Cleaningvalidationacompleteknowhow 140528034627 Phpapp01

CLEANING VALIDATION
Know How of an Effective Cleaning

Program
Sambhujyoti Das, Quality Assurance
CLEANING VALIDATION... AT
A GLANCE
After completing this session well come to know :
Acceptance criteria
Definition
Sampling Methods
Purpose
Analytical Methods
Cleaning mechanisms
Hold time studies
Cleaning agents
USFDA 483
Cleaning Methods
Citations
Cleaning parameters
Cleaning continuum
Grouping strategies
Worst Case considerations
1
Quality Assurance
CLEANING VALIDATION THE

DEFINITION
The process of removing contaminants
from process equipment and monitoring
the condition of equipment such that the
equipment can be safely used for
subsequent product manufacturing.
Dustin A. Leblanc.
2
Quality Assurance
CLEANING
VALIDATION........... PURPOSE
Product integrity
Cross contamination
Microbial integrity
Product impurity
Batch integrity
Equipment reuse
Regulatory issues
3
Quality Assurance
CLEANING VALIDATIONCLEANING
MECHANISMS
The chemistry of contaminant removal :
Solubility
Wetting
Emulsification
Dispersion
Hydrolysis
Oxidation
Physical removal
Antimicrobial action
4
Quality Assurance
MECHANISMS
Solubility :
Solubility involves the dissolution of one
chemical (the contaminant) in a liquid solvent.
For example, salts may be soluble in water, and
certain organic actives may be soluble in acetone
or methanol.
One of the primary cleaning mechanisms to
be considered during design phase.
Rate of solubility, Insoluble form, Soluble
Insoluble species
Quality Assurance
MECHANISMS
Wetting :
Wetting involves the displacement of one fluid from
a solid surface by another fluid. Wetting can be
improved by the addition of surfactants.
It improve penetration of the cleaning solution
into cracks and crevices, which are usually
difficult-to clean locations.
Courtesy: Validated Cleaning Technologies for Pharmaceutical

Manufacturing, D. A. LeBlanc
Quality Assurance
MECHANISMS
Emulsification :
Breaking up an insoluble liquid residue into smaller
droplets and then suspending those droplets
throughout the water.
Emulsion = Mechanical energy + Surfactants /
Polymers.
Emulsions are thermodynamically unstable (say, 5
to 10 mins.).
Redeposition of the cleaned residue back onto the
equipment surfaces.
Agitation should be continued till the time to
7
discharge the cleaning solution to the drain.
Quality Assurance
MECHANISMS
Dispersion :
Dispersion is similar to emulsification, except that it
involves the wetting and deaggregation of solid
particles and then the subsequent suspension of those
particles in water.
More important in dry product manufacturing.
Hydrolysis :
This involves the cleavage of certain bonds in an
organic molecule.
The resultant hydrolyzed residues must either
be water soluble or solubilized at the pH of the
8
cleaning solution.
Quality Assurance
MECHANISMS
Oxidation :
This involves the cleavage of various organic
bonds, such as carbon-carbon bonds, by the action
of a strong oxidizing agent.
Large Non-polar Mol.
Smaller more
polar Mol.
Antimicrobial Action :
Mechanisms that may kill organisms but leave
behind nonviable microbial residues.
Special type of mechanism, sterilization,
disinfection.
9
Quality Assurance
MECHANISMS
Physical Removal:
Cleaning by some mechanical force. the objective
is to physically displace the residue.
Pressurized water + Scrubbing
In real life situation, more
than one cleaning
mechanisms are being
used.
1
0
Quality Assurance
CLEANING
VALIDATION.CLEANING AGENTS
Cleaning Agents
Aqueous
Cleaning
Water
Organic
Solvents
Surfactants
Chelants
Solvents
(miscible)
Acids / Bases
Oxidants
1
1
Quality Assurance
CLEANING
VALIDATION.CLEANING AGENTS
Organic
Solvents
Surfacta
nts
Acetone
SLS
Methan
SDS
ol
Fatty
Ethyl
acid
Acetate
salts
Bases
NaOH
KOH
Chelants
EDTA
NTA
SHMP
Solvents
(miscibl
e)
Glycol
Ethers
Acids
Oxidants
Glycolic
Acid
H3PO4
Citric
Acid
NaOCl
Peraceti
c Acid
H2O2
1
2
Quality Assurance
CLEANING
VALIDATION.CLEANING METHODS
Automated
Cleaning:
o Fixed CIP
o Portable CIP
o Parts Washer
o Ultrasonic
Manual Cleaning:
Soak
Brush
Wipe
Spray
Extent of automation..Extent of
disassembly
1
3
Quality Assurance
CLEANING
Fixed CIP :
1
4
Quality Assurance
CLEANING
Portable CIP :
1
5
Quality Assurance
CLEANING
Parts Washer :
Ultrasonic Washer :
1
6
Quality Assurance
CLEANING VALIDATION.
CLEANING PARAMETERS
Time
Action
Cleaning chemistry
Concentration
Temperature
Mixing / flow /
turbulence
Water quality
Rinsing
1
7
Quality Assurance
CLEANING PARAMETERS
Parameter interactions :
Time vs Concentration :
Temp. vs Concentration :
Courtesy: Validated Cleaning

Technologies for
Pharmaceutical Manufacturing,
D. A. LeBlanc
1
8
Quality Assurance
CLEANING PARAMETERS
Parameter interactions :
Time vs Temperature :
Time (min)
Courtesy: Validated Cleaning

Technologies for
Pharmaceutical Manufacturing,
D. A. LeBlanc
1
9
Quality Assurance
CLEANING CONTINUUM
Continuum represent the extremes in the
range of operating differences found within
the industry.
The continuum should be used during the
initial
phases
of
defining
a
cleaning
validation
Manual . . . .program
. . . . . . . or
. . . during
. . . . . . .new
. . . .product
......
development.
Automated Cleaning
COP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . ..CIP
Dedicated Equipment . . . . . . . . . . . . . NonDedicated Equipment
Product Contact Surfaces . . . . . . . Non-Product
2
Contact Surfaces
0
Non-Critical Site . . . . . . . . . . . . . . . . . . . .Quality
. . . Assurance
....
CLEANING CONTINUUM
Low Risk Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . .
High Risk Drugs
Highly Characterized . . . . . . . . . . . . . . . . . . .
Poorly Characterized
Sterile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . Non-Sterile
Solid Formulations . . . . . . . . . . . . . . . . . . . . .
Liquid Formulations
Soluble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . Insoluble
Single Product Facility . . . . . . . . . . . . . . . Multiple
Product Facility
Campaigned Production . . . . . . . . . Non-2
1
Campaigned Production
Quality Assurance
Simple Equipment Train . . . . . . . . . . . Complex
GROUPING STRATEGIES
"Grouping" is the concept of demonstrating that
certain elements of cleaning are of a similar type,
and selecting one (or more) representative
object(s) on which to conduct the Cleaning
Validation (Cleaning Process Qualification).
Product grouping :
Same manufacturing equipments being used.

Same cleaning SOPs being followed.
Similar formulations.
Similar risk / therapeutic group.
Equipment
grouping,
grouping,
Cleaning
.., etc.
Cleaning
method
agent
grouping,2
2
Quality Assurance
GROUPING STRATEGIES
All products in a facility
(hypothetical):
Sr.
Formulat Cleaning
Name of product
No.
ion
methods
Equipment
train
Risk /
Therap.
class
Product A
Tablet
(FC)
Method 1
Train A
General
Product B
Tablet
Method 1
Train B
General
Product C
Parenteral
Method 2
Train C
Cytotoxic
Product D
Tablet
Method 3
Train B
General
Product E
Tablet
(EC)
Method 4
Train A
General
Product F
Parenteral
Method 2
Train C
Cytotoxic
Product G
Tablet
(FC)
Method 1
Train A
Cytotoxic
Product H
Tablet
Method 3
Train B
General
Product I
Tablet
(EC)
Method 4
Train A
General
10
Product J
Parenteral
Method 2
Train C
Cytotoxic
2
3
Quality Assurance
GROUPING STRATEGIES
Before Grouping :
Sr.
No.
Name of product
Formulat
ion
Cleaning
methods
Equipment
train
Risk /
Therap.
class
Product A
Tablet
(FC)
Method 1
Train A
General
Product B
Tablet
Method 1
Train B
General
Product C
Parenteral
Method 2
Train C
Cytotoxic
Product D
Tablet
Method 3
Train B
General
Product E
Tablet
(EC)
Method 4
Train A
General
Product F
Parenteral
Method 2
Train C
Cytotoxic
Product G
Tablet
(FC)
Method 1
Train A
Cytotoxic
Product H
Tablet
Method 3
Train B
General
Product I
Tablet
(EC)
Method 4
Train A
General
10
Product J
Parenteral
Method 2
Train C
Cytotoxic
2
4
Quality Assurance
GROUPING STRATEGIES
After Grouping :
Sr.
No.
Name of product
Formulat
ion
Cleaning
methods
Equipment
train
Risk /
Therap.
class
Product A
Tablet
(FC)
Method 1
Train A
General
Product B
Tablet
Method 1
Train B
General
Product G
Tablet
(FC)
Method 1
Train A
Cytotoxic
Product C
Parenteral
Method 2
Train C
Cytotoxic
Product F
Parenteral
Method 2
Train C
Cytotoxic
Product J
Parenteral
Method 2
Train C
Cytotoxic
Product D
Tablet
Method 3
Train B
General
Product H
Tablet
Method 3
Train B
General
Product E
Tablet
(EC)
Method 4
Train A
General
10
Product I
Tablet
(EC)
Method 4
Train A
General
2
5
Quality Assurance
CLEANING VALIDATION..WORST CASE

CONSIDERATIONS
Once the product groups have been established,
the next step is to determine the so-called worst
case representative of each group.
It is that member(s) who shows the highest
challenge on cleaning program.
Worst case product
: Toxicity / solubility /
highly characterized / difficult to
clean ingredients.
Worst case eq. train
: Longest train.
Worst case equipment : Larger size equipment
(identical design).
Worst case acc. criteria: Stringent acceptance
2
criteria.
6
Assurance
Hold time studies
: Longest Quality
possible
CLEANING VALIDATION..WORST CASE

CONSIDERATIONS
There is no hard & fast rule on worst case
selection.
A good logic and science should always be
used.
Grouping and worst case selection help to
demonstrate cleaning method robustness.
It smartly reduces the load from cleaning
validation program.
These philosophies should always be verified
against the actual capability of cleaning
program.
2
7
The ultimate cost benefit ratio should
be
Quality Assurance
VALIDATION...ACCEPTANCE
CRITERIA
How clean is clean ?
What are the bases of defining
limits ?
What are the impacts of after
cleaned residue ?
Human Drug CGMP Notes, 9:2, 2Q 2001 :
Should equipment be as clean as the best
possible method of residue detection or
quantification?
Answer: No,absolute cleanliness is
neither valuable nor feasible. It should be
as clean as can be reasonably be achieved, to
a residue limit that is medically safe and2
8
that
causes
no
product
quality
Quality Assurance
CRITERIA
Three criteria :
It should be scientifically
justifiable.
Pacifically achievable.
Methodically verifiable.
Possible
limits :
types
of
Visual
Chemical
Microbiological
Endotoxin
2
9
Quality Assurance
CRITERIA
Visual clean criteria :
GMPs require inspection for visual cleanness
before manufacture.
Key items to consider :
o Angle of view
o Distance from equipment surface
o Lighting conditions
o Viewers knowledge
o Surface usually must be dry
Visual aids :
Additional lighting / Magnifying glass / Mirror /
Fiber-optic scope / UV light
3
0
Quality Assurance
CRITERIA
Application for visual limits :
A typical visual limit is NLT 4 g / cm2.
Visually clean may not be enough by itself
Potent drugs
Microbial contamination
Endotoxin
More suitable method for non-potent drug
products and APIs.
PIC/S advocates spiked coupon study for
determination of visual inspection limits (and
for training of inspectors).
3
1
Quality Assurance
CRITERIA
Chemical residue limits (Therapeutically or
Toxicologically safe criteria) :
Therapeutic dose based criteria
Most suitable for drug product
product) manufacturing facility.
(finished
Toxicological criteria
Most
suitable
for
active
drug
(API)
manufacturing facility.
Where cleaning agents are used (other than
water).
10 PPM criteria
CGMP requirement widely applicable.
3
2
Quality Assurance
CRITERIA
Therapeutic dose based criteria :
Based on the assumption that 1/1000 part of
therapeutic dose does not have any clinical impact
Step
on
human (animal) body.
1
Determination
of
MAC
(Maximum
Allowable Carryover) of Product A (Previous) to
Product B (Next)
SRDD (A) BS (B) SF
MAC
=
(unit of mass)
LRDD (B)
Where, SRDD = Smallest Recommended Daily Dose3
3
(Product A ACTIVE CONTENT),
Quality
Assurance
BS = batch size (Product B), SF = safety factor and
LDD
and
CRITERIA
Step
2
Determination of Surface contamination
(Shared Equipment)
L1
MAC
=
(mass / surface area)

SESA
Where, SESA = Shared Equipment Surface Area (for both products)
3
4
Quality Assurance
CRITERIA
Step
3
Determination of Sampled residue (for swab
sample)
L2
L1 Swab Area (mass / swab)
SRDD value represents the ACTIVE drug

content only.
e.g. 5 mg or 10 mg, the dose
strength.
LRDD value represents the mass or volume of

3
entire dose.
5
e.g. 250 mg or 20 mL (drug + excipients).

Quality Assurance
CRITERIA
Safety Factors :
Approach
0.1 to 0.01
0.01 to 0.001
0.001 to 0.0001
0.0001 to
0.00001
Approach Typically
Applicable To
Topical products
Oral products
Parenterals, opthalmic
products
Research, investigational
products
3
6
Quality Assurance
CRITERIA
Therapeutic
Step
example)
:
1
dose
Determination
Carryover
of
based
criteria
Maximum
(an
Allowable
10 mg 150 kg 0.001 1000000

(250 mg 3)
= 2000 mg
(MAC value)
3
7
Quality Assurance
CRITERIA
Therapeutic
Step
example)
:
2
dose
based
criteria
(an
Determination of Surface contamination level

2000 mg
3170 cm2
=
0.63 mg / cm2
(L1 value)
3
8
Quality Assurance
CRITERIA
Therapeutic
Step
example)
:
3
dose
based
criteria
(an
Determination of Swab residue

0.63 mg / cm2 25 cm2
=
15.75 mg / swab
(L2 value)
3
9
Quality Assurance
CRITERIA
Toxicological criteria :
Based on the toxicological information available in
Material Safety Data Sheets.
Step
1A
Determination of NOEL (No Observed
Effect Level)
NOEL
LD50 Emperical Factor

(unit of mass/kg of body
weight)
Where, LD50 = lethal dose for 50% of animal population in
study (mg/kg/day),
4
Emperical Factor = derived from animal model developed by
0
Layton, et.al : 0.001*
Quality Assurance
CRITERIA
Step
1B
Determination of ADI (Acceptable Daily
Intake)
ADI
NOEL AAW SF
(unit of mass)
Where, AAW = average adult weight : 70 kg,

SF = safety factor (0.01)
Consider average body weight of child where

there is any pediatric dose available.
Use LD50 value of mice.
4
1
Quality Assurance
CRITERIA
Step
1C
Determination
of
Allowable Carryover)
MAC
(Maximum
ADI BS
MAC
=
LRDD (any next product)
Step
of mass) Step
2
3
Then use
and
final swab residue limit.
(unit
to derive
4
2
Quality Assurance
CRITERIA
Toxicological criteria (an example) :
Step
1A
Determination of NOEL
(1750 mg /kg/day) 0.001 = 1.75 mg/kg
(NOEL value)
Step
1B
Determination of ADI
(1.75 mg/kg) 70 kg 0.01
mg
(ADI value)
1.225
4
3
Quality Assurance
CRITERIA
Toxicological criteria (an example) :
Step
1C
Determination of MAC
1.225 mg 150 kg 1000000
(250 mg 3)
= 245000 mg
The final Swab residue (L2) :
245000 mg 25 cm2 =
3170 cm2
1932 mg/swab
4
4
Quality Assurance
CRITERIA
10 PPM criteria :
Based on the hypothesis that 10 parts of previous
product is therapeutically ineffective if presents in
million parts of next product.
Step
1
10 BS
MAC
=
(unit of mass)
1000000
Where, BS = batch size (smallest available batch size)
Step
Step
Then use
and
2
3
final swab residue limit.
to derive
4
5
Quality Assurance
CRITERIA
10 PPM criteria (an example) :
Step
1
10 150 kg 1000000
MAC
=
= 1500 mg
1000000
The final Swab residue (L2) :
1500 mg 25 cm2
3170 cm2
11.83 mg/swab
4
6
Quality Assurance
CRITERIA
The most stringent acceptance criteria shall
be chosen for cleaning validation study (The
worst case approach).
15.
75
11.
83
mg / swab
193
2
In real life cases, therapeutic or 10 PPM

criteria become final acceptance criterion for4
cleaning validation.
7
Quality Assurance
CRITERIA
Microbiological criteria :
Internal specifications
Official specifications: e.g. USP <1111>,
Microbial Examination of nonsterile Products:
Acceptance
criteria
for
Pharmaceutical
Preparations and Substances for Pharmaceutical
Use
Total
Adminstration
route
Total aerobic
combined
count (cfu/g or yeasts/molds
cfu/mL)
count (cfu/g or
cfu/mL)
Nonaqueous
oral
103
102
Aqueous oral
102
10
Most topicals
102
10
4
8
Quality Assurance
CRITERIA
Microbiological criteria :
Environmental specifications: EU GMP, Annex
1, Recommended limits for microbiological
monitoring of clean areas during operation
Grade
Contact plates (diam. 55 mm),

cfu/plate
<1
25
50
i.e.
recommended
limit
for
contamination in grade D area is :
(5.5/2)2}= 2.10 cfu/cm2
microbial
50/{
4
9
Quality Assurance
CRITERIA
Microbiological
specifications:
criteria
from
internal
Driven by SOP.
Must be backed up by justifiable scientific
rationale.
Microbiological
specifications:
criteria swab
from
area
official
Spec. limit factor Wt. product

SESA
25 cm2 = 3943
An example:
cfu/swab
1000 cfu/g 0.1 5 kg 103
3170 cm
5
0
Quality Assurance
CRITERIA
Microbiological criteria from environmental
specifications:
50/{ (5.5/2)2} swab area
An example:
2.10 cfu/cm2 25 cm2
= 52 cfu/swab
5
1
Quality Assurance
CRITERIA
Determining acceptance criteria with more
than
one
next
products
(The
Matrix
approach):
Prod.
Prod.
Prod.
Prod.
Prod.
NEXT PRODUCT
PREVIOU
S
PRODUCT
(mg)
(kg)
(cm2)
B.
Size
200.0
75.0
100.0
150.0
355.5
S.
Area
4525
3960
4015
3770
4008
SRDD
LRDD
GENERAL SOLID FACILITY
Product
A
10.0
450.0
Product
B
1.0
320.0
3.4
Product
C
25.0
600.0
46.0
19.7
Product
D
5.0
300.0
18.4
7.9
10.4
Product
E
125.0
800.0
172.6
74.0
97.3
10.5
13.8
22.1
49.3
1.9
3.1
6.9
41.4
92.4
36.9
155.4
5
2
Quality Assurance
VALIDATION......SAMPLING
METHODS
The sampling procedure refers to the method of
collecting the residues from the surface so that
they
can be measured.
Types
Advantages
Limitations
Swabs &
Wipes
Dissolves & physically

removes sample,
adaptable to wide variety
of area
May introduce fibers,

technique dependent,
hard-to-reach areas
Rinse
Easy, quick, non-intrusive,

large surface area
Limited information
about actual surface
cleanliness
Coupon
Non-technique dependent,
reduces variability in
recovery
Invasive, might
interfere with cleaning
process
Placebo
Placebo contacts the same

surfaces as the product
Difficult to determine
recovery
Direct
Surface
Rapid, non-invasive,
economical
5
Some techniques not 3
widely developed
Quality Assurance
METHODS
Swab sampling techniques:
(1)One of the most widely used technique for
chemical and microbial sampling.
(2)Swabs are being wet with solvent aiding
solubilization and physical removal of
surface residues.
(3)Results are technique dependent.
Microbial swab
(sterile)
Chemical swabs
(Texwipe)
Cotton
wipes
5
4
Quality Assurance
METHODS
(5)Generally 1 swab sample per location is
adequate.
(6)Multiple swabs can be taken to improve
surface recovery.
(7)Typical swabbed per site varies from 25 cm2 to
100 cm2. There is no magic number.
2.
5
(8)PTFE (chemically inert) templates
may
be
5
cm
used for accurate swabbing area. 5 cm
cm
(9)Difficult to clean equipment surfaces
Swab
shall be identified and sampled. area
template 1
(10) Representative surfaces of different
5
s
0
5
c
materials (MOCs) should be sampled.
Qualitym
Assurance
METHODS
(11)Wiping should be unidirectional at a time.
Parallel strokes should be employed to cover
entire swab area.
Courtesy: Validated Cleaning Technologies for Pharmaceutical

Manufacturing, D. A. LeBlanc
5
6
Quality Assurance
METHODS
Example of Difficult to clean locations of an
Courtesy: Rapid mixer
RMG:
granulator, Kevin.
The design aspect of the equipment should be

considered to identify difficult to clean locations.
5
7
Quality Assurance
METHODS
Rinse sampling techniques:
Rinse sampling involves using a liquid to cover the
surfaces to be sampled.
(1)One of the easy and widely used sampling
method.
(2)Most preferable liquid for rinsing is water.
(3)The rinse volume is an important factor that
has to be determined.
Rinse volume (1/Residue conc. in
rinse sample)
(4) Forced rinsing is advisable for collection of5
8
less soluble residues.
Quality Assurance
METHODS
Determination rinse volume:
(1)Variability in magnitudes of surface areas gives
rise of variable residue concentrations in rinse
samples (fixed rinse volume).
(2)Variable acceptance criteria for a single
product creates confusion.
(3)It is a good idea to chose variable rinse
volumes to keep constant residue concentration
in rinse samples (fixed acceptance criteria).
Formula :
L1 ESA
Rinse vol. for Equipment A =
5
9
Anticipated rinse conc.
Quality Assurance
METHODS
Determination rinse volume:
Example :
0.63 mg / cm2 1760 cm2
Rinse vol. for Equipment A =
10 g / mL
= 110.9 L
(considering mg/L = PPM)
0.63 mg / cm2 810 cm2
Rinse vol. for Equipment B =
10 g / mL
= 51.0 L
6
0
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Specific vs non-specific methods:
(1)A non-specific assay may detect a variety of
residues.
(2)A specific assay may quantify any anticipated
residue.
(3)It is essential to correlate the results from a
specific method to the results from other nonspecific methods that might be used for routine
monitoring of cleaning effectiveness.
HPL
C
pH
meter
6
1
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Specific Test Methods
UV/Visible
Spectrophotometry
Near Infrared
Spectrophotometry (NIR)
High Performance Liquid
Chromatography (HPLC)
Mid Infrared
Spectrophotometry (MIR)
Atomic Absorption
Capillary Zone
Electrophoresis
Enzyme Linked
Immunosorbant Assay
(ELISA)
Non-Specific Test Methods
Total Organic Carbon

(TOC)
pH
Titration
Conductivity
Gravimetric
6
2
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
The analytical methods used for testing
cleaning samples must be validated for [ICH
Q2 (R1)]:
Limit of Detection (LOD)
Limit of Quantification (LOQ)
Specificity
Accuracy
Repeatability
Precision
Range
Linearity
Recovery
6
3
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
The analytical method used for evaluation of
cleaning sample is different that used for
product assay.
If the target limit in the analytical sample were
5.2 g / mL, and a method was only able to
detect down to 7.0 g / mL, that method would
not be useful for cleaning validation purposes.
The target value should be within the linearity
range of the specific method.
What if the calculated acceptance value is
less than the detectable level of an
analytical method?
6
There may be two options available.
4
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Choose more efficient analytical
method !
Example:
Derived acceptance limit = NMT 4.0 g / mL
Analytical LOQ
=
5.5 g / mL
Analytical Method
= UV/Visible
Spectrophotometry
New method adopted = Ion mobility
spectrometry
6
5
New LOQ
= 2.0 g / mL
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Increase the sampling area to achieve
at least LOQ value!
Example:
Derived acceptance limit = NMT 4.0 g / mL
Analytical LOQ
=
5.5 g / mL
Swab area
=
25 cm2
Revised swab
area =
25 cm2
5.5 g /
4.0 g /
mL
mL
= 35 cm2 (7 cm 5
cm)
6
6
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Recovery studies :
Procedure :
o Spike coupon with known amount
o Allow to dry
o Remove in swab or simulated rinse procedure
o For swab, desorb
o Analyze sample
o Compare to expected 100% value
This is done at surface acceptance (or below)
limit.
6
7
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Swab recovery schematic :
1. Spike control diluent
directly
Standa
rd
solutio
n
A
g/mL
2a.
Spike
coupon
2b.
Swab
coupon
2c. Extract
swab
Contro
l
B
g/mL
Contro
l
C
g/mL
6
8
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Recovery calculation
Standard):
(Spiked
against
(C g/mL) (mL)
% Recovery =
100
(A g/mL) (mL)
Recovery depends on spiked standard of known
concentration.
Disorbing solvent may be of any volume (mL).
Recovery depends on material surface,
sampling method and some what on analytical
method.
6
9
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Recovery calculation
Positive control) :
(Spiked
against
(C g/mL) (mL)
% Recovery =
100
(B g/mL) (mL)
More useful if defined standard is not readily
available.
Swab recover study with multiple analysts :
Usually 3 replicates by one sampler.
Use lowest value of any one run.
7
0
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Rinse recovery schematic :
Case 1
Pipette with
rinse
solution
(known
volume)
Spiked
coupon
Case 2
Spike
bottom of
SS beaker
Lab sheker
Collection
beaker
7
1
Quality Assurance
CLEANING VALIDATION
ANALYTICAL METHODS
Minimum acceptable recovery:
Specify in cleaning validation master plan or
master protocol.
Minimum swab recovery of 70 % - 80 %.
Minimum rinse recovery of 50 %.
Carry out recovery study for different material
surfaces (Material Of Constructions).
Chose right wetting solvent (soluble) and
absorbent swab material to improve recovery.
May allow <50 % recovery with written
justification.
7
2
Quality Assurance
CLEANING VALIDATION
HOLD TIMES
Cleaning Hold Time
studies
Cleaned
Equipment
Hold Time
(CEHT)
o DEHT = Max. allowed time, between end of
usage and
employing cleaning
o CEHT = Max. allowed time, between end of
cleaning and
further usage
7
Dirty Equipment
Hold Time
(DEHT)
3
Quality Assurance
CLEANING VALIDATION
HOLD TIMES
Dirty equipment hold time study (DEHT) :
Soils may become more difficult to clean over
time.
Maximum DEHT should be in SOPs.
Maximum time shall be set in conjunction with
production.
Representative / worst case product can be
selected for study.
Equipments support wet processing can be
selected.
If extra cleaning is desirable, then it should be
7
in SOP.
4
May be expressed in days but preferably
by Assurance
Quality
CLEANING VALIDATION
HOLD TIMES
Dirty equipment hold time study (DEHT) :
Method
Carry out microbiological sampling at 24 hr., 48
hr., 36 hr., ... from the dirty equipments.
Clean the equipments as per SOPs.
Carry out chemical sampling after cleaning.
Compile all results (chemical and microbial).
Successful results shall standardize the
maximum DEHT.
Failure of any results shall reduce the max.
DEHT followed by another 3 verification runs. 7
5
Quality Assurance
CLEANING VALIDATION
HOLD TIMES
Cleaned equipment hold time study (CEHT) :
Microbiological evaluation is the key focus area.
Maximum CEHT should be in SOPs.
Representative / worst case product can be
selected for study.
Vitamins, nutritional supplements, product
containing Starch or Gelatin may represent
worst cases.
Avoid conducting study on antibiotic or
antimicrobial products.
Three runs at maximum time..safe harbor.
7
Protection during storage of cleaned
6
equipments should be as per SOPs.
Quality Assurance
CLEANING VALIDATION
HOLD TIMES
Cleaned equipment hold time study (CEHT) :
Method
Clean the equipments as per SOPs.
Store under protection (as per routine
procedure).
Carry out microbiological sampling at 24 hr., 48
hr., 36 hr., ...
Verify the results against limit (less than
validation limit).
Successful results shall standardize the
maximum CEHT.
7
7
Failure of any results shall reduce the max.
Quality Assurance
CEHT followed by another 3 verification runs.
CLEANING VALIDATION
HOLD TIMES
Campaign hold study (CHS) :
Cleaning after production of definite number
consecutive batches.
Negotiate with production related to number of
batches.
Simulate max. anticipated hours of campaign
production.
Cumulative deposition of residues may
accelerate product degredation.
Perform cleaning and sampling at the end of
campaign.
Max. CHS (no. of batches + time) should be in 7
8
SOPs.
Quality Assurance
CLEANING VALIDATION....ALL
ASPECTS OF CV
Courtesy: Biopharm
international
7
9
Quality Assurance
CLEANING VALIDATIONUSFDA
483 CITATIONS
Cleaning Parameters
.. cleaning of .. has not been
validated, nor is the spray
temperature, volume or time
defined.
8
0
Quality Assurance
483 CITATIONS
Time of Cleaning
Equipment cleaning is performed on a
clean until clean basis. There has been
no determination of the number of
cleanings required to ensure the
cleanliness of the equipment.
8
1
Quality Assurance
483 CITATIONS
Manual Cleaning
Hands on training for equipment
cleaning operations is not provided and
there is no program in place to assure
cleaning consistency between
operators.
8
2
Quality Assurance
483 CITATIONS
Cleaning Log
There is no assurance that cleaning is
conducted as stated in their
SOPs There are no cleaning logs to
indicate that this has been done.
8
3
Quality Assurance
483 CITATIONS
Poor Cleaning
.. we observed foreign material on
the filter grates.. Daily cleaning as per
SOP..failed to remove the material.
End of process cleaning as per
SOP..failed to remove the material.
Weekly cleaning as per SOPfailed to
remove the material.
8
4
Quality Assurance
483 CITATIONS
Detergent Concentration
Detergent is dispensed into the
Stopper Washer reservoir every third
cycle. No data has been collected to
determine the detergent concentration
each cycle..
8
5
Quality Assurance
483 CITATIONS
Cleaning Agent Labeling

The firms control over IPA 100% used to
clean equipment in production is
inadequate. ..bottles are not
labeled..with date, expiration or who
dispensed, .no scientific
information.which would establish an
expiration date..
8
6
Quality Assurance
483 CITATIONS
Acceptance Limit
.. acceptance criteria.shall not
exceed..g/cm2. There is no data to
justify this limit.
8
7
Quality Assurance
483 CITATIONS
Sampling Locations
Swabbing was performed on general
contact areas without taking into
consideration area such as edges and
crevices.
8
8
Quality Assurance
483 CITATIONS
Sampling Locations
Exact / precise swab locations are not
identified.
8
9
Quality Assurance
483 CITATIONS
Swab Sampling
Swab samples collected..from different
locations from each piece of equipment
are combined into one sample and
tested such.
9
0
Quality Assurance
483 CITATIONS
Rinse Sampling
.firms validation..is inadequate in
that the rinse solutions were not
analyzed for the presence of the
active ingredient residues that might
be present.
9
1
Quality Assurance
483 CITATIONS
Rinse Sampling
There is not an exact sampling procedure
for the collection of rinse water samples
which takes into account the surface area
involved, time of contact.., volume of
rinse, and temperature of rinse, along
with a formula to calculate the amount of
possible contamination based on analysis.
9
2
Quality Assurance
483 CITATIONS
Dirty Equipment Hold Time

No time frames / limitations have been
established for production equipment
from end of use to start cleaning.
9
3
Quality Assurance
483 CITATIONS
Cleaned Equipment Hold Time

A time limit for the length of time
allowed between cleaning and the use
of the manufacturing equipment..has
not been established.
9
4
Quality Assurance
483 CITATIONS
Recovery Studies
Equipment cleaning validation studies
for..did not include..present
recovery studies on rinse samples.
9
5
Quality Assurance
483 CITATIONS
Recovery Studies
..each drugs recovery test was
performed only once, therefore there
is no data to show reproducibility.
9
6
Quality Assurance
483 CITATIONS
Recovery Studies
Your firm is using the average of
recovery results (from different amounts
of spiked solution) instead of the worst
case result. Using a value that
represents the average does not ensure
that contamination is not higher than
calculated.
9
7
Quality Assurance
483 CITATIONS
Change Control
The SOP has been revised twice. No
review was performed to determine if
a re-validation was necessary for the
changes
9
8
Quality Assurance
CLEANING
VALIDATION................................???
Are we missing
anything
Quality Assurance
CLEANING VALIDATION...SOURCES
OF INFORMATION
Guide to Inspections Validation of Cleaning
Processes, Inspection note by FDA (US).
Recommendation on VMP, IQ and OQ, nonsterile process validation and cleaning
validation, (PIC/S).
GMP guide for API, (ICH, Q7).
Guidance on Cleaning Validation, Health
Canada.
Technical sources :
Points to Consider for Cleaning Validation, PDA
29.
10
Points to Consider for Biotechnology Cleaning
0
Sambhujyoti Das, Quality Assurance
Validation, PDA 49
CLEANING VALIDATION

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CLEANING VALIDATION

Know How of an Effective Cleaning

Sambhujyoti Das, Quality Assurance

CLEANING VALIDATION THE

Courtesy: Validated Cleaning Technologies for Pharmaceutical

Courtesy: Validated Cleaning

Courtesy: Validated Cleaning

Same manufacturing equipments being used.

CLEANING VALIDATION..WORST CASE

CLEANING VALIDATION..WORST CASE

(mass / surface area)

Where, SESA = Shared Equipment Surface Area (for both products)

L1 Swab Area (mass / swab)

SRDD value represents the ACTIVE drug

LRDD value represents the mass or volume of

e.g. 250 mg or 20 mL (drug + excipients).

10 mg 150 kg 0.001 1000000

Determination of Surface contamination level

Determination of Swab residue

LD50 Emperical Factor

Where, AAW = average adult weight : 70 kg,

Consider average body weight of child where

In real life cases, therapeutic or 10 PPM

Contact plates (diam. 55 mm),

Spec. limit factor Wt. product

GENERAL SOLID FACILITY

Dissolves & physically

May introduce fibers,

Easy, quick, non-intrusive,

Placebo contacts the same

Courtesy: Validated Cleaning Technologies for Pharmaceutical

The design aspect of the equipment should be

Non-Specific Test Methods

Total Organic Carbon

Cleaning Agent Labeling

Dirty Equipment Hold Time

Cleaned Equipment Hold Time

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