Corporate

STANDARD OPERATING PROCEDURE

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

PURPOSE :

 The objective of cleaning validation is to prove that the equipment / accessories cleaning procedure
can consistently clean the previous product, cleaning agent, microbial residues solvent / solution,
odour and colour to an acceptable level, to prevent possible contamination and cross contamination
in subsequent product.
 To describe the methodology for assessment of product for cleaning validation introduced in facility.
 To establish conditions for Matrixing products or equipment.

SCOPE :

Applicable to cleaning procedures of equipment and accessories used in manufacturing of

pharmaceutical products.

RESPONSIBILITY :

Production:
 Form a part of the validation.
 Carrying out cleaning of equipment as per established cleaning procedure.

Quality Control:
 Form a part of the validation.
 To provide the cleaned accessories for sampling such as rinse sample glass bottle, test tubes,
Texwipe swab stick, Nylon membrane filter etc.
 Ensure availability of validated analytical methods for measurement of product in swabs and rinses
and measurement of solvent in the rinses (wherever applicable).
 Analyse the cleaning validation samples as per TI sheet.

Engineering:
 Form a part of validation.
 To provide utility services during validation.
 To provide the surface area of equipment.

Quality Assurance:
 Form a part of validation.
 Preparation of validation master plan for cleaning validation.
 Establishment of worst case products.
 Collection of validation samples as per approved sampling plan of equipment.
 Performing cleaning validation as per approved validation protocol and recording the same.
 Approval of the cleaning validation report.

Unit Head: Acknowledgement of cleaning validation activities and cleaning validation report.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

DEFINITION :

Cleaning Validation : A documented evidence that a cleaning procedure is consistent in reducing

product residue and removal of cleaning agents, bioburden, flavour, colour (if applicable) from
equipment and accessories within the limits of acceptance.

Grouping Strategy: A strategy for establishing similar cleaning processes, usually based on similar
products or similar equipment, and to validate the cleaning process based primarily on validation data
for a representative of the group.

Worst Case: A process condition or set of process conditions encompassing the upper and lower
processing limits for operating parameters and circumstances within SOPs 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.

Worst case product : The product selected from a group of products that present the greatest risk of
carry over contamination to other products made in the same equipment by virtue either of its poor
solubility, potency, toxicity or a combination of these factors.

Acceptance criteria : To demonstrate during validation that the cleaning procedure, routinely
employed for a piece of equipment, limits potential carryover to an acceptable level. That limit
established must be calculated based on sound scientific rationale.

Revalidation: The repeat of initial validation either after changes or periodically to provide assurance
that the changes done / time do not affect the cleaning effectiveness.

LD50 : The 50% lethal dose of the target residue in an animal, typically in mg / kg of body weight (by the
appropriate route of administration)

PDE : The PDE represents a substance specific dose that is unlikely to cause an adverse effect if an
individual is exposed at or below this dose every day for a lifetime.

LOAEL: The dose at which a significant adverse effect is first observed is the Lowest-Observed-
Adverse -Effect-Level (LOAEL).

NOAEL: No Observed Adverse Effect Level is the highest tested dose at which no “critical” effect is
observed.

STV : Safe Threshold Value is the toxicologically derived health based acceptance limit.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

1.0 HEALTH, SAFETY AND ENVIRONMENT :

Depending on the product, appropriate safety apparel shall be worn during cleaning of
equipment.

2.1 PROCEDURE :

2.2 Ensure that the prerequisites for cleaning validation as listed below are available:

2.2.1 Validation Master Plan defining the programme for cleaning validation.

2.2.2 Cleaning Validation Protocol, “Prerequisite checklist for cleaning validation” 1035-G-
0038/A13 and Validation Report.

2.2.3 Validated analytical method for measurement of product in the rinses.

2.2.4 Validated analytical method for measurement of product in the swabs.

2.2.5 Validated analytical method for measurement of cleaning agent in the rinses/swabs (if
applicable).

2.2.6 Validated analytical method for measurement of solvent in the rinses (wherever applicable).

Note : The efficiency of sampling recovery of API by the analytical method shall be assessed.

2.2.7 Validated microbiological method for measurement of bioburden on the equipment.

2.2.8 Standard Operating Procedures detailing the cleaning process for various parts / pieces of
equipment.

2.2.9 Approved sampling plan (for both chemical and microbiological sampling) taking the
complexity and design of the equipment into consideration.

2.2.10 Approved surface area calculation for equipment.(Basic information may be taken from
equipment manufacturer)

2.2.11 Approved swab locations for equipment’s.

2.3 Ensure that the product, process and equipment for which the validation is planned are valid
according to a worst case concept.

2.4 Time frames for storage of unclean equipment for cleaning shall be established.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

Note : 1. Three validation exercises shall be carried on equipment for establishment of the time frame
of the Uncleaned equipment. Selection of the worst case equipment and worst case
product shall be justified based on logic and scientific rationale.
For non-worst case products, risk assessment / coupon study shall be performed to
evaluate need of subjecting each product for DHT.
2. Swab sampling for hold time study of uncleaned equipment to be performed for different
location for different time intervals.

2.5 Clean the equipment as per respective Standard Operating Procedure available at the unit
level ensuring the following:

2.5.1 Concentration of the specific cleaning agent, cleaning agent quantity, scrubbing time, water
quality, volume of rinse solution required for cleaning is established.

2.5.2 If hot water is used, the temperature of water shall be established.

2.5.3 The number of cleaning cycles to be performed shall be established if a “Clean In Place”
system is used.

2.6 As per the sampling plan, collect the rinses / swabs from the equipment.

Note : 1. The rinse samples collected shall represent the entire rinse volume.
2. During cleaning validation, while cleaning the equipment as per respective Standard
Operating Procedure available at the unit if the cleaning parameters are in range then,
lower limit value mentioned in equipment cleaning procedure to be considered.

2.7 Withdraw about 100 ml aliquot per active ingredient from the final rinse for measurement of
active ingredient and about 50 ml aliquot from final rinse for measurement of cleaning agent
as per Standard Operating Procedure.

2.8 Withdrawal of rinse samples for measurement of content at every stage is not required for
established cleaning procedure of equipment’s. Sampling to be done only from the final
rinse / sample rinse and given to QC for measurement, however rinse at each stage to be
analysed during the cleaning SOP developmental stage.

2.9 Withdraw about 50 ml aliquots from the final rinse / sample rinse for measurement of solvent
/ solution, if used for cleaning.

2.10 Send 100 ml blank of final rinse (potable water / purified water / water for injection) along
with rinse samples.

2.11 Swab individually various parts of the equipment per active ingredient after cleaning the
parts as detailed in the sampling plan as per Standard Operating Procedure.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

Note : Selection of swabbing sites shall be hard to clean and difficult to sanitise sites. Refer
individual sampling plan for parts to be swabbed.

2.12 The cleaning of the equipment’s done in all the three validation runs shall be done preferably
by different operators to verify the ruggedness of the cleaning procedure.

2.13 Labelling and storage of cleaning validation samples.

2.13.1 Label each rinse/ swab sample appropriately. Refer annexure 1035-G-0038/A1 for specimen
label.

2.13.2 Sample storage: The sample shall be stored in a proper container / bottle with proper
labelling so as to prevent contamination or alteration during storage.

Note : Cleaning Validation sample analysis shall be initiated within 24 hours after receipt of
cleaning validation sample until and unless solution stability studies are available to justify
the analysis period

2.14 Visual verification:

2.14.1 Visually inspect the final rinse / sample rinse of each part of equipment to ensure that it is
clear and colourless.

2.14.2 Visually inspect the equipment and its parts to ensure that it is clean.

2.14.3 Usage of torches, mirrors etc. can be done for verification of cleanliness visually wherever
required.

2.14.4 Officers / operators assessing visual cleanliness shall be trained for observing and
identifying drug substance residue at low level concentration. Training can be provided by
subjecting officers to review and identify drug substance residue at lower level which is
generated by spotting solutions of lower concentrations on stainless steel plates performed
during recovery studies conducted by laboratory for validation of analytical method.

2.15 Odour verification criteria:

2.15.1 In formulations where flavours are used, ensure that final rinse / sample rinse and
equipment are free from the characteristic odour of flavours used in the previous product.

2.16 Water for injection / Distilled water shall be used as the last rinse for equipment to be utilised
in production of sterile products and purified water / steam shall be used for
equipment in case of non sterile products. For aerosols, alcohol / purified water can be used
for final rinse followed by propellant rinse.
2.16.1 Selection of solvent for swabs shall be based on Active ingredient solubility.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

2.17 Measure the content of active ingredient in rinses / swabs as per the Quality Control
method.
2.18 Also confirm if the presence of cleaning agent used, in the final rinse /sample rinse/swab (if
applicable) is within acceptance level.

2.19 For solvents other than water and volatile organic solvents, when used for cleaning, residues
of solvents shall be checked in addition to API and cleaning agent.

2.20 Based on the analysis, calculate the amount of residue present in each rinse / swab and
measure probable contamination in the next product.

2.21 Microbiological aspects of cleaning validation:

2.21.1 Bioburden study of equipment shall be performed, after cleaning / sanitisation, to ensure
microbiological cleanliness.

2.21.2 No stagnant water shall be allowed to remain in the equipment subsequent to cleaning
operations.

2.21.3 Equipment shall be dried before storage by an appropriate method of drying as per SOP or
allow all the water to drain from the equipment and its parts.

2.22 Time frames for storage of cleaned equipment shall be established.

Note : Three validation exercises can be carried on equipment for establishment of the time frame
of the cleaned equipment. Selection of the equipment and number of run shall be justified
based on logic and scientific rationale.

2.23 Acceptance Criteria:

2.23.1 The limits for acceptance criteria are based on therapeutic dose, batch size, LD 50 and
surface area.

2.23.2 The established limit ensures that product residue meets the following criteria:

2.23.2.1 Dose criterion: Not more than 0.001 part of the minimum therapeutic dose of the previous
Active substance shall appear in the maximum daily dose of the next considered product.

Scientific rationale for the above statement is:

 Pharmaceuticals 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 (1/10th of the above).

 The third factor of 10 is included to make the cleaning procedure robust and to overcome
variations due to personnel and sampling methodology (1/10th of the above).
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

2.23.2.2 10 ppm criterion: Not more than 10ppm of the previous product shall appear in a
subsequently produced product.
Scientific rationale for the above statement is:

 Not more than 10ppm of any product will appear in another product.

 Scientific rationale for above is based on regulations for food industry which provides for
maximum permissible limit of certain levels of hazardous substances considered as
acceptable in products that enter human food chain.

2.23.2.3 PDE criterion: To consider the Health based limits.

Scientific rationale for the above statement is:

 PDE (permitted daily exposure) is toxicologically derived and not simply on dosage. The
PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an
individual is exposed at or below this dose every day for a lifetime.

 Determination of a PDE involves (i) hazard identification by reviewing all relevant data, (ii)
identification of “critical effects”, (iii) no-observed-adverse-effect-level (NOAEL) of the
findings that are considered to be critical effects, and (iv) use of several adjustment factors
to account for various uncertainties.

 For details of PDE criterion defined by the toxicologist refer SOP 1035-G-0209.

2.23.2.4 Visual verification: No quantity of residue shall be visible on the equipment after cleaning
procedure is performed.

The most stringent limit of acceptance that would emerge from Dose criterion and 10ppm
criterion and PDE criterion shall be applied during validation exercise along with visual
Verification.

Swab recovery factor shall be considered for calculation during validation.

2.23.3 Procedure For Rinse and Swab Analysis :

2.23.3.1 Analyse the rinse and swab samples in laboratory using validated analytical method. Apply
recovery factor (obtained from validation study) for calculating the content if the same is
found less than 100 %. If recovery is observed more than 100 %, do not apply factor for
calculation.
Observed value X 100
Results =
% Recovery
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

For example,

If the % recovery of the method is 79 % and result obtained is 2.0 ppm, then apply recovery
factor as follows:

Content (ppm) = 2.0 x 100 = 2.53 ppm.

79
Limit of detection shall be reported in the Technical Information sheet for cleaning
validation.

2.23.4 Acceptance criteria for Residual solvents: Results obtained for residual solvent shall be less
than 1/10th of the ICH specified limit.

2.23.5 Cleaning agents: Cleaning agents used shall be easily removable. The acceptance criteria
for cleaning agent shall be calculated for each equipment by determining the carryover to
next product through Safe Threshold Value derived from PDE criteria similar to that used for
API, for every equipment. The cleaning agent shall not be more than this calculated
acceptance criteria.

Note: Acceptance criteria for cleaning agent can be calculated by using PDE value. STV
(Acceptance criteria) can be derived by using below mentioned formula.

Formula to get safe threshold value (STV) for Rinse:

PDE X K X A = Jppm of cleaning agent

L B
Where,

PDE = Permitted daily exposure

J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipment’s common for both the products (previous and
considered next product)
K = Number of dosage units per batch of next considered product
A = Area of specific equipment sampled
B = Quantity of final rinse / sample rinse in kg or Litre
Note : For Veterinary and topical products where safe threshold value (STV) cannot be calculated,
in such cases 10 ppm criteria shall be used.

2.23.6 Total product contact surface area shall include the area of major / minor equipment and
accessories for calculation of acceptance criteria.
2.23.7 Analytical method validation of residue estimation methods for the products selected as
worst cases shall be performed prior to analysis of cleaning validation samples.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

2.23.8 During analytical cleaning method validation, recovery study shall be applied on the worst
case active, whenever we have products with two or more actives.

2.23.9 Quality Control Laboratory shall provide result of samples analysed along with limit of
detection value (for rinse as well as swab technique) of analytical method used to analyse
cleaning validation samples.

2.23.10 Quality Assurance shall verify the compliance of all the results obtained for final rinse and
swabs which shall be less than the acceptance criteria established.

2.23.11 If results reported for swab samples by laboratory are below detection limit (Below LOD),
detection limit shall be considered as residue and evaluated against acceptance criteria for
compliance. Detection limit of swab shall be less than the acceptance criteria.

2.23.12 Any failure to meet the acceptance criteria must be investigated to determine the cause and
appropriate actions (for example, re analysis) shall be taken as necessary.

2.23.13 In case the Acceptance Criteria is found less than the Limit of Detection (LOD) of the
analytical method, following actions to be initiated :

 Analytical method to be optimized to achieve lower limit of detection by slight modification

such as increasing injection volume in case of chromatographic method like HPLC/ GC/
UPLC etc or increasing cell length in case of UV methods from 1 cm to 4 / 5 cm path length
cell. If above modification does not provide limit of detection lower than acceptance criteria
established, new method to be developed which can achieve required lower detection
concentration. In case of modification, method shall be re validated.

 More surface area can be considered for swabbing (For example, 16 sq. inches). In case of
rinse sampling, volume of sample rinse can be decreased, resulting into increase in the
residue concentration and hence can be easily detected. If swabbing area or rinse volume is
modified, acceptance criteria also need to be corrected and re calculated with revised area
or revised rinse volume.

Note : Swab and Rinse sampling shall be done for routine cleaning validation. However, swab
sampling shall be considered as the primary criteria for cleaning validation. If the results of
rinse sampling considering the final rinse volume and the Limit of Detection for rinse
samples are observed to be more than the acceptance criteria, then only swab sampling
shall be done and the cleaning validation exercise shall be concluded based on results of
the swab sampling.

2.23.14 If the cleaning procedure consistently reduces the contaminants to a level within the limits of
acceptance criteria, then the procedure being followed for cleaning can be regarded as
validated.

2.24 Calculation of the amount of residue present in rinse and swab:

 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

2.24.1 Rinse Method:

2.24.1.1 Content of target residue (Active substance and cleaning agent) in the rinse is reported in
ppm by Quality Control.

2.24.1.2 Compare the results obtained from QC in ppm with limits of acceptance criteria for rinse
collected from the part of equipment.

2.24.2 Swab Method:

2.24.2.1 Content / Residue of previous product is reported in microgram per 4 inch2 by QC.

2.24.2.2 It is to be converted into milligram by dividing the residue in µg reported by QC by 1000.

This is the possible contamination in next considered product in mg/4 inch2
Example:
Content/residue in µg /swab from results of analysis = 10.18
µg/4inch2 Possible contamination in next considered product =
10.18mg
1000
= 0.01018 mg/4 inch2.

2.24.2.3 If swabbing area is less than 4 sq. inch then QC shall report the results mg/swab
Example:
Content/residue in µg /swab from results of analysis = 10.18 µg/swab

If swab is collect from 2.5 sq. inch then =10.18 x 4 sq. inch
Surface area of the part

= 10.18 x 4
2.5
= 16.288 µg/4inch2

Contamination in next considered product = 16.288 mg

1000
= 0.01629 mg/4 inch2.
Note:1. In case of thermolabile API, for cleaning validation, only swab method shall be followed, as
for rinse method, the rinse will be evaporated at high temperature and this can cause
degradation of the temperature sensitive API and will affect the subsequent analytical
results.

2. For live culture like Lactic Acid Bacillus containing products, the cleaning validation
assessment shall be done by “Sterile swabbing” method where the media used for
swabbing shall be Normal saline. In this case, rinse method shall not be followed.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
PRODUCT
DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

2.25 Procedure for Rinse Sampling:

2.25.1 Clean the equipment as per the respective cleaning procedure.

2.25.2 Collect the rinse samples as specified in individual sampling plan.

2.25.3 Rinse sampling shall primarily be used in cases where the surfaces are difficult to reach.

2.25.4 Rinse sampling shall be done by using clean bottles toward any potential contaminant
carryover.

Note : 1.) Final rinsing of equipment using the cleaning medium shall be carried out as mentioned
in the cleaning SOP. While, sample collection shall be performed by using established
additional cleaning medium (sample rinse) following final rinse.

2.) Established additional cleaning medium (sample rinse) derived after performing the study
shall be the minimum possible quantity required to cover the intended part of the equipment
to be rinsed and shall be mentioned in the sampling plan.

2.25.5 Type of rinse sampling:

2.25.5.1 Holding type: Collect sample in vessel, swirl and then collect sample.

2.25.5.2 Non approachable piping: Collect samples by passing solution from one end and collect
from the other end.

2.25.6 Rinse samples can be collected using any type mentioned above, depending upon the
requirement.

2.26 Procedure for Swab Sampling:

Preparation: As per the information obtained from the production arrange for the required
number of flasks, bottles with screw cap, swab (Membrane filter/ swabstick), forceps /
tweezer, hand gloves, nose masks and sampling kit.

Note: Do not touch the swab with hand. Use tweezers / forceps for swabbing (as applicable).
2.26.1 Depending on the product, moisten the swab (Membrane filter/ swabstick) with appropriate
solvent. Use hand gloves, nose mask and snood whenever required.

2.26.2 Immediately after wetting the membrane filter / swabstick, swab the specific equipment
surface as per the sampling plan. The surface area shall be swabbed is 4 square inch. If
the surface area is less than 4 square inch, complete surface area shall be swabbed. Swab
sample will be taken after final rinse from equipment surface which is hard to clean. Swab
locations shall be determined based upon logic and practical experience. Equipment
geometry also shall be considered. Same shall be justified in respective sampling plan.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
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DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

2.26.3 In case of surfaces where 4 square inch measurement for swab sampling is not possible like
pipes, cavities, groves, mesh etc. Following approach shall be adopted.

2.26.3.1 Swab the surface such that it will cover the maximum possible accessible area, for example,
in case of pipes, do the swabbing in circular motion from outer edge to inner surface in
clockwise direction and from inner surface to outer edge in anti clock wise direction or as per
requirement ensuring that the maximum area is covered. For calculation, retain the area of 4
square inches.

2.26.3.2 Wherever dismantling of such equipment / components is possible, dismantle and wash the
same with known amount of solvent / cleaning solution and determine the content in rinse.

2.26.4 Stainless steel / Teflon / PVC template shall be used for determining the surface area of the
swab, or eye ball method be practiced and validated for each sampling personnel.

2.26.5 Do the swabbing in a “Painting” motion across the surface, first applying the swab in a
vertical direction and rotate 90° to horizontal position as shown below in figure 1.
2” 2”
R
O
T
A
T
2” 2”
E

S
W
Vertical swabbing A Horizontal swabbing
B

2.26.6 Transfer the swab using tweezer (as applicable) into the flask/bottles/Test tube and analyse
as per the validated analytical method.

Note: For swab use nylon membrane filter (Pall Gelman Science/Pall Life Science/Membrane
Disc Filter) or swabstick (texwipe). Dimension for swab shall be as mentioned in the unit
SOP. Before using swabstick (texwipe), ensure that swab recovery data is available.

2.26.7 Swab for microbiological testing shall be taken from any one location, generally a site that is
difficult to clean and this shall be done by a microbiologist / trained person as per 1035-L-
0071 and from a different surface than the chemical swabs withdrawn. Ensure that the
surface is not wet and at ambient temperature.

Note : Micro swab sample shall be collected prior to chemical swab sample.
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DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

2.26.8 After taking swab, wipe out the part equivalent to which swab is taken with lint free cloth and
visually inspect the part for cleanliness for non sterile products and water for injection /
distilled water for sterile products as per respective cleaning SOP, (final rinse only) followed
by steaming with pure steam.

2.26.9 Recovery of swab technique shall be considered “Good” if it is more than 80% and
“Moderate” if it is more than 60%. If it below 60%, investigation of the same shall be done.

2.27 Establishment of worst case product:

In order to minimise the amount of validation required, a worst case approach for validation
shall be used by means of a worst case procedure. There shall be documented scientific
rationale for the chosen worst cases. Bracketing of products shall be done by grouping of
products manufactured using a particular equipment chain or equipment.

2.27.1 Individual Equipment Concept:

2.27.1.1 A flow chart showing the product manufactured using the equipment shall be prepared at
unit level.

2.27.1.2 Group the products manufactured using each equipment and perform the cleaning validation
on worst case products.

2.27.1.3 Batches meant for registration/feasibility shall not be considered as next product for
calculation of acceptance criteria.

2.27.1.4 However, for feasibility batch evaluation shall be done as similar to routine product that is
one full cleaning validation run as per annexure 1035-G-0038/A6 and 1035-G-0038/A7 and
if product taken for feasibility batch is identified as worst case, inline with routine approach
cleaning validation on minimum three batches shall be done for the said product (these
three runs can be combination of feasibility / registration / commercial) and matrix to be
updated with first registration batch.
2.27.2 Equipment Chain Concept:

2.27.2.1 A flow chart exhibiting the equipment chain shall be prepared.

2.27.2.2 The code number of the individual equipment shall be documented, along with their
capacities and surface areas. Total surface area of the equipment chain shall be calculated
by adding up all the individual surface areas.

2.27.2.3 Surface area of accessories, if used at any stage shall be accounted in the total surface
area.

2.27.2.4 If the cleaning procedure of different products differs with respect to different cleaning
solvents used, grouping of products shall be done as per that.
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
DOCUMENT NAME
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DOCUMENT No. 1035-G-0038

VERSION No. 6.5, CURRENT

DATE OF ISSUE 14-May-2018 EFFECTIVE DATE 12-Jun-2018

2.27.2.5 For complete equipment chain along with capacities and surface areas, give the reference
chain number. Record the data in Annexure 1035-G-0038/A2.

2.27.3 Selection of the worst case product/s for performing cleaning validation is as follows :

2.27.3.1 Worst Case Products on basis of solubility :

Active ingredient having least solubility in their cleaning solvent are most difficult to clean
and possibility of carryover contamination of that ingredient into the next product is
maximum. Hence the products having worst solubility profile in their cleaning solvent shall
be selected as the worst case product in this criterion.
In case where the solubility profile of two or more products is identical, product having the
highest strength shall be selected as worst case in this criterion.

In case there are two products having same solubility and same strength, then the higher
potent drug (least therapeutic dose) among the two drugs shall be selected as worst case
in this criterion.

Whenever we have worst case products with 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

Interpretation of solubility

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
 Practically insoluble More than 10000 parts

2.27.3.2 Worst Case product on basis of least therapeutic dose (potency):

Product having maximum potency poses maximum health hazard if contaminated in other
product. Product having least therapeutic dose is considered to be most potent.

Note: 1) In case there are two products having same potency then one having higher strength shall
be considered
 CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE
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2) In case there are two products having the same potency and same strength, then
practically insoluble product shall be considered as worst case product.

2.27.3.3 Worst Case product on basis of toxicity (least PDE value):

LD50 (Toxicity data) for the new drug shall be obtained from authentic source such as
drugbank.com, MSDS, Scientific Journals, etc. and shall be entered in the data bank. Same
data bank shall be referred whenever required. Record the NOAEL and PDE value of each
drug in annexure 1035-G-0038/A2. Product having lowest PDE value shall be selected as
worst case in ‘toxicity’ criterion and record in annexure 1035-G-0038/A2. PDE evaluation
report can be made by toxicologist (If applicable) as per SOP 1035-G-0209.

In case where the PDE value of two or more products is identical, product having the least
solubility shall be selected as worst case in this criterion.

In case there are two products having same PDE value and same solubility, then the higher
potent drug (lowest therapeutic dose) among the two shall be selected as worst case in this
criterion.

2.27.4 Perform three cleaning validation studies of the respective equipment, or equipment chain
and the product selected as Worst case. Calculate the acceptance criteria by considering
following parameters by referring the equipment chain of that product.
For Dose criteria:
 Product having minimum K/J ratio
 Surface area of equipment common for both the products (previous product and considered
next product)

For 10 ppm Criteria:

 Minimum batch size in kilograms/ litres of next considered product.
 Surface area of equipment common for both the products (previous product and considered
next product)
Record the data in Annexure 1035-G-0038/A2.

For PDE criterion:

 LD 50 / NOAEL / PDE value of product.
 PDE value considering various extrapolating factors.
 Product having minimum K/J ratio
 Surface area of equipment common for both the products (previous product and considered
next product)

Note: For new molecules introducing in the facility the PDE value considering NOAEL value shall
be obtained from toxicologist as per the SOP 1035-G-0209. In case of Legacy products
NOEL shall be considered in place of NOAEL till the PDE value is not available as per the
SOP 1035-G-0209.
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If worst case product is not planned within 3 months and can not be validated then review
and validation of the 2nd or subsequent worst case product shall be considered. Record the
subsequent worst case product details in Annexure 1035-G-0038/A14. Next product shall
be selected for calculation of acceptance criterion based on the minimum batch size and
maximum daily dose. Cleaning validation shall be re-run for the first worst case product
when it is available.

Carryover contamination of a particular amount of product residue of previous product shall

be distributed throughout the batch size of the next product. Content of residue of previous
product, per dose of next product shall be highest for a minimum batch size of next product,
as the dilution of the residue shall be least in a minimum batch size of next product.

Moreover, as the batch size of the next product comes in the numerator of the formula for
calculation of acceptance criteria, the product which has the minimum batch size, shall be
considered as the worst case product to make the acceptance criteria stringent.

2.27.4.1 Next product to be selected for calculation of acceptance criterion based on the
maximum daily dose of the product and minimum batch size:

Risk of health hazard due to carryover contamination in next product is maximum for those
products which have maximum number of daily doses. As per day intake of the previous
product residue by a patient shall be maximum in case of next product having maximum
daily dosage units.

Moreover, as batch size of subsequent product is in numerator, maximum daily dose is in

the denominator of the formula for calculating acceptance criteria, the product having
maximum daily dose, shall be considered as the worst case product as the acceptance
criteria will be most stringent in this case.
The product having maximum daily dose in the chain shall be considered as “Worst case”
product. Maximum daily dosage number to be considered as “J” in Dose criteria calculation.
Based on the above justification product having minimum K/J ratio shall be considered as
next product for calculation.

2.27.5 Common surface area of equipment’s used between previous and considered next product
shall be considered as “L” in Dose criteria, in PDE Criteria and “T” in 10ppm criteria
calculation as per Annexure 1035-G-0038/A9.

2.28 If a product having more than one active ingredient, then validate the product for active
ingredient which is identified as worst case based on solubility/potency/toxicity.

2.29 Based on all the above, ‘WORST CASE” product for calculating acceptance criteria shall be
established.
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2.30 Identify and Record the products which are considered as “WORST CASE” based on the
solubility, therapeutic potency, PDE value and the “WORST CASE” product based on batch
size in Kg / litres and maximum Daily Dose in Annexure 1035-G-0038/A2.

2.31 Perform cleaning validation for each equipment on the product/s decided as “WORST
CASE” product. Carry out 3 consecutive successful cleaning validation for the product / (s)
considered “WORST CASE” product and record in Annexure 1035-G-0038/A3.

2.32 Calculate the limits for Acceptance Criteria as follows:

Note:1. For all external use preparations, only 10ppm criteria shall be followed.

2. For ophthalmic preparations following points shall be considered:

The most stringent limit of acceptance that will emerge from 10 ppm criteria, dose criteria
and PDE criteria shall be applied during validation exercise instead of applying only 10ppm
criteria, (considering criticality and systemic absorption of ophthalmic product compared to
other external formulations).

a) The unit dose of previous product shall be considered as 0.035 ml, which is ocular capacity
(average) of human eye and the minimum dose of previous product shall be considered as
concentration of API in 0.035ml dose (or single drop volume if it is less than the ocular
capacity & minimum dose recommended is single drop).

b) Number of dosage units per batch of next considered product shall be calculated
considering 0.035ml unit dose.

2.32.1 Limits of acceptance criteria for swab:

2.32.1.1 Dose criterion:

Formula:

I X K XM= Jmg of previous product / 4 inch2 or 16 inch2

L

Where,
I = 0.001 of minimum therapeutic dose of previous product in mg.
J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipment’s common for both the products (previous and
considered next product)
K = Number of dosage units per batch of next considered product
M = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

2.32.1.2 10 ppm Criterion :

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Formula:

RXSXU= Tmg of previous product / 4 inch2 or 16 inch2

Where,
R = 10 mg active ingredient in previous product / kg of next considered product.
S = Minimum Batch size in kilograms / litres of next considered product.
T = Surface area of equipment’s common for both the products (previous and
considered next product)
U = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

2.32.1.3 PDE criterion:

Formula to get safe threshold value (STV) :

PDE X K X M = mg of previous product / 4 inch2 or 16 inch2

J L

Where,

PDE = Permitted daily exposure

J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipment’s common for both the products (previous and
considered next product)
K = Number of dosage units per batch of next considered product
M = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

 The Permitted Daily Exposure (PDE) is determined by following equation:

NOAEL X weight adjustment
PDE =
F1 X F2 X F3 X F4 X F5

The modifying factors are as follows:

F1 = A factor to account for extrapolation between species
F1 = 5 for extrapolation from rats to humans
F1 = 12 for extrapolation from mice to humans
F1 = 2 for extrapolation from dogs to humans
F1 = 2.5 for extrapolation from rabbits to humans
F1 = 3 for extrapolation from monkeys to humans
F1 = 10 for extrapolation from other animals to humans
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F2 = A factor of 10 to account for variability between individuals

F3 = A variable factor to account for toxicity studies of short-term exposure
F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for
cats, dogs and monkeys).
F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.
F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents.
F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents.
F3 = 10 for studies of a shorter duration
F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic carcino-
genicity, neurotoxicity or teratogenicity. In studies of reproductive toxicity, the following
factors are used:
F4 = 1 for fetal toxicity associated with maternal toxicity
F4 = 5 for fetal toxicity without maternal toxicity
F4 = 5 for a teratogenic effect with maternal toxicity
F4 = 10 for a teratogenic effect without maternal toxicity
F5 = A variable factor that may be applied if the no-effect level was not established. When
only an LOEL is available, a factor of up to 10 could be used depending on the severity of
the toxicity.

Note: 1. If values of individual factors are not available then consider highest value.
2. If the NOEL value is available, F5 factor shall be considered as 1.
3. If body weight is considered while calculation of NOEL, then weight adjustment factor
shall be considered as 1 while calculation of PDE.

 For this approach NOEL shall be estimated from the LD50 value using the following equation:

LD50 X BW
NOEL =
MF1
NOEL = No Observable Effect Level
LD50 = The 50% lethal dose of the target residue in an animal, typically in mg / kg of body
weight (by the appropriate route of administration)
BW = body weight of patient taking next product (50 kg)
MF1 = The modifying factor selected shall be not more than 1000.
For example, If Alprazolam molecule is considered,

Toxicity NOEL PDE

Oral, mouse: LD50=1020 = 1020 x 50 = 51 = 51 = 0.004
mg/kg. 1000 12 x 10 x 10 x 10

STV (safe threshold value) :

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0.004 X K X M = Jmg of previous product / 4 inch2 or 16 inch2

L

Note :1. In case of low acceptance criteria more area can be considered for swabbing For example
– 16 sq inch and cleaning method validation shall be updated accordingly.

2. If NOEL is not available then go for LOEL.

3. If NOEL/NOAEL/LOEL value is not available then NOEL shall be calculated based LD 50.

4. For single drug, LD50 value may be available for more than 1 species, but sensitivity may
vary from species to species. Sensitivity is shown in decreasing order as Monkey-----------
Dog------------Rat--------------Mice. LD50 value of Rat / Mice shall be considered for calculation.

5. LD50 value differ based on the type of formulations/Route of administration. While doing
calculations for cleaning validation LD50 value to be selected based on formulations/Route of
administration. If LD 50 value is not available for other route of administration/ formulation
then oral route LD 50 shall be considered.
6. If LD50 varies with respect to API supplier then lowest LD 50 value of same species between
two suppliers shall be considered.

7. For new molecules introducing in the facility the PDE value considering NOAEL value shall
be obtained from toxicologist as per SOP 1035-G-0209.

8. If the product information for the next medicinal product to be manufactured expresses the
daily dose on a per patient basis rather than on a mg/kg body weight basis, a standard body
weight of 50 kg shall be used for human medicinal products. For medicinal products for
veterinary use doses are generally expressed on a mg/kg body weight basis. In those
instances where this is not the case, a standard body weight of 1 kg shall be assumed as
this would represent the lower end of animal body weights.

2.32.2 Limits of acceptance criteria for rinse:

The most stringent limits of acceptance criterion of swab that would emerge from dose
criterion, 10 ppm criterion and PDE criterion, that acceptance criterion shall be used to
derive the limits for the acceptance criterion of rinse.
Derive the acceptance criterion for rinse by using following formula:

2.32.2.1 Dose criterion:

Formula:

I X K X A = ppm of previous product

J L B
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Where,

I = 0.001 of minimum therapeutic dose of previous product in mg.

J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipment’s common for both the products (previous and
considered next product)
K = Number of dosage units per batch of next considered product
A = Area of specific equipment sampled
B = Quantity of final rinse/ sample rinse in kg or Litre

2.32.2.2 10 ppm Criterion :

Formula:

RX S X A= ppm of previous product

T B
Where,

R = 10 mg active ingredient in previous product / kg of next considered product.

S = Minimum Batch size in kilograms / litres of next considered product.
T = Surface area of equipment’s common for both the products (previous and
considered next product)
A = Area of specific equipment sampled
B = Quantity of final rinse/ sample rinse in kg or Litre

2.32.2.3 PDE criterion:

Formula to get safe threshold value (STV) :

PDE X K X A = Jppm previous product

L B
Where,

PDE = Permitted daily exposure

J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipment’s common for both the products (previous and
considered next product)
K = Number of dosage units per batch of next considered product
A = Area of specific equipment sampled
B = Quantity of final rinse/ sample rinse in kg or Litre

2.33 Compare the amount of residue of the previous product against respective established
acceptance criteria for swab and rinse.
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2.34 Record observation, conclusion and recommendations in the report.

2.35 Get the report approved by Head Unit Quality Assurance. The report shall be noted by Unit
Head.

2.36 Attachments: Following shall be attached to the validation report:

 Approved sampling plan for the equipment.
 Technical information sheet of cleaning validation sample analysis.
 Prerequisite checklist for cleaning validation
 Common surface area of equipment

Note: Approved surface area calculation and swab location of validated equipment shall be
available.

2.37 During worst case determination, if the previous product and the next product happen to be
same, still attributes of the product shall be considered for acceptance criteria calculation.
2.38 The most stringent criteria that would emerge from Dose criterion, 10 ppm criterion and PDE
criterion shall be applied during validation exercise along with visual verification for both
Rinse and Swab.

Note: In case of failure of visual verification for other than new products, a deviation shall be
logged to identify if this is an operator failure or the cleaning procedure failure. In case of
operator error, a recleaning can be performed once and same shall be recorded in the area
and equipment cleaning log.

2.39 Approved surface area calculation of equipment shall be available at unit.

Note: If similar equipment is used repeatedly in a chain, surface area to be considered only once
during calculation of the total surface area.

2.40 When non-betalactum antibiotic and non-sexual hormones -corticosteroids products are
made in same areas and equipment that are used for manufacture of other products that do
not require special manufacturing area, the batches to be manufactured on campaign basis
to the extent possible. The equipment cleaning rinses and swabs should be subjected to
traces analysis prior to starting a new production which should be testable through
production records or alternate shall have a validated cleaning methodology in use for
periodic monitoring of traces of previous product.

2.41 During a campaign (production of several batches of the same product), cleaning between
batches may be reduced. The number of lots of the same product which could be
manufactured before a complete/full cleaning is done shall be determined. If campaign
cleaning validation is not performed on worst case product, then batch wise cleaning shall
be performed.
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Note : In case any new product is introduced in facility, Risk assessment to be performed for
evaluation of worst case product for cleaning validation, if the product is identified as worst
case, then update the existing matrix for inclusion of new product and perform full cleaning
validation on a minimum of three batches as per annexure 1035-G-0038/A6 and annexure
1035-G-0038/A7.

If the product is not identified as worst case, then full cleaning validation will be performed
for the first batch of the product as per annexure 1035-G-0038/A6 and 1035-G-0038/A7.
Based on result generated from first batch validation study; risk assessment shall be
reviewed to decide need of two more batches for cleaning validation and matrix to be
updated accordingly.

Risk assessment shall be performed as per SOP no. 1035-G-0024, It shall cover the
physical characteristics such as viscosity, processes creating sticky or caked on solids,
materials reacting with water (cleaning solvent) to form solid or sticky gel like material, etc.
(as applicable) and record the observations in Annexure 1035-G-0038/A11.

Interview the operator for feasibility of cleaning procedure and record the observations in
Annexure 1035-G-0038/A11. Record any unusual observation or deviation occurred during
cleaning procedure.

Note: Cleaning validation shall be extended for two more batches if any one of the factor listed in
Annexure 1035-G-0038/A11 is identified.
Prepare a summary report by referring annexure 1035-G-0038/A12, to have a
comprehensive review of all the cleaning validation activities whenever new product is
introduced in facility.

2.42 If there is an introduction, elimination or modification of any equipment, or change in next

product considered for calculation, the surface area calculation shall be revised and if the
acceptance criteria emerged from the new calculations is more stringent than the existing
limit, the cleaning validation results shall be compared with the new limits and if required,
revalidation to be done for all worst case products.

Note: If justification / supporting data not available, cleaning procedure shall be verified each
time, until validations of all the worst case products are completed.

2.43 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 latter, then validation of worst cases of the
former equipment chain will also justify the cleaning validation of the latter, even if the worst
case products of both the chains do not match. For example, Aerosol product.
This statement can be justified as, if worst case product/s of the worst chain (having
maximum surface area) is validated successfully, then the worst case products of any other
chain (lower surface area) need not be validated separately (provided product list of the
worst chain includes products of other chains also and cleaning procedure are same for
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equipment used in both chain). This is 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
Product A and C are the worst cases.
Similarly, Chain 2 has Products B, D, E and F in its product list and among which Product B
and E are worst cases.

If the surface area of Chain 1 is greater than Chain 2 and if Product A and C are validated in
Chain 1, then the cleaning procedure will stand validated in Chain 2 also, even if Product B
and E are not validated in Chain 2.
This can be justified as although product B and E are not validated in Chain 1, but still the
same cleaning procedure is effective in cleaning of products worse than the above products
(Product A and C).

Note : 1. If cleaning procedures are different, all products in equipment worst case shall be
validated.
2. If cleaning procedure is ineffective then use dedicated equipment.

2.44 New or transferred equipment must be subjected to a cleaning verification by visual

inspection, traces of cleaning agent and determination of the bioload.

2.45 For new equipment cleaning methodology, refer CTG-18.

Note : Ensure that consideration is given to non-contact parts like fans of PLC panels and ovens,
mixing shafts, heating elements etc. during performance qualification of equipment and
preparation of standard procedures for cleaning of equipment.

2.46 Regular validation review must be established to maintain the validated status of the
cleaning procedures.

2.47 Frequency for updation of cleaning validation matrix,

 As and when equipment worst case changes or next product changes for acceptance
criteria, version of individual equipment chain shall be changed. (if applicable)
 Respective chain shall be reviewed for inclusion / deletion of equipment’s or entry of new
product / transfer of product / discontinuation of product from the site from the site as per
Annexure 1035-G-0038/A4.

2.48 Unit shall have control on the following formats with help of version number on it. Below
mentioned data shall be updated as and when required.

2.48.1 Equipment Chain (Product / Product group wise) with surface area.
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Note: Equipment which is similar in design and function may be grouped and a worst case can be
established for validation.

2.49 Revalidation: Revalidation shall be carried out in the following situations:

2.49.1 Revalidation in case of changes in equipment / product contact parts / change in source of
API, if required, based on impact assessment, cleaning procedure or cleaning aid (For
example: Cleaning agent) cleaning validation shall be initiated.
Revalidation to be carried out if the formulation of an existing cleaning agent is changed.

2.49.2 Periodic revalidation:

2.49.2.1 For non-betalactum antibiotics and non-sexual hormones-corticosteroids: one batch cleaning
validation for each worst case product shall be done once in a year.

2.49.2.2 For other products:

2.48.2.2.1 Perform an annual cleaning review report in a scheduled manner and document as per
annexure no. 1035-G-0038/A14. Based on the review there could be one of the conclusion:

1. The data review definitely supports the conclusion that the cleaning process is in a state of
control, and therefore is still validated. With such a conclusion, there is no need for protocol
runs on any products within group.
2. The data review suggests that the cleaning process may not be in a state of control. Perform
one protocol run on the worst case product. If successful, the cleaning process is
considered validated for all products in the group. For example but not limited to: An OOS is
observed but there is insufficient evidence to prove that it is due to the previous product.
3. The data review supports the conclusion that the cleaning process is definitely not in a state
of control. Conduct an investigation to bring it into a state of control and then perform three
protocol runs on the worst case product. For example but not limited to: An OOS is observed
but there is sufficient evidence to prove that it is due to contamination from previous product.

2.48.2.2.2 Revalidation shall be done for one batch per worst case product in 5th year after the last
successful run.

2.50 Refer Annexure 1035-G-0038/A5 for flow diagram of cleaning validation.

2.51 Following are the documents which shall have specific document numbers and shall be
version controlled :
 List of equipment chains (applicable for equipment chain concept)
 Worst case document
 Sampling plans

2.51.1 Document number for Worst case document shall be;

WC/XXXXXXX/01
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WHERE;
WC- WORST CASE
XXXXXXX- Equipment name in short with capacity (if applicable)
01-serial number
For example : For octagonal blender 2250 litres
WC/BLD2250/01

2.51.2 Sampling plan for each equipment / equipment chain shall be prepared unit wise and the
document number shall be;
SP/XXXXXXX/01
SP-sampling plan
XXXXXXX- Equipment name in short with capacity (if applicable)
01-serial number
For example : For octagonal blender 2250 litres
SP/BLD2250/01
Refer specimen Annexure 1035-G-0038/A10 for sampling plan.

The numbering system for above documents shall be decided as per different dosage
forms, unit wise. List of document numbers shall be available at the unit as per Annexure
1035-G-0038/A8.

2.52 The worst case document shall have following contents:

 Equipment chain (applicable for equipment chain concept)

 Equipment details, such as equipment code, capacities and surface area.
 Product list
 Determination of worst case products for both present and next product of each criterion.
 Summary of worst case products.

3.1 ABBREVIATIONS :
% : Percentage
° : degree
µg : Micro gram
API : Active Pharmaceutical Ingredient
B. No. : Batch number
BW : body weight of patient taking next product (50 kg)
cGMP : Current Good Manufacturing Practices
cm : Centimetre
DHT : Dirty hold time
GC : Gas Chromatography
HPLC : High Performance Liquid Chromatography
ICH : International Conference on Harmonisation
inch2 : square inch
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Kg : Kilogram
LD50 : The 50% lethal dose of the target residue in an animal
LOD : Limit of detection
LOEL : Lowest Observed Effect Level
Lt. : Litre
mg : Milligram
ml : Millilitre
mm : millimetre
MSDS : Material Safety and Data Sheet
NOAEL : No Observed Adverse Effect Level
NOEL : No Observable Effect Level
OOS : Out of specification.
PDE : Permitted Daily Exposure
PLC : Programmable Logic Control
ppm : Parts per million
PVC : Polyvinyl Chloride
QC : Quality Control
SOP : Standard Operating Procedure
Sq. : Square
Sr. no. : Serial Number
STV : Safe threshold value
TI : Technical Information typically in mg / kg of body weight (by the
appropriate route of administration)
TOC : Total organic carbon
UPLC : Ultra Micro High Performance Liquid Chromatography
UV : Ultra Violet
WHO : World Health Organisation

4.0 REFERENCES :

WHO Technical Report series 937, fortieth report

1035-G-0024 : Risk Management By Failure Mode, Effect And Criticality Analysis
1035-G-0209 : To determine and implement permitted daily exposure (PDE) value.
CTG 18 : Development of cleaning procedure.
1035-L-0071 : Microbiological monitoring of surfaces in production area.
PDA Technical Report 29 – Points to consider for cleaning validation.
EMA’s Guideline on setting health based exposure limits for use in risk identification in the
manufacture of different medicinal products in shared facilities.
ISPE guide Volume 7 “Risk-based Manufacture of Pharmaceutical Products”.
ICH Topic Q3C (R4) : Impurities: Guideline for Residual Solvents.
MINISTRY OF SOCIAL PROTECTION RESOLUTION NUMBER 3028 OF 2008 (August 13)
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5.1 ANNEXURES :

Annexure Annexure Name To be used as

Number
1035-G-0038/A1 “Label for cleaning validation samples”(1035-G- Specimen Copy
0038/LA1/1)
1035-G-0038/A2 Cleaning validation matrix and establishment of worst Specimen Copy
case product (1035-G-0038/F1/2)
1035-G-0038/A3 Summary of cleaning validation (For single equipment) Specimen Copy
(1035-G-0038/F2/1)
1035-G-0038/A4 Review of worst case product (1035-G-0038/F3/1) Specimen Copy
1035-G-0038/A5 Flow diagram of validation and implementation of Reference Copy
validated cleaning procedure (1035-G-0038/FL1)
1035-G-0038/A6 Validation Protocol for cleaning of equipment Specimen Copy
(1035-G-0038/P1/4)
1035-G-0038/A7 Validation Report for cleaning of equipment Specimen Copy
(1035-G-0038/R1/4)
1035-G-0038/A8 List of documents (1035-G-0038/F4/1) Specimen Copy

1035-G-0038/A9 Common surface area of equipments (1035-G-0038/F11) Specimen Copy

1035-G-0038/A10 Cleaning validation sampling plan(1035-G-0038/F6/2) Specimen Copy

1035-G-0038/A11 New Product Introduction Cleaning Review Report Specimen Copy
(1035-G-0038/F7/1)
1035-G-0038/A12 Cleaning validation summary of new product Specimen Copy
(1035-G-0038/F8/2)
1035-G-0038/A13 Prerequisite checklist for cleaning validation Specimen Copy
(1035-G-0038/CL1/3)
1035-G-0038/A14 Annual cleaning review report Specimen Copy
(1035-G-0038/F9/2)
 ANNEXURE 1035-G-0038/A1
(SPECIMEN COPY)

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LABEL FOR CLEANING VALIDATION SAMPLES

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VALIDATION SAMPLE : RINSE / SWAB

PRODUCT:
B.NO.:
EQUIPMENT / PART NAME : SAMPLE / VOLUME :
STATUS: ACTIVE / CLEANING AGENT NAME OF ACTIVE :
SAMPLE NO.:
SIGNATURE:DATE: SAMPLING TIME:
ANALYSIS DUE DATE/ TIME:
(1035-G-0038/LA1/1)

Page 1 of 1
 ANNEXURE 1035-G-0038/A2
(SPECIMEN COPY)

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No.: WC/XXXXXXX/01 Version No.:

Supersedes: CLEANING VALIDATION MATRIX AND ESTABLISHMENT OF WORST CASE PRODUCT Effective Date:
---
Equipment / Equipment chain no.: Department :

PRODUCT Active Solubility Streng Potenc *LD 50 NOEL/ PDE Suitable Batch Maximu Referenc Commo K/J
Ingredien in Washing t h y (mg) NOAE Value Swabbin size m Daily e Chain n Ratio
t solvent (mg) L (permitted g Solvent Kg (S)/ dose (J) No. Surface
/ LOEL daily Batch Area
exposure) size (inch2)
Nos. (K)

Page 1 of 2 (1035-G-0038/F1/2)
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 Very Soluble : VS  Soluble : S  Slightly Soluble : SLS

 Freely Soluble : FS  Sparingly Soluble : SPL  Very Slightly Soluble : VSLS
 NOEL : No observed effect level.  Practically Insoluble : INS

LD 50 : If NOEL not available then only LD 50 value should be considered.

Conclusion :

Worst Products to be validated

Product having least solubility :

Product having least Therapeutic dose (potent drug)

Product having least PDE value (Toxic drug) :

Worst Product for Calculation of Acceptance Criteria

Product having Minimum batch size and Maximum Daily Dose (Based on Minimum K/J Ratio)

Prepared By Approved By Noted By

Quality Head Unit Quality Assurance Unit Head
Assurance
 ANNEXURE 1035-G-0038/A3
(SPECIMEN COPY)

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SUMMARY OF CLEANING VALIDATION (FOR SINGLE EQUIPMENT)

PRODUCT: EQUIPMENT:
CONTENT: EQUIPMENT CODE NO. :
CLEANING SOP NO.:

LIMIT OF DETECTION (FOR RINSE):

LIMIT OF DETECTION (FOR SWAB):
LIMIT OF DETECTION CLEANING AGENT (FOR RINSE/SWAB if applicable):

CONTEN
T OF BIOBURDEN
CONTENT CONTENT CONTENT SOLVENT
PART OF ACTIVE OF OF IN FINAL
OF INGREDIEN DETERGEN ACTIVE RINSE VISUA
SR. TOTAL FUNGA
THE T IN FINAL T IN FINAL INGREDI- (IF L
NO. APPLICA COUN L
EQUI RINSE (mg/4 RINSE (mg/4 ENT IN INSPE-
- or 16 sq. or 16 sq. SWAB - BLE) CTION T COUNT
MEN inch) inch) (mg/4 or (mg/4 or (Cfu/ (Cfu/
T 16 sq. 16 sq. swab swab
inch.) inch) ) )
Limit Visually
Clean
Batch No.: Name of operator:

Chemical A.R.
No. Micro A.R. No.

Batch No.: Name of operator:

Chemical A.R.
Micro A.R. No.
No.

Batch No.: Name of operator:

Chemical A.R.
Micro A.R. No.
No.

Page 1 of 2 (1035-G-0038/F2/1)
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SUMMARY OF CLEANING VALIDATION (FOR SINGLE EQUIPMENT)

DEVIATION, IF ANY :

OUT OF SPECIFICATION, IF ANY :

CONCLUSION :

From the data of validation, it is concluded that cleaning of as per SOP No.:
removes previous product residues, cleaning agent and microbial contaminant up to
predetermined acceptance level and there is no risk of cross contamination in subsequent
product.

RECOMMENDATIONS :

From above data it is concluded that SOP for cleaning procedure of equipment
stands validated. It is recommended to follow standard cleaning procedure
for equipment .

REVALIDATION :

PREPARED BY: APPROVED BY:

QUALITY ASSURANCE HEAD UNIT QUALITY ASSURANCE

Date: Date:

NOTED BY:

UNIT HEAD
Date:
 ANNEXURE 1035-G-0038/A4
(SPECIMEN COPY)

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REVIEW OF WORST CASE PRODUCT

Equipment/ Equipment chain no.:

Date

Product

Active Ingredient

Batch
Size In
Kg/Nos.
Strength
(mg / unit dose)
Solubility in
washing solvent
Suitable
Swabbing solvent
Least
therapeutic
potency (mg)

LD50

NOEL/ NOAEL/ LOEL

PDE Value
(Permitted Daily
Exposure)
Maximum Daily
Dose (Nos.)

K/J Ratio

Remark

Done by/Date

Reviewed by/Date

NOTE :
1. If NOEL is not available then go for LOEL.
2. If NOEL/NOAEL/LOEL value is not available then NOEL should be calculated based LD 50.
NOEL: No observed effect level.

Page 1 of 1 (1035-G-0038/F3/1)
 ANNEXURE 1035-G-0038/A5

Corporate

Location:

FLOW DIAGRAM OF VALIDATION AND IMPLEMENTATION OF VALIDATED

CLEANING PROCEDURE

Define the programme and validate the

method Identify the scope of the exercise

Develop a cleaning procedure based on cGMP and past

experience Write and execute validation protocol / report for

cleaning

Collect data for each product

Perform cleaning validation for each product till the worst case product identification

Identify worst case product

Calculate the acceptance criteria

Perform cleaning validation

exercise

Introduction of new product in facility

Risk assessment for cleaning validation of new product

Worst case product

Yes No

Perform cleaning validation exercise with Perform cleaning validation exercise with 1 batch
3
batches Monitoring of
cleaning
procedure for
physical
characteristics
and record the
results in
Annexure 1035-G-
0038/A12

Review of risk assessment based on test result of first batch and review of Annexure 1035-G-
0038/A12

Page 1 of 1 (1035-G-0038/FL1)
ANNEXURE 1035-G-0038/A6
Decision for two more batches of cleaning validation

Page 1 of 1 (1035-G-0038/FL1)
 ANNEXURE 1035-G-0038/A6
(SPECIMEN COPY)

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VALIDATION PROTOCOL
Protocol No.: CVP 01 Date of Issue :

Version No. : Effective Date :

CLEANING OF EQUIPMENT
Supersedes : Page 1 of 12

1.0 Objective :

To validate the effectiveness of the cleaning procedure for removal of product residues of the
previous product, cleaning agents, solutions/solvents microbial residue, odour and colour up
to a predetermined acceptance level and to ensure that there is no risk associated with
contamination into subsequent product.

2.0 Scope :

Applicable to cleaning procedures of equipment and accessories used in manufacturing of

pharmaceutical products.

3.0 Justification for selection of item/ equipment /accessory /process /product / system.

Justification for selection shall be recorded in the report.

4.0 Site of the Study :

The site of study shall be entered in the validation report.

5.0 Description of Equipment / accessory which is cleaned and details of the Next product:

Details of Equipment / accessory name and code no. used for (product name), Batch
Number, active ingredients, date of validation and details of next product shall be recorded in
the report.

6.0 Responsibility and Training:

Trained personnel shall perform cleaning validation. Details of training shall be

recorded in the report for : Production, Quality Assurance, Quality Control,
Engineering and others (Individual names shall be entered in the report).

7.1 Standard Operating Procedures (SOPs) to be followed:

7.2 Standard Operating Procedure for cleaning of equipment. SOP No. along with version number
shall be recorded in the report.

7.3 Standard Operating Procedure for sampling of rinses and swabs. SOP No. along with version
number shall be recorded in the report.

7.4 Standard Operating Procedure for cleaning validation and establishment of worst case
product. SOP No. along with version number shall be recorded in the report.

(1035-G-0038/P1/4)
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7.5 Microbiological method along with version number for Bioburden studies of equipment shall
be recorded in the report.

7.6 Approved sampling plan no. shall be recorded in the report.

8.1 Controls :

8.2 Requirements:

8.2.1 Measurement of the following shall be done using validated analytical methods:
a) active ingredient of previous product in swabs and rinses.
b) removal of cleaning agent in the final rinse
c) removal of solvent / solution used for cleaning

8.2.2 Swab used and its Lot. No. to be recorded in the report.

Note: Reference analytical method validation protocol number for the above shall be recorded in the
validation report.

8.1.2 Visual inspection of cleaned parts.

8.1.3 Non contact parts like seals, flanges, heating elements, ductings of Fluid Bed Drier, Fluid
Bed Processor, Ganscoater and outer surface of equipment shall be cleaned to ensure
absence of traces of previous product.

8.1.4 Time frames for storage of unclean equipment shall be established.

8.1.5 Date and time of completion of manufacturing shall be recorded in the report.

8.1.6 Date and time of commencement of cleaning shall be recorded in the report. Name of the
person who has cleaned the equipment shall be written in the validation report.

8.1.7 Concentration of the cleaning agent, water quality, and volume of rinse solution required shall
be recorded in the report. As per the approved sampling plan; collect the rinses / swabs from
the equipment and its parts separately. The temperature of water shall be recorded in the
report, in case hot water is used.

8.1.8 Time frames for storage of clean equipment based on bioburden studies shall be recorded in
the report.

8.1.9 The number of cleaning cycles to be performed shall be recorded in the report (for clean in
place equipment).
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8.3 Calibration :

Calibrated equipment / instruments shall be used and calibration details shall be recorded in
the report.

8.4 Precautions :

Ensure that the Main Switch of the equipment is ‘OFF’ before commencement of cleaning.

9.1 Validation Procedure:

Note : Swab and Rinse sampling shall be done for cleaning validation. However, swab sampling shall
be considered as the primary criteria for cleaning validation. If the results of rinse sampling
considering the final rinse volume and the Limit of Detection for rinse samples are observed to
be more than the acceptance criteria, then only swab sampling shall be done and the cleaning
validation exercise shall be concluded based on results of the swab sampling. Rinse sampling
shall primarily be used in cases where the surfaces are difficult to reach.

9.2 Clean the equipment as per Standard Operating Procedure.

9.3 Fill checklist 1035-G-0038/A13 “Prerequisite checklist for cleaning validation” before
execution of each cleaning validation activity.

9.4 As per the approved sampling plan, collect the rinses / swabs from the equipment and its
parts separately.

9.5 Withdraw about 100 ml aliquots per active ingredient from final rinse / sampled rinses for
estimation of active ingredient along with about 100ml of blank of final rinse (potable water /
purified water / water for injection) as control sample. Send this 100 ml blank of final rinse
(potable water / purified water / water for injection) along with rinse samples.

9.6 Collect about 50 ml sample from final rinse for estimation of cleaning agent.

Note: The rinse sample shall represent the entire rinse volume.

9.7 Collect about 50 ml of sample from final rinse for estimation of solvent / solution (if
applicable).

9.8 Swab individually various parts of the equipment per active ingredient for chemical and
microbial analysis, after cleaning the parts, as detailed in the sampling plan.

9.9 Microbial swabs shall be taken prior to chemical swab sampling.

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9.10 Estimate the content of active ingredient in rinses / swabs as per the validated equality
Control method.

9.11 Analyse the swabs for microbial growth.

9.12 Confirm the removal of cleaning agent and solution/solvent used in the final rinses.

9.13 Visually inspect the final rinse of each part of equipment to ensure that it is clear and
colorless.

9.14 Visually inspect the equipment surface to ensure that it is clean and ensure that it is free from
the characteristic odour of flavours if used in the previous product.

9.15 Based on the results of analysis, calculate the amount of active ingredient and cleaning agent
present in each rinse / swab, microbial growth in the swab and estimate probable
contamination in the next considered product.

9.16 Calculate the limits for acceptance criteria as follows:

9.16.1 Limits of acceptance criteria for swab:

9.16.1.1 Dose criterion

FORMULA:

I x K x M = mg of previous product / 4inch2 or 16 inch2

J L
where,

I = 0.001 of minimum therapeutic dose of previous product in mg.

J = Maximum number of dosage units of next considered product
taken/day.
L = Surface area of equipments common for both the products
(previous product and considered next product)
K = Number of dosage units per batch of next considered product.
M = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

9.16.1.2 10 ppm criterion

FORMULA:

Rx S x U = mg of previous product / 4 inch2 or 16 inch2

T
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where,
R = 10 mg active ingredient in previous product / kg of next considered product.
S = Minimum Batch size in kilograms / litres of next considered product.
T = Surface area of equipments common for both the products (previous product
and considered next product)
U = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

9.16.1.3 PDE criterion:

Formula to get safe threshold value (STV) :

PDE X K X M = mg of previous product / 4 inch2 or 16 inch2

J L

Where,

PDE = Permitted daily exposure

J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipments common for both the products (previous
and considered next product)
K = Number of dosage units per batch of next considered product
M = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

 The Permitted Daily Exposure (PDE) is determined by following equation:

NOAEL X weight adjustment

PDE =
F1 X F2 X F3 X F4 X F5

The modifying factors are as follows:

F1 = A factor to account for extrapolation between species
F1 = 5 for extrapolation from rats to humans
F1 = 12 for extrapolation from mice to humans
F1 = 2 for extrapolation from dogs to humans
F1 = 2.5 for extrapolation from rabbits to humans
F1 = 3 for extrapolation from monkeys to humans
F1 = 10 for extrapolation from other animals to humans
F2 = A factor of 10 to account for variability between individuals
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F3 = A variable factor to account for toxicity studies of short-term exposure

F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for
cats, dogs and monkeys).
F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.
F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents.
F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents.
F3 = 10 for studies of a shorter duration
F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic
carcinogenicity, neurotoxicity or teratogenicity. In studies of reproductive toxicity, the
following factors are used:
F4 = 1 for fetal toxicity associated with maternal toxicity
F4 = 5 for fetal toxicity without maternal toxicity
F4 = 5 for a teratogenic effect with maternal toxicity
F4 = 10 for a teratogenic effect without maternal toxicity
F5 = A variable factor that may be applied if the no-effect level was not established.
When only an LOEL is available, a factor of up to 10 could be used depending on the
severity of the toxicity.

Note: 1. If values of individual factors are not available, then consider highest value.
2. If the NOEL value is available, F5 factor shall be considered as 1.
3. If body weight is considered while calculation of NOEL, then weight adjustment
factor shall be considered as 1 while calculation of PDE.
 For this approach NOEL shall be estimated from the LD50 value using the following equation:

LD50 X BW
NOEL =
MF1

NOEL = No Observable Effect Level

LD50 = the 50% lethal dose of the target residue in an animal, typically in mg / kg of
body weight (by the appropriate route of administration)
BW = body weight of patient taking next product (50 kg)
MF1 = The modifying factor selected shall be not more than 1000.

For example, If Alprazolam molecule is considered,

Toxicity NOEL PDE
Oral, mouse: LD50=1020 = 1020 x 50 = 51 = 51 = 0.004
mg/kg. 1000 12 x 10 x 10 x 10
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STV (safe threshold value) :

0.004 X K X M = Jmg of previous product / 4 inch2 or 16 inch2

L

9.16.2 Limits of acceptance criteria for rinse:

The most stringent limits of acceptance criterion of swab that would emerge from dose
criterion, 10 ppm criterion and PDE criterion, that acceptance criterion shall be used to derive
the limits for the acceptance criterion of rinse.
Derive the acceptance criterion for rinse by using following formula:

9.16.2.1 Dose criterion:

Formula:

I X K X A = ppm of previous product

J L B

Where,

I = 0.001 of minimum therapeutic dose of previous product in mg.

J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipment’s common for both the products (previous and
considered next product)
K = Number of dosage units per batch of next considered product
A = Area of specific equipment sampled
B = Quantity of final rinse/ sample rinse in kg or Litre

9.16.2.2 10 ppm Criterion :

Formula:

RX S X A= ppm of previous product

T B
Where,

R = 10 mg active ingredient in previous product / kg of next considered product.

S = Minimum Batch size in kilograms / litres of next considered product.
T = Surface area of equipment’s common for both the products (previous and
considered next product)
A = Area of specific equipment sampled
B = Quantity of final rinse/ sample rinse in kg or Litre
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9.16.2.3 PDE criterion:

Formula to get safe threshold value (STV) :

PDE X K X A = Jppm previous product

L B

Where,

PDE = Permitted daily exposure

J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipment’s common for both the products (previous and
considered next product)
K = Number of dosage units per batch of next considered product
A = Area of specific equipment sampled
B = Quantity of final rinse/ sample rinse in kg or Litre

9.17 Compare the amount of residue of the previous product against respective established
acceptance criteria for rinse and swab.

Note :1. In case of low acceptance criteria more area can be considered for swabbing for example – 16
sq inch.
2. If NOEL is not available then go for LOEL.
3. If NOEL/NOAEL/LOEL value is not available then NOEL shall be calculated based LD50.
4. For single drug, LD50 value may be available for more than 1 species, but sensitivity may vary
from species to species. Sensitivity is shown in decreasing order as Monkey-----------Dog-------
-----Rat--------------Mice. LD50 value of Rat / Mice shall be considered for calculation.
5. LD50 value differ based on the type of formulations/Route of administration. While doing
calculations for cleaning validation LD50 value to be selected based on formulations/Route of
administration. If LD 50 value is not available for other route of administration/ formulation then
oral route LD 50 shall be considered.
6. If LD50 varies with respect to API supplier then lowest LD 50 value of same species between two
suppliers shall be considered.
7. For weight adjustment consider 50 kg for human medicinal product and 1 kg for veterinary
products.

10 Acceptance criteria:

10.1 The most stringent limit of acceptance that would emerge from Dose criterion 10ppm criterion
and PDE criterion shall be applied during validation exercise along with visual verification.
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10.2 Cleaning agents used shall be easily removable. The acceptance criteria for cleaning agent
shall be calculated by determining the carryover to next product through Safe Threshold
Value derived from PDE criteria similar to that used for API, for every equipment. The
cleaning agent shall not be more than this calculated acceptance criteria.

Note: Acceptance criteria for cleaning agent can be calculated by using PDE value. STV (Acceptance
criteria) can be derived by using below mentioned formula

Formula to get safe threshold value (STV) for Rinse:

PDE X K X A = Jppm of cleaning agent

L B
Where,

PDE = Permitted daily exposure

J = Maximum number of dosage units of next considered product taken / day.
L = Surface area of equipment’s common for both the products (previous and
considered next product)
K = Number of dosage units per batch of next considered product
A = Area of specific equipment sampled
B = Quantity of final rinse/ sample rinse in kg or Litre

Note : For Veterinary and Topical products where safe threshold value (STV) cannot be calculated,
in such cases 10 ppm criteria shall be used.

10.3 The equipment and its parts shall be free from odour when flavours are used in the
formulation.

10.4 The final rinse/ sample rinse shall be visually clear and colourless when colours are used in
the formulation.

10.5 Bioburden on equipment shall comply the limits of Microbiological specification.

10.6 There shall not be any traces of solvent / solution in the final rinse, if solvent / solution used
for cleaning.

10.7 Cleaning procedure that consistently ensures all the above can be regarded as validated.

Note: Swab recovery factor shall be considered for calculation during validation, apply recovery
factor (obtained from validation study) for calculating the content if the same is found less
than 100 %. If recovery is observed more than 100 %, do not apply factor for calculation.
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11 Details of Deviation / OOS:

Details of deviations (including justification of acceptance, if any) to successfully carry out the
validation exercise and any OOS results obtained shall be reported. (Attach the details in the
Validation report).

12 Type of Validation:

Concurrent validation / Revalidation (Type of validation to be recorded in the validation report)

13 Frequency:

13.1 Concurrent validation: Three consecutive successful validation studies per equipment based
on the worst case.

13.2 New Product as per worst case / new equipment / Change in cleaning procedure: Three
successful validation studies per equipment.

13.3 In case any new product is introduced in facility, Risk assessment to be performed for
evaluation of worst case product for cleaning validation. if the product is identified to be a
worst case three successful validation studies, If the product is not identified as worst case,
then full cleaning validation will be performed for the first batch.

13.4 Revalidation: Revalidation shall be carried out in the following situations:

13.5 Periodic revalidation:

13.5.1 For non-betalactum antibiotics and non-sexual hormones-corticosteroids: one batch cleaning
validation for each worst case product shall be done once in a year.

13.5.2 For other products:

13.5.2.1 Perform an annual cleaning review report and document as per annexure no. 1035-G-
0038/A14. Based on the review there could be one of the conclusion:
1. The data review definitely supports the conclusion that the cleaning process is in a state of
control, and therefore is still validated. With such a conclusion, there is no need for protocol
runs on any products within group.
2. The data review suggests that the cleaning process may not be in a state of control.
Perform one protocol run on the worst case product. If successful, the cleaning process is
considered validated for all products in the group. For example but not limited to: An OOS
is observed but there is insufficient evidence to prove that it is due to the previous product.
3. The data review supports the conclusion that the cleaning process is definitely not in a
state of control. Conduct an investigation to bring it into a state of control and then perform
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three protocol runs on the worst case product. For example but not limited to: An OOS is
observed but there is sufficient evidence to prove that it is due to contamination from
previous product.

13.5.2.2 Revalidation shall be done for one batch per worst case product in 5 th year after the last
successful run.

13.6 Revalidation in case of changes in equipment / product contact parts / change in source of
API, if required, based on impact assessment, cleaning procedure or cleaning aid (For
example: Cleaning agent) cleaning validation shall be initiated.

Note: Revalidation to be carried out if the formulation of an existing cleaning agent is changed.

14 Risk Management Study :

The Details of the Risk Management Study to be recorded in the Validation Report.

15 Results / Observations:
Record the observations during the study and results obtained from Quality Control
Department in the Validation Report.

16 Summary of the validation activity:

Summarize the findings of the validation study to draw an inference.
17 Recommendations (Including requirements of any additional documentation / changes
to be made in the cleaning SOP):
Record the recommendations based on the interpretation of the results of the Validation
Report.

18 Team approval:
The personnel who have performed the validation study, supervised the validation, completed
the records, monitored the maintenance of equipments, performed the testing of the product
shall approve the validation report.

19 Review (inclusive of follow up action, if any):

The Validation Report shall be reviewed by Head Unit Quality Assurance. The report shall
include any follow up action if required.

20 Approved and Noted by :

Validation Report shall be finally approved by Head Unit Quality Assurance and noted by Unit
Head
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21 Attachments :

 Technical information sheet of cleaning validation sample analysis.

 Approved sampling plan with swab location.
 Common surface area of equipment
 Prerequisite checklist for cleaning validation
22 ABBREVIATIONS :

No. : Number
A.R.No. : Analytical Reference number
ml : Millilitre
QC : Quality Control
mg : Milligram
inch2 : square inch
ppm : Parts Per Million
µg : Microgram
% : Percentage
OOS : Out of specification
MSDS : Material Safety and Data Sheet
PDE : Permitted Daily Exposure
NOEL : No Observable Effect Level
NOAEL : No Observed Adverse Effect Level
LD50 : the 50% lethal dose of the target residue in an animal,
typically in mg / kg of body weight (by the appropriate route
of administration)
BW : body weight of patient taking next product (50 kg)
LOEL : Lowest Observed Effect Level
STV : Safe threshold value
 ANNEXURE 1035-G-0038/A7
(SPECIMEN COPY)

[
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VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : CLEANING OF EQUIPMENT Effective Date :

Supersedes : Page 1 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

Product Name:

1.0 Objective :
To validate the effectiveness of the cleaning procedure for removal of product residues of the
previous product, cleaning agents, solutions/solvents microbial residue, odour and colour upto a
predetermined acceptance level and to ensure that there is no risk associated with
contamination into subsequent product.

2.0 Scope :
Applicable to cleaning procedures of equipment and accessories used in manufacturing of
pharmaceutical products.

3.0 Justification for selection of item / equipment / accessory / process / product / system.

4.0 Site Of The Study :

5.0 Description Of Equipment / Accessory Which Is Cleaned :

Carry out validation as per Validation Protocol No. CVP 01, Version

Equipment :
Date of validation:
Previous product:
Code Number /
Equipment chain no.:
Active ingredients:
Next considered worst product based on least batch size and maximum daily dose from the list
of the products manufactured using the equipment for which validation to be done
Next considered worst product:
Batch Size: Maximum daily dose:

(1035-G-0038/R1/4)
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VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : CLEANING OF EQUIPMENT Effective Date :

Supersedes : Page 2 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

6.0 Responsibility And Training: (Individual Names Shall Be Entered)

Training Trained
Training reports For activity (for Ckd.
Department Name
Status availability example, Testing / by
Operation / Sampling)

Production

Quality
Assurance

Quality
Control

Engineering

Others

7.1 STANDARD OPERATING PROCEDURE (SOP) TO BE FOLLOWED :

7.2 SOP for cleaning of equipment: SOP No.: , Version No.: .

7.3 SOP for sampling of rinses and swabs: SOP No.: , Version No.: .

7.4 SOP for cleaning validation and establishment of worst case product and sampling of rinses
and swabs: SOP No.: , Version No.: .

7.5 Microbiological method for Bioburden studies of equipment: No.: , Version No.
.

7.6 Approved sampling plan No.: .

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VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : CLEANING OF EQUIPMENT Effective Date :

Supersedes : Page 3 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

8.1 Controls:

8.2 Requirements:

8.2.1 Measurement of the following shall be done using validated analytical methods:

Sr. Analytical Method Validation Protocol No.

Residue
No. Rinse Swab

1 Active ingredient

Estimation of cleaning
2 agent in final rinse/swab
(as applicable)
Removal of solvent /
3 solution used for
cleaning

8.2.2 *Material of swab: Nylon membrane filter paper / Texwipe

Lot No. of the Swab used:
*Note: Encircle whichever swab is appropriate.

8.2.3 Visual inspection of cleaned contact parts, checked by :

8.2.4 Visual inspection of Non-contact parts: checked by :

8.2.5 Time frame for storage of unclean equipment (hours) :

8.2.6 Manufacturing completed on : at

8.2.7 Cleaning started on : at

8.2.8 Cleaning done by :

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VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : CLEANING OF EQUIPMENT Effective Date :

Supersedes : Page 4 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

8.2.9 Concentration of the cleaning agent, water quality used for cleaning and for final rinsing,
volume of final rinse and hot water temperature. (if used) required for cleaning :

If hot water is
Quality of water Volume of
Cleaning agent and Quality of water used, the
used for final final rinse Ckd. by
its concentration used for cleaning temperature of
rinsing (kg)
water (0C)
Refer
attached
sampling
plan

8.2.10 Clean equipment storage period after cleaning (days/hours): .

8.2.11 Number of cleaning cycles performed: (for clean in place equipment).

8.3 Calibration :

Calibration Calibration due

Sr. No. Equipment/ instrument Code number Ckd. by
done on on

8.4 Precautions:

Ensure that the Main Switch of the equipment is ‘OFF’ before commencement of cleaning.
Checked By: .
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VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : CLEANING OF EQUIPMENT Effective Date :

Supersedes : Page 5 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

9.0 Validation Procedure:

Note: Refer Cleaning Validation Protocol No: CVP01 Version No:

Refer attached prerequisite checklist 1035-G-0038/A13 for calculations of limits for acceptance
criteria.

10.1 ACCEPTANCE CRITERIA:

10.2 Limits of acceptance criteria for swab:

Visually PDE
LOD Limit for API Most
clean Dose criterion 10 ppm criterion criterion
stringent limit
(µg / 4 inch2 / (µg / 4 inch2 / (µg /
Swab (µg/ from three
16inch2) 16inch2) 4 inch2 /
swab) criteria
16 inch2)

10.3 Limits of acceptance criteria for rinse :

LOD Limit for API rinse (ppm):
For the limits of acceptance criteria for rinse refer point no. 15.1.

10.4 Limits of acceptance criteria for cleaning agent rinse:

LOD Limit for Cleaning agent rinse (ppm):
For the limits of
acceptance criteria for rinse refer point no. 15.1.

11.0 Details of deviation / OOS:

Deviation No./ report dated OOS No./ Report dated Checked by / Date

12.0 Type Of Validation:

.
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VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : CLEANING OF EQUIPMENT Effective Date :

Supersedes : Page 6 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

13.1 Frequency :

13.2 Concurrent validation: Three consecutive successful validation studies per equipment based on
the worst case.

13.3 New Product as per worst case / new equipment / Change in cleaning procedure: Three
successful validation studies per equipment.

13.4 In case any new product is introduced in facility, Risk assessment to be performed for
evaluation of worst case product for cleaning validation. if the product is identified to be a worst
case three successful validation studies, If the product is not identified as worst case, then full
cleaning validation will be performed for the first batch.

13.5 Revalidation: Revalidation shall be carried out in the following situations:

13.6 Periodic revalidation:

13.5.1 For non-betalactum antibiotics and non-sexual hormones-corticosteroids: one batch cleaning
validation for each worst case product shall be done once in a year.

13.5.2 For other products:

13.5.2.1 Perform an annual cleaning review report and document as per annexure no. 1035-G-
0038/A14. Based on the review there could be one of the conclusion:

1. The data review definitely supports the conclusion that the cleaning process is in a state of
control, and therefore is still validated. With such a conclusion, there is no need for protocol
runs on any products within group.
2. The data review suggests that the cleaning process may not be in a state of control.
Perform one protocol run on the worst case product. If successful, the cleaning process is
considered validated for all products in the group. For example but not limited to: An OOS
is observed but there is insufficient evidence to prove that it is due to the previous product.
3. The data review supports the conclusion that the cleaning process is definitely not in a
state of control. Conduct an investigation to bring it into a state of control and then perform
three protocol runs on the worst case product. For example but not limited to: An OOS is
observed but there is sufficient evidence to prove that it is due to contamination from
previous product.

13.5.2.2 Revalidation shall be done for one batch per worst case product in 5th year after the last
successful run.
 [
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VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : CLEANING OF EQUIPMENT Effective Date :

Supersedes : Page 7 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

13.7 Revalidation in case of changes in equipment / product contact parts / change in source of
API, if required, based on impact assessment, cleaning procedure or cleaning aid (For
example: Cleaning agent) cleaning validation shall be initiated.

Note: Revalidation to be carried out if the formulation of an existing cleaning agent is changed.

14.0 Risk management study :

Risk Management Study document number : .

 ANNEXURE 1035-G-0038/A7
(SPECIMEN COPY)

Location
VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : Effective Date :

CLEANING OF EQUIPMENT
Supersedes : Page 7 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

15.1 RESULTS / OBSERVATION:

15.2 Rinses (for Active ingredient, cleaning agent and Solvent/Solution).
A.R.Number:
Visual Done Ckd. Content of Solvent / Checked By
Surface inspection by1 by2 Cleaning Solution
Equipment Qty. of
Area Content of Agent in Content in
Part rinse in Acceptance
(inch2) in ppm final rinse Final Rinse / final Rinse
name/Rinse Kg. criteria in ppm
(A) from QC (Acceptance Swab
no. (B)
criteria :
clear) Limit Content Limit Content

1 Production Officer; 2 Quality Assurance Officer

(1035-G-0038/R1/4)
 Location
VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. :
CLEANING OF EQUIPMENT Effective Date :

Supersedes : Page 8 of 13
Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

15.0 RESULTS / OBSERVATION: (continued...)

Visual Done Ckd. Content of Solvent / Checked By

Surface inspection by1 by2 Cleaning Solution
Equipment Qty. of
Area Content in of Agent in Content in final
Part rinse in Acceptance
(inch2) ppm final rinse Final Rinse / Rinse
name/Rinse Kg. criteria in
(A) from QC (Acceptance Swab
no. (B) ppm
criteria :
clear) Limit Content Limit Content

1
Production Officer; 2 Quality Assurance Officer
 ANNEXURE 1035-G-0038/A7
(SPECIMEN COPY)

Location

VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. :
CLEANING OF EQUIPMENT Effective Date :

Supersedes : Batch Number: Page 9 of 13

REFERENCE PROTOCOL NO. : CVP 01, Version -

15.2 Chemical Swabs (for Active ingredient)

A. R. Number:

Possible Contamination
in next product
Acceptance (mgs/ 4 inch2 or 16 inch2)
Content in µg
Equipment limit = Contents in µg / swab
Part name
/swab
(mg / 4 inch2 (from QC)
(from QC) 1000
or 16 inch2)
= mg / 4 or 16
sq inch

(1035-G-0038/R1/4)
 ANNEXURE 1035-G-0038/A7
(SPECIMEN COPY)

Location
[

VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : Effective Date :

CLEANING OF EQUIPMENT
Supersedes : Batch Number: Page 10 of 13

REFERENCE PROTOCOL NO. : CVP 01, Version -

15.3 Microbial Swabs
A. R. Number :
Acceptance Limit Results
Equipment Total Count Fungal Count Total Count Fungal Count
Part name
(unit: ) (unit: ) (unit: ) (unit: )

15.4 Odour Verification

Equipment parts including non Acceptance

Observation for Odour Verification
contact parts as per the sampling plan criteria

(1035-G-0038/R1/4)
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[

VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : Effective Date :

CLEANING OF EQUIPMENT
Supersedes : Batch Number: Page 11 of 13

REFERENCE PROTOCOL NO. : CVP 01, Version -

16.1 Summary Of The Validation Activity:

16.2 Based on the results of swabs for

various parts of the
(equipment/accessories),
the carryover of (previous product) to next
considered product is found to be meeting / not meeting acceptance criteria.

16.3 Based on the results of final rinse for

various parts of the
(equipment/accessories),
the carryover of (previous product) to next
considered product is found to be meeting / not meeting acceptance criteria.

16.4 Equipment parts on visual inspection found : visually clean / not clean ; meeting / not
meeting acceptance criteria

16.5 Final rinse of equipment parts on visual inspection found clear / not clear; meeting / not
meeting acceptance criteria.

16.6 Content of cleaning agent in final rinse/swab of equipment parts found: meeting / not
meeting acceptance limit. (if applicable).

16.7 Content of solvent / solution in final rinse of equipment parts found: meeting / not
meeting acceptance criteria. (if applicable).

16.8 Count of fungi and total count for contact / non contact parts found: meeting / not
meeting acceptance limit.

16.9 Cleaning procedure that consistently meeting/ not meeting all the above can be
regarded as validated / Not validated.

17.0 Recommendations (including requirements of any additional documentation /

changes to be made in cleaning sop):
 Location
[

VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : Effective Date :

CLEANING OF EQUIPMENT
Supersedes : Batch Number: Page 12 of 13

REFERENCE PROTOCOL NO. : CVP 01, Version -

18.0 Team approval:

Quality Assurance Production Quality Control Engineering

Date: Date: Date: Date:
19.0 Review (inclusive of follow up action, if any):

20.0 Approved By : Noted by :

Head Unit Quality Assurance Unit Head

Date: Date:

21.0 Attachments :

Document name: Attachment No:

 Location
[

VALIDATION REPORT
Report No.: CVR 01 Date of Issue :

Version No. : Effective Date :

CLEANING OF EQUIPMENT
Supersedes : Batch Number: Page 13 of 13

REFERENCE PROTOCOL NO. : CVP 01, Version -

22.0 Abbreviations :
µg : Microgram
A.R.No. : Analytical Reference Number
B. No. : Batch Number
BW : body weight of patient taking next product (50 kg)
Ckd. by : Checked by
Inch2 : square inch
Kg. : Kilogram
LD50 : the 50% lethal dose of the target residue in an animal,
LOD : Limit Of Detection
LOEL : Lowest Observed Effect Level
mg. : Milligram
No. : Number
NOEL : No Observable Effect Level (of administration)
NOAEL : No Observe adverse effect level
OOS : Out of specification
PDE : Permitted Daily Exposure
ppm : Parts per million
QC : Quality Control
Qty. : Quantity
SOP : Standard Operating Procedure
STV : Safe threshold value typically in mg / kg of body weight (by
the appropriate route
 ANNEXURE 1035-G-0038/A8
(SPECIMEN COPY)

Location

LIST OF DOCUMENTS
Seria
Documents Document Number
l
No.

Prepared Approved By: Noted By:

By: Date: Date: Date:
USER DEPARTMENT HEAD UNIT QUALITY ASSURANCE UNIT HEAD

Page 1 of 1 (1035-G-0038/F4/1)
 ANNEXURE 1035-G-0038/A9
(SPECIMEN COPY)

Location

COMMON SURFACE AREA OF EQUIPMENT

Previous Product :

Batch No. :

Next Product :

Equipment / chain no. :

Equipment of Previous Equipment of Next Surface Area of Common

Product: Product: Equipment
Equipment Surface Area

Total Surface Area of Common Equipment

Prepared By: Checked By:

Date: Date:

Page 1 of 1 (1035-G-0038/F4/1)
 ANNEXURE 1035-G-0038/A10
(SPECIMEN COPY)

Location

CLEANING VALIDATION SAMPLING PLAN

No. : Date of Issue :

Version No. : Effective Date :

EQUIPMENT NAME
Supersedes : Page

Equipment code no. :

Reference SOP No. : , Version No. :

Sampling Quantity of rinse :

Table - 1 : Equipment parts and rinse quantity

WASHING FINAL MICRO

RINSE QTY. AS CHEMICAL SWABS
PARTS CLEANED
PER SWABS
SOP (kg) /
Sample rinse

SAMPLING PLAN :

Prepared by Approved by Noted by

Quality Assurance Date : Head Unit Quality Assurance Unit Head Date :
Date :

Page 1 of 2 (1035-G-0038/F6/2)
 Location

CLEANING VALIDATION SAMPLING PLAN

NO. : Date of Issue :

Version No. : Effective Date :

EQUIPMENT NAME
Supersedes : Page

Table 2 : Swab Location Diagram

JUSTIFICATION FOR
SR. NO. EQUIPMENT PART
SWAB LOCATION

C = Swab Location For Chemical M = Swab Location For Micro

 ANNEXURE 1035-G-0038/A11
(SPECIMEN COPY)

Location

NEW PRODUCT INTRODUCTION CLEANING REVIEW REPORT

Reference Risk assessment number:

Product name:

Active pharmaceutical ingredient name:

Review date:

FACTORS IDENTIFIED

Sr. Factors identified Yes No Unknown Remark

No
.

1. Process creating sticky or caked

on solid which is difficult to clean

2. Highly viscous or shear

thickening material resistant to
cleaning

3. Material reacting with water to

form solid or sticky gel like
material.

4. Feasibility of cleaning procedure

5.

6. *

*Any additional parameter considered

Review :

Page 1 of 2 (1035-G-0038/F7/1)
 Location

NEW PRODUCT INTRODUCTION CLEANING REVIEW REPORT

Reference Risk assessment number:

Recommendation :

TEAM APPROVAL:

Production Quality Control Engineering Quality Assurance

Date: Date: Date: Date:

APPROVED BY :

Head Unit Quality Assurance Unit Head

Date: Date:
 ANNEXURE 1035-G-0038/A12
(SPECIMEN COPY)

Location

SUMMARY OF CLEANING VALIDATION

PRODUCT : COMMON BLEND FOR ENTECAVIR TABLETS 0.5 / 1.0 MG, ENTECAVIR TABLETS 0.5 MG AND ENTECAVIR TABLETS 1.0 MG

CLEANING VALIDATION SUMMARY OF NEW PRODUCT

As per 1035-G-0038 Cleaning validation -whenever a new product is introduced into the facility, the procedure mentioned in the flow diagram (see below)
1.0 OBJECTIVE :
is followed.

As common blend for Entecavir tablets 0.5/1.0 mg, Entecavir tablets 0.5 mg and Entecavir tablets 1.0 mg is a new product introduced into the facility.
The common blend follows the same equipment train for each drug product. Therefore this equipment train was evaluated for cleaning validation.

During the cleaning validation exercise, a total of 30 reports were generated along with other supporting documents.

Thus to have a comprehensive review of all the cleaning validation activities, this summary report has been prepared. All the reports with supporting
documents are available in validation section.

Page 1 of 11 (1035-G-0038/F8/2)
 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT
FLOW DIAGRAM OF VALIDATION AND IMPLEMENTATION OF VALIDATED CLEANING PROCEDURE

Introduction of new product in facility

Risk assessment for cleaning validation of new product

Worst case product

Yes No

Perform cleaning validation exercise with 3 batches Perform cleaning validation exercise with 1 batch

Monitoring of
cleaning procedure
and record the results
in Annexure 1035-G-0038/A12

Review of risk assessment based on test result of first batch and review of Annexure 1035-G-
0038/A12

Decision for two more batches of cleaning validation

 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT
2.0 PRODUCT DETAILS :

Product Name Batch No. Stage

Common Blend For Entecavir Tablets 0.5 / 1.0 mg FD3G82 Manufacturing

Entecavir Tablets 0.5 mg FD3G88 Compression and Coating

Entecavir Tablets 1.0 mg FD3G89 Compression and Coating

Entecavir Tablets 1.0 mg FD3H52 Packing

3.0 RISK ASSESSMENT NUMBER: FMECA/13/002/Cleaning Validation for Entecavir tablets 0.5 mg/1.0 mg /01

Based on the risk assessment review report (compiled after first batch cleaning validation results), it is concluded that two additional batches for cleaning
validation are required as mentioned in Section 12.0 at the end of this report.

4.0 REVIEW OF RISK ASSESSMENT NUMBER: FMECA/13/008/Cleaning Validation for Entecavir tablets 0.5 mg /1.0 mg /02

5.0 CLEANING VALIDATION PROTOCOL NO. : CVP 01, version No. 12. Reference document number 1035-G-0038/A6.

6.0 CLEANING VALIDATION REPORT NO. : CVR 01, version No. 12. Reference document number 1035-G-0038/A7.

7.0 ANALYTICAL METHOD VALIDATION PROTOCOL NUMBER FOR MEASUREMENT OF ENTECAVIR IN SWAB AND RINSE: MV/PD/EA210/S,R/01

8.0 ANALYTICAL METHOD VALIDATION PROTOCOL NUMBER FOR MEASUREMENT OF TEEPOL IN RINSE: MV/PD/TEEPOL/S,R/01
ANALYTICAL SPECIFICATION FOR CLEANING VALIDATION : CIE008, version No. 01
9.0
 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT

10.0 LIMIT OF DETECTION (LOD):

Entecavir in swab : 0.1 µg/swab

Entecavir in rinse : 0.01 ppm

Teepol in rinse : 0.25 ppm

11.1 EQUIPMENTS SUMMARY AND RESULTS:

11.2 Common Blend For Entecavir Tablets 0.5 / 1.0 mg

 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT
Results
Accept-ance Content
Content
Sr. Name of Equipment Cleaning Worst case matrix Criteria Limit Sampling Plan Content of of
of API
No. Equipment code no. SOP no. Document No. (mg/4 sq. No. Visual API in Swab Detergent
in Final Bioburden
inch) Inspection (µg/4 Inch in Final
Rinse
sq.) Rinse
(PPM)
(PPM)
#
Total Fungal
≤
≤ Count Count
Should be acceptan
Limits→ acceptance 0.25 ppm Less than Less than
Visually Clean ce criteria
criteria limit (50 (05
limit
cfu/swab) cfu/swab)

1 Telescopic Stirrer C/100 CT-050 WC/TSR/01 0.007 SP/TSR/01 Visually Clean BDL BDL BDL 0 A

Fluid Bed
2 T/010 CT-043 WC/FBE125/01 0.001 SP/FBE125/01 Visually Clean BDL BDL BDL 0 A
Equipment 125

3 Rotor Mill T/011 CT-044 WC/RTM/01 0.001 SP/RTM/01 Visually Clean BDL BDL BDL 0 A

Octagonal
4 T/012A CT-046 WC/OGB450/01 0.003 SP/OGB450/01 Visually Clean BDL BDL BDL 0 A
Blender 450 Liter

5 SS Jar T/JA-001 MT-279 WC/SSJAR/01 0.007 SP/SSJAR/01 Visually Clean BDL BDL BDL 0 A

SP/SSCONT/0
6 SS Tank T/TA-001 MT-279 WC/SSCONT/01 0.007 Visually Clean BDL BDL BDL 0 A
1

SP/SSCONT/0
7 SS Container ENT-001 MT-279 WC/SSCONT/01 0.007 Visually Clean BDL BDL BDL 0 A
1

MA/FS/100/0
8 Filtration Sieve CT-061 WC/FS/01 0.007 SP/FS/01 Visually Clean BDL BDL BDL 0 A
4/03.2010

Blender Pot PH/BS/04/01

9 CT-061 WC/BS/01 0.001 SP/BS/01 Visually Clean BDL BDL BDL 0 A
Sieve /01.2011
 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT

Results
Name of Accept-ance Content of Content of
Sr. Equipment Cleaning Worst case matrix Sampling Content of
Equipme Criteria Limit Visual API in Detergent in
No. code no. SOP no. Document No. Plan No. API in Swab Bioburden
nt (mg/4 sq. inch) Inspection Final Rinse Final Rinse
(µg/4 Inch sq.)
(PPM) (PPM)
#
Total
≤ Fungal Count
Should be Count
≤ acceptance acceptanc Less than
Limits→ Visually 0.25 ppm Less than
criteria limit e criteria (05
Clean (50
limit cfu/swab)
cfu/swab)
SP/SPOON Visually
10 Spoon AC/13 MT-279 WC/SPOON/01 0.007 BDL BDL BDL 0 A
/01 Clean

Visually
11 Scoop T/SO-001 MT-279 WC/SCOOP/01 0.001 SP/SCP/01 BDL BDL BDL 0 A
Clean

Visually
12 Scoop T/SO-002 MT-279 WC/SCOOP/01 0.001 SP/SCP/01 BDL BDL BDL 0 A
Clean

Visually
13 Bin B-137 CT-069 WC/BIN/01 0.001 SP/BIN/01 BDL BDL BDL 0 A
Clean

Visually
14 Bin B-77 CT-069 WC/BIN/01 0.001 SP/BIN/01 BDL BDL BDL 0 A
Clean

Visually
15 IPC I-609 CT-069 WC/IPC/01 0.001 SP/IPC/01 BDL BDL BDL 0 A
Clean

Sampling Visually
16 UST-01 MT-279 WC/STF/01 0.001 SP/SPT/01 BDL BDL BDL 0 A
Thief Clean
Bulk
Visually
17 Sampling BST-01 MT-279 WC/BST/01 0.001 SP/BST/01 BDL BDL BDL 0 A
Clean
Thief

#Total count includes fungi

Note: “A” indicates Absent for fungal count.
BDL: Below detection limit.
 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT

11.3 Entecavir Tablets 0.5 mg

Accept- Results
Worst ance
Sr. Equipme case Criteria Content of
Name of Cleaning Sampling Content of Content of
No nt code matrix Limit Visual Detergent
Equipment SOP no. Plan No. API in API in Final
. no. Documen (mg/4 Inspectio in Final Bioburden
Swab (µg/4 Rinse
t No. sq. n Rinse
Inch sq.) (PPM)
inch) (PPM)
Should ≤ #Total Fungal Count
≤ Count
be acceptanc Less than
Limits→ acceptance 0.25 ppm Less than
Visually e criteria (05
criteria limit (50 cfu/swab)
Clean limit cfu/swab)
Compressi
WC/CPM Visually
1 on Machine T/046 CT-088 0.007 SP/CPM/01 BDL BDL BDL 0 A
61/01 Clean
Fette 3090i
Deduster
WC/DCM Visually
2 cum Metal T/190 CT-049 0.001 SP/DCMD/01 BDL BDL BDL 0 A
D/01 Clean
Detector
Tablet
Coating WC/TCM1 SP/TCM125/0 Visually
3 T/014 CT-052 0.001 BDL BDL BDL 0 A
Machine 25/01 1 Clean
GCS 125
Balance WC/BB/0 Visually
4 T/152 MT-279 0.001 SP/BB/01 BDL BDL BDL 0 A
Bowl 1 Clean
WC/SAM/ Visually
5 Sampler T/SM-001 MT-279 0.001 SP/SAM/01 BDL BDL BDL 0 A
01 Clean
#Total count includes fungi
Note: “A” indicates Absent for fungal count.
BDL: Below detection limit.
 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT
11.4 Entecavir Tablets 1.0 mg
Results
Accept- Content
Worst case ance Content of of
Sr. Name of Equipment Cleaning Sampling Plan Visual Content of
matrix Criteria API in Detergent
No. Equipment code no. SOP no. No. Inspectio API in Final Bioburden
Document No. Limit (mg/4 Swab (µg/4 in Final
sq. inch) n Rinse (PPM)
Inch sq.) Rinse
(PPM)
#
≤ Total Count
Should be Fungal Count
acceptance ≤ acceptance Less than
Limits→ Visually 0.25 ppm Less than
criteria criteria limit (50
Clean (05 cfu/swab)
limit cfu/swab)
Compression
Visually
1 Machine Fette T/046 CT-088 WC/CPM61/01 0.007 SP/CPM/01 BDL BDL BDL 0 A
Clean
3090i
Deduster cum Visually
2 T/190 CT-049 WC/DCMD/01 0.001 SP/DCMD/01 BDL BDL BDL 0 A
Metal Detector Clean
Tablet Coating
WC/TCM125/0 Visually
3 Machine GCS T/014 CT-052 0.001 SP/TCM125/01 BDL BDL BDL 0 A
1 Clean
125
Visually
4 Balance Bowl T/152 MT-279 WC/BB/01 0.001 SP/BB/01 BDL BDL BDL 0 A
Clean
Visually
5 Sampler T/SM-001 MT-279 WC/SAM/01 0.001 SP/SAM/01 BDL BDL BDL 0 A
Clean
Tablet/Capsule
Visually
6 Counting and P/004 PCP-028 WC/TCCFM/01 0.006 SP/TCCFM/01 BDL BDL BDL 0 A
Clean
Filling Machine
Count
Visually
7 verification P/007 PCP-052 WC/CVM/01 0.006 SP/CVM/01 BDL BDL BDL 0 A
Clean
Machine
Visually
8 Tablet Lifter P/003 PCP-027 WC/TLR/01 0.006 SP/TLR/01 BDL BDL BDL 0 A
Clean

#Total count includes fungi

Note: “A” indicates Absent for fungal count.
BDL: Below detection limit.
 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT
Cleaning validation study of common blend for Entecavir tablets 0.5mg / 1.0 mg, entecavir tablets 0.5 mg and entecavir tablets 1.0 mg
12.0 REVIEW :
was

carried out from 23.09.2013 to 08.10.2013, as per reference Protocol No. CVP 01 version 12. As Entecavir monohydrate is a new
molecule,

physical parameters were evaluated during cleaning and no discrepancies were observed. Detailed results are recorded in the risk
assessment

review report. All chemical and microbial results of all parts of equipments were within the predetermined acceptance criteria. No
deviations and

no non-compliances were observed during validation.

: Based on the risk assessment review report, it is recommended to perform two additional cleaning validation runs on the following
13.0 RECOMMENDATION
equipment & accessories since Entecavir monohydrate has been identified as the worst case molecule on this equipment:
1. Telescopic stirrer 6. SS tank
2. Fluid bed equipment 125 7. SS jar
3. Rotor mill 8. Filtration sieve
4. Tablet Coating Machine GCS 125 9. Sampler
5. SS container

For the remainder of the equipments and accessories, Entecavir monohydrate is not the worst case molecule. Those equipment and
accessories with their identified worst case molecule are listed below.
 ANNEXURE 1035-G-0038/A12
(SPECIMEN COPY)

Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT
Worst case product
Sr. No. Equipment
Based on solubility Based on potency
1. Octagonal blender 450 Benedex tablets 400 mg Alprazolam Tablets 0.25 mg (Zopax)
Compression machine fette 3090 Triomune 30 Tablets (
2. Alprazolam Tablets 0.25 mg (Zopax)
i Nevirapine)
3. Deduster cum metal detector Efavirenz Tablets 600 mg Alprazolam Tablets 0.25 mg (Zopax)
4. Blender pot sieve Efavirenz Tablets 600 mg Foracort 400 DP caps

5. Spoon Efavirenz Tablets 600 mg Foracort 400 DP caps

6. Bin Efavirenz Tablets 600 mg Alprazolam Tablets 0.25 mg (Zopax)

Sr. No. Equipment Worst case product

Based on solubility Based on potency

1. Intermediate product container Efavirenz Tablets 600 mg Alprazolam Tablets 0.25 mg (Zopax)

2. Sampling thief Efavirenz Tablets 600 mg Alprazolam Tablets 0.25 mg (Zopax)

3. Bulk Sampling thief Efavirenz Tablets 600 mg Alprazolam Tablets 0.25 mg (Zopax)

4. Balance bowl Efavirenz Tablets 600 mg Alprazolam Tablets 0.25 mg (Zopax)

5. Scoop Efavirenz Tablets 600 mg Alprazolam Tablets 0.25 mg (Zopax)

6. Tablet/ capsule counting & filling machine Efavirenz Tablets 600 mg Asthalin 200 DP caps

7. Count verification machine Efavirenz Tablets 600 mg Asthalin 200 DP caps

8. Tablet lifter Efavirenz Tablets 600 mg Asthalin 200 DP caps

Page 10 of (1035-G-0038/F8/2)
 Location
CLEANING VALIDATION SUMMARY OF NEW PRODUCT
Also based on results of physical parameters recorded in the risk assessment review report, it is concluded that one run cleaning validation is
sufficient on the above equipment and accessories.

Cleaning validation of further two more batches will be carried out on the identified 9 equipment/accessories whenever manufacturing of Entecavir tablets is planned. If
Entecavir tablets production is not planned within 3 months and respective equipment/accessories cannot be validated for Entecavir then a review of the validation
matrix to determine a 2nd worst case product will be performed.

PREPARED BY APPROVED BY NOTED BY

Unit Quality Assurance Head Unit Quality Assurance Unit Head

Date: Date: Date:
 ANNEXURE 1035-G-
0038/A13 (SPECIMEN COPY)

PRE REQUISITE CHECK LIST FOR CLEANING VALIDATION

Equipment Name and Code
Batch No.
No./ Equipment Chain No.

Product Name

Reference Protocol No.

Sampling Plan No.

--- Rinse Swab

Active ingredient
Analytical Method
Validation No.: Cleaning agent
solvent / solution used for
cleaning
Acceptance Criteria Calculation
 Dose Criteria
Formula:

I×K×M = mg of previous product /4 or 16 sq. inch J

L
= mg of previous product /4 or 16 sq. inch

= mg of previous product /4 or 16 sq. inch X 1000

= µg of previous product /4 or 16 sq. inch

Where,
I = 0.001 of minimum therapeutic dose of previous product in mg.
J = Maximum number of dosage units of next product taken / day.
K = Number of dosage units per batch of next product.
L = Surface area of equipments common for both the products.
M = 4 or 16 sq.inch (For reporting results per 4 or 16 sq. inch)

 10 ppm Criterion :
RxSxU = mg/4 or 16 sq. inch
T
= mg/4 or 16 sq. inch

= mg of previous product /4 or 16 sq. inch X 1000 = µg /4 or 16 sq. inch

Page 1 of 4 (1035-G-0038/CL1/3)
 ANNEXURE 1035-G-
0038/A13 (SPECIMEN COPY)

PRE REQUISITE CHECK LIST FOR CLEANING VALIDATION

Equipment Name
and Code No./
Batch No.
Equipment Chain
No.

Acceptance Criteria Calculation

Where,
R = 10 mg active ingredients in previous product / kg of next considered product.
S = Batch size in kilograms / litres of next considered product.
T = Surface area of equipments common for both the products.
U = 4 or 16 sq.inch (For reporting results per 4 or 16 sq. inch)
 PDE criterion:

LD50 X BW
NOEL = =
MF1
NOEL = No Observable Effect Level
LD50 = the 50% lethal dose of the target residue in an animal, typically in mg / kg
of body weight (by the appropriate route of administration)
BW = body weight of patient taking next product (50 kg)
MF1 = The modifying factor selected shall be not more than 1000.

NOAEL X weight adjustment

PDE = =
F1 X F2 X F3 X F4 X F5
Formula to get safe threshold value (STV) :
PDE × K × M = mg of previous product /4 or 16 sq. inch J
L
= mg of previous product /4 or 16 sq. inch X 1000 = µg /4 or 16 sq.
inch

 Most stringent limit from three criteria = µg of previous product / 4

to be applied during Validation inch2 or 16 inch2
exercise

Page 2 of 4 (1035-G-0038/CL1/3)
 ANNEXURE 1035-G-
0038/A13 (SPECIMEN COPY)

Location

PRE REQUISITE CHECK LIST FOR CLEANING VALIDATION

Equipment Name and Code No./ Equipment
Batch No.
Chain No.

Acceptance Criteria Calculation For rinse for API

:
Dose criterion 10 PPM criterion PDE Criterion
Name of the part \
IxKx A= ppm of previous Rx S xA= ppm of previous PDE x K x A= ppm of previous product
rinse number
product J L B product T B J L B
= . = . = .

= ppm of previous product = ppm of previous product = ppm of previous product

= . = . = .

= ppm of previous product = ppm of previous product = ppm of previous product

= . = . = .

= ppm of previous product = ppm of previous product = ppm of previous product

= . = .
= .
= ppm of previous product = ppm of previous product
= ppm of previous product
Where : A = Area of specific equipment sampled B = Quantity of final rinse / Sample rinse in kg or Litre

Page 3 of 4 (1035-G-0038/CL1/3)
 ANNEXURE 1035-G-
0038/A13 (SPECIMEN COPY)

PRE REQUISITE CHECK LIST FOR CLEANING VALIDATION

Equipment Name and Code
Batch No.
No./ Equipment Chain No.

Acceptance Criteria Calculation (For cleaning agent)

PDE criterion:

Formula to get safe threshold value (STV) For Rinse:

PDE x K x A= PPM of cleaning agent
Name of the part \ rinse number
J L B
= .

= PPM of cleaning agent

= .

= PPM of cleaning agent

= .

= PPM of cleaning agent

= .

= PPM of cleaning agent

Where : A= Area of specific equipment sampled B = Quantity of final rinse/ Sample rinse in kg or Litre

Done By Approved By
Quality Assurance Quality Assurance

Page 4 of 4 (1035-G-0038/CL1/3)
 ANNEXURE 1035-G-0038/A14
(SPECIMEN COPY)

Location

ANNUAL CLEANING REVIEW REPORT

Name of equipment/ Equipment

S. No.
chain/ Criteria →

A. WORST CASE CLEANING VALIDATION:

Worst Case Product
Initial Periodic Initial Periodic
Batch No. validation validation Batch No. validation validation
Done on due on Done on due on
1. Solubility
validation Status

Worst Case Product

Initial Periodic Initial Periodic
Batch No. validation validation Batch No. validation validation
2. Potency Done on due on Done on due on
validation Status

Worst Case Product

Initial Periodic Initial Periodic
validation Status Batch No. validatio validatio Batch No. validatio validation
3. Toxicity n Done n due on n Done due on
on on

Page 1 of 7 (1035-G-0038/F9/2)
 Location

ANNUAL CLEANING REVIEW REPORT

B. Subsequent Worst Case Product if Worst case is not validated:

Criteria Product Batch No. Done on Product Batch No. Done on

Second Worst
Case

4. Solubility Third Worst Case

Fourth Worst Case

Second Worst
Case

5. Potency Third Worst Case

Fourth Worst Case

 Location

ANNUAL CLEANING REVIEW REPORT

B. Subsequent Worst Case Product if Worst case is not validated:
Criteria Product Batch No. Done on Product Batch No. Done on

Second Worst
Case

6. Toxicity Third Worst Case

Fourth Worst Case

C. EVALUATION OF OTHER DETAILS:

7. Is there change in worst case product

8. Is there change in cleaning procedure

Is there change in cleaning agent/

9. Composition and concentration of
cleaning agent
 Location

ANNUAL CLEANING REVIEW REPORT

Is there change in cleaning validation

10.
sampling plan of the equipment

Is there change in equipment design/

11.
Surface area

Whether cleaning procedure is verified

12.
for newly introduced product

Is there change in cleaning validation

13.
approach

Is there change in acceptance criteria

14.
calculation

Was any deviation/incidence/OOS/ OOT

15.
reported related to equipment cleaning
 Location

ANNUAL CLEANING REVIEW REPORT

Was any complaint received related to

16. contamination for Product which is
manufactured using the equipment

Was any analytical Incidence reported

related to extraneous peaks observed
17.
during analysis of cleaning validation /
verification sample

Are there any operational issues during

18.
the period impacting the Cleaning
 Location

ANNUAL CLEANING REVIEW REPORT

Summary of findings/Observations:

Recommendation (Including requirements of any additional documentation):

Team approval:

Production Engineering Quality Control Quality Assurance

Date : Date: Date: Date:
 Location

ANNUAL CLEANING REVIEW REPORT

s

Review (Inclusive of follow up action, if any):

Approved by: Noted by:

HEAD UNIT QUALITY ASSURANCE UNIT HEAD

Date : Date :