CV: Cleaning Validation Documentation

CLEANING
VALIDATION
9 April ' 08 P.piensiripinyo
Cleaning Validation
Documented evidence that an approved
cleaning procedure will provide equipment
which is suitable for proceeding of active
pharmaceutical ingredients or pharmaceutical
products.

EQUIPMENT
References & Regulation
CLEANING VALIDATION
PIC/S WHO usFDA ……
A P R I L ….. 2 0 0 8
CV : Reference Documents
1. Key resource for cleaning

FDA’s cleaning validation guideline validation
2. PIC/S PI 006-3 The basis of Draft Annex 15.
3. WHO cleaning validation TRS 937 appendix 3

guidelines
4. Annex 15 to EU GMPs

CV : Reference Documents
5. CANADIAN
cleaning validation guidelines
6. 21CFR 210-211 (GMPs)
7. Destin A. LeBlanc / cleaning validation www:cleaningvalidation.co

technology m
8. PDA Technical report # 29

PIC/S : PI 006-3

PIC/S : PE 009-7
Annex 15 : Qualification and Validation

PE 009 ….CLEANING VALIDATION
36. Cleaning validation should be performed

in order to confirm the effectiveness of a cle
aning procedure. The rationale for selecting li
mits of carry over of product residues, cleani
ng agents and microbial contamination should
be logically based on the materials involved.
The limits should be achievable and verifiabl
e.
37. Validated analytical methods having

sensitivity to detect residues or contaminants
should be used. The detection limit for each an
alytical method should be sufficiently sensitive
to detect the established acceptable level of t
he residue or contaminant.

38. Normally only cleaning procedures for

product contact surfaces of the equipment
need to be validated.
Consideration should be given to non-contact
parts.

38. . Normally only cleaning procedures for product contact

CEHT // DEHT
surfaces of the equipment need to be validated.
Consideration should be given to non-contact parts.
The intervals between use and cleaning

as well as cleaning and reuse should be v
alidated. Cleaning intervals and methods
should be determined.

39. For cleaning procedures for products and

processes which are similar, it is considered
acceptable to select a representative range of si
milar products and processes.
A single validation study utilising a “worst case”
approach can be carried out which takes account
of the critical issues.

40. Typically three consecutive applications of

the cleaning procedure should be performed
and shown to be successful in order to prove
that the method is validated.

41. "Test until clean " is not considered

an appropriate alternative to cleaning vali
dation.

42. Products which simulate the Physico-

chemical properties of the substances to be
removed may exceptionally be used instead o
f the substances themselves, where such su
bstances are either toxic or hazardous.

EQUIPMENT
CLEANING VALIDATION
Equipment System
 Appropriate design, size, location, non-reactive
product contact surfaces
 Identification clearly marked
 Qualification (DQ, IQ,OQ, PQ)
 Calibration
 Preventive Maintenance schedule and procedures
 Records of use, cleaning, maintenance
 Cleaning procedures and validation

Utilities
 Water
 Steam
 Compressed air
qualified and
controlled.
Cleaning Validation
cleaning procedure will provide equipment
products.

Documented evidence
 CVMP
 CV protocol
 Test result report
 Summary report
Detail : next period

Documented evidence
- Cleaning process - Monitoring record
- CP development record - Deviation / Investigation record
- Surface area calculation record - Revalidation report
- Limits calculation record - Change control record
- Analytical method validation - IQ , OQ ( Equipments )
- Method of analysis - Maintenance & Calibration record
- Sampling procedure - Training record
- Recovery test

CONTAMINANTS
► PRODUCT RESIDUE
► DECOMPOSITION OF PRODUCT
► CLEANING AGENT
► MICROBIAL ( Bacteria, Mold, Pyrogen )
► AIRBORNE MATTER
► LUBRICANT
► OTHERS (e.g. pieces of brushes, insects )

Cleaning Validation

Cleaning procedure
will provide equipment
products.
Cleaning Procedures
Only CP for product contact surfaces of equipment
need to be validated
Non-contact parts should be consideration
High safety risk products & difficult to remove

products : should consider Dedicated equipment

Cleaning Methods
 Manual
 Semi-Automated
 Clean-In-Place ( CIP)

Manual Cleaning Procedures
 Equipment disassembly (if required)

 Prewash and inspection
 Wash (cleaning agent, temperature, multiple steps until visually clean)
 Initial rinses (rinse water, temperature)
 Final rinse
 Reassembly (if required)

Automated Cleaning Procedures
 Clean-in-place (CIP) systems
 Control system qualification

( IQ, OQ & PQ : reproducibility, water temperature & pressure control )
 Sampling ( sampling port, pause capability )
 Material supply ( hard-plumbed supply lines, volume and

dispensing controls ; potential impact )

Automated Cleaning Procedures
Coverage Study ( CIP )

 Milk powder  visual
 Rivoflavin  UV detection

Cleaning Materials and Tools
 Solvents (source and quality controlled)
 Cleaning agents (acids, bases, surfactants, etc., qualified type and
brand QC-controlled)
 Ancillary utilities (steam and compressed air qualified)
 Cleaning tools (standard sets of brushes, rags, sponges)
 Equipment (thermometers, metering pumps, heat exchangers, etc.
maintained and kept in calibrated status)

Frequency of Cleaning
 Cleaning between batches of the same product
 Cleaning between batches of different products
 Cleaning after maintenance
 Cleaning after accidental contamination

Cleaning Procedures
( Microbial aspect )
Microbial proliferation
 Water stagnant
 Final rinse water purity
 Storage condition
 Storage time
CEHT and Protection

Cleaning Procedures
Clearly defined parameters & essential content
E N T
L EM
 DEHT
 Temperature , Time ,PPressure
I M RE S
MaterialsOP & E D U

L R O C
V E
E of action ING P

DSteps N
L E A

E C
Type & Concentration of detergent
 THRinsing ( amount , cycle , solvent )
 CEHT
 Protection

Cleaning Procedures
must be ready before start to perform CV
- grouping
- optimized & effective trial result
- trained

Cleaning Procedures Grouping
PRODUCT TIME TEMP RINSE DETERGENT
(min) (oc) CONC.
- 0.10%
A 10 3x50L
- -
B 10 3x25L
- 0.10%
C 20 4x50L
0.25%
D 40 50 5x50L
• Group A, B, C together and clean 20min. RT. 4x50L

• Separate D to be individually validated

Cleaning Procedures
must be ready before start to perform CV
- grouping
- optimized & effective trial result
- trained

Cleaning Procedures
now! we got the (developed)

developed
Cleaning SOP
Equipment Train
PE
009
processes which are similar, it is considered accept
able to select a representative range of similar pro
ducts and processes.
approach can be carried out which takes account o
f the critical issues.

Manufacturing Process
☻ Equipment trains
☻ Products within this process
☻ CP concerned

Active
Ingredient
Diluent
Disintegrant
Mixing
in
High Speed Mixer
Granulating
Liquid
Kneading
in
High Speed Mixer
Wet Granulation
through sieve 4.0 mm
(High Speed Granulator)
Drying at
60 Deg. C
(Fluid Bed Dryer)
Dried Granules
Active
Ingredient
Diluent
Disintegrant
Mixing
in
High Speed Mixer
Granulating
Liquid
Kneading
in
High Speed Mixer
Wet Granulation
through sieve 4.0 mm
(High Speed Granulator)
Drying at
60 Deg. C
(Fluid Bed Dryer)
Dried Granules

Dried Granules
Sifting through
sieve 1.0 mm
(Hi Speed
Disintegrant Granulator)
Blending
in
Cube Blender
Lubricant
Final Blending
in
Cube Blender
Blended Granules
Compression
(Tablet Machine)
Core Tablets
Film Coating Film-Coated

(Film-Coating Machine) Tablets

Dried Granules
Sifting through
sieve 1.0 mm
(Hi Speed
Granulator)
Disintegrant
Blending
in
Cube Blender
Lubricant
Final Blending
in
Cube Blender
Blended Granules
Compression
(Tablet Machine)
Core Tablets
Film Coating Film-Coated

(Film-Coating Machine) Tablets

Equipment Trains
Drawing Diagram
Surface Area Calculation

Surface area calculation
amount Equipment trains Parts Area (cm2)
- Cover lid 6,362
- Bowl 16,965
1 1. High Speed Mixer/Granulator - Agitator 1,350
( for wet mass/Granulation ) - Chopper 150
/ = 90 cm. , height = 60 cm. - Discharge chute 5,026
Total 29,853
- Housing 2,165
1 2. High speed Granulator - Rotor 950
- Screen 1,750
( for wet granulation )
Total 4,865
- Tower 62,832
2 3. Fluid Bed Dryer - Filter Bag 75,398
- Product container 17,593
Total 155,823

Surface area calculation
amount Equipment Parts Area (cm2)
- Housing 2,165
4. High Speed Granulator - Rotor 950
1 - Screen 2,750
( for dry screening )
Total 5,865
- Bowl 86,400
1 x 750 L 5. Cube Blender - Shaft 1,550
2 x 1500L - Discharge chute 2,750
Total 90,700
- Turret Surface 1,570

3 6. Compression ( Tablet m/c) - Punch Tip Surface 14
- Discharge Surface 750
Total 2,334
- Pan Surface 34,557

7. Film Coating Machine - Baffle 640
2
Total 35,197
Total surface area = 29853 + 4865 + 155823 + 5865 + 90700 + 2334 + 35197
= 324,637 cm2

EQUIPMENT
CLEANING VALIDATION
Grouping
Strategy
Grouping Strategies
PE
009
processes which are similar, it is considered accept
able to select a representative range of similar pro
ducts and processes.
approach can be carried out which takes account o
f the critical issues.

Grouping Strategies
simplify the validation

time & workload saves
grouping by
- products
- equipments
- cleaning procedures

Cleaning Procedures Grouping
PRODUCT TIME TEMP RINSE DETERGENT
(min) (oc) CONC.
- 0.10%
A 10 3x50L
- -
B 10 3x25L
- 0.10%
C 20 4x50L
0.25%
D 40 50 5x50L
• Group A, B, C together and clean 20min. RT. 4x50L

• Separate D to be individually validated

Equipment Grouping
- Same type / model

- May be different size
- Same cleaning process
- Exclude dedicated equipment
Drawing Diagram
Sampling method and sites set up

Product Grouping
- Similar product type

- Similar level of risk/toxicity
- Same equipment train
- Same cleaning process
Choose : hardest to clean & highest risk

PRODUCTS
Products Grouping
SOLUBILITY Cleaning ACTIVE
difficulty CONSIDERATION
mg/tab.
(high - least) (easy – hard)
( 1- 3 ) ( 1- 3 )
A 2 3 100
B
√ Hardest to clean
1 1 20
C 2 1 250
D 1 1 50
E 3 2 20
F 2
√ 1 2
Least Solubility
G 1 1 500
√ Most potent, Highest Risk ?
H 2 1 25

Products Grouping
Hardest to clean // Least solubility
Verify the CP capability
N Y
Develop CP All products could pass the

most stringent limit.
Pick the worst

PRODUCTS
Products Grouping
mg/tab.
( 1- 3 ) ( 1- 3 )
A 2 3 100
B
1 1 20
C 2 1 250
D 1 1 50
E 3 2 20
F 2
√ 1 2
Least Solubility
G 1 1 500
√ Most potent, Highest Risk ?
H 2 1 25
Representative (worst case) : product …A / E

Acceptance Limit
CONTAMINANTS
PE
009
36. Cleaning validation should be performed in order
► PRODUCT RESIDUE
to confirm the effectiveness of a cleaning
► DECOMPOSITION OF PRODUCT
procedure. The rationale for selecting limits of carry
► CLEANING
over of product AGENT
residues , cleaning agents and micro
bial contamination should( be
► MICROBIAL logically
Bacteria, based
Mold, on the
Pyrogen ) m
aterials involved. The limits should be achievable and
verifiable.

Acceptance Limit
Visually clean
Medical dose
Toxicity
Analytical detectability
Capability of CP
Default 10 ppm

PI 006-3 : 7.11 Establishment of limit
7.11.3 Carry-over of product residues should meet defined criteria, for example
the most stringent of the following three criteria:

(a) No more than 0.1% of the normal therapeutic dose of any product will appear in
the maximum daily dose of the following product,
(b) No more than 10 ppm of any product will appear in another product,
(c) No quantity of residue should be visible on the equipment after cleaning procedures
are performed. Spiking studies should determine the concentration at which most active ingredie
nts are visible,
(d) For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and
cytotoxics, the limit should be below the limit of detection by best available analytical metho
ds. this may mean that dedicated plants are used for these products.

Medical dose-based limit
( chemical residue )
MACO : Maximum Allowable Carry Over
MACO = lowest therapeutic dose A x smallest batch size B x

safety factor
max. daily dose B
daily dose of B contains ≤ 1/1000 lowest therapeutic dose A
Acceptance limit = MACO / total

area
Toxicity - based limit
MACO = ADI X smallest batch size B

max. daily dose B
ADI = NOEL X Safety factor

NOEL = LD50 X body weight X 0.0005
ADI : Acceptable daily intake

NOEL : No observed effect level

MACO = ( LD 50 x body wt. x 0.0005 ) x smallest batch size B x safety factor
max. daily dose B
Compare to
medical dose-
MACO = lowest therapeutic dose Abased
x smallest batch size B x safety factor
max. daily dose B

Acceptance Limit
( microbial contaminants )
- General guideline
- contact plate : ≤ 5-25 cfu / 25cm2
- swab : ≤ 5-25 cfu / 25cm2
- rinse : < 1 cfu / ml
- The limit should be less than the product spec.

Acceptance Limit
USP <1111> “Microbial content of Non-sterile Pharmaceuticals”
Solid oral : ≤ 1,000 cfu/g

Liquid oral : ≤ 100 cfu/g
Topical : ≤ 100 cfu/g
.General in-house limit for oral products : ≤ 50 –100 cfu / gm

Acceptance Limit
CFU / surface area = microbial limit x factor x

wt.product
shared surface area
factor : 0.1

Acceptance Limit
Not only the contaminant level on cleaned equipment surface
consideration
- proliferation
- contamination while holding ( CEHT )
- process ( heat, warm, purge etc.) of next product
- preservatives, formulation of next product
- species of m/o

Acceptance Limit
Calculation
Exa
mpl
Safety Factor
Safety Factors Application to

1/10 - 1/100  Topical product
1/100 - 1/1,000  Oral product
1/1,000 - 1/10,000  Injection , Ophthalmic prod.
1/10,000 - 1/100,000  Research product
Ref : PDA Technical Report # 29

Calculation
Example :
A : Prednisolone tablet 5 mg ( wt. 60 mg/tab ) …. Dose 1 tab. qid

B : Ofloxacin tablet 100 mg ( wt. 350 mg/tab ) …. Dose 1-2 tab. tid
Batch size B …. 25, 100 kg.
MACO = lowest therapeutic dose A x smallest batch size B x safety factor

max. daily dose B
MACO = 5 mg x 25,000,000 mg. x 1/1000 = 59.5 mg

( 350 x 6 ) mg

Calculation …continue
Total surface area : ( 30,000 + 45,000 + 25,000 ) = 100,000 cm2
Acceptance limit = 59.5 mg = 0.595 mcg/cm2

100,000 cm2
= 14.88 mcg / swab 25 cm2
LOQ should be less than ……?

max. daily dose B
Compare to medical dose-based
MACO = lowest therapeutic dose A x smallest batch size B x safety factor

max. daily dose B

Toxicity-based limit
Example :
A : Prednisolone tablet 5 mg ( wt.60 mg/tab ) …. Dose 1 tab. qid

B : Ofloxacin tablet 100 mg ( wt. 350 mg/tab ) …. Dose 1-2 tab. tid
Cleaning agent …. LD 50 = 8 g./ kg.
max. daily dose B
MACO = ( 8 g./kg x 70 kg. x 0.0005 ) x 25,000 g. x 1 = 3.33 g.

6 x 0.35 g. 1,000

Toxicity-based limit ( cont.)
Total surface area : ( 30,000 + 45,000 + 25,000 ) = 100,000cm2
Acceptance limit = 3.33 g. = 33.3 mcg/cm2

100,000 cm2
= 832.5 mcg / swab 25 cm2

Acceptance Limit
USP <1111> “Microbial content of Non-sterile Pharmaceuticals”
Solid oral : ≤ 1,000 cfu/g

Liquid oral : ≤ 100 cfu/g
Topical : ≤ 100 cfu/g
CFU / surface area = USP limit x factor x smallest batch size B

shared surface area

Acceptance Limit
General in-house microbial limit of oral products :

≤ 50 – 100 cfu / gm.
CFU / surface area = in-house limit x factor x smallest batch size B

shared surface area

Acceptance Limit
Example :
A : Prednisolone tablet 5 mg ( wt.60 mg/tab ) …. Dose 1 tab. qid

B : Paracetamol tablet 500 mg ( wt.625 mg/tab ) …. Dose 1-2 tab. qid
Microbial limit of oral solid dosage form …. ≤ 100 cfu /g.
CFU / surface area = microbial limit x factor x smallest batch size B

shared surface area
CFU / surface area = 100 cfu/g. x 0.1 x 25,000 g. = 2.5 cfu/cm2

100,000 cm2
= 62.5 cfu / 25 cm2

Acceptance Limit
Calculation
Applic
ation
PRODUCTS
Products Grouping
mg/tab.
( 1- 3 ) ( 1- 3 )
A 2 3 100
B
1 1 20
C 2 1 250
D 1 1 50
E 3 2 20
F 2
√ 1 2
Least Solubility
G 1 1 500
√ Most potent
H 2 1 25
Representative ( worst case ) : product …A / E

Products Grouping
Hardest to clean // Least solubility
N Y

most stringent limit.
Pick the worst

SOLUBILITY
(mg/ml )
PRODUCTS
Cleaning
ACTIVE Wt./tab.
difficulty
DOSE LTD MDD
mg/tab. (mg)
(mg) (mg)
A 2 3 100 250 1-2’s bid

100 1000
B 1 1 20 180 1’s tid
20 540
C 2 1 250 300 1-2’s tid
250 1800
D 1 1 50 160 2’s once
100 320
E 3 2 20 100 1’s once
20 100
F 2 1 2 80 1-2’s bid
2 320
G 1 1 500 750 1-2’s ,8hr.
500 4500
H 2 1 25 250 1’s bid
25 500
MACO = LTD of A x smallest batch size B x safety factor

MDD of product B

SOLUBILITY
PRODUCTS
(mg/ml )
Batch
ACTIVE Wt./tab. LTD MDD size
MACO
mg/tab. (mg)
(mg) (mg) ( gm.)
(kg.)
A 2 100 250 50,100
100 1000
B 1 20 180 20 100
540 18.5
C 2 250 300 250 100,200
1800 5.5
50,100
D 1 50 160 100
320 15.6
E 3 20 100 20 50,100
100 50.0
F 2 2 80 2 50
320 15.6
G 1 500 750 500 100,200
4500 50,100 2.2
H 2 25 250 25
500 10.0
MACO = 100 mg x 100,000,000 mg. x 1/1000 = 18.5 gm.

( 540 ) mg

SOLUBILITY
PRODUCTS
(mg/ml )
Batch
ACTIVE Wt./tab. LTD MDD size
MACO
mg/tab. (mg)
(mg) (mg) ( gm.)
(kg.)
A 2 100 250 50,100
100 1000
B 1 20 180 20 100
540
C 2 250 300 250 100,200
1800
50,100
D 1 50 160 100
320
E 3 20 100 20 50,100
100
F 2 2 80 2 50
320
G 1 500 750 500 100,200
4500 50,100 0.044
H 2 25 250 25
500
MACO = 2 mg x 100,000,000 mg. x 1/1000 = 0.044 gm.

( 4500 ) mg

Products Grouping
Hardest
Product
to clean
A or//Product
Least solubility
E
N Y

limit.
most MAC
stringent
= 0.044
limit.g.
Pick the worst

Acceptance Limit
Calculation
Grouping strategy Equipment Trains
&
Medical dose Concept Surface Area
Calculation
Acceptance limit = MACO / total area

now! we are able to calculate
the Acceptance limit
Sampling
&
Test method
Sampling method
√ 1. Direct surface sampling ( Swab, Contact plate )
2. Rinse sampling …. Water or Solvent rinse

3. Placebo / Dilution approach
√ 4. Direct surface : FTIR e fiber optic

Swabs

Sampling tools

Sampling tools

FTIR.e fiber-optic probes
Remspec’s fiber-optic probes combined with a compact FTIR module

Small
Business
Innovation Fiber Optic FTIR Spectroscopy
Research
Foster-Miller, Inc.
Waltham, MA 02154
INNOVATION
Infrared Transmitting optical fibers

are combined with FTIR spectroscopy
to enable remote on-line chemical
composition analysis in difficult process
environments
 NASA/DOD
- Surface monitoring and analysis
Fiber Optic ATR prove and typical system schematic

Sampling site set up for SWAB
Concept :
1. hard to be cleaned
2. different material representatives
3. general area
4. slowest to dry
5. valve, orifice , site for non-uniform contamination

Sampling sites set up
7 6
4
1 5
3
SWAB RINSING
2 1 Agitator (bottom/nook)
2 Chopper grill OVERALL AREA
3 Bottom bowl
4 Side bowl
5 Rubber gasket
6 Funnel port ( inner lid )
7 Filter bag port ( inner lid )
9 April ' 08 8 Orifice / Outlet
P.piensiripinyo
Swab pattern example

Swab pattern example
start start
flip swab
end
end

Rinse sampling
1. Final ( process ) rinse : usually non-uniform
2. Sampling rinse :
 Mix before sampling
 Done after process rinse is complete
 Solution may be difference from process rinse

Advantages Dis-Advantages
Dried out residues Interfere / adsorb

Generate particle
Swab Adjustable area versus
limit Not for hose , pipe
Any surface Not a true
Specific area representative
Economical
Large area Solubility of residue

Rinse
Easy ( combine test Not specific area
sample ) Dilute sample

PE 009

should be used. The detection limit for each an
alytical method should be sufficiently sensitive
to detect the established acceptable level of t
he residue or contaminant.

QC Responsibilities
Acceptance limit
Target residue
Surface area
Develop test method (…LOD,

Equipment diagram LOQ )
Validate test method
Visual limit
Sampling method & technique
Recovery test
9 April ' 08 Calculate
P.piensiripinyo /Conclude test results
QC Responsibilities
Develop test method (…LOD, LOQ )

Validate test method
Visual limit
Sampling method & technique
Recovery test
Calculate /Conclude test results

Method Validation Parameters
Accuracy
Precision
Limit of Detection
Method Limit of Quantitation
Validation
Specificity
Linearity and Range
Ruggedness/Robustness
System Suitability

Method validation
Sensitivity of target residue
LOD : the assay value which show the

existence of the residue but can not be quantified
with exact value.
LOQ : the lowest precise assay value.

Develop test method
Example
CP condition
PREDNISOLONE DECOMPOSITION ?
Trial & Develop

Test method
SAMPLING METHOD
Setting limit LOD, LOQ Recovery

( > 50% )
VALIDATE METHOD

Develop test method ( cont.)
Example ( micro-organism )
Acceptance limit consideration
Absent E.coli ≤ 10 cfu / 25 cm2
RINSE CONTACT PLATE RINSE / SWAB
FILTRATION COUNT MAKE DILUTION

& SELECTIVE AGAR & COUNT
DEVELOP SAMPLING & TESTING METHOD : > 25 % recovery

Recovery test
Spike Product for specific test Surface type / Coupon
method Uniformity of residue
Spike Target residue for non Drying time ( min / max )
specific Spiked level :
test method ≤ the acceptance limit
Use the appropriate lowest Trained and verified
recovery ( samplers & analysts )
amount ( not the mean )

Use recovery factor to correct the
limit
or test result
Recovery test
1.Spike control diluent directly
contro
standard l
solution
2a. Spike
coupon
2b. Swab coupon
test
2c. Extract
swab

Recovery test : interference check
Prepare solution of product/residue
Spike diluent Spike 50-100% residue limit
Spread to uniform layer
Let it dry
swab / rinse for

analysis
Recovery test
% Recovery = amount detected x 100
amount spiked
The recovery which is ≤ 50% improve
Low recovery …. Residue adhesion to swab or surface

…. Sampling technique
…. Hold time consideration
High recovery …. Interferences from swab or coupon

Visually clean
Condition
Surface must be dry
Consideration - viewer
- angle
- lighting
- distance
Typical visual limit is 1-4 mcg/cm2

Visually clean ( cont.)
Exception of using instead quantitative method
Potent drug
Microbial contamination
Endotoxin

Visual limit determination
13 32 10 1
2 7 0 24
15 4 26 21
16 9 31 3

Visual limit determination
Spiked amount of target residue
Viewers ( mcg / cm2 )
1 4 6 8
× √ √ √
A
B
× × √ √
C × √ √ √
Viewing condition : exactly the same for all viewers ( light, distant, angle )
……….. But worse ≥ real condition.

Test method
Specific method
• HPLC, GC, IR, UV, TLC , IMS
Non-specific method
• TOC, Conductivity, pH, TDS, Titration


should be used. The detection limit for each a
nalytical method should be sufficiently sensit
ive to detect the established acceptable level
of the residue or contaminant.

Comparison between
HPLC and TOC
High Performance Liquid Total Organic Carbon
Chromatography
Specific analytical technique Non-specific analytical technique
Extensive sample preparation Little sample preparation
One or two days to process Rapid analysis time
High cost Low cost

Total Organic Carbon
TOC
Advantages Dis-Advantages
High sensitivity ( low LOQ ) Sample must be soluble in water
Online / Offline sampling Sample can not be prepared in

application organic solvent
High recovery of samples Non specific : false positive
Easy method development

Comparison between
HPLC and IMS
HPLC IMS
Specific analytical technique Specific analytical technique
Extensive sample preparation Little sample preparation
Extensive analysis time Rapid analysis time

( method validation : 17 - 27 hrs ) ( method validation : 1.8 – 4.2 hrs )
( sample : 10 -25 min./sample ) ( sample : 30 – 45 sec./sample )
sensitivity : mcg - ng Sub-nanogram sensitivity
High cost Economic impact

HPLC VS TOC
Sample
HPLC TOC
UV/ persulfate Heat
H2O + CO2 H2O + CO2

Chromatogram
NDIR
(non-dispersive infrared)
Ion Mobility Spectrophotometer

FTIR.e fiber-optic probes
Remspec’s fiber-optic probes combined with a compact FTIR module

Statistics of the use of some analytical
methods in Cleaning Validation on
Other
industries
9%
Infrared
High Spectroscopy
Performance (IR)
Liquid Others 15%
Chromatography
(HPLC) 9%
37%
IR 15%
HPLC
37%
Ion Mobility
IMSSpectroscopy
18%
(IMS)
TOC 18%
21%
Total Organic
Carbon (TOC)
21%
Diagram 1. Percent of use of methods for cleaning validation.
Source: The Global Assessment Report 8th Edition: The Laboratory Life Science and Analytical Instrument Industry, June 2004.
Are U ready to perform
Cleaning Validation ?

40. Typically three consecutive applications of

the cleaning procedure should be performed
and shown to be successful in order to prove
that the method is validated.

Cleaning Validation Master Plan
( CVMP )
To Guide, Control & Guarantee

the development of
Cleaning Validation

CVMP
1. Purpose
2. Strategy of approach
3. Selection of products for validation
4. Cleaning in development area
5. Analytical method
6. Approach to setting limit
7. Approach to sampling
8. Schedule of activities

CVMP ( cont.)
9. Assignment of responsibilities
10. Review and approval process
11. Qualification of Equipments
12. Training of personnel
13. Documentation
14. Use of consultant
15. Validation maintenance & Revalidation

CV flow chart
Process / Products / Equipments ……
consideration
Drawing diagram Develop test

method.
Surface area calc. Validate test method
Schedule plan Sampling method

Sampling site set up
Recovery test
Acceptance limit set up
Visual check

CV flow chart ( cont.)
CV Protocol
RUN ( 3 runs )
N Y Adopt CP
Investigate & Correction Report Training
Maintain

CV Protocol
☻ Specific guide for validate CP of all equipments
directly contact the represented product.
☻ Elements of the Protocol

- purpose - acceptance criteria
- scope - sampling plan / method
- responsibility - test method
- equipments / materials - procedure
- reference documents

CV flow chart
CV Protocol
RUN ( 3 runs )
N Y Adopt CP
Maintain

CV Summary report
Elements of the Summary
report
- purpose
- scope
- reference documents
- sampling record
- testing result
- deviation & discussion
- overall conclusion
CV flow chart
CV Protocol
RUN ( 3 runs )
N Y Adopt CP
Maintain

CV maintenance
Consideration after CV is completed :
☻ Change control
√☻ Monitoring
☻ Equipment maintenance
☻ Training program
☻ New products
☻ Use / Cleaning log book
☻ Calibration program
√☻ Revalidation

Monitoring
Once the CV has been validated
Not necessary for every batch of each product
Monitoring schedule with certain frequency
Using non-specific method as screening
Monitoring only worst site / Rinse overall area

Revalidation
When Change is significantly affect the validity of

Cleaning
When Monitoring results : show a trend toward higher
and
higher residues.
Fix revalidation program
Review processes every 1-2 years and revalidate

only
those that need to be revalidated.

Future
Approach to
Limit
Reference Documents
G UIDE T O INSP EC T IO NS V A LIDA T IO N O F C LEA NING P R O C ESSES.
CV guide CANADA..mht

Reference Documents
Appendix 3 : p 139

Reference Documents


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CLEANING

9 April ' 08 P.piensiripinyo

PIC/S WHO usFDA ……

1. Key resource for cleaning

2. PIC/S PI 006-3 The basis of Draft Annex 15.

3. WHO cleaning validation TRS 937 appendix 3

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6. 21CFR 210-211 (GMPs)

7. Destin A. LeBlanc / cleaning validation www:cleaningvalidation.co

8. PDA Technical report # 29

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36. Cleaning validation should be performed

37. Validated analytical methods having

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38. Normally only cleaning procedures for

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38. . Normally only cleaning procedures for product contact

The intervals between use and cleaning

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39. For cleaning procedures for products and

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40. Typically three consecutive applications of

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41. "Test until clean " is not considered

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42. Products which simulate the Physico-

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which is suitable for proceeding of active

pharmaceutical ingredients or pharmaceutical

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 Test result report

Detail : next period

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► OTHERS (e.g. pieces of brushes, insects )

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Documented evidence that an approved

Non-contact parts should be consideration

High safety risk products & difficult to remove

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 Equipment disassembly (if required)

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 Clean-in-place (CIP) systems

 Control system qualification

 Sampling ( sampling port, pause capability )

 Material supply ( hard-plumbed supply lines, volume and

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Coverage Study ( CIP )

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 Cleaning between batches of the same product

 Cleaning between batches of different products

 Cleaning after maintenance

 Cleaning after accidental contamination

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CEHT and Protection

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