Microbial acceptance criteria for cleaning validation are used to show that the cleaning process provides the required level of control over microbial contamination for the intended use of the equipment. A single universal microbial limit is not a valid approach to all pharmaceutical cleaning validation studies. The microbial limits should be scientifically justified based on product, process, equipment design, risk of contamination and subsequent processing steps.
In contrast to chemical residue limits which may be based on toxicological or carryover considerations, the microbial limits must consider viable microorganisms and their ability to proliferate and the risk they pose to the product. This is especially important for aqueous manufacturing, microbial supporting products and equipment used in sterile manufacturing.
Ex. Equipment used for the manufacture of a dry tablet product may have a different microbial risk than equipment used to make an aqueous oral liquid product. For the production of a sterile product, especially careful control of the equipment is warranted since residual contamination can affect the ability to subsequently sterilize or aseptically process the product.
A risk assessment should consider:
These units are not equivalent directly: for example, it is not possible to just say 5 CFU/ml in a rinse are equivalent to 5CFU per sampled surface area. It depends on the method of sampling, size of surface / volume sampled, efficiency of recovery, how you calculate it.
Only if the sampling and analysis techniques used can detect the contamination level at a defined microbial level is the concept of an acceptable level of contamination meaningful. If the recovery is poor, or if the handling of samples for analysis permit the loss of micro-organisms, then the apparently acceptable level may not be sufficiently reassuring.
The acceptance criterion should be defined prior to execution of the protocol. Where to take the sample, how to take it, how to handle sample (conditions), how to incubate it and how to calculate the result (if applicable) etc.
A better way would be to set the limits based on knowledge of the product, process and if applicable the history of monitoring, the appropriate microbiological control strategy and the application of the equipment. You should provide the reason why the chosen level is acceptable to control the risk.
E.g. when using an equipment train for a water-based product there could be moisture remaining in a transfer hose or pump housing, etc. So, despite good cleaning at the initial step, the equipment could end up with microbial proliferation during storage if it stays wet. In such a case, it is important that the cleaning validation approach includes aspects such as drainage, drying, clean holding time, sampling points, etc., rather than just focusing on the final CFU result.
If a facility employs internal alert and action levels, it is important to differentiate them from formal cleaning validation acceptance criteria. Alerts can provide some indication of unfavorable trends; and then there is the established acceptance criterion that tells you if the result of the validation meets the pre-defined requirement.
Automatic copy & paste of pharmacopoeial microbial limits for finished products is not a good approach for the cleaning validation protocols. Justification for the different aspects of finished product specifications and equipment cleanliness criteria are different and need to be justified separately.
Swabs can be used for defined surfaces, e.g., joints, gaskets, discharge valves, etc. and other product contact areas which can be sampled directly. Rinse samples may be useful for assessment of internal surfaces that may not be swab-able (e.g. certain pipes/systems that are enclosed). Both approaches can be used to complement each other if justified.
Justification of the sampling sites, as representative of the microbial risk of the equipment should be given in the sampling plan. The sampling should be performed at the appropriate stage (e.g., post cleaning/drying or at the end of validated clean hold time as per protocol).
The following points should be considered in the assessment of the suitability of the microbiological method.
1. Efficiency of recovery: Evidence that the method of sampling can recover the microorganism from the representative equipment surfaces.
2. Neutralization: If there is a possibility that some cleaning agents or disinfectants could be left behind, demonstrate that no suppression of recovery occurs in the test due to residual antimicrobial activity.
3. Sample handling: Setting up appropriate transport, storage and testing conditions to minimize any changes in microorganism recovery.
4. Capability of the method: Make sure that culture medium, incubation conditions and method are suitable for detecting the organisms of concern.
5. Data interpretation: Document the area or volume sampled, dilution factors, calculations and pertinent reporting limits.
No microorganism detected does not mean surface is free from microorganisms. It means there were no microorganisms detected under the conditions and limitations of the method used.
Not all microbial contamination risk issues may be adequately addressed by total counts alone. An objectionable microorganism may be significant at a low total count depending on product, route of administration and environment of manufacture.
Is there a need to identify or target test for specific microorganism(s)? Based on the risk assessment, is there a need to focus on some microorganism(s) which may survive in the formulation of the product or may pose a patient risk beyond the general CFU limit?
For some applications, need to consider endotoxin separately. Endotoxin is not the same as viable microorganisms. The routine method for microbial count is not evidence of endotoxin acceptability. When equipment used in a process with endotoxin control, the cleaning strategy must include some method for removal or control of endotoxins (with appropriate method and justified acceptance criteria).
Microbial cleanliness after cleaning for sterile products is not a substitute for a validated sterilization process. There are related, but different, goals for cleaning, microbial control, sterilization and endotoxin control.
The investigation should examine:
- Cleaning performance
- Detergent concentration
- Contact time
- Rinse
- Drainage of equipment
- Dry
- Hold times
- Conditioning of difficult to clean items
- Method of sampling
- Effectiveness of neutralization
- Lab control
- Transport of sample
- Potential sources of contamination during sampling.
As appropriate, the possibility of identification and comparison of the organism with environmental or water trend monitoring can be used in assessing the probable source. Also consider other equipment, products or batches that may be involved.
CAPA for the demonstrated cause may include, for example, improving drainage; changing cleaning instructions; correction of sampling technique; repair of damaged seals; better control of clean hold time, etc. Further validation/re-qualification should be considered in cases where the findings suggest the validated approved cleaning process may no longer be effective.
The report of the validation should include the approved microbial criteria (record), scientific justification, sample locations, method of test, results, deviations, investigation of deviation results, conclusion. Transparency of limitations.
Ongoing control and review. After successful validation, ongoing control and review of results should be proportionate to risk and in line with procedures at the site. Reoccurrences of increases in microbial recovery, reoccurrences of a same location contamination or long time of equipment storage should trigger assessment (even if individual results are within limits).
Setting a Scientifically Justified Microbial Limit
Determine if the risk of microbial contamination is a concern for the cleaning validation. And what level of control is required? Consider the dosage form, route of administration, product composition, exposure to water, equipment design and time between cleaning and use.Ex. Equipment used for the manufacture of a dry tablet product may have a different microbial risk than equipment used to make an aqueous oral liquid product. For the production of a sterile product, especially careful control of the equipment is warranted since residual contamination can affect the ability to subsequently sterilize or aseptically process the product.
A risk assessment should consider:
- Product permissiveness for growth of microorganisms
- Possibility of objectionable microorganisms
- Dampness of equipment surfaces after cleaning
- Time between manufacture and cleaning (dirty hold time)
- Time between cleaning and next use (clean hold time)
- Presence of dead legs, gaskets, valves, hoses etc. (areas of difficult cleaning)
- Involvement of subsequent sanitization or sterilization as part of the approved process.
Understanding Microbial Acceptance Criteria
While microbiology results are often reported in terms of colony forming units (CFU), the unit for reporting varies depending upon the method of sample collection.| Sampling method | Typical reporting unit |
|---|---|
| Surface swab | CFU per defined sampled area, such as CFU/25 cm² |
| Rinse sample | CFU/mL of rinse fluid |
| Direct contact method, where suitable | CFU per sampled surface or contact area |
These units are not equivalent directly: for example, it is not possible to just say 5 CFU/ml in a rinse are equivalent to 5CFU per sampled surface area. It depends on the method of sampling, size of surface / volume sampled, efficiency of recovery, how you calculate it.
Only if the sampling and analysis techniques used can detect the contamination level at a defined microbial level is the concept of an acceptable level of contamination meaningful. If the recovery is poor, or if the handling of samples for analysis permit the loss of micro-organisms, then the apparently acceptable level may not be sufficiently reassuring.
The acceptance criterion should be defined prior to execution of the protocol. Where to take the sample, how to take it, how to handle sample (conditions), how to incubate it and how to calculate the result (if applicable) etc.
How to Set Limits Without Using Arbitrary Numbers
Quite often, pharmaceutical companies set an arbitrary limit that applies to all the equipment / products, not considering sufficiently differences in the risk associated with the presence of microbes.A better way would be to set the limits based on knowledge of the product, process and if applicable the history of monitoring, the appropriate microbiological control strategy and the application of the equipment. You should provide the reason why the chosen level is acceptable to control the risk.
E.g. when using an equipment train for a water-based product there could be moisture remaining in a transfer hose or pump housing, etc. So, despite good cleaning at the initial step, the equipment could end up with microbial proliferation during storage if it stays wet. In such a case, it is important that the cleaning validation approach includes aspects such as drainage, drying, clean holding time, sampling points, etc., rather than just focusing on the final CFU result.
If a facility employs internal alert and action levels, it is important to differentiate them from formal cleaning validation acceptance criteria. Alerts can provide some indication of unfavorable trends; and then there is the established acceptance criterion that tells you if the result of the validation meets the pre-defined requirement.
Automatic copy & paste of pharmacopoeial microbial limits for finished products is not a good approach for the cleaning validation protocols. Justification for the different aspects of finished product specifications and equipment cleanliness criteria are different and need to be justified separately.
Sampling & Suitability of Microbiological Method
It is important to have a good sampling plan since microbial contamination on equipment surfaces could be non-uniform. This means that not all easy-to-reach surfaces are necessarily the most challenging cleaning areas.Swabs can be used for defined surfaces, e.g., joints, gaskets, discharge valves, etc. and other product contact areas which can be sampled directly. Rinse samples may be useful for assessment of internal surfaces that may not be swab-able (e.g. certain pipes/systems that are enclosed). Both approaches can be used to complement each other if justified.
Justification of the sampling sites, as representative of the microbial risk of the equipment should be given in the sampling plan. The sampling should be performed at the appropriate stage (e.g., post cleaning/drying or at the end of validated clean hold time as per protocol).
The following points should be considered in the assessment of the suitability of the microbiological method.
1. Efficiency of recovery: Evidence that the method of sampling can recover the microorganism from the representative equipment surfaces.
2. Neutralization: If there is a possibility that some cleaning agents or disinfectants could be left behind, demonstrate that no suppression of recovery occurs in the test due to residual antimicrobial activity.
3. Sample handling: Setting up appropriate transport, storage and testing conditions to minimize any changes in microorganism recovery.
4. Capability of the method: Make sure that culture medium, incubation conditions and method are suitable for detecting the organisms of concern.
5. Data interpretation: Document the area or volume sampled, dilution factors, calculations and pertinent reporting limits.
No microorganism detected does not mean surface is free from microorganisms. It means there were no microorganisms detected under the conditions and limitations of the method used.
Total Counts, Objectionable Organisms and Endotoxins
Not all microbial contamination risk issues may be adequately addressed by total counts alone. An objectionable microorganism may be significant at a low total count depending on product, route of administration and environment of manufacture.
Is there a need to identify or target test for specific microorganism(s)? Based on the risk assessment, is there a need to focus on some microorganism(s) which may survive in the formulation of the product or may pose a patient risk beyond the general CFU limit?
For some applications, need to consider endotoxin separately. Endotoxin is not the same as viable microorganisms. The routine method for microbial count is not evidence of endotoxin acceptability. When equipment used in a process with endotoxin control, the cleaning strategy must include some method for removal or control of endotoxins (with appropriate method and justified acceptance criteria).
Microbial cleanliness after cleaning for sterile products is not a substitute for a validated sterilization process. There are related, but different, goals for cleaning, microbial control, sterilization and endotoxin control.
Investigate Failed Microbial Result
If a cleaning validation sample fails the acceptance criterion, proceed as per your sites approved deviation/investigation procedures. Simply re-testing (and re-testing) until you get a pass is not an adequate replacement for understanding the failure. The investigation needs to look at things like cleaning execution, detergent concentration, contact time, rinse, equipment drainage, drying, hold times and status of difficult to clean parts. Examine sample technique, neutralization effectiveness, lab controls, sample transport, potential contaminants during sampling.The investigation should examine:
- Cleaning performance
- Detergent concentration
- Contact time
- Rinse
- Drainage of equipment
- Dry
- Hold times
- Conditioning of difficult to clean items
- Method of sampling
- Effectiveness of neutralization
- Lab control
- Transport of sample
- Potential sources of contamination during sampling.
As appropriate, the possibility of identification and comparison of the organism with environmental or water trend monitoring can be used in assessing the probable source. Also consider other equipment, products or batches that may be involved.
CAPA for the demonstrated cause may include, for example, improving drainage; changing cleaning instructions; correction of sampling technique; repair of damaged seals; better control of clean hold time, etc. Further validation/re-qualification should be considered in cases where the findings suggest the validated approved cleaning process may no longer be effective.
Documentation and Ongoing Control
The report of the validation should include the approved microbial criteria (record), scientific justification, sample locations, method of test, results, deviations, investigation of deviation results, conclusion. Transparency of limitations.
Ongoing control and review. After successful validation, ongoing control and review of results should be proportionate to risk and in line with procedures at the site. Reoccurrences of increases in microbial recovery, reoccurrences of a same location contamination or long time of equipment storage should trigger assessment (even if individual results are within limits).
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