Richard J. Forsyth is principal consultant with Forsyth Pharmaceutical Consulting, 907 Shamrock Ct, Royersford, PA 19468, tel. 484.535.1688, forsythpharmaconsulting@gmail.com.

Richard J. Forsyth

Submitted: June 23, 2021
Accepted: September 13, 2021

Continued process verification (CPV) for a cleaning validation (CV) program begins once the validation study is complete. Planning for the CPV needs to be considered, however, as the cleaning validation is planned. Otherwise, the necessary parameters for the CPV might not be captured in a way to allow the smooth transition from the CV study to the CPV program to maintain the validated state of cleaning.

Validating cleaning in a pharmaceutical manufacturing facility is a regulatory requirement (1–4). In regulatory guidance documents, program basics, regulatory expectations including prerequisites, and acceptance criteria are reviewed along with the strategy for selection of the product(s) and equipment to validate. Although cleaning validation (CV) execution is described in general terms, guidance documents are limited to describing what to do, but not how to do it. The more recent the guidance update (2), the greater level of specific expectations are included.

The guidance documents include general instructions on how to proceed once cleaning validation is completed. The validated state of cleaning is to be monitored using ongoing testing of the cleaning process to demonstrate continued control of cleaning. This linear approach to cleaning validation resulted in the cleaning maintenance part of the program being slowly neglected, resulting in programs that fell out of compliance. The concept of lifecycle control of manufacturing process validation (5) addressed the shortcomings of the linear approach to process validation using Stage 3–Continued Process Verification (CPV). Using a similar approach, an ongoing program to collect and analyze cleaning parameter data can be applied to cleaning validation. Although the lifecycle approach better addresses the post-validation cleaning program, it still leaves the details up to the individual facility. And the concept of CPV is not mentioned until after the initial validation is complete.

Waiting for the completion of cleaning validation to address CPV will prove problematic as to how to document, gather, and trend the appropriate cleaning process data, critical process parameters (CPPs), hold times, and campaign lengths to clearly demonstrate continued control of the validated cleaning process. CPV is a factor to be considered as the cleaning validation strategy is defined. Addressing cleaning parameters for the long term needs to be addressed as part of the cleaning strategy. Otherwise, there might not be a viable mechanism to capture and trend ongoing cleaning parameters. The CPV strategy should address what cleaning parameters to check only for compliance and what parameters to check for compliance as well as to track and check trends.

To understand the issues of addressing CPV after completion of cleaning validation, start by considering the requirements for cleaning validation:

Demonstration of acceptable and consistent cleaning

There are alternatives for establishing the products and equipment to execute cleaning validation, but a grouping strategy is accepted by the regulatory agencies (1–4) and is the most practical approach. A hardest-to-clean product for cleaning can be established using solubility of the formulation API, but this approach ignores excipients and practical experience. A more rugged approach is to look at the cleanability of the formulations using a three-prong methodology (6): formulation composition, personnel experience, and formulation cleanability.

The cleaning limit should be established for every product (6), and the lowest cleaning limit should be the target for the cleaning validation study.Equipment needs to be grouped for validation so that one piece of equipment is representative for the entire group. The product/equipment matrix, which contains the equipment train for each product, is used to decide the most efficient cleaning validation strategy to cover all products and equipment groups.

The product and equipment selection must be made before cleaning validation can commence. The cleaning data to demonstrate acceptable and consistent cleaning as well as the critical cleaning parameters (CCPs) (e.g., time) are captured during cleaning validation execution. The agreed upon DHT, CHT, and campaign length are targeted prior to execution and then confirmed during execution. The CCPs, DHT, CHT, and campaign length can be conveniently captured in the cleaning validation study protocol documentation along with the product and equipment being validated.

Once cleaning validation is successfully completed and a final report documented, the controlled, validated state needs to be maintained.

 To ensure a smooth transition, a flexible plan or protocol to address CPV should be in place as the cleaning validation study draws to completion. The CPV plan should be drafted by the same team that implemented the CV program and should address all the captured parameters and their ongoing status. The worst-case product, cleaning limit, and equipment grouping will not be affected unless a change is made to the validated state. Changes could include: a new product or a new piece of equipment is introduced; a change is made in a product manufacturing process or equipment configuration; or a product or equipment is retired from service. Any change should go through the change control system and an assessment made as to whether an additional CV study is required. The assessment should include an update of the original product or equipment assessment documentation. The assessment and document update should fall on the CV representative to the Change Control Committee.

 CCPs were established during cleaning development and are those parameters that have a direct impact on the level on cleanliness from the cleaning process. A clean-in-place (CIP) cleaning cycle records all cleaning parameters and issues a report at the conclusion. A manual cleaning procedure is a more problematic situation as far as identifying and recording CCPs. During development, it can be shown that detergent concentration and water temperature are not critical. Personnel can be trained and qualified for consistent cleaning. Minimum cleaning times can be established, and specific cleaning tools can be identified. During CV of a manual procedure, the CCPs can be recorded by an observer to corroborate the cleaning outcome. However, post-CV recording of CCPs falls on the personnel cleaning the equipment, which is problematic for someone wearing wet, soapy gloves and could lead to CCPs being captured immediately after cleaning.

Trending of CCP data is even more challenging. The CCP data must be extracted from the cleaning checklists, entered into a logbook or database, and trended over time.

 The CPV plan should include periodic testing of equipment after cleaning to demonstrate continued control of the validated cleaning. The frequency of the testing should be risk-based with the rationale clearly defined in the CPV plan. Factors that might increase testing frequency include manual cleaning methods vs. CIP methods; low cleaning limits; and CV data that passed but are close to the acceptable residue limit (ARL); all of which increase the risk of subsequent cleaning failures. Capturing and trending CV and CPV data is probably the clearest demonstration of continued control of equipment cleaning in the facility. All data should be trended to demonstrate consistency of cleaning. The challenge here is to update and maintain the CV database. Data processing and trending could fall on the personnel assigned to perform sampling or testing. An alternative would be to mirror the effort used to trend in-process manufacturing data.

 DHT is established in the CV protocol execution. The end of manufacturing activity is recorded in the product batch record. After a designated DHT, the beginning of cleaning is recorded in the cleaning record or checklist. The executed CV protocol captures both times and determines the effective dirty hold time. DHT is captured for the three validation runs, and the longest of the three is designated the validated DHT based on the equivalency of all CV data. A single DHT, which is applied to all equipment for all products, is applied going into the CPV stage of the cleaning lifecycle.

Post-validation, capturing and relating the two times with the established DHT becomes more problematic. The two times and DHT are in separate documents, and personnel filling out the manufacturing batch record do not see the cleaning record, while personnel cleaning the equipment do not have easy access to the manufacturing batch record. The established DHT is reported in the CV final report, and because the DHT is a cleaning parameter, the end of manufacturing time and established DHT need to be readily available to personnel performing the subsequent cleaning.

There are several options how to capture, maintain, and trend DHT data. A logbook kept with the equipment is the most straight-forward solution. The validated DHT is known and is recorded in the logbook header. The date and time of completion of manufacturing activity are entered each time the piece of equipment is used. At the beginning of cleaning, the date and time are recorded, the DHT is calculated and confirmed to be less than the established DHT.

A second alternative can be capturing DHT electronically in a production record system. This is preferable because system checks can be included to prevent moving forward without appropriate action if the DHT is exceeded.

A third alternative is to capture the DHT at the beginning of the equipment cleaning checklist or record. This would ensure that the DHT is captured but makes trending more difficult in that there is no centralized documentation of the DHT data in a logbook.

Attempting to trend the DHT data is more problematic, because collating DHT data from logbooks for all equipment or individual cleaning records is resource intensive. The best option is to periodically download the DHT information into a database for ongoing trending.

If an electronic manufacturing batch record is used and the equipment cleaning information is captured electronically, then DHT data can be captured. Trending of electronically captured DHT would have to be programmed to download and trend, but once implemented, would not require continued personnel involvement.

The value of the logbook option is limited because the records are paper-based and all entries and data analysis are handwritten. However, the advantage is that the logbook stays with the equipment and compliance is more readily confirmed.

Trending of DHT data provides another level of control to the CPV program. If DHT times increase over time, trending could indicate a problem with scheduling equipment cleaning or manpower resource issues, which could be addressed before a DHT excursion by extending the DHT.

Alternatively, depending on how the equipment is handled at the end of manufacturing, it could be argued that DHT is not critical (7). If the equipment is scraped, vacuumed, and wiped down with solvent (e.g., 70% isopropyl alcohol) to minimize the amount of product residue left on the equipment, then the DHT might be a non-issue because the equipment would be rid of most residue and would already be dry. This strategy would minimize the API released into the wastewater stream during cleaning and limit exposure of personnel during cleaning.

 The issues for tracking and trending CHT are comparable to the DHT issues. CHT is established in a separate CV protocol execution. The end of cleaning activity is recorded in the cleaning record or checklist. After a designated CHT, the beginning of manufacturing is recorded in the product batch record. The executed CV protocol captures both times and determines the effective CHT. The CHT is captured for the three validation runs, and the longest of the three is designated the validated CHT based on the equivalency of all CV data. A single CHT, which is applied to all equipment after cleaning, is applied going into the CPV stage of the cleaning lifecycle.

The options to capture, maintain, and trend CHT data parallel those for DHT. For the logbook option, it might be able to capture both the CHT and DHT in the same logbook and trend quarterly. Downloading and trending the DHT and CHT from a logbook for every piece of equipment is labor intensive.

CHT criticality could also be minimized during validation (7). If CHT is established for an extended period (e.g., > 45–60 days), then equipment held in the same controlled conditions can be used up to the validated CHT.

For clean equipment held outside the manufacturing area, a standard policy of recleaning any equipment being brought into the manufacturing area is customary.

A second option to minimize concern for CHT post validation is to routinely rinse or wipe the equipment with 70% isopropyl alcohol immediately before use.This action further mitigates risk of bioburden proliferation during the CHT.

Trending of CHT data also provides a level of control to the CPV program. If CHT times increase over time, trending could indicate a problem with scheduling of manufacturing batches or manpower resource issues, which could be addressed before a CHT excursion by extending the CHT through a protocol execution.

 The maximum campaign length is established in the CV protocol execution. The number of batches manufactured and the length of time to manufacture are captured both on the equipment logs and the protocol. The campaigns are executed three times for validation, and the longest campaign length is designated as the maximum campaign length based on comparable cleaning data.

Post validation, the batch campaign length is known based on scheduling and equipment use. However, the length of time to manufacture a campaign is not typically noted and would normally only be unduly extended due to mechanical equipment issues. And while bulk hold times are considered for manufacturing process validation, the potential effect of increased campaign time on the subsequent cleaning is not considered. One option is to have the equipment card designed to include a check of the maximum campaign parameters, both number of batches and number of days.The campaign data can be periodically downloaded into a database for ongoing trending.

 The risk of not complying with validated parameters is low as long as the validated parameters are readily available, limited in complexity (e.g., one DHT value of 10 days for all equipment), and the parameters are recorded contemporaneously. If there is a non-compliance with any parameter, it should be immediately recognized and addressed before a non-compliant situation develops.For example, if the DHT is exceeded, testing after cleaning can be arranged after cleaning to verify a successful level of cleaning before the cleaned equipment is used again. Additionally, if this type of occurrence could be addressed proactively and a protocol documented and approved prior to equipment cleaning, the cleaning data might be used to lengthen the DHT for the cleaning process. Any delay in recording data increases the risk of non-compliance.

 If a non-compliance for a cleaning parameter is only recognized after the equipment is reused, an investigation is necessary. If a critical cleaning parameter (time, temperature, detergent concentration), DHT, or campaign length is non-compliant, then the equipment might not have been sufficiently cleaned, and carry-over into the next batch is possible. A risk assessment should determine the level of risk of the non-compliance. The higher the cleaning limit of the cleaned API, the lower the risk of unacceptable carry-over. Conversely, an API with a low cleaning limit increases the risk of an unacceptable carry-over.

If not already established, a visible residue limit (VRL) of the cleaned API should be determined (8, 9). If the VRL is lower than the cleaned API cleaning limit, it provides a clear indication that the visually clean equipment was sufficiently cleaned and further batch investigation might be avoided.

The cleaning records and equipment log need to be checked to verify the extent of the non-compliance and what subsequent batches are potentially impacted. As necessary, the subsequent batches should be tested for the presence of the carry-over API, which might require some analytical method development and validation. Personnel should be interviewed to determine the root cause and corrections implemented.

Verification of cleaning validation parameters on an ongoing basis is critical for maintaining the validated state of the cleaning program. If a parameter is exceeded, then action must be taken to correct the non-compliant condition. The value of trending some cleaning validation parameters might not be as obvious. Certainly, trending cleaning data in the form of swab sample or comparable data results adds value in that it provides an ongoing picture of the consistency of cleaning and the level of risk for a potential cleaning failure in the future. But once cleaning validation is complete, cleaning data are not generated after every equipment cleaning. Based on the risk of a cleaning failure, the frequency of swab testing can decrease, and the lower frequency of cleaning data points presents a periodic snapshot of cleaning rather than a continuous record of equipment cleanliness. In addition, relying solely on cleaning data for CPV is akin to solely relying on release testing for manufacturing process control, which is not acceptable to the regulatory agencies.

Therefore, other cleaning parameters that continue to be captured after every post-validation cleaning become more indicative of continued cleaning verification. They include CCPs (times, temperature, detergent concentration as necessary), DHT, CHT, and campaign length. Along with a visual inspection performed by qualified personnel, trending of these parameters individually might not provide assurance of CPV, but taken together, provide a picture of a cleaning system that continues to be in a state of control.

Tracking and trending CPV parameters are necessary to demonstrate that a cleaning validation system is maintained in a state of control. Options are available, but the easiest path forward is often the more labor-intensive approach. Consideration for long-term use of CCPs, cleaning swab test data, DHT, CHT, and campaign length should be taken during the CV planning phase rather than waiting until CV is complete, to ensure a robust ongoing CV program.

Guide to Inspection of Validation of Cleaning Processes


(Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, Washington, D.C., July 1993).

EudraLex Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

, Annex 15: Qualification and Validation, Section 10: Cleaning Validation (2015) Section 39, Page 243.

3. Health Canada, Canada Health Products and Food Branch
Inspectorate Guidance Document, Cleaning Validation Guidelines GUIDE-0028 (2008).

4. PIC/S, PIC/S Validation-Master Plan, IQ, OQ, Non-sterile Process Validation, Cleaning Validation (PI 006-3) (September 2007).

Guidance for Industry Process Validation: General Principles
and Practices

, (Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, Washington, D.C., January 2011).

Richard Forsyth* is a Principal Consultant with Forsyth Pharmaceutical Consulting. Dr. Sabine Imamoglu is Product Supply, Pharmaceuticals, Pharmaceutical Affairs, Bayer AG.

*To whom all correspondence should be addressed.

 
Vol. 46, No. 1 
January 2022 
Pages: 34–37

When referring to this article, please cite it as R. Forsyth and S. Imamoglu, “Continued Process Verification for Cleaning Validation–Challenges and Pitfalls,” 

Articles

Continued process verification for a cleaning validation program begins once the validation study is complete. 

Continued Process Verification for Cleaning Validation– Challenges and Pitfalls

Submitted: December 1, 2020
Accepted: February 5, 2021

Cleaning validation requires a significant effort to design a strategic and effective program that is defendable with regulatory agencies. Of primary concern is what to validate. A robust selection of which product(s) and equipment to validate for cleaning is the cornerstone of a successful cleaning validation program. A strategy for selection of products and equipment for cleaning validation is presented.

Richard Forsyth is a Principal Consultant with Forsyth Pharmaceutical Consulting.

 
Vol. 45, No. 8 
August 2021 
Pages: 44–51

When referring to this article, please cite it as R. Forsyth, "Grouping Products and Equipment for a Worst-Case Cleaning Validation Study," 

A robust selection of which product(s) and equipment to validate for cleaning is the cornerstone of a successful cleaning validation program. A strategy for selection of products and equipment for cleaning validation is presented.

Grouping Products and Equipment for a Worst-Case Cleaning Validation Study

Submitted: October 12, 2015
	Accepted: December 2, 2015.

Parameters affecting cleaning validation swab recovery studies include: the material of construction coupon, residue spike level(s), swab recovering the residue, swab personnel, swab extraction, and test method. Each of these swab recovery parameters are reviewed in detail to define best practices and highlight common mistakes to assure successful recovery studies using a risk-based approach.

	Residue assays are a critical quality attribute in establishing a validated cleaning program. They are essential to accurately determine amounts of residual API or formulation component in comparison to the acceptable residue limit (ARL) for a given cleaning process or equipment train (1). The residue assays are validated for the following parameters: linearity, precision, sensitivity, specificity, detection limit (LOD), quantitation limit (LOQ), and recovery. From an analytical standpoint, recovery is from the cleaning test sample (i.e., the swab). From the cleaning program standpoint, the concern is the recovery of the residue from the manufacturing equipment.

	Recovery factors for cleaning validation residue testing are an essential element of any cleaning validation program. The FDA 

Guide to Inspection of Validation of Cleaning Processes 

states that firms need to “show that contaminants can be recovered from the equipment surface and at what level…” (1). The updated EU Guidelines for GMP Annex 15 expands this concept to state that “recovery should be shown to be possible from all materials used in the equipment with all sampling methods used” (2). The Health Canada (3) and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) (4) cleaning validation guidances also require that recovery experiments be completed. Recoveries are necessary for direct surface sampling using a swab.

	It is a common practice to set baseline limits for a minimum acceptable recovery, for example, a minimum product recovery of 70%. However, the most important aspects for product residue recovery factors are that the data are consistent, reproducible, and provide an adjusted ARL that is higher than the analytical test method LOQ. ARLs must also be achievable and practical. If recoveries are too low, the recovery parameters should be investigated and optimized to increase recovery. If swab recoveries cannot be improved, a low recovery can be used with the understanding that the accuracy and precision are somewhat compromised and a higher variability (% relative standard deviation [RSD]) criteria will most likely be necessary.

	Although it does not occur as often, recoveries that are too high should also be a concern. Recoveries of API residues rarely are above 100%, but it is more common for recoveries of detergent to be above 100%. However, consistent recoveries above 100% should be a cause for concern. Single recoveries up to 105% can be considered acceptable, but any recovery greater than 105% should be considered suspect and investigated.

	A recovery factor is determined through experiments in which sample equipment materials of construction (MOC) spiked with known amounts of the substance of interest are recovered and tested. The recovery must be capable of capturing a sufficient amount of material to allow an accurate and precise measurement of the spiked component. As shown in 

, blank samples are also tested to assure that the swab recovery components do not interfere with the test sample analyte of interest. The parameters that go into a successful swab study include the coupon MOC, residue spike level, number of spike levels and replicates, recovery factor determination, swab area, swab, number of swabs, swab solvent, swab technique, personnel, sample container, extraction solvent, extraction method, extraction time and test method.

	There is some flexibility with all of these parameters. Flexibility allows one to optimize the recovery procedure. Spike levels, volumes, times, and materials can all be changed to benefit the recovery process. The parameters, however, can be made too diverse or overly conservative, which will take more time and resources with little or no added value to the recovery. Also, many of the parameters influence the flexibility of other recovery parameters. Once a recovery parameter is set, it could limit other parameters, resulting in a recovery that is not optimized.

	Best practices for selection and execution of swab recovery parameters are defined to increase efficiency. Common mistakes are noted as potential pitfalls to avoid. Some parameters are fairly straightforward, while others are more subjective to the individuals defining the process.

	The obvious first choice for coupon MOC is stainless steel, which comprises the majority of material in pharmaceutical manufacturing equipment in many plants. Regulatory expectations are that recovery studies are performed from every product-contact MOC, regardless of how prevalent it is in the manufacturing equipment. For example, gaskets with very little product-contact surface area require recoveries because they typically represent a worst-case location, and these types of materials have been the source of recovery issues in the past (5). Testing every MOC for every product is the more conservative approach, but can be labor- and resource-intensive.

	Reductions in the amount of testing for a cleaning validation program are desirable, but efficiencies must have technical merit and be scientifically justified. Within a company, for each new drug product manufactured, quantitative studies determine acceptable swab recoveries from each MOC that requires surface sampling. One of the ways to reduce the amount of testing is to test a new substance on only a subset of materials. Data have shown (5) that MOCs can be grouped based on existing recovery data. A follow-up study (6) concluded that MOC porosity was a contributing factor to low recoveries of swab samples from MOC coupons. If feasible, porous materials should be replaced to avoid the possibility of residue from the porous material contaminating the next batch.

	The recommended strategy for recovery studies is to perform the recovery studies on stainless steel for all products or compounds. Then take a subset or cross-section of the products or compounds and perform recovery studies on all MOCs at the site. If the data generated agree with the literature groupings, then continue using stainless steel for recovery studies and perform recoveries from other MOCs as necessary. If the recovery data generated do not agree with the literature groupings, then continue using all MOCs for recovery studies until enough data are generated to allow grouping at the site.

	The swab recovery study should be centered on the ARL for the product or compound. Accuracy is most important in the region of possible cleaning failure. The range should be extended above the ARL, approximately 25%. Any higher is unnecessary because the cleaning procedure fails at any level above the ARL. The recovery range can go down to the LOQ (see 

) of the method because most cleaning data should be near or below the LOQ of the analytical method.

	The recommended strategy for recovery levels is to spike 125% of the ARL, 100% of the ARL, and 50% of the ARL at a minimum, and to extend down to the LOQ of the test method as practical.

	Number of swab recovery levels and replicates

	All recovery levels should be done in triplicate, to allow for variability of the factors affecting the recovery. There should be at least three recovery levels for each recovery study: at the ARL level, one above the ARL, and one below the ARL. Each additional recovery level results in three recovery assays for each product on each MOC. A balance needs to be struck between the amounts of data needed against the amount of work required to generate the data. An additional factor affecting the number of recovery levels is the number of products requiring recovery. The fewer the products, the greater number of recovery levels can be conveniently spiked, recovered, and tested.

	The recommended strategy is to perform triplicate recoveries at the four levels noted above. An example of a recovery data set is shown in 

. The recoveries at the three higher levels should be at least 70% and should agree within a %RSD of 15%. If the average recoveries are <70% or >105%, an investigation should attempt to optimize the recoveries. If the recovery at the LOQ agrees with the other three, then the range is extended. If the recovery at the LOQ does not agree with the other three, then the limitations of the accuracy at low levels is known, the risk of which decreases the further the ARL is from the LOQ of the test method.

	The recovery factor is determined from the recovery data generated from the spiked 
	coupons. There should be at least nine data points from three different spike levels. The data for the three levels can be averaged to determine the recovery factor. Recovery data can be somewhat variable; therefore, a variability limit is also used. Typically, a %RSD of <15% is considered acceptable variability, although experienced personnel can perform recoveries at <10% RSD. If data for additional spike levels are generated, all data in the recovery average should be included.

	If the variability of the data exceeds the 15% variability parameter at lower levels, they should not be included in the average for the recovery factor. This approach will not impact the resulting cleaning data. For example, a swab result of 0.1 µg/swab will not change for recovery factors between 50-100%. The importance of the accuracy of the data near the LOQ of the method is inversely proportional to the importance as the accuracy of the data near the ARL based on the difference between the two levels.

	A seemingly conservative approach is to use the single lowest recovery as the recovery factor. Scientifically and statistically, this approach does not make sense. Scientifically, using this approach would cause samples near the ARL to fail cleaning when in fact they pass. Statistically, the single lowest recovery is not representative because it ignores the majority of the recovery data. Qualification of personnel is also compromised when tested by? a lower recovery factor. The potential damage caused by this approach increases the further the lowest value is from the average.

	The recommended approach is to use the average of the recovery data set as the recovery factor for all cleaning samples.

	The size of sample area to take will dictate several of the recovery parameters. A sample size of 5 cm x 5 cm area (25 cm

) has been accepted as large enough for a representative sample size (7) and is small enough for areas that have limited surface area and/or require taking multiple samples from the same location (e.g., API and detergent). There are multiple practical advantages for taking a 25-cm

 sample size almost always requires only one swab to achieve adequate recovery. It is also less likely to require the need for a template to take a 25-cm

	Taking a larger sample size, for example a 10 cm x 10 cm area (100 cm

), although resulting in a larger sample size and a potentially lower LOD for the residue assay, is limited to sections of the manufacturing equipment that have sufficient surface area to accommodate these samples, which usually are not the hardest to clean sections of the equipment. Many hard-to-clean locations (e.g., equipment outlets) do not have sufficient area to take an API and detergent sample and would be difficult to justify. Because of the larger swab area, swabs wetted with volatile organic solvents have a greater tendency to dry out before swabbing the entire area, making recoveries more difficult. It is also advisable when taking a larger sample area to make a final swab pass around the perimeter of the swab area to pick up residue that has been pushed to the sides of the swab sample area. The larger sample size is more likely to require the need for a template and the problems associated with that, including sample cross-contamination. A larger swab area would increase the need to use multiple swabs and could increase variability among personnel.

	A large swab area will also limit flexibility of other swab parameters including the swab chosen for the recovery, the number of swabs used for the recovery, and volume of extraction solvent. The disadvantages of using a larger swab area far outweigh the advantage of obtaining a larger sample. Thus, the recommended strategy is to swab a 
	5 cm x 5 cm area (25 cm

	Swab characteristics, material, and size

	Swabs and swab materials should be convenient to use, able to pick up residue from coupon and equipment surfaces, release residues into solution, and not cause interference with the residue assay. There are several types of swabs and vendors, but the most popular is the Texwipe brand of swabs. Other vendors include Berkshire and Lym Tech. The swabs are made of a woven polyester fiber that wets with most solvents. It adsorbs the dissolved residue material, removes it from the surface being tested, and releases the residue into the extracting solvent. Texwipe swabs contain no adhesives and only exhibit interference peaks when they are extracted with a strong organic solvent, such as acetonitrile, over an extended period of time. There are also low total organic carbon (TOC) and sterile swabs for TOC and bioburden applications respectively.

	Swabs come in two general sizes, large and small (see 

). A mistakenly conservative approach is to default to the large swab size to better assure that the residue is sufficiently recovered. In fact, the smaller swab head can adequately recover several hundred micrograms of residue from a coupon. This should be a high enough level for just about all recovery studies and allows more flexibility with other recovery parameters. The small swab head uses 0.1 mL of swab solvent and can be extracted into as little as 2 mL of extraction solvent. The larger size swab head requires more swab solvent 0.5 mL) and a greater volume of extraction solvent, and it limits the sensitivity of the analytical method.

	The recommended strategy for swabs is to select one model of small size swabs for all recovery studies. Only resort to a large swab if other options are exhausted, because having different swabs available for swabbing could lead to using the wrong swab, resulting in a non-conformance.

	As noted in the previous section, the sample area and the swab can influence the number of swabs necessary for adequate recovery. A single swab will provide adequate recovery, require a minimal extraction solvent to maximize the LOD for the residue assay, and simplifies the swab process to take the sample. A larger area will more often require multiple swabs to achieve a sufficient recovery factor. If using multiple swabs, it must be determined whether to use a wet or a dry swab for the second swab, but multiple swabs will increase recovery on an incremental basis only. Multiple swabs will also require a larger extraction solvent volume and potentially limit any advantage gained form the increased sample size. Using multiple swabs increases the work of the swab personnel (i.e., two swabs is double the work of a single swab). Using multiple swabs also increases the risk of mistakes and potential contamination of the equipment.

	The recommended strategy is to use a single swab for recovery. If adequate recoveries cannot be achieved, other recovery parameters should be explored, including swab solvent and the extraction technique and time, before resorting to using multiple swabs.

	The swab solvent must be one in which the analyte of interest is soluble and be compatible with both the extraction solvent and the analytical test method. The best choices are purified water or an organic solvent that will evaporate and leave no residue behind, for example isopropyl alcohol (IPA), which is often used as a final wipe or rinse of equipment to aid drying and removal of any residual water.

	If the samples are being analyzed using TOC analysis, the swab solvent is limited to purified water. If high-performance liquid chromatography (HPLC) is used for analysis, then the choice of swab solvent is more flexible. The amount of swab solvent is important and somewhat technique related. The swab needs enough solvent to wet the entire surface to solubilize and recover the residue of interest, but not so wet that solvent is left behind on the coupon. This amount will differ slightly for water and organic solvents and for small and large swab heads. As noted previously, small swab heads hold approximately 0.1 mL of solvent while the large swab heads hold approximately 0.5 mL of solvent.

	The recommended strategy is to thoroughly wet the swab head in the solvent and then squeeze the excess solvent from the swab head using the side of the solvent container. It is important to ensure that both sides of the swab are squeezed out.

	The swab technique has always been assumed to be a major factor in the variability of swab recovery data. Although person-to-person variability is a factor, it has been shown that this variability is fairly consistent across sites (5), making swab recovery factors transferrable among sites.

	There are numerous descriptions of swab technique, and generally most are acceptable, as long as the technique is described in sufficient detail for ease of training, and covers the sample area completely and consistently. The swab technique should be successful for performing recoveries and routine swab sampling. One of the best and most practical is also the most straightforward.

	The recommended strategy is to wet a swab with solvent. Remove any excess solvent from the swab as described previously. Swab an area of 25 cm2 (5 cm x 5 cm).

	Using the flat side of the swab, apply slight pressure to the swab stick and make full contact with the surface. Swab the surface using a back-and-forth motion for about 10 seconds. Flip the swab over and swab the surface in a perpendicular direction using a back-and-forth motion for about 10 seconds (see 

). Cut the swab above the swab head into the sample container. Cap the sample container. Repeat the process for each recovery or sample location.

	Swab personnel variability, and qualification

	Personnel performing the recoveries have an effect on the outcome of the recovery study. Variability is generally inversely proportional to the training and experience of the personnel. All personnel should be thoroughly trained on the techniques involved 
	in a swab recovery. The easiest way to train swab personnel is to have them involved in the initial recoveries to establish the swab recovery factors.

	Qualification of personnel that perform swab sampling demonstrates successful training and is a regulatory expectation. Personnel must demonstrate that they can accurately and consistently recover residue from MOC coupons. This ability can be demonstrated through participation in the recovery studies. Otherwise, multiple coupons are spiked with API or product and personnel recover the residue. The recovery obtained must pass acceptance criteria for accuracy and precision.

	The recommended strategy is to have personnel participate in recovery studies and meet the criteria noted above: greater than 70% recovery with less than 15%RSD. For qualification, personnel perform recoveries of a single API from three coupons at the ARL level.

	To qualify to perform swab sampling, the average of three recoveries at the acceptance criteria must be within 15% of the established recovery factor with a %RSD of <15%.

	The sample container stores the swab sample until it is delivered to the laboratory for assay. The sample container must be large enough for the volume of the extraction 
	solvent, be compatible with the extraction solvent, and not contain anything that might be extractable into the solvent and a source of contamination (extra peaks or higher TOC value) in the extracted sample. General-use glass vials with lined caps have been known to cause issues with cleaning sample analysis.

	The recommended strategy is to use inert, disposable vials. Examples include plastic centrifuge vials and glass TOC vials. It should be ensured that any plastic vials used are compatible with the extraction solvent.

	Most solvents used for HPLC analysis are compatible with these type of centrifuge vials. The glass TOC vials with Teflon-lined lids are acceptable, but tend to be more expensive.

	The extraction solvent will be adapted from the validated test method. It will be compatible with the analytical test method and will dissolve the analyte of interest. If using TOC, the extraction solvent must be purified water.

	The volume of extraction solvent will depend upon the cleaning limit, the test method sensitivity, and the size of the swabs. TOC testing typically requires 30-40 mL of purified water for extraction based upon the sampling needs of the instrument. For HPLC testing, the extraction solvent requirements are far less. For a single small swab head, the minimum volume can be as little as 2 mL, although typical extraction volumes are in the 5-10 mL range.

	The recommended strategy is to use a minimum practical volume of extraction solvent because the majority of cleaning samples are expected to have little or no residue. Nonetheless, the volume of extraction solvent should result in a sample concentration such that a sample at the cleaning limit falls within the linear range of the test method.

	The most common swab extraction techniques are: vortex mixing, shaking, or sonicating. The technique and length of time used depend, to some extent, on how long the swab samples might sit before they are processed. If samples will sit for a relatively short time, for example less than one day, and they do not dry out, then vortex mixing for up to one minute might be enough to effectively extract the sample from the swab. If the swab samples will be held for a longer period of time, or if there is a chance they could dry out, a more vigorous, longer extraction is probably necessary, such as mechanical shaking or sonication for a period of 15-30 minutes.

	A comprehensive approach to establish extraction conditions is to take a residue and spike aliquots onto swabs and let the swabs dry completely to approximate worst-case conditions. Extract the swabs in multiples of three under increasingly rigorous conditions and then assay them. Choose extraction conditions at least rugged enough to extract the sample consistently with good recovery.

	The recommended strategy is to match the extraction technique and time to the anticipated hold time for the swab samples prior to extraction and apply the sample extraction parameters to all cleaning validation swab samples for consistency going forward.

	Testing of cleaning validation samples requires a validated test method. The extent of validation is dependent upon the type of method employed and the capabilities of the method. For any test method to be suitable for its intended purpose, it must be appropriate for measuring analytes at and below the ARL. The analytical performance characteristics, or validation parameters, as defined by the 

(8) include: accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness.

	Even if they are well below the ARL, establishing the LOQ and LOD of the method are important. Because the expectation is that most cleaning validation samples will assay at zero or below the method LOD, the LOQ and LOD parameters greatly help define and put context around the process capability of the cleaning procedure. Without the LOQ and LOD, there would be far less information regarding the effectiveness and control of the cleaning procedure, and the cleaning procedure could be drifting towards being out of control before any data makes it evident.

	The swab recovery study should be part of the method validation. Once method parameters are established and validated, the swab recovery should be executed to assure that the method will provide meaningful swab sample data.

	Unless all samples are going to be tested immediately, then sample solution stability should be established. This evaluation would include stability of the unextracted swab as well as the extracted swab solutions. Stability of at least two to three days is recommended in case of instrument failure during testing, or if unexpected results need to be confirmed.

	Test methods such as pH and conductivity, while limited to certain residues, can provide cleaning data and require only instrument calibration. Many analytical test methods require validation. The most prevalent of these methods requiring validation are discussed in the following.

	HPLC for testing of cleaning validation samples is well established (9-12) and can address all validation parameters. HPLC is a chromatographic method that involves a sample in a liquid stream that passes through a packed column and separates from the other components of the sample. An HPLC method can separate the residue of interest from the components of the formulation as well as the detergent. A well-designed HPLC recovery study can demonstrate accuracy, precision, linearity, range, LOD, and LOQ in a single run. Typically, HPLC methods for assay are designed to quantitate levels down to 0.1% of the API, making sensitivity well below most calculated ARLs. However, the sensitivity of HPLC is dependent on the chemical structure of the residue of interest and the detector, which can quantitate the residue. A residue with no UV chromophore requires either a specialized detector (fluorescence, electrochemical) or derivatization to achieve the desired sensitivity. HPLC assay methods can be lengthy (i.e., 30-40 minutes per injection), which could be an issue for quick turnaround of samples.

	TOC analysis is also well established for testing cleaning validation samples (13-15). TOC analysis involves the oxidation of carbon and the detection of the resulting carbon dioxide produced from the oxidation reaction. Sensitivity is down to the ppm or ppb level. TOC is a non-specific method of analysis. All organic carbon is detected. Therefore, any residue detected must be considered the residue of interest. A well-designed TOC recovery study can also demonstrate accuracy, precision, linearity, range, LOD, and LOQ in a single run. Residues for TOC analysis must dissolve in water. This requirement could limit the effective linear range of the residue assay. Other types of chromatography or spectrophotometry are appropriate for testing cleaning validation samples as long as they are validated and have sufficient sensitivity.

	The recommended strategy is to select a familiar method with which the operator has experience. Validate the method using all validation parameters and then execute the recovery study.

	Swab recovery studies are a critical part of a cleaning validation program and must be executed in a scientifically sound, compliant, and consistent manner. The parameters of a swab recovery study can enhance or limit the value of the recovery study and, therefore, all of the data generated in support of the cleaning validation program. 

, the components of the swab study affect one another based on the choices made. The choice of swab area and swab selection also affect subsequent parameters all the way to the sample test results. A well-designed and well-executed swab recovery study can help ensure a robust site cleaning validation program.

 (Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, Washington, D.C. July 1993).
	2. EC, 

EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

, Annex 15: Qualification and Validation (2014).
	3. Health Canada, 

Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation and Cleaning Validation

, 2004.
	5. R. J. Forsyth, J. C. O’Neill, J. L. Hartman, 

., 31 (10) 102-116 (2007).
	6. R. J. Forsyth, J. 

., 15 (4) 91-96 (2009).
	7. G. L. Fourman and M. V. Mullen, 

., 29 (11) 1663-1673 (2006).
	10. M. A. Boca, Z. Apostolides and F. Pretorius, “

 37 (3) 461-468 (2005).
	11. R. J. Forsyth and D. Haynes, 

., 22 (9) 104-110 (1998).
	12. E. Pang et al., 

29 (1) 84-94 (2005).
	13. K. M. Jenkins, et al., 

., 50 (1) 6-15 (1996).
	14. J. Walsh, “Using TOC Analysis for Cleaning Validation,“ presented at 
	The Validation Council’s Conference of Cleaning Validation, Eton, NJ 
	(Oct. 27, 1999).
	15. R. Clifford and M. Tanaka, 

	Richard J. Forsyth is a senior consultant at Forsyth Pharmaceutical Company, 907 Shamrock Ct. Royersford, PA 19468, forsythpharmaconsulting@gmail.com.

	When referring to this article, please cite as R. Forsyth, “Best Practices for Cleaning Validation Swab Recovery Studies," 

Swab recovery parameters are reviewed in detail to define best practices and highlight common mistakes to assure successful recovery studies using a risk-based approach.

Best Practices for Cleaning Validation Swab Recovery Studies

Submitted: Sept. 14, 2015
	Accepted: Oct. 2, 2015

Cleaned equipment must be visually inspected, both after cleaning and again before product manufacturing begins. Manufacturing and quality professionals must be qualified to do visual inspections. Small training groups are recommended for the training required, but a different approach can be used for larger groups. This article presents recommendations based on a program that was set up to qualify members of a large, diverse team at one oral solid-dosage-form manufacturing facility.

(2) require that cleaned pharmaceutical manufacturing equipment be visually inspected and determined to be clean, both after completion of the cleaning process and again immediately before manufacturing of the next batch or product begins. Visual inspection is designed to assess all of the visually accessible product contact surfaces of the pharmaceutical manufacturing equipment, and determine that the equipment is free from any visible residues. Manufacturing cannot begin until this assessment has been made, because it is crucial to patient safety and to verifying that the equipment has been adequately cleaned. A visual inspection is a routine part of cleaning and the first criterion for cleaning validation, and inspection results must be deemed acceptable before any swab samples can be collected from the cleaned equipment.

	Visual inspections are conducted by a variety of site personnel. Equipment cleaning staff routinely inspect equipment during and after manual cleaning. A second person, in addition to the cleaning crew, must confirm and document visual cleanliness of cleaned equipment.  Before manufacturing of the next batch of product can begin, manufacturing and quality staff must visually inspect all process equipment for cleanliness and document cleanliness in the manufacturing batch record. Quality and validation personnel also inspect cleaned equipment periodically as part of their work function.

	Staffers responsible for conducting visual inspections have traditionally been trained by observing a seasoned employee perform this work. More experienced staffers would coach and advise them on issues or intricacies of the individual pieces of equipment, and then observe them when they conducted their own visual inspections. The approach worked, but could lead to subjectivity and inconsistent visual inspection results. Professionals at regulatory agencies believed that this approach could be improved if it were formalized and documented.

	As part of a cleaning validation program, staff members who take swab samples have been routinely qualified to determine that they can adequately recover residues from equipment surfaces. Laboratory personnel are qualified to test the cleaning samples. Cleaning and testing procedures are validated to demonstrate consistent execution. Establishing a qualification criterion for the visual inspection of cleaned equipment is a logical extension of this philosophy that would improve cleaning validation and ensure that the training for all people who visually inspect cleaned equipment is objectively documented.

	Training staffers in visual inspection poses a number of logistical challenges, however. Ideally, such training is done for small groups, within a laboratory setting (3). Qualifying a large, diverse group of personnel would be beneficial because it would provide a site with a routine, redundant, and rugged confirmation of the effectiveness of site cleaning procedures. Such training and qualification, however, is not practical in a laboratory setting.

	At one oral solid-dosage-form manufacturing site, such a training program was offered to all operations and inspections staff. Due to the size and diverse schedules of members of this group, it proved to be more practical to bring the visual qualification testing to the personnel in the manufacturing area. Qualification was conducted using spiked coupons, and, because the coupons were spiked with formulations that contained API, for safety reasons, the qualification was conducted in an empty suite in the manufacturing area rather than a meeting room.

	The site did not have visible residue limits (VRLs) established for its product portfolio. Rather than expend the time and resources required to establish the product VRLs, the company  decided to spike coupons with the formulation at two levels only. One coupon was spiked at the acceptable residue limit (ARL) for the compound, and a second coupon was spiked at 50% of the ARL.It was reasoned that, if  personnel could see the two spiked coupons, then they would be qualified to distinguish visually soiled equipment before it became a cleaning failure based on the ARL. By spiking coupons at 50% of the ARL, there would be a margin of safety between the visual level detected and a cleaning failure against the ARL. The choice of spiking at the 50% ARL level was a compromise between spiking at as low a level as practical while assuring personnel had the best opportunity to detect the residues visually.


	Training and qualification for visual inspection for small groups was discussed in a previous article (3). There are a number of options for presenting the spiked coupons, including presenting just the VRL levels or several spike levels down to the VRL. The former option uses fewer coupons but requires additional training to reduce the risk of qualification failure. The latter approach uses more coupons but has a lower risk of failure, and offers a more thorough approach that provides a greater understanding of visual inspection parameters.

	Neither option, however, works well to train and qualify a large group. Qualification using just the VRL levels requires extensive up-front training to acquaint personnel with the appearance of residues at their VRL levels. Qualification using several spike levels down to the VRL would require more time for each individual of the large group to understand the concepts of visual inspection parameters. The use of more coupons might prevent the opportunity to spike and present all site residues for qualification during one training session, which would lengthen the time required for qualification.


	Training and qualification for visual inspection for a large group were subject to several practical constraints to qualify all personnel most efficiently and minimize disruption of ongoing operations. Three shifts were trained; therefore, training sessions were held at the end or beginning of the shift. One large group training session was held for each shift to familiarize personnel with the concepts and goals of the training and qualification exercise. A knowledge assessment was conducted with each group to confirm its grasp of the training concepts.

	Visual inspection qualification was conducted in one of the manufacturing suites with more limited space. Space in which to view the spiked coupons was also limited. Therefore, smaller groups of 5-10 were brought in to observe the spiked coupons. The small groups were qualified either after their shift completed or during their shift, as job duties allowed. Once the groups were assembled, additional instructional training was conducted prior to the qualification to emphasize the effects of the viewing parameters, especially the viewing angle, the condition of the coupon surface, and the relative appearance of the spiked residues.


	A survey of manufacturing equipment at the site concluded that all equipment surfaces could be visually inspected from a distance of 10 feet or less. The light levels measured in the manufacturing suites ranged from 725-1930 lux. The viewing angles of the equipment were only slightly restricted, but multiple viewing angles were possible for all cleaned equipment surfaces. The viewing parameters for the qualification were based on these findings.

	The material of construction (MOC) for the visual inspection qualification was stainless steel, the most prevalent MOC at the site. Residues for visual inspection qualification included all products manufactured at the site. Each residue was spiked at 100% and 50% of the ARL as shown in 

. The residues tested for the visual inspection qualification showed that the qualified inspector should be able to visually detect residues on the manufacturing equipment during a visual inspection both after cleaning and again before manufacturing.

	For viewing, coupons were presented on a table and positioned at a 15Âº-20Âº angle so that, when viewed at 10 feet, the minimum viewing angle for the coupons was greater than or equal to 30Âº. Staffers in the training program first viewed the coupons at two feet, where they were acquainted with the appearance of the residues and the effect on stainless steel. The grain of the stainless steel had little impact on their ability to see the easily visible residues, but had a more significant impact on how easily they could detect residues that were more difficult to see (e.g., the detergent). Personnel were also instructed on the effects of the viewing distance and the viewing angle.

	After recording observations at two feet and 90Âº, trainees moved into a position at five feet with a 60Âº viewing angle to repeat the observations, and then moved back 10 feet at a 30Âº viewing angle. The ambient light level in the suite was 950 lux and, based on past ruggedness work (4), this was deemed suitable for light levels down to 200 lux. Trainees responded whether or not they were able to see the 100% and 50% ARL level residues.


	Qualification for visual inspections of cleaned equipment is just one part of the training required to assure reliable, thorough visual inspection of cleaned pharmaceutical manufacturing equipment. As shown in 

, adequate training should start with a review of the standard operating procedures (SOPs) for visual inspection and visual inspection qualification, which describe the process for inspection and documentation of cleaned equipment, and the visual inspection qualification process. If available, equipment diagrams showing dimensions and swab locations with associated justification should be reviewed to familiarize trainees with the manufacturing equipment and problem areas for cleaning.

	Before they can be qualified, each staff member must be trained in how to determine VRLs of different types so that they can detect low levels of residues for cleaning. It is a good idea to discuss the relationship of the VRL to the cleaning limit or ARL, and to clarify the relationship between the cleanability of the different residues from various MOCs. This clarification would help impart an understanding of the confidence level in the cleaning procedure and the visual inspection.

	On-the-job training should consist of a supervised inspection of the manufacturing equipment, including the hard-to-clean locations and those most likely to have product buildup, for each piece of cleaned equipment identified for cleaning validation. The final step, after training and qualification, should consist of a monitored visual inspection of a cleaned piece of equipment, ensuring that the proper procedures are followed, a thorough visual inspection is conducted for the equipment, and the visual inspection is properly documented.

	These aspects of training required considerably more time with a large group. Training consisted of a group session for each shift and then, as each small group was brought in for qualification, a short (three-to-five-minute) discussion of the viewing parameters, the residues and their appearance was completed at the two-feet distance. The risk for the abbreviated training was that some trainees might not sufficiently understand the importance of the viewing parameters or the significance of the training for their day-to-day jobs, and that they might misidentify coupons.


	Individual formulations were suspended into organic or aqueous solvents and diluted as necessary to obtain concentrations at five times the ARL level. To obtain the 100% ARL level, 200ÂµL of the stock solutions were spiked onto individual coupons; to obtain the 50% ARL level, 100ÂµL of the stock solutions were spiked onto individual coupons. The ARL spike levels of the 11 residues are shown in 

. The cleaning residue limits ranged from 1.1 Âµg/swab up to 497.8 Âµg/swab. Blank coupons spiked with solvent were also prepared.
	The spiked and blank coupons were arranged for qualification in a manufacturing suite, the light level was measured, viewing distances were marked, and small group subsets of the large group were brought in for additional instruction and qualification.


	The logical acceptance criteria for visual inspection qualification are that all personnel identify all of the spiked coupons as “visible,” and all of the blank coupons as “blank.” Realistically, with a large group, the risk of misidentification of a coupon is more likely. For a blank coupon, a misidentified coupon would not necessarily have to be considered a failure. A blank coupon deemed visible is a mistake on the side of caution and could be tolerated. If a spiked coupon is not identified as such, it is more problematic. Potentially, a visually soiled piece of equipment could be deemed as clean and released for subsequent manufacturing. The equipment could be used to manufacture a different product, which could be cross-contaminated. Or the visible residue on the equipment could be identified during redundant visual inspections, either by quality assurance personnel (QA) or before the next batch. In either case, the equipment would need to be re-cleaned and an investigation would need to be launched to identify the root cause of the visual failure. Both options could cause problems for the site.

	As a result of the accepted risk of abbreviated training, the qualification resulted in misidentification of spiked coupons for a small percentage (<5%) of the trainees.


	The visual inspection qualification for a large group presents several logistic and timing challenges. Processing a large group requires a fair amount of time and must be conducted in an area with sufficient space. In-depth training for VRLs and viewing parameters, although preferable, is neither practical nor does it add sufficient value. It is also more difficult to gauge the effectiveness of training in a large group environment. Therefore, a scaled-back, more expedient and efficient training program was implemented for large group qualification. This approach did not employ the true VRLs for production residues, but did assure that personnel could visually detect process residues prior to a cleaning failure based on the swab limit. The margin of safety between the lower residue level tested and the swab limit provided some measure of confidence that visually soiled equipment would not pass visual inspection.  The majority of personnel were able to visually detect all residues within the viewing parameters, and any risk of inadequate visual inspection was mitigated by redundant visual inspection proceduralized at the facility.

	Results of the qualifications are summarized in 

, and the individual residue results are shown in 

 shows that a two-thirds majority were able to see the residues under the established viewing parameters, although there was some variability in a number of responses: the ability to see one of the spiked residues for a particular formulation while not seeing the other was the variation most often noted. Of the 46 observations where residues were not visually detected, the vast majority were for Product 7 and/or the detergent. 

 provides a more detailed list of the number of personnel that were able to detect the individual residues. Eight of the 11 residues were visible out to 10 feet and beyond with less than a 5% standard deviation. Product 5 was not consistently visible at 10 feet but was visible at five feet. Of the 11 residues, the Product 7 formulation and the detergent were not consistently visible at all distances on a consistent basis.

	The detergent (DTG) results are not applicable unless a component of the detergent is identified for the cleaning limit because the results are based on the total weight of the detergent.  The detergent is 66% water, which means that only 34% or 31.3 Âµg of total solids were spiked onto the 100% level coupon.

The individual personnel results were examined for consistency and to determine if there were any individuals who had a particular problem visually detecting residues. The results for Product 7 and the detergent were ignored because they were difficult to detect for a large number of personnel. The results of the individual analysis are shown in 

. One individual missed the visible residue on seven coupons, suggesting that he or she either be trained on the appearance of residues, encouraged to perform any visual inspection from two feet, or be excluded from signing off on visual inspections. Additional training might also be advised for the two individuals who missed the visible residue on four coupons and the five individuals who missed the visible residue on three coupons.


	A large group of personnel were successfully qualified for visual inspection of cleaned equipment at an oral solid-dose manufacturing facility. The qualification was implemented for all products made at the facility and conducted within the time and space constraints of the production schedule.
	The visual inspection procedure for a large personnel group were considered qualified for Products 1-4, 6, 8, 9, and 10 for a light level of > 200 lux; a viewing distance of < 10 ft; and a viewing angle of > 15Âº. The visual inspection procedure is appropriate to verify cleaning process effectiveness to acceptably remove formulation residues from equipment during cleaning validation and routine monitoring. The visual inspection procedure was considered qualified for Product 5 for a light level of > 200 lux; a viewing distance of < 5 ft; and a viewing angle of > 15Âº. Equipment cleaned after manufacture of Product 7 formulations should be viewed from as close a distance as practical using multiple angles under ambient light (> 200Lux) to provide the highest confidence of visually detecting any remaining formulation. Trainees who had difficulty visually detecting the spiked residues could receive additional training on the appearance of the residues and be retested. In this case, the risk of visually soiled equipment passing visual inspection is mitigated by validation of the respective cleaning procedures, by the restricted viewing parameter limitations (e.g., five feet) for specific residues and by the redundant visual inspection immediately after cleaning by the equipment cleaner, the confirmatory inspection after cleaning and the visual inspection immediately prior to the subsequent manufacturing.

	Risk could be further mitigated or eliminated by adding training using spiked coupons prior to the qualification exercise. This would acquaint personnel with the viewing parameters and their effect on the ability to visually detect spiked residues. This could be done with the entire large group but would probably be more effective with each small group prior to qualification. The small group training could be done immediately prior to qualification using an additional trainer and would extend the entire process by an additional 10-15 minutes.
	Qualification of personnel for visual inspection of cleaned pharmaceutical manufacturing equipment product contact surfaces is a necessary complement to both a cleaning validation program and the manufacturing operations at a site. Visual inspection qualification is just one facet of an overall training program to assure that personnel are equipped to provide a consistent, thorough and accurate evaluation of cleaned surfaces for ongoing pharmaceutical operations.

, Annex 15: Qualification and Validation, Section 10.2
	2. FDA, 

, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 211.67
	3. R. J. Forsyth, 

. 38 (1), 42 - 46 (2014)
	4. R. J. Forsyth, 


	When referring to this article, please cite it as R. Forsyth, "Qualifying Personnel to Visually Inspect Cleaned Equipment Part II: Small vs. Large Group Training," 

This article presents recommendations based on a program that was set up to qualify members of a large, diverse team at one oral solid-dosage-form manufacturing facility.

Qualifying Personnel to Visually Inspect Cleaned Equipment Part II: Small vs. Large Group Training

	Peer reviewed:
	Submitted: July 31, 2015. Accepted: September 11, 2015.

Visible residue limits (VRLs) have been shown to be a valuable tool in a validated cleaning validation program. As an organization gains experience in establishing VRLs, the established levels generally go lower as personnel become more familiar with the appearance of visible residues and spike increasingly lower levels of residue to observe. These lower levels have led to a conundrum that requires an adjustment in the way VRLs are defined.

	Visible residue limits (VRLs) can be quantitatively established for pharmaceutical products, APIs, excipients, and detergents (1-3). The VRL is the lowest level of residue that can be seen by a panel of observers under a defined set of observation parameters. If a VRL is lower than the calculated acceptable cleaning residue limit for a piece of equipment or an equipment train, then the VRL could be considered the cleaning limit for that equipment. The regulatory agencies have accepted the use of VRLs as a valuable tool to help develop, validate, and maintain a robust cleaning validation program (4, 5).

	The ruggedness of VRLs has been established for different residues, personnel and viewing conditions (6), presentation of coupons for personnel observation (7), and for different materials of construction (MOCs) (8). Through all of these studies, the method of preparation of the VRL samples was held constant. A solution or suspension was prepared in a volatile solvent, typically methanol, serial dilutions were made to decreasing concentration levels and coupons were spiked by pipetting 100 µL onto the MOC coupon. The methanol spread out to a circle of about 5-cm diameter and rapidly evaporated, leaving a ring of visible residue.

There have been two primary outstanding concerns with this approach to establishing VRLs. The first concern was that a VRL established under defined viewing conditions might not be replicated in the field and that a practical VRL might be higher. Although this issue has been explored (9), it has not been definitively addressed and taking spiked coupons into the field or replicating VRL spike level on actual equipment is not practical on an ongoing basis, but it does warrant additional work.

	The second concern was that the residues formed a ring and were not evenly distributed over the coupons. While it was acknowledged that the residues were not evenly distributed over the coupons, in the field, residues on cleaned equipment were more likely to show up as rings than as an even coverage on the equipment, especially at low residue levels. The entire area of the resulting circle was used in the calculation of the VRL (

Visible residue limits have been shown to be a valuable tool in validated cleaning validation program.