Psychotropics India Limited

Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 1 of 21

PROTOCOL

FOR

CLEANING VALIDATION

BASED ON WORST CASE

PRODUCTS
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 2 of 21

INDEX

Sr. No. Contents Page No.

Protocol Approval 3
1.0 Introduction 4
2.0 Scope……………………………………………………………… 4-5
3.0 Organization Committee………………………………………… 5
4.0 Pre- requirement…………………………………………………. 8
5.0 Product / Equipment Grouping…………………………………. 8-9
6.0 Selection of analytical method…………………………………. 10-11
7.0 Selection of cleaning method…………………………………… 11-12
8.0 Selection of sampling method…………………………………. 12-13
9.0 Establishment of limit and acceptance criteria……………….. 13-14
10.0 Cleaning Validation methodology 15
11.0 Pre-Requirement 16
12.0 Validation procedure and acceptance criteria 16-18
13.0 Data Recording 18
14.0 Deviation and corrective action 18-19
15.0 Summary report 19
16.0 Conclusion 19
17.0 Revalidation 19
18.0 Definition and Abbreviation 19-20
19.0 Abbreviations 21
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 3 of 21

PROTOCOL APPROVAL

This protocol describes the procedure to be followed & test to validate the cleaning method of product
contact part of equipment.

This protocol has been prepared, checked and approved for implementation by the following
personnel.

Functional Area Name Signature Date

Prepared By

Executive-Quality Assurance

Checked By

Head-Production

Head-Quality Control

Approved By

Head- Quality Assurance

Authorized By

Director - Technical
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 4 of 21

1.0 Introduction

1.1 Philosophy

Psychotropic India Limited is engaged in the operation and renovation of solid & Liquid
dosage form and External Application product manufacturing facilities at Plot No. 46 & 49,
Sector -6A, SIDCUL, Haridwar.

The cleaning validation program is designed to demonstrate that the quality features built into
facility, utilities and processes ensure that they are fully functional, remain in place and
conform to the relevant regulatory requirements.

The described herein have been designed to conform to the requirements of current Good
Manufacturing Practices as described in the directives of the World Health Organization as
well as Drug and Cosmetics Act 1940 of India.

The main aim is that once cleaning procedure is validated, the procedure will be used for the
cleaning of equipments, utensils to ensure that the subsequent product manufactured is not
contaminated by previous one and is safe and quality product.

1.2 Purpose & Objective

1.2.1 The objective of cleaning validation protocol of equipment, utensils and components is to
establish sufficient documented evidence to assure that, cleaning procedures can repeatedly and
reproducibly remove residue of the subjected product- below established acceptance limit. The
acceptance limit is maximum allowable quantity of product residue, which does not affect
quality and safety of the subsequent product to be manufactured, by using same equipment and
facility.

1.2.2 To establish acceptable time limit for storage after cleaning. Equipment is not expected to be
free from all microorganisms, particularly when the final stage in cleaning does not involve
final rinsing with purified water. The objective shall be to demonstrate that there is under limit
microbial proliferation in equipments during storage. The main purpose of cleaning validation
protocol is to set up guideline to establish cleaning, sampling, testing procedure and residue
limits that are practical, achievable, and verifiable and assure safety.

2.0 Scope

This cleaning validation protocol cover validation of cleaning processes performed in the plant.
This protocol is limited to the contamination due to active material of previous product and
cleaning agent. This plan does not cover sanitation and disinfecting processes.
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 5 of 21

This guideline is for cleaning validation of surface directly in contact with the products/
material.
This validation programme will include:
2.1 Grouping and worst-case selection.
2.2 Selection of sampling method.
2.3 Selection of cleaning method.
2.4 Selection of analytical method.
2.5 Establishment of limit and acceptance criteria

3.0 Organization Committee

Cleaning Validation Organization Committee

Committee
QA Head
Production Manager
QC Head

Validation Team for

Cleaning Validation

Persons from Users

QC & QA
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 6 of 21

3.1 Responsibilities of Validation Organization Committee:

 The responsibilities of the overall scope of cleaning validation protocol.

 Overall co-ordination of the cleaning validation program.
 To report to Management on the progress of the cleaning validation report.
 Establish the cleaning validation schedule and maintain thereof.
 Review and approval of cleaning validation Protocols.
 Approval of any protocol amendments if necessary.
 Review and approval of the final cleaning validation report.

3.2 Responsibilities of Validation Team:

 Prepare the cleaning validation protocols, seek & obtain approval from Validation Organization
Committee.
 Identify the resources required to carry out the cleaning validation study within the given
schedule.
 Monitor the conduct of the study.
 Collection, review of data.
 Preparation of the draft report.
 Preparation of final report and submit Validation Organization Committee.
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 7 of 21

The following flow chart represents development of cleaning validation for any particular product /
equipment
Classification of different cleaning levels
(Extent of cleaning)

Identity & study the nature of potential

residue / contaminants

Divide the products in-group & select the

worst-case situation

Select suitable cleaning method

(CIP, COP or manual)

Calculation & finalization of

Acceptance criteria / Limit

Selection & Development of suitable

analytical test method

Validation of analytical test method

NO
Approved
YES

Execution of validation protocol

Training and implementation of the validated

cleaning procedure
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 8 of 21

4.0 Pre-Requirements:

Following are the pre-requirements for the cleaning validation activity.

The strategy of exactly what is to be validated should be defined.

Operator performing cleaning activity should be fully trained.
SOPs would typically be written for the following:
 Equipment/ machine operations
 Product processes
 Method of cleaning
 Sampling and testing methods

For automated or clean-in-place cleaning processes, DQ, IQ, and OQ should have been
completed prior to commencement of Performance Qualification (PQ). The relative merits of
manual cleaning, Clean in Place (CIP) with manual intervention or fully automatic CIP systems
should be considered during DQ.
The test method for potential contaminants of the process operation should be developed. These
methods should be validated for their specificity, accuracy, sensitivity and limit of detection
level.
The sampling plan should be specified.

5.0 Product / Equipment Grouping

A Psychotropic India Limited has designed the multi-product facility to manufacture solid and
liquid dosage form. It may not be possible to validate cleaning process of all products
manufactured within the facility during start up of facility. In order to prioritize cleaning
validation program, a matrix approach is applied. The approach evaluates overall cleaning
requirement of the product range and concentrates the validation effort. On ‘Worst Case’
situation, the approach is applied where there are common cleaning procedures.

The ‘Worst Case’ is considered on the basis of following factors:

 Physical characteristic i.e. solubility, cleanability

 Minimum therapeutic Dose of the Product
 Largest Daily Dose to amongst next product to be manufacture in the same equipment
 Smallest Batch Size of the next product manufacture in the same equipment.
 Highest Concentration of dosage form.

5.1 Based on solubility

From Annexure I it is observed that the product having least solubility in water and higher
strength is as following.
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 9 of 21

S. No. Name API Solubility

1

5.2 Based on Minimum therapeutic dose

From Annexure I it is observed that the product having minimum therapeutic dose / most potent
is as following.

S.No Name API Minimum Therapeutic Dose

1

5.3 Based on concentration of active material (Highest Strength or Concentration)

Refer Annexure-I

5.4 Largest Daily Dose:

Refer Annexure-III

5.5 Equipment combination

Refer Annexure-II

5.6 Based on batch size of subsequent batch and product contact surface area

Product having minimum batch size & maximum surface area should be considered as ‘Worst
Case’.
Minimum batch size taken of the subsequent product manufactured in the same equipment.
Refer Annexure-I

Sr. Worst Case Product Product to be considered as next

No. product
1

When new product is started manufacturing and it becomes the worst case then cleaning
validation is to be done.
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 10 of 21

6.0 Selection of Analytical Method.

It is equally important to select an appropriate method for detection of residue in the cleaning
sample. Method must be selected carefully for the specific situation; a non-specific analytical
method may lead to false analytical results.

During validation of the cleaning procedure, the test methods used should be able to specifically
quantify concentrations of all compounds of interest that may be present in samples. During
subsequent verification of cleaning, non- specific methods should be employed.
6.1 Specific Analytical Test Methods
Any instrumental analytical procedures used to test samples taken during cleaning validation
studies need to be specified and sufficiently sensitive to determine the low levels of residues
typically found in samples. The methods used to test samples that will allow the equipment to be
released for manufacture of another product must themselves be validated to ensure that it meets
following requirements.

 Detailed analytical method including equipments and reagents to be

Used.
 Limit of detection level
 Recovery of contaminant from cleaning sample
 Recovery of contaminant from equipment surface
 Qualification of specificity, sensitivity & accuracy of the test.
Chromatographic technique may be appropriate for active ingredients, as they are sensitive and
specific. Consideration should be given to the presence of degradation products and other related
substances, which may have an adverse effect on the next product manufactured. Following are
some of the specific analytical methods, which are commonly used for cleaning validation.
 UV spectrophotometer
 HPLC
 GC
 TLC
 Atomic absorption spectrophotometer method
 Flurometry.

6.2 Non-Specific Analytical Test Methods

Although it is expected to follow specific analytical test methods for the cleaning samples, but
many of the non-specific methods such as visual, pH, conductivity and TOC are simple, fast and
still provide valuable information related to the level of cleaning and presence of any
contaminant. Due to these properties these methods can be effectively used for evaluation of
cleaning and on-line monitoring application. Following are some of the non-specific analytical
methods, which are commonly used for cleaning verification.
 Visual Examination
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 11 of 21

 PH.
 Conductivity.
 Microscopy.
 Titration.
 Total Organic Carbon. (TOC).

TOC is likely to be most suitable for aqueous samples, and is ideal for checking for removal of
complex cleaning agents such as detergents if specificity is not a requirement. Conductivity and
pH measurements may be useful to monitor removal of any acid or alkali used as a cleaning
agent.
Whichever technique is selected, the production equipment should be visually clean.
7.0 Selection of Cleaning Method:
There are following three types of cleaning methods utilized in the drug product manufacturing
facilities:
7.1 Clean-In-Place (CIP) Method
 Cleaning of the equipment is performed in place without disassembling
 Cleaning process may be controlled manually or by an automated program.
 Very consistent and reproducible cleaning method.
 Can be validated readily.
 Being a closed system visual inspection of all components is difficult.

7.2 Clean-Out-Of-Place (COP) Method

 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, detergent quantity dispensed etc.

7.3 Manual Cleaning Method

 Most extensive and elaborate cleaning procedures are required.
 A high quality and extensive training program is required.
Psychotropic India Limited has designed the facility with manual cleaning operations.
Following were taken into consideration for selecting manual cleaning method.
 “Seeing is Believing”
 Product diversity
 Risk of failure of cleaning equipments
 Validation of automated cleaning equipments
 Trained and experienced working staff
The equipment design and manual cleaning method are taken into consideration for selection
of equipment. All equipments selected viewing following cleaning consideration:
 Ease of disassembling of contact parts.
 All contact surfaces are non-reactive to cleaning method
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 12 of 21

The risk involve in manual cleaning processes is taken care of with following:
 Proper wash room design with drying, protection and storage requirement.
 Detailed cleaning SOP
 Training / Qualification of cleaning operators
Once the cleaning method is validated, it should be ensured that the method is not changed. If
required any change in the validated cleaning method should be governed by the change
control policy and cleaning method should be re-validated.

Experimental Plan – Cleaning Procedure

 Clean the equipment as per respective SOP after the processing of the product.
 Inform the IPQA Chemist to collect the water wash sample
 Attach the status label on the equipment.
 Repeat this cleaning procedure for three different batch runs.
Compile and evaluate three validation run results and revise the existing SOP, if
required.

8.0 Sampling Techniques

Following sampling technique shall be followed for cleaning validation studies

 Swab sampling
 Wash Water sampling

8.1 Swab Sampling - Experimental Plan

Swab sampling technique for drug contamination:
 Wear the hand gloves
 Pipette out 5ml of sampling solvent in transport container bearing identification label.
 Remove a swab from its protective bag using a clean latex hand glove.
 Avoid unnecessary touch to swab tip to prevent from contamination.
 Transfer the swab in transport container (test tube) containing 5ml of sampling solvent
and allow the swab to soak completely.
 Take out the swab from sampling solvent and squeeze the tip (by means of SS forceps)
against inner surface of test tube to remove excess solvent in such a manner that excess
sampling solvent drips inside the test tube.
 Hold the stem of swab without touching the head of swab.
 Using one side of moistened swab wipe the test surface of 4” x 4” with 10 firm horizontal
strokes as illustrated in figure 1. Wherever 4” x 4” area is not available for swab
sampling, carry out sampling from hardest to clean area.
 At the end of the each stroke lift the swab carefully.
 Turn the swab over to its other side, wipe the test surface of 4” x 4” with 10 firm
vertical strokes as illustrated in figure 2
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 13 of 21

 At the end of the each stroke lift the swab carefully.

 Cut the handle of swab and put in transport container having solvent.

. 4 inches 4 inches

4 inches 4 inches
Figure 1 Figure 2
Swab sampling technique for microbial evaluation: Refer relevant microbiology department SOP
for swab sampling for microbial evaluation.

8.2 Wash Water Sampling – Experimentation Plan

Wash water sample shall be collected after rinsing the equipment with specified quantity of
Purified water as defined in individual protocol.
The samples taken shall be analyzed   for the content of   residual Active ingredient   to
establish that the residual levels after cleaning are below the set acceptance criteria.

9.0 Establishment of Limit and Acceptance Criteria for Maximum Allowable Carry-Over for
Previous Product Residue.

There cannot be a standard fixed limit to determine the effectiveness of a cleaning procedure, due
to the reason that variety of equipment and products are used throughout the drug product
manufacturing facility of Psychotropic India Limited. Rationale for the residue limit established
should be scientific, logical and based upon knowledge of the material. As per the guide to
inspections of Validation of Cleaning Processes the limits should be “practical, achievable and
verifiable”.
To arrive at the quantitative acceptance limit for cleaning validation of particular equipment there
has to be a good scientific and logical rationale. A quantitative limit should be based on one or
more of the following:
 Therapeutic dose.
 Strength of the material.
 Difficulty of cleaning.
 Use/ Application of the product.
 Nature of other products manufactured in the equipment
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 14 of 21

 Batch size of other product manufactured in the same equipment.

 Largest Daily Dosage of the product to be manufactured in the same equipment.
(A) DOSE Criteria
Maximum allowable carry over is calculated considering worst case products as previous
product and rest entire products present in product matrix as subsequent products (minimum
batch size).

Maximum Allowable carry over (MAC) of previous product in the subsequent product is
calculated by using the formula mentioned below,
STD x SBS x SF
MAC=
LDD
Where,
MAC= Maximum Allowable Carryover
STD= Single Therapeutic Dose of the previous product
SBS= Smallest Batch size (in Kg) of the next product to manufactured in the same
equipment
SF= Safety Factor (1/1000)
LDD= Largest Daily Dose of the next product to be manufactured in the same equipment
Assuming the contamination is present uniformly on the entire contact surface area, the
limit for one square inch of surface is calculated by dividing above MAC value by total
contact surface area in square inch.
Limit for one sq. inch= MAC/Total surface area in sq. inch
Now the limit of residual contamination for a swab area of 4” x 4” can be calculated as
follow,
The limit of residual contamination = Limit for one sq. inch x 16

(B) 10 PPM Criteria

Industrial Trend of Using default limit of maximum allowable residue is 10 ppm, which is 10
mg per Kg of the next batch output.

R (S/T) U
The Maximum allowable residue per swab of 4 X 4 in2 can be mathematically expressed as
R = 10mg active ingredient in product A /kg of product B
S = Number of kilograms per batch of final mixture of product B
T = equipment surface area in common between products A and B expressed as square
inches.
U = 16 in.2 swab
Factor R is always 10mg of active ingredient of the product being cleaned per kilogram of
final mixture of the recipient product. This is simply 10ppm stated a different way.
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 15 of 21

Factor S appears in the numerator. Residues of product A appearing in product B will be

diluted by product B. a larger batch size of product B will diluted the residue more and
therefore a larger limit is acceptable for product A.
Factor T is the number of square inches of product-contact surface area in common between
the two products as before.
Factor U is the standard 16 in.2 swab as before.

FINAL LIMIT
This minimum value from both criteria shall be considered as acceptance limit for previous
product into subsequent product.
After considering both criteria (Dose Criteria and 10ppm Criteria), the acceptance limit for
cleaning validation shall be finalized.
The finalized limit shall be valid as long as equipment used & product combination
manufactured in the facility remains same.
If any new product is added, the cleaning limits to be recalculated.

10.0 Cleaning Validation Methodology

 Ensure that operator for cleaning are trained
 Clean the equipment as per respective SOP after the processing of the product.
 Collect the swab samples from the location described in Annex-II.
 Simultaneously collect the Rinse sample for analysis purpose.
 Send the sample to QC for analysis with Analysis request form.
 QC analyst shall perform the test as per the STP and record the result in the data sheet.
 Prepare the report of the sample test result.
 Evaluate the results of the compliance with the acceptance criteria.
 Prepare the Validation report.

10.1 Laboratory Procedure Rationale

10.1.1 Brief Outline of Procedure
Laboratory procedure is a limit test performed on HPLC. The swab sampling of cleaned
equipment is done as per SOP. This procedure is used to validate the cleaning of equipments
subsequent to use in manufacturing of products containing least soluble drug (for aqueous and
non-aqueous). The method is to be validated for the drug at acceptance limit per 4 x 4 sq. inch
test surface. Results are reported as pass or fail at the stated acceptance limit.
10.1.2 Sampling Procedure Rationale
The appropriate diluting solvent will be used as sampling solvent with respect to their
individual solubility profile of API (Active Pharmaceutical Ingredient).
Clean room laundered polyurethane foam tip swabs shall be selected as sampling medium due
to their non-leaching and non-fibers shedding property. The swabs were pre-treated to get rid
of any possible interference as precautionary measure.
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 16 of 21

10.1.3 Extraction Procedure Rationale

Based on the individual solubility of API, select the solvent for the extraction of drug from
swabs.
10.1.4 Analytical Detection Rationale
Select the respective absorbance maxima of API.
10.1.5 Related Documents
Swab sampling for validation of test surfaces analysis of API in swabs.
10.2 Experimental Plan
10.2.1 Equipments and Materials
a. High Performance Liquid Chromatography.
b. Clean room laundered polyurethane foam tip swabs with polypropylene Stick
c. S.S Plates
d. Transportation container (stoppered glass test tube)
e. Other glassware
f. API working standard
10.2.2 General Instructions
Utmost care to be taken during handling of swabs while sampling and analysis to avoid
touching the swab with anything to prevent swab from contamination.
All glassware must be clean and dry.

11.0 Pre-Requirement
11.1 Requirements for chemical testing
11.1.1 Working Standard................
Lot No/Batch No.: -----------
Assay: -------------
11.1.2 Equipments
Analytical Balance
(Instrument No. -----------------)
Make: -------------
Model: ----------
HPLC
(Instrument No. -----------------)
Make: ---------
Model: ----------
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 17 of 21

12.0 Validation Procedure and Acceptance Criteria:

A UV method has been developed to estimate the ................ content in the swab samples
collected from the different equipment surfaces of the manufacturing area. The method has
been further validated to demonstrate Specificity, Precision, and Ruggedness, linearity, swab
sample recovery from plates, lowest detection limit and the limit of Quantitation etc.
12.1 Specificity:
HPLC specificity check the method so that there is no any interference in sample
solution by Diluent or any other. Scan the solutions of ................ of 10-ppm
concentration solution
Acceptance criteria: There is no any peak comes other than standard and sample in
their solutions.
12.2 Precision:
System Precision System precision shall be evaluated by calculating RSD of Five
replicates measurements of standard solution.
Acceptance criteria: Relative standard deviation (RSD) shall not be more than 2%.

Method Precision: Six samples set preparation of a same batch shall be analysed.
Acceptance criteria: Relative standard deviation (RSD) shall not be more than 2%.
12.3 Ruggedness: Ruggedness will be determined by analyzing sample from same batch by two
different analysts on different days. Ruggedness shall be evaluated by calculating overall
%RSD of both the analyst.
Acceptance criteria: Relative standard deviation (RSD) shall not be more than 3 %.
12.4 Limit of Quantitation: LOQ of ................ will be determined from linearity data. It will be
verified by showing precision at that concentration.
Acceptance criteria: RSD shall not be more than 10%
12.5 Limit of Detection: LOD of ................ will be determined from linearity data. It will be
verified by showing precision at that concentration.
Acceptance criteria: RSD shall not be more than 33%

12.6 Holding Time: Holding time of rinse and swab samples shall be evaluated by analyzing
sample solution at time interval 0, 3, 6, 12, 18, 24, and 36hrs.
Acceptance criteria: The Holding Time value shall not vary by more than + 10% of the Zero
time value.

12.7 Linearity:
Serial dilution of ................ standard stock preparation,
concentration ranging from 0.5 mcg/ml to 20 mcg/ml, will be prepared
and assayed by the afore-said procedure.
The linearity of the method shall be established in the range 20 ppm to
limit of Quantitation. The sample absorbance shall be plotted against
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 18 of 21

Concentration and correlation coefficient shall be calculated.

If method is already validated for assay of the API , then LOD, LOQ , Liniarity & Holding
time shall be performed.
Acceptance criteria: Correlation coefficient shall be NLT 0.99

12.8 Linearity of Spiked Swab Extract

Prepare 3 standard solutions of different concentrations (should fall in linear range) from API
working standard.
Take 3 swabs and apply to each of them known volume of respective standard solutions with
help of graduated pipette. Touch the pipette on the tip of the swab and slowly deliver the
solution by slightly pressing so as to absorb the solution properly by the swab.
These spiked swabs will contain known concentrations of the drug respectively.
Place these spiked swabs individually in stoppered test tubes containing know volume of
extracting solvent. Stopper the test tube and shake vigorously to extract the drug in solution.
Filter the extracting solvent through filter paper as per test requirement and inject known
volume and note the detector response.
Simultaneously measure the detector responses of corresponding standard solutions
(Concentrations corresponding to that in swabs)
Calculate the API content in each swab and percentage recovery from each swab. Calculate
mean percentage recovery and RSD. Tabulate the results Annex-IV.
To consider this experiment to be satisfactory the recovery should be established and RSD
should not be more than 10.0% of three determinations.
Calculate mean detector response of each concentration and plot a graph of detector response Vs
Concentration. It should be straight line.

12.9 Recovery Of Spiked Swab Extract

Prepare 3 standard solutions of different concentrations (should fall in linear range) from API
working standard.
Spike uniformly 4” x 4” surface of S.S.Plate with known concentrations of solution with the
help of graduated pipette and allow the surface to dry at room temperature.
Swab each of the 4” x 4” surfaces treated as above using different swabs.
Place these swabs individually in stoppered test tubes containing known volume of extracting
solvent. Stopper the test tube and shake vigorously to extract the drug in solution.
Filter the extracting solvent through filter paper as per test requirerment and inject known
volume and note the detector response.
Simultaneously measure the detector responses of corresponding standard solution
(Concentrations corresponding to that in swabs)
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 19 of 21

Calculate the API content and % recovery in each of the swabs. Calculate mean, % recovery
and RSD and tabulate the results in Annex-V.
The recovery shall not be less than 80% then it is a Very good recovery, if greeter than 65% then
recovery is good and if gretter than 50% then it is acceptable and RSD shall not be more than 10%.

13.0 Data Recording:

Annexure-IA Products covered under cleaning validation for equipment Chain II
Annexure-IB Products covered under cleaning validation for equipment Chain I
Annexure-II Sampling Plan for entire equipment chain
Annexure-IIIA Determination of Acceptance Criteria for equipment Chain II
Annexure-IIIB Determination of Acceptance Criteria for equipment Chain I
Annexure-IV Linearity and recovery in swabs spiked with API
Annexure-V Recovery of drug from swabs sampled from spiked S.S. plates
Annexure-VI Swab Analysis Results by HPLC method
Annexure-VII Wash Water Analysis Result by HPLC method
Annexure-VIII Swab Analysis Results by UV Method
Annexure-IX Wash Water Analysis Result by UV Method
Report for cleaning validation

14.0 Deviation & corrective action report:

Any deviations observed during the protocol execution shall be discussed and
resolved. All deviations will be handled as per SOP No. PIL/SOP/QA/015.
of corrective action will be recorded in the deviation summary.
15.0 Summary Report
The validation report shall describe in narrative form a summary of the procedure followed.
Observation and any other relevant data. All data shall be compiled as per exhibits.

16.0 Conclusion
Write down the conclusions of the data obtained as per the cleaning validation plan. The
validation report shall be evaluated by the Quality Assurance Manager and necessary
conclusions shall be drawn based on the comparison of experimental data with acceptance
criteria.

17.0 Revalidation Criteria

The revalidation of cleaning procedure shall be required in case of

1) Change in cleaning procedure.

2) Change in the processing equipment.
3) Significant change in the equipment used to clean the processing equipment

18.0 Definitions and Abbreviations

18.1 Definitions:
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 20 of 21

(a) Validation: The documented act of providing that any procedure, process, equipment,
material, activity or system actually leads to the expected results.

(b) Process Qualification: “Providing documented evidence that the process does what it
purports to do”.

(c) Revalidation: “Repeated validation of an approved process to ensure continued

compliance with established requirements”.

(d) Challenge Test: “A condition or set of conditions encompassing upper & lower
processing limits and circumstances, within Standard Operating Procedure, that poses
the greatest chance of product or process failure when compared to ideal conditions”.
Such conditions do not necessarily induce product or process failure.

(e) Cleaning Validation: A process giving evidence that the cleaning operation can
consistently meet predetermined standards.

(f) Contaminant: Extraneous substance that exists in a product. The material to be

removed by the cleaning process.

(g) Specificity: The ability to unequivocally assess the analyte in the presence of
components, which may be expected to be present.
 Psychotropics India Limited
Plot No. – 46 & 49, Sector -6A, IIE, SIDCUL, Haridwar (U.K.)

Department: Quality Assurance Document No.: PIL/QA/CV/T/00

Title: Protocol for Cleaning Validation Revision No.: 00
Effective Date: 10/05/2015
Page No.: 21 of 21

19.0 Abbreviations:
ADI Acceptable Daily Intake
CIP Clean- In -Place
COP Clean- Out- Of-Place
DQ Design Qualification
IQ Installation Qualification
MAR Maximum Allowable Residue
OQ Operational Qualification
PPM Parts Per Million
PQ Performance Qualification
QA Quality Assurance
QC Quality Control
SOP Standard operating Procedure
TOC Total organic Carbon
RSD Relative Standard Deviation
NMT Not more than
NLT Not less than
LOD Limit of Detection
LOQ Limit of Quantitation
Mcg Microgram
ppm Parts per million