Ten most common cleaning validation mistakes!
2026-03-15
This article presents ten of the most common cleaning validation errors, including:
1. Commencement of cleanup validation activities without a proper and pre-approved plan or protocol
2. Commencement of cleaning validation work until the necessary preconditions are determined
3. Cleaning procedures are not sufficiently detailed and/or documented to support cleaning validation.
4. Conduct cleaning validation tests for each product
5. Combine cleaning and disinfection into one process
6. Consider only API residues when assessing chemical residues
7. Direct application of LD50 in MACO toxicity calculations
8. The need to apply the process flow concept when calculating surface area and residue limits for all drug manufacturing processes
9. Sufficient rinse water to confirm the effectiveness of the cleaning process
10. The need to use analytical methods specifically designed for the residues to be analyzed
Common Mistakes When Implementing Cleanup Validation Plans
Introduction
Since the initial discussions of cleaning validation in the early 1990s, even after the publication of FDA guidance in 1993, there has been considerable confusion in the application of cleaning validation (CV) requirements. Some businesses use incorrect or ineffective practices when implementing CV programs due to misunderstanding of cleanliness testing procedures and/or taking an overly conservative approach that places unrealistic resource demands. This article will explore some of the most common pitfalls and shortcomings in CV program implementation strategies.
1.Initiation of cleanup validation activities in the absence of an appropriate and pre-approved plan or flowchart
When a plant decides (or is required by regulators) to begin a cleaning validation activity/program, the first thought that comes to mind is to complete the job as quickly as possible. Acting too quickly results in developing a plan to complete a task without proper planning and strategy. This can lead to activities that are not fully implemented and do not bring added value, and ultimately the company wastes time on completely unnecessary tasks. It is good practice to develop a process for implementing this plan.
The manufacturing process is a matrix that includes all combinations of equipment and cleaning procedures used to produce all manufactured products. If necessary, you can use grouping by product lines. This is the main step in selecting combinations of equipment and cleaning procedures (including the worst performing products for each CV task defined in the CV design). For example, I work at a factory where 2000 types of drugs are produced, the range of which is constantly changing. After developing these matrices, we proposed 16 combinations to test using a specific CV design.
In some cases, the equipment grouping method can also be used. For example, we may select one device (or a combination of several components) from a group of similar devices for testing if there are no significant differences in size between them.
The next step is to answer the question of which product component will be the target for residue detection. Please note that when quantifying the formulation of a finished product, the use of the term “product” is incorrect.
Based on this selection, one can begin to search for analytical methods that can determine the residue levels of these target components. To do this, it is necessary to establish acceptable residue limits (also called maximum carryover limits or MACOs) so that these methods can accurately detect residues that do not exceed the established limits.
At the same time as analytical methods are developed/validated/validated, equipment cleaning procedures should be reviewed to determine whether they are sufficiently detailed, include all required key parameters (time, temperature, contact time, flow rate/pressure), and whether personnel are adequately trained to perform them. Particularly for manual cleaning procedures, accuracy and completeness of detail in documentation is critical to confirm compliance and ensure that each step of the process is considered “validated.” It should be remembered that when using detergents, detergent residues must also be taken into account, which requires the development of analytical methods to detect them. Detergent suppliers can provide support in this regard.
Cleaning training programs/procedures should be reviewed and refined to include the appropriate level of difficulty and testing required to properly perform cleaning. In addition, it is necessary to develop methods to test the contamination retention time and the cleanliness retention time.
Once all of these steps have been successfully completed, specific CV designs can begin to be developed in which each document will reflect the level of complexity appropriate for the combination of equipment and cleaning procedure with the worst-case product selected.
2. Before specific cleaning validation activities/programs can be carried out, prerequisites must be identified.
As stated above, the preconditions of a CV plan should be established as early as possible. In addition, these prerequisites must be confirmed, and such confirmation must be recorded in the documentation for each CV program. Prerequisites that need to be checked for each CV program include:
Compliance of equipment design with the cleaning procedure used. For example, for CIP it is considered sufficient that the design of the equipment meets certain requirements. If a fixed CIP system is installed, has it been validated? The same applies to the use of stand-alone CIP modules. The requirements for proper design also apply to the CIP modules themselves.
Methods for analysis of selected target components and detergents (if applicable) have been validated/validated. These methods can detect target components with detection limits below the cutoff value for these residues. The equipment used in the laboratory has also been validated.
The cleaning procedure is adequate, contains all the details and parameters required, and is documented to confirm that the written procedure has been followed.
Personnel have been trained in analytical methods, sampling, and cleaning procedures (if applicable).
All instruments used are calibrated.
3. Verification of cleaning effectiveness is not possible unless the cleaning procedure is sufficiently detailed and/or documented
In my many years of work evaluating cleaning processes and verifying cleaning, I have encountered many company representatives who do not understand the importance of ensuring that proper cleaning procedures are in place before starting cleaning verification activities. In almost all cases, changes to cleaning procedures were required. It is critical to understand how purification steps, conditions/parameters, and documentation are developed. In most cases, companies simply use their usual cleaning processes without developing a cleaning plan. One company once used mineral oil as a “detergent.” When the mixing tank recirculation piping needed to be removed, various residues leaked out because the piping had never been removed for cleaning. Fortunately, more companies have recently begun to understand the importance of this work, albeit after having spent a significant amount of time and resources attempting to validate ill-defined cleaning processes. Some key decisions when determining cleaning procedures:
Is cleaning done by hand? If so, the procedure must be carefully reviewed to ensure that personnel can follow all steps in a consistent manner.
If cleaning is carried out using automated systems such as CIP modules or stationary installations? In this case, it is necessary to analyze the procedure from different points of view, including the operation of the system, as well as the data that needs to be collected and verified. Sometimes such equipment is equipped with online TIOC and/or conductivity monitoring systems that can be used to continuously monitor the cleaning process.
4. Conduct cleaning validation tests for each product
Many companies still conduct research/develop CV programs for each product. With a small number of products this is possible, but more often than not, conducting CV studies for each product can be very impractical (and practically impossible). This is one of the main reasons why it is necessary to develop a strategy/plan at a very early stage, before any action is taken (see step 1 above). Ask yourself: - Should we conduct a cleaning testing program for each product? The answer is no. As mentioned above, the strategy is to first select the combination of equipment and cleaning procedures that will be tested. Products can then be selected based on the "worst case" method, otherwise each product will need to be tested.
5.Combining cleaning and disinfection into one process
Combining cleaning and disinfection into one process is a common mistake. Although cleaning and disinfection can be said to be combined into one step, the purposes of the two steps are completely different. Some companies mistakenly believe that after combining the two stages, equipment may be idle longer. This is not good practice. Cleaning is aimed at removing residues of the previous product (as well as detergent) while maximizing the time spent in a dirty state. Disinfection is related to the condition of the equipment before the next use, especially from a microbiological point of view.
Once the CV program has proven that cleaning is effective at maximum residence time, the fact that the equipment has been idle for some time will lead to a whole new set of problems:
How long does the equipment remain idle? Under what conditions is it stored?
How does this combination of downtime and storage conditions affect the microbiological load on equipment surfaces?
As an optimal solution, many companies develop disinfection procedures/steps before equipment reuse that are validated separately from cleaning validation. Or, after the cleanliness period has expired under worst-case conditions, they can separately test the microbiological load on equipment surfaces to determine the need for disinfection. If the test fails, disinfection measures are applied. Of course, these considerations will depend on the type of product/process being manufactured (ranging from topical drugs, solid oral medications, to more critical sterile products, especially those undergoing sterile filling).
6. When assessing chemical residues, only API residues are taken into account
In some cases, the residues that need to be accounted for in a product formulation or API manufacturing facility will be the API itself, but this is not always the case. There are other components to consider that may be more difficult to purify, more toxic, or simply present in higher concentrations than the API. In such cases, it is recommended that worst-case scenario analyzes of the API and formulation components be performed based on these standards.
7.Direct use of LD50 in calculating maximum permissible concentration (MACO)
Calculating maximum permissible concentrations is much more complex than most companies realize. It is not enough to simply take the LD50 value from reference sources or a material safety data sheet (MSDS), plug it into a formula, and use an arbitrary empirical factor. In fact, this formula includes at least one empirical coefficient, which requires careful consideration by highly trained scientific analysts such as toxicologists. If the toxicity of any component of the formulation is considered to be relatively high, it is advisable to involve experts.
8. The process flow concept should be applied when calculating surface area and residue limits for all drug manufacturing processes.
Some industry experts argue that the process chain concept "must" be applied. However, this concept may not be applicable in all cases. In particular, when calculating the total surface area of the entire chain of processing equipment in order to take into account the total amount of residues along the entire chain. For example, the concept of a process chain makes sense if refining is actually carried out as a “process chain,” which is not the case in most cases. Since cleaning each device is different, it is recommended that you check the cleaning of each device separately.
9. Is there enough rinse water to confirm the effectiveness of the cleaning process?
The decision as to whether there is sufficient rinse water to confirm the effectiveness of the cleaning procedure and reduce residue levels to an acceptable level depends on several factors, such as the design/physical characteristics of the equipment and the composition of the product. Are there hard-to-reach areas that the rinsing water cannot come into contact with and need to be cleaned with cotton swabs? Are the selected components of the drug completely soluble under washing conditions?
The final decision will be made taking into account these issues, as well as the risks associated with the product itself (injectables and topical products).
10. The method of analysis must be specific to the residues being tested.
This issue is widely discussed in the industry, and the general consensus is that if a non-specific method can be developed or found to detect or calculate target residues under the sampling conditions used, then that method can be used. This solution will reduce the time required to complete the CV plan, which has a significant impact. Another reason to consider using a non-specific method is that for some operations, developing and validating a specific method for each residue will require a significant investment of time and resources that they may not have, and the added value of this work will be disproportionate to the resources required.
