Cleaning validation presentation(1)

• Normally only cleaning procedures for product contact surfaceNormally only cleaning procedures for product contact surface
need to be validated. Consideration shall be given to nonneed to be validated. Consideration shall be given to non
contact parts where there are chances of product migration.contact parts where there are chances of product migration.
• E. G. Mixing shafts, seals, flanges, fans and oven heatingE. G. Mixing shafts, seals, flanges, fans and oven heating
elements.elements.
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Objective:Objective:
To attain documentedTo attain documented
evidence, which provides a highevidence, which provides a high
degree ofdegree of assuranceassurance that thethat the
Cleaning procedure canCleaning procedure can effectivelyeffectively
remove residues of a product and aremove residues of a product and a
cleaning agentcleaning agent from thefrom the
manufacturing equipment, to a levelmanufacturing equipment, to a level
that does not raisethat does not raise patient safetypatient safety
concerns.concerns.

Possible contaminantsPossible contaminants
• Product residuesProduct residues
• Cleaning agent residues and breakdownCleaning agent residues and breakdown
• Airborne matterAirborne matter
• Lubricants, ancillary materialLubricants, ancillary material
• Decomposition residuesDecomposition residues
• Bacteria, mould and pyrogensBacteria, mould and pyrogens
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Strategy on cleaning validationStrategy on cleaning validation
• Product contact surfacesProduct contact surfaces
• After product changeoverAfter product changeover
• Between batches in campaignsBetween batches in campaigns
• Periodic re-evaluation and revalidationPeriodic re-evaluation and revalidation
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Cleaning validation protocolCleaning validation protocol
Should include :Should include :
• Objective and scopeObjective and scope
• Responsibility for performing andResponsibility for performing and
approving validation studyapproving validation study
• Description of equipment to be usedDescription of equipment to be used
• Time interval between production end,Time interval between production end,
starting of cleaning.starting of cleaning.
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• Details of cleaning procedureDetails of cleaning procedure
• Sampling position and area and diagramSampling position and area and diagram
with difficult to clean area.with difficult to clean area.
• Sampling procedureSampling procedure
• Acceptance criteriaAcceptance criteria
• Analytical method including limit ofAnalytical method including limit of
detection and limit of quantification ofdetection and limit of quantification of
those method.those method.
• Protocol should be formally approved byProtocol should be formally approved by
the responsible and authorized person.the responsible and authorized person.
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Cleaning validation reportCleaning validation report
Should include :Should include :
• Analytical methods including Limit ofAnalytical methods including Limit of
Detection and Limit of QuantitationDetection and Limit of Quantitation
• Acceptance criteria and rationaleAcceptance criteria and rationale
• Results of validation of analyticalResults of validation of analytical
methods.methods.
• Any deviation of manufacturing orAny deviation of manufacturing or
cleaning procedure.cleaning procedure.
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• When revalidation will be requiredWhen revalidation will be required
• Time period during which validation wasTime period during which validation was
performed.performed.
• Summary of the results.Summary of the results.
• The report should be approved.The report should be approved.
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CLEANING PROCEDURE (SOP)CLEANING PROCEDURE (SOP)
Standard Operating Procedure (SOP)Standard Operating Procedure (SOP)
should be required duly approved byshould be required duly approved by
approving authority and it shouldapproving authority and it should
specify the following:specify the following:
1.1. PrecautionsPrecautions andand safety warningsafety warning..
2.2. Cleaning tools and materialsCleaning tools and materials with theirwith their
name, concentration, their dilutionname, concentration, their dilution
instruction, volume requirement,instruction, volume requirement,
storage period and requirements.storage period and requirements.

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3.3. Time limitationsTime limitations::
a. time between end of manufacturinga. time between end of manufacturing
and start of cleaning.and start of cleaning.
b. time between final rinse and drying.b. time between final rinse and drying.
c. frequency of major cleaning for mfg.c. frequency of major cleaning for mfg.
batches of the same product inbatches of the same product in
campaign.campaign.
d. time until additional cleaning isd. time until additional cleaning is
performed for unused cleanperformed for unused clean
equipment.equipment.

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44.. Cleaning levelCleaning level::
MINORMINOR  between two batches of samebetween two batches of same
product or between different strengths (interproduct or between different strengths (inter
convertible formula) of the same product.convertible formula) of the same product.
For minor cleaning, cleaning validation is notFor minor cleaning, cleaning validation is not
required, since cross contamination is not anrequired, since cross contamination is not an
issue.issue.
MAJORMAJOR  between two products.between two products.
In this case, validation of the effectiveness ofIn this case, validation of the effectiveness of
the cleaning procedure in removing residuesthe cleaning procedure in removing residues
to the required level is mandatory.to the required level is mandatory.

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5.5. Cleaning procedureCleaning procedure covers followingcovers following
steps…steps…
Dismantling, Initial washing, FinalDismantling, Initial washing, Final
washing & Parameters such aswashing & Parameters such as
Time,Time,
Temperature,Temperature,
Volume,Volume,
Flow rate etc. should beFlow rate etc. should be
mentioned.mentioned.

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6.6. Drying :Drying :
is very important to preventis very important to prevent
microbiological proliferation. Sometimesmicrobiological proliferation. Sometimes
the final rinse is conducted with hotthe final rinse is conducted with hot
purified water to facilitate evaporation ofpurified water to facilitate evaporation of
the water. Drying time and temperaturethe water. Drying time and temperature
should defined.should defined.
7.7. Visual inspectionVisual inspection ::
No traces or particles visible toNo traces or particles visible to
thethe
naked eye should benaked eye should be
observed after the cleaning.observed after the cleaning.

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CLEANING PROCEDURESCLEANING PROCEDURES
8.8. Cleaned statusCleaned status has to be indicated by puttinghas to be indicated by putting
a label or a card on the clean equipmenta label or a card on the clean equipment..
9.9. StorageStorage place of cleaned equipment /place of cleaned equipment /
utensils withutensils with proper wrappingproper wrapping &&
instructions clearly mentionedinstructions clearly mentioned..
10.10. Cleaning logCleaning log should be maintained.should be maintained.

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THE CLEANING VALIDATIONTHE CLEANING VALIDATION
PROGRAMMEPROGRAMME
1. Selection of cleaning method1. Selection of cleaning method
2. Selecting the Scientific basis for the2. Selecting the Scientific basis for the
contamination limitcontamination limit
3. Selecting the Worst case related to the3. Selecting the Worst case related to the
equipmentequipment
4. Selecting the Worst case related to the4. Selecting the Worst case related to the
productproduct
5. Establishing the storage period after5. Establishing the storage period after
cleaning.cleaning.
6. Selecting the sampling method6. Selecting the sampling method
7. Selecting the analytical method7. Selecting the analytical method
8. Documentation8. Documentation

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1. SELECTION OF CLEANING METHOD1. SELECTION OF CLEANING METHOD
• The equipment design and manual cleaning method areThe equipment design and manual cleaning method are
taken into consideration for selection of equipment. Alltaken into consideration for selection of equipment. All
equipments selected viewing following cleaningequipments selected viewing following cleaning
considerations:considerations:
 Ease of disassembling of contact partsEase of disassembling of contact parts
 All contact surfaces are non-reactive to cleaning methodAll contact surfaces are non-reactive to cleaning method
 Dedicated disposable materials where difficult to cleanDedicated disposable materials where difficult to clean
e.g. FBD bags, filters, Disposable bags in transite.g. FBD bags, filters, Disposable bags in transit
containerscontainers
Least chance of contamination from equipment non-Least chance of contamination from equipment non-
contact parts e.g. lubricants, gaskets, drive system,contact parts e.g. lubricants, gaskets, drive system,
mechanical seal etc.mechanical seal etc.

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1. SELECTION OF CLEANING METHOD1. SELECTION OF CLEANING METHODThe risk involved in manual cleaningThe risk involved in manual cleaning
processes is taken care of with following:processes is taken care of with following:
 Proper washroom design with drying,Proper washroom design with drying,
protection and storage requirement.protection and storage requirement.
 Detailed cleaning SOPDetailed cleaning SOP
Training of cleaning operatorsTraining of cleaning operators

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2. SELECTING THE SCIENTIFIC BASIS FOR THE2. SELECTING THE SCIENTIFIC BASIS FOR THE
CONTAMINATION LIMITCONTAMINATION LIMIT (Acceptance criteria.)(Acceptance criteria.)
• The acceptance criteria:The acceptance criteria:
The acceptance criteria for each piece ofThe acceptance criteria for each piece of
equipment and for the complete manufacturingequipment and for the complete manufacturing
process has to be determined. The carryover ofprocess has to be determined. The carryover of
product residue should meet the most stringentproduct residue should meet the most stringent
of the following criteria.of the following criteria.
1)1)Visibly clean criteria: No quantity of residue willVisibly clean criteria: No quantity of residue will
be visible on the equipment after the cleaningbe visible on the equipment after the cleaning
procedure are performed.procedure are performed.

2)10 PPM criteria:2)10 PPM criteria:
To have least MACO for A product, considerTo have least MACO for A product, consider
the next API with smallest batch size.the next API with smallest batch size.
In case of product A the MACO in mg isIn case of product A the MACO in mg is
calculated using following abbreviatedcalculated using following abbreviated
formula. MBS =35 Kgformula. MBS =35 Kg
MACO= MAX CONC x MBS in mgMACO= MAX CONC x MBS in mg
Where,Where,
•MAX CONC= General limit for maximumMAX CONC= General limit for maximum
allowed concentration of previous substanceallowed concentration of previous substance
in next batch.in next batch.
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MBS = Minimum batch size for the next APIMBS = Minimum batch size for the next API
MACO= 0.00001x 35000000MACO= 0.00001x 35000000
MACO= 350 mgMACO= 350 mg
3) 1/1000 Dose criteria:3) 1/1000 Dose criteria:
MACO=MACO= TDDprevious x MBSTDDprevious x MBS
SF x TDD nextSF x TDD next
MACO= Maximum allowable carryoverMACO= Maximum allowable carryover
acceptable transferred amount from theacceptable transferred amount from the
investigated APIinvestigated API
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• TDD previous= Standard therapeutic doseTDD previous= Standard therapeutic dose
of the investigated APIof the investigated API
• TDD next= Standard therapeutic dose ofTDD next= Standard therapeutic dose of
the next product.the next product.
• MBS = Minimum batch size for the nextMBS = Minimum batch size for the next
APIAPI
• SF= safety factor (1000 is used inSF= safety factor (1000 is used in
calculation based on TDD)calculation based on TDD)
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SAFETY FACTORSAFETY FACTOR
Normally accepted Safety Factor for differentNormally accepted Safety Factor for different
dosage forms are given in the followingdosage forms are given in the following
table:table:
Dosage FormDosage Form Safety FactorSafety Factor
• Research compoundResearch compound 1/100000 – 1/100001/100000 – 1/10000
• Parentral productsParentral products 1/10000-1/50001/10000-1/5000
• Ophthalmic productsOphthalmic products 1/50001/5000
• Oral dosage formsOral dosage forms 1/10001/1000
• Topical productsTopical products 1/100-1/101/100-1/10

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2. SELECTING THE SCIENTIFIC2. SELECTING THE SCIENTIFIC
BASIS FOR THE CONTAMINATIONBASIS FOR THE CONTAMINATION
LIMITLIMIT
•   Contamination Limit Based on OtherContamination Limit Based on Other
Considerations:Considerations:
••  Not DetectableNot Detectable     This type of limit refers to aThis type of limit refers to a
specific analytical method.specific analytical method.
••  Absolute LimitAbsolute Limit  An absolute limit also termedAn absolute limit also termed
“single limit” or “blanket specification” means“single limit” or “blanket specification” means
that the same limit is set for any product,that the same limit is set for any product,
without consideration to toxicological data or towithout consideration to toxicological data or to
the detection level of the analytical method, andthe detection level of the analytical method, and
is usually expressed in parts per million (ppm)is usually expressed in parts per million (ppm)

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3. SELECTING THE WORST CASE3. SELECTING THE WORST CASE
RELATED TO THE EQUIPMENTRELATED TO THE EQUIPMENT
• The worst case for a group ofThe worst case for a group of
equipment is represented by theequipment is represented by the
equipment with the larger productequipment with the larger product
contact surface and the hardest-to-contact surface and the hardest-to-
clean locations.clean locations.

2727
RELATED TO THE PRODUCT:RELATED TO THE PRODUCT:
Only one product out of a group ofOnly one product out of a group of
product processed in a piece ofproduct processed in a piece of
equipment is selected for the cleaningequipment is selected for the cleaning
validation study, based on the lowestvalidation study, based on the lowest
solubility of the active ingredient andsolubility of the active ingredient and
its therapeutic dose.its therapeutic dose.

2828
RELATED TO THE PRODUCT:RELATED TO THE PRODUCT:
• To arrive at theTo arrive at the worst case equipmentworst case equipment
andand worst case productworst case product we needwe need
Equipment Database and ProductEquipment Database and Product
Database.Database.

2929
5. ESTABLISHING THE STORAGE5. ESTABLISHING THE STORAGE
PERIOD AFTER CLEANINGPERIOD AFTER CLEANING The objective for establishing time The objective for establishing time
limit between equipment cleaning and limit between equipment cleaning and
reuse is to ensure that the equipment reuse is to ensure that the equipment
remains clean till the next use. This remains clean till the next use. This
needs demonstration that there is no needs demonstration that there is no
microbial proliferation in cleaned microbial proliferation in cleaned
equipments during storage.equipments during storage.

3030
PERIOD AFTER CLEANINGPERIOD AFTER CLEANING
For establishing the time limit, the For establishing the time limit, the
equipment should be dried. Initial swab equipment should be dried. Initial swab
samples for surface should be taken. samples for surface should be taken.
Thereafter, the equipment should be Thereafter, the equipment should be
protected as prescribed in the SOP and protected as prescribed in the SOP and
stored in its designated area. Periodic stored in its designated area. Periodic
samples of product contact surface for samples of product contact surface for
microbiological contamination should be microbiological contamination should be
taken. (1taken. (1stst
day, 2 day, 2ndnd
day, 3 day, 3rdrd
day etc.) day etc.)
Based on the data generated establish Based on the data generated establish
the acceptable time limit. the acceptable time limit.

3131
PERIOD AFTER CLEANINGPERIOD AFTER CLEANING
• Cleaned equipment surface sample (contact Cleaned equipment surface sample (contact
surface only) test results should demonstrate surface only) test results should demonstrate
absence of specified micro organisms (E. absence of specified micro organisms (E.
Coli, Salmonella etc.) Coli, Salmonella etc.)
• The acceptance level for surface sampling is The acceptance level for surface sampling is
25CFU per 25 sq. cm. 25CFU per 25 sq. cm.

3232
6. SELECTING THE SAMPLING METHOD6. SELECTING THE SAMPLING METHODThe two main sampling methods are:The two main sampling methods are:
1. Swab sampling.1. Swab sampling.
2. Rinse sampling.2. Rinse sampling.

3333
6. SELECTING THE SAMPLING METHOD6. SELECTING THE SAMPLING METHOD
6.1 Swab sampling method6.1 Swab sampling method
Selection of samling point are madeSelection of samling point are made
based on multiple criteria asbased on multiple criteria as
1.1.Area exposed most to API contactArea exposed most to API contact
2.2.Area difficult to cleanArea difficult to clean
Selection of sampling points based onSelection of sampling points based on
Worst case identification.Worst case identification.
Swab samling: Take reaymade swab forSwab samling: Take reaymade swab for
samplingsampling

• Pipette out 5 mL solvent in test tubePipette out 5 mL solvent in test tube
• Pour the swab in test tube & cover it.Pour the swab in test tube & cover it.
• Swab the surface approximately 10 x 10 Swab the surface approximately 10 x 10
CM area (100sq. Cm)CM area (100sq. Cm)
• After the swabbing, put the swab in test After the swabbing, put the swab in test
tube.tube.
• Identification as sampleIdentification as sample
• Submit the sample in QC for analysis.Submit the sample in QC for analysis.
3434

• Rinse sampling: Rinse sampling:
• Initially take appropriate quantity of solvent Initially take appropriate quantity of solvent
in suitable containers as mentioned in in suitable containers as mentioned in
respective SOP.respective SOP.
• Rinse the equipmentRinse the equipment
• Collect the rinse at the discharge port in Collect the rinse at the discharge port in
suitable container.suitable container.
• Discharge the rinse completely and Discharge the rinse completely and
recycle the total content twice.recycle the total content twice.
• Stir the content in container and sample Stir the content in container and sample
the required quantitythe required quantity
• Submit the sample to QC for analysis.Submit the sample to QC for analysis. 3535

3636
SAMPLE SURFACE AREASAMPLE SURFACE AREA
Sample surface areas usually vary from 25Sample surface areas usually vary from 25
sq.cm to 100 sq.cm. The swab area chosen issq.cm to 100 sq.cm. The swab area chosen is
100 sq.cm.100 sq.cm.
SWAB RECOVERY STUDYSWAB RECOVERY STUDY
A swab recovery study is performed toA swab recovery study is performed to
determine the ability of the swab todetermine the ability of the swab to
quantitatively remove the contaminant fromquantitatively remove the contaminant from
the surface sampled.the surface sampled.
The swab taken isThe swab taken is Whatman– Carbon freeWhatman– Carbon free
paperpaper..

3737
7. SELECTING THE ANALYTICAL7. SELECTING THE ANALYTICAL
METHODMETHOD
• The Basic Requirements for the AnalyticalThe Basic Requirements for the Analytical
Method.Method.
1. The sensitivity of the method shall be appropriate to1. The sensitivity of the method shall be appropriate to
the calculated contamination limit.the calculated contamination limit.
2. The method shall be practical and rapid, and, as2. The method shall be practical and rapid, and, as
much as possible use instrumentation existing in themuch as possible use instrumentation existing in the
company.company.
3. The method shall be validated in accordance with3. The method shall be validated in accordance with
ICH, USP and EP requirements.ICH, USP and EP requirements.
4. The analytical development shall include a recovery4. The analytical development shall include a recovery
study to challenge the sampling and testingstudy to challenge the sampling and testing
methods.methods.

3838
METHODMETHOD
• SPECIFIC METHODSSPECIFIC METHODS
 Chromatographic methods such as GC andChromatographic methods such as GC and
HPLCHPLC
 Thin layer chromatographyThin layer chromatography

3939
METHODMETHOD
The chromatography methodThe chromatography method
(HPLC) was selected for cleaning(HPLC) was selected for cleaning
validation studies because of theirvalidation studies because of their
sensitivity, specificity, and abilitysensitivity, specificity, and ability
to quantify. The method should beto quantify. The method should be
validated.validated.

4040
METHODMETHOD
• NON-SPECIFIC METHODS.NON-SPECIFIC METHODS.
    Spectrophotometric methods in the visible,Spectrophotometric methods in the visible,
infrared, or UV rangesinfrared, or UV ranges
        Total organic carbon (TOC)Total organic carbon (TOC)
        Other MethodsOther Methods
For monitoring cleaning procedure TOCFor monitoring cleaning procedure TOC
method is used. It offers at a moderatemethod is used. It offers at a moderate
cost and in addition to its rapidity, acost and in addition to its rapidity, a
detection capability down to thedetection capability down to the ppbppb
range.range.

4141
8. DOCUMENTATION8. DOCUMENTATION
• Validation Master PlanValidation Master Plan
• Technical Transfer InformationTechnical Transfer Information
      such as solubility of product ingredients, such as solubility of product ingredients,
therapeutic dose, equipments to be used and therapeutic dose, equipments to be used and
its contact surface area, batch size, minimum its contact surface area, batch size, minimum
daily dose, maximum daily dose etc for the daily dose, maximum daily dose etc for the
preparation of preparation of Equipment Matrix &Equipment Matrix &  ProductProduct
MatrixMatrix..
• Equipment Qualification ReportsEquipment Qualification Reports
(DQ/IQ/OQ/PQ)(DQ/IQ/OQ/PQ)

4242
8. DOCUMENTATION8. DOCUMENTATION
• Equipment logsEquipment logs
• Training recordsTraining records
• Method validation of analytical testMethod validation of analytical test
methodmethod..
• Cleaning Validation ProtocolCleaning Validation Protocol
• Cleaning Validation ReportsCleaning Validation Reports

4343
At least At least three consecutivethree consecutive applications of applications of
the cleaning procedure should be the cleaning procedure should be
performed and shown to be successful in performed and shown to be successful in
order to prove that the method is order to prove that the method is
validated.validated.
It is usually not considered acceptable to It is usually not considered acceptable to
“test until clean”.“test until clean”.

4444
The validation of cleaning method isThe validation of cleaning method is
only meaningful if the written cleaningonly meaningful if the written cleaning
procedures (on which the validation isprocedures (on which the validation is
based) are always meticulouslybased) are always meticulously
followed.followed.

Cleaning validation presentation(1)

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