Why Is Cleaning Still on FDA’s Radar?
- Mindful Quality Team
- 7 days ago
- 15 min read
Every year, the FDA publishes statistics detailing inspection findings and citations issued on the online FDA inspection dashboard. Based on data from January 2024 through September 2025, the top 10 most common citations issued for biologic and drug product types are listed in Figure 1, Top 10 FDA Citations for 2024-2025 below.
Cleaning specific citations 211.67(a) and (b) continue to rank among the top 10 observations issued, accounting for a combined total of 12.9% of all observations. Additionally, cleaning program-related observations may also be cited under:
211.22(d), “The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedure shall be followed” applies to procedures that support cleaning, such as visual inspection and line clearance.
211.25(a), “Each person engaged in manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions” applies to training and qualification programs that support cleaning activities, such as swab sampling, visual inspection, and manual cleaning.
211.25(d), “There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product” is a general requirement that applies to cleaning, including visual inspection and sampling.
211.63, “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance” requires equipment used in manufacturing processes to be of a hygienic design and accessible for cleaning.
211.100(a), “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess...” is applicable to procedures that support the cleaning program, such as equipment cleaning, visual inspection, sampling, and line clearance.
211.100(b), “Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance” requires adherence to procedures and contemporaneous (real-time) documentation of activities performed, such as during cleaning and line clearance.
211.160, “Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures…” requires that analytical methods used to quantify cleaning samples are demonstrated as suitable for their intended purpose.
211.192, “…Any unexplained discrepancy…or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed…” requires thorough investigations in the event of cleaning or line clearance failures.
A review of published FDA Form 483s regarding these observations revealed consistent themes related to processes and programs that support cleaning. Based on a more in-depth review of this data, we identified 10 cleaning themes behind these findings. In our experience, there are consistent potential root causes, and we will discuss recommendations for improvement to address these findings.
#1 - Inadequate cleaning validation
Inadequate cleaning validation FDA observations, often cite concerns such as:
Cleaning validation not performed, or an inadequate number of runs performed to demonstrate reproducibility
The purpose of cleaning validation, including campaign length (CL), dirty equipment hold time (DEHT), and clean equipment hold time (CEHT), is to demonstrate that the cleaning process is effective and reproducible under routine and worst-case conditions. Typically, at least three consecutive successful runs are required to validate the cleaning process. It is acceptable, when using a product or equipment grouping strategy, to perform a single confirmation validation run where existing cleaning validation data is leveraged.
Cleaning agent removal is not demonstrated
Process materials, including cleaning agents, that are introduced to equipment surfaces must be demonstrated to be removed to an acceptable level during cleaning validation. Acceptance criteria for process materials should be established based on toxicological data. If the cleaning agent is a commodity chemical, such as NaOH, that is inherent in the process, a rationale could be written to justify why cleaning agent removal is not required for the cleaning program.
Cleaning validation does not include dirty equipment hold time (DEHT) or campaign length (CL)
In alignment with industry guidance, worst-case conditions (i.e., DEHT and CL) should be challenged during cleaning validation to represent routine manufacturing scenarios where process soils may accumulate, degrade, and dry, making them harder to clean. During cleaning validation, equipment should be held for the DEHT to demonstrate that the cleaning process is repeatable and effective under worst-case conditions. If multiple batches are produced within a campaign, the maximum number of batches and days of continuous manufacturing should be challenged and impurity levels monitored as part of the validation.
Clean equipment hold time (CEHT) is not established and/or validated
Similarly, the CEHT should also be validated to demonstrate that any potential microbial proliferation that can accumulate on equipment surfaces during clean storage is controlled and will not contaminate the next product manufactured. If a risk-based decision has been made not to validate the CEHT, the risk assessment should document that appropriate controls are in place to protect the equipment and reduce the risk of microbial contamination.
References: [10][11][16][17][18][23][24]
#2 - Failure to establish or follow procedures
Establishing and following procedures is a fundamental CGMP requirement. Typical gaps Mindful Quality has observed related to cleaning procedures include:
Failure to establish procedures for sampling techniques (e.g., swab, rinse, and visual inspection)
Personnel responsibilities defined in written cleaning procedures are not being followed
Failure to document cleaning activities in a contemporaneous manner
Failure to follow established cleaning procedures
If a procedure is not established or lacks sufficient details to ensure the process can be consistently repeated (especially for manual cleaning, visual inspection, or swab sampling procedures), there is an increased risk of deviations or regulatory observations.
Responsibilities for all personnel involved in performing a procedure should be clearly defined. Mindful Quality has often observed that responsibilities are either not explicitly stated or described with ambiguous language. For example, quality is often assigned the responsibility to ensure procedural adherence; however, there is no quality supervision on the floor when activities are performed. If personnel are unclear about who is responsible for activities such as cleaning equipment, visual inspection, sampling, line clearance, etc., there is an increased risk that these activities will not be performed or completed within the specified timeframes.
Contemporaneous secondary person verification in cleaning and line clearance records should be performed for critical manual activities such as cleaning agent preparation, equipment scrub time, and visual inspection.
References: [11][12][14][19]
#3 - Failure to maintain equipment
Manufacturing activities cause unavoidable and cumulative wear and tear on equipment, such as erosion, corrosion, rouge, scratches, dents, and pitting, which can make surfaces more difficult to clean as product can harbor in the surface anomaly or particles can be released into the product.
Observations related to inadequately maintained equipment include:
Damaged parts and sealants
Equipment with significant scratches that were not evaluated for potential impact
To prevent these types of concerns, a procedure that outlines the identification, documentation, and, if needed, correction of surface anomalies is crucial on a periodic or routine basis. Visual inspection and line clearance procedures should include requirements to check parts, gaskets, and equipment surfaces for damage and to take appropriate corrective action if issues are found.
References: [9][12][18][19]
#4 - Visual inspection & line clearance failures
Line clearance is a crucial control measure to prevent cross-contamination by ensuring that all manufacturing equipment and surrounding areas are visually clean and free of product residue and contaminants such as oils and debris. Companies have been cited for inadequate line clearance practices that allowed equipment and areas to be released when indirect product-contacting equipment and surfaces were observed to be visually dirty by the investigator.
Another common issue seen by Mindful Quality in line clearance documentation is that procedures state two-person verification (i.e., performer and verifier) is required before release, but the line clearance record only documents the performer’s verification that the equipment surfaces are visually clean. When equipment is released during product changeover based solely on visual inspection, two qualified individuals should confirm and document that the equipment is visually clean and ready for use in the line clearance record.
References: [12][13][14][22][23]
#5 - Inadequate cleaning procedures
There are several reasons why a cleaning procedure and cleaning record might be considered inadequate; the most common is a lack of the necessary details to ensure that all direct and indirect product-contacting surfaces are consistently cleaned.
Inadequate identification of an equipment’s cleaning boundary often results from misclassifying product-contacting surfaces as non-product-contacting. For example, in oral solid dosage manufacturing, the inlet and exhaust ducts of the fluid bed dryer are often excluded from the cleaning boundary as non-product-contacting surfaces, when in fact they are indirect product contacting that have the potential to introduce contaminants into subsequent batches. Similar issues have been seen with chromatography skids where gradient skids or chrome skid valves, transfer lines, sensors, or sampling ports are incorrectly left out of the cleaning scope. To develop a cleaning boundary, the process flow path through the equipment train must be clearly understood. A cross-functional team should carefully walk the equipment and review equipment drawings and process flow diagrams, paying particular attention to any areas that could allow backflow, condensate dripping, or aerosol contact, and potential hard-to-clean locations. All areas that contact the product directly or indirectly should be identified and documented before developing the cleaning process to ensure all surfaces that could contaminate the product are cleaned.
For manual cleaning processes, it is essential that the cleaning procedures emphasize the cleaning of hard-to-clean locations. For both manual and automated cleaning processes, the visual inspection performed after cleaning should require inspection of all hard-to-clean locations. Hard-to-clean locations should be identified through a documented risk assessment which takes into consideration factors such as:
Areas with potential for heavy residue accumulation
Air-liquid interface where additional environmental conditions impact the residue drying process
Shadowed locations identified during spray coverage studies
Hard to access areas within the equipment that cannot be disassembled
Locations where residues may accumulate (e.g., agitator wells, vent lines, welds, crevices, dents, or scratches)
Cleaning procedures, especially for manual processes, often lack sufficient detail to ensure repeatable execution of critical cleaning parameters to effectively clean equipment surfaces and utensils. For example, a manual cleaning procedure might instruct to rinse the equipment with no less than five liters of solvent, but does not specify how to perform the rinse to ensure all equipment surfaces are contacted or identify which solvent should be used. Common details missing in cleaning procedures identified by Mindful Quality include:
Clearly defined responsibilities for all tasks, including, cleaning, visual inspection, and sampling (when required)
A description of any materials or accessories needed to perform the cleaning, such as non-shedding wipes or pressure jets
Detailed instructions for how to perform each cleaning step, including the critical cleaning parameters to be met and any materials or accessories to be used
Detailed instructions for the disassembly and reassembly of equipment, including sequence of disassembly and reassembly, bolt tightening patterns, torque specifications, and return to service leak checks
Similarly, swab sampling and line clearance procedures often do not instruct personnel on how to perform consistent swab sampling or lack enough detail to conduct thorough and repeatable inspections. Key details such as the swab pattern, application of even pressure, frequency of flipping the swab head, and when to saturate or express the swab head prior to beginning sampling are essential to ensure repeatable swab sampling. Line clearance procedures and checklists should, at a minimum, provide detailed instructions on the level of disassembly needed to properly access and inspect the equipment, including all hard-to-clean areas, and verify that the equipment is free from residue or damage that may cause residue buildup.
References: [14][16][18]
#6 - Cross-contaminated equipment
Visible residue, such as powder, observed on clean equipment that is later confirmed to be previous product through analytical analysis, indicates a major cleaning failure. When addressing this type of observation, it is essential to conduct a comprehensive review of the cleaning program, as such failures often result from multiple ineffective controls.
Based on Mindful Quality’s industry experience in evaluating company cleaning programs, the main cause of visible residue on cleaned equipment is usually due to one or more of the following:
Misclassification of direct and indirect product-contacting equipment surfaces during cycle development.
No established written cleaning procedure, or there is insufficient detail or a lack of critical cleaning parameters in cleaning procedures and associated cleaning records.
No established or insufficient detail in visual inspection and line clearance procedures to verify equipment cleanliness.
Cleaning validation was not challenged under actual worst-case conditions allowed during manufacturing (e.g., no DEHT or lack of campaign length).
Inadequate grouping strategies resulting in equipment or products not being evaluated as part of the validation.
Insufficient ongoing monitoring of the validated cleaning process to detect process drift over time.
Insufficient training and qualification programs to enable operators to clean or evaluate cleanliness in a reproducible manner.
Failure to investigate visible residues after validation due to allowing clean until clean practices.
Inadequate assessment of variability in cleaning validation results in relation to the established acceptance criteria.
References: [13][14][23]
#7 - Insufficient deviation investigations
When cleaning deviations occur, it is essential to thoroughly investigate them and implement effective corrective and preventative actions (CAPA) to minimize the risk of recurrence. Observations generally include:
Failure to assess the risk of cross-contamination for all affected batches when cleaning is inadequate
When a cleaning failure occurs in a multi-product facility and there is potential risk of cross-contamination, it is critical to identify and quantify the residue present. Justification for the scope of batches impacted should be documented and based on the last time the soiled equipment surface was confirmed to be clean through analytical testing or visual inspection.
Failure to initiate a deviation when a validated cleaning process fails to effectively clean equipment
If a validated process fails to properly clean equipment, a deviation should be initiated before performing recleaning activities. The investigation should determine potential root causes and appropriate CAPAs should be implemented to prevent recurrence.
Inadequate assessment of all potential root causes
For manual cleaning processes, it is common to blame the personnel for the failure without further examining contributing factors such as inadequate procedures (e.g., insufficient instructions or documentation of critical parameters) or lack of proper personnel training and qualification.
Implementation of CAPAs that fail to effectively prevent the recurrence of the failure
Initiating recleaning will remediate the failure of soiled equipment so it can be returned to service, but it will not prevent it from happening again. To put effective preventive actions in place, a thorough root cause investigation should be carried out. The process of investigating a cleaning failure varies between manual and automated cleaning processes, and the following should be evaluated:
For manual cleaning processes,
Review changes since last validation
Interview personnel to inquire about the cleaning performed
Review cleaning documentation from the failure
Review the level of detail in cleaning procedure
Audit the next cleaning
For automated cleaning processes,
Review the CIP cycle profile (including alarms) vs. baseline to look for drifts and trends
Review recipe and procedural changes since last validation
Interview personnel to inquire about manual set up or observations during cleaning
Once the most probable root cause is identified, preventive actions can be implemented to decrease the chance of it happening again.
Once implemented, CAPA effectiveness monitoring should be performed over a timeframe that allows for data from multiple cleaning activities to be evaluated. If a repeat of the failure occurs, this indicates that the original CAPA opened is not sufficient to address the root cause or the probable root cause was misidentified.
Failure to implement CAPAs in a timely manner
CAPAs should have a target completion date to ensure the actions are implemented promptly after the CAPA is initiated. The target date should be appropriate for the scope of the corrective action (e.g., revision of procedures vs. equipment design modifications). Quality management reviews should verify that CAPAs are completed on time to prevent repeated deviations.
References: [15][21]
#8 - Training
Effective cleaning, line clearance, and sampling depend heavily on properly trained and qualified personnel. In Mindful Quality’s experience, qualification programs for manual cleaning, visual inspection, and swab sampling often do not demonstrate or document the capability of personnel to perform the activity effectively and consistently.
Manual cleaning process qualification specifically should include on-the-job training (OJT) where personnel demonstrate their ability to perform each step properly. Mindful Quality’s memo, How to Train and Qualify Personnel on Manual Cleaning Processes, outlines this qualification process.
#9 - Analytical method validation
Analytical methods used to assess cleaning effectiveness (i.e., cleaning analytical methods) should be appropriate for their specific purpose [3][6][7]. Common validation issues observed by Mindful Quality include failing to demonstrate all necessary performance characteristics and not qualifying sampling methods through recovery studies.
When validating cleaning analytical methods, it is essential to have a well-defined procedure with requirements aligned with industry guidance. Sampling techniques (e.g., swab and rinse) should be qualified either during method validation or in a separate recovery study. Often, validation packages are inadequate because companies frequently conflate sampling recovery with method accuracy. For more information, read Mindful Quality’s memo, Why Your Cleaning Analytical Methods Might Not Be Validated.
In addition, it is important to use the recovery factor determined by the recovery study to adjust cleaning limits as appropriate. For example, if a swab method has a recovery factor of 65% and the cleaning limit established is 10 ppm, then the new cleaning limit should be 6.5 ppm.
Reference: [20]Reference: [12]
#10 - Inappropriate product & equipment grouping
Product and equipment grouping strategies can significantly improve cleaning validation efficiency if performed correctly. However, these strategies are often improperly implemented or do not have scientific rationale for the determination of the worst-case product or grouping of products and equipment, resulting in inadequate demonstration and a less than robust cleaning validation.
As mentioned in PDA (2012), ICH (2016), and ISPE (2020), during product grouping the worst-case representative should be selected based on the following characteristics:
Toxicity
Potency
Solubility
Cleanability
As mentioned in PDA (2012) and ISPE (2020), similar or identical equipment can be grouped based on the criteria below:
Design (configuration and material of construction)
Function
Cleaning procedure
A worst-case representative equipment from the group is selected typically based on capacity, size, and complexity.
Reference: [15]
Conclusion
Given the critical role of equipment cleaning in maintaining product quality and patient safety, cleaning will likely continue to rank among the FDA’s top observations. We should proactively evaluate our programs against the points above to strengthen our cleaning programs and to meet regulatory expectations.
References
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2009). ICH Q10: Pharmaceutical quality system.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2016). ICH Q7: Good manufacturing practice guidance for active pharmaceutical ingredients.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2024). ICH Q2(R2): Validation of analytical procedures.
International Society for Pharmaceutical Engineering (ISPE). (2020). Guide: Cleaning validation lifecycle - Applications, methods, and controls. ISPE.
Parenteral Drug Association (PDA). (2012). PDA technical report no. 29: Points to consider for cleaning validation. PDA.
United States Pharmacopeia (USP). (2017). <1225> Validation of compendial procedures. U.S. Pharmacopeial Convention.
U.S. Food and Drug Administration (FDA). (2015). Analytical procedures and methods validation for drugs and biologics: Guidance for industry. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2025). 21 CFR Part 211: Current good manufacturing practice for finished pharmaceuticals. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (n.d.). FDA dashboards - Inspections. United States Food and Drug Administration’s Data Dashboard. U.S. Department of Health and Human Services. https://datadashboard.fda.gov/oii/cd/inspections.htm
U.S. Food and Drug Administration (FDA). (2024, January 19). Form FDA 483: Brassica Pharma Pvt. Ltd. (FEI 3014129013), Plot No. T068, MIDC Tarapur, Boisar Thane, Maharashtra, India; inspection dates January 15-19, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, February 2). Form FDA 483: Jubilant Generics Limited (FEI 3006895982), Village Sikandarpur Bhainswal, Bhagwanpur, Roorkee, Uttarakhand, India; inspection dates January 25-February 2, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, March 19). Form FDA 483: Qualgen LLC (FEI 3011286349), 14844 Bristol Park Blvd, Edmond, OK, USA; inspection dates February 6-March 19, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, March 22). Form FDA 483: Second Tokushima Factory, Otsuka Pharmaceutical Co., Ltd. (FEI 3002807834), 224-18 Kawauchi-Cho, Tokushima, Japan; inspection dates March 13-22, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, April 5). Form FDA 483: Denver Solutions, LLC dba Leiters Health (FEI 3013438582), 13796 Compark Blvd, Englewood, CO, USA; inspection dates March 20-April 5, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, April 23). Form FDA 483: Zydus Lifesciences Limited (FEI 3013712903), Survey No. 434/6/B & 434/1/K, Vadoora-Halol Highway, Jarod, Gujarat, India; inspection dates April 15-23, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, June 21). Form FDA 483: Carie Boyd Pharmaceuticals (FEI 3010589333), 8400 Esters Blvd Ste 190, Irving, TX, USA; inspection dates May 28-June 21, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, June 21). Form FDA 483: Cipla Limited (FEI 3004081307), Verna Industrial Area, Verna, Salcette, Goa, India; inspection dates June 10-21, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, November 8). Form FDA 483: F.H. Investments Inc. (FEI 3010348724), 7004 Champion Blvd Ste 100, Birmingham, AL, USA; inspection dates October 28-November 8, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2024, December 20). Form FDA 483: SCA Pharmaceuticals, LLC (FEI 3013736415), 755 Rainbow Rd Ste B, Windsor, CT, USA; inspection dates December 2-20, 2024. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2025, May 3). Form FDA 483: Eugia Pharma Specialties Limited (FEI 3009883410), Unit-2, A-1228 & B-1127, Bihiwadi, Riico Industrial Area, Rajasthan, India; inspection dates April 25-May 3, 2025. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2025, June 13). Form FDA 483: Sun Pharmaceutical Industries Ltd. (FEI 3002809586), Halol-Baroda Highway, Halol, Gujarat, India; inspection dates June 2-13, 2025. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2025, June 19). Form FDA 483: NATCO Pharma Limited (FEI 3004540906), Pharma Division, Kothur Village, Rangareddy, Telangana, India; inspection dates June 9-19, 2025. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2025, September 5). Form FDA 483: Aurobindo Pharma Limited (FEI 3004446312), Unit XII, Survey No. 314, Bachupally, Hyderabad, India; inspection dates August 25-September 5, 2025. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration (FDA). (2025, September 5). Form FDA 483: Dr. Reddy’s Laboratories (EU) Ltd. (FEI 3002807544), Steanard Lane, Mirfield, West Yorkshire, UK; inspection dates September 1-5, 2025. U.S. Department of Health and Human Services.
Contributors: Jenna Carlson, Tim Cirbo, Alec Fufidio, Joanna Joseph, Helen Stranahan, and Harrison Sweeney
