknown peaks from past trials determined to be
formulation flavors ((hydrophobic
y p oils))
5. Documentation

10
 PHYSICAL AND CHEMICAL PROPERTIES OF RESIDUE
BASIS FOR CLEANING PROCEDURE
C
Case study
t d #2
#2: S
Smallll molecule
l l API orall liliquid
id product
d t . API iinsoluble
l bl
Original cleaning method
Alkaline cleaningg agent
g with manual intervention
Acid cleaning agent (full strength) when white residue noted.
Small parts soaked in acid cleaning agent (full strength)
Cleaning method difficult,
difficult ineffective,
ineffective and unsafe
Liquid product alcohol / glycol solvent system
Change g cleaningg method to alcohol initial rinse. API soluble
Final method: Alcohol rinse/soak, alkaline wash, water, PurW, dry
Significant improvement
No residues
Easy and safe method
Consider active drug and other residue chemistry in development
of cleaning process
11
EXPERIMENTAL DEVELOPMENT PROCEDURE
1. Evaluate formulation and chemical properties
2. Laboratory comparison 2 L beaker and mixer
Small amount of product into beaker + water to disperse
Add cleaning agents to be screened acid, neutral, alkaline,
solvent
Visual observation
3. Coupons with residue in beaker
4 Simulated
4. Si l t d cleaning
l i procedure.
d
Swab sampling
Analytical
y determination
5. Conclusions and recommendations
6. Confirmation in pilot equipment

12
 CLEANING PROCEDURE DEVELOPMENT PROCESS
Stage 1 R&D
1. API technical analysis.
2. pH solubility profile pH 1-12.
3. Solubility in proposed cleaning liquid.
4. pH-stability profile pH 1-12.
5. Laboratory cleaning studies confirmation.
6. Analytical method development based on stability data.
7
7. Testing of all excipients with analytical method
method.
Source of unknown peaks

CLEANING PROCEDURE TECHNICAL BASIS

pH-SOLUBILITY AND Ph-STABILITY IS BASIC R&D WORK
ANALYTICAL METHOD MEASURES ACTUAL RESIDUE
ANALYTICAL METHOD DETECT OTHER EXCIPIENTS
13
 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.

14
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.

15
 CLEANING AGENT OPTIONS
Water
Commodityy alkalis and acids
Organic solvents
Surfactants
Anionic
Cationic
Amphoteric
Nonionic
Formulated detergents

16
 COMPONENTS OF FORMULATED DETERGENTS
Surfactants
Alkalis
A id
Acids
Sequestrants / chelants
Dispersants / anti-redeposition agents
Corrosion inhibitors
Oxidizing
g agents
g
Enzymes
Buffers / builders
Preservatives

17
 RESIDUE SOLUBILITY IN MOST DIFFICULT TO CLEAN MATRIX
BASIS FOR CLEANING PROGRAM

PROBLEM: Wrong basis for worst-case residue

Water solubility USP Tables

Is this adequate? Depends on cleaning procedure
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

18
 pH SOLUBILITY
p SO U PROFILE,
O , pH
p 1-12

Solubility
mg/ml

Drug A

Drug B

pH 1 7 12

19
 SULFAMETHOXAZOLE pH-SOLUBILITY
Amount
Dissolved

Note pKa

1 pH
p 12

20
 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

21
 CLEANABILITY IN DETERMINING
MOST DIFFICULT-TO-CLEAN
DIFFICULT TO CLEAN RESIDUE IN MATRIX

PROBLEM: Incomplete evaluation of worst-case residue

What factors should be considered to determine worst case residue?

Most companies use
Solubility (pH?)
Toxicity

OK for site with simple dosage forms

All aqueous solution products (LVP, SVP)

22
 CLEANABILITY IN DETERMINATING MOST
DIFFICULT TO CLEAN RESIDUE IN MATRIX
DIFFICULT-TO-CLEAN

Matrix = Products cleaned byy same cleaning

gpprocedure

Other considerations
Solubility in cleaning liquid
Toxicity
Concentration in dosage g form
Cleanability
Formulation components major effect
Cl
Cleaning
i personnell iinputt
Dirty hold time
Soil-surface interactions (e.g., air-liquid interface)

23
 CLEANABILITY IN DETERMINATING MOST
DIFFICULT TO CLEAN RESIDUE IN MATRIX
DIFFICULT-TO-CLEAN

IR Tablet ER Tablet
API API
Microcrystalline cellulose Same
L t
Lactose Same
S
--- Wax
--- Cellulosic polymer
Crospovidone ---
Talc Same
Magnesium stearate Same

COMPARE EASE OF CLEANING

24
 OTHER CONSIDERATIONS
Consider flavor and color oils
Dyes/lakes
D /l k may b be more diffi
difficultl to clean
l
than active drug
Consider solubility of all components
Alcohol explosivity
p y
Solvent toxicity

25
 2. EQUIPMENT PROBLEMS

Non-uniform contamination transfer

Non-uniform contamination is a worst-case situation and should be
addressed. Calculations are demonstrated.

Most difficult-to-clean locations in equipment

Sites should have an SOP with a defined procedure for identification
of most-difficult to clean locations in equipment. These locations are
then used in sampling for cleaning validation.

26
 NON-UNIFORM CONTAMINATION TRANSFER
PROBLEM: Non-uniform contamination not considered

Cleaning Processes
1. Make product A
2. Clean
3. Make product B. Remaining Product A residue contaminates
Product B

Equipment categorization
Uniform contamination equipment
Equipment with all contamination uniformly transferred.
Example: Mixing tank
Non-uniform contamination equipment
Example: Filling needles, compressing machine.

27
 NON-UNIFORM CONTAMINATION
1. Make 50 L tank of lemonade.
2. Fill 2 L pitcher from tank.
3. Fill cups from pitcher
4. Clean tank and pitcher.
5. Make ice tea in 50 L tank All lemonade residue in tank uniformly
transferred to ice tea.
6. Fill 2 L pitcher from
f tank All lemonade residue in pitcher transferred
f to
ice tea. Fill cups. HIGHEST LEVEL OF CONTAMINATION.
7. Fill same 2 L pitcher from tank Much less lemonade residue left in
pitcher transferred to ice tea
tea. Fill cups
cups.
8. Fill same 2 L pitcher from tank Even less lemonade residue in pitcher
transferred to ice tea. Fill cups.
9. And so on..

#6, 7, 8, 9.. NON-UNIFORM CONTAMINATION

#6 HIGHEST LEVEL
28
 UNIFORM CONTAMINATION CALCULATION

Typical calculation considers total surface area of all

shared product contact equipment, and assumes all lot A
residue
id ffrom ttotal
t l surface
f area transferred
t f d uniformly
if l to
t
all lot B product

R id lilimit
Residue it = Min
Mi ddose A x B
Batch
t h size
i BxS Safety
f t ffactor
t
Max dose B x Surface area

References:
Fourman and Mullen. Pharmaceutical Technology 17, #4, 1993.
LeBlanc. Validated Cleaning Technologies for Pharmaceutical Manufacturing.
Interpharm/CRC Press, 2000.

29
 EQUIPMENT TO BE CLEANED
SAMPLING LOCATIONS
UNIFORM AND NON
NON-UNIFORM
UNIFORM CONTAMINATION
Product A = X
Product B = X
Product B flushes filling lines with A residue

xxxxxxxxxx x x x x x x x
xxxxxxxxxx x
xxxxxxxxxx x
xxxxxxxxxx
xxxxxxx
MANUFACTURING TANK PRODUCT
30
 NON-UNIFORM CONTAMINATION CALCULATION
Residue non-uniformly flushed into initial product units

Residue content = Residue level x surface area

5 ml
Determine how many 5 ml vials to be discarded to be <
limit.

Reference:
LeBlanc.
L Bl V lid t d Cleaning
Validated Cl i T Technologies
h l i ffor Ph
Pharmaceutical
ti l MManufacturing.
f t i
Interpharm/CRC Press, 2000.

31
 NON-UNIFORM CONTAMINATION
Contaminated product may be eliminated
p
in set-up.
Sites must be prepared to answer
questions from auditors based on
calculations.

32
 MOST-DIFFICULT-TO-CLEAN
EQUIPMENT LOCATIONS

PROBLEM: No rationale for sampling of

cleaned equipment.
Sampling
p g locations chosen arbitrarily.
y
Easiest-to-clean locations chosen

33
 MOST DIFFICULT TO CLEAN EQUIPMENT
LOCATIONS
Equipment Technical Evaluation
Deadlegs
Corners
Undersides
Pipe bends
Flow velocity
Coverage studies
Drainability
Other considerations (e.g., baseline visual inspection)

34
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

35
 SAMPLING PAGES

DIGITAL PICTURES
One
O sampling li page ffor each h equipment
i t
Assemble pages for process train
All pages in cleaning validation protocol
Arrows for specific sampling locations
Random locations unspecified
Use for all cleaning validation

36
EQUIPMENT SAMPLING INSTRUCTIONS FOR CLEANING VALIDATION
EQUIPMENT: IMPACT MILL
PRODUCT
EQUIPMENT SAMPLING
CONTACT SAMPLE TYPE RATIONALE
LOCATION
MATERIAL
Maximum residue accumulation.
1. Rotor Stainless Steel Swab
Maximum product contact
Maximum residue accumulation.
2. Screen Stainless Steel Swab
Maximum product contact
Maximum residue accumulation
3. Discharge Chute Stainless Steel Swab
Maximum product contact

X SAMPLED
EQUIPMENT ASSET# EQUIPMENT NAME LOCATION

Equipment #XXX Impact Mill Room XXX

Equipment #XXX Impact Mill Room XXX
Equipment #XXX Impact Mill Room XXX

2
1
3

Pictures are representative of all impact mills.

SAMPLED BY BY: _________________________________ DATE
DATE: _______________
VERIFIED BY: _________________________________ DATE: _______________

37
 3. CLEANING PROCESS PROBLEMS
Manual
M l cleaning
l i qualification
lifi ti
Manual cleaning is an inherently high risk activity.
Cleaning procedure documentation
Cleaning procedure documentation should be equivalent to
manufacturing process documentation -- Exact requirements with
personnel accountability.
accountability
Dirty hold time (time to initiate cleaning)
At lease one run at worst-case DHT
Worst-case DHT is not always longest DHT
Campaign length
Max number of lots must be controlled
Between lot procedure.

38
 MANUAL
U C
CLEANING
G QU
QUALIFICATION
C O

PROBLEM: Manual cleaning process

Variation sources
Different
Diff t persons
Different motivation
Different physical strength
shift, 2nd shift,
Day shift shift night shift
And on and on and on ..

39
 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

40
 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 problem -- Well get the residue when we set up.

Q to operator: Why dont you follow the cleaning procedure?

A: The cleaning procedure really doesnt work.

Q to operator: You cleaned the gasket with pure soap this is not the
procedure?
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.

41
 MANUAL CLEANING -- Do you really know what is happening?
Q to
t operator:
t Why
Wh is
i there
th powder
d on th
the clean
l equipment?
i t?
A: Its clean enough.
Q to QA (equipment inspection person): Did you approve that the equipment
is clean?
clean?
A: Its clean enough.
Q to management: Do you know that your equipment is not clean?
A: Its
It s clean enough
enough.

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

swab for cleaningg validation.
A: We cleaned the equipment three times so that 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.
42
 CLEANING PROCEDURE DOCUMENTATION

PROBLEM: Exact documentation for process

reproducibility
Fill volume
Amount of cleaning agent = concentration
Time
Temperature
Flow rate (impact)
Verification
V ifi ti off kkey steps
t

43
 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

44
 CLEANING PROCEDURE DOCUMENTATION
(Cleaning Batch 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 __________
Dry with compressed air

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

45
 DIRTY HOLD TIME
TIME TO INITIATE CLEANING

PROBLEM: No control of dirty hold time

Residue
R id changes
h
Drying
Chemical changes
Physical changes

46
 DIRTY HOLD TIME

What is Dirty Hold Time?

1 Make Product A
1.
2. Clean
3 Make
3. M k P Product
d tB
How long between end of #1 and start #2?
Is residue same? Does residue change?
What can happen to the residue?
Hydrolysis,
Hydrolysis oxidation
oxidation, photolysis
photolysis, physical changes
changes, etc
etc.
Especially important in wet processes wet residue
becomes dry, hardens, cakes, changes?

47
 LABORATORY STUDY DIRTY HOLD TIME
1. Develop simulated cleaning process
Coupon in beaker with stirrer
2 W
2. Weigh
i h coupons. Ali
Aliquott residue
id onto t coupon surface
f
per time schedule. Allow to air dry. Weigh coupons.
3. Example time schedule:
1-1-2014 Day 30
1-10-2014 Day 20
1-20-2014 Day 10
1-25-2014 Day 5
1-28-2014 Day 2
1-29 2014 Day 1
1 30 2014
1-30-2014 D 0
Day

4. Perform simulated cleaning. Observe. Air dry.

Observe.
5. Weigh dry coupons. Calculate residuals.
48
 CAMPAIGN LENGTH

How many lots in manufacturing campaign before

cleaning must be done?
What about cleaning between batches?
Equipment should be visually clean (FDA)
Between
B t lot
l t procedure
d ((nott cleaning
l i
procedure)

49
 4. LABORATORY PROBLEMS
Residue stability in cleaning residue analysis
Analytical methods must measure actual residues that are present.

Residue recovery studies

Analytical methods must include recovery studies, i.e., proof that
process residue may be quantitatively recovered by sampling
sampling.
Without recovery studies, analysis of cleaning validation samples is
questionable

Swab sampling technique, reliability, and training

Personnel who perform swab sampling must be qualified through
training with quantitative performance requirements
requirements. Training
should utilize worst-case sampling methods and worst-case
sampling equipment.

50
 ANALYTICAL METHOD DEVELOPMENT
PROBLEM: Analytical method does not
measure actual residues
Analytical method must measure actual residue
Small molecules
API
API degraded
g specific
p or non-specific
p method
Biotech molecules
API degraded
g non-specific
p method
(e.g., TOC or amino acid)

UNDERSTAND RESIDUE CHEMISTRY

51
 RESIDUE STABILITY IN CLEANING RESIDUE ANALYSIS

ACTUAL RESIDUE PRESENT MUST BE MEASURED

Solubility
Stability
y

Solubility considerations
Hydrophilic and hydrophobic molecules
Ionization Effect of pH
Effect of temperature

Stability considerations
Hydrolysis, oxidation, photolysis, physical changes

What residue is really present?

Consider chemistry of residues

52
 RESIDUE RECOVERY STUDIES
PROBLEM: Is residue able to be quantitavely
recovered from surfaces?
Product
P d t contact
t t materials
t i l
High % of total surface area identify all areas to be sampled
Obtain representative coupons from equipment fabricators
Order coupons with new equipment
Recovery should be consistent and high (e.g., >50%)
Recovery
y factor used in calculations
Multiple approaches
Done in lab by lab personnel consideration for future training

ANALYSIS IS MEANINGLESS
WITHOUT RECOVERY STUDIES
53
 RESIDUE RECOVERY STUDIES
C
Case study
t d
Tablet formulation, stable API, all processing on stainless steel except
compressing machine (cast iron)
Stainless steel recovery = 100%
Audit identified no recovery on cast iron

Cast iron recovery = 0%

Lab analyst spiked dye tablet with active drug.

D 5 minutes
Dry i t
Swab
Recovery = 0%

Resolution: Install stainless steel dye table.

54
 RESIDUE RECOVERY STUDIES
Caution with plastics, resins, porous materials.
Obtain materials from equipment fabricators
Material composition
Material porousity
Surface roughness

Example: % Recovery
Neoprene smooth 79.4%
Neoprene rough 11.7%
Reference: Forsyth. J. Validation Technology, Vol15, #4, 2009.

55
 RECOVERY STUDIES -- CALCULATION
Recovery data = 50% recovery
= 0.5 recovery factor

Actual residue level = analytical

y results
Recovery factor
= 25 mcg/sq
mcg/sq. cm
0.5
= 50 mcg/sq
mcg/sq. cm

56
 SWAB SAMPLING TECHNIQUE, RELIABILITY,
AND TRAINING

PROBLEM
PROBLEM:
Swab sampling must recover product residue.
Sampling personnel must be trained and qualified
qualified.
Periodic retraining should be considered.

57
 ANALYTICAL METHOD DEVELOPMENT

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
Problem: Solvents evaporate quickly = false negative
Worst case sampling equipment
Extension poles
58
 ANALYTICAL METHODOLOGY

Case study: Swab sampling with extension pole

Interface

Biotech tank

59
 SAMPLING PERSONNEL TRAINING

Representative sampling sites

Use of auxiliary equipment

Representative of most difficult analytical methods

Volatile solvents time constraints

Retraining considerations
Who does sampling?
Personnel skills

60
 SUMMARY
Cleaning personnel identified frequent
overlooked problems.
Residue
Equipment
E i t
Process
Analytical

61
 WHICH ARE MOST IMPORTANT?
Risk analysis
Type (potency) of drug in facility?
Multi-product facility multi use equipment?
Matrix?
Manual cleaning?
SOP cleaning processes how detailed? Signatures?
Analytical recovery?
Swab sampling by trained personnel?

Depending on situation, many of these could

be extremely serious issues
62
 AUDIT QUESTIONS
Is residue chemistry considered in developing cleaning procedure?
Is pH-solubility profile considered in worst-case matrix analysis?
Is resid
residue
e cleanabilit
cleanability considered in worst-case
orst case resid
residue
e
determination?
Is non-uniform contamination considered in residue calculations?
Are most difficult-to-clean equipment locations proceduralized?
Are manual cleaning personnel qualified and requalified?
Are cleaning procedures quantitative and documented?
Are dirty hold times controlled?
Is residue stability considered in cleaning residue analytical?
Have analytical recovery studies been conducted? On
representative materials?
Are swab sampling personnel trained / qualified?

63
 FUTURE DEFICIENCY
Lifecycle approach requires ongoing
monitoring of processes
Cleaning processes must be periodically
reviewed ((~2 yyears?))
Review deviations
Review non-conformities
non conformities
Review re-cleans
Management awareness
Improvement projects

64
 REFERENCES

LeBlanc, Destin A.
Validated Cleaning Technologies for Pharmaceutical Manufacturing. Interpharm/CRC Press,
2000.
Cleaning Validation Practical Compliance Solutions for Pharmaceutical Manufacturing. PDA
andd DHI Publishing,
P bli hi 2006.
2006
Cleaning Validation Practical Compliance Solutions for Pharmaceutical Manufacturing, Volume
2. PDA and DHI Publishing, 2010.
www.cleaningvalidation.com
Pluta, Paul L., editor. Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and
Principles. PDA and DHI Publishing, 2009.
Pluta, Paul L., editor. Cleaning and Cleaning Validation, Volume 2. Application of Basics, and
Principles. PDA and DHI Publishing, 2013.
K di k C
Kendrick, Canhuto,
h t and dKKreuze. A
Analysis
l i off D
Degradation
d ti P Products
d t off Bi
Biopharmaceutical
h ti l API C
Caused
d
by Cleaning Agents and Temperature. Journal of Validation Technology, V15, #3, Summer 2009.
Cleaning Validation Forum. Coordinated by Jennifer Carlson. Journal of GXP Compliance.
New Perspectives on Cleaning: Coordinated by Rizwan Sharnez. Journal of Validation Technology.
Pluta and Sharnez. Avoiding Pitfalls in Cleaning Validation. Journal of GXP Compliance, V 14, #3,
Summer 2010.

65
PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications, Iselin, NJ, USA
Adjunct Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Editor and Chapter Author
Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and
Principles, 2009
Cleaning and Cleaning Validation, Volume 2. Application of Basics and
Principles 2013
Principles,
PDA and Davis Healthcare International (DHI) Publishing
Contact: paul.pluta@comcast.net

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