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CLEANING VALIDATION PROTOCOL OF |
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PROTOCOL
NUMBER |
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CLEANING VALIDATION PROTOCOL APPROVAL |
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(NOT VALID WITHOUT SIGNATURE) |
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PERSONNEL INVOLVED IN VALIDATION STUDY |
SIGNATURE |
DESIGNATION |
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PREPARED BY |
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PRODUCTION PHARMACIST |
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REVIEWED BY |
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MANAGER QUALITY CONTROL |
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APPROVED BY |
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PRODUCTION MANAGER |
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The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of API residues, degradation products, preservatives, excipients, and/or cleaning agents as well as the control of potential microbial Contaminants. In addition one need to ensure there is no risk associated with cross-Contamination of active ingredients
Objective
This document on Cleaning Validation aims to address special considerations and issues pertaining to validation of cleaning procedures for Filling & sealing Machine (Dry Suspension) used in the manufacture of pharmaceutical products. The document is also intended to establish inspection consistency and uniformity with respect to equipment cleaning procedures.
Scope
The document is intended to cover cleaning Validation of Filling & sealing Machine (Dry Suspension) for the removal of contaminants associated with previous products, residues of cleaning agents as well as the control of potential microbial contaminants
Sampling Procedure
There are two general types of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable;
However the Rinse sample technique will be applied for sampling according to following plan:
Direct Surface Sampling (Swab Method)
Area difficult to clean and which are reasonably clean can be evaluated by direct surface sampling method (Swab Method), leading to establish a level of contamination or residue per given area i.e. 60 – 100 in2. The residue that are dried out or are insoluble can be sampled by Swab Method.
The suitability of the method to be used for sampling and of sampling medium should be determined. The ability to recover the sample accurately may be affected by the choice of sampling method. It is important to assure the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.
For determination of the Microbiological Contamination on surfaces is to use sterile cotton swabs moistened with sterile peptone water, WFI, or Phosphate Buffer. Using sterile forceps and aseptic technique, an area of predetermined size, e.g. 60 - 100 in2, is wiped with a sterile swab. The swab is then aseptically transferred to a sterile tube containing a suitable diluent. The tube is then agitated to suspend any viable microorganisms and aliquots are placed in a semisolid medium to obtain quantitative results.
Passive Air Sampling (Settle Plate Method)
A sterile 60-mm Petri Dish containing a semi solid medium nutrient agar with a convex surface is pressed directly onto the previously decontaminated surface to be settled.
The medium is then incubated for a predetermined period and the plate is examined for the evidence growth. The contamination is reported in term of Colony Forming Units (CFU) per plate. The plate is of standard size and the assumption is made that any contamination is uniformly distributed, the results can be extrapolated to determine the residual bio burden on the entire surface.
Rinse Sampling
Rinse samples allow sampling of large surface area and of inaccessible system or parts that cannot be routinely disassembled. However consideration should be given to the fact that the residue or contaminant may be soluble or may be physically occluded (Hidden somewhere) in the machine.
Placebo
Placebo sampling method provide the best simulation of the actual production of the subsequent batch of product, to use this techniques a suitable placebo formulation must first be chosen, solubility of the compounds being studied and accurate simulation of the actual production conditions.
For liquid production either sterile or non-sterile, water is often the best placebo formulation. For sterile liquids WFI is usually selected, where purified water is generally best for non-sterile liquids.
If a single placebo batch can be processed through most or all of the processing steps, it will be exposed sequentially to all possible sources of contamination of the residuals.
If the Placebo method is used to validate the cleaning process it should be used in conjugation with rinse or swab method.
Along with taking any type of the samples, it is important to use visual inspection as well to ensure the process acceptability
Test the samples Swab Sample, Rinse Sample or Placebo for detection of active or inactive impurity according to relevant testing procedure of the ingredient to be detective and provide quantitative results.
Analytical methods.
Physical Testing
Along with taking any type of the samples, it is important to use visual inspection as well to ensure the process acceptability. Visual inspection must be satisfactory before sampling. Visual inspection will be done for visible contamination.
Microbiological Testing
As per Product Testing method, rinse to be checked.
Chemical Testing
The specificity and sensitivity of the analytical methods should be determined. If levels of contamination or residue are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that the level of contaminant is lower than the sensitivity or detection limit of the analytical method.
Acceptance Criteria
Following Acceptance area will be applied for the cleaning validation.
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Sr.# |
Test |
Acceptance criteria |
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1. |
Physical inspection |
On inspection, all surfaces must be
visually clean i.e. must be free of product and detergent residues, foaming
and accumulation of water when dry. |
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2. |
Chemical test |
The Maximum allowed carry-over for
product residue must be less than 10PPM· The pH and Conductivity of the rinse
water samples tested must meet the BP specification for purified water. This
specification is not more than 4.3 µS/cm-1 at 20°C and between 5.0 and 7.0 pH
units. |
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3. |
Microbiological Testing |
All equipment must have microbial
contamination at acceptable levels |
Change Control
A change control system is to ensure that all changes that might impact the cleaning process are assessed and documented. Significant changes should follow satisfactory review and authorization of the documented change proposal through the change control procedure. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system. The review should include consideration of re-validation of the cleaning procedure.
Changes which should require evaluation and likely re-validation include but not limited to:
Changes in the cleaning procedure.
Changes in the raw material sources.
Changes in the formulation and/or process of products.
New products.
Changes in the formulation of detergents.
New detergents.
Modifications of equipment
Cleaning Procedure
Put the distilled water in relevant equipment and keep it on for 15 minutes then remove it.
Put the hot distilled water having temperature at least 80oC and keep it on for 15 minutes.
Wash the equipment and manufacturing area with hot distilled water (80oC) for three times.
Give three samples of washing water to QC for previous product traces test.
If ok from QC, than apply swab test for cleaning of manufacturing area.
If not ok from QC, clean the mixer and manufacturing area with detergent.
Check all parts thoroughly, if cleaned then stick identification slip of status (Cleaned)
Facilities/Responsible Personnel/Equipment/Material and Documentation
Facilities
The cleaning validation of each equipment will be performed in Facility of organization.
Identification of Responsible Personnel
Name
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Job Title
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Responsibility
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Signature
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Operator
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Responsible for the cleaning of Machines as per SOP’s
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Production Pharmacist
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To ensure that Machines are cleaned as per SOP’s
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QC Analyst
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Responsible for chemical analysis of Rinse Samples
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Microbiologist
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Responsible for the Microbial analysis of Swab samples
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QC Manager
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Responsible for validating analytical method used to analyze
traces of API of previous product & test samples according to validated
analytical method.
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Production Manager
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Checking of Protocol & Final Report.
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Identification of Machines/Equipment
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Machine/Equipment |
Code No. |
SOP Reference No. |
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Inspection Criteria:
Inspection Criteria is based on cleaning procedure as per Sops.
sampling procedure & acceptance criteria for three consecutive products.
Product:
Product Name:
Batch Number:
Procedure
After receiving intimation for cleaning of machine/equipment or area, witness the cleaning according to predetermined cleaning procedure.
During cleaning checked and noted the following points.
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1.
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Description of Machine/equipment/area |
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2.
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Major Product contact components |
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3.
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Previous product |
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4.
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Batch No. |
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5.
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Equipment Cleaned on |
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6.
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Detergent/Solvent used |
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7.
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Cleaning Cycles |
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8.
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Cleaned by |
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9.
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Supervised by |
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10. |
Sampled by (Chemical Analysis) |
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11. |
Sampled By (Microbial Analysis) |
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12. |
After Cleaning Equipment Used on |
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13. |
Subsequent Product |
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14. |
Batch Number |
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15. |
Name of API |
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16. |
Batch Size of Subsequent Product |
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After
cleaning take sample either by direct surface sample (Swab Method) or rinse
sample depending upon the nature of machine/equipment and product.
·
Send
the sample to QCD along with Technical Information Sheet for analysis.
·
QCD
analyzes the results, if the results comply with the specified limit, then the
machine/equipment or area is considered as cleaned and is allowed for further
process.
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If
the results do not comply with the specified limit, then test until clean. This
concept involves cleaning, sampling & testing until an acceptance residue
limit is obtained.
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a). Sampling
Method followed |
Rinse sample
& Swab sampling |
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b).
Analytical
Method followed |
Determination of
product Residue by UV method |
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Sr.# |
Testing Parameters |
Acceptance Criteria |
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1.
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Physical Determination |
On inspection, all surfaces must be
visually clean i.e. must be free of product and detergent residues, foaming
and accumulation of water when dry. |
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2.
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Microbial Determination |
All equipment must have microbial
contamination at acceptable levels |
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Testing Parameter |
Assay |
pH |
Conductivity |
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Chemical
Determination |
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Observations for Filling & Sealing Machine Dry Suspension after washing with RO water
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Sr# |
Testing Parameters |
Findings |
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1.
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Physical Determination (Visual Inspection) |
No
physical residue should be found on machine after washing with RO Water. |
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2.
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Microbial Determination (Swab Test) |
No growth was
found in Petri dishes |
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Cleaning Validation Rinse Sample |
Testing Parameters |
Assay |
pH |
Conductivity |
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Rinse Sample 01 |
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Rinse Sample 02 |
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Rinse Sample 03 |
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Product # 02
Product Name:
Batch Number:
Procedure
After receiving intimation for cleaning of machine/equipment or area, witness the cleaning according to predetermined cleaning procedure.
During cleaning check and note down the following points.
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Description
of Machine/equipment/area |
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Major
Product contact components |
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Previous
product |
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Batch
No. |
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Equipment
Cleaned on |
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Detergent/Solvent
used |
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Cleaning
Cycles |
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Cleaned
by |
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Supervised
by |
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Sampled
by (Chemical Analysis) |
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Sampled
By (Microbial Analysis) |
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After
Cleaning Equipment Used on |
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Subsequent
Product |
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Batch
Number |
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Name
of API |
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Batch
Size of Subsequent Product |
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After cleaning take sample either by direct surface sample (Swab Method) or rinse sample depending upon the nature of machine/equipment and product.
Send the sample to QCD along with Technical Information Sheet for analysis.
QCD analyzes the results, if the results comply with the specified limit, then the machine/equipment or area is considered as cleaned and is allowed for further process.
If the results do not comply with the specified limit, then test until clean. This concept involves cleaning, sampling & testing until an acceptance residue limit is obtained.
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a). Sampling Method followed |
Rinse sample
& Swab sampling |
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b). Analytical Method followed |
Determination of
product Residue by UV method |
Acceptance
Criteria:
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Sr # |
Testing Parameters |
Acceptance
Criteria |
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1. |
Physical Determination (Visual Inspection) |
On inspection, all surfaces must be
visually clean i.e. must be free of product and detergent residues, foaming
and accumulation of water when dry. |
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2. |
Microbial Determination (Swab Test) |
All equipment
must have microbial contamination at acceptable levels |
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Testing Parameter |
Assay |
PH |
Conductivity |
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Chemical Determination |
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Observations
for Filling & Sealing Machine Dry Suspension after washing with RO water
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Sr # |
Testing Parameters |
Findings |
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1. |
Physical Determination (Visual Inspection) |
No
physical residue is found on Filling & Sealing Machine after washing with
RO Water. |
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2. |
Microbial Determination (Swab Test) |
No growth was
found in Petri dishes |
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Cleaning Validation Rinse Sample |
Testing Parameter |
Assay |
PH |
Conductivity |
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Rinse Sample 01 |
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Rinse Sample 02 |
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Rinse Sample 03 |
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1. |
Description of Machine/equipment/area |
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2. |
Major Product contact components |
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3. |
Previous product |
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4. |
Batch No. |
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5. |
Equipment Cleaned on |
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6. |
Detergent/Solvent used |
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7. |
Cleaning Cycles |
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8. |
Cleaned by |
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9. |
Supervised by |
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10. |
Sampled by (Chemical Analysis) |
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11. |
Sampled By (Microbial Analysis) |
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12. |
After Cleaning Equipment Used on |
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13. |
Subsequent Product |
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14. |
Batch Number |
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15. |
Name of API |
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16. |
Batch Size of Subsequent Product |
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a). Sampling Method followed |
Rinse sample
& Swab sampling |
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b). Analytical Method followed |
Determination of
product Residue by UV method |
Acceptance
Criteria:
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Sr # |
Testing Parameters |
Acceptance Criteria |
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1. |
Physical Determination (Visual Inspection) |
On inspection, all surfaces must be
visually clean i.e. must be free of product and detergent residues, foaming
and accumulation of water when dry. |
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2. |
Microbial Determination (Swab Test) |
All equipment must have microbial
contamination at acceptable levels |
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Testing Parameter |
Assay |
PH |
Conductivity |
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Chemical
Determination |
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Observations for
Filling & Sealing Machine Dry Suspension after washing with RO water
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Sr # |
Testing Parameters |
Findings |
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1.
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Physical Determination (Visual Inspection) |
No physical residue is found on Filling
& Sealing Machine after washing with RO Water. |
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2.
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Microbial Determination (Swab Test) |
No growth was
found in Petri dishes |
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Cleaning Validation Rinse Sample |
Testing
Parameters |
Assay |
PH |
Conductivity |
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Rinse Sample 01 |
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Rinse Sample 02 |
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Rinse Sample 03 |
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Cleaning Validation Report
Protocol
No:
Machine/Area: Code
No:
Date
Started: Dated Completed:
Summary:
Objective:
The Cleaning Validation report is intended to document cleaning procedure, sampling procedure
establishment of acceptance criteria, Observations, deviations and conclusions
for Filling & sealing Machine (Dry Suspension) used in the manufacture of
pharmaceutical products.
Scope:
The scope of this document apply on Filling and Sealing Machine
Dry suspension.
Cleaning
Validation Team:
Following persons were dedicated for the cleaning validation of
the specific machine.
Responsibility:
Production Manager
QC Manager
QA Manager
Procedure for Cleaning:
The below mentioned cleaning procedure followed as per cleaning
sop.
RO water was put in the hopper and funnel of filling and sealing machine & kept it for 15 minutes & then removed it.
Ø And
then the hot RO water having temperature at least 80oC was put in the Hopper
& funnels and kept it on for 15 minutes.
Ø The
Filling & Sealing Machine Dry Suspension & manufacturing area was
washed with hot RO water (80oC) for three times.
Ø Three
cleaning cycles were used.
Ø Three
samples of one liter washing water were given to QC for previous product traces
test.
Procedure for Sampling:
Two Sampling
techniques were used for the cleaning of Filling & Sealing Machine Dry
Suspension.
Ø
Rinse
Sample
Ø
Swab
Sample
Rinse Sample:
Ø Rinse
samples are usually taken into account more oftenly as it covers larger surface
area of the machine and also covers those area areas which are difficult to
clean and are not dissembled.
Ø Three
different samples of one liter rinse water and one liter blank water were taken
in each product & checked for chemical analysis.
Ø Cleaning
Validation Rinse Sample Form.
Swab
Sample:
Ø Distilled
water was taken in a beaker and dipped the swab in a beaker.
Ø Beaker
was covered with parchment/batter paper than sterilized this beaker at 121oC
for ½ hour.
Ø The
swab was broken into few pieces for different area & these pieces were
rubbed with floor, roof, walls and different part of machines and then put
these pieces of swab in a Petri dish.
Ø Petri
dishes were incubated at 30-35oC for 12 hours.
Ø After required incubation Petri dishes were observed keenly for growth of microorganism.
Analysis for previous product traces:
Sample Preparation:
Take
1ml of sample and make the volume up to 100ml with suitable solvent in the
volumetric flask.
Standard Preparation:
Weigh
accurately on analytical balance 100mg of powder of standard and make the
volume up to 100ml with suitable solvent in the volumetric flask. Take 1ml of
this and make the volume up to 100ml with the same solvent.
Measure
the absorbance of sample and standard at its own wavelength on UV
spectrophotometer.
Establishment of Acceptance Criteria:
The Following acceptance
criteria was established as per Cleaning Validation SOPs.
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Sr # |
Testing Parameters |
Acceptance criteria |
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1. |
Physical Determination (Visual Inspection) |
On inspection, all surfaces must be
visually clean i.e. must be free of product and detergent residues, foaming
and accumulation of water when dry. |
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2. |
Chemical test |
The Maximum allowed carry-over for
product residue must be less than 10PPM· The pH and Conductivity of the rinse
water samples tested must meet the BP/USP specification for purified water.
This specification is not more than 4.3 mS/cm-1 at 20°C and between 5.0 and
7.0 pH units. |
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3. |
Microbial Determination (Swab Test) |
All equipment
must have microbial contamination at acceptable levels |
Observations:
The Following are the Observations of three
consecutive products to be validated as per Cleaning Validation Sops
Product
# 01
Product
to be cleaned:
QC
Number:
Equipment
Name:
Equipment
Location:
Sampling
Type:
Sampling
Date:
Hold
Time:
Subsequent
Product:
Observations
for Machine after washing with RO water
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Sr # |
Testing Parameters |
Findings |
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1. |
Physical Determination (Visual Inspection) |
No physical residue is found on Filling
& Sealing Machine after washing with RO Water. |
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2. |
Microbial Determination (Swab Test) |
No growth was
found in Petri dishes |
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Cleaning Validation Rinse Sample |
Testing
Parameters |
Assay |
PH |
Conductivity |
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Rinse Sample 01 |
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Rinse Sample 02 |
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Rinse Sample 03 |
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Product
#02
Product
to be cleaned:
QC
Number:
Equipment
Name:
Equipment
Location:
Sampling
Type:
Sampling
Date:
Hold
Time:
Subsequent
Product:
Observations
for Filling and Sealing Machine Dry Suspension after washing with RO water.
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Sr # |
Testing Parameters |
Findings |
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1. |
Physical Determination (Visual Inspection) |
No physical residue is found on Filling
& Sealing Machine after washing with RO Water. |
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2. |
Microbial Determination (Swab Test) |
No growth was
found in Petri dishes |
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Cleaning Validation Rinse Sample |
Testing Parameter |
Assay |
PH |
Conductivity |
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Rinse Sample 01 |
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Rinse Sample 02 |
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Rinse Sample 03 |
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Product
#03
Product
to be cleaned:
QC
Number:
Equipment
Name:
Equipment
Location:
Sampling
Type:
Sampling
Date:
Hold
Time:
Subsequent
Product:
Observations
for Filling and Sealing Machine Dry Suspension after washing with RO water.
|
Sr # |
Testing Parameters |
Findings |
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1.
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Physical Determination (Visual Inspection) |
No physical residue is found on Filling
& Sealing Machine after washing with RO Water. |
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2.
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Microbial Determination (Swab Test) |
No growth was
found in Petri dishes |
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Cleaning Validation Rinse Sample |
Testing
Parameters |
Assay |
PH |
Conductivity |
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Rinse Sample 01 |
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Rinse Sample 02 |
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Rinse Sample 03 |
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Validation
Status:
As per cleaning validation sops doc #
NOR/SOP/QA/36 cleaning validation of the Filling and Sealing Machine of Dry
suspension has been completed successfully.
Deviations:
No deviations were found during the whole
validation process.
Conclusion:
The cleaning cycles & procedures are considered validated on completion of three consecutive successful evaluations.
The results shows that the procedure opted for cleaning of Equipment is efficient, robust & documented and after cleaning the results are within the established limits.
All Cleaning Procedure SOP’s used are current and in place. All identified training are completed and documented.
Analytical method and recovery procedures used in cleaning validation of Filling and Sealing Machine Dry Suspension are validated.
All equipment and instrumentation used for testing are calibrated. No unexplained intervening failures occurred.
Recommendations:
Changes to the qualified procedure can only be made in accordance with in-house change control procedure.
Re-validation shall be performed as necessary, in accordance with the recommendations made on the change control documentation.
The Validation status must be re-evaluated for any significant change in processing, cleaning procedure or cleaning agent.