Guideline :
Health Products and Food Branch Inspectorate Cleaning Validation Guideline- Health Canada.
Definition:
Cleaning Validation:
Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.
Types of contaminants
- Chemical – Residues of the previous product
- Biological – Microorganisms
- Physical – Particulate matter
Solubility of API shall be mentioned as per following Table:
| Solubility | Approximate volume of solvent in milliliters per gram of solute |
| Very soluble | Less than 1 part (< 1) |
| Freely soluble | From 1 to 10 parts (1 : 10) |
| Soluble | From 10 to 30 parts (10 : 30) |
| Sparingly soluble | From 30 to 100 parts (30 : 100) |
| Slightly soluble | From 100 to 1000 parts (100 : 1000) |
| Very slightly soluble | From 1000 to 10000 parts (1000 : 10000) |
| Practically insoluble | More than 10000 parts (> 10000) |
LD50 of API shall be mentioned as per following Table:
| Probable oral Lethal dose for humans (Mg/ kg) | Included descriptive terms |
| >15000 | Practically non toxic |
| 5000-15000 | Slightly toxic |
| 500-5000 | Moderately toxic |
| 50-500 | Very toxic |
| 5-50 | Extremely toxic |
| <5 | Super toxic |
Cleanability of API shall be mentioned as per following Table:
| Solubility | Approximate volume of solvent in milliliters per gram of solute | Cleanability Index |
| Very soluble | Less than 1 part (< 1) | Easily cleanable |
| Freely soluble | From 1 to 10 parts (1 : 10) | Easily cleanable |
| Soluble | From 10 to 30 parts (10 : 30) | Easily cleanable |
| Sparingly soluble | From 30 to 100 parts (30 : 100) | Hard to clean |
| Slightly soluble | From 100 to 1000 parts (100 : 1000) | Hard to clean |
| Very slightly soluble | From 1000 to 10000 parts (1000 : 10000) | Mechanical water forced required |
| Practically insoluble | More than 10000 parts (> 10000) | Mechanical water forced required |
All equipments parts shall be identified as per rational criteria and categories as per bellow
- Hard to clean
- Direct contact with product
- No direct contact with product
Sampling Techniques :
Visual Inspection (Method For Validation of Cleaning of Equipments):
After cleaning of the equipment visual inspection shall be done using a torch held inclined to the surface being inspected, and a mirror (attached to stainless steel rod) to inspect the surface of equipment. Visual inspection shall be done by unaided naked eye.
For visual cleaning;
Verify the cleanliness of the product contact surfaces. Verify the cleanliness of hard to clean areas.
Verify all the product contact dismantled parts before and after assembling.
Surface Swab Sampling:
The direct Sampling technique is also commonly referred to as “Direct Surface Sampling” method. This is done by Swabbing Technique using Swabs. The direct surface sampling method is the preferred technique.
Sampling Procedure:
Surface sampling is identified as a sampling method considering the design, size and number of equipment.
After the completion of equipment cleaning, visual inspection shall be done.
In case, the surface of equipment is difficult to inspect, a mirror attached to a stick shall be used to inspect the cleanliness of equipment.
Complete product contact surface area shall be sampled for critical hard to clean area/ critical accessories like spray gun, punch, dies, and butter fly valve etc.
Swab Sampling for Chemical analysis:
After visual inspection is found satisfactory swab sampling shall be carried out. Wear hand gloves and nose mask before commencing swab sampling.
The swab must be wetted in purified water or suitable diluents.
Swab area shall be measured with the help of template for swabbing and the area must be 5cm x 5cm or as per protocol.
Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical strokes as described below to assure that the entire area is swabbed.
After swabbing, place the swab into a stoppered test tube, wrap with aluminum foil and label the test tube for identification of swab sample.
Swab samples must be collected from different areas of equipment as stated in the cleaning validation protocol.
Send the stoppered test tube with swab to Quality Control Laboratory for analysis.
Swab sampling for Microbial analysis:
Wear sterile hand gloves and nose mask before commencing swab sampling to avoid the microbiological contamination. Sterile cotton swab shall be used for swabbing.
The sterile cotton swab shall be soaked in sterile saline.
Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical strokes as described below to assure that the entire area is swabbed.
Swab area shall be measured for swabbing and the area must be 5cm x 6cm.
Microbial swab sample shall be collected before chemical swab.
Swabbing shall be done on the surface of equipments and the area is different from the area of swab taken for chemical analysis.
After swabbing, place the swab into a sterilized stoppered test tube and label the test tube for identification of swab sample.
Swab samples must be collected from different areas of equipment as stated in the cleaning validation protocol.
Send the sterile stoppered test tube with swab to Quality Control – Microbiology Laboratory for analysis.
Rinse Sampling Procedure:
After visual inspection is found satisfactory, the equipment shall be rinsed with the volume of rinsing solvent (purified water) as described in respective cleaning validation protocol (rinse sample shall be performed whenever necessary).
Rinse sample shall be collected in the bottles used for the collection of routine purified water samples.
After the collection of rinse sample, (stopper) close the bottle and label it for identification of rinse sample. Send the rinse sample bottle to Quality Control Laboratory for analysis.
Product Container Lid for Example
Method of analysis:
Methods of analysis used for determination of possible contaminant residues must be specific and sensitive.
The selection of analytical methods shall be validated for at least below mentioned parameters based on at least the following but not limited to;
- Precision,
- Specificity
- Linearity and Range,
- Limit of Detection,
- Limit of Quantification,
- Stability of solutions,
- Recovery from Equipment Surface.
FOR WORST CASE APPROACH;
10 PPM Criteria:
MACO =[Mac10] x [Swab Area]/[Shared equipment surface area between products]
Where,
Mac10 = 10 ppm x Minimum Batch Size of Product ‘B’ in kg.
Dose Criteria :
ACCEPTABILITY LIMITS:
Visual inspection criteria:
No quantity of residue should be visible to naked eyes on the equipment after cleaning procedures are performed (i.e. less than 100 mcg /25 cm2).
10ppm criteria: Not more than 10ppm of active pharmaceutical ingredient of previous product is permitted in next product.
Dose based criteria:
Not more than 1/1000 of minimum daily therapeutic dose of the previous product in the maximum daily dose of the next product The acceptability limits for microbiological sample shall be determined based on;
| Parameters | Limit Dirty Equipment Surfaces | Limit Cleaned Equipment Surfaces |
| Total Aerobic Microbial Count (TAMC) | NMT 1000 cfu/swab | NMT 100 cfu/ swab |
| Total Combined Yeasts and Molds Count (TYMC) | Less Than 10 cfu/swab | Less Than 10 cfu/ swab |
Re-validation:
Re-validation shall be performed in case of any change, (at least the following but not limited to)
- Introduction of a new facility, equipment, process or product.
- Change in cleaning procedure.
- Change in cleaning agent used for cleaning.
- Reduction in minimum batch size and lowest dose of the product i.e change in MACO limit.
- Major Modification in processing equipment.
- Periodic revalidation after every three years.
- Change in regulatory requirements.
Dirty Equipment Hold Time (DEHT) –
The time from the end of manufacturing till the beginning of
the cleaning process of equipment (also called things like “soiled hold time”)
The Hold Time Study of Dirty Equipments shall be carried out by keeping equipment in idle for a period of 24 hours in dirty condition. (The Maximum possible hold period under normal conditions) to evaluate microbial contamination on equipment surface and effectiveness of cleaning process.
Clean Equipment Hold Time (CEHT) –
The time from the end of equipment cleaning till subsequent use of equipment (subsequent use includes product manufacturing).
The Hold Time Study of Clean Equipments shall be carried out after completion of “Type B Cleaning”, visual inspection by keeping equipment in idle clean condition up to 72 hours to establish the expiry of cleaning in view of microbiology.
After the equipments surfaces are found visually clean, sampling and testing shall be carried out for Microbiological enumeration Tests and residual determination (chemical analysis) on the cleaned equipment surfaces at 0 hour interval, then sampling and testing shall be carried out only for Microbiological enumeration Tests at rest intervals as per the sampling plan. (i.e., after 24 hours, 48 hours and 72 hours).
Dirty Equipment Hold Time Period : 24 Hours
Cleaned Equipment Hold Time Period : 48 Hours
Pharmaceutical Updates 