A cleaning validation recovery study is used to determine the effectiveness of a specified sampling technique in collecting residues from pharmaceutical equipment and rendering them available for analysis. A cleaning validation recovery study will assess the efficiency of swab/rinse sampling technique and determine if the resulting analytical data is a good representative of residual levels (if any) that may be present after cleaning.
In cleaning validation for the pharmaceutical industry it is important to note that just because the residue is low does not mean the surface of the equipment is clean. The residue could be on the surface, yet not be transferred/dissolved/extracted into the swab/rinse solvent/sampling material. A cleaning validation recovery study should be performed to assess potential limitations before placing reliance on the sampling technique for determining the effectiveness of the cleaning process.
For instance: suppose a known amount of active pharmaceutical ingredient was placed on a (say) stainless steel coupon. The residue is allowed to dry. Then an analyst takes a swab sample and extracts the swab in some specified solvent. If only part of the deposited amount appears in the analysis, then the other part could be lost because of incomplete surface sampling, inefficient extraction, etc.
The recovery study assesses the efficiency of relevant sampling and/or extraction procedure (together) in combination. Such a study should be representative of the actual method that will be applied in cleaning validation and not necessarily a simplified laboratory method that is not representative of usual practice.
Health Canada's cleaning validation guidance recommends recovery studies for relevant sampling method and product contact material of construction. Also, low or variable recovery can be an indication that sampling/extraction technique is insufficient.
It should include the specifics of the amount of spiked material, coupon area, application method of residue, drying conditions, type of swab, wettting solvent, sampling pattern, extraction solvent, volume of extraction solvent, and analytical method.
As close as possible to the real life situation should be reproduced by the analyst. Factors such as amount of swab pressure, direction of swab, number of passes, fresh swab as specified, etc. can affect amount of residue collected. Good method for flat coupon may not be the same for roughed up or scratched or geometrically complicated surface.
It should be determined for (justified) levels of residue, including those applicable to cleaning acceptance limits. Replicates to prove the consistency of procedure. Proper blankers, if any, for interference from swabs, solvents, coupons, lab handling, etc.
%age recovery = (amount recovered)/(amount applied) x 100
For example, if one applies 10 microgram of residue to the coupon, and one has a validated analytical procedure which gives a reading of 7.5 microgram after swabbing and extraction, then the percent recovery is 75%.
This says that one was able to recover 75% of the amount that was applied under these conditions. Note that it does not mean that 75% of the residue was removed by the cleaning process. The recovery is related to the process of sampling, not cleaning efficiency.
You should also look at the reproducibility or variability of the results, and an average recovery that is reasonably high, but which is very variable might be a bad thing. Have some scientifically justified and approved acceptance criteria before proceeding. There is no magic % recovery which is right for all kinds of residue, surface, and sampling procedure.
A rinse recovery study should show that the proposed rinse medium will be able to collect and carry the residue of interest at relevant levels for the criteria for cleaning acceptance.
This could include applying known amounts of residue to representative surfaces, and then determining recovery by the proposed rinse procedure and analytical method (depending on the equipment and type of study). Aspects of the study include suitability of solvent, contact conditions, volume of rinse, solubility of residue, collection of sample, and possibly sample handling.
The limitation of rinse sampling is that the residue may not be soluble in the rinse medium, may be trapped in a crevice, or may be too strongly bound to the surface. Another factor is that a relatively large volume of rinse may dilute the residue and make it more difficult to detect. Consequently, the presence of clear rinse sample or a negative result (below detection limit of the analytical method) does not by itself guarantee that all the relevant surfaces are clean.
The US FDA notes that rinse sampling can be used for large and/or difficult to reach surfaces but that certain residues may not be removed. It also recommends that direct surface sampling be used if possible and that scientific justification is provided for the selection of the sampling methods.
1. Surface Material and State: Materials such as stainless steel, glass, or polymers have different characteristics of the surface properties, interaction with residues, different types of surfaces, and their variable surface properties. Any properties of the surface such as roughness, presence of scratches or damaged surfaces will contribute.
2. Residue Characteristics: The coating properties play a big role in the recovery efficiency. One can mention the solubility of the residue, its effectiveness, its physical state, and whether it is dry or not.
3. Sampling Method: The efficiency of the sampling method depends on the kind of swabbing, the reagent used, the pressure applied, and the meaning of the extraction process.
4. Washing Conditions: Solvents used, their volume, contact time, and accessibility will be an influential factor in recovery.
5. Analytical Conditions: Properties and the efficiency of the analysis are factors affecting the amount of the residue detected.
Practical use of actual residue should be used, when possible, and relevant product contact materials. Use of surrogate, if required, due to handling hazards with the target material should be justified scientifically with the limitations.
When low recovery is observed, evaluation of possible factors should be considered. For example, types of swab material, type of solvent used, extraction efficiency, drying condition, surface characteristics, and technician skill may be evaluated. In case of rinse sampling, the solubility of the residue, the amount of rinse used, the conditions of contact, and collection efficiency may be evaluated.
Any change in procedure should be documented and also evaluated for its effect on the study. Do not simply keep going until you get the right answer. A scientifically justified plan should be approved for the additional testing.
Recovery data must be used consistently in evaluating cleaning validation results. If recovery correction is applied, the procedure for calculation and justification should be included in an approved procedure or protocol. For example, if the recovery factor is determined as a reciprocal of fractional recovery, the amount measured of 7.5 µg and 75% recovery indicates a total surface amount of 10 µg in the estimate. Such calculation is valid only if there is an authorized procedure which allows this correction to be done and recovery data relate to residue, surface and sampling conditions.
The report must describe the experimental method used, provide raw data, calculations, recovery values, the variability of results, possible deviations, or acceptance criteria and draw conclusions. QA has to make sure that the arguments imply applicability of the sampling method selected before it can be admitted for cleaning acceptance decisions.
Why Recovery Must Be Demonstrated Before Cleaning Validation
Cleaning validation involves two interrelated activities: 1) collection of the residue from the equipment 2) measurement of the collected residue using an appropriate analytical technique. A sensitive HPLC/UV/TOC technique is not enough to make up for a poor sampling technique for collecting the residue.For instance: suppose a known amount of active pharmaceutical ingredient was placed on a (say) stainless steel coupon. The residue is allowed to dry. Then an analyst takes a swab sample and extracts the swab in some specified solvent. If only part of the deposited amount appears in the analysis, then the other part could be lost because of incomplete surface sampling, inefficient extraction, etc.
The recovery study assesses the efficiency of relevant sampling and/or extraction procedure (together) in combination. Such a study should be representative of the actual method that will be applied in cleaning validation and not necessarily a simplified laboratory method that is not representative of usual practice.
Health Canada's cleaning validation guidance recommends recovery studies for relevant sampling method and product contact material of construction. Also, low or variable recovery can be an indication that sampling/extraction technique is insufficient.
Swab Recovery Study: Evaluating Direct Surface Sampling
Swab sampling is a method to directly sample residues from a specific equipment surface. This approach is especially beneficial for readily accessible points that may be identified by risk assessment (e.g., a point where residue could collect or where cleaning is difficult).How to perform the study
Mostly the method involves use of typical (or representative) coupons from the applicable equipment surface material (stainless steel, etc. or product contact material, etc.). The known amount of residue of choice is applied and allowed to dry under controlled conditions. Sample with proposed swab procedure.It should include the specifics of the amount of spiked material, coupon area, application method of residue, drying conditions, type of swab, wettting solvent, sampling pattern, extraction solvent, volume of extraction solvent, and analytical method.
As close as possible to the real life situation should be reproduced by the analyst. Factors such as amount of swab pressure, direction of swab, number of passes, fresh swab as specified, etc. can affect amount of residue collected. Good method for flat coupon may not be the same for roughed up or scratched or geometrically complicated surface.
It should be determined for (justified) levels of residue, including those applicable to cleaning acceptance limits. Replicates to prove the consistency of procedure. Proper blankers, if any, for interference from swabs, solvents, coupons, lab handling, etc.
Calculating swab recovery
Basic formula:%age recovery = (amount recovered)/(amount applied) x 100
For example, if one applies 10 microgram of residue to the coupon, and one has a validated analytical procedure which gives a reading of 7.5 microgram after swabbing and extraction, then the percent recovery is 75%.
This says that one was able to recover 75% of the amount that was applied under these conditions. Note that it does not mean that 75% of the residue was removed by the cleaning process. The recovery is related to the process of sampling, not cleaning efficiency.
You should also look at the reproducibility or variability of the results, and an average recovery that is reasonably high, but which is very variable might be a bad thing. Have some scientifically justified and approved acceptance criteria before proceeding. There is no magic % recovery which is right for all kinds of residue, surface, and sampling procedure.
Rinse Recovery Study: Assessing Residue Collection by Rinsing
Rinses can be useful in situations where you have some equipment with inaccessible surfaces, long transfer lines, complex internals, or a system that you can't sample by swab directly. You are contacting a specified volume of appropriate solvent/rinse medium to the relevant areas of the equipment and then analyzing that sample.A rinse recovery study should show that the proposed rinse medium will be able to collect and carry the residue of interest at relevant levels for the criteria for cleaning acceptance.
This could include applying known amounts of residue to representative surfaces, and then determining recovery by the proposed rinse procedure and analytical method (depending on the equipment and type of study). Aspects of the study include suitability of solvent, contact conditions, volume of rinse, solubility of residue, collection of sample, and possibly sample handling.
The limitation of rinse sampling is that the residue may not be soluble in the rinse medium, may be trapped in a crevice, or may be too strongly bound to the surface. Another factor is that a relatively large volume of rinse may dilute the residue and make it more difficult to detect. Consequently, the presence of clear rinse sample or a negative result (below detection limit of the analytical method) does not by itself guarantee that all the relevant surfaces are clean.
The US FDA notes that rinse sampling can be used for large and/or difficult to reach surfaces but that certain residues may not be removed. It also recommends that direct surface sampling be used if possible and that scientific justification is provided for the selection of the sampling methods.
Key Factors That Influence Recovery Results
The effectiveness of recovery is dependent upon the interaction between the residue, surface, sampling medium, solvent, and method used for analysis. When discussing the recovery effectiveness, there are a few essential points to be made.1. Surface Material and State: Materials such as stainless steel, glass, or polymers have different characteristics of the surface properties, interaction with residues, different types of surfaces, and their variable surface properties. Any properties of the surface such as roughness, presence of scratches or damaged surfaces will contribute.
2. Residue Characteristics: The coating properties play a big role in the recovery efficiency. One can mention the solubility of the residue, its effectiveness, its physical state, and whether it is dry or not.
3. Sampling Method: The efficiency of the sampling method depends on the kind of swabbing, the reagent used, the pressure applied, and the meaning of the extraction process.
4. Washing Conditions: Solvents used, their volume, contact time, and accessibility will be an influential factor in recovery.
5. Analytical Conditions: Properties and the efficiency of the analysis are factors affecting the amount of the residue detected.
Practical use of actual residue should be used, when possible, and relevant product contact materials. Use of surrogate, if required, due to handling hazards with the target material should be justified scientifically with the limitations.
Interpreting Results and Applying Recovery Data
Review of the recovery results in the context of the analytical method performance, study design, replication variation, and use of the sampling procedure.When low recovery is observed, evaluation of possible factors should be considered. For example, types of swab material, type of solvent used, extraction efficiency, drying condition, surface characteristics, and technician skill may be evaluated. In case of rinse sampling, the solubility of the residue, the amount of rinse used, the conditions of contact, and collection efficiency may be evaluated.
Any change in procedure should be documented and also evaluated for its effect on the study. Do not simply keep going until you get the right answer. A scientifically justified plan should be approved for the additional testing.
Recovery data must be used consistently in evaluating cleaning validation results. If recovery correction is applied, the procedure for calculation and justification should be included in an approved procedure or protocol. For example, if the recovery factor is determined as a reciprocal of fractional recovery, the amount measured of 7.5 µg and 75% recovery indicates a total surface amount of 10 µg in the estimate. Such calculation is valid only if there is an authorized procedure which allows this correction to be done and recovery data relate to residue, surface and sampling conditions.
The report must describe the experimental method used, provide raw data, calculations, recovery values, the variability of results, possible deviations, or acceptance criteria and draw conclusions. QA has to make sure that the arguments imply applicability of the sampling method selected before it can be admitted for cleaning acceptance decisions.
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