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Cleaning Validation (CV) FIND HERE

Procedure and Protocol Search

 Janki Singh (https://guideline-sop.com/author/janki-singh/) -  22/11/2020 A B O U T T H E AU T H O R

Mrs. Janki Singh is the

Standard Operating Procedure (SOP) and Guideline for performing Cleaning professional pharmaceuticals
Validation (CV) of drug product manufacturing equipments. Blogger. She has already posted
more than #1000 articles on
Cleaning Validation (CV) varrious topics at different
blogging plateforms.
Contact :
1.0   Objective : guideline.sop@gmail.com

To lay down the procedure for Cleaning Validation (CV) of J O I N U S FO R

U P DAT E S
manufacturing equipments. 
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This Guideline describes the validation of cleaning procedures (CV) for
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residues of cleaning agents as well as the control of potential microbial
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contamination-mix-ups-microbial-contamination/).
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2.0   Scope :
C L A S S I F I C AT I O N
This Guideline is applicable for Cleaning Validation (CV) of
manufacturing equipments in production. Ask Question (https://guideline-
sop.com/category/ask-question/)
3.0   Responsibility :
Calibration (https://guideline-
Quality Control Department & Microbiology : sop.com/category/calibration/)

Checklist (https://guideline-
Preparation and review cleaning validation (CV) protocol and report.
sop.com/category/checklist/)
Preparation and review of cleaning validation (CV) product matrix /
equipment train. Maintenance (https://guideline-
sop.com/category/engg/)
Evaluation of cleaning validation (CV) for new product / new
equipment. Microbiology (https://guideline-

Calculation of the maximum allowable carry over. sop.com/category/microbiology/)

Calculation of shared equipment surface area between products Production (https://guideline-

Collection of samples for cleaning validation (CV) . sop.com/category/production/)

Monitoring of cleaning validation (CV) activities.

Quality (https://guideline-
Review of analytical reports sop.com/category/quality/)
Collection of the sample for microbiological analysis by microbiologist.
Quality Assurance
Analysis of the cleaning validation (CV) samples. (https://guideline-
Performing recovery study for cleaning validation (CV) . sop.com/category/quality/qa/)

Compilation and review the data To follow the procedure

Quality Control (https://guideline-
Review the cleaning validation (CV) matrix, protocol and report. sop.com/category/quality/qc/)
To review the analytical data.
Quality IT (https://guideline-
Production Department: sop.com/category/quality-it/)

SOP's (https://guideline-
Review of cleaning validation (CV) protocol and report.
sop.com/category/sops/)
Provide equipment details, Equipment cleaning SOPs.
Provide information to build database. Stores (https://guideline-
sop.com/category/stores/)
Identifies difficult to clean locations on equipment.
Clean the equipment by trained operators. Validation (https://guideline-
Execute the cleaning validation (CV) schedule. sop.com/category/validation/)

Follow the procedure

FO L LO W U S
Head – Engineering:

Review the cleaning validation (CV) matrix 

 Review cleaning validation (CV) protocol and report.

Calculate & review the equipment contact surface area.
Quality Assurance Department :
 (https:/
To approve the cleaning validation (CV) matrix.
To approve cleaning validation (CV) protocol and report.  (https:/ /www.

4.0   Procedure for Cleaning Validation (CV) :

(https:/ /www. instag
Principle – Cleaning Validation (CV):
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In many cases, the same equipment may be used for processing of
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To avoid contamination of the pharmaceutical product, adequate
cleaning procedures are essential. ) sop.9) hl=en)
Cleaning Validation (CV) is documented evidence that an approved
cleaning procedure will provide equipment which is suitable for
processing of pharmaceutical products.
Objective of the Cleaning Validation (CV) is the confirmation of a reliable
cleaning procedure so that the analytical monitoring may be omitted or
reduced to a minimum in the routine phase.

General Procedure for Cleaning Validation (CV):

Normally only cleaning procedures for product contact surfaces of the

equipment need to be validated.
Consideration should be given to non contact parts into which product
may migrate.
For example Outer surface, seals, flanges, are mixing shaft, fans of
ovens, heating elements etc.
Cleaning procedures for product changeover in the case of marketed
products should be fully validated.
Generally in case of batch-to-batch production it is not necessary to
clean after each batch.
However, cleaning intervals and methods should be determined.
Several questions should be addressed when evaluating the
cleaning process. For example:

At what point does a piece of equipment or system become clean?

What does visually clean mean?

Does the equipment need to be scrubbed by hand?
 What is accomplished by hand scrubbing rather than just a solvent
wash?
How variable are manual cleaning processes from batch to batch
and product to product?
What is the most appropriate solvent or detergent?
Are different cleaning processes required for different products in
contact with a piece of equipment?
How many times need a cleaning process be applied to ensure
adequate cleaning of each piece of equipment?

Cleaning procedures for products and processes which are very similar,
do not need to be individually validated.
It is considered acceptable to select a representative range of similar
products and processes concerned and to justify a validation
programme which addresses the critical issues relating to the selected
products and processes.
A single validation study under consideration of the “worst case” can
then be carried out which takes account of the relevant criteria.
This practice is termed “Bracketing”.
At least three consecutive applications of the cleaning procedure should
be performed and shown to be successful in order to prove that the
method is validated.
Control of change to validated cleaning procedures is required.
Documentation of Cleaning Validation (CV):

A Cleaning Validation (CV) Protocol is required for laying down the

procedure on how the cleaning process will be validated.
It should include the following but not limited to:
The objective of the validation process.
Scope of Validation activities
Responsibility for performing and approving the validation studies.
Validation Team.
Cleaning Validation (CV) approach-

Product Matrix
Selection of Products
Selection of Equipments
Risk assessment of cleaning validation (CV)
Process Overview
Pre cleaning validation (CV) requirements
Precaution and Instruction
Calculation of MACO

Dose Criteria ( or safety based criteria or medical limit criteria)
10 ppm criteria
Toxicity based criteria on LD50 value
Toxicity based criteria on ADE/PDE value
Microbial Contamination
Cleaning Validation (CV) Program
Selection of Cleaning Procedure
Clean-In- Place (CIP)
Clean- out-place (COP)
Manual Cleaning
Water Quantity
Selection of Analytical Method for Cleaning Validation (CV) –

Analytical Method Validation

Specificity Potential interferences
Selection of extraction solvent
Recovery Study
Recovery from Spiked plates/ Coupons or different MOC,s
Correction Factor (Recovery)
Sampling Plan, type of Sampling and Selection of Sampling Method
Evaluation of Cleaning Procedures
Sampling – Cleaning Validation (CV) –

Sampling technique for Chemical Analysis

Technique (sampling) for Microbial Analysis
Status Label
Sampling documentation
Determination of Sampling Points
Equipment Hold time Study
Testing Procedure
Ongoing Monitoring
Training
Acceptance Criteria

Selection of Worst case Product Review of Data

Justification of selection of Worst case
Smallest recommended daily dose (TD)
Solubility
LD50
Calculation of swab Limit
Revalidation

Deviation and Failure investigations


Cleaning Validation (CV) final report
 The Validation Protocol & reports shall be prepared by QA, reviewed by
Quality Assurance, Head production, Head QC & Head Engineering and
approved by Head QA and Head Operation.
A final Validation Report should be prepared.
The conclusions of this report should state if the cleaning process has
been validated successfully.
Limitations that apply to the use of the validated method should be
defined (for example, the analytical limit at which cleanliness can be
determined).
The cleaning process should be documented in SOP.
Records should be kept for cleaning performed in such a way that the
following information is readily available :
The area or piece of equipment cleaned,
The person who carried out the cleaning,
When the cleaning was carried out,
The SOP defining the cleaning process,
The product which was previously processed on the equipment
being cleaned.
The cleaning records should be signed by the operator who performed
the cleaning and checked by the Production chemist and should be
reviewed by Quality Assurance.
Personnel:

Operators who perform cleaning routinely should be trained in the

application of validated cleaning procedures.
Training (https://www.pharmabeginers.com/sop-for-training-
management/) records should be available for all training carried out.
It is difficult to validate a manual, i.e. an inherently variable/cleaning
procedure.
Therefore, operators carrying out manual cleaning procedures should be
supervised at regular intervals.
Equipment:

The design of the equipment should be carefully examined.

Critical areas (those hardest to clean) should be identified, particularly
in large systems that employ semi-automatic or fully automatic clean-
in-place (CIP) systems.
Dedicated equipment should be used for products which are difficult to
remove, for equipment which is difficult to clean (e.g. bags for fluid bed
dryers), or for products with a high safety risk (e.g. biologicals or
products of high potency which may be difficult to detect below an
acceptable limit). 
Microbiological Aspects:

The existence of conditions favorable to reproduction of micro

organisms (e.g. moisture, temperature, crevices and rough surfaces) and
the time of storage should be considered.
The aim should be to prevent excessive microbial contamination.
The period and when appropriate, conditions of storage of equipment
before cleaning and the time between cleaning and equipment reuse,
should form part of the validation of cleaning procedures.
This is to provide confidence that routine cleaning and storage of
equipment does not allow microbial proliferation.
In general, equipment should be stored dry, and under no circumstances
should stagnant water be allowed to remain in equipment subsequent to
cleaning operations.
Guidelines for Cleaning Validation (CV) :

It deals with the validation of equipment cleaning procedures used in

the pharmaceutical industry to prevent cross-contamination or
adulteration of drug products.
Active ingredients:
The most obvious area for evaluation in cleaning validation (CV) is
removal of active ingredients from the equipment.
This evaluation can be carried out by a number of methods, but all have
in common the need for adequate analytical methodology and the
establishment of practical yet meaningful acceptance criteria for
residuals.
Analytical methods requirements:

The analytical methods should be validated before the Cleaning

Validation (CV) Study is carried out.
Methods used to detect residuals or contaminants should be specific for
the substance to be assayed and provide a sensitivity that reflects the
level of cleanliness determined to be acceptable.
Methods should be challenged in combination with the sampling
methods used, to show that the contaminants can be recovered from the
equipment surface and to show the level of recovery as well as the
consistency of recovery.
This is necessary before any conclusions can be made based on the
sample results.
A negative result may also be the result of poor sampling techniques
Calculation for residuals:


Product Residue Contamination
The rationale for selecting limits of carryover of product residue shall be
logically based on the materials involved.
The limits should be practical, achievable and verifiable. On the basis of
following criteria acceptance limits i.e. Maximum Allowable Carry Over
(MACO) shall be established:
Dose Based Criteria (or Safety Based Criteria):
As per this criteria not more 0.001 dose of any product shall appear in
the maximum daily dose of the next product
The following equation shall be used for the calculation of MACO from
previous product (let be a product ‘A’) to next product (let be a product ‘B’)


                                                                                                   SRDDX SF X BS
Maximum Allowable Carry Over (mg per batch) =        ———————
                                                                                                          LRDD

Where,

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SRDD: Smallest recommended daily dose of previous product (Product ‘A’)

SF:      Safety Factor (0.001)

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BS:      Batch size of the next product (product ‘B’) i.e. Minimum Batch Size

LRDD: Largest recommended daily dose; milligram of dosage units of the product ‘B’ taken   per day

10 PPM Criteria:

As per this criterion, not more than 10 ppm of any product will appear in
another product.
The following equation is used to calculate the limit of product ‘A’ if the
next product on the production schedule is product ‘B’.

Maximum Allowable Carry Over (mg per batch) = 0.00001(mg/mg) X BS in mg

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Where,

0.00001 mg of product ‘A’ per 1000000mg of the product ‘B’

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BS: Minimum Batch size of the next product in mg.

Toxicity based criteria (LD50 Criteria):

Calculate the maximum allowable carry over (MACO) based on toxicity

criteria of active ingredient in mg per swab, for the piece of equipment
by following the equation given below, if swab sampling is to be done.
NOEL shall be calculated by following equation:
                                                                            LD50  (mg / kg) x 50 (kg a person) 
                                           NOEL  =          ———————————————— 
                                                                                                         2000


                                                                                       S.F x [NOEL (A)] x [BS (B) in
mg]
MACO (Total equipments in mg) =            ——————————————————
                                                                                                  [LRDD (B) in mg]

Where,

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A = Product to be cleaned

B = Product to be manufactured

S.F. = Safety factor (value based on dosage form/route of

administration).

NOEL (A) = No Observed Effect Level of Product “A”

LRDD (B) = Largest recommended daily dose of Product ‘B’ in ‘mg’

BS (B) = Minimum Batch Size of Product ‘B’ in ‘mg’

Toxicity Based Criteria (ADE/PDE Criteria):

Calculate the maximum allowable carry over (MACO) based on ADE/PDE

following the equation given below, if swab sampling is to be done.
                                                                                           PDE x BS (mg) 
                                                           MACO =         ——————————
                                                                                             LRDD (mg) 

Where,

MACO = Maximum allowable carry over


PDE = Permitted daily Exposure (The maximum acceptable intake per day of residual solvent
in pharmaceutical product).

BS. = Batch size of next product (in mg) (Product having least batch size shall be consider)

LRDD = Largest recommended daily dose (mg) among the entire product manufactured at site.
(B)

Note = ADE/PDE value shall be provided by RA/R&D as per handling of technology transfer
(https://www.pharmabeginers.com/technology-transfer-of-drug-product/) document
at receiving site.

ADE/PDE based MACO calculation done only for EU market products.

On the basis of dose criteria, 10 ppm criteria and Toxicity Criteria the
MACO limit shall be calculated.
After establishing MACO (with minimum value) the swab limits and / or
rinse limits shall be established with respect to total product contact
surface area and total rinse volume respectively.


                                                                                                                 MACO X 100
Swab Limit (drug in mg per 100 cm2 swabbed area) = ———————-
                                                                                                                           TS

Where,

100: Sampled swab area (100 cm2)

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TS: Total product contact surface area (cm2)

               

                                                                               MACO X Surface area of

Equipment (A)
           Rinse Limit (drug in mg/ml) = ————————————————————–
                                                                              TS X Total water used for final
rinse (A)

Where,


A: Equipment from which rinse sample taken
TS: Total product contact surface area (cm2)

Visually Clean Criteria:

No quantity of residue should be visible on the equipment after cleaning

procedure is performed.
Active ingredient in most of the products is visible at the approximately
100 µg per 10 cm sq of surface area. Below this level the residue is not
visible to human eye.
Stringent Acceptance criteria shall be selected as worst case either from
dose criteria or 10 ppm criteria or Toxicity criteria.
LOQ shall be considered during selection of acceptance criteria.
Calculation of amount of residue present in rinse & swab:

Calculation of amount of residue present in rinse & swab done as per

analytical method validation of individual molecules.
% Recovery Factor shall be applied to calculated results to get the actual
residue.
                                                                                          100
                                Recovery Factor =   ————————————-
                                                                          % Recovery (From AMV)

Actual residue = Calculated result X Recovery factor

Procedures for cleaning Validation (CV) Based on Bracketing &

worst case Rating:

The cleaning processes of multiple product equipment are subject to

requirements for cleaning validation (CV) .
In order to minimize the amount of validation requirement a worst case
approach for the validation can be used.
Collect the following information before starting cleaning
validation. 
 Materials needed to be cleaned from the equipment i.e. active
ingredient.
Equipment chain used during manufacturing of a particular product.
A list of product that are manufactured using above chain of equipment
in the facility.
Data of surface area of each piece of equipment that is in contact of the
product, used in the manufacturing of the product(s) at the formulation
site with respect to the batch size.
For each product collect the following details
Batch size in Kg.
Number of dosage units per batch.
Active ingredient
Smallest batch manufactured
Maximum daily dosage
Solubility in water.
Product contact surface area of each piece of equipment in the facility.
Cleaning Validation (CV) matrix shall be prepared as per Annexure No.
VII.
Worst Case Rating:

Decide the worst case product(s) based on the following :

Select the worst case product based on lowest strength (high
potency) lowest solubility of its active ingredient in water from the
product matrix and followed by difficulty in cleaning.
Worst Case Rating shall be as follows:

Potency (TD) >Solubility >Toxicity (LD50)/ (PDE/ADE)> Difficult to clean

Methods of evaluation:

There are several reasonable ways to evaluate the

effectiveness of cleaning procedures and the choice of one over

the others should be based on the unique characteristics of the
equipment and product(s) involved.

Swab test:

After cleaning the equipment, product contact surfaces can be swabbed

to evaluate surface cleanliness. Swabs used should be compatible with
the active, in that they should not interfere with the assay, should not
cause degradation of the compound, and should allow extraction of the
compound for analysis.
The solvent used for swabbing should provide good solubility for the
compound and should likewise not encourage degradation.
Sampling considerations:

The area to be sampled should be in its final condition, as it would be

when ready to use.
In some cases, it is reasonable to swab the entire product contact
surface.
However, when this is not reasonable, a known surface area should be
tested, and the approximate overall surface area which is represented by
the swab(s) should be known.
The area to be sampled should be selected using judgment about which
areas are most difficult to clean.
To ensure accuracy of the overall procedure, it can be applied to a
surface which has been deliberately contaminated with a known, low
level of the active.
Obviously, the surface used for this challenge must be made of the same
material as the equipment to be tested.
Advantage:

Advantage of direct sampling of that areas, hardest to clean and which

are reasonable accessible can be evaluated, leading to establishing a
level of contamination or residue per given surface area.
Additionally, residues that are dried out or are insoluble can be sample
by physical removal.
Rinse samples:

Sampling and testing of rinse samples for residual active ingredient is

commonly used method to evaluate cleanliness the solvent used should
be selected based on the solubility of the active ingredient or at least
provide adequate solubility.
If possible, steps should be taken to ensure the uniformity of the residual
material in the rinse prior to sampling.

It is also critical that the volume of rinse solvent used be controlled.
 For equipment designed to hold liquids, either the volume of rinse
solvent used should be sufficient to ensure contact with all product
contact surfaces, or the method of introducing the rinse solvent should
ensure adequate contact with all surfaces.
Placebo samples:

The placebo sampling method provides the best simulation of actual

production of a subsequent batch of product.
To use this technique, a suitable placebo formulation must first be
chosen.
Factors to consider in making this selection include placebo
manufacturability, solubility of the compound being studied (liquid) and
accurate simulation of actual production conditions for liquid products,
water is often the best placebo formulation.
Cleaning Agent:

A second important focus of cleaning validation (CV) is the removal of

cleaning agents.
These are known equipment contaminants which are added, ironically,
to assist in the cleaning operation itself.
In most cases, more than one cleaning agent is approved for use.
The removal of each may have to investigate to ensure that no problems
will be encountered with their use.
For this reason, it is prudent to limit the number of approved cleaning
agents to minimum required for effective cleaning in various situations.

Applications of Sampling Methods

Sampling Common applications (processing equipment)

Method
Solids Liquids

Swab Scoop, Sifter, Multimill, RMG, FBD, Manufacturing & storage

Sample Blender bin, Compression vessels, Filter press &
machine, Metal detection and Homogenizer Holding tank
dedusting devices, Coating of filling machine
machine, Capsule filling machine
and line equipment and tablet
packing machine.


Rinse Sieve of sifter, RMG, FBD, Blenders
samples bin, Powder transfer pipe or Y
chute, coating pans and Tablet
feeding  Channel of packing
machine
Vessels and tanks
(including agitators), filter
housings & Nozzle of filling
machine

Placebo All equipment All equipment

samples

Cleaning Validation (CV) Approach:

The strategy for the cleaning validation must cover all these activities
and ensure that all equipments are adequately cleaned before it is used
for manufacturing of product.
To cover this wide range of activities, a matrix approach has been
adopted for each cleaning procedure.
Whenever any new product introduced in the facility cleaning
validation (CV) review and assessment will be carried out to evaluate
the need of further cleaning validation (CV) or to show that existing
cleaning method stands valid in future.
For any major change in the cleaning procedure change control shall be
filed and initiated to revise the cleaning validation (CV) protocol to
include the major changes.
The acceptance criteria shall be calculated by using 10 ppm criteria,
dose based criteria and Toxicity based criteria and the criterion having
lowest value shall be selected for study.
Worst-case approach shall be adopted.
Cleaning Validation (CV) is carried out on Non-dedicated equipments
(product contact surfaces) which may become the source of
contamination.
However, emphasis is also given on non product contact parts and area
which may become the source of potential contamination.
Acceptability limits for Cleaning Validation (CV):

Determination of acceptability limit is a critical factor while preparing

cleaning validation (CV) protocol.
The calculation of acceptable level for previous product as contaminant
is important while determining the acceptability limit for cleaning
validation (CV) .

The Product matrix must include the list of all products manufactured
in the equipment/facility and in which the cleaning validation (CV)
shall be performed.
Carry-over of product residues should meet defined criteria, the most
stringent limit of the following three criteria shall be considered for
carry-over of product residues:
Visual inspection criteria:

Visual inspection of equipment/ subject shall be done before taking

swab sample from the sampling location.
Examination (visually) of the whole equipment /subject from product
contact as well as product non contact parts shall be done.
It shall be checked by production personnel and then verified by QA
personnel.
The observation shall be maintained in format for recording of visual
inspection record.
No quantity of residue should be visible to naked eye on the whole
equipment/subject after cleaning procedures are performed (i.e. less
than 100 mcg /100 cm2).
Visual examination of cleaning shall be done from the distance of NMT
5 feet with observing angle of 150 to 900 in suitable light condition at
least 200 Lux intensity.
The equipment/subject shall demonstrate the absence of any noticeable
“off” odor during visual inspection.
10ppm criteria:

Not more than 10ppm of active pharmaceutical ingredient of previous

product is permitted in next product.
Dose based criteria:

Not more than 1/1000 of minimum daily therapeutic dose of the previous
product in the maximum daily dose of the next product, calculated with
respect to the total weight of the dosage form.
It defines that 0.001 (Safety factor) of the normal therapeutic active dose
of previous product must not appear in largest recommended daily dose
of the subsequent product.
Toxicity based criteria:

Environmental Protection Agency and toxicologists suggest that an

acceptable level of a toxic material may be that which is no more than
1/1000 of a toxic dose for solid oral products (Topical products 10- 100,
Oral products 100 – 1000 and Parenteral products 1000 – 10000) of an

 amount which is not known to show any harmful biological effect in the
most sensitive animal system known, e.g., no effect.
The acceptability limits for microbiological sample shall be determined
based on;

Parameters Specification

Cleaned equipment surface samples

Total NMT 100 cfu/swab

Microbial
Count

Remark: Total Microbial Count for manufacturing area shall be studied

after completion of  cleaning, by Active /Passive monitoring (Only for
reference purpose).
Hold Time Studies:

The objective of hold time study is for establishing time limit between
equipment cleaning and reuses it to ensure that the equipment remains
clean till the next use.
Dirty Equipment Holding Studies:

The interval between the end of production and the beginning of the
cleaning process shall be established through equipment holding
studies prior to cleaning.
It is important to consider the effect that weekends, holidays and delays
might have on the cleaning schedule.
For example, a piece of equipment that is utilized first in the morning
shift may contaminate with product, until the second shift starts.

 Having the product ‘dry’ on equipment, therefore, considered as worst
case.
To establish the expiry of cleaning in view of microbiology, equipment
shall be kept ideally after Type B cleaning for 72 hours (3 days) and
microbiological swab shall be taken and analyzed at different intervals
(0 hour, 24 hours, 48 hours and 72 hours).

Cleaned Equipment Hold Time Studies (Microbiological Study

only)

Concerns relative to microbial control are lessened in the production of

non-sterile products but are still important.
Practices which minimize the potential for contamination by
‘objectionable organisms’ are common in the manufacture of non-sterile
formulations.
To establish the expiry of cleaning in view of microbiology, equipment
shall be kept ideally after Type A cleaning for 96 hours (4 days) and
microbiological swab shall be taken and analyzed at different intervals
(0 hour, 24 hours, 48 hours, 72 hours and 96 hours).
This will be considering as worst case and microbial load should
remain well within limit.
Training:

Operator training is critical, especially for manual cleaning.

During cycle development, operators should be trained in the
requirements of the evolving or existing SOPs.
Proper training consists of understanding the SOP, apprenticeship with
qualified, trained operators and review to ensure that the training is
successful.
The effective training or qualification of the operators may be confirmed
by monitoring of the equipment after cleaning, including, where
necessary, analytical testing for residuals.
It is important not only has that operator training occurred, but also that
the training be well documented.
Operators should be retrained each time a cleaning procedure is
changed and the new training must be documents, just as in the case of
a change to a manufacturing procedure.
Revalidation of Cleaning Procedure:

Any change impacting a parameter of a previously establishes

validation study may require revalidation.
Appropriate assessment by manufacturing and QA to determined the
necessity of revalidation is required, on a periodic basis, consistent with 
the Validation Master Plan.
Re-validation shall be performed in case of any change, (at least the
following but not limited to)
Cleaning verification after every 1 year on one batch of worst case
product after compilation of study.
Introduction of a new facility, equipment, process or product.
Change in cleaning procedure.
MACO limit change.
Change in cleaning agent used for cleaning (If applicable)
Major Modification in processing equipment.
As per regulatory requirements.
Deviations and Investigations:

Any deviation observed during cleaning validation (CV) shall be

recorded and investigated as per respective SOP.
If the observed deviation does not have any major impact on the
validation the final conclusion shall be provided.
If the observed deviation has major impact on the validation, deviation
shall be reported to the concerned department for the corrective action
and validation activity shall be redone.
Cleaning verification:

Cleaning Verification shall be done after 1 year for one batch.

A document for cleaning verification shall be prepared before execution
of study on annexure-II. The document shall have pre-approval before
execution and post approval shall be done after compilation of report.
New product/ Equipment Evaluation:

When a new product is introduced in the plant an evaluation is made to

determine if cleaning validation (CV) is required.
If the new product carryover limit is above the previously determined
carryover limit and the new product is more soluble and less potent
than the target component of the previous product, then cleaning
validation is generally not required.
This will be documented in the cleaning validation plan.
Introduction of any new product in existing product matrix shall be
carried out through new product evaluation sheet (Annexure -IV) and
shall be updated in Cleaning validation (CV) product matrix (Annexure-
VII)
Review and update the cleaning validation (CV) product matrix before a
new product is introduced in production facility accordingly.
If any new molecule is selected as worst case, re-validate the cleaning

process.
 Introduction of any new equipment in existing train shall be carried out
through new equipment evaluation sheet (Annexure -V) and shall be
updated in cleaning validation (CV) matrix (Annexure- VII) accordingly.
Review and update the cleaning validation (CV) equipment train if any
change in existing equipment train, re-validate the cleaning process if
required.

5.0   Reference – Cleaning Validation (CV) :

PIC/S – ‘Recommendations on Validation Master Plan, Installation and

Operational 18. Qualifications, Non-Sterile Process Validation & Cleaning
Validation’
APIC (https://apic.cefic.org/pub/APICCleaningValidationGuide-
updateSeptember2016-final.pdf) – ‘Guide on Aspects of Cleaning
Validation in Active Pharmaceutical Ingredient Plants (December 2000)
Validation Master Plan
Guideline on setting health based exposure limits for use in risk
identified in the manufacture of different medical products in shared
facilities. By EMA/CHMP/CVMP/SWP/169430/2012 in Nov 2014

6.0   Glossary:

SOP : Standard Operating Procedure

RSD : Relative Standard Deviation

QA : Quality Assurance

QC : Quality Control (https://guideline-sop.com/general-

information-pharmaceuticals-quality-control/)

API : Active Pharmaceutical Ingredient

CIP : Clean-In- Place

COP : Clean- out-place

TD : Smallest recommended daily dose

LOD : Limit of Detection

LOQ : Limit of Quantitation

MACO : Maximum Allowable Carry Over

MDD : Largest recommended Daily Dose 

BS : Batch size

SOP : Standard operating Procedure

ID. No : Identification number

STP : Standard Test Procedure

ppm : Parts per million

Kg : Kilogram

mg : Milli gram

cfu : Colony forming unit

cGMP : Current Good manufacturing Practice

ss : Stainless Steel

ml : Milli liter

µg : Micro gram

Fig : Figure

cm : Centimeter

cm2 : Square Centimeter

Annexure I   : Template for Cleaning Validation Protocol

Sr. Content Page No.

No.

Protocol Approval

General Information

Objective

Scope

Responsibility


Reference document

Validation Team

Training

Pre-requisites for cleaning validation

Precaution and Instruction

Product detail

Cleaning Validation Approach

Product Matrix

Selection of worst case product

Equipment Selection

Selection swab sampling location of Non detected

process equipment

Calculation of Maximum Allowable Carry over (MACO)

Limit

Selection of Acceptance criteria

Methodology for cleaning validation

Action taken if cleaning swab results not meet the

acceptance criteria

Revalidation

Change Control

Deviations and Failure Investigations

Observation & results

Conclusion

Annexure

Abbreviations

 Revision History

Annexure II: Template for Cleaning Validation Report

Sr. Content Page No.

No.

Approval

Objective

Scope

Responsibility

Reference document

Validation Team

Training

Pre-requisites for cleaning validation

Product detail

Observation and results

Revalidation

Deviations and Failure Investigations

Conclusion

Annexure

Abbreviations

Revision History

Annexure III: Cleaning Validation Protocol Number Issuance Log


Sr. Date Protocol Area/ Issued Checked Report Issued Checked Remark
No. & section By by No. & by by
Effective Effective
date

                   

                   

Annexure IV: New Product Evaluation Sheet

Download the pdf : New Product Evaluation Sheet (https://guideline-

sop.com/wp-content/uploads/2020/11/New-Product-Evaluation-Sheet.pdf)

Annexure V: New Equipment Evaluation Sheet

Equipment :
Name

Location :

Capacity : Make

Total surface : Total product

area contact surface
area

Equipment : New Equipment          Replacement

train Introduction

Compare the above data with data provided in cleaning validation protocol,
and draw the conclusion whether above equipment falls under the existing
matrix or required cleaning verification / validation or change in
acceptance criteria is required.

Change in Yes No   NA Change      Yes      No       NA

operating in
principles à design

Is surface Area       Yes      No Change in cleaning      Yes No

of any train will procedure à
be affectedà 
Total surface Area of particular
train in cm2 (After considering
area of new equipment)

IMPACT ON CLEANING VALIDATION:

Validation required à             Yes             No Verification required Yes No

JUSTIFICATION FOR ACCEPTANCE CRITERIA:

Change in Acceptance criteria required Yes No

Evaluated By Checked By Approved By

Annexure VI: Planner for cleaning validation study

Sr. Product Composition Dosage Selection Batch Validation Updated Remark

No. Name Form criteria No. Status By

(Sign/Date)

1.  

2.  

3.  

Particulars Prepared By Checked By Approved By

Sign.

Date

Annexure VII: Cleaning validation Matrix

Download the pdf :Cleaning Validation Matrix (https://guideline-sop.com/wp-

content/uploads/2020/11/Cleaning-Validation-Matrix.pdf)

Janki Singh (Https://Guideline-

Sop.Com/Author/Janki-Singh/)
Mrs. Janki Singh is the professional pharmaceuticals
(https://guideline
Blogger. She has already posted more than #1000 articles
-
on varrious topics at different blogging plateforms.
sop.com/author/j
Contact : guideline.sop@gmail.com
anki-singh/)

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