Cleaning Validation ProtocolRevision HistoryDocument No.:CVP/ 001

Effective Date:

Revision No: R0Supersedes: N/APage No.:Page 1 of 1

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COMPANY NAMECompany Address

CLEANING VALIDATION PROTOCOL

FOR

AT:

INDEXS. No.ContentPage No.

1. Preapproval of Protocol3 of 15

2. Introduction4 of 15

3. Objective4 of 15

4. Scope4 of 15

5. Responsibilities5 of 15

6. Protocol Training Record6 of 15

7. Product Profile6 of 15

8. Equipment Description7 of 15

9. Methods of Cleaning7 of 15

9.1 Cleaning Procedures7 of 15

9.2 Materials and Equipments used for cleaning8 of 15

9.3 Cleaning SOP Index for each equipment8 of 15

10. Sampling Method9 of 15

10.1 Selection of Sampling Method9 of 15

10.2 Scientific rational for selecting Sampling Points9 of 15

10.3 Visual Inspection9 of 15

10.4 Swab Sampling for Chemical Analysis of API9 of 15

10.5 Sampling Patterns10 of 15

10.6 Swab sampling for Microbial analysis10 of 15

10.7 Swab sampling Location11 of 15

11. Analytical Procedure12 of 15

12. Establishment of Acceptance Criteria12 of 15

12.1 Visual Inspection12 of 15

12.2 Active Residue12 of 15

12.3 Rational to Calculate Maximum Allowable Carry-Over Taking the Worst-Case12 of 15

12.4 Rational to Calculate Maximum Allowable Carry-Over Taking the 10 ppm Criteria13 of 15

12.5 Establishment of Acceptance Limits13 of 15

12.5.1 Acceptance Limits per Equipment (ALE) for API13 of 15

12.5.2 Acceptance Limits per Swab (ALS) for API13 of 15

12.6 Acceptance Limits for Microbial Bio-burden14 of 15

13. Acceptance Limits for the Cleaning Agent14 of 15

14. Hold Time Study15 of 15

15. Revalidation Criteria15 of 15

1. Preapproval of Protocol:Signing of this Protocol indicates agreement with the Cleaning validation approach established for . Further, if any changes in this Master Plan would be required, it will be revised and duly approved.

Compiled By:

Functional areaNameDesignationSignatureDate

Quality Control

Production

Quality Assurance

Reviewed and Approved By:

Functional areaNameDesignationSignatureDate

Head-Quality Control

Head-Production

Quality Assurance

Authorized By:

Functional areaNameSignatureDate

Head-Quality Assurance

2Introduction:

Cleaning Validation in the context of manufacture of the solid oral products at 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.

3Objective:

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 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

4Scope:

The scope of this protocol is applicable for the Cleaning validation of Also, to evaluate the acceptability of cleaning procedure used in cleaning of equipment using well-established 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 .

5Responsibilities:

5.1Quality Assurance:

5.1.1 To prepare the Cleaning Validation Protocol.

5.1.2 To review the Cleaning Validation Protocol.

5.1.3 To monitor cleaning activities.

5.1.4 To collect swab/rinse samples from cleaned equipment.

5.1.5 To review analytical reports.

5.1.6 To prepare and review cleaning validation report.

5.2Production:

5.2.1 To review the Cleaning Validation Protocol.

5.2.2 To provide details of equipments.

5.2.3 To get the equipments cleaned by trained operators.

5.2.4 To schedule cleaning validation program.

5.2.5 To maintain log-books for equipment cleaning.

5.2.6 To review cleaning validation report.

5.3Quality Control:

5.3.1 To review the Cleaning Validation Protocol.

5.3.2 To analyze the swab/rinse samples collected for cleaning validation.

5.3.3 To compile the analytical data.

5.3.4 To review cleaning validation report.

5.4Quality Control (Microbiology):

5.4.1 To review the Cleaning Validation Protocol.

5.4.2 To collect Microbiological samples from cleaned equipment.

5.4.3 To analyze the cleaning validation samples.

5.4.4 To compile the Microbiological data.

5.4.5 To review cleaning validation report.

5.5Head Quality Assurance:

5.5.1 To review and to approve cleaning validation protocol and report.

6Protocol Training 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.

7Product Profile:

7.1 is the existing product of the of .

7.2

7.3

7.4

7.5 Chemical Skeletal Structure the API :

7.6

7.7

7.8 Three batches of the product shall be validated for Cleaning.

8Equipment Description:

Following Equipments of same design and operating principles shall be deployed for cleaning validation of the three batches of .

S. No.Name of EquipmentCapacityID NumberSurface Area (cm2)**Surface Area (cm2)

8.1.

8.2.

8.3.

8.4.

8.5.

8.6.

** Surface Area + 10% of Surface Area

9Methods of Cleaning:

9.1 There are three types of cleaning procedures deployed at :

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 of Type B cleaning, as it is done after product to product changeover and cleaning process deploys water and detergent.

9.2 Materials and Equipments used for cleaning:

9.3 a) Purified Waterb) Tap waterc) Vacuum Cleanerd) Scrubbere) Dry sponge or lint free cloth.f)

9.4 Cleaning SOP Index for each equipment:

Sr. No.Name of EquipmentID NumberCleaning SOP Number

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 . Swabs of the cleaned equipments shall be taken as per the sampling points given in the DRS.

10Sampling Method:

10.1Selection of Sampling Method:

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: 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.

10.2Scientific 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.

10.3Visual 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.

10.4Swab Sampling for Chemical Analysis of API:

Description of swab:

MakeTexwipe Swab ,USA

ModelTX714A

Head MaterialKnitted Alp halite Polyester

Handle MaterialPolypropylene

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. in 50ml Test-Tube. Swab samples from different areas of equipment shall be collected. Swab area shall be measured for swabbing.

Sampling error: During swab sampling following care to be taken: area of sampling (should not be less than 100 cm2), apply proper force during collection of sample to avoid any sampling errors.

Sampling area: 10 x 10 cm. = 100 cm2 or equivalent (for the parts, where 100 cm2 is not available as whole)

10.5Sampling 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

10cm OREnd 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.

10.6Swab 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.

10.7Swab sampling Location:

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 samplingMicrobial swab sampling

Sr. No.EquipmentLocationNo. of swab locationsLocationNo. of swab locations

1

2

3

4

5

6

11Analytical 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.

12Establishment 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.

12.1Visual Inspection:

Equipment should be visually clean and dry and must contain NO visible residues.

12.2Active 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 Product-A can be carried-over to the maximum allowable daily dose of Product-B manufactured in the same equipment train.

12.3Rational to Calculate Maximum Allowable Carry-Over Taking the Worst-Case:

The Maximum Allowable Carry-Over (MACO) shall be calculated the following factors:

STD(A):Single Therapeutic Dose of Product A (in mg).

SBS(B):Smallest Batch Size of Product B (in mg).

SF:Safety Factor (constant) = 1000 for solid dosage forms

LDD(B):Largest Daily Dose of Product B (in mg).

Thus, the formula to calculate MACO is:

MACO for a specific Equipment Train = STD(A) x SBS(B)

SF x MDD(B)

12.4Rational to Calculate Maximum Allowable Carry-Over Taking the 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" Product-B. 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.

12.5Establishment of Acceptance Limits:

12.5.1Acceptance 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:

ALEMACO x Surface Area of individual equipment

Total Surface Area of all equipment in the train

12.5.2Acceptance 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:

ALSALE x Swab Surface Area

Note: The swab surface area is considered as 10 x 10 cm or equivalent.

Surface Area of individual equipment

Acceptance Limit per Swab for Chemical Analysis =

12.6Acceptance 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 SurfaceMicrobiological Bio-burden (cfu/ 25cm2)Corrective Action(If the counts go beyond limit)

Total Plate CountMould and Yeast

Alert LevelAbsent No action required.

Action LevelAbsent Investigate possible causes Perform re-cleaning Perform extra microbial testing

LimitAbsent

13Acceptance Limits for the Cleaning Agent:

To establish the effectiveness of cleaning process to remove the cleaning agent; i.e. , the acceptance limits shall be prepared based on the toxicological data of the . 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 Level2000: an empirical constantLBSB= Largest Batch Size of Product BMDDB: Maximum normal daily dose for next prodSafety factor: 1000 (Constant for Oral Solid Dosage)

Thus, the Acceptance Limit per Swab (ALS) =

14Hold 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.

15Revalidation 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 determined.

Cleaning Validation ProtocolFor Document No.:CVP/001

Effective Date:

Revision No: R0Supersedes: N/APage No.:Page 2 of 15

End of DocumentRevision No.Date of ReviewChangesReviewed By

R0 First issue.Sandeep Mehra