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Cleaning Validation Protocol
Posted By: Pharmaceutical Guidanace on: November 06, 2016 In: Cleaning Validation(CV), Validation & Quali cation No Comments
CONTENTS
S. No.
Topic
1.0
Protocol Preparation and Approval Sheet
2.0
Objective
3.0
Scope
4.0
Responsibility
5.0
Validation Team
6.0
Abbreviations and De nitions
7.0
Cleaning Validation Approach
7.1
Selection of Products
7.2
Selection of Equipments
7.3
Type Cleaning after every ve consecutive batches of the same product
8.0
Pre – Cleaning Validation Requirements
9.0
Precautions and Instructions
10.0
Acceptance Criteria
10.1
Product Residue Contamination
10.2
Cleaning agent residue contamination
10.3
Microbial Contamination
11.0
Cleaning Validation Programme
11.1
Selection of Cleaning Procedure
11.2
Water Quality
11.3
Selection of Analytical Method
11.4
Analytical Method Validation
11.5
Sampling Plan, Type of Sampling and Selection of Sampling method
11.6
Evaluation of Cleaning Procedure
11.7
Analytical Testing Procedure
11.8
Cleaning Veri cation
11.9
Ongoing Monitoring
Page No.
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11.10
Ancillary Equipment
11.11
Cleaning of Manufacturing Area
12.0
Hold Time Studies
12.1
Equipment Holding Studies Prior to Cleaning
12.2
Cleaned Equipment Hold Time Studies
13.0
Training
14.0
Revalidation
15.0
Deviations and Investigations
16.0
Cleaning Validation Report
17.0
List of Annexures / Formats Attached
18.0
Reference Documents
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Protocol Preparation and Approval Sheet
Prepared By
Department
Name
Designation
Signature
Date
Quality Assurance
Reviewed By
Department
Name
Designation
Signature
Date
Production
Quality Control
Quality Assurance
Approved By
Name
Designation
Signature
Date
Head Operation
Head QC
Head QA
Objective
To evaluate the capability of cleaning procedure Type A in removing the drug residue and microbiological bio burden on
equipment within established acceptance criteria, through the validation of cleaning procedures.
To establish su cient documented evidence to assure that, cleaning procedures can repeatedly and reproducibly
remove residue of the subjected product and / or cleaning agent i.e. Sodium Lauryl Sulphate (wherever applicable) –
within established acceptance limit. The acceptance limit is maximum allowable quantity of product residue and / or
cleaning agent, which does not a ect quality and safety of the subsequent product to be manufactured, by using
same equipment and facility.
To establish acceptable time limit for storage of cleaned equipment, utensils and components after cleaning (Cleaned
Equipment Hold Time Study). Equipments are not expected to be free from all microorganisms. The objective shall be
to demonstrate that there is no microbial proliferation in equipments during storage.
Scope
This protocol is applicable for validation of cleaning procedure to be followed in Tablet & Capsule section of Pharmaceutical
Formulation Plant .
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Demonstrate that the cleaning procedure shall perform consistently according to predetermined acceptance criteria.
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No unauthorized or unrecorded modi cations have been taken
place.
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and updates.
Cleaning validation shall be performed after Type A cleaning.
After satisfactory visual inspection only, the equipment shall be allowed for sampling.
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Swab samples and Rinse samples shall be collected to verify the presence of active residue content and
Microbiological bio burden as per given sampling plan.
Samples should be taken from pre-de ned locations as mentioned in this protocol.
All Sampling and testing reports have been made available.
All precautions and instructions have been followed.
Three runs of cleaning are required to prove that the process has been validated.
Responsibility
Department
Responsibilities
Responsible for ensuring the overall validation of cleaning methods, used to clean
the process equipment, utensils and areas. These responsibilities for cleaning
validation include:
Preparation, Review and approval of Cleaning Validation Protocols, Reports and
Cleaning Validation Summary Reports.
The approval of SOPs, STPs, GTPs and Cleaning Method Validation Protocols &
Reports.
Quality Assurance
:
Execution of Cleaning Validation Activities.
Sampling during cleaning validation.
Handling of Deviations.
Training of team involved in cleaning validation.
Compile and review of Report
Verifying the cleaning activities
Responsible for ensuring the validation of cleaning methods, followed within this
department. These responsibilities for cleaning validation include:
Review of Cleaning Validation Protocols, Reports and Cleaning Validation Summary
Reports.
The preparation and approval of general operating and cleaning procedures (SOPs).
Production
:
Execution of Cleaning Validation Activities
Provision of personnel for the cleaning of equipment during validation studies.
Initiation of Deviations
Training on equipment and area cleaning SOPs.
Checking of Cleaning activities
Responsible for ensuring the validation of analytical methods used to analyze
cleaning validation samples. These responsibilities for cleaning validation include:
Preparation and Approval of Cleaning Method Validation Protocols and Reports.
Review and Approval of Cleaning Validation Protocols, Reports and Cleaning
Validation Summary Reports.
Quality Control
:
The approval of SOPs, STPs and GTPs.
Analysis of cleaning validation samples and report submission
Initiation of Deviations
Training responsibilities
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Department
Responsibilities
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Responsible for ensuring the
Calculation of equipment contact surface area.
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Engineering
:
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Equipment, components, utensils and area drawings.
Drawings and Quali cation documents of supporting utilities.
Validation Team
Validation team shall comprise of the representatives from following functions:
Quality Assurance
Production
Quality Control
Engineering
Abbreviations and De nitions
API:
:
Active Pharmaceutical Ingredient
LOD
:
Limit of Detection
LOQ
:
Limit of Quantitation
MACO
:
Maximum Allowable Carry Over
MDD
:
Maximum Daily Dose
SLS
:
Sodium Lauryl Sulphate
BS
:
Batch size
SOP
:
Standard operating Procedure
GTP
:
General Test Procedure
ID.No
:
Identi cation number
STP
:
Standard Test Procedure
TD
:
Therapeutic Dose
ppm
:
Parts per million
Kg
:
Kilogram
mg
:
Milli gram
cfu
:
Colony forming unit
cGMP
:
Current Good manufacturing Practice
ss
:
Stainless Steel
ml
:
Milli litre
µg
:
Micro gram
Fig
:
Figure
cm
:
Centimetre
cm
:
Square Centimetre
Clean
:
2
The implementation of procedures to render a piece of equipment, or a system,
free of adulterants and contaminants.
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The process of providingWe'd
documented
evidence
that the cleaning
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employed within a facilitynews
consistently
controls potential carryover of product
Cleaning Validation
:
(including intermediates and impurities), cleaning agents and extraneous
material into subsequent product to a level,
is below predetermined
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levels.
Drug active, excipient, degradant, processing aid, cleaning agent, bio burden or
Contaminant
:
foreign matter that, at a high enough level remaining after cleaning may
potentially contaminate the equipment surfaces or the next product.
Dedicated Equipment/
Accessories
:
Equipment Train
:
Manual Cleaning
:
Objectionable
Equipment/Accessories only used for the manufacture of one product or one
related product line.
Series of individual pieces of equipment linked together for a given process
which may be cleaned individually or as a process train.
A cleaning procedure requiring operator performed critical steps (e.g.,
scrubbing with a brush or rinsing with a hose)
Any organisms that can cause infections, when the drug product is used as
Micro organisms
:
Protocol
:
A document with agreed upon set of standards and tests.
Rinse
:
To clean or treat an equipment as part of a cleaning procedure.
Swab
:
An absorptive device used to remove a sample from a surface.
Visually Clean
:
Absence of visible contaminants.
Worst case
:
Lacs
:
directed or any organism capable of growth in the drug product.
Worst case is those conditions within normal parameters most likely to give
failure.
This is an Indian system of counting and 10 lacs is equal to 1 million.
Cleaning Validation Approach
This speci c protocol shall be applicable to Tablet and Capsule section only.
Due to complexity of manufacturing and packing of multiple products using same equipment a Bracketing approach shall
be applied to prioritize Cleaning Validation Program based on scienti c rationale.
The approach evaluates overall cleaning requirement of the product range and concentrates the validation e ort to
develop Worst Case situation, where common cleaning procedures are followed for similar type (Operating Principle and
Capacity) of equipment.
The Worst Case is considered on the basis of following factors:
Physical characteristic i.e. Solubility, Cleanability
Therapeutic Dose of the Product
Concentration of Active Ingredient
Equipment combination (Equipment Train)
In this bracketing approach cleaning validation of each equipment train shall be performed based upon the worst-case
product selected for that equipment train.
A Matrix of products with the details of active ingredient, therapeutic category, strength, maximum daily dose (mg
& No. of dosage units), and batch size (kg & Lacs) and solubility shall be prepared.
A Matrix of Equipment combination with the details of equipment name, I.D. No., area, capacity, contact surface
area, equipment usage and preferred rinse volume for sampling shall be prepared.
On the basis of matrix of Products and Equipments, Worst Case situation (Product to Product Change Over) shall be
derived. The rationale for each Worst Case shall be justi ed scienti cally.
Rationale for the residue limit established should be scienti c, logical and based upon knowledge of the material. The limits
should be practical, achievable and veri able.
Type cleaning shall be done in the following situations:
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Product to Product change over
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After every ve consecutive batches of the same product
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Production of same products in descending potency
After any major changes of product contact parts
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Receiving of new equipment
Selection of Products
Refer Annexure 1 (Product matrix and selection or worst case products) for Products manufactured in tablet and capsule
section .
Selection of Equipments
Refer Annexure 2 (Equipment matrix) for equipments used in manufacturing of tablet and capsule section.
Cleaning of equipments that are not within the equipment train
If any equipment is not used in the production of worst case products (i.e. not covered under equipment train),
e ectiveness of cleaning shall be accomplished by deliberately contaminating the equipment.
Type A Cleaning after every ve consecutive batches of the same product
Type A cleaning after every ve consecutive batches of the same product shall be assessed by charging accelerated stability
th
studies and results derived from Impurity pro le for 5
batch & microbiological analysis data for all ve batches.
Pre Cleaning Validation Requirements
The cleaning shall be done by following the SOP for cleaning of equipment.
Three successful runs of batches or di erent strength of the same product shall be considered for completion of
cleaning validation activity.
Sampling shall be done from all the pre-decided locations and as per surface area mentioned.
The equipment’s used for manufacturing shall be as per list of equipment’s.
The critical parts of equipment, which are di cult to clean, shall be considered for sampling.
Critical in-process control shall be evaluated with respect to the laid down speci cation.
Swab/ Rinse samples shall be analyzed as per laid down test procedures and comply with respect to the
predetermined speci cations.
Pre Cleaning Validation requirements viz. Product details, Batch Numbers taken for validation, Equipments
used for manufacturing & SOPs for cleaning and Approval status of applicable documents (STPs, GTPs, and
Analytical Method Validation protocols & reports e.t.c.).
Precaution and Instructions
Uncleaned and cleaned equipments shall be transferred to cleaning area in closed condition. (If the cleaning is
not done in the same area).
All the steps shall be followed by same sequence mentioned in the respective cleaning SOP / Cleaning validation
test record.
Cleaning Agent (SLS) shall be used wherever applicable.
Visual inspection shall be performed after completion of cleaning and drying of equipments. After satisfactory
observation, the equipment shall be allowed for sampling. A successful visual inspection is a pre requisite for
sampling. If any residue is detected during the visual inspection, this represents a deviation which must be
processed according to a pre de ned procedure and the equipment shall be cleaned again until visual
inspection is satisfactory.
The rst step of the sampling sequence is the test for microbiological contamination to prevent false positive
results from preceding tests.
The second step of the sampling sequence is the swab test.
The last step of the sampling sequence is the rinse sampling.
For cleaned equipment hold time studies the cleaned equipments must be kept completely closed (covered with
cling lm).
Acceptance Criteria
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 veri able. On the basis of following criteria acceptance limits i.e. Maximum
Allowable Carry Over (MACO) shall be established:
Dose Criteria (or safety based criteria or medical limit criteria)
As per this criteria not more 0.001 dose of any product shall appear in the maximum daily dose of the next product
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The following equation shall be used for the calculation of MACO from previous product (let be a product A to next product
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(let be a product B)
TDX SF X BS
Maximum Allowable Carry Over (mg per batch) = ———————
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MDD
Where,
TD: Single therapeutic dose (smallest strength based on number of mg of active ingredient) of previous product (Product A)
SF: Safety Factor (0.001)
BS: Batch size of the next product (product B) i.e. Minimum Batch Size
MDD:Maximum 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
Where,
0.00001 mg of product A per 1000000mg of the product B
BS: Batch size of the next product in mg.
On the basis of dose criteria and 10 ppm criteria the MACO limit shall be calculated and the dose criteria limit shall be
selected as a Worst Case condition.
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
2
Swab Limit (drug in mg per 100 cm swabbed area) = ———————TS
Where,
2
100: Sampled swab area (100 cm )
2
TS: Total product contact surface area (cm )
MACO
Rinse Limit (drug in mg per liter) = ————————————Total Volume used in liters
Visual Inspection
Visual inspection shall be performed after completion of cleaning. After satisfactory observation, the equipment shall be
allowed for sampling.
Cleaning Agent Residue Contamination
The rationale for selecting limits of carryover of cleaning agent (sodium lauryl sulphate) residue shall be logically based on
the material involved. The limits should be practical, achievable and veri able. On the basis of following criteria acceptance
limits i.e. Maximum Allowable Carry Over (MACO) shall be established:
In case of Cleaning agent (SLS) residue, MACO shall be calculated as follows as per medical limit criteria:
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LD50 (g/kg) X 70(kg a person)
No Observable E ect Level = —————————————
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Conversion Factor (1000)
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From the NOEL number a MACO can then be calculated according to
NOEL XÂ MBS
Maximum Allowable Carry Over (mg per batch) = ————————SF X MDD
Where,
LD50: LD50 value (lethal dose) of the cleaning agent i.e. Sodium lauryl sulphate
SF: Safety Factor (10000)
BS: Batch size of the next product (product B) i.e. Minimum Batch Size
MDD: Maximum Daily Dose; milligram of dosage units of the product Btaken per day
Based on the Bracketing approach the following products were selected for Worst case as per 0.001 dosage criteria and the
limits shall be followed as below:
Type of Dosage Form
Tablet“
Tablet“
Un coated
Film Coated
Hard Gelatine
Capsule
Tablet
Uncoated
Worst case Product
API
Location / Area
Limit as per Dose Criteria
Limit as per 10 ppm Criteria
Swab Limit
Limit for validation -Swab Limit
(including Recovery factor)
Limit for validation -Rinse Limit
Limit Of Quanti cation
Make the computerised report after getting swab/rinse sample Chemical and micro analysis and hold time study.
Combine the rinse water sample and swab sample results and to determine the total carryover.
Cleaning agent limits shall be followed as below
Cleaning Agent
Location/Area
Worst case product
API
Next product
MACO limit
Rinse Limit for validation
Microbial Contamination
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Swab samples shall be collected from product contact surface area immediately after completion of cleaning activities and
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satisfactory visual inspection. For cleaned equipment hold time studies
shall be collected as per speci ed intervals
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(0 days, 3 days, 7 days, 10 days & 14 days). The limits for the microbiological bio burden criteria for product contact surface
are presented below.
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2
Total Aerobic Microbial Count
Swab sampling (cfu / 25 cm )
Limit
NMT 100
During this study, identify all of the micro-organisms isolated so that the data obtained may serve as the baseline for a
trend analysis program.
Once validation e orts are complete and results have established the e ectiveness of the cleaning and sanitization
procedures, a good microbiological control program must be implemented.
Cleaned equipment hold time studies shall be performed in one area with covering of each type of equipment.
Total Aerobic Microbial Count for manufacturing area shall be studied after completion of cleaning, by contact plate technique
(Only for reference purpose only).
Cleaning Validation Programme
Selection of Cleaning Procedure
There are following three types of cleaning methods utilized in the drug product manufacturing facilities.
Clean-In-Place (CIP)
Cleaning of the equipment is performed in place without disassembling and transferring to the Washing area which is
also de ned as In Situ Cleaning.
Cleaning process may be controlled manually or by an automated program.
Clean-Out-Of-Place (COP)
Cleaning of disassembled equipment is performed in a central washing machine.
The washing machine also requires validation such as the temperature, ultrasonic activity, cycle time, cleaning
operation sequence, water quantity, and detergent quantity dispensed etc.
Manual Cleaning
Di cult to clean.
Most extensive and elaborate cleaning procedures are required.
A high quality and extensive training program is required.
Tablet and Capsule section has designed with manual cleaning operations. Wherever, CIP or automated cleaning feature is
designed for the Equipment, those methods of cleaning shall be validated in conjunction with manual cleaning.
The risk involve in manual cleaning processes is taken care of with following factors:
Designing and Construction of washing area with segregation of used equipment cleaning with treated water, nal
cleaning with puri ed water and wiping with clean non-shredding cloth /drying with compressed air.
Adequate protection (covering with cling lm) and storage facility of cleaned equipment.
Detailed SOPs for cleaning.
Training/Quali cation of cleaning operators.
Water Quality
Water to be used for the cleaning of manufacturing equipment is treated water (Potable water) and Puri ed water to be
used for nal rinsing of equipment.
Selection Of Analytical Method
The development and validation of analytical procedures for detection of product residue in cleaning validation sample
requires the selection of appropriate analytical methods.
A speci c method must be selected carefully for detection of product residue; a non-speci c analytical method may lead to
false analytical results.
During validation of the cleaning procedure, the analytical methods used should be able to speci cally quantify
concentrations of all compounds of interest that may be present in samples.
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Speci c method shall be employed during cleaning validation and for subsequent cleaning veri cation or ongoing
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monitoring of cleaning, non- speci c methods shall be employed. news and updates.
Analytical Method Validation
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Any instrumental analytical procedures used to analyze cleaning validation samples need to be speci ed and su ciently
sensitive to determine the low levels of residues typically found in samples. The methods used to analyze samples that
allow the equipment to be released for manufacture of another product shall be validated to ensure that it meets following
requirements.
Speci city
Limit of Detection (LOD)
Limit of Quantitation (LOQ)
Linearity
Precision
Recovery of drug from spiked swabs
Recovery of drug from spiked SS plates, Te on sheets and other product contact materials.
Range
Stability of Analytical Solution
Robustness
Sampling Plan, Type of Sampling and Selection of Sampling Method
Sampling shall be done as per sampling plan.
Samples shall be taken.
The e ectiveness of cleaning procedures shall be evaluated by following methods.
Visual Inspection: Visual inspection of equipment for cleanliness immediately before use is required by the cGMP
regulations.
Swab sampling: The area to be sampled should be selected using judgement about which areas are hard to clean.
Rinse Sampling: Collection of rinse samples should consider hard to access locations and volume.
Evaluation Of Cleaning Procedures
The e ectiveness of cleaning procedures shall be evaluated by following sampling methods.
Visual Inspection
Visual cleanliness criteria shall be the primary criteria for the cleaning of equipment.
Easy and preferred pre-sampling criteria
Qualitative and subjective.
Visual inspection shall be performed after completion of cleaning. After satisfactory observation, the equipment shall be
allowed for sampling.
Visual cleanliness can be evaluated by visual inspection of the equipment after cleaning as per the test record
Organoleptic techniques (i.e. visual, smell, touch) shall be used as a component of the cleaning program and additionally as
one of the tests useful for the validation of the cleaning procedure.
Ensure that equipment visual inspection shall be done at a distance of less than 25 cm and lighting level should be more
than 325 lux.
Swab sampling
Wet the cotton tip of swab with puri ed water and squeeze the cotton tip by pressing gently against the wall of test
tube to remove excess of puri ed water.
2
2
Swab sample shall be collected from 10 x 10 cm (100 cm ).
Selection of sample position shall be based on di cult to clean equipment surface area.
Before collection of swab sample visual inspection of the equipment shall be done to check the cleanliness.
For cleaning validation swab sample shall be collected for chemical/ microbiological analysis from the locations
speci ed as per the sampling locations.
Most of the equipments shall be swabbed for at least 5 locations, depends on equipment size, accessibility and
compliancity.
Strongly preferred method, as some residues may need a mechanical or physical action to remove from the surface.
2
Swab the surface of equipment for 100 cm area
rmly and swab horizontally with one side of the swab and
vertically with other side of the swab (10 strokes on each side).
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Do not rub the surface in to & fro motion.Â
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Put the swab into a clean tube and transfer to the quality control laboratory in a dry state,
Pour 10 ml of sample medium (which was speci ed in method validation protocol)
to the test tubeALLOW
and extract the
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residual drug from the swab in sample medium by sonication of the test tube for about 5 minutes.
Take out the swab from the test solution, squeeze the cotton tip of the swab against the wall of the test tube and
discard the swab. Shake the test tube to make the homogenous solution. This solution shall be used as test solution
and shall be analysed for drug swabbed, from the equipment surface.
Sample for the microbial analysis shall be taken by microbiologist as per procedure mentioned in Protocol for
validation of techniques used for bio burden analysis in cleaning validation.
Rinse Sample (Wherever applicable)
Rinse sample shall be collected from the hard-to-access locations of the equipments.
Equipment surface shall be rinsed with the given quantity of rinse volume with puri ed water and the sample shall be
collected from the rinsate.
After collecting the sample visually inspects the sample it shall be clear, colourless and free from particulate matter.
This solution shall be used as test solution and shall be analysed for the presence of the previous product .
However results of rinse sample alone can not be used for the evaluation of cleaning validation results and its
conclusion.
Samples shall be mentioned Batch Number, Name of product, Equipment Id.No, Sampling Location, Sampled by and Date.
The samples shall be stored at 2-8°C up to testing.
Analytical Testing Procedure
Follow the procedure  for the analysis of cleaning validation samples to determine drug residues.
Cleaning Veri cation
Cleaning veri cation approach will be applied for the unique condition where the product being manufactured for the rst
time is not tting / does not exit in the established product / equipment matrix, until cleaning procedure has been validated
or it is one time activity / event the product will not be manufactured in the same manner on the commercial scale
equipment.
Cleaning veri cation approach will be also applied while introducing/ replacing the any equipment of the train, after
appropriate evaluation. Based on evaluation, veri cation will be performed if required for particular equipment until
cleaning procedure has been validated.
Cleaning veri cation will establish / demonstrate the proper removal of target product residue and microbial load by which
it will not alter the safety, identity, strength, purity and/ or quality of subsequent drug product being manufactured on the
same equipment.
Following criteria shall be adopted:
Selection of swabbing position based on the experience for di cult to clean location of equipment or history for worst-case
sampling.
Method adopted shall be quali ed for the sensitivity and swab recovery.
Cleaning veri cation approach will be also applied while introducing/ replacing the any equipment of the train, after
appropriate evaluation.
Based on evaluation, veri cation will be performed if required for particular equipment until cleaning procedure has been
validated.
Ongoing Monitoring
Once validated, it is advisable to recon rm cleaning e ectiveness from time to time. For manual processes this is essential
until su cient data has been generated to con rm the reproducibility of the cleaning procedure.
Ongoing monitoring shall be performed with de ned criteria on validation report to verify / monitor the cleaning process is
able to con rm the ongoing appropriateness of the training program as well as operator ability to perform the cleaning
process.
Ancillary Equipment
Ancillary equipment is utilized along with the main equipment illustrated in the equipment list. They aid in the
manufacturing process in terms of product transfer. Examples of ancillary equipment are SS scoops, SS spatulas, SS
beakers / measuring cylinders and SS containers etc. Cleaning validation will be established for ancillary equipment.
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Cleaning of Manufacturing Area (Non contact surface area -reference purpose only)
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Cleaning of manufacturing area shall be studied (for Reference purpose only) through this protocol to evaluate the area
cleanliness level. The limits shall be taken as given in product contact surface area and the nal conclusion shall be drawn
after completion of cleaning validation.
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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.
Equipment Holding Studies prior to cleaning
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 e ect that weekends, holidays and delays might have on the cleaning schedule. For example,
a piece of equipment that is utilized rst thing in the morning may sit, contaminated with product, until the second shift
starts. Having the product dry on equipment, therefore, considered as worst case.
An equipments shall be kept ideally for 72 hours at production area, prior to cleaning and consider as worst case.
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 organism 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 cleaning for 336 hours (14
days) and microbiological swab shall be taken and analysed at di erent intervals (0 hour, 36 hours, 168 hours, 240 hours
and 336 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
quali ed, trained operators and review to ensure that the training is successful. The e ective training or quali cation of the
operators may be con rmed by monitoring of the equipment after cleaning, including, where necessary, analytical testing
for residuals.
It is important not only that operator training occur, 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
The cleaning process of speci ed equipment for the speci c product shall be revalidated in one or more of following cases
Change of formulation procedures or quality of pharmaceutical ingredients.
Major changes of process parameters.
Change in facilities
Equipment changes
Changes in cleaning procedure
On appearance of new ndings based on current knowledge.
Batch size change.
Implementation of these changes shall be carried out as per change control system.
Deviations and Investigations
Any deviation observed during cleaning validation shall be recorded and investigated
If the observed deviation does not have any major impact on the validation the nal conclusion shall be provided.
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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.
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Cleaning Validation Report
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Based on the outcome from this validation study, a report shall be prepared by Quality Assurance. The
validation report shall be reviewed and then approved by all functional heads of all the concerned departments.
References
Validation Master Plan
21 Code of Federal Regulations, parts 210 & 211
US FDA Guide to Inspections Validation of Cleaning Process
PIC/S Recommendations on Validation Master Plan, Installation and Operational Quali cations, Non-Sterile Process
Validation & Cleaning Validation
APIC Guide on Aspects of Cleaning Validation in Active Pharmaceutical Ingredient
PDA Technical Report No. 29:Points to Consider for Cleaning Validation
Ira R. Berry, Robert A. Nash, Pharmaceutical Process Validation
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