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STANDARD OPERATING PROCEDURE – Quality Assurance

CLEANING VALIDATION
Document No. :

Version No. : 09

Supersedes Version No.: 08

Effective Date : Review Date :

Issued by (sign/date) :

CIRCULATION LIST :

Copy No. of Copies

Department Details of copies
No. to be Issued

QUALITY ASSURENCE - - MASTER COPY

APPROVAL LIST
Name Department Designation Signature/date
Prepared By

Reviewed By

Approved By

1.0 PURPOSE:
To lay down a procedure to prove that the equipment cleaning procedure can
consistently clean the previous product, cleaning agent (if any), and microbial
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residues to an acceptable level to prevent possible contamination and cross-

contamination and To decide the worst-case product performing cleaning validation
for common equipment.

2.0 SCOPE:
This SOP is applicable for validating cleaning procedures followed for process
equipment and accessories used in manufacturing of pharmaceutical products.

3.0 RESPONSIBILITY:
3.1 Production:
3.1.1 Cleaning of equipment and accessories as per respective SOP.
3.2 Quality Assurance:
3.2.1 Preparation of the cleaning validation protocol
3.2.2 Sampling and data compilation
3.3 Maintenance:
3.3.1 Equipment surface area calculation
3.4 Quality Control/Microbiology:
3.4.1 Microbial sampling & Analysis of samples

4.0 ACCOUNTABILITY:
Head QA, QC & Production shall be accountable for the implementation of systems
and procedures.

5.0 PROCEDURE:
5.1 Definitions:
5.1.1 Cleaning Validation: It is a validation program to verify that the process and
procedures used to clean product residue from process equipment and components
will consistently and significantly reduce the amount of active and /or excipients and
cleaning agents to a concentration within calculated acceptance limits.
5.1.2 Worst case: A product or set of conditions encompassing the upper and lower
processing limits for operating parameters and circumstances with SOP which pose
the greatest chance of product or process failure when compared to ideal conditions.
Such conditions do not necessarily include product or process failure
5.1.3 Worst case product: The product selected from a group of products that represents
the greatest risk of carry-over contamination to other products made in the same
equipment by virtue of its poor solubility, potency, and toxicity, or a combination of
these factors

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5.1.4 Bracketing: Grouping of products manufactured in identical equipment chains from

which the worst-case product will be selected based on batch size, solubility, daily
doses, and therapeutic dose.
5.1.5 Acceptance Criteria: To demonstrate during validation that the cleaning procedure,
routinely employed for a piece of equipment, limits potential carryover to an
acceptable level.
5.1.6 Revalidation: The repeat of initial validation either after changes/introduction to
equipment, new product or periodically to provide assurance that the changes are
done, do not affect the cleaning effectiveness.
5.2 Ensure that the prerequisites for cleaning validation as listed below are available:
5.2.1 Approved Cleaning Validation Protocol.
5.2.2 Validated analytical Method for estimation of the previous product (API) in the rinse
and swab sample.
5.2.3 Note: the efficiency of the recovery of API by the analytical method should be
assessed.
5.2.4 The product matrix shall be available w.r.t. details of solubility, dosage, the toxicity of
active ingredient(s), and batch sizes of products manufactured in the SPPL.
5.2.5 The validated analytical method for estimation of cleaning agent (if any) in the
rinse/swab.
5.2.6 Approved contact surface area of equipment involved in the manufacturing of
pharmaceutical products.
5.2.7 The basic information or contact surface area of equipment pieces may be taken from
manufacturer documents also.
5.2.8 Approved sampling plan (for both chemical and microbiological sampling) taking the
sample from complexity and design of equipment into consideration.
5.2.9 Approved swab locations for the equipment involved in the manufacturing of
pharmaceutical product.
5.2.10 Product Vs. Equipment matrix with contact surface area.
5.2.11 Approved equipment cleaning SOPs involved in manufacturing.
5.2.12 The time frame for storage of un-cleaned equipment for cleaning shall be established
(unclean equipment may be stored up to 72 hours).
5.3 Cleaning of equipment:
5.3.1 Clean the equipment as per respective approved SOP available ensuring the
following:
5.3.1.1 The number of cleaning steps and/or cycles shall be performed as per respective
equipment SOP.
5.3.1.2 The volume of purified water / WFI shall be used for the final rinsing of
equipment/equipment parts as per individual SOPs or respective annexure of
cleaning validation protocol.
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5.3.1.3 Purified water shall be used as a final rinse for equipment, to be used in the
production of non-sterile products.
5.3.1.4 WFI shall be used as the final rinse for equipment to be used in the production of
sterile products.
5.4 Collection of samples for chemical and microbial analysis:
5.4.1 Swab Sampling:
5.4.1.1 Strongly preferred method, as some residues may need a mechanical or physical
action to remove from the surface.
5.4.1.2 Most of the equipments shall be swabbed for at least 1-5 locations, depends on
equipment size, accessibility and compliance.
5.4.1.3 For cleaning validation swab sample shall be collected for chemical/microbiological
analysis from the locations specified as per the sampling locations.
5.4.1.4 Before collection of swab sample visual inspection of the equipment shall be done to
check the cleanliness.
5.4.1.5 Selection of sample position shall be based on difficult to clean surface area.
5.4.1.6 Swab sample shall be collected from (approximate 25 sq.cm) 5x5 sq.cm.
5.4.1.7 The recommended direction and motions used in actual swabbing of an area as
shown below.
5.4.1.8 Swabbing is done in painting motion across the surface, first applying the swab in a
vertical motion, and then applying the swab (after rotating it 90°) in a horizontal
motion with the reverse surface of the swab.
Vertical swabbing Horizontal swabbing

______5cm______ ______5cm______

5.4.1.9 Recommended swab sampling procedures ensure complete residue pick up from the
defined surface area.
5.4.1.10 If the surface area is less than 25 sq. cm, complete surface area should be swabbed.
5.4.1.11 The swab sample will be taken after the final rinse of the equipment surface, which
is hard to clean. Swab locations shall be determined based upon logic and practical
approach.
5.4.1.12 In pipes, do the swabbing in a circular motion from the outer edge to the inner
surface in the clockwise direction and return the swabbing in a similar procedure. i.e.
from inside to outside in an anti-clockwise direction. For calculation retain the area
of 25 cm2.
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5.4.1.13 Stainless steel/ Teflon/ Silicon/ PVC etc templates shall be used for determining the
surface area of the swab, or eyeball method be practiced and validated for each
sampling personals.
Note: Ensure that micro swab samples are collected prior to the chemical
swab sample
5.4.2 Rinse sampling:
5.4.2.1 Collect the rinse sample of each equipment involved for manufacturing after final
cleaning as per the approved sampling plan.
5.4.2.2 The final rinse sample shall be collected in a way that the sample representative of
the entire rinse volume.
5.4.2.3 Withdraw about 100 ml rinse volume for active ingredient from the final rinse for
measurement of the active ingredient and cleaning agent used, from the equipment
part.
5.4.3 Refer individual sampling plan of different equipment’s parts to be sampled (as per
cleaning validation protocol).
5.4.4 Microbial swab samples shall be collected prior to a chemical swab sample.
5.4.5 The Selection of solvent for a swab, if other than water shall be based on the
solubility of the active ingredient.
5.4.6 The cleaning of the equipment (CIP and COP) shall be done in all the three validation
runs by different operators to verify the ruggedness of the cleaning procedure.
5.4.7 Labelling and storage of samples:
5.4.7.1 Label each swab and rinse sample appropriately
5.4.7.2 The rinse sample shall be stored in an amber color bottle and swab sample
inappropriately covered glass test tube or vial with proper labeling so as to prevent
contamination or alteration during storage.
5.4.7.3 Microbial swab samples shall be store in the sterile well-closed test tubes with
proper labelling.
5.4.8 Visual evaluation of cleaning:
5.4.8.1 Visually inspect the final rinsed equipment/each part of the equipment to ensure that
it is clean, clear and colourless before sampling.
5.4.8.2 Use a torch, mirror, etc. for verification of cleanliness wherever direct access of area
is not possible.
5.4.8.3 Production/QA personal assessing visual cleanliness shall be trained for observing
and identifying drug substance at low-level concentration.
5.4.8.4 Training shall be provided by subjecting officers to review and identify the drug
substance residue at a lower level which is generated by spotting solutions of lower
concentration (at LOD level) on all MOC involved in equipment cleaning,
performed during recovery studies conducted by the laboratory for method
validation of the analytical method.
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5.4.9 Odour verification:

5.4.9.1 In formulation where flavours/pungent are used or where the materials are used has
itself typical odor.
5.4.9.2 Ensure that final rinse/sample rinse and equipment are free from the characteristic
odor of the previous product shall be verified by the smelling of cleaned equipment
part.
5.4.10 Measure the content of API in rinse/swab as per the approved analytical method in
QC.
5.4.11 Confirm the presence of the cleaning agent used (if any), in the final rinse, swab/rinse
within an acceptable level.
5.4.12 For solvents other than water and volatile organic solvents, when used for cleaning of
equipment, residues of solvents shall be checked in addition to API and cleaning
agent.
5.4.13 Based on the analysis, calculate the amount of residue present in each rinse/swab, and
on the basis of rinse/swab result and measure probable contamination in the next
product, calculate the amount of residue present in each equipment involved.
5.4.14 Swabbing and analysis for micro swab sample analysis shall be carried out as per
respective SOP.
5.4.15 Swab and rinse sampling shall be done for routine cleaning validation.
5.4.16 However, swab sampling shall be considered as the primary criteria for cleaning
validation.
5.4.17 The cleaning validation samples analysis shall be carried out on HPLC and UV
both(If the analysis is possible on both and analytical method has been carried out
successfully on both) for rinse as well as swab samples to verify the result of samples
and comparison between them for equipment train.
5.4.18 If the first swab sample result is out of limit re-clean the same equipment with a
suitable solvent or by water and the same shall be addressed during cleaning
validation
5.4.19 Swab sampling site shall not be repeated and swabbing shall not be done from the
same location of equipment where the swab sample is already collected before.
5.4.20 The swab sample shall be collected adjacent to the defined sampling location where
the sample is already collected.
5.4.21 The cleaning validation activity shall be planned further for three consecutive batches
with the consideration of a validated cleaning procedure as applied to previous
batches.
5.4.22 The same procedure shall be applicable for that particular product during routine
cleaning activities after the successful completion of cleaning validation
5.4.23 While carrying out hold time study for dirty and clean equipment, swab samples
should be collected from the surface of equipment as per swab sampling location
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5.4.24 Swab sampling site shall not be repeated and re-swabbing shall not be done from the
same location of equipment where the swab sample is already collected before.
5.5 Microbial aspects of cleaning validation:
5.5.1 Bioburden study of equipment shall be performed, after cleaning/sanitization to
ensure microbiological cleanliness.
5.5.2 Check visually no stagnant water shall be allowed to remain in the equipment
subsequent to cleaning operation.
5.5.3 Equipment should be dry before storage by an appropriate method of drying as per
SOP or allow all the water to drain from the equipment and its parts.
5.6 Establishment of Acceptance Criteria:
 The limits for Acceptance Criteria shall be decided based on factors such as batch
size, therapeutic dosage, solubility, toxicology, and equipment surface area.
 The limit for cleaning validation’s acceptance criteria shall be established following
four criteria.
5.6.1 Criteria 1 (Dose Criteria):
5.6.1.1 NMT 0.1 % of the normal therapeutic dose of any product will appear in the
maximum daily dose of the next product. OR
5.6.1.2 Not more than 0.001 part of the minimum dose of the previous preceding product
should appear in the maximum daily dose of the next considered product.
5.6.1.3 Dose criteria shall be calculated by the following formula.

MAR (mg/swab) = STD X 0.001 X Mini B. size (mg) X 25 cm2

MDD (mg) X TSA

Where,
STD : Smallest therapeutic dose in mg of product
0.001 : Safety factor
25 cm2: Swab surface area
MDD: Maximum daily dose in mg of product
TSA : Total equipment surface area
Mini B. size: Minimum batch size of the next product

OR following formula also can be used:

I x K x M = ______mg of previous product/25 cm2

J L

Where,
I = 0.001 of the minimum dose of previous product in the equipment chain in mg
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J = Maximum number of dosage units of next considered product taken/day in the

equipment chain
L = Surface area of equipment common for both the products (previous & next product)
in equipment chain
K = Minimum number of dosage units (Batch size) per batch of next considered
product in equipment chain
M = 25 (for reporting results per 25 cm2)
5.6.1.4 Scientific Rationale:
 Drug products are often considered to be non-active at 0.1 part of their normally
prescribed dosage (1/10th).
 The second is a safety factor of 10 (i.e. 1/10th of the above step).
 The third factor of 10 is included to make the cleaning procedure robust and to
overcome variations due to personnel and sampling methodology (i.e. 1/10th of
the above step).
 If similar equipment is used repeatedly in a chain, surface area to be considered
for each time of usage during the calculation of the total surface area.
5.6.2 Criteria 2 (10 ppm criteria):
5.6.2.1 NMT 10ppm of the previous products should appear in a subsequently produced
succeeding product.
5.6.2.2 The 10 ppm criteria shall be calculated as per the following formula

mg/swab = R X S X U = ______mg of previous product/25 cm2

T
Where,
R = 10 mg of active ingredients in previous product/kg of next considered product
S = Batch size in kg of next considered product.
T = Surface area of equipment common for both the products (previous and considered
next product)
U = swab surface 25 cm2 (for reporting results per 25 cm2)
5.6.2.3 Scientific rationale: It is based on regulations for the food industry which provides for
a maximum permissible limit of certain levels of hazardous substances considered as
acceptable in products that enter the human food chain.
5.6.3 Criteria 3 ( Toxic Dose criteria):
5.6.3.1 Wherever therapeutic dose is not known then toxicity criteria shall be applicable for
cleaning validation study.
5.6.3.2 The toxicity is expressed as LD50 can be used to calculate the maximum allowable
limit.
5.6.3.3 The following methodology can be used.

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ADI = NOEL X AAW X SF

Where:
NOEL = LD50 X empirical Factor
NOEL: No Observed Effect Level
LD50: Lethal dose for 50% of the animal population in the study
Empirical factor: Derived from animal model
ADI: Acceptable Daily Intake
AAW: Average Adult Weight (i.e. 70 Kg)
SF: Safety factor, to be taken as 1/1000
5.6.3.4 This equation can be applied to a pharmaceutical cleaning validation study for the
purpose of calculating a limit.
5.6.3.5 The result would be as follows…

MAR = ADI X B and mg / swab = MAR x 25 cm2

R Total equip. surface area
Where:
MAR: Maximum Allowable Residue
B: The smallest batch size of any subsequent product.
R: Largest daily dose of any product made in the same equipment

Toxicity table:
Probable oral lethal dose for Included descriptive terms Group
humans (mg/kg)
>15000 & 5000 – 15000 Practically non toxic Slightly toxic 1
500 – 5000 Moderately toxic 2
50-500 Very toxic 3
5 – 50 Extremely toxic 4
>5 Super toxic 5
5.6.4 Criteria 4 (Visually clean criteria):
5.6.4.1 No quantity of residue should be visible with naked eyes on the equipment after the
cleaning procedure is performed.
5.6.4.2 The scientific rationale for the above statement is:
 Most of the product is visible to a normal human eye at approximately 100 µg
per 25 cm2 of surface area.
 Generally, below this level, the residues are not visible to the human naked
eye.
5.6.5 The most stringent value from the above four criteria shall be considered as
acceptance criteria for cleaning validation including visual criteria.

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5.7 Selection of the worst case product:

5.7.1 Worst case product based on solubility:
5.7.1.1 Active ingredients having the least solubility (Refer Table-2) in their cleaning solvent
are most difficult to clean and the possibility of carryover contamination of that
ingredient into the next product.
5.7.1.2 The product having the worst solubility profile in their cleaning solvent/media shall
be selected as the worst case product in the criterion.
5.7.1.3 The data of solubility of API in solvents shall be taken from “Martindale/Merck
index/Pharmacopoeias/Internet etc.
5.7.1.4 In the case where the solubility profile of two or more products is identical, the
product having the highest strength shall be selected as the worst case in this criterion.
5.7.1.5 Whenever a worst-case product has two or more actives with different solvents used
for cleaning, for both actives, study the solubility of each of the actives in both the
solvents and shall be taken into consideration for validation activity of poor solubility
in solvents and the highest strength.
Solubility Table 2:
Solubility Approximate quantities of solvent by volume
for 1 part of solute by weight.
Very soluble Less than 1 part.
Freely soluble From 1 to 10 parts
Soluble From 10 to 30parts
Sparingly soluble From 30 to 100 parts
Slightly Soluble From 100 to 1000 parts
Very slightly soluble From 1000 to 10000 parts
Insoluble Or Practically insoluble More than 10000 parts

5.7.2 Worst case product on the basis of least therapeutic dose (Potency):
5.7.2.1 The product having maximum potency possess maximum health hazard if
contaminated in other product.
5.7.2.2 The product having the least therapeutic dose is considered to be most potent and use
for the establishment of acceptance criteria.
5.7.2.3 Perform the cleaning validation studies with the selected worst-case product on the
identified equipment chain for three consecutive runs.
5.8 Analysis and evaluation of results for rinse and swab sample:
5.8.1 Analyse the swab and rinse sample in the laboratory using a validated analytical
method.

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5.8.2 Apply recovery factor (obtained from validation study) for calculating the content, if
the same is found less than 100%. If recovery is obtained more than 100%, do not
apply factor for calculation.

Results = Observed value X 100

Recovery factor
For example,
 If the recovery of the method is 80% and result obtained is 2.0 PPM, then apply
recovery factor as follows:
Content (PPM) = (2.0 X 100)/80 = 2.5 ppm
 Limit of detection and limit of quantification shall be reported by QC after the
establishment of the analytical method in Annexure-I after each introduction of
the new product.
5.8.3 Acceptance criteria for residual solvent:
5.8.3.1 If any solvents are used for cleaning of equipment, results obtained for residual
solvent should be less than 1/10th of the ICH specified limit. The same shall be
reported in the respective cleaning validation report.
5.8.3.2 Cleaning agents: Cleaning agents used should be easily removable. The cleaning
agent should be absent (at LOD level) in the final rinse.
5.8.3.3 Quality control laboratory shall provide the results of samples analysed along with the
limit of detection (for rinse as well as swab technique) of the analytical method used
to analyse cleaning validation samples.
5.8.3.4 The quality assurance shall verify the compliance of all the results obtained for the
final rinse and swabs, which should be less than the acceptance criteria established.
5.8.3.5 If results reported for rinse/swab samples by the laboratory are below the detection
limit (Below LOD), the detection limit shall be considered as residue and evaluated
against acceptance criteria for compliance.
5.8.3.6 The detection limit of swab/rinse should be less than the acceptance criteria.
5.8.3.7 Any failure to meet the acceptance criteria shall be jointly investigated by production,
QC, and QA to determine the cause and appropriate actions (for example reanalysis,
re-cleaning, cleaning by another method, etc.) shall be taken as necessary.
5.8.3.8 Note: If the cleaning method is being changed after the failure of the result then
again three consecutive cleaning runs should be validated using a changed
cleaning method
5.8.3.9 In the case of the theoretical acceptance criteria are found less than the LOD of the
analytical method, the following actions to be initiated:
 An analytical method to be optimized to achieve the lower limit of detection by
slight modification such as increasing injection volume in case of chromatographic

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method like HPLC/GC etc or increasing cell length in case of UV methods from 1
cm to 4/5 cm path length cell.
 If the above modification does not provide a limit of detection lower than the
acceptance criteria established, a new method to be developed, which can achieve
the required lower detection concentration. In case of modification, the method
should be revalidated
 More surface area can be considered for swabbing (for example 100 sq. cm).
 In the case of rinse sampling, the volume of sample rinse can be decreased
resulting in an increase in the residue concentration and hence can be easily
detected
 If the swabbing area is modified, acceptance criteria also need to be corrected and
recalculated with the revised area
 When no methods can compliance the required acceptance criteria then LOD may
be taken into consideration for acceptance criteria and calculation purposes.
 If the cleaning procedure consistently reduces the contaminants to a level within
the limit of acceptance criteria, then the procedure being followed for cleaning can
be regarded as validated.
5.8.4 Calculation of the amount of residue present in rinse and swab:
5.8.4.1 Rinse method:
 Content/residue of previous product in the rinse is reported in ppm by QC.
 It should be converted into milligram by multiplying the QC result with the
quantity of rinse in Kg (i.e. quantity of water for final rinsing in Kg).
 The resultant value is the residue of previous product/s in milligram from entire
equipment/part of equipment cleaned.
 For possible contamination per 25 sq. cm in the next considered product, the
resultant value is multiplied by 25 and divided by surface area of the
equipment/part of the equipment cleaned.

Example:
The residue of the previous product (from QC) = 2.58 ppm
Quantity of final rinse for equipment/equipment parts = 5 kg
Content/residue of previous product in mg = 2.58×5 = 12.9mg
Possible contamination in next considered product per 25 sq. cm = 12.9 x 25
9500
= 0.034 mg/25 cm2
2
Where 9500 cm is the surface area of the equipment/part of the equipment.

5.8.4.2 Swab method:

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 Content/residue of previous product is reported in mg per 25 cm2 by QC.

 If the result reported in ppm then calculate as follows:
 The observed ppm value is to be converted into mg by dividing the ppm value with
1000.
 This is the possible contamination in the next considered product in 25 cm2.
Example:
Content residue in ppm from result of analysis = 9.12 ppm
Possible contamination in next considered product = 9.12/1000 mg x dilution factor
= 0.091 mg/25 cm2 (with consideration of 10 ml dilution factor)
 If swabbing area is less than 25 cm2 then QC have to report the result in mg/swab.
Example:
Content/residue in ppm from results of analysis = 9.12 ppm
If swab is collected from 15 cm2 then = (9.12 x 25)/15
= 15.2 ppm/25 cm2
Contamination in next considered product = 15.2/1000 mg x dilution factor
= 0.152 mg/25 cm2(with consideration of 10 ml dilution factor)
Note: In the case of thermolabile API, for cleaning validation, only the swab method
should be followed, as for the rinse method, the rinse will be evaporated at high
temperature and this can cause degradation of temperature-sensitive API and will
affect the subsequent analytical results.
 In the case of new product introduction in the facility, evaluation/assessment shall
be done as per Annexure-I against existing worst-case products based on
assessment report shall be decided that the product becomes worst-case or not.
 If the product is worst-case then cleaning validation must be carried out with
the same equipment chain.
5.8.5 One batch of every new product shall be taken as a cleaning verification study with
swab sampling only and shall be reported as per the annexure of the cleaning
verification protocol.
5.8.6 Whenever introduction, elimination or modification of any equipment evaluation
/assessment shall be done as per annexure no. II, or
Change in the next product considered for calculation, the surface area calculation
shall revise and if the acceptance criteria emerged from the new calculation more
stringent than the existing limit.
5.8.7 If the equipment which has the minimum surface area is removed from the facility
and the same equipment with maximum surface area and same cleaning procedure
still is in the area then not required for validation or not required to revise the surface
area of equipment due to worst-case study.

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5.8.8 But if the equipment with maximum surface area is removed then only total surface
area shall be revised and thereafter the acceptance criteria may be revised (lower than
existing) but revalidation is not required.
5.8.9 If the equipment which has the minimum surface area than existing is introduced in
the facility and the same equipment with maximum surface area and same cleaning
procedure (validation) still is in the area then not required for validation or not
required to revise the surface area of equipment in the chain due to worst-case study.
5.8.10 But if the equipment which has the maximum surface area than existing is introduced
in the facility then the total surface area shall be revised accordingly and assessment
shall be made for cleaning validation result for acceptance criteria and actually carry
over to the next product during cleaning validation
5.8.11 If the actual carryover is more than the new acceptance criteria, the cleaning
validation study shall be planned on three consecutive batches.
5.8.12 If one equipment chain has products which are common for another equipment chain,
and if the surface area of the former is greater than the later
5.8.13 Then validation of the worst case of the former equipment chain will also justify the
cleaning validation of the later, even the worst-case product of both the chains does
not match.
5.8.14 The statement can be justified as if worst-case products of the worst equipment chain
(having maximum surface area) are validated successfully
5.8.15 Then the worst-case products of any other equipment chain (lower surface area) need
not be validated separately
5.8.16 Provided the worst list of the worst chain includes products of other chains also and
cleaning procedure is the same for equipment used in both chains.
5.8.17 This because, the worst product is already considered in the worst chain, and is being
validated.
For Example:
 Consider chain 1 having products A, B, C, D, E, and F in its product list and
among which products A and C are the worst cases.
 Similarly chain 2 has products B, D, E, and F in its product list and among which
products B and E are the worst cases.
 In the surface area chain, 1 is greater than chain 2 and if products A and C are
validated in chain 1, then the cleaning procedure will stand validated in chain 2
also, even if products B and E are not validated in chain 2.
 This can be justified as although products B and E are not validated in chain 1,
still, the same cleaning procedure is effective in cleaning products more worst than
the above products (A and C).

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 Note: If cleaning procedures are different, worst products in the equipment chain,
the worst-case shall be validated.
5.8.18 Whenever the introduction & deletion of equipment and products following
document shall be updated but not limited to:
 Equipment matrix
 Product matrix with their solubility profile
 MAR calculation sheet
5.8.19 A regular validation review must be established to maintain the validated status of the
cleaning procedure
5.8.20 Carry out re-validation in case of a change in equipment (if not identical and surface
area is more than the existing and actual validated result is more than the new
acceptance criteria), changes in established cleaning method, the introduction of the
new worst-case product (May not be required if the assessment is satisfactory on the
existing worst-case actual result and new worst-case acceptance criteria).
5.9 Periodic cleaning re-validation:
5.9.1 If no cleaning validation required or not done on the next worst-case within a years
then revalidation shall be carried out on existing worst in the frequency of one year
5.9.2 Whenever worst-case products to be planned for manufacturing.

6.0 ABBREVIATIONS:
SOP - Standard Operating Procedure
QA - Quality Assurance
ICH - International Conference on Harmonization
LOD - Limit of Detection
LOQ - Limit of quantification
HPLC - High-performance liquid chromatography
MACO - Maximum allowable carry-over

7.0 REFERENCE:
WHO Technical Report Series 937, 14
European Commission
APIC A sector group of CEFIC

8.0 ANNEXURES:

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CLEANING VALIDATION

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Annexure I Comparison of worst case product

Annexure II Comparison of worst case equipment

9.0 HISTORY:

Version No Date Description of Change

THIS IS THE END OF THE DOCUMENT

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