cleaning validation protocol tablet manufacturing equipment
| Scope of validation | Tablet Manufacturing Equipment |
| Document No. | |
| Supersede No. | |
| Effective Date |
1.0 PROTOCOL APPROVAL:
1.1 This protocol is prepared by
| Department | Quality Assurance |
| Signature
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| Name | |
| Designation | |
| Date |
1.2 This protocol is reviewed by
| Department | Quality Assurance | Quality Control | Production | Engineering |
| Signature
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||||
| Name | ||||
| Designation | ||||
| Date |
1.3 This protocol is approved by
| Signature
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|
| Name | |
| Designation | |
| Date |
2.0 TABLE OF CONTENT:
| SR.
NO. |
CONTENT | PAGE
NO. |
| 1.0 | PROTOCOL APPROVAL | |
| 2.0 | TABLE OF CONTENT | |
| 3.0 | OBJECTIVE | |
| 4.0 | SCOPE | |
| 5.0 | RESPONSIBILITIES | |
| 6.0 | INTRODUCTION OF CLEANING VALIDATION | |
| 7.0 | CLEANING PROCESS DESCRIPTION | |
| 7.1 | Brief description of the manufacturing process and processing equipment | |
| 7.2 | Review of cleaning document and cleaning procedure | |
| 7.3 | Equipment evaluation data for Select product | |
| 7.4 | Selection of worst case product for cleaning validation study | |
| 8.0 | METHODOLOGY OF CLEANING PROCESS VALIDATION | |
| 8.1 | Sampling plan & Sampling Location | |
| 8.2 | Acceptance Criteria | |
| 8.3 | Maximum allowable carryover | |
| 8.4 | Recovery study | |
| 8.5 | Analytical Method Validation (Laboratory procedures and its rationale) | |
| 8.6 | Sampling Technique | |
| 8.7 | Swab sampling and analysis technique | |
| 8.8 | Rinse sampling and analysis technique | |
| 8.9 | Visual Inspection technique | |
| 8.10 | Un-Cleaned equipment hold time | |
| 8.11 | Cleaned equipment hold time | |
| 10.0 | FAILURE INVESTIGATION AND CORRECTIVE ACTION | |
| 11.0 | DOCUMENTATION | |
| 12.0 | REVALIDATION | |
| 13.0 | CONCLUSION | |
| 14.0 | REFERENCE |
3.0 OBJECTIVE:
The objective of this protocol is to define approach to validation of cleaning procedures for tablet manufacturing, and Packing . In addition to assure that there is no risk associated with cross-contamination of active ingredients.
4.0 SCOPE:
This protocol is applicable to validate the cleaning procedure of equipment used for the manufacturing and Packing of Tablet.
5.0 RESPONSIBILITIES:
5.1 Quality Assurance department shall be responsible for
5.1.1 Preparation of protocol.
5.1.2 Scheduling & conducting of validation
5.1.3 Monitoring of protocol completeness, accuracy, technical excellence and applicability
5.1.4 Data compilation and review the data/report
5.1.5 Validation reports preparation and recommendation thereafter (if required)
5.1.6 Approval of validation protocol
5.2 Production department shall be responsible for
5.2.1 To provide all applicable cleaning and operational procedures and documentation necessary for the generation of this protocol
5.2.2 To release equipment and accessories for validation
5.2.3 To provide personnel to assist in the preparation and execution of this protocol
5.2.4 Review the protocol and report.
5.3 Quality Control department shall be responsible for
5.3.1 To provide all applicable methodologies, analytical procedures and documentation necessary for generation and execution of this protocol.
5.3.2 All collected samples received from QA and analysis as per sampling plan.
5.3.3 To compile the analytical data.
5.3.4 To provide personnel to assist in the preparation and execution of this protocol.
5.3.5 Review the protocol and report.
5.4 Engineering department shall be responsible for
5.4.1 To provide all equipment contact surface area.
5.4.2 To provide the utilities for CIP and manual cleaning.
5.4.3 Review the protocol and report.
6.0 INTRODUCTION OF CLEANING VALIDATION:
This cleaning validation is to verify the effectiveness and consistency of the cleaning procedure for removal of product residues, preservatives, Excipients and/or cleaning agents as well as the control of potential microbial contaminants in product Selection of “Worst case” product on the basis of toxicity, solubility and Pharmacological action (Potency) of Active pharmaceutical Ingredients (API). if required the grouping approach for the equipment can be considered in the cleaning validation. Three consecutive applications of the cleaning procedure shall be performed during cleaning validation to justified effectiveness & reproducibility of the cleaning.
If any product introduced or discontinue into the line then revise the product matrix and perform cleaning validation accordingly if get any change in ‘Worst case’.
7.0 CLEANING PROCESS DESCRIPTION
7.1 Brief description of the cleaning process and processing equipment :
Manufacturing:- As per SOP
Compression:- As per SOP.
Coating:- As per SOP .
Packing:- followed by carton and corrugated Box Pack.
7.1.1 Process equipment : The equipment used in the processing and with direct contact to the
product
7.2 Review of Cleaning Documents & Cleaning procedure :
7.2.1 List of equipment to be cleaned & rationale :
This protocol will address the cleaning of the following product contact equipment used to manufacture the Carvit Tablet.
| Sr. No. | Sop No. | Title | Effective date | Equipment | Criticality Rating |
| 1 | Operation & Cleaning Procedure of Vibro Sifter | Vibro Sifter | Critical | ||
| 02 | Operation & Cleaning Procedure of Rapid Mixer Granulator | Rapid Mixer Granulator | Critical | ||
| 03 | Operation & Cleaning Procedure of FBD | Fluid Bed Dryer | Critical | ||
| 04 | Operation & Cleaning Procedure of Co-Mill | Co-Mill | Critical | ||
| 05 | Operation & Cleaning Procedure of Bin Blender | Bin Blender | Critical | ||
| 06 | Operation & Cleaning Procedure of Co-Mill | Compression 35 Station | Critical | ||
| 07 | Operation & Cleaning Procedure of De-duster | De-duster | Critical | ||
| 08 | Operation & Cleaning Procedure of Metal Detector | Metal Detector | Critical | ||
| 09 | Operation & Cleaning Procedure of Coating Pan | Coating Pan | Critical | ||
| 10 | Operation & Cleaning Procedure of Tablet Inspection | Tablet Inspection | Critical | ||
| 11 | Operation & Cleaning Procedure of Blister Packing Machine | Blister Packing Machine | Critical |
7.2.2 List of contact parts which are directly contact with the product during manufacturing
| Sr. No. | Equipment Name | Equipment ID | Contact parts |
| 1 | Vibro Sifter | Lid & Sieve | |
| 2 | Rapid Mixer Granulator | Bowl, Flange, Chopper, Impeller | |
| 3 | Fluid Bed Dryer | FBD Bowl, FBD Bag | |
| 4 | Co-Mill | Hopper, Blade & Shaft | |
| 5 | Bin Blender | Lid & Vessel, Blade | |
| 6 | Compression 35 Station | Hopper, Die & Punch Fid Frame & Chutes | |
| 7 | De-duster | Lid & Mess | |
| 8 | Metal Detector | Acrylic Feed Frame | |
| 9 | Coating Pan | Coating Pan | |
| 10 | Tablet Inspection | SS Feed hopper | |
| 11 | Blister Packing Machine | Hopper & Chute
|
7.2.3 Cleaning Procedure:
7.2.3.1 Manual Cleaning Process:
The cleaning procedure as per reference SOP No. given in point 7.2.1 provides details of the procedure ,equipment and material; is required in order to conduct manual cleaning of the product manufacturing process equipments.
7.2.4 Holding Times:
| Sr. No. | Equipment name | Un cleaned Equipment Hold time | Cleaned Equipment hold time |
| 1 | Vibro Sifter | Minimum 30 hr | Minimum 72 hr |
| 2 | Rapid Mixer Granulator | Minimum 30 hr | Minimum 72 hr |
| 3 | Fluid Bed Dryer | Minimum 30 hr | Minimum 72 hr |
| 4 | Co-Mill | Minimum 30 hr | Minimum 72 hr |
| 5 | Bin Blender | Minimum 30 hr | Minimum 72 hr |
| 6 | Compression 35 Station | Minimum 30 hr | Minimum 72 hr |
| 7 | De-duster | Minimum 30 hr | Minimum 72 hr |
| 8 | Metal Detector | Minimum 30 hr | Minimum 72 hr |
| 9 | Coating Pan | Minimum 30 hr | Minimum 72 hr |
| 10 | Tablet Inspection | Minimum 30 hr | Minimum 72 hr |
| 11 | Blister Packing Machine | Minimum 30 hr | Minimum 72 hr |
7.3 Equipment evaluation (Surface area) data:
| Sr. No. | Equipment | Make | Equipment ID | Material of Construction | Surface area
(square inch) |
| 1 | Vibro Sifter | Techx Process Automation | SS 316 | ||
| 2 | Rapid Mixer Granulator | Techx Process Automation | SS 316 | ||
| 3 | Fluid Bed Dryer | Alliance India | SS 316 | ||
| 4 | Co-Mill | Techx Process Automation | SS 316 | ||
| 5 | Bin Blender | Techx Process Automation | SS 316 | ||
| 6 | Compression 35 Station | Cadmach Machines | SS 316 | ||
| 7 | De-duster | Techx Process Automation | SS 316 | ||
| 8 | Metal Detector | NA | SS 316 | ||
| 9 | Coating Pan | Mixo Fill | SS 316 | ||
| 10 | Tablet Inspection | Propack | SS 316 | ||
| 11 | Blister Packing Machine | NA | SS 316 | ||
| Total | |||||
7.4 Selection of worst case product for cleaning validation study
The ‘worst-Case’ product has been determined on the basis of toxicity, solubility, and Pharmacological action (Potency).
| SR.NO | PRODUCT NAME | GENERIC NAME | ACTIVE PHARMACEUTICAL INGREDIENT (API) | Potency mg per tablet
|
Solubility in water | Toxicity (mg/kg) | B.Size
(Tablets)
|
| 1 | Levocetrizine Dihydrochloride Tablet | Each tablet Contains: Levocetrizine Dihydrochloride IP 5 mg | Levocetrizine Dihydrochloride 5 mg | Freely Soluble | 1,00,000 | ||
| 2 | Calcium Carbonate Calcitriol & Zinc Sulphate Tablet
|
Each Film Coated Tablets Contains Calcium Carbonate IP 625 mg Eq. to Elemental Calcium 250 mg Zinc Suplhate Mono. USP20.6 mg Eq. to Elemental Zinc 7.5 mg Calcitriol BP 0.25 mcg | Elemental Calcium 250 mg
Elemental Zinc 7.5 mg Calcitriol 0.25 mcg |
Slightly Soluble
Very Soluble In soluble |
|
1,00,000 | |
| 3 | Calcium Carbonate Magnesium Hydrate,
Zinc Sulphate & Vit. D3 Tablet |
Each Film Coated Tablet Contains Calcium Carbonate IP 1000 mg Magnesium Hydroxide IP 240 mg Zinc Sulphate Monohydrate USP 11 mg Vitamin D3 IP 200IU | Calcium Carbonate 1000 mg
Magnesium Hydroxide 240 mg Zinc Sulphate Monohydrate 11 mg Vitamin D3 200IU |
Slightly Soluble
Practically insoluble Very Soluble Practically insoluble |
|
50,000 | |
| 4 | Paracetamol Tablet | Each un Coated tablet Contains Paracetamol IP 500 mg
|
Paracetamol 500 mg | Sparingly soluble | 2,00,000 | ||
| 5 | Ciprofloxacin & Tinidazole Tablets | Each Film Coated Tablet Contains Ciprofloxacin Hydrochloride Eq. to Ciprofloxacin 500 mg Tinidazole IP 600 mg
|
Ciprofloxacin 500 mg
Tinidazole 600 mg |
Soluble
Insoluble |
|
50,000 |
Note:- 1) Based on the above data Carvit Tablet is become as “Worst Case” product hence it is considered in Cleaning Validation.
8.0 METHODOLOGY OF CLEANING PROCESS VALIDATION
When the process is completed then note the time and date step wise. Record the start of un cleaned hold time, after 30 hrs note the time with date for evaluation of un-cleaned hold time.
After 30 hr take swab and rinse sample for microbial evaluation as per respective SOP QM-047-02
Take the sample for un-cleaned hold time as per sampling plan given at page no. 30.
Clean all equipments as per respective SOP for all equipment given at point no. 7.2
Initially take the microbial swab as point no. 8.7 then Take rinse sample for chemical analysis as per point no. 8.8
After collection of samples hold all equipments and accessories for 72 hrs. After 72 hrs again collect the samples of all equipments and accessories as per sampling plan . After 72 hr. note the time and date as per sampling plan for evaluation of cleaned equipment hold time. First take swab sample for microbiology, then chemical rinse. Send these samples to QC for analysis.
Sample shall be taken from hardest to clean surface of the equipment(i.e Dead legs, Dead spots).
Continue the above procedure for another two batches.
8.1 SAMPLING PLAN AND SAMPLING LOCATION FOR MICROBIAL TESTING (HOLD TIME)
| Sr. No. | Equipment | Sample Type | Sample Location | Sample Quantity
required |
Sample ID | Test Parameter | Acceptance Criteria |
| 1 | Vibro Sifter | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 2 | Rapid Mixer Granulator | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 3 | Fluid Bed Dryer | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 4 | Co-Mill | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 5 | Bin Blender | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 6 | Compression 35 Station | Swab | Compression | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 7 | De-duster | Swab | Compression | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 8 | Coating Pan | Swab | Inspection | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 9 | Metal Detector | Swab | Coating | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 10 | Tablet Inspection | Swab | Inspection | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 11 | Blister Packing Machine | Swab | Packing | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
8.1.1 SAMPLING PLAN AND SAMPLING LOCATION FOR CHEMICAL TESTING CLEANED EUIPMENT
| Sr. No. | Equipment | Sample Type | Sample Location | Sample Quantity
required |
Sample ID | Test Parameter | Acceptance Criteria |
| 1 | Vibro
Sifter |
Rinse | Granulation | 100ml | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 2 | Rapid Mixer Granulator | Rinse | Granulation | 100ml | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 3 | Fluid Bed Dryer | Rinse | Granulation | 100ml | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 4 | Co-Mill | Rinse | Granulation | 100ml | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 5 | Bin Blender | Rinse | Granulation | 100ml | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 6 | Compression 35 Station | Swab | Compression | 100ml | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 7 | De-duster | Swab | Compression | NA | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 8 | Coating Pan | Swab | Inspection | NA |
|
pH | 5.0-7.5 |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 9 | Metal Detector | Rinse | Coating | 100ml | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 10 | Tablet Inspection | Swab | Inspection | NA | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb | ||||||
| 11 | Blister Packing Machine | Swab | Packing | 100ml | pH | 5.0-7.5 | |
| Conductivity | NMT 5.1 µS | ||||||
| TOC | NMT 500ppb |
8.1.2 SAMPLING PLAN AND SAMPLING LOCATION FOR MICROBIAL TESTING CLEANED EQUIPMENT
| Sr. No. | Equipment | Sample Type | Sample Location | Sample Quantity
required |
Sample ID | Test Parameter | Acceptance Criteria |
| 1 | Vibro
Sifter |
Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 2 | Rapid Mixer Granulator | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 3 | Fluid Bed Dryer | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 4 | Co-Mill | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 5 | Bin Blender | Swab | Granulation | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 6 | Compression 35 Station | Swab | Compression | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 7 | De-duster | Swab | Compression | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 8 | Metal Detector | Swab | Inspection | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 9 | Coating Pan | Swab | Coating | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 10 | Tablet Inspection | Swab | Inspection | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
| 11 | Blister Packing Machine | Swab | Packing | NA | Total Aerobic Count | ||
| Bacteria | NMT100 cfu | ||||||
| Fungi | Nil | ||||||
8.2 ACCEPTANCE CRITERIA :
8.2.1 For cleaned equipment
For Chemical:
No more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product.
No more than 10 ppm of any product will appear in another product.
No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible.
For microbial:
NMT100cfu / ml for rinse sample and NMT 100cfu /swab for swab sample.
8.2.2 For un-cleaned equipment
For microbial: For Information for rinse sample and swab sample.
8.3 Maximum Allowable Carryover:
Cleaning Limits Selection Criteria based on Maximum Allowable Carryover (MAC) :
8.3.1 MAC Based on 0.1 % Safety Factor
MAC = Lowest daily dose (mg) x Lowest B.Size (Kg) x 1000000
Largest Daily Dose (mg) x 1000
8.3.2 MAC based on 10 ppm = 0.00001mg
= 10 ppm x B.Size
= 0.00001 x 1808 x 1000000 = 18080 mg
Based on above criteria 1468 mg is the lowest value, hence it is consider as acceptance criteria.
8.3.3 MAC for each square inch.
MAC value =
Total surface area
(Equipments)
8.3.4 MAC for swab sample.
Surface area for swab sample 5”x 5” .
Total surface area in swab sample = 5 x5= 25 square inch.
MAC for each swab = MAC for each square inch x total surface area of swab
= 0.44 x 25 = 11 mg/swab
MAC for each swab = 11 mg/swab = NMT 1100µg/swab
8.3.5 MAC for rinse sample of each equipment.
| Sr. No. | Equipment | MAC/square inch (mg) | Surface area
(square inch) |
MAC (mg) | MAC (µg) |
| 1 | Vibro Sifter | ||||
| 3 | Rapid Mixer Granulator | ||||
| 3 | Fluid Bed Dryer | ||||
| 4 | Co-Mill | ||||
| 5 | Bin Blender | ||||
| 6 | Compression 35 Station | ||||
| 7 | De-duster | ||||
| 8 | Metal Detector | ||||
| 9 | Coating Pan | ||||
| 10 | Tablet Inspection | ||||
| 11 | Blister Packing Machine | Sr. No. Equipment MAC/square inch (mg) Surface area
(square inch) MAC (mg) MAC (µg) 1 Vibro Sifter 3 Rapid Mixer Granulator 3 Fluid Bed Dryer 4 Co-Mill 5 Bin Blender 6 Compression 35 Station 7 De-duster 8 Metal Detector 9 Coating Pan 10 Tablet Inspection 11 Blister Packing Machine |
8. 4 Recovery study:
8.4.1 Recovery study shall be cover in Analytical method validation.
8.4.2 Perform analytical method validation and swab recovery studies. Spiking Studies for determining the concentration at which most active pharmaceutical ingredients.
8.4.3 Report the results applying the recovery factor for active pharmaceutical ingredients with consideration also taken for any chemical variants (active decomposition materials), write summary and conclusion. Record the recovery study .
8.4.4 ACCEPTANCE CRITERIA: Shall be Not Less than 80%.
8.5 Analytical Method Validation (Laboratory procedures and its rationale)
8.5.1 Analytical method to be used for cleaning validation shall be specific (i.e. either or combination of HPLC, TLC,) and validated for following parameters:
Specificity
Linearity
Limit of detection
Limit of quantification
8.5.2 Attach analytical method validation report.
8.6 Sampling technique :
There are two sampling technique :
8.6.1 Swab sample technique : This is direct surface technique use wet swab.
8.6.2 Rinse sample technique : This Technique is applicable where difficult to carry swab sample.
8.6.3 For uncleaned/cleaned equipment sample detail:
For microbial analysis: Purified water shall be use for microbial evaluation.
For chemical analysis : Purified water shall be used for swab & rinse sample.
8.7 Swab sampling and analysis technique
8.7.1 Take swab as per SOP NO
8.7.2 Select 5 square inch area of the surface and swab it by sterile cotton swab by dipping it in Peptone water tube test tube containing 2 ml Peptone water.
8.7.3 After swabbing , dip the swab in same peptone tube and shake it properly so as that it liberate adhered microbes into the Peptone water and immediately transfer it to microbiology department.
8.7.4 Add this 2 ml of activated peptone water to a sterile Petri dish and add approximately 20 ml of autoclaved media (Molten). Shake it and allow to solidify.
8.7.5 Incubate the plate at 20° C to 25° C for 72 hour. Then incubate the same plate at 30°C to 35°C for 48 hour for Bacterial Count.
8.7.6 Count the CFU of the plate and Record the observation in report.
8.6.1 Selection of Surface Area, using one side of moistened swab wipe the test surface of 5” x 5” with 10 firm horizontal strokes as illustrated in figure 1. Turn the swab stick over to its other side, wipe the test surface of 5” x 5” with 10 firm vertical strokes as illustrated in figure 2 . Wherever 5” x 5” area is not available for swab sampling, carry out sampling from hardest to clean area.
8.6.2 Wherever 5” X 5” is not available , carryout sample from hardest to clean area of the entire area .
8.6.3 At the end of the each stroke lift the swab carefully and keep the swab stick in the container.
8.8 Rinse sample and analysis technique
8.9.1 For Chemical:- Use Purified water and collect it into a container. Rinse the equipment & accessories from top to cover all areas of equipment and collect the 100 ml puriedfied water from drain point of equipment. Sample quantity 100ml shall be use for rinse.
8.10 Visual Inspection technique.
8.10.1 Inspect the cleaned equipment by using necessary visual aids (Torch, Lights, etc) while performing the inspection rather than peeping through the glass/ into the machine.
8.10.2 During inspection focus on hard –to- clean areas of the equipments.
8.10.3 Ensure complete dryness of the surface so that all cleaning solutions have been removed and there is no potential for residue formation after wards.
8.11 Un-cleaned equipment hold time
| Stage | Equipment | Time and date of manufacturing process completed (T1) | Time and date of before start of cleaning of equipment (T2) | Observed un cleaned hold time
(T2-T1) |
Hold time of un cleaned equipment. Minimum time (Hrs) |
| After completion of process and before cleaning | Vibro Sifter | 30 Hrs | |||
| Rapid Mixer Granulator | 30 Hrs | ||||
| Fluid Bed Dryer | 30 Hrs | ||||
| Co-Mill | 30 Hrs | ||||
| Bin Blender | 30 Hrs | ||||
| Compression 35 Station | 30 Hrs | ||||
| De-duster | 30 Hrs | ||||
| Coating Pan | 30 Hrs | ||||
| Tablet Inspection | 30 Hrs | ||||
| Metal Detector | 30 Hrs | ||||
| Blister Packing Machine | 30 Hrs |
8.12 Cleaned equipment hold time
Stage Equipment Time and date of cleaning process completed (T3) Time and date of hold time of cleaned equipment (T4) Observed cleaned hold time (T4-T3) Hold time of cleaned equipment. Minimum
After Cleaning Process Vibro Sifter 72 Hrs
Rapid Mixer Granulator 72 Hrs
Fluid Bed Dryer 72 Hrs
Co-Mill 72 Hrs
Bin Blender 72 Hrs
Compression 35 Station 72 Hrs
De-duster 72 Hrs
Coating Pan 72 Hrs
Tablet Inspection 72 Hrs
Metal Detector 72 Hrs
Blister Packing Machine 72 Hrs
10.0 FAILURE INVESTIGATION AND CORRECTIVE ACTION:
If result is comes out of limit then investigate the route cause . On the basis of investigation necessary corrective action shall be implemented. Again repeat the study on worst case for three consecutive run.
11.0 DOCUMENTATION:
11.1 After verifying visual cleanliness, record the observation in report.
11.2 After analyzing the Swab/Rinse samples, record the observation in report.
12.0 REVALIDATION :
12.1 Any major change in equipment
12.2 Any change in cleaning procedure.
12.3 Change in analytical procedure
12.4 Change in worst case.
12.5 Change in regulatory requirement
12.6 Change in site location.
13.0 CONCLUSION:
Provide the conclusion and recommendation on the basis of execution results of the cleaning validation protocol.