Cleaning validation is the process of validating cleaning methods to ensure equipment is cleaned adequately between product batches. It aims to remove residues from previous products and prevent cross-contamination. The document discusses cleaning validation requirements like protocols, teams, equipment selection, sampling plans and acceptance criteria. It also explains the steps of cleaning validation including cleaning methods, direct swab sampling to collect residue samples, and testing samples against acceptance limits. Regulatory agencies require documented cleaning validation evidence to ensure product quality and safety.

1. Cleaning Validation In Pharmaceutical Industry
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10 April 2022

2. Cleaning Validation
Page 2
"Cleaning validation is a process that is gaining
more & more attention day by day in the
pharmaceutical industries. The reason behind its
highest demand is that most of the regulatory
bodies are now strict on the process of cleaning
validation.
Cleaning validation is the process of validating the
cleaning method or process so first have a look at
what is cleaning?"

3. What is Cleaning?
Page 3
The process of removal of residues of previous
products from any equipment used for
manufacturing/packaging or area is known as
cleaning.
Cleaning we do for the contaminants and will have
a look of contaminant types in the next slide

4. How many types of contaminants?
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 API Of Previous Product
 Excipients Of Previous Product
 Microbes
 Airborne Particles
 Residues Of Detergents
If all the steps and processes involved in cleaning are
written and documented, it is known as cleaning method
validation.

5. What Is Cleaning Validation?
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Cleaning validation is a process that ensures that the
method or process used for cleaning is so accurate that it
removes not only residues of previous product, APIs &
excipients but also removes microbes, chemicals &
residues of the detergent up to defined limits.
Cleaning Validation is documented evidence that gives us
a strong assurance that the process which we are using
to clean equipment, parts, utensils or an area will -

6. What Is Cleaning Validation?
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-produce a predetermined level of cleanliness by
removing the residues of previous product, microbes and
detergents.
The process of cleaning is documented and validated to
prevent cross-contamination of manufactured products
from carryover of the previous product, microbes,
chemicals or detergents.

7. Theme / Principle Of Cleaning Validation
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The theme or basic principle of cleaning validation is as
follows:
To give assurance that the performed cleaning activity is
done in such a way that it removes all carryover or
residues of previous product, microbes or detergents or
all above mentioned are removed up to the acceptance
criteria.

8. Cleaning Validation Explanation By Simple Example
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 Cleaning validation is used to ensure that the cleaning procedure
used is accurate to remove the contaminants
 It can easily be explained by the example of Building Construction
& its inspection process to award the clearance certificate.
 For large buildings when the construction is completed it is
inspected by the inspection bodies to ensure that the contractor
built it by following all the required measures and it is completely
suitable to use or live in.
 The inspectors may take some samples of concrete and marbles to
ensure that the high-quality material is used during building
construction.
 On surety of all the required parameters, the building is awarded
the license or certificate to use and live.

9. Cleaning Validation Explanation By Simple Example
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 In the same way, any equipment in the pharmaceutical industry
cleaned by the designated staff is then inspected by the inspection
body to cross-check that the cleaning procedure used is adequate
to ful-fill the regulatory requirement.
 The inspectors collect the samples from the surface of cleaned
equipment and test it in the Quality Control Department to
ensure that the required level of cleanliness is achieved.
 If the results of samples meet the requirements then it is said that
the method used for cleaning is validated and it can be used with
confidence.

10. Importance Of Cleaning Validation
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Cleaning validation importance in pharmaceutical industries can be
described by some following key points:
 Cleaning validation protocols ful-fill the regulatory requirements.
 Cleaning validation provides a high level of assurance that by using
the written procedure we can achieve the same level of cleanliness
all the time.
 The cleaning validation method assures that there are no chances
of cross-contamination.
 Cleaning Validation gives surety that microbial growth is
prevented.
 With proper cleaning, equipment life is increased & downtimes are
reduced.
 Product quality is improved.

11. Cleaning Validation Requirements
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A common question is how a cleaning validation is started? or what
are the requirements for cleaning validation in pharmaceutical
industries?
Following are the main requirements:
a. Cleaning validation protocol
b. Validation team
c. Equipment selection.
d. Cleaning Method
e. Sampling plan
f. Acceptance plan

12. Cleaning Validation Requirements
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A common question is how a cleaning validation is started? or what
are the requirements for cleaning validation in pharmaceutical
industries?
Following are the main requirements:
a. Cleaning validation protocol:
 For any cleaning validation process, first of all, a protocol is
prepared.
 Cleaning validation protocol is a basic document like BMR or Batch
Manufacturing Record.
 As we know that in BMR every step is mentioned which guides us
on how a batch is manufactured.
 In the same way, the cleaning validation protocol includes all the
details regarding how the cleaning validation will be performed.

13. Cleaning Validation Requirements
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A common question is how a cleaning validation is started? or what
are the requirements for cleaning validation in pharmaceutical
industries?
Following are the main requirements:
a. Cleaning validation protocol:
 Cleaning validation protocol also includes information regarding the
following:
 Cleaning Method Used, Amount Of water/solvent Used, Type Of
detergent, Cleaning Type, Sampling Type, Sample Size,
Analytical Method Used & Acceptance criteria

14. Cleaning Validation Requirements
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A common question is how a cleaning validation is started? or what
are the requirements for cleaning validation in pharmaceutical
industries?
Following are the main requirements:
b. Validation Team:
 For performing cleaning validation a team is established & the roles
of each individual or department are defined:
Team Structure
The structure of the validation team may vary pharma to pharma but
a basic team may consist of all the related departments.
The personnel or team involved in cleaning process validation should
be trained regarding all the cleaning steps and must be aware of the
cleaning protocols

15. Cleaning Validation Requirements
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A common question is how a cleaning validation is started? or what
are the requirements for cleaning validation in pharmaceutical
industries?
Following are the main requirements:
c. Equipment Selection:
 The equipment for which cleaning validation is to be performed is
checked critically to establish how to clean
 The parts of equipment which are in direct contact with the product
are selected for cleaning validation.
 The parts or locations of the equipment which are difficult to clean
are highlighted to ensure proper cleaning & sampling.

16. Cleaning Validation Requirements
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A common question is how a cleaning validation is started? or what
are the requirements for cleaning validation in pharmaceutical
industries?
Following are the main requirements:
d. Type Of detergent:
 The detergent used for cleaning validation should be selected
carefully and those which are easily removed by rinsing are
encouraged.
 Before using any detergent its composition should be known and
acceptance criteria should be given to calculate the results.

17. Cleaning Validation Requirements
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A common question is how a cleaning validation is started? or what
are the requirements for cleaning validation in pharmaceutical
industries?
Following are the main requirements:
e. Sampling Plan:
 The Sampling plays an important role during cleaning validation
and the sampling plan should carefully be defined, meaning how to
take samples i.e direct sampling or indirect sampling.

18. Cleaning Validation Requirements
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A common question is how a cleaning validation is started? or what
are the requirements for cleaning validation in pharmaceutical
industries?
Following are the main requirements:
e. Acceptance Criteria:
 The Before starting the cleaning validation the acceptance criteria
or acceptance limit should be defined based on the product
properties and size of equipment used.
 Here swab limits and rinse samples limits are defined and our
cleaning results should comply with the defined limits.

19. When Should Cleaning Validation be Performed?
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Cleaning validation is generally performed in the following
circumstances:
 Cleaning Validation is performed first time during qualification or
validation of the manufacturing process
 When we make any critical change in the cleaning process.
 When there is a critical change in formulation.
 Cleaning validation is also performed when there is a change in
Equipment.
 When there is any modification or change of cleaning agent.

20. FDA Guidelines For Cleaning Validation
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21. Reference:
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US-FDA or U.S Food and Drug Administration describes guidelines for
cleaning validation in 21 CFR section 211.67.(21 CFR cleaning validation)
Section 211.67 (A) states that,
Equipment & utensils should be cleaned, maintained as recommended for
the nature of the drug, sanitized / sterilized at suitable intervals to prevent
contamination which would alter the safety, identity, strength, quality of
the drug beyond the official or other established requirements.
Section 211.67 (B) states that
Written methods should be developed and followed for cleaning &
maintenance of equipment and utensils used in manufacturing,
processing,
packaging and holding of drug products.
APIC Guidance on Cleaning Validation
Guidelines
on
Cleaning
Validation

22. Steps of Cleaning validation in the Industry:
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For basic and easy understanding the cleaning validation after the
above-mentioned requirements is divided into the following steps:
Step-1: Cleaning
Step-2: Sampling
Step-3: Testing/Analysis
Step-4: Acceptance Criteria

23. Step-1: Cleaning
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Following are main types of cleaning which are used in pharmaceutical
industries for the cleaning of equipment:
1. Manual Cleaning
2. Cleaning In Place (CIP)
3. Cleaning Out Of place
4. Immersion cleaning Method
5. Ultrasonic Cleaning

24. Step-1: Cleaning
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Following are main types of cleaning which are used in pharmaceutical
industries for the cleaning of equipment:
1. Manual Cleaning
As the name indicates it is the most traditional type of cleaning
performed by hands. It is usually the most difficult method to validate
due to person to person variation.
This cleaning method consists of the following main steps like:
 Wiping with water/solvent
 Brushing or scrubbing
 Thorough Cleaning With Detergent
 Rinsing with water/solvent
 Disinfection

25. Step-1: Cleaning
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Following are main types of cleaning which are used in pharmaceutical
industries for the cleaning of equipment:
2. Cleaning in place (CIP)
Cleaning in place is also known as CIP and it is the automated type of
cleaning. In the CIP method following are commonly used
 Fixed or Rotating Spray Balls
 Washing Tank
 Recirculating Pump
 Detergent Tank
 Piping’s
In this type of cleaning the inputs are given and all the parameters like water
quantity, water pressure, amount of detergent and drying time remain constant
or fixed during all the cleaning process of a specific equipment.

26. Step-1: Cleaning
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Following are main types of cleaning which are used in pharmaceutical
industries for the cleaning of equipment:
3. Cleaning out of place
As the name indicates this cleaning is not done at the equipment
place, here parts removed are washed and dried outside the area in a
specific place using cabinets or tunnels.
4. Immersion Cleaning Method
In the immersion cleaning method, the equipment to be cleaned is
dipped in the cleaning agent to achieve the required level of cleaning.
5. Ultrasonic washing
This type of cleaning is done using ultrasonic waves to ensure proper cleaning.

27. Step-1: Cleaning
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Bracketing Method In Cleaning Validation
To perform Cleaning validation for all the products is not possible
because it will require a lot of time and money for testing so we decide
the cleaning validation for a product based on bracketing or matrix
approach.
Bracketing Approach
In the bracketing approach, we select only one drug from many which
are manufactured using the same equipment, procedures and may
have the same class of excipients.
Worst Case Scenario In Cleaning Validation
We select the one product based on the Worst Case Scenario. Worst
worst-case is also known as 'difficult to clean' and product for the
worst case is selected on the following basis.

28. Step-1: Cleaning
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Worst Case Scenario In Cleaning Validation
Following basis:
The least soluble drug product manufactured on the equipment.
Most toxic drug product
A product having a low therapeutic daily dose
Higher concentration of API
Color Product

29. Step-2: Sampling
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Sampling means to take samples after cleaning of equipment which is
used for manufacturing or packaging.
The samples are collected from the cleaned equipment and then these
samples are analyzed for acceptance criteria.
Types Of Sampling Method
The sampling method used for cleaning validation in pharma may be of
two types:
I. Direct Sampling Method / Swab Sampling Procedure
II. Indirect Sampling Method
Direct Sampling Method / Swab Sampling Procedure
In the direct sampling method, the surface Swab sampling procedure is
used. The swab is usually a sterile cotton bud-like structure that is
physically rubbed over the hotspots or defined places of the equipment.

30. Step-2: Sampling
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Direct Sampling Method / Swab Sampling Procedure
Swab Recovery Method
The swab recovery method is the procedure that is used to recover the
residues or carryovers from the swab bud into the solvent and then it is
analyzed to calculate whether it is within limits or not.
Validated Swab Recovery
The swab recovery method used for a specific worse case drug product
is validated to ensure that the residues are dissolved or recovered from
the solvent or not.

31. Step-2: Sampling
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Direct Sampling Method / Swab Sampling Procedure
During establishing a validated swab recovery method we check the
following,
Is the solvent used, properly recover the residues or not?
The swabbing procedure used is accurate or not.
Procedure
Take swab needles or swab sticks (usually 2) according to the
requirements (surface area) and dip them into a flask
containing the solvent.
The solvent is selected according to the solubility of the worst-case drug.

32. Step-2: Sampling
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Direct Sampling Method / Swab Sampling Procedure
The swab needles are pressed along the walls of the flask to remove
excess solvent.
The swab needles are then placed in covers or vials and are closed.
The swab needles are then delivered to the production or packaging area
where the equipment or part is to be sampled.
As we are validating the method, the worst-case selected drug samples
are randomly applied at the surface of equipment
above & below the acceptance criteria to calculate acceptance limits for
swab samples.
The constant surface area is required for calculations so a constant area
is sampled with a swab.

33. Step-2: Sampling
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Direct Sampling Method / Swab Sampling Procedure
To ensure the constant area for swab the plates of SS 316L are used.
Usually, a 10cm×10cm plate is used so the total surface area is 100cm².
Place a 10cm×10cm plate on the equipment surface containing applied
residues.
The swab stick is removed from the cover & and is rubbed inside the
area of the plate from right to left or left to
right.
Rotate the swab stick face and rub it from up to down side within the
same surface area.

34. Step-2: Sampling
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Direct Sampling Method / Swab Sampling Procedure
One or two swab sticks can be used depending upon the validated
method
All the swab sticks are placed in covers & are delivered to the Validation
department for testing.
The swabs are removed from the cover and heads or buds of the swab
sticks are cut with a sterile cutter and are dipped
inside the same solvent vessel which was previously used.
These swab bulbs or buds are stirred in the extraction solvent for some
time and later are removed.

35. Step-2: Sampling
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Direct Sampling Method / Swab Sampling Procedure
The solvent is then analyzed by using specified testing methods to
calculate the acceptance criteria.
If analysis gives required results then it indicates that the method is
validated and if not then the solvent used or swab procedure can be
changed & again validation is done to establish a proper acceptance
criteria.
Actual Swab Sampling during Cleaning Validation / Swab Sample
Collection
For most cases the surface of the equipment may not be smooth and it
may be difficult to take swab samples in pharma
from 100cm².

36. Step-2: Sampling
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Direct Sampling Method / Swab Sampling Procedure
It may be the case where surfaces are difficult to reach so here the area
taken is calculated and adjustments are made for acceptance criteria
according to the validated sampled area.
Cautions while swab sampling:
During Swab sampling, rub swab stick only in one direction and don't
rub the swab stick back and forth.
Immediately after taking swab samples, place the swab stick in the
cover and close it.

37. Step-2: Sampling
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Direct Sampling Method / Swab Sampling Procedure
Advantages Of direct Sampling:
Following are some main advantages of swab or direct method of
sampling:
Samples can easily be taken from places that are difficult to clean and
are accessible.
If the residue is insoluble in the cleaning solvent then it can be physically
removed by swab and then tested.
This method is also suitable for taking samples of the material which is
dried out on the equipment surface.

38. Step-2: Sampling
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Indirect Sampling Method / Rinse Sampling Technique:
Following are some main advantages of swab or direct method of
sampling:
The indirect method of sampling in cleaning validation is also known as
the rinse sampling technique or rinse sampling method in pharma.
In this method the equipment is rinsed with water or solvent and then
this sample is tested for acceptance criteria.
During the rinse sampling technique used in pharmaceutical industries,
the samples of water or solvent are taken after final cleaning and are
analyzed by the method specified in the validation protocol.

39. Step-2: Sampling
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Indirect Sampling Method / Rinse Sampling Technique:
In the rinse sampling technique, the amount of water used for rinsing
samples and the time of rinsing is also measured.
Advantages:
The advantage of this indirect method of sampling in cleaning validation
is that a large surface area can be analyzed.
This method is also used for the places to take samples that are not
accessible for swab samples.
Note:
1) One important point to remember before sampling either by the swab
or rinse method is that, first of all, organoleptic senses are used.

40. Step-2: Sampling
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Indirect Sampling Method / Rinse Sampling Technique:
Note:
2) It Means visual inspection & checking the equipment for smell or
odor.
3) If the equipment is visually not cleaned or there is some type of smell
or odor it means the method used for cleaning was not accurate so first
ensure accurate cleaning.

41. Step-3: Testing
Page 41
For testing or analysis, two types of methods are used,
1) Specific Method
2) Non-Specific Method
Specific Method
For accurate testing of toxic contaminants, the specified method is used
and it involves following:
 LC method like HPLC/GC/LC-MS/LC-MS/MS
 Flame Photometry
 Titration
 Ion Selective Electrode
 UV spectrometry
 Enzyme Detection

42. Step-3: Testing
Page 42
For testing or analysis, two types of methods are used,
1) Specific Method
2) Non-Specific Method
Non-Specific Method
It involves following:
 pH
 Conductivity
 Total Organic Carbon (TOC)

43. Step-4: Acceptance Criteria
Page 43
Acceptance criteria are calculations that we have done and established
during method validation and then during cleaning validation, the results
are compared.
Acceptance criteria can be established by following three methods:
 Visual Inspection
 Dose Percent
 Parts Per Million
Visual Inspection:
Acceptance criteria for cleaning validation by visual inspection is that
there should be no visible contamination on the equipment or area.
Note: Visual Inspector Challenge test is mandatory

44. Step-4: Acceptance Criteria
Page 44
Dose Percent
Not more than 0.1% of the normal therapeutic dose of one product
should appear in the maximum daily dose of subsequent products.
Usually this criteria will be applied for lot to lot cleaning of same stage of
same product for degradable products…
Parts Per Million
Not more than 10 parts per million (ppm) of one product will appear or
occur in another product.
Acceptance criteria should have the following properties:
 Achievable
 Practical
 Verifiable
 Scientifically Sound

45. Step-4: Acceptance Criteria
Page 45
Calculations Of Acceptance Criteria
Main important point to keep in mind is that acceptance criteria
calculations are made before starting the cleaning validation as we
discussed earlier & actual results are compared with these values.
Based On Therapeutic Daily Dose
This method of calculation is used when we have the value of TDD or
therapeutic daily dose /Health based limits like ADE or PDE or LD50 else
the general criteria of NMT 10ppm whichever comes less
It is commonly used during final product changeover or cleaning.
Principle: The basic principle of this calculation is that the standard
therapeutic daily dose of the contaminated product(next,)
may be contaminated by not more than a specific proportion, usually
1/1000 of the therapeutic daily dose of the drug substance which is
under investigation(previous) in cleaning validation.

46. Step-4: Acceptance Criteria
Page 46
MACO Method In Cleaning Validation
To establish a method for allowable carryover also known as Maximum
Allowable carryover (MACO) use the following formula,
MACO = TDD(previous) × MBS
SF × TDD(next)
MACO = Maximum Allowable carryover (It is the acceptable transferred amount from the
previous product)
TDD(previous) = Standard therapeutic daily dose of the investigated product in the same
dosage form.
MBS = Minimum size of Batch (Of the Next product)
TDD(next) = Standard therapeutic daily dose of the next product.
SF = Safety Factor (Usually 1000 is used)

47. Step-4: Acceptance Criteria
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MACO = TDD(previous) × MBS
SF × TDD(next)
Example
In the pharmaceutical industry, Product A was manufactured having
TDD of 15 mg with a batch size of 150 kilograms.
Cleaning was done for product B having TDD of 300 mg with a batch size
of 60 kilograms.
Both are tablet products and the safety factor is 1000.
Calculate Maximum Allowable carryover (MACO) for Product A In Product
B
Now put values according to the statement
MACO = 15(mg) × 60,000,000(mg)
1000 × 300 (mg)
After calculation, the answer is 3000 mg or 3 grams.

48. Step-4: Acceptance Criteria
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Based On Toxicological Data
During the situation where the therapeutic daily dose is not given then in
those circumstances, the toxicity data are used to calculate the MACO.
This method is used for following:
 Detergents
 Intermediates
The calculation method used is known as NOEL
No Observable Effect Level (NOEL)
No Observable Effect Level or NOEL method is also used to calculate the
MACO but first, we have to calculate the NOEL by using lethal dose as
follows:
NOEL = LD⁵⁰(g/kg) 70(kG person)
2000

49. Step-4: Acceptance Criteria
Page 49
Using the NOEL value the MACO can be calculated from the following
equation:
MACO = NOEL × MBS
SF × TDD(next)
MACO= This term represents Maximum Allowable Carryover.
NOEL= No Observed Effect Level
LD⁵⁰ = Lethal dose 50 g/kg
70kg = Weight Of An Average Adult
2000 = Empirical Constant
TDD(next) = Largest Normal daily dose for Next Product
MBS = Minimum size of Batch (Of the Next product)
SF= Safety Factor

50. Step-4: Acceptance Criteria
Page 50
Safety factor 200 is used when API is taken Orally & it varies depending
on the dosage form.
Safety Factor for Topical = 10-100
Safety Factor for Oral Products = 100-1000
Safety Factor for Parenterals = 1000-10,000
Limits For Swab
If we assume a homogeneous distribution then a general recommended
value can be set for swabs content.
It is used for the preparation of method of analysis & limit of detection.
For whole equipment, the target value can be set using the following
equation:
Target Value(ug/dm²) = MACO(ug)
Total Surface Area(dm²)

51. Step-4: Acceptance Criteria
Page 51
Example
If MACO is 600 mg and total surface area is 1600 dm² calculate the
swab value.
Solution
Put values in above
600×1000/1600 = 375ug/dm²
Rinse Limits
The amount of residue on the equipment is assumed to be equal to the
amount of residue in the rinse volume.
The rinse limit can be calculated by following:
Target Value(mg/l) = MACO(mg)
Total Rinse Volume

52. Page 52
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