Cleaning validation acceptance criteria state the maximum allowed levels of product residues, cleaning agents and other relevant contaminants left on pharmaceutical production equipment after its cleanliness, in order to scientifically justify, quantify and sustain these limits to protect the next product from potential contamination or cross-contamination.
The most effective approach is based on such elements as toxicological assessment, residue calculation, equipment surface consideration, analytical method capability and risk-based evaluation. It is wrong to apply the same historical limit (e.g., 10 ppm or a particular fraction of a therapeutic dose) for different products and equipment systems without scientifically proving this.
The risk shall depend on a number of factors, including both the toxin level of the substance and the size of the possible transfer, as well as the dosage of next product batch and the equipment utilized for the manufacturing line. Issues with the transfer of the uncomfortable-soluble residue may require special consideration as well: cleaning may not ensure complete removal of all contaminants even when washing a sample brings reasonable results.
As concerns the shared equipment, application of health-based exposure limit (HBEL), which is usually referred to as permitted daily exposure (PDE), may give a proper initial basis for evaluation of the risk of cross-contamination. However, it should be noted that proper evaluation of risks related to cross-contamination should be run by qualified staff.
Another important consideration in the setting process is whether any equipment or facility needs to be dedicated to some products. It is crucial to realize that cleaning validation does not replace the requirement for proper containment and other measures if there is a significant risk for cross-contamination.
The commonly used formula is as follows:
MACO = (PDE of previous product × minimal batch size of next product) ÷ maximal daily dose of next product
Ensure that the units used in this calculation are the same and that the method used to perform the calculation is cited properly. For instance, if PDE is presented in mg per day, the size of the batch of the next product is given in mg as well and the maximal daily dose of the next product is described as mg per day, the resulting MACO is expressed in mg.
The calculations must be made according to the worst-case assumptions. The next product's minimum batch size and maximum daily dose must be taken into account since they can result in increased potential exposure to carryover residue. Product specifics and accepted procedures should be considered, not simply values that create a convenient limit.
The MACO value should be the total carryover value which must be based on the assumptions made in the calculations. It is not necessary that the value is automatically an acceptance limit for each of the surface swabs, rinse samples, or individual pieces of equipment.
In the inspection guide for cleaning validation of the FDA, the author talks about historical limits and emphasizes that there should be a logical scientific basis for limits on residues and these limits should be practical, achievable and verifiable. The EMA HBEL directive offers a systematic approach to deriving health-based thresholds by means of measuring the risk of cross-contamination.
While a company can use some additional limits or conservative requirements wherever it has scientific support for it, it has to explain how these limits are connected to the toxicological analysis, product risks and requirements that are applicable.
Surface limit = MACO/overall product contact surface area
For instance, if the MACO calculated is 100 mg and the right shared surface area is 200,000 cm2, then the theoretical average surface limit is 0.0005 mg/cm2, equivalent to 0.5 µg/cm2.
This is an example calculation but cannot be applied universally. There should be support on the equipment train, the sequence of products and the assumptions regarding surface distribution and sampling. Residue may not be evenly distributed on the equipment.
Swabbing limit = surface limit × swab area swabbed
A surface limit of 0.5 µg/cm² will correspond to a theoretical residue amount of 12.5 µg per swab from an area of 25 cm² assuming that sampling and analytical procedures are validated.
The protocol should explain the defined area of swabbing, volume used for extraction, the methods for recovery correction used and units used for reporting. Low recovery during swabbing or wrong extraction solvent can question the validity of the otherwise acceptable result.
A simple way of calculating the rinse concentration limit is:
Rinse concentration limit = allowable residue level designated for flushing ÷ volume of rinse used in the sampling
This includes not only the sampling design but also the degree to which the rinse is a representative of the surface of equipment. A clean rinse does not automatically mean that all surfaces are free of contaminants, especially in those cases when residues exhibit very low solubility and are retained or stuck to surfaces.
It is thus necessary to develop limits for swabs and rinses based on documented rationale and not through independent decision making as far as the overall carryover evaluation is concerned.
In the case of the use of the detergent, the criterion for acceptance should be dependent on detergents' composition, any information on toxicology or safety matters, a planned application, cleaning properties, an analytical method employed.
The criteria for microbiological acceptance should consider the product, the equipment, the environment of production and both intended purpose and use of the product in the future. For the products intended for sterile production or products sensitive to microorganisms, it is necessary to include bioburden and endotoxins in the assessment. The limits may not be substituted with chemical residue assessment.
For ensuring cleanliness, the key point is visual cleanliness. The equipment is required to show no visible residues that need to be one of the conditions of assessment, but visual assessment alone is not adequate.
Validation studies should cover important factors such as recovery from different surfaces, extraction efficiency, specificity, as well as the limit of detection or quantitation of analytical technique. All materials being used for analysis and extraction must not interfere with the determination.
For instance, if the defined value is 12.5 µg/m2 but detection of this level in analysis is difficult, the whole process of defining the limit is not valid. Either changes in the analytical method should be reported or the limit-setting in the protocol should be rewritten in a more optimal way.
QA will confirm that toxicology assessment, MACO, surface area information and sampling limits align. QC is responsible for confirming the analytical technique. Operations and Engineering will ensure that the cleaning process and equipment description is accurate.
While reviewing data, research all excessive findings instead of continuing to clean and resample until a passing result is found. The research must evaluate the initial finding, the sampling method that was used, how the cleaning was performed, what type of residue was present and how this residue will affect past and necessary future batches.
Acceptance criteria for cleaning validation must be based on the risks associated with remaining contamination and they should be converted into quantitative limits verified by appropriate sampling and analytical techniques. A validation system relates toxicologic criteria to the carryover estimation, the design of the equipment, the cleaning process efficacy and quality decisions that are documented. Without a justification for the acceptability of the residue that also includes a valid assessment of the measurement of the said quantity, the cleaning validation acceptance criteria would not be defensible.
Start With the Risk From Residual Contamination
The initial step is to determine what substances need to be eliminated during the cleaning operation. In this context, it shall be noted that the manufacturing procedure may involve the residues of active pharmaceutical ingredients (API), excipients, degradation products, intermediaries, cleaning agents and microbial impurities.The risk shall depend on a number of factors, including both the toxin level of the substance and the size of the possible transfer, as well as the dosage of next product batch and the equipment utilized for the manufacturing line. Issues with the transfer of the uncomfortable-soluble residue may require special consideration as well: cleaning may not ensure complete removal of all contaminants even when washing a sample brings reasonable results.
As concerns the shared equipment, application of health-based exposure limit (HBEL), which is usually referred to as permitted daily exposure (PDE), may give a proper initial basis for evaluation of the risk of cross-contamination. However, it should be noted that proper evaluation of risks related to cross-contamination should be run by qualified staff.
Another important consideration in the setting process is whether any equipment or facility needs to be dedicated to some products. It is crucial to realize that cleaning validation does not replace the requirement for proper containment and other measures if there is a significant risk for cross-contamination.
Establish a Scientifically Justified Carryover Limit
The maximum allowable carryover (MACO) calculation converts the health effect evaluation into a value that may be transferred from one product to another.The commonly used formula is as follows:
MACO = (PDE of previous product × minimal batch size of next product) ÷ maximal daily dose of next product
Ensure that the units used in this calculation are the same and that the method used to perform the calculation is cited properly. For instance, if PDE is presented in mg per day, the size of the batch of the next product is given in mg as well and the maximal daily dose of the next product is described as mg per day, the resulting MACO is expressed in mg.
The calculations must be made according to the worst-case assumptions. The next product's minimum batch size and maximum daily dose must be taken into account since they can result in increased potential exposure to carryover residue. Product specifics and accepted procedures should be considered, not simply values that create a convenient limit.
The MACO value should be the total carryover value which must be based on the assumptions made in the calculations. It is not necessary that the value is automatically an acceptance limit for each of the surface swabs, rinse samples, or individual pieces of equipment.
Why the Traditional 10 ppm Rule is not Enough
The traditional 10 ppm criterion has been used in some validation programs in conjunction with various additional methods, such as a fraction of the therapeutic dose. However, these ancient limits do not signify that every active substance is safe in terms of residual exposure.In the inspection guide for cleaning validation of the FDA, the author talks about historical limits and emphasizes that there should be a logical scientific basis for limits on residues and these limits should be practical, achievable and verifiable. The EMA HBEL directive offers a systematic approach to deriving health-based thresholds by means of measuring the risk of cross-contamination.
While a company can use some additional limits or conservative requirements wherever it has scientific support for it, it has to explain how these limits are connected to the toxicological analysis, product risks and requirements that are applicable.
Convert MACO into Equipment and Sampling Limits
After determining the overall carryover that can be permitted, it must be converted to limits that can be used in the cleaning validation.Surface residue limit
When the shared product contact surface area is known, MACO can be divided by relevant overall surface area.Surface limit = MACO/overall product contact surface area
For instance, if the MACO calculated is 100 mg and the right shared surface area is 200,000 cm2, then the theoretical average surface limit is 0.0005 mg/cm2, equivalent to 0.5 µg/cm2.
This is an example calculation but cannot be applied universally. There should be support on the equipment train, the sequence of products and the assumptions regarding surface distribution and sampling. Residue may not be evenly distributed on the equipment.
Swab sample limit
A surface limit can be translated into the limit of acceptance for swabbing, knowing how much surface was swabbed:Swabbing limit = surface limit × swab area swabbed
A surface limit of 0.5 µg/cm² will correspond to a theoretical residue amount of 12.5 µg per swab from an area of 25 cm² assuming that sampling and analytical procedures are validated.
The protocol should explain the defined area of swabbing, volume used for extraction, the methods for recovery correction used and units used for reporting. Low recovery during swabbing or wrong extraction solvent can question the validity of the otherwise acceptable result.
Rinse sample limit
Rinse sampling is effective for assessing surfaces on equipment that is not directly accessible or complicated systems like transfer lines and clean-in-place systems.A simple way of calculating the rinse concentration limit is:
Rinse concentration limit = allowable residue level designated for flushing ÷ volume of rinse used in the sampling
This includes not only the sampling design but also the degree to which the rinse is a representative of the surface of equipment. A clean rinse does not automatically mean that all surfaces are free of contaminants, especially in those cases when residues exhibit very low solubility and are retained or stuck to surfaces.
It is thus necessary to develop limits for swabs and rinses based on documented rationale and not through independent decision making as far as the overall carryover evaluation is concerned.
Set Limits for Cleaning Agents and Microbiological Residues
In cleaning validation, just one aspect is active ingredient limits. The second point is the cleaning agent that includes solvents and any residues related to the process.In the case of the use of the detergent, the criterion for acceptance should be dependent on detergents' composition, any information on toxicology or safety matters, a planned application, cleaning properties, an analytical method employed.
The criteria for microbiological acceptance should consider the product, the equipment, the environment of production and both intended purpose and use of the product in the future. For the products intended for sterile production or products sensitive to microorganisms, it is necessary to include bioburden and endotoxins in the assessment. The limits may not be substituted with chemical residue assessment.
For ensuring cleanliness, the key point is visual cleanliness. The equipment is required to show no visible residues that need to be one of the conditions of assessment, but visual assessment alone is not adequate.
Confirm That the Analytical Method Can Measure the Limit
An acceptance limit is valuable if it can be reliably determined by sampling and analytical techniques. The analytical method should have an adequate level of sensitivity to measure the limit defined and the specificity needed for the substance being analyzed.Validation studies should cover important factors such as recovery from different surfaces, extraction efficiency, specificity, as well as the limit of detection or quantitation of analytical technique. All materials being used for analysis and extraction must not interfere with the determination.
For instance, if the defined value is 12.5 µg/m2 but detection of this level in analysis is difficult, the whole process of defining the limit is not valid. Either changes in the analytical method should be reported or the limit-setting in the protocol should be rewritten in a more optimal way.
Document the Rationale Before Validation Begins
The cleaning validation plan should include residue limits, the scientific justification for these limits, the location of samples, the sampling techniques to be utilized, the analytical techniques that will be followed and the assumptions to be validated in the cleaning process.QA will confirm that toxicology assessment, MACO, surface area information and sampling limits align. QC is responsible for confirming the analytical technique. Operations and Engineering will ensure that the cleaning process and equipment description is accurate.
While reviewing data, research all excessive findings instead of continuing to clean and resample until a passing result is found. The research must evaluate the initial finding, the sampling method that was used, how the cleaning was performed, what type of residue was present and how this residue will affect past and necessary future batches.
Acceptance criteria for cleaning validation must be based on the risks associated with remaining contamination and they should be converted into quantitative limits verified by appropriate sampling and analytical techniques. A validation system relates toxicologic criteria to the carryover estimation, the design of the equipment, the cleaning process efficacy and quality decisions that are documented. Without a justification for the acceptability of the residue that also includes a valid assessment of the measurement of the said quantity, the cleaning validation acceptance criteria would not be defensible.
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