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COMPANY LOGO

COMPANY NAME
Company Address

CLEANING VALIDATION PROTOCOL
FOR <NAME OF THE WORST CASE PRODUCT> AT: <LOCATION>

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

Document No. Effective Date Page No.

: : :

CVP/001

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INDEX
S. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. Content Preapproval of Protocol Introduction Objective Scope Responsibilities Protocol Training Record Product Profile Equipment Description Methods of Cleaning 9.1 9.2 9.3 10. 10.1 10.2 10.3 10.4 10.5 10.6 10.7 11. 12. Cleaning Procedures Materials and Equipments used for cleaning Cleaning SOP Index for each equipment Selection of Sampling Method Scientific rational for selecting Sampling Points Visual Inspection Swab Sampling for Chemical Analysis of API Sampling Patterns Swab sampling for Microbial analysis Swab sampling Location Page No. 3 of 15 4 of 15 4 of 15 4 of 15 5 of 15 6 of 15 6 of 15 7 of 15 7 of 15 7 of 15 8 of 15 8 of 15 9 of 15 9 of 15 9 of 15 9 of 15 9 of 15 10 of 15 10 of 15 11 of 15 12 of 15 12 of 15 12 of 15 12 of 15 12 of 15 13 of 15 13 of 15 13 of 15 13 of 15 14 of 15 14 of 15 15 of 15 15 of 15

Sampling Method

Analytical Procedure Establishment of Acceptance Criteria 12.1 12.2 12.3 12.4 12.5 Visual Inspection Active Residue Rational to Calculate Maximum Allowable Carry-Over Taking the Worst-Case Rational to Calculate Maximum Allowable Carry-Over Taking the 10 ppm Criteria Establishment of Acceptance Limits 12.5.1 12.5.2 12.6 Acceptance Limits per Equipment (ALE) for API Acceptance Limits per Swab (ALS) for API

Acceptance Limits for Microbial Bio-burden

13. 14. 15.

Acceptance Limits for the Cleaning Agent Hold Time Study Revalidation Criteria

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

Document No. Effective Date Page No.

: : :

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1.Preapproval of Protocol: Signing of this Protocol indicates agreement with the Cleaning validation approach established for <LOCATION, WHERE THE VALIDATION IS TO BE PERFORMED>. Further, if any changes in this Master Plan would be required, it will be revised and duly approved. Compiled By: Functional area Quality Control Name Designation Signature Date

Production

Quality Assurance

Reviewed and Approved By: Functional area HeadQuality Control Name Designation Signature Date

HeadProduction

Quality Assurance

Authorized By: Functional area HeadQuality Assurance Name Signature Date

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

Document No. Effective Date Page No.

: : :

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2

Introduction: Cleaning Validation in the context of manufacture of the solid oral products at <COMPANY NAME> may be defined as: “The process of providing documented evidence that the cleaning method of the equipments and ancillary utensils employed within the facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels.” (Source: APIC, September 1999) It is necessary to Validate Cleaning procedures for the following reasons: a) It is a customer requirement - it ensures the safety and purity of the product. b) It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacture. c) It also assures from an internal control and compliance point of view the quality of the process.

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Objective: The objective of this protocol is;  Objective of Cleaning Validation is to establish and assure with documented evidence that the cleaning procedures used after manufacturing of <PRODUCT NAME> is effective and consistently performs as expected and produce a result that meets a predetermined acceptance criteria when manufactured.  To provide documented evidence through the scientific data to show that the cleaning procedure used after manufacturing of Tablet is effective and consistently performs as expected and produce a result that meets a predetermined acceptance criteria when manufactured.  To establish that the cleaning process shall provide a high degree of assurance for removal of residues of the last manufactured product, so that those residues are not transferred to the subsequently manufactured product.  To prove that equipment is consistently cleaned of product to an acceptable level to prevent contamination and cross-contamination

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Scope:  The scope of this protocol is applicable for the Cleaning validationof<NAME OF THE PRODUCT WITH API STRENGTH>  Also, to evaluate the acceptability of cleaning procedure used in cleaning of equipment using wellestablished analytical and microbiological method to determine the chemical and microbiological residue after cleaning of the equipment. This will also cover the responsibilities, sampling plan, acceptance criteria, re-validation criteria, and change control procedure. This protocol is applicable for <NAME OF THE COMPANY>.

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

Document No. Effective Date Page No.

: : :

CVP/001

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5

Responsibilities: 5.1 Quality Assurance:

5.1.1 5.1.2 5.1.3 5.1.4 5.1.5 5.1.6
5.2

To prepare the Cleaning Validation Protocol. To review the Cleaning Validation Protocol. To monitor cleaning activities. To collect swab/rinse samples from cleaned equipment. To review analytical reports. To prepare and review cleaning validation report.

Production: 5.2.1 5.2.2 5.2.3 5.2.4 5.2.5 5.2.6 To review the Cleaning Validation Protocol. To provide details of equipments. To get the equipments cleaned by trained operators. To schedule cleaning validation program. To maintain log-books for equipment cleaning. To review cleaning validation report.

5.3

Quality Control: 5.3.1 5.3.2 5.3.3 5.3.4 To review the Cleaning Validation Protocol. To analyze the swab/rinse samples collected for cleaning validation. To compile the analytical data. To review cleaning validation report.

5.4

Quality Control (Microbiology): 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 To review the Cleaning Validation Protocol. To collect Microbiological samples from cleaned equipment. To analyze the cleaning validation samples. To compile the Microbiological data. To review cleaning validation report.

5.5

Head – Quality Assurance: 5.5.1 To review and to approve cleaning validation protocol and report.

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

Document No. Effective Date Page No.

: : :

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Protocol Training Record: Record – All the personnel involved in the cleaning validation activity, sampling and testing of cleaning validation samples must be appropriately trained in their assigned job responsibilities and on the Cleaning validation protocol. Personnel or operator who performs cleaning routinely should be trained and should be trained and should be effectively supervised. Record the training details of the persons involved in the sampling and testing.

– – 7

Product Profile: 7.1 7.2 7.3 7.4 7.5 <NAME OF THE API WITH STRENGTH>is the existing product of the <LOCATION , WHERE THE VALIDATION IS TO BE PERFORMED> of <COMPANY NAME> NAME>. <A STATEMENT RELATED TO THE SOLUBILITY PROFILE OF THE API> <IUPAC NAME OF THE API> <CAS NUMBER UMBER OF API> Chemical Skeletal Structure the API <FOR EXAMPLE PARACETAMOL> PARACETAMOL>:

7.6 7.7 7.8

<A STATEMENT RELATED TO THE POTENCY OF THE API> <A STATEMENT RELATED TO THE EQUIPMENT USAGE BY THE API> Three batches of the product shall be validated for Cleaning.

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
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Equipment Description: Following Equipments of same design and operating principles shall be deployed for cleaning validation of the three batches of <NAME OF PRODUCT>. Surface **Surface S. No. Name of Equipment Capacity ID Number 2 2 Area(cm ) Area(cm ) 8.1. 8.2. 8.3. 8.4. 8.5. 8.6. <EQUIPMENT 1> <EQUIPMENT 2> <EQUIPMENT 3> <EQUIPMENT 4> <EQUIPMENT 5> <EQUIPMENT 6>

** Surface Area + 10% of Surface Area <This Neutralizes any Calculation Errors and also takes Ancillary Equipments like Scoops, Spatulas etc in account> 9 Methods of Cleaning: 9.1 There are three types of cleaning procedures deployed at<COMPANY NAME>: <WE ARE TAKING THE FOLLOWING CLEANING TYPES AS EXAMPLE> a) Type A  For batch to batch changeover.  End of the shift cleaning or whenever required.  Change over to ascending strength of same colour and flavour. b) Type B  During changeover of product with different API, colour/flavour and products having same API/colour/flavour but with descending strengths.  After five consecutive batches of same product.  Equipment kept in ideal condition for more than 48 hours.  Equipment kept in idle condition for more than 7 days subsequent to Type “B” Cleaning.  After carrying out preventive maintenance or any major maintenance activity. c) Type C  On “Type B” cleaned equipment just prior to use, when required to be used within 7 days from the date of Type “B” cleaning. Note: Cleaning Validation is required only in the scenario ofType B cleaning, as it is done after product to product changeover and cleaning process deploys water and detergent.

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 9.2 Supersedes: N/A

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Materials and Equipments used for cleaning:

a) Purified Water b) Tap water c) Vacuum Cleaner

d) Scrubber e) Dry sponge or lint free cloth. f) <NAME OF THE DETERGENT>

<ADD ANY ADDITIONAL MATERIAL OR EQUIPMENT, DEPLOYED FOR CLEANING IN THE COMPANY, IF NOT IN THE LIST ABOVE> 9.3 Cleaning SOP Index for each equipment: Sr. No. 9.3.1. 9.3.2. 9.3.3. 9.3.4. 9.3.5. 9.3.6. NOTE: Equipments shall be cleaned as per the respective cleaning SOPs followed during product changeover only <ALSO DESCRIBE IN DATA RECORDING SHEETS (DRS)>. Swabs of the cleaned equipments shall be taken as per the sampling points given in the DRS. Name of Equipment <EQUIPMENT 1> <EQUIPMENT 2> <EQUIPMENT 3> <EQUIPMENT 4> <EQUIPMENT 5> <EQUIPMENT 6> ID Number Cleaning SOP Number

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 10 Sampling Method: 10.1 Selection of Sampling Method: Supersedes: N/A

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Swab sampling shall be considered as sampling method. Justification for swab sampling:Looking to the Design and Size of equipment, swab sampling shall be considered main method for validation; however, rinse will also be taken wherever necessary. Most difficult to clean locations are selected for sampling to determine the efficacy of cleaning. Advantage of swab sampling: – – – 10.2 Direct evaluation of surface contamination Insoluble and poorly soluble substance may be physically removed Hard to clean but accessible areas are easily incorporated in final result.

Scientific rational for selecting Sampling Points: The product contact surface area which is most difficult to clean shall be selected as sampling point. The location selected for swabbing are generally those locations that are most difficult to clean representative of different materials and representative of different functional locations (side corners, agitator, blades etc.). If these locations are swabbed and if residues in these materials are acceptable then residues on another location shall also be acceptable. Performing swab on these locations and materials can be helpful in terms of providing higher assurance in validation results.

10.3

Visual Inspection: After cleaning of the equipment visual inspection shall be done. To carry out a visual inspection, use a torch if required and a mirror (attached to stainless steel rod) to inspect the surface of equipment. This should be done under viewing conditions (Lighting, angle, Distance), that simulate the viewing of Equipment.

10.4

Swab Sampling for Chemical Analysis of API: Description of swab:<FOR EXAMPLE, WE TAKE COMMONLY USED TEXWIPE SWAB >

Make Texwipe Swab ,USA Model TX714A Head Material Knitted Alp halite Polyester Handle Material Polypropylene Swab samples shall be taken after the final cleaning of the equipment, once the equipment qualifies the visual inspection test. The swab shall be dipped in swabbing media; i.e. <SOLVENT FOR THE API AS PER THE METHOD VALIDATION>in 50ml Test-Tube. Swab samples from different areas of equipment shall be collected. Swab area shall be measured for swabbing.

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

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Sampling error: During swab sampling following care to be taken: area of sampling (should not be less 2 than 100 cm ), apply proper force during collection of sample to avoid any sampling errors. Sampling area: 10 x 10 cm. = 100 cm or equivalent (for the parts, where 100 cm is not available as whole) 10.5 Sampling Patterns: Wipe the defined area in zigzag directions as shown in the figure. Apply only one time at a surface for one time only. Collect the swab by application of normal force. Note: Avoid lifting the swab stick from contact surface during collection of swab. Refer the diagram to collect the sample-using swab. Start Start End
2 2

10cm

OR

End

10 cm

10 cm (Direction of swabbing strokes)

Handling of swab Samples: Swab and Swabbing Media shall be prepared by quality control, The test tubes shall be covered with paraffin film, proper precaution shall be taken during handling of swab. After swabbing, each sample shall be placed inside the test tube duly labelled and covered with paraffin film and should be sent to QC Laboratory for testing of determination. 10.6 Swab sampling for Microbial analysis: – – – – – Sterile hand gloves and face mask shall be worn before taking the swab. Sterile swab shall be from the test tube and dipped into 0.9% sterile saline solution. Now the Swab shall be stroked over a 5 x 5 cm (or equivalent) of the product contact surface. The strokes should be as per the procedure for chemical swab only. Immediately the Swab shall be processed as per the procedure for Microbial Testing.

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 10.7 Supersedes: N/A Swab sampling Location:

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Prior to swab sampling, cleaned equipment shall meet “Visual Clean” criteria. Sampling shall be carried out as per current version of SOP. Chemical and microbial sampling location shall be different from each other. The locations from where, swab sample is to be taken is identified are below: Chemical swab sampling Sr.No. Equipment Location No. of swab locations Microbial swab sampling Location No. of swab locations

1

<EQUIPMENT 1>

2

<EQUIPMENT 2>

3

<EQUIPMENT 3>

4

<EQUIPMENT 4>

5

<EQUIPMENT 5>

6

<EQUIPMENT 6>

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

Document No. Effective Date Page No.

: : :

CVP/001

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Analytical Procedure: Analytical methods for Specific analysis were validated as per Analytical Method Validation Protocol. Validated methods shall be employed to analyse the cleaning validation samples.

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Establishment of Acceptance Criteria: The cleaning procedure shall be considered validated, when the acceptance criteria, as specified in the protocol, is met. Failure of individual sampling points will not necessarily mean that the cleaning method is inadequate. Each deviation shall be investigated and based on the investigation, corrective actions will be taken and that my require further follow-up or further validation. 12.1 Visual Inspection: Equipment should be visually clean and dry and must contain NO visible residues. 12.2 Active Residue: Calculation of active residue after cleaning shall be based on product contact surface area. This approach is based on acceptable daily intake. Based on the Acceptable Daily Intake and Safety Factor (1000 for Oral dosage forms) the Maximum Allowable Carry-Over (MACO) is calculated; i.e. it is assumed that only a fraction (1/1000) of the smallest daily dose of ProductA can be carried-over to the maximum allowable daily dose of Product-B manufactured in the same equipment train. 12.3 Rational to Calculate Maximum Allowable Carry-Over Taking the Worst-Case:

The Maximum Allowable Carry-Over (MACO) shall be calculated the following factors: STD(A) SBS(B) SF LDD(B) : : : : Single Therapeutic Dose of Product A (in mg). Smallest Batch Size of Product B (in mg). Safety Factor (constant) = 1000 for solid dosage forms Largest Daily Dose of Product B (in mg).

Thus, the formula to calculate MACO is: MACO for a specific Equipment Train = STD(A) SF x x SBS(B) MDD(B)

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<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

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12.4

Rational to Calculate Maximum Allowable Carry-Over Takingthe 10 ppm Criteria: Maximum Allowable Carry-Over (MACO) can also be calculated for the products manufactured in the Tablet section using the following formula:

Starting point is the amount of contaminant (Product-A) accepted as being taken with the "next" ProductB. The approach is to regard the active ingredient of the Product-A as the contaminant to look for. For solids, an active ingredient intake of 1/1000th of the lowest therapeutic dosage of that active is usually regarded as harmless.  The maximum amount of contaminant Product-A allowed to be taken in per day is STD (A) / 1000 per day.This means that with the daily intake of the next product, the maximum allowed of contamination is 1/1000th of the daily therapeutic dosage of the contaminant, which has been mentioned in the Master Plan as “Safety Factor”. To be on the safe side, the maximum daily intake of the next product is considered.  In case of 10 ppm (or 10 mg/ kg) criteria, the STD (A)is considered to be 10 mg/ kg, regardless of the actual amount of dose.  Thus, the quantity Product-A allowed in a single dose of Product-B is: Q = 10/ [1000 x MDDB (in numbers)]=0.01/ MDDB (in numbers)– This quantity is for one dose unit of Product-B.  For the entire batch of Product-B is, MACO(10 ppm) = Q x SBS (B) / One Dose Unit of Product-B (Subject to Recovery Factor) Where SBS (B) is the Smallest Batch Size of product B. (Refer Annexure- VII) Based on the current scenario, we shall be taking 10 ppm criteria under consideration as the acceptance limit obtained from MACO index is more than the acceptance limit obtained from the 10ppm criteria. 12.5 Establishment of Acceptance Limits: 12.5.1 Acceptance Limits per Equipment (ALE) for API:

On getting the MACO value for the whole equipment train, an acceptance limit of maximum allowable carry-over per equipment is required to be calculated for individual equipments of the train. The calculations are as follows: MACO x Surface Area of individual equipment ALE Total Surface Area of all equipment in the train 12.5.2 Acceptance Limits per Swab (ALS) for API:

On getting the ALE value, acceptance limit per swab is calculated, to get an acceptable quantity maximum allowable Carry-Over per swab. The calculations are as follows: Note: The swab surface area ALE x Swab Surface Area ALS isconsidered as 10 x 10 cm or Surface Area of individual equipment equivalent. Acceptance Limit per Swab for Chemical Analysis = <MENTION THE OBTAINED LIMIT>

<COMPANY NAME>
<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 Supersedes: N/A

Document No. Effective Date Page No.

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12.6

Acceptance Limits for Microbial Bio-burden: Swab samples for Microbial Analysis shall be collected from product contact surface area immediately after the completion of cleaning activities and after specified hold time period of total aerobic microbial count. The limits for microbiological bio-burden criteria for product contact surface area is as follows:

Product Equipment Contact Surface Alert Level Action Level

Microbiological Bio-burden (cfu/ 25cm ) Total Plate Count <AS PER THE REQUIREMENTS> <AS PER THE REQUIREMENTS> Mould and Yeast Absent Absent    

2

Corrective Action (If the counts go beyond limit) No action required. Investigate possible causes Perform re-cleaning Perform extra microbial testing

Limit

<AS PER THE REQUIREMENTS>

Absent

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Acceptance Limits for the Cleaning Agent:

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<ADDRESS>

Cleaning Validation Protocol
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Revision No: R0 Supersedes: N/A

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To establish the effectiveness of cleaning process to remove the cleaning agent; i.e. <NAME OF THE DETERGENT>, the acceptance limits shall be prepared based on the toxicological data of the <DETERGENT>. The calculations are as follows: NOEL= LD50 (of Detergent) x 70kg/2000 Maximum Allowable Carry-Over for Detergent(MACOD)= NOEL (of Detergent) x SBS/SF x MDDB Where, NOEL: No Observed Effect Level 2000: an empirical constant LBSB= Largest Batch Size of Product B MDDB: Maximum normal daily dose for next prod Safety factor: 1000 (Constant for Oral Solid Dosage) Thus, the Acceptance Limit per Swab (ALS) =<CALCULATE AND DEFINE THE LIMIT>

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Hold Time Study: To establish the effectiveness of cleaning, equipment shall be kept idle for 72 hrs in controlled conditions. To establish the expiry of cleaning in view of microbiology, equipment shall be kept idle after cleaning for 72 hrs and microbiological swab shall be taken and analyzed. This shall be considered as worst case and microbial load should remain within the limits.

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Revalidation Criteria: Cleaning procedure should only need to be validated once. Periodic monitoring using swab samples is required to ensure compliance. Revalidation shall be done when  Change in cleaning procedure  Change in cleaning agent used for cleaning  Change in minimum batch size and lowest dose of the product i.e. Change in MACO limit  Major Modification in processing equipment  Any regulatory requirements Note:Any change must be formally requested, documented with Change Control. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be

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<ADDRESS>

Cleaning Validation Protocol
For <PRODUCT NAME>
Revision No: R0 determined. Supersedes: N/A

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End of Document

<COMPANY NAME>
<ADDRESS>
Cleaning Validation Protocol Revision History Revision No: R0 Supersedes: N/A Document No. Effective Date Page No. : : : Page 1 of 1 CVP/001

Revision No. R0

Date of Review First issue.

Changes

Reviewed By Sandeep Mehra