REFERENCE DOCUMENT:

Cleaning Validation A practical

approach by Gil Bismuth and Shosh
Neumann
PDA Journal of Pharmaceutical
Science and Technology
Establishing Scientifically Justified
Acceptance Criteria for Cleaning
Validation of Finished Drug
Products by Desitin A. LeBlanc 2
Objective of Training
To impart the basics and
fundamentals of
Cleaning validation in
general.

3
CLEANING VALIDATION

The validation of cleaning

method is an important
element for both
qualification and process
validation of drug
substance and drug product
manufacturing.
4
Objective:
To attain documented
evidence, which provides a high
degree of assurance that the
Cleaning procedure can
effectively remove residues of a
product and a cleaning agent
from the manufacturing
equipment, to a level that does
not raise patient safety concerns.
5
Advantages of Validation

a. Reduction of quality costs.

b. Assurance of Quality & Safety.
c. Government regulations.
d. Making good business sense.
e. Less down time, fewer batch
failures and may operate / clean
more efficiently.

6
Limitations

a. Cost incurred.
b. People.
c. Delays.
d. Inadequate equipments.

7
 Elements / components
of validation

a. Analytical test procedure.

b. Calibration of instruments.
c. Operator qualification.
d. Equipment qualification.

8
REGULATORY REQUIREMENTS
• As per the FDA, 21 CFR part 211,
subpart D, “Equipments and utensils
shall be cleaned, maintained and
sanitized at appropriate intervals to
prevent malfunctions or
contamination that would alter the
safety, identity, strength, quality or
purity of the drug product beyond
the official or other established
requirement. Written procedures
shall be established and followed for
cleaning”. 9
CLEANING MECHANISMS

• Several basic mechanisms exist to

remove residues from equipment,
including
mechanical action,
dissolution,
detergency and
chemical reaction.

10
CLEANING MECHANISMS
• Mechanical action
refers to physical actions
such as
brushing,

scrubbing and

pressurized water to remove

particulates. 11
CLEANING MECHANISMS
• Dissolution involves dissolving residues
with a suitable solvent.
• The most common and practical solvent
is water because of its advantages:
water is non-toxic,
cheap,
does not leave residues, and
is environment friendly.

12
CLEANING MECHANISMS

However, in some cases it may be

preferable to use a non-aqueous
solvent or a combination of both
aqueous and non-aqueous solvents
due to the solubility characteristics
of the materials.
Alkaline or acidic solvents, for
example, can enhance dissolution
of the materials and could be
advantageous. 13
CLEANING MECHANISMS
• Detergency requires the use of surfactant,
usually in an aqueous system. Detergents
act in four different ways:
wetting agents,
solubilizers,
emulsifiers, and
dispersants.
Usually detergents posses all these
properties which broaden their action.
14
CLEANING MECHANISMS

• Chemical reactions, such as oxidation

and hydrolysis in which the residues
are chemically changed.
Example: Sodium Hypochloride

• During cleaning validation, the

effectiveness of these mechanisms
must be challenged and checked as a
whole in the cleaning procedure.
15
CLEANING PROCEDURE
(SOP)
Standard Operating Procedure (SOP)
should be required duly approved by
approving authority and it should
specify the following:
1. Precautions and safety warning.
2. Cleaning tools and materials with
their name, concentration, their
dilution instruction, volume
requirement, storage period and
requirements. 16
CLEANING PROCEDURE (SOP)
3. Time limitations:
a. time between end of
manufacturing and start of
cleaning.
b. time between final rinse and
drying.
c. frequency of major cleaning for
mfg. batches of the same product in
campaign.
d. time until additional cleaning is
performed for unused clean
equipment. 17
CLEANING PROCEDURE (SOP)
4. Cleaning level:
MINOR  between two batches of same
product or between different strengths
(inter convertible formula) of the same
product. For minor cleaning, cleaning
validation is not required, since cross
contamination is not an issue.
MAJOR  between two products.
In this case, validation of the effectiveness
of the cleaning procedure in removing
residues to the required level is mandatory.
18
CLEANING PROCEDURE (SOP)
5. Cleaning procedure covers following
steps…
Dismantling, Initial washing, Final
washing & Parameters such as
Time,
Temperature,
Volume,
Flow rate etc. should be
mentioned. 19
CLEANING PROCEDURE (SOP)
6. Drying :
is very important to prevent
microbiological proliferation. Sometimes
the final rinse is conducted with hot
purified water to facilitate evaporation
of the water. Drying time and
temperature should defined.
7. Visual inspection :
No traces or particles visible to
the
naked eye should be
observed after the cleaning. 20
CLEANING PROCEDURES
8. Cleaned status has to be indicated by
putting a label or a card on the clean
equipment.

9. Storage place of cleaned equipment /

utensils with proper wrapping &
instructions clearly mentioned.

10. Cleaning log should be maintained.

21
THE CLEANING VALIDATION
PROGRAMME
1. Selection of cleaning method
2. Selecting the Scientific basis for the
contamination limit
3. Selecting the Worst case related to the
equipment
4. Selecting the Worst case related to the
product
5. Establishing the storage period after
cleaning.
6. Selecting the sampling method
7. Selecting the analytical method
8. Documentation 22
1. SELECTION OF CLEANING METHOD
A. CLEAN-IN-PLACE ( CIP ) METHOD
v Cleaning of the equipment is performed in
place without disassembling
v Cleaning process may be controlled manually or
by an automated program.
v Very consistent and reproducible cleaning
method.
v Can be validated readily.
v Being a closed system visual inspection of all
components is difficult.
23
1. SELECTION OF CLEANING METHOD
B. CLEAN-OUT-OF-PLACE (COP)
METHOD
v Cleaning of disassembled equipment is
performed in a central washing machine.
v The washing machine also requires
validation such as the temperature,
ultrasonic activity, cycle time, cleaning
operation sequence, detergent quantity
dispensed etc.
24
1. SELECTION OF CLEANING METHOD

C. MANUAL CLEANING METHOD

v Difficult to validate
v Most extensive and elaborate cleaning
procedures are required.
v A high quality and extensive training
program is required.

25
1. SELECTION OF CLEANING METHOD
Torrent Pharmaceuticals Limited have designed
the facility with manual cleaning operations.
Following were taken into consideration for
selecting manual cleaning method.
§ “Seeing is Believing”
§ Product diversity / range
§ Risk of failure of cleaning equipments
§ Validation of automated cleaning equipments
§ Trained and experienced working staff

26
1. SELECTION OF CLEANING METHOD
• The equipment design and manual cleaning method are
taken into consideration for selection of equipment. All
equipments selected viewing following cleaning
considerations:
§ Ease of disassembling of contact parts
§ All contact surfaces are non-reactive to cleaning
method
§ Dedicated disposable materials where difficult to clean
e.g. FBD bags, filters, Disposable bags in transit
containers
Least chance of contamination from equipment non-
contact parts e.g. lubricants, gaskets, drive system,
mechanical seal etc.
27
1. SELECTION OF CLEANING METHOD
The risk involved in manual cleaning
processes is taken care of with following:
§ Proper washroom design with drying,
protection and storage requirement.
§ Detailed cleaning SOP
§ Training of cleaning operators

28
2. SELECTING THE SCIENTIFIC BASIS FOR THE
CONTAMINATION LIMIT
• Limit calculation is done on the basis of
smallest therapeutic dose:
Factors such as the batch size of the
next product, the route of administration,
and the largest daily dose of subsequent
product, which might be administered, are
important in the calculation.
All of these factors mentioned
previously are usually summarized in an
equation, which may take the following
general form:
29
2. SELECTING THE SCIENTIFIC BASIS FOR
THE CONTAMINATION LIMIT
MAR = TD x BS x SF
LDD
Where, MAR = the max. allowable Residue
TD = Smallest therapeutic dose amongst all
products.
BS = Batch size of the next product to be
manufactured
in the same equipment, which has the least
value
of BS/LDD within the group, is taken
SF = The safety factor
LDD = The largest daily dose amongst the next
product
to be manufactured in the same equipment.
30
 SAFETY FACTOR
Normally accepted Safety Factor for
different dosage forms are given in the
following table:

Dosage Form Safety Factor

• Research compound 1/100000 – 1/10000
• Parentral products 1/10000-1/5000
• Ophthalmic products 1/5000
• Oral dosage forms 1/1000
• Topical products 1/100-1/10
31
2. SELECTING THE SCIENTIFIC
BASIS FOR THE CONTAMINATION
LIMIT
• Contamination Limit Based on Other
Considerations:
 Not Detectable  This type of limit refers to
a specific analytical method.
 Absolute Limit  An absolute limit also
termed “single limit” or “blanket
specification” means that the same limit is
set for any product, without consideration to
toxicological data or to the detection level of
the analytical method, and is usually
expressed in parts per million (ppm)

32
2. SELECTING THE SCIENTIFIC
BASIS FOR THE CONTAMINATION
LIMIT

• Acceptance Criterion based on Visual

Inspection:

The visual detection limits of most

active ingredients is approximately
4g / cm2

33
2. SELECTING THE SCIENTIFIC
BASIS FOR THE CONTAMINATION
LIMIT
THE APPROACH TAKEN
Dose related contamination limit shall be
determined.
If this limit is more than 10 ppm, then a value
of less than 10 ppm shall be the acceptance
limit.
Samples for testing the residue shall be
taken only if the equipment surface is
visually clean.
34
MAR LIMIT IN PPM
To determine the MAR in ppm would be =
MAR limit in milligram .
B. Size of subsequent product in kg
If this calculation gives a value more than
10 ppm, equivalent value of 10 ppm in
milligram has to be calculated, this would
be …….
10 x MAR limit in subsequent batch in units of
milligram
MAR limit in subsequent batch in units of ppm
35
MAR LIMIT CALCULATION

Following is the relevant data for calculation.

 Previous Product :
 Active ingredient : Alprazolam.
 Strength / tablet : 0.25 mg.
 Minimum Dose / day : 1 tablet.
 Next product tablet.
 Average weight of tablet : 742 mg.
 Maximum dose /day : 9 tablets.
 Batch Size of T 500 tablet : 48.23 kg.

36
MAR LIMIT CALCULATION
MAR = TD x BS x SF
LDD
TD = Therapeutic Dose of tablet
= 1 x 0.25 mg = 0.25 mg
BS = Batch Size of tablet = 48.23 kg
SF = Safety Factor for Tablet dosage form
= 1/1000
LDD = Largest Daily dose of tablet
= 9 x 742 mg = 6678 mg

37
 MAR LIMIT CALCULATION

• MAR = 0.25 x 48.23 x 1000 x 1000 / 6678 x

1000 = 1.8 mg.
• Therefore, 1.8 mg of Alprazolam in 48.23 kg of
tablet is the MAR limit.
• This, in units of ppm, is equivalent to
1.8 mg / 48.23 kg = 0.0373 ppm.
• Since the value of 0.0373 is less than the 10-
ppm criteria, 1.8 mg is considered as the
acceptance criteria.
38
3. SELECTING THE WORST CASE
RELATED TO THE EQUIPMENT

• Identical, interchangeable piece of

equipment with the same cleaning
procedure can be grouped together.
• Equipment with the same operating
principle and the same cleaning
procedure, but with different product
contact surface area, can be grouped,
if they can be interchanged.
39
3. SELECTING THE WORST CASE
RELATED TO THE EQUIPMENT

• The worst case for a group of

equipment is represented by the
equipment with the larger product
contact surface and the hardest-to-
clean locations.

40
4. SELECTING THE WORST CASE
RELATED TO THE PRODUCT:

Only one product out of a group of

product processed in a piece of
equipment is selected for the
cleaning validation study, based on
the lowest solubility of the active
ingredient and its therapeutic dose.

41
4. SELECTING THE WORST CASE
RELATED TO THE PRODUCT:

• To arrive at the worst case

equipment and worst case product
we need Equipment Database and
Product Database.

42
5. ESTABLISHING THE STORAGE
PERIOD AFTER CLEANING
The objective for establishing time
limit between equipment cleaning and
reuse is to ensure that the equipment
remains clean till the next use. This
needs demonstration that there is no
microbial proliferation in cleaned
equipments during storage.

43
5. ESTABLISHING THE STORAGE
PERIOD AFTER CLEANING
For establishing the time limit, the
equipment should be dried. Initial swab
samples for surface should be taken.
Thereafter, the equipment should be
protected as prescribed in the SOP and
stored in its designated area. Periodic
samples of product contact surface for
microbiological contamination should be
taken. (1st day, 2nd day, 3rd day etc.)
Based on the data generated establish
the acceptable time limit.
44
 5. ESTABLISHING THE STORAGE
PERIOD AFTER CLEANING
• Cleaned equipment surface sample (contact
surface only) test results should demonstrate
absence of specified micro organisms (E.
Coli, Salmonella etc.)
• The acceptance level for surface sampling is
25CFU per 25 sq. cm.
• Representative colonies of the
microorganisms isolated should be identified
in order to build a plant microbial flora
baseline with the aim of locating and
eliminating potential contamination sources. 45
6. SELECTING THE SAMPLING METHOD
The two main sampling methods are:
1. Swab sampling.
2. Rinse sampling.

46
6. SELECTING THE SAMPLING METHOD
6.1 Swab sampling method
• This method is based on the physical removal
of residue left over on a piece of equipment
after it has been cleaned and dried. A swab
wetted with a solvent is rubbed over a
previously determined sample surface area to
remove any potential residue, and thereafter
extracted into a known volume of solvent in
which the contaminant active ingredient
residue is soluble. The amount of contaminant
per swab is then determined by an analytical
method of adequate sensitivity.
47
6. SELECTING THE SAMPLING METHOD
Advantages of swab sampling method.
• Direct evaluation of surface contamination.
• Insoluble or poorly soluble substances may be
physically removed from the equipment
surfaces.
• Hard-to-clean but accessible areas are easily
incorporated into the final evaluation.
Disadvantages of swab sampling method.
• Difficult to implement in large-scale
manufacturing equipment.
• Extrapolation of results obtained for a small
sample surface area to the whole product
contact surface area.
48
6. SELECTING THE SAMPLING METHOD
6.2 Rinse sampling method
• This method is based on the
analytical determination of a sample
of the last rinsing solvent (generally
water) used in the cleaning
procedure. The volume of solvent
used for the last rinse must be
known to allow for the quantitative
determination of the contamination.
49
6. SELECTING THE SAMPLING METHOD
Advantages of Rinse sample method.
• Ease of sampling.
• Evaluation of entire product contact surface.
• Accessibility of all equipment parts to the rinsing
solvent.
• Best fitted to sealed or large scale equipment and
equipment which is not easily or routinely
disassembled.
Disadvantages of Rinse sample method.
• No physical removal of the contaminant.
• The rinsing solvent may not reach inaccessible part
of equipment.
• Use of organic solvents for water insoluble
materials. 50
6.SELECTING THE SAMPLING METHOD
Looking at the advantages and
disadvantages of both the sampling
methods swab sampling method
was selected. The cleaning
procedure uses water as a solvent
and we have dosage forms having
active ingredient which is insoluble
in water.
51
SAMPLING LOCATIONS & NUMBER
OF SAMPLES
The sample locations are dictated by
worst-case conditions. The
equipment’s hard to clean locations
are identified based on cleaning
experience and the design of
equipment. The number of samples
should take into consideration the
equipment surface area, design,
shape, operating principle and
construction material. 52
SAMPLING LOCATIONS & NUMBER
OF SAMPLES

53
 SAMPLE SURFACE AREA

Sample surface areas usually vary from 25

sq.cm to 100 sq.cm. The swab area chosen
is 100 sq.cm.

SWAB RECOVERY STUDY

A swab recovery study is performed to
determine the ability of the swab to
quantitatively remove the contaminant
from the surface sampled.
The swab taken is Whatman– Carbon free
paper. 54
7. SELECTING THE ANALYTICAL
METHOD
• The Basic Requirements for the Analytical
Method.
1. The sensitivity of the method shall be appropriate
to the calculated contamination limit.
2. The method shall be practical and rapid, and, as
much as possible use instrumentation existing in
the company.
3. The method shall be validated in accordance with
ICH, USP and EP requirements.
4. The analytical development shall include a
recovery study to challenge the sampling and
testing methods.
55
7. SELECTING THE ANALYTICAL
METHOD
• SPECIFIC METHODS
 Chromatographic methods such as LC/MS,
GC/MS, and HPLC
 Thin layer chromatography
 Specific ion meter
Of the above methods, chromatography
methods are the methods of choice, as
they separate analytes, are highly
specific, highly sensitive, and
quantitative. But the methods are costly
and time consuming.
56
7. SELECTING THE ANALYTICAL
METHOD

The chromatography method

(HPLC) was selected for cleaning
validation studies because of
their sensitivity, specificity, and
ability to quantify. The method
should be validated.

57
7. SELECTING THE ANALYTICAL
METHOD

• NON-SPECIFIC METHODS.
 Spectrophotometric methods in the
visible, infrared, or UV ranges
 Total organic carbon (TOC)
 Other Methods
For monitoring cleaning procedure
TOC method is used. It offers at a
moderate cost and in addition to its
rapidity, a detection capability down to
the ppb range.
58
8. DOCUMENTATION
• Validation Master Plan
• Technical Transfer Information
such as solubility of product ingredients,
therapeutic dose, equipments to be used and
its contact surface area, batch size, minimum
daily dose, maximum daily dose etc for the
preparation of Equipment Matrix &
Product Matrix.
• Equipment Qualification Reports
(DQ/IQ/OQ/PQ)

59
8. DOCUMENTATION

• Equipment logs
• Training records
• Method validation of analytical test
method.
• Cleaning Validation Protocol
• Cleaning Validation Reports

60
 8. DOCUMENTATION

Cleaning Validation Protocol contains:

Protocol pre-approvals
Objective of the validation process.
Scope
Responsibility for performing & approving
validation study.
Product details
Acceptance criteria
61
8. DOCUMENTATION
Cleaning procedure (Ref. SOP) for each
equipment.
Sampling location for chemical and microbial
testing
Sampling procedure and sampling plan for
chemical and microbial testing.
Verification and Revalidation criteria.
Sampling location – Diagrammatic
Test data slip for chemical and microbial
analysis.
62
8. DOCUMENTATION

Summary report contains

Summary Report approval.
Equipments used
Study performed ( Including recovery studies where
appropriate. Analytical Methods including the limit of
detection and limit of quantitation of those methods.)
Acceptance criteria
Observation and Results
Evaluation
Conclusion and recommendation

63
At least three consecutive applications of
the cleaning procedure should be
performed and shown to be successful in
order to prove that the method is
validated.

It is usually not considered acceptable to

“test until clean”.

64
The validation of cleaning method is
only meaningful if the written
cleaning procedures (on which the
validation is based) are always
meticulously followed.

65
Thanks

66