TITLE Protocol Number: JML/CVP/P/BT/001

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Revision No.: 00 PROTOCOL Effective Date: 19/01/2018
Department : QA

CLEANING METHOD VALIDATION

PROTOCOL

FOR COATED TABLETS

(PENICILLIN)
 TITLE Protocol Number: JML/CVP/P/BT/001

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Department : QA

Protocol Contents
Sr. No Section Title
1.0 Protocol Preparation and Approval Sheet
2.0 Objective
3.0 Scope
4.0 Responsibility
5.0 Validation Team
6.0 Abbreviations and Definitions
7.0 Cleaning Validation Approach
7.1 Selection of Products
7.2 Selection of Equipment
7.3 Type ‘A’ Cleaning consider for cleaning validation
8.0 Pre – Cleaning Validation Requirements
9.0 Precaution 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 Evaluation Of Cleaning Procedures
11.5 Analytical Testing Procedure
11.6 Cleaning Verification
11.7 Ongoing Monitoring
12.0 Revalidation
13.0 Deviations and Investigations
14.0 Cleaning Validation Report
15.0 List of Annexure / Formats attached
16.0 References

1.0 Protocol Preparation and Approval Sheet

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Department : QA

Prepared By
Department Name Designation Signature Date
Vandana Sharma Sr. Officer
Quality Assurance

Reviewed By
Department Name Designation Signature Date
Attar Singh Manager
Head Production

Hem Raj Manager

Engineering

Ajay Saklani Manager

Quality Control

Approved By
Name Designation Signature Date
Head –
Quality Assurance

2.0 Objective
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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 sufficient documented evidence to assure that, cleaning procedures can
repeatedly and reproducibly remove residue of the subjected product and / or cleaning agent (if
applicable) - within established acceptance limit. The acceptance limit is maximum allowable
quantity of product residue and / or cleaning agent, which does not affect 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.

3.0 Scope

This protocol is applicable for validation of cleaning procedure to be followed in production block
(Tablet, Capsule & dry powder Oral suspension section) of Pharmaceutical Formulation JM
Laboratories, Solan.
 Demonstrate that the cleaning procedure shall perform consistently according to predetermined
acceptance criteria.
 No unauthorized or unrecorded modifications have been taken place.
 Cleaning validation shall be performed after Type ‘A’ cleaning.
 After satisfactory visual inspection only, the equipment shall be allowed for sampling.
 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-defined 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.

4.0 Responsibility
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Department Responsibilities
Production Responsible for ensuring the validation of cleaning methods, followed within this
Department 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).
:  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
Engineering Responsible for ensuring the
Department  Calculation of equipment contact surface area.
:
 Equipment, components, utensils and area drawings.
 Drawings and Qualification documents of supporting utilities
Responsible for ensuring the validation of analytical methods used to analyze cleaning
Quality Control
validation samples. These responsibilities for cleaning validation include:
Department
 Preparation and Approval of Cleaning Method Validation Protocols and Reports.
 Review and Approval of Cleaning Validation Protocols, Reports and Cleaning
: Validation Summary Reports.
 The approval of SOPs, STPs and GTPs.
 Analysis of cleaning validation samples and report submission
 Initiation of Deviations
 Training responsibilities
Quality Responsible for ensuring the overall validation of cleaning methods, used to clean the
Assurance process equipment, utensils and areas. These responsibilities for cleaning validation
Department 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.
 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
5.0 Validation Team
Validation team shall comprise of the representatives from following functions:
 Quality Assurance
 Production
 Quality Control
 Engineering

6.0 Abbreviations and Definitions

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API: : Active Pharmaceutical Ingredient

API: : Active Pharmaceutical Ingredient
LOD : Limit of Detection
LOQ : Limit of Quantitation
MACO : Maximum Allowable Carry Over
MDD : Maximum Daily Dose
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BS : Batch size
SOP : Standard operating Procedure
GTP : General Test Procedure
ID No. : Identification 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
2
cm : Square Centimetre
Clean
: The implementation of procedures to render a piece of equipment, or a
system, free of adulterants and contaminants.
Cleaning Validation : The process of providing documented evidence that the cleaning methods
Contaminant : employed within
Drug active, a facility
excipient, consistently
degradant, controls
processing aid,potential
cleaningcarryover of
agent, bio
Dedicated Equipment/ : burden or foreign matter
Equipment/Accessories that,
only usedat for
a high enough levelof remaining
the manufacture after
one product or
Accessories one related product line.
Equipment Train : Series of individual pieces of equipment linked together for a given
Manual Cleaning : process which
A cleaning may be cleaned
procedure individually
requiring operator or as a process
performed train.steps (e.g.,
critical
Objectionable : scrubbing with athat
Any organisms brush
canorcause
rinsing with a hose)
infections, when the drug product is used as
Micro organisms directed or any organism capable of growth in the drug product.
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 : Worst case is those conditions within normal parameters most likely to
Lacs : give
This failure.
is an Indian system of counting and 10 lacs is equal to 1 million.

7.0 Cleaning Validation Approach

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JM Laboratories has designed the multi-product facility to manufacture and pack Oral Dosage
Form which includes Solid dosage forms (Tablets & Capsules and Dry Syrup manufacturing.

This specific protocol shall be applicable to Amoxycillin & Potassium Clavulanate Tablets
(Coated Tablets) of Penicillin section of oral block manufacturing.

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
scientific rationale.

The approach evaluates overall cleaning requirement of the product range and concentrates the
validation effort 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 justified scientifically.

Rationale for the residue limit established should be scientific, logical and based upon knowledge of
the material. The limits should be “practical, achievable and verifiable”.

 Type ‘A’ cleaning shall be done in the following situations:

o Product to Product change over
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o After every five consecutive batches of the same product

o Production of same products in descending potency
o After any major changes of product contact parts
o Receiving of new equipment
o After completion of validity (108 hours) of type “A”
o After completion of preventive maintenance work if product contact parts are disturbed/
contaminated.

7.1 Selection of Products

Refer Annexure –I (Product matrix and selection or worst-case products) for Products manufactured
in specify the dosage form section of Area.

7.2 Selection of Equipment

Refer Annexure -II (Equipment matrix) for equipments used in manufacturing of mention the
dosage forms with manufacturing area.
7.3 Cleaning of equipment 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), effectiveness of cleaning shall be accomplished by deliberately contaminating
the equipment.

7.4 Type ‘A’ Cleaning after every five consecutive batches of the same product

Type ‘A’ cleaning after every five consecutive batches of the same product shall be
assessed by chemical & microbiological analysis.

8.0 Pre – Cleaning Validation Requirements

 The cleaning shall be done by following the SOP for cleaning of equipment.
 Three successful runs of batches or different 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 equipments used for manufacturing shall be as per list of equipments.
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 The critical parts of equipment, which are difficult to clean, shall be considered for
sampling.
 Critical in-process control shall be evaluated with respect to the laid down specification.
 Swab/ Rinse samples shall be analyzed as per laid down test procedures and comply with
respect to the predetermined specifications.
8.1 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.) shall be
mentioned in as a separate annexure before execution.
9.0 Precaution and Instructions
9.1 Uncleaned and cleaned equipments shall be transferred to cleaning area in closed condition. (If
the cleaning is not done in the same area).
9.2 All the steps shall be followed by same sequence mentioned in the respective cleaning SOP /
Cleaning validation test record.
9.3 Cleaning Agent shall be used wherever applicable.
9.4 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 defined procedure and the
equipment shall be cleaned again until visual inspection is satisfactory.
9.5 The first step of the sampling sequence is the test for microbiological contamination to prevent
false positive results from preceding tests.
9.6 The second step of the sampling sequence is the swab test.
9.7 The sample is taken with help of cotton swab from the machine parts.
9.8 The last step of the sampling sequence is the rinse sampling.

10.0 Acceptance Criteria

10.1 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:
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10.1.1 Dose Criteria (or safety-based criteria or medical limit criteria)

As per dose 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’)

TDX SF X BS
Maximum Allowable Carry Over (mg per batch) = ---------------------
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

10.1.2 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
limit shall be selected as a ‘Worst Case’ condition whichever minimum MACO limit.
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 25
2
Swab Limit (drug in mg per 25 cm swabbed area) = ----------------------
TS
Where,
25: Sampled swab area (25 cm2)
TS: Total product contact surface area (cm2)
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MACO
Rinse Limit (drug in mg per liter) = -------------------------------------
Total Volume used in liters

10.1.3Visual Inspection
Visual inspection shall be performed after completion of cleaning. After satisfactory observation,
the equipment shall be allowed for sampling.

Based on the Bracketing approach the following products were selected for Worst case as per
0.001dosage criteria and the limits shall be followed as below:

Product Amoxycillin & Potassium Clavulanate Tablets 375mg

API Amoxycillin Trihydrate Potassium Clavulanate

Swab Limit as per Dose

NMT 0.3192 NMT 1.1173
Criteria (mg/swab)

Swab Limit as per 10 ppm

NMT 0.0223 NMT 0.0223
Criteria (mg/swab)

Make the computerised report after getting swab/rinse sample Chemical and micro analysis report
as per the Annexure.

Combine the rinse water sample and swab sample results and to determine the total carryover as per
specify the annexure. Cleaning agent will be used as purified water.

10.2 Microbial Contamination

Swab samples shall be collected from product contact surface area immediately after completion of
cleaning activities and satisfactory visual inspection. The limits for the microbiological bio burden
criteria for product contact surface are presented below.
Total Aerobic Microbial Count Swab sampling (cfu / 25 cm2)
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 efforts are complete and results have established the effectiveness of the cleaning
and sanitization procedures, a good microbiological control program must be implemented.
Total Aerobic Microbial Count for manufacturing area shall be studied after completion of
cleaning, by contact plate technique (Only for reference purpose only).
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11.0 Cleaning Validation Programme

11.1 Selection of Cleaning Procedure
There are following three types of cleaning methods utilized in the drug product manufacturing
facilities.
11.1.1 Clean-In-Place (CIP)
 Cleaning of the equipment is performed in place without disassembling and transferring to
the washing area which is also defined as In Situ Cleaning.
 Cleaning process may be controlled manually or by an automated program.
11.1.2 Clean-Out-Of-Place (COP)
 Cleaning of disassembled equipment is performed in a Bin 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.
11.1.3 Manual Cleaning
 Difficult to clean.
 Most extensive and elaborate cleaning procedures are required.
 A high quality and extensive training program are required.
Here the specifics dosage forms with area e.g.: Tablet, Capsule & dry syrup section of Oral
production block in JM Laboratories, Solan 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, final cleaning with purified water and wiping with clean non-shredding cloth
/drying with compressed air.
 Adequate protection (covering with cling film) and storage facility of cleaned equipment.
 Detailed SOPs for cleaning.
 Training/Qualification of cleaning operators.
11.2 Water Quality
Water to be used for the cleaning of manufacturing equipment is treated water (Potable water) and
Purified water to be used for final rinsing of equipment.
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11.3 Sampling Plan, Type of Sampling and Selection of Sampling Method

Sampling shall be done as per sampling plan given in annexure.

Samples shall be taken as per given locations in annexure.
The effectiveness 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.

11.4 Evaluation Of Cleaning Procedures

The effectiveness of cleaning procedures shall be evaluated by following sampling methods.

11.4.1 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 given in annexure.

 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.

11.4.2 Swab sampling

 Strongly preferred method, as some residues may need a mechanical or physical action to remove
from the surface.
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 Most of the equipment shall be swabbed for at least 1 – 5 locations, depends on equipment size,
accessibility and compliancity.
 For cleaning validation swab sample shall be collected for chemical/ microbiological analysis
from the locations specified as per the sampling locations (specify as -refer annexure).
 Before collection of swab sample visual inspection of the equipment shall be done to check the
cleanliness.
 Selection of sample position shall be based on difficult to clean equipment surface area.
 Swab sample shall be collected from 5 x 5cm2 (25 cm2).
 Wet the cotton tip of swab with purified water and squeeze the cotton tip by pressing gently
against the wall of test tube to remove excess of purified water.
 Swab the surface of equipment for 25 cm2 area firmly and swab horizontally with one side of the
swab and vertically with other side of the swab (10 strokes on each side).
 Do not rub the surface in to & fro motion. Refer the typical diagram (Fig. 1 & Fig.2) given below
to collect swab sample.
10 cm

10 cm

5 cm

5 cm
Fig. 2
Fig. 1

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 specified in method validation protocol) to the test tube
and extract the 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
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solution shall be used as test solution and shall be analysed for drug swabbed, (specify as a -as per
Annexure,) from the equipment surface.
 Sample for the microbial analysis shall be taken by microbiologist as per procedure mentioned in
the respective SOP.
11.4.3 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 purified water
(specify as a refer annexure) 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.

11.5 Analytical Testing Procedure

The API considered for cleaning validation and attached with this report and follow the
procedure as given in for the analysis of cleaning validation samples to determine drug residues
of Particular drug and Cleaning Agent.

11.6 Test Method for Cleaning Validation and Swab/Solvent Rinse analysis for residual traces in
MFG/Packing/In-process equipment’s:
11.6.1 Reagents:
Sodium Dihydrogen Phosphate
Orthophosphoric Acid
Methanol
Water (Mille-Millipore, academic)
11.6.2 Preparation of Reagent:
Sodium Dihydrogen Phosphate: Dissolve 7.8gm in 1000ml Adjust to pH 4.4 with Orthophosphoric Acid.
11.6.3 Preparation of Mobile Phase:
A mixture of 95volmes Sodium Dihydrogen Phosphate buffer and 5 volumes of Methanol.
11.6.4 Chromatography
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 Column: C18, (250mm x 4.6mm), 5µm

 Pump Mode: Isocratic
 Flow Rate: 2.0ml/minute
 Injection Volume: 20µl
 Wavelength: UV, 220nm
 Column Temperature: Ambient

11.6.5 Preparation of Standard Solution: Standard Stock Solution:

Weigh to transfer accurately 50 mg equivalent Amoxycillin R.S to a 100 ml Class A volumetric flask.

Add 100ml of water and sonicate to Dissolve the Sample.

 Make up the volume up to mark with water.

Mix well to get a homogeneous and uniform solution.

11.6.6 TEST SOLUTION

Compromises two phases

Cleaning validation sample of plate spiking

Swab and residual recoveries of various equipment’s and in- process materials
11.6.7 Test Solution prepared by the swab recovery of spiked on SS plate:

 Stainless steel plate (30 cmx15 cm) to be used for the surface testing.

 Spiking solution is prepared by dissolving 50 mg in 100 ml of methanol to get the concentration of

500 mcg/ml.

 Heads of the TXTM 714 swab sticks to be rinsed with Methanol. These solutions were spread on the
recovery plate in the area of 5 cm X 5 cm and were allowed to dry.
 Swab sticks previously placed into glass tube containing 5 ml of methanol used for the swabbing
the stainless plate.
 Swabbing done first in the horizontal and the in the vertical direction.
 Finally swab sticks put again into the glass test tube containing water and sonicated.
 For 10 minutes at an ambient temperature and volume was made with the methanol.
 Analysed with HPLC.

11.6.8 Swab/Solvent recovery from Manufacturing/ Packing/in-process Equipment

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District. Solan (H.P.) -173211 VALIDATION
Revision No.: 00 PROTOCOL Effective Date: 19/01/2018
Department : QA

S.No. Equipment’s
01 Bin Blender
02 Sifter
03 Tray Dryer
04 Roll Compactor
05 20/27 Station Tablet compression machine
06 Tablet De-duster
07 Auto-coater
08 Strip packing machine
09 Alu- Alu Packing machine

11.6.9 Wherever swab is mentioned follow the following procedure:

Swab sticks previously placed into glass tube containing 5 ml of Methanol used for the swabbing the
Areas of the above-mentioned components with the specified areas as mentioned.
Swabbing done first in the horizontal and the in the vertical direction.
Finally swab sticks put again into the glass test tube containing methanol and sonicated for 10
minutes at an ambient temperature and volume to be made with the methanol.

11.6.10 EVALUATION OF SYSTEM SUITABILITY:

Inject the reference solution. The resolution between the Amoxycillin and Clavulanic Acid peak is
NLT 2.0. The test is not valid unless column efficiency determined from each analyse peak is NMT
550v theoretical plates, the tailing factor for each analyse peak is NMT 2.0 and the relative standard
deviation for replicate injection is NMT 2.0%. Inject alternatively the test solution and the reference
solution.

11.6.11 PROCEDURE
Inject sample preparation in duplicate and record the chromatogram. Inhibit the integration due to
blank peak in the chromatogram of sample preparation.

CACULATIONS:

AT WS 100 P
Amoxycillin [mg / tablet] = ------- X -------- X ------ X --------- X Avg.wt.
AS 100 Sample wt. 100

Where,
AT = Mean area of the peak due to Amoxycillin in the chromatogram of sample
preparation
AS = Mean area of the peak due to Amoxycillin in the chromatogram of standard
preparation.
WS = Weight of Amoxycillin working standard taken for standard preparation, in mg.
WT = Weight of sample taken for sample preparation, in mg.
AW = Average weight of tablet, in mg.
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Department : QA

P = % Assay of Amoxycillin working standard taken for standard preparation, on as is

basis.
L = Label claim of a Amoxycillin in a tablet, in mg

11.7 Cleaning Verification

Cleaning verification approach will be applied for the unique condition where the product being
manufactured for the first time is not fitting / does not exit in the established product / equipment
matrix (i.e. Exhibit batch, scale up batch, trial batch), 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 verification approach will be also applied while introducing/ replacing the any
equipment of the train, after appropriate evaluation. Based on evaluation, verification will be
performed if required for particular equipment until cleaning procedure has been validated.

Cleaning verification 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.

11.7.1 Following criteria shall be adopted:

Selection of swabbing position based on the experience for difficult to clean location of
equipment or history for worst-case sampling.

Method adopted shall be qualified for the sensitivity and swab recovery.

Cleaning verification approach will be also applied while introducing/ replacing the any
equipment of the train, after appropriate evaluation.

Based on evaluation, verification will be performed if required for particular equipment until
cleaning procedure has been validated.

11.8 Ongoing Monitoring

Once validated, it is advisable to reconfirm cleaning effectiveness from time to time. For manual
processes this is essential until sufficient data has been generated to confirm the reproducibility
of the cleaning procedure.
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Department : QA

Ongoing monitoring shall be performed with defined criteria on validation report to verify /
monitor the cleaning process is able to confirm the ongoing appropriateness of the training
program as well as operator’s ability to perform the cleaning process.

12.0 Revalidation

The cleaning process of specified equipment for the specific 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 findings based on current knowledge.
Batch size change.
Implementation of these changes shall be carried out as per change control system.

13.0 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 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.

14.0 Cleaning Validation Report

14.1 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. Validation Report shall include following and
these are prepared as separate annexure and attached with is protocol:
14.2 Product matrix
14.3 Equipment matrix
14.4 Sampling Plan and Location
14.5 Chemical Swab/Rinse Water Report for cleaning validation-Chemical/Microbiological
14.6 Microbiological Swab/ Rinse Report for cleaning validation-Hold time study
14.7 Cleaning Validation report summery and conclusion
15.0 List of Annexure / Formats attached
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Department : QA

S.No. Title of the Annexure Annexure No.

1 Product Matrix Annexure-I
2 Equipment Matrix List Annexure-II
3 Sampling Plan and Location Annexure-III
Swab/Rinse Water Report for cleaning
4 Annexure-IV
validation-Chemical/Microbiological
Microbiological Swab Report for cleaning validation- Hold time
5 Annexure-V
study
6 Validation Report Summary & Conclusion Annexure-VI
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Department : QA

16.0 References

3.1 Validation Master Plan

3.2 21 Code of Federal Regulations, parts 210 & 211
3.3 US FDA – ‘Guide to Inspections Validation of Cleaning Processes’
3.4 PIC/S – ‘Recommendations on Validation Master Plan, Installation and Operational 18.
Qualifications, Non-Sterile Process Validation & Cleaning Validation’
3.5 APIC – ‘Guide on Aspects of Cleaning Validation in Active Pharmaceutical Ingredient
Plants (December 2000)’
3.6 PDA – Technical Report No. 29: ‘Points to Consider for Cleaning Validation’
3.7 Ira R. Berry, Robert A. Nash, ‘Pharmaceutical Process Validation’
3.8 SOP on ‘Cleaning Validation’
3.9 Batch Manufacturing Records
3.10 Batch Packing Records
3.11 Protocol & Reports for ‘Validation of techniques used for bio burden analysis in
cleaning validation’.