CLEANING VALIDATION FOR DRUG PRODUCTS
To establish and explain the procedure to be followed for the Validation of Standard Cleaning Procedures (SOP’s), in order to demonstrate that cleaning procedures are effective, adequate and shall consistently remove the residues (chemical, microbial and cleaning agent, if any) from the equipment to a pre-determined level of acceptance.
SCOPE OF CLEANING VALIDATION:
This procedure is applicable for cleaning validation of all manufacturing/process equipment, process aids (like spatula, transfer containers, transfer lines-, sampling accessories etc.) That comes in direct contact or indirect contact (under close proximity with open
Product) with the product at the drug product manufacturing
RESPONSIBILITY:
Quality Assurance department –
To prepare, review & approve cleaning validation master plan, cleaning validation protocols, cleaning validation reports, matrix to derive the acceptance criteria, identification of worst case products.
To ensure availability of toxicology data of molecule while technology transfer.
To identify sampling locations for swab/rinse sampling.
To execute periodic cleaning verification as per schedule.
To perform the swab/ rinse sampling for the respective equipment.
To ensure cleaning validation activity is conducted in compliance with cleaning validation master plan, cleaning validation protocol and applicable cGMP requirements.
Production department –
To establish cleaning procedure for manufacturing equipment and prepare equipment cleaning checklist.
To identify hard to clean locations of equipment.
To review cleaning validation/verification protocols and reports.
To perform cleaning validation/verification as per approved protocol.
Engineering department –
To provide the surface area of each piece of equipment for deriving the acceptance criteria.
To support and provide required utilities during execution of cleaning validation/verification.
Quality Control department –
To analyze the chemical swab and rinse samples.
Microbiologist department –
To sample and analyze the microbiological swab and rinse samples.
R&D department-
To provide toxicology (PDE) data of molecules, approved by toxicologist.
To share required information of molecules and drug product, during new product introduction.
To develop the analytical methods for testing of swab/rinse samples.
To provide information with respect to cleaning agent, if any.
DEFINITIONS:
Acceptance Criteria – Numerical limits, ranges, or other suitable measures for acceptance of test results.
Cleaning Agent – The solution or solvent used in the cleaning process. Examples of cleaning agents are water, organic solvent, etc.
Cleaning Process – A process of removing contaminant from the process equipment such that equipment can be safely used for subsequent product manufacture.
Cleaning Validation – The process of providing documented evidence with high degree of assurance that the cleaning methods employed within a facility consistently controls potential carryover of product, cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels.
Cleaning Verification – The process of providing documented evidence through analysis (Chemical and Microbial) after each batch/campaign or through schedule periodic monitoring to show that the residue of previous products or cleaning agents/microbes have been removed below the predefined acceptance criteria.
Cleaning Validation Master Plan (CVMP) – Document that summarizes the firm’s / manufacturing site’s overall philosophy, intentions and approach to be used for establishing performance adequacy of the cleaning process(s).
Cleaning Validation Protocol (CVP) – The document describing strategy and procedure for conducting and recording the test and results of cleaning on manufacturing / process equipment to confirm and to demonstrate that the cleaning process is capable of removing residue of the product or material used in the manufacturing equipment below the defined limit.
Cleaning Validation Report (CVR) – The document which includes assessment, evaluation and conclusion of cleaning validation study results conducted as prescribed in the CVP.
Acceptable Daily Exposure (ADE) – A dose that is unlikely to cause an adverse effect if an individual is exposed, by any route, at or below this dose every day for a lifetime.
No Observed Adverse Effect Level (NOAEL) – The dose in toxicology study which produces no adverse effects.
Maximum Allowable Carryover (MACO) – Maximum Allowable Carryover defined as acceptable amount of residue from previous product to next product.
Worst case Product – The worst case are those conditions or set of conditions encompassing upper and lower processing limits or circumstances, within standard operating procedures, which pose greatest chance of product or process failure when compared to ideal conditions. In grouping strategies, ‘worst case products’ means selecting those products with predefined acceptance limits that after cleaning, possess greatest chance of cross contamination leading risk to the product quality and patient health & safety.
Limit of Detection (LOD) – The lowest amount of analyte in a sample that can be detected but not necessarily quantified as an exact value.
Limit of Quantification (LOQ) – The lowest amount of analyte in a sample that can be quantitatively determined with suitable precision & accuracy.
Recovery Study – A laboratory study combining the sampling method and analytical method to determine the quantitative recovery of a specific residue for a defined surface.
Dirty Equipment Hold Time (DEHT) – Dirty Equipment Hold Time is defined as the time between end of use of the equipment and the start of equipment cleaning. DEHT can be also referred as Dirty Hold Time (DHT).
Clean Equipment Hold Time (CEHT) – Clean Equipment Hold Time is defined as the time between end of cleaning and beginning of production usage. CEHT can be also referred as Clean Hold Time (CHT).
PROCEDURE:
Pre-requisites for cleaning validation:
SOPs for cleaning of equipment with detailed instruction including defined critical cleaning parameters.
Trained cleaning operators.
Trained visual inspector and swab/rinse sampler.
Qualified utilities such as water system, HVAC and compressed air system etc.
Cleaning validation Lifecycle Approach:
| Stage | Purpose/ Activities |
| I – Design Stage (Cleaning Process Design) | Design stage refers to below factors:New cleaning procedures.Identification of Sampling locationsAnalytical Method development/ validation for any new molecule. (Covered vide respective SOP)This stage is commonly required in case of new facility, equipment and sometime products where special cleaning is advised. |
| II – Cleaning Process performance qualification (Cleaning Validation) | Cleaning validation for minimum 3 consecutive runs on the worst case products or based on the assessment.• Establishment of CEHT & DEHT• Campaign study• Cleaning Operator qualification in case of manual cleaning process• Visual Inspector qualification• Swab sampler qualification |
| III – Continuous process Verification ofCleaning | Periodic Cleaning verification on worst case product (annually)Cleaning verification for new products Cleaning verification of highly hazardous drug products |
Also read -Air Filtration by Membrane
Cleaning Process Design:
Introduction of any new product / new equipment at site shall be triggered through Change control and subsequently assessment shall
be performed to evaluate impact on cleaning validation.
New product introduction:
Any new product introduced at manufacturing facility shall be assessed.
In case new product requires new testing procedure or revision of existing testing procedure, QA shall inform to R & D team for availability of suitable testing method to analyse swab/rinse samples.
After first cleaning run of any new product, cleaning verification shall be performed and cleavability assessment shall be done. The outcome and final risk rating (if updated) shall be recommended in the respective report.
If new product is not a worst case and existing cleaning procedure is applicable, then cleaning verification on one run shall be adequate to
prove cleaning effectiveness.
If new product requires revised cleaning procedure, establish the critical process parameters (reflux, number of rinses, solvent quantity,
cleaning agent, time, pressure, temperature etc.) during pre-validation / exhibit / trial / scale up batches. And upon optimization of process,
the cleaning validation shall be performed.
New Equipment introduction:
During introduction of any new equipment, Equipment with product contact surface area shall be updated and assessment shall be performed.
In case the equipment requires new cleaning procedure, production person shall design cleaning procedure based on the previous experience, knowledge, products that are going to be manufactured by using the new equipment. OEM manual/recommendations, but not limited to.
While designing of any cleaning procedure, the critical cleaning parameters (time, pressure, temperature, cleaning agent etc.) shall be
defined for optimization.
If new procedure is required, below should be the desired process steps for manual cleaning:
- Dry Cleaning/ Dismantling
- Pre Washing/ Soaking
- Scrubbing
- Washing
- Preliminary Inspection
- Final Rinsing
- Drying
- Visual Inspection
In case of CIP, cleaning recipe/ number of cycles shall be provided to optimize along with other applicable steps.
In case the existing procedure is identified as suitable to clean the equipment, then proceed with one cleaning verification run to prove the
effectiveness. First cleaning run of equipment used in manufacturing of any product shall be considered for cleaning verification.
Cleaning Validation:
The cleaning procedure for all equipment that come in contact with the product shall be cleaned as per the validated procedure given in their respective equipment cleaning SOPs and same shall be used for documentation of cleaning process.
Product dedicated equipment/equipment parts/accessories, shall not be under the scope of cleaning validation. The cleaning of such equipment shall be evaluated for microbial attributes.
Cleaning procedures are broadly divided for oral solid dosage form into two types. i.e., Type ‘A’ and Type ‘B’. Refer respective equipment cleaning SOP’s for detailed cleaning procedures.
The type ‘B’ cleaning is one that is considered for the cleaning validation/ verification.
Product Grouping:
Product grouping shall be performed if products are manufactured on the same or equivalent equipment/equipment train, and cleaned by
same cleaning procedure. The product grouping shall be maintained.
Wherever product grouping approach is applied, cleaning validation shall be executed on the identified worst case product.
Equipment Grouping:
The manufacturing equipment shall be grouped together according to following criteria:
| Sr. No. | Grouping Strategy | Examples |
| 1. | Identical, interchangeable piece of equipment with same cleaning procedure. | Dispensing scoops, table top balance, table de-dusters, metal detectors, mechanical sifters, multi-mills, Inspection belts etc. |
| 2. | Equipment with similar design, working principle and same cleaning procedure but with different size/capacity/working volume and product contact surface areas shall be grouped together. | Rapid mixer granulators, Fluid Bed dryers, Blenders, Manufacturing tanks etc. |
| 3. | Equipment with similar design, working principle and same cleaning procedure but with different working capacity and product contact surface areas. | Compression machines, Capsule filling machines, Packing machines, Inspection machines etc. |
The cleaning validation carried on any one representative equipment of respective group, shall be applicable for all equipment in the group. In case of equipment of different size/complexity (for RMGs, FBDs, Blenders, storage tanks etc.,) preference should be given to equipment with higher surface area or complexity. Equipment train matrix shall be prepared, to map products manufactured on respective train.
The cleaning validation shall be performed for all equipment groups or equipment types present in the facility. In case any of the equipment is
not covered in the cleaning validation executed on the equipment train , separate worst case product shall be identified for cleaning validation
execution of respective groups.
Approach I – Identification of worst case molecule for cleaning validation based on Risk Rating:
Selection of worst case product shall involve a scientific rationale and risk based approach. The criteria to be considered for risk rating of the products for determining the worst case shall include following:
- Cleanability i.e. Hardest to Clean
- Solubility (of API) in cleaning solvent
- Toxicity i.e. Permitted Daily Exposure (PDE)
- Potency i.e. Minimum therapeutic dose
Cleanability i.e. Hardest to Clean:
The hardest to clean product shall be classified in below three criteria:
- Easy
- Moderate
- Difficult
The operators having experience in cleaning of equipment after manufacturing of products shall be interviewed to gather the information and categorize in above 3 criteria. Minimum 3 operators involved in major operations having combination of different stages, shall be interviewed.
Interview shall be conducted
- Name
- Equipment Name
- Manufacturing Stage
- Sticky Nature
- Coloured Product
- Colour is difficult to remove
- Leaves stains on surface when comes in contact with water/cleaning solvent
- Easily removable during cleaning
- Overall experience in difficulty in cleaning
The rating shall be provided as below:
| Rating | Cleanability (A) |
| 3 | Difficult |
| 2 | Moderate |
| 1 | Easy |
Solubility of API in cleaning solvent:
A solubility rating shall be carried out based on the solubility of active ingredients (APl) present in the drug products. The solubility of the molecules in the solvent used for cleaning shall be considered:
| Rating | Solubility (B) |
| 3 | Practically Insoluble(> 10,000 parts)Very Slightly Soluble (1000 to 10000 parts)Slightly Soluble (100 to 1000 parts) |
| 2 | Sparingly Soluble (30 to 100 parts)Soluble (10 to 30 parts) |
| 1 | Freely Soluble (1 to 10 parts)Very Soluble (< 1 part) |
Toxicity i.e. Permitted Daily Exposure:
The PDE (Permitted daily exposure) shall be next factor applicable for rating based on the toxicity of the active substance present in the drug products:
| Rating | Toxicity (PDE) (μg/day) (C) |
| 5 | <1 |
| 4 | 1 to 9 |
| 3 | 10 to 99 |
| 2 | 100 to 500 |
| 1 | > 500 |
Potency i.e. lowest therapeutic dose
Depending on the smallest recommended daily dose of the actives present in the drug product, rating for this factor shall be provided:
| Rating | Potency (mg) (D) |
| 5 | <1 mg |
| 4 | 1 to 9 mg |
| 3 | 10 to 99 mg |
| 2 | 100 to 1000 mg |
| 1 | >1000 mg |
Final Risk rating number for any product shall be calculated by multiplying individual ratings provided on each criteria for the respective products and product with highest risk rating number shall be concluded as worst case:
Final Risk Rating = Cleanability (A) X Solubility (8) X Toxicity (C) X Potency (D)
Wherever the identified worst case products are manufactured in multiple strengths, higher strength of the product shall be preferred for execution of cleaning validation. However, in case of non-availability of higher strengths, the cleaning validation can be executed on the anyone of the available strength.
In case more than one products are identified as worst case product, below tie breaker rule shall be applied:
Product with least soluble API (If more than one, go for next tie breaker)
Product with higher quantity of API (If more than one, go for next tie breaker)
Product with API having lower PDE (If more than one, go for next tie breaker)
Product with API having lowest therapeutic dose.
If still there are more than one products identified as worst case product, then CV need to be executed on all identified worst case product.
Approach II – Cleaning validation based on Health Based exposure level:
Cleaning Validation shall be performed for initial three batches of all drug products having PDE value less than or equal to 10 μg/day.
After Completion of cleaning validation and during routine manufacturing, cleaning verification shall be performed after every product to product changeover of such products.
The Cleaning Verification shall be performed to verify the absence of the chemical residue only.
Establishment of MACO:
Maximum Allowable Carryover (MACO) for the drug product shall be derived by using following criteria:
- Permissible Daily Exposure (i.e. PDE in mg/day) of molecule.
LD50 (Toxicity) criteria for detergent residue
In product grouping approach, to have stringent acceptance limit, below approach to be followed during calculation:
- Lowest PDE of drug product among the group shall be considered as product A
- Lowest ratio of minimum, batch size and maximum daily dose shall be considered as next product i.e. product B.
- Maximum total contact surface area of all equipment in the equipment train shall be considered in the calculation.
- In case the existing MACO limit (calculated using dose based criteria) of historically manufactured product is observed stringent, then the same shall be considered as MACO limit for execution of cleaning validation.
PDE (Health Based Exposure Limit criteria) Criteria for active drug residue:
The MACO values for PDE criteria shall be calculated using the following formula: MACO for Swab sample:
MACO (μg/swab) = PDE of product A (in mg/day) X Smallest Batch Size of Product B (mg) X Swab Surface Area (cm2) X1000/Maximum Daily Dose of Product B (mg) X Surface Area of Shared Equipment between Product A and B (cm2)
MACO (ppm)= PDE of product A (in mg/day) X Smallest Batch Size of Product B (mg) X Swab Surface Area (cm2) X 1000 /Maximum Daily Dose of Product B (mg) X Surface Area of Shared Equipment between Product A and B (cm2) X Volume of Solvent Used for Swabbing (ml).
Where,
Product A: Previous product i.e. product to be cleaned
Product B: Next product to be manufactured
Note: For any product, if the acceptance limit is above 100 mcg, the limit shall be considered as 100 mcg.
LD50 (Toxicity) Criteria for detergent residue
The MACO values for detergent considering LD50 criteria shall be calculated using the following formula:
MACO (μg/swab) = NOEL X Minimum batch size of product B (mg) X Swab Surface Area (in Sq. cm) X 1000 /Safety Factor X Maximum Daily Dose of Product B (mg) X Surface area of Shared Equipment Between Product A and B (in Sq. cm)
Or
MACO (ppm)= NOEL X Minimum batch size of product B (mg) X Swab Surface Area (in Sq. Cm) X 1000 /Safety Factor X Maximum Daily Dose of Product B (mg) X Surface area of Shared Equipment Between Product A and B (in Sq. Cm) X Volume of Solvent Used for Swabbing (ml).
NOEL= LDso (mg/kg) X Weight of Average Adult (70 kg)/ 2000
Note-1: For Oral Solid & Ophthalmic dosage forms the Safety Factor is considered as 1000
Note-2: For Parenteral the Safety Factor is considered as 10000
Note-3: For Topical the Safety Factor is considered as 100
Note-4: LDso value can be obtained from material safety Data sheets or any relevant documents
Note-5: 1 /2000 or 5 X 10-4 (empirical constant) times LDso has no pharmacological effects on humans.
Sampling methodologies
Sampling for cleaning validation / cleaning verification shall be performed by the following method.
Direct sampling (Surface Swab Method)
Indirect sampling (Rinse Method)
Swab sampling is the most desirable method for collection of samples for cleaning validation / cleaning verification. In circumstances where equipment area is not accessible to swab sampling, rinse sampling shall be performed along with swab sampling of maximum possible area.
Identification of swab sampling locations
Swab sampling locations shall be identified for each equipment by considering below aspects:
Hard to clean (including uneven surfaces/grooves/perforated plates) These are the locations/parts in the equipment which difficult to clean due to their design, geometry and accessibility. For e.g. Sieves, screes, Force feeder, Coating Pans, Large size blender & manufacturing tank etc. In case of any new equipment hard to clean location shall be supported by operator interview.
Functional location –
These are the location which are the major exposed part of the equipment to the product during processing. For e.g. Hoppers, FBD
Retarding Chamber, RMG Bowl etc.
Representative Material of construction (MOC) –
These are the location to cover different type of MOCs present in the equipment, as the cleanability may vary between different materials. For
e.g. Gaskets, View glasses etc.
Non-uniform contamination –
Certain locations of the equipment may lead to non-uniform contamination of drug product if remained uncleaned. Non-uniform contamination refers to the carrying of contaminants on the limited amount of next products, most often the initially passed material from the equipment surfaces. For e.g. Discharge chute, sampling ports etc.
At least two swab sampling locations shall be identified for each and every equipment.
A pictorial representation for selection of sampling locations with rationale shall be prepared for each and every equipment / similar equipment and shall be updated.
Material of construction of the swab location shall be assessed and appropriate recovery for the MOC shall be employed for calculating the results of the analyte. When the MOC of the swab surface constitute less than 5% of the product contact surface then the lowest recovery value among the MOC shall be employed.
Swab sampling procedure:
Guidance for swab sampling procedure is given below. Site specific swab sampling procedure incorporating similar methodology may be adapted and followed.
Preparation of clean test tube and swab for Active Drug Substances, Cleaning Agent and Colorant (if applicable) analysis shall be done as per current version of STP for the respective product under evaluation and current version of STP for cleaning agent.
The swab stick used during the execution of cleaning validation shall be as per the method validation.
Wear clean/pre-sterilized hand gloves and then take swab sample.
Take out the swab from the tube and hold the swab at one end. For microbial analysis take out the pre sterile swabs from sealed container and hold at one end.
Moisten the swab in the diluent (as described in the respective STP) and squeeze out the swab against side of the tube to remove the excess of solution.
Swab for chemical analysis shall be performed preferably in 2 X 2 inches’ surface area of the equipment using the template from the predefined location. However, if required swab area can be increased up to 4 X 4 inches, in such cases the selected area shall be applied in calculation. In case of microbial swab sampling, the swab area shall be considered as 2 X 2 inches.
Swabbing shall be done using horizontal and vertical strokes in specified area.
In case 2 X 2 inches’ area is not possible due to equipment geometry and/or hard to reach like pipes, cavities, groves, mesh etc. approximate area to cover 2 X 2 inches area shall be sampled.
Swab samples shall be collected from pre-identified sampling locations for each equipment as defined in respective cleaning validation /verification protocol.
Swab sampling shall be carried out by trained personnel. Sampling shall be carried out by following below sequence.
- Microbial Sampling
- API residue Swab Sampling
- Cleaning agent residue swab sampling
Swab sampling for chemical, detergent and microbial attributes shall be collected such that there shall be no overlapping between sampling area of respective samples.
Identify the sample with the details like “Name of the sample, Type of Sample, Product under cleaning, Batch number, Equipment name,
Equipment Number, date, sign,” and submit the sample to Quality Control laboratory for analysis.
Rinse sampling procedure:
One type of rinse sampling technique is using ‘grab sample. The acceptance criteria obtained for swab (in ppm) shall be considered as acceptance criteria of rinse sample by converting it into ppm.
Another type of rinse sampling technique is to utilize a separate sampling rinse after completion of the process rinse.
This separate rinse shall involve filling the equipment to an appropriate level with solvent and agitating that solvent to make the composition of
the residue in the sampling rinse.
The rinsed volume shall be collected in container as aliquot and required amount of sample from that solution shall be taken and analysed.
Collect final rinse water during cleaning of respective equipment and submit to QC as rinse sample. Quantity of rinse sample shall be defined in respective protocol.
Rinse the parts of equipment in contact with product as per procedure mentioned in respective cleaning SOP’s, with known quantity of purified after collect the purified water into container and send sample after labelling it as per validation / verification protocol to QC for analysis.
Rinse limit for the individual equipment shall be derived as per the below formula:
Rinse Limit (ppm) = PDE of product A (in mg/day) X Smallest Batch Size of Product B (mg) X SA(e) /Maximum Daily Dose of Product B (mg) X TSA XV in Liter.
Where –
SA (e) – Surface area of the individual equipment
TSA – Total surface area of equipment chain
V – Rinsing solvent volume in Liter for the individual equipment
If the product contains multi-active drug substances, the active substance considered as worst case shall be evaluated.
In case of piping collect samples by passing solution/cleaning agent from one end and collect from the other end.
The swab samples / rinse samples collected shall be sent to QC for analysis through “Test Request Form”.
Collection of swab samples shall only be initiated once the equipment is visually clean verified with appropriate light source and no evidence of dirt or residues of product / cleaning agent on the product contact surfaces found during visual inspection.
Analytical Method:
Analytical methods used for analysis of cleaning sample (chemical and microbial) shall be validated to demonstrate the reproducibility and recovery from the contact surfaces as per current version of site procedure.
In case the acceptance criteria is found less than the limit of quantification (LOQ) of the analytical method, following approaches can be considered:
Analytical method to be optimized to achieve lower limit of detection by slight modification such as-
- increasing injection ‘volume in case of chromatographic method like HPLC/GC etc.
- increasing injection cell length in case of UV methods from 1 cm to 4/5 cm path length cell.
- Increase the swabbing surface area (for example, 4 X 4 sq.in).
- In case of rinse sampling, volume of sample rinse can be decreased, resulting into increase in the residue concentration and hence can be easily detected.
If swabbing area or rinse volume is modified, acceptance criteria also need to be corrected and recalculated with revised area or revised rinse volume.
If modification of analytical method as per options provided. Does not make the limit measurable, then below options shall be evaluated:
Dedicate the equipment to that one product, thereby reducing the need to measure the active ingredient except by visually clean criteria.
- Restrict the order of manufacture such that certain products, which drive the limit lower are not manufactured after the clean product with low limit. In such case appropriate measures shall be put in place to restrict the manufacturing sequence.
- Increase the minimum batch size of next product, thereby increasing the limit.
If above modification does not provide limit of detection lower than acceptance criteria established, new method to be developed which can achieve required lower detection concentration. In case of modification, method should be revalidated.
Recovery Study:
Validate the recovery of the extraction process by spiking the analyte at known concentrate to determine the recovery.
Piece of the equipment (test coupon) used to study recovery factor (Rf.) is similar material of construction of equipment used for the process.
Recovery study shall not be required for residue that are known to be freely soluble as per USP (eq. NaOH etc.) provided residue are not reactive with or absorbed into surface.
Execution of Cleaning validation/verification:
Cleaning validation shall be performed on worst case product on a minimum of three (03) consecutive product to product change over cleaning or as per assessment.
NOTE: Cleaning validation shall be performed during first three commercial batches and cleaning verification shall be performed for minimum one batch during submission batches.
Cleaning procedures shall be considered as validated, if each cleaning cycle/run complies with the acceptance criteria.
Cleaning verification approach shall be applied for the unique condition mentioned below:
- New product is introduced at site.
- Product manufacturing is one-time activity.
- Event where the product shall not be manufactured in the same manner on commercial scale equipment, (For example, execution of exhibit batch/scale up/trial of new products).
- New equipment introduced at site
- Annual periodic verification
- During product changeover until cleaning validation is established i.e. 3 successful cleaning runs on worst case product.
Cleaning Validation Protocol (CVP):
Cleaning validation protocol and report numbering:
Cleaning validation protocol and report numbering shall be assigned as below and the same shall be entered in the cleaning validation numbering log.
Cleaning validation protocol shall be prepared.
Cleaning Validation Report (CVR):
Upon completion of cleaning validation/ verification, report shall be prepared as per the standard format for “cleaning validation /verification report”.
ACCEPTANCE CRITERIA:
The equipment shall be visually clean and there shall be no evidence of dirt or residues of product / cleaning agent on the product contact surfaces and other surfaces after cleaning.
The acceptance criteria of worst case product under cleaning validation shall be stringent of all products in the group i.e. the lowest residue limit.
Limit for microbial load Table 3-
| S. No. | Parameter | Limits/Swab | Rinse/ml |
| 1. | Total Aerobic Microbial Count (TAMC) | NMT 50 CFU /25 Cm2 | NMT 100 CFU/ml (PW Water) |
| 2. | Total Combined Yeasts and Moulds count {TYMC) | Should be absent | Should be absent |
| 3. | Bacterial Endotoxins | NA | Less than 0.25EU/ml |
| 4. | Microbial bioburden (for Sterile) | NA | NMT 10 cfu/100 ml |
Evaluation of results:
If cleaning validation/verification results meets the acceptance criteria, conclude the validation/ verification process.
If cleaning validation/verification results does not meet the acceptance criteria, failure investigation shall be carried through Deviation/OOS.
In event of cleaning verification failure, the equipment shall be recleaned with respective cleaning procedure and can be used if results are found complying. From investigation outcome if cleaning procedure is identified as root cause, then same shall be validated whenever subsequent batches of product is planned.
The cleaning validation/verification report shall also contain the details of failure results and their investigation and corrective actions taken.
Cleaning test samples shall be analyzed within the stipulated time derived based on the solution stability.
Cleaning Operator Qualification:
There are different types of cleaning modes applied for cleaning of manufacturing equipment to remove the previous contaminant and remove the previous product reside below the predefined acceptance level.
Wherever manual cleaning methods is used, operator qualification shall be performed by fulfilling below requirements:
Eye sight test of the, Operator
Training on the cleaning SOPs
Training on CGMP
Execution of three satisfactory cleaning runs on any major equipment.
Satisfactory visual inspection of cleaned equipment by Supervisor.
The operator shall be certified by respective HOD and approved by QA.
Visual Inspector Qualification:
Visual inspector qualification shall be performed to qualify personnel involved in the equipment cleanliness certification such as production supervisors and IPQA supervisors.
Coupons of all equipment surface materials shall be spiked with solutions of the residue at different levels based on the derived visual detection limit.
Visual inspection shall be performed with same set of condition such as viewing angle and lighting condition.
The outcome of visual inspector qualification shall be concluded in report.
Swab Sampler Qualification:
Training shall be provided to personnel involved in swab sampling.
Training shall cover (but not limited to), reading of sampling procedure and demonstrating the correct procedure by a trained person. Emphasis shall be given on consistency of wetting the swab head, consistency of the swabbing motion (including overlapping strokes), consistency in applied pressure, and consistency in swabbing of the correct surface area while training on swab sampling.
Coupons shall be prepared by spiking 100 % of LOO level for different MOC of coupons.
The swab sampler qualification shall be performed.
After successful demonstration, sampler shall be certified for swab sampling.
In case of microbiology, microbiologist analyst certification shall be considered.
Continuous Process verification of cleaning:
Routine compliance of the validated cleaning SOP shall be confirmed by verification of the cleaning process control parameters on the machine print-out or cleaning check-list in automatic or manual cleaning process respectively for each cleaning cycle.
Periodic Cleaning Verification:
The validated cleaning procedure shall be checked for its validity in the routine operation.
The evaluation shall be done once in a year with single cleaning run for the worst case product through a cleaning verification protocol. The cleaning verification shall include the trending of the current residue results against the initial cleaning validation and previous year verification results for the product.
Annual planner for cleaning verification shall be prepared at the beginning of each year for the list of equipment.
In the event where worst case product is not planned for manufacturing as per schedule, cleaning verification shall be executed on the subsequent worst case product.
If the existing worst case product is obsolete and no more manufactured the periodic verification shall be carried on subsequent worst case product, however existing cleaning validation shall remain valid.
Revalidation:
Requirement of re-validation of the cleaning procedure shall be evaluated in one or more of the following conditions, but not limited to:
- Changes in cleaning procedure
- Changes in cleaning agent
- Addition of new product if it impacts on worst case
- In case any changes in minimum batch size/change in highest surface area of equipment chain have any impact on the earlier cleaning validation. For instance, the residue limit observed during earlier validation is above the revised MACO.
- Any Change or Modification that has impact on efficiency of cleaning process.
Cleaning Validation Master Plan (CVMP):
The CVMP is a high level document, which establishes a broad plan for the complete cleaning validation project and is used as a guidance document to the cleaning validation project team for general guidance, resource and technical planning.
Cleaning Validation Master Plan shall be prepared for all manufacturing plant/ facility/ block/ site engaged in manufacturing of finished dosage forms.
Handling of Products with Highly Hazardous API (PDE value ≤10 μg/day):
List of products with API having PDE ~1 0μg/day shall be maintained at manufacturing site.
Such products shall be handled with additional precautions and manufacturing controls considering the risk on the patient safety as well as operator safety.
Risk assessment shall be carried out considering below factors, but not limited to:
- Cross contamination due to shared equipment/accessories
- Cross contamination due to shared HVAC
- Cross contamination due to man and material movement
- Personal safety of operators getting directly exposed to the material
The cleaning verification to be carried out only in case of molecule changes. The samples can be exempted in case of change over at end of campaign to start same molecule or different strength of same molecule.
Dirty Equipment Hold Time Study (DEHT):
Dirty Equipment Hold Time Study shall be carried out considering the worst case molecule for the appropriate set of equipment and cleaning procedure.
Worst case product molecule shall be selected for dirty equipment hold time study based on the following parameters (but not limited to):
- Difficulty to Clean
- Product prone for microbial contamination as this poses high risk to product, environment as well as equipment microbial load.
Note: The study will be executed on product which has no antimicrobial nature. Thus a monitoring product shall be the most appropriate representative of all type of products & will simulate the actual manufacturing environment.
Hold Time Study shall be performed for all major types/groups of equipment. Rationale for selecting the equipment’s and product may be for hold time study must be clearly mentioned in the respective hold time study protocol.
During the holding of dirty equipment, storage condition shall be simulated as per routine practices.
Conduct the sampling as mentioned in the Table or as defined in the Protocol.
| Activities | Sample details | Responsibility |
| Hold the equipment for 48 Hrs. 3 Days/ 5 Days/ 7 Days or as specified in the protocol and swab sample analysis for bioburden at each interval. For parenteral – sampling at initial (0 hrs.), 4 hrs. 8 hrs. 12 hrs. 24 hrs. 48 hrs. or as specified in the protocol | Swab Samples for microbiological analysis | Microbiology Department |
| Perform the cleaning as per the procedure defined in respective equipment cleaning Record/ batch cleaning record/SOP. | Visual Checking for cleanliness | User department /QA |
| Swab/Rinse Samples for microbiological analysis | Microbiology Department | |
| Swab/Rinse Sample(s) for residue of previous product. For parenteral – Rinse sample for TOC, pH, Conductivity. | QA Department |
Based on conclusion of Dirty Equipment Hold time study report, further recommendation for hold time shall be drawn.
Clean Equipment Hold Time Study:
Clean Equipment Hold Time is independent of the product manufactured, provided that the equipment is cleaned, and meets the applicable acceptance criterion, and is stored under the same environmental condition and location.
During the holding of cleaned equipment, storage condition shall simulate as per routine practices.
Take adequate protection during holding, to maintain the required cleanliness by following means:
- By covering/wrapping with plastic film or any other suitable means.
- Closing the inlet or 9utlet or probable opening of equipment’s.
- During study, impact of regular intervention shall be considered to simulate the actual storage condition for cleaned equipment like AHU shutdown during weekly-off day, man movement for routine cleaning and sanitization of area etc.
Activities shall be performed as per details mentioned in Table-5 and/ or specified in the protocol with the scientific justification.
Table
| Activities | Sample details | Responsibility |
| Initial Sample after completion of cleaning | Visual Checking for Cleanliness & Dryness | User department |
| Hold the cleaned equipment for 3 Days/ 5 Days/ 7 Days/ 10 Days/ 15 Days or as specified in the protocol | Swab Samples for microbiological analysis | Microbiology Department |
| Swab Samples for microbiological analysis | Microbiology Department |
Based on conclusion of Clean Equipment Hold time study report, recommendation for clean equipment shall be drawn.
In case of repetitive samples in regular interval, separate sampling location should be identified, to avoid repeat sampling from same location & thereby dilution of contamination load.
Numbering of DEHT and CEHT Protocol/Report:
The DEHT and CEHT study shall be executed by preparing the protocol.
The outcome of the study and recommendation shall be compiled in the report.
Protocol numbering shall be assigned by QA department.
Campaign cleaning:
Campaign is series of batches of the same product manufactured one after the other after minor cleaning (Type A cleaning).
However, consideration shall be given to the number of batches and/or the total elapsed time for a campaign. Elapsed time might be critical if the active ingredient left on equipment surfaces degrades over time due to exposure to heat or light.
Also, repetitive production of a single product without validated cleaning between batches might also result in the penetration of materials into a location where single lot production might not present a problem.
Cleaning Validation of Non-Product Contact Surfaces:
There are some non-product contact surfaces which may not come into direct product contact however may come in contact with process inputs such as by air borne route. The examples of such contact parts are inlet air ducts of Fluid bed dryer, coating and bowl of stoppering machine etc.,
Considering that these equipment surfaces does not comes directly in contact with product during manufacturing, cleaning of such surface shall be verified visually before any operation and shall be validated one time; preferably during performance qualification by using any product at the acceptance limit NMT 100 mcg per sq. inch (referring maximum visual acceptance limit) or at established visual detection limit whichever is stringent.
ABBREVIATIONS:
CVMP: Cleaning Validation Mater Plan
CVP: Cleaning Validation Protocol
CFU: Colony Forming Unit
MACO; Maximum Allowable Carryover
Ppm : Part per Million
Rf: Recovery Factor
ADE: Acceptable Daily Exposure
NOAEL: No Observed Adverse Effect Level
REFERENCES:
EU Guideline for Good Manufacturing Practices for Medicinal product for Human and Veterinary use,
Annex 15: Qualification and Validation
APIC-Cleaning validation in Active pharmaceutical ingredient manufacturing plants.
PDA Technical Report No.: 29 – Points to consider for Cleaning Validation.
ISPE – Volume 7 Risk Based Manufacture of Pharmaceutical Products.