sop for cleaning validation protocol ointment manufacturing equipment

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cleaning validation protocol ointment manufacturing equipment

Scope of validation	Ointment Manufacturing Equipment
Reason for validation	New
Document No.
Supersede No.	Nil
Effective Date

1.0 PROTOCOL APPROVAL:
1.1 This protocol is prepared by

Department	Quality Assurance
Signature
Name
Designation
Date

1.2 This protocol is reviewed by

Department	Quality Assurance	Quality Control	Production	Engineering
Signature
Name
Designation
Date

1.3 This protocol is authorized by

Signature
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 of stainless steel
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 Ointment 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

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 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 Ointment.

Sr. No.	Sop No.	Title	Effective date	Equipment	Criticality Rating
1		Operation & Cleaning Procedure of Base Preparation Tank		Base Preparation Tank	Critical
2		Operation & Cleaning Procedure of Compound Manufacturing Tank		Compound Manufacturing Tank	Critical
3		Cleaning Procedure of Bulk Storage Tank		Bulk Storage Tank	Critical
4		Cleaning & Sanitization of Transfer Line		Transfer Line	Critical
5		Operation & Cleaning Procedure of Tube Filling & Sealing Machine		Tube Filling & Sealing 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	Base Preparation Tank		Lid, Stirrer, Tank
2	Compound Manufacturing Tank		Lid, Stirrer, Tank
3	Bulk Storage Tank		Lid, Tank
4	Transfer Line		Transfer Line
5	Tube Filling & Sealing Machine		Hopper, Nozzle

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	Base Preparation Tank	Minimum 30 hr	Minimum 72 hr
2	Compound Manufacturing Tank	Minimum 30 hr	Minimum 72 hr
3	Bulk Storage Tank	Minimum 30 hr	Minimum 72 hr
4	Transfer Line	Minimum 30 hr	Minimum 72 hr
5	Tube Filling & Sealing 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	Base Preparation Tank	Propack Technologies		SS 316
2	Compound Manufacturing Tank	Propack Technologies		SS 316
3	Storage Tank	Propack Technologies		SS 316
4	Transfer Line	Propack		SS 316
5	Tube Filling & Sealing Machine	Techx Process Automation		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 solubility, and Pharmacological action (Potency).

SR.NO	PRODUCT NAME	GENERIC NAME	ACTIVE PHARMACEUTICAL INGREDIENT (API)	Potency	Solubility in water	B. Size (Kg)
1	Dynadin Ointment	Metronidazole & Povidone-Iodine	Each gm Contains: Metronidazole IP 1%w/w Povidone-Iodine IP 5%w/w Eq. to Available Iodine 0.50%w/w	Metronidazole 1%w/w Povidone-Iodine 5%w/w	Slightly soluble Soluble	120
2	Cogen Cream	Clotrimazole, Neomycin Sulphate & Beclomethasone Dipropionate Ointment	Each gm Contains: Clotrimazole IP 1%w/w Neomycin Sulphate IP 05%w/w beclomethasone Dipropionate IP 0.025%w/w	Neomycin Sulphate 5%w/w Beclomethasone Dipropionate 0.025%w/w	Soluble Slightly soluble	150
3	Dubic Gel	Diclofenac Diethylamine , Oleum Lini, Methyl Salicylayte & Menthol Ointment	Each gm Contains: Diclofenac Diethylamine BP 1.16%w/w Eq. to Diclofenac Sodium 1%w/w oleum Lini BP 3%w/w (containing predominantly Alpha Linolenic Acid) Methyl Salicylayte IP 10%w/w Menthol IP 8%w/w	Diclofenac Sodium 1%w/w Oleum Lini 3%w/w Methyl Salicylayte 10%w/w Menthol 8%w/w	Sparingly soluble Insoluble Slightly soluble Slightly soluble	300
4	Copzole Cream	Ketoconazole Ointment	Each gm Contains: Ketoconazole USP 2 % w/w	Ketoconazole 2 % w/w	Practically insoluble	170

Note:- 1) Based on the above data Ointment 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	Base Preparation Tank	Swab	Manufacturing	NA		Total Aerobic Count
						Bacteria	NMT100 cfu
						Fungi	Nil
2	Compound Manufacturing Tank	Swab	Manufacturing	NA		Total Aerobic Count
						Bacteria				NMT100 cfu
						Fungi				Nil
3	Storage Tank	Swab	Manufacturing	NA		Total Aerobic Count
						Bacteria				NMT100 cfu
						Fungi				Nil
4	Transfer Line	Swab	Manufacturing	NA		Total Aerobic Count
						Bacteria		Bacteria
						Fungi		Fungi
5	Tube Filling & Sealing Machine	Swab	Filling	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	Base Preparation Tank	Rinse	Manufacturing	100ml		pH	5.0-7.5
						Conductivity	NMT 5.1 µS
						TOC	NMT 500ppb
2	Compound Manufacturing Tank	Rinse	Manufacturing	100ml		pH	5.0-7.5
						Conductivity	NMT 5.1 µS
						TOC	NMT 500ppb
3	Storage Tank	Rinse	Manufacturing	100ml		pH	5.0-7.5
						Conductivity	NMT 5.1 µS
						TOC	NMT 500ppb
4	Transfer Line	Swab	Manufacturing	NA		pH	5.0-7.5
						Conductivity	NMT 5.1 µS
						TOC	NMT 500ppb
5	Tube Filling & Sealing Machine	Swab	Filling	NA		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	Base Preparation Tank	Swab	Manufacturing	NA		Total Aerobic Count
						Bacteria	NMT100 cfu
						Fungi	Nil
2	Compound Manufacturing Tank	Swab	Manufacturing	NA		Total Aerobic Count
						Bacteria	NMT100 cfu
						Fungi	Nil
3	Storage Tank	Swab	Manufacturing	NA		Total Aerobic Count
						Bacteria	NMT100 cfu
						Fungi	Nil
4	Transfer Line	Swab	Manufacturing	NA		Total Aerobic Count
						Bacteria	NMT100 cfu
						Fungi	Nil
5	Tube Filling & Sealing Machine	Swab	Filling	NA		Total Aerobic Count
						Bacteria		Bacteria
						Fungi		Fungi

8.2 ACCEPTANCE CRITERIA :
8.2.1 For cleaned equipment

For Chemical:
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:

8.3.2 MAC based on 10 ppm = 0.00001mg

= 10 ppm x B.Size
= 0.00001 x 300 x 1000000 = 3000 mg
Based on above criteria 3000 mg is the lowest value, hence it is consider as acceptance criteria.

8.3.3 MAC for each square inch.

MAC value = 3000 = 0.637 = mg/ square inch
Total surface area 4704.3851
(Equipments)

8.3.4 MAC for swab sample.

Surface area for swab sample 5”x 5” .
Total surface area in swab sample = 5 x 5= 25 square inch.
MAC for each swab = MAC for each square inch x total surface area of swab
= 0.637 x 25 = 15.94 mg/swab
MAC for each swab = 15.94 mg/swab = NMT 1594 µg/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	Base Preparation Tank	3000
2	Compound Manufacturing Tank
3	Storage Tank
4	Transfer Line
5	Tube Filling & Sealing Machine

8. 4 Recovery study of Stainless Steel :

8.4.1 Perform analytical method validation and swab recovery studies. Spiking Studies for determining the concentration at which most active pharmaceutical ingredients.
8.4.2 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 .
8.4.3 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 4 to 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	Base Preparation Tank				30 Hrs
	Compound Manufacturing Tank				30 Hrs
	Storage Tank				30 Hrs
	Transfer Line				30 Hrs
	Tube Filling & Sealing 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	Base Preparation Tank				72 Hrs
	Compound Manufacturing Tank				72 Hrs
	Storage Tank				72 Hrs
	Transfer Line				72 Hrs
	Tube Filling & Sealing Machine				72 Hrs

9.0 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.

10.0 DOCUMENTATION:
10.1 After verifying visual cleanliness, record the observation in report.
10.2 After analyzing the Swab/Rinse samples, record the observation in report.

11.0 REVALIDATION :
11.1 Any major change in equipment
11.2 Any change in cleaning procedure.
11.3 Change in analytical procedure
11.4 Change in worst case.
11.5 Change in regulatory requirement
11.6 Change in site location.

12.0 CONCLUSION:
Provide the conclusion and recommendation on the basis of execution results of the cleaning validation protocol.

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