Common Pitfalls During Implementation of a Cleaning Validation Program
Since the initial discussions on Cleaning Validation in the early 1990’s and even after the FDA Guidance was published in 1993, there has been a lot of confusion related to the application of the Cleaning Validation (CV) requirements in our industry. Some operations apply incorrect or ineffective approaches for the implementation of a CV program due to misunderstanding the purpose of validating cleaning procedures and/or taking an extremely conservative approach making for an impractical demand on resources. This article will cover some of the most common pitfalls/faults of a strategy for implementing a CV program.1 , 2
1. Starting the Cleaning Validation activities without an adequate and pre-approved plan or strategy
When a site decides (or is asked by regulators) to start a cleaning validation activity/program, their first thought is completing the effort quickly. At times that haste can lead to the development of protocols to complete the task without proper planification and strategy development. This causes execution of activities which may not be adequate, nor have value added, and, in the end, the company can spend time in totally unnecessary tasks. A helpful initial strategy is to develop a process flow for implementing the program.
Process flow includes the development of matrices for equipment/cleaning procedure combinations for those products being manufactured. It is acceptable to use product family grouping if applicable. This is a primary step to select the combinations of equipment/cleaning procedures including a worst-case product for each of the CV efforts defined by the CV protocols. For example, I worked at a facility with 2,000 drug product codes that were changing rather continuously. After developing these matrices, we came up with 16 combinations to be challenged with a specific CV protocol.
In some cases, equipment grouping approaches may also be applied. For example, we can select a piece of equipment (or a bracket composed of several pieces) to be challenged from a group of similar equipment when there are no differences between them beyond the size.
The next step is to answer the question of which component of the product will be used as the target for quantification of residues. Please note that using the term “product” is incorrect when quantifying finished drug formulations.
Based on this selection, work can start on finding the analytical methods to be able to quantify residue levels of these target components. To support this effort, the acceptable limits for the residues (also called Maximum Carryover or MACO) must be established so that the methods will be accurately quantify residue levels below the limits.
Parallel to the development/validation/verification of the analytical methods, the equipment cleaning procedures must be reviewed to determine if they are sufficiently detailed, include all necessary critical parameters (times, temperatures, contact times, flows/pressures) and that personnel are properly trained on their execution. Especially for manual cleaning procedures, the accuracy and completeness of details on the documentation are critical for demonstrating consistency and ensuring that the process can be considered “validated” for each step. Remember, if a cleaning agent is used, then the cleaning agent residues must also be considered for the development of an analytical method for testing those residues. The cleaning agent supplier can provide support in this task.
The training program/process for the cleaning procedures must be reviewed and revised as necessary to incorporate adequate levels of challenges and qualifications to properly conduct the cleaning. In addition, approaches for the testing of dirty and clean hold times needs to be established.
Once all of these steps are well on their way to execution, specific CV protocol(s) can be established where each document represents the challenges for an equipment/cleaning procedure combination with a worst-case product(s) already selected.
2. Pre-requisites must be identified before starting the execution of a specific cleaning validation activity/protocol
As stated above, the pre-requisites for the CV program must be established early and, in addition, they must be verified, and such verification must be documented within each CV protocol execution. These establishments must be in effect before any testing can be started. The pre-requisites that must be verified within each CV protocol include:
- Equipment design that is adequate for the applied cleaning procedure. For example, a CIP application will require certain conditions on the equipment design to be considered adequate. If a CIP system is installed permanently, was this system qualified? If a stand-alone CIP skid is used, the same question applies. The question in terms of the adequate design also applies to the CIP skid itself.
- Analytical methods were validated/verified for the selected target components and the cleaning agent formula component (if applicable). The methods can quantify the target components with a limit of quantification which is lower than the limit for those residues. The equipment used in the laboratory are also qualified.
- The cleaning procedure is adequate, has all the details and required parameters and the documentation will provide evidence that the procedure was followed as written.
- Personnel were trained on the analytical methods, sample collection and the cleaning procedures as applicable.
- Calibrations of instruments used are current.
3. Cleaning Validation cannot be executed unless the procedures for cleaning are properly detailed and/or are being documented
In my extensive years of assessing cleaning processes and cleaning validation efforts, I have seen plenty of company representatives that do not understand the criticality of assuring an adequate cleaning procedure is implemented before a CV activity can start. In nearly every case such as this, the cleaning procedures needed to be revised. It is critical to understand how the cleaning steps, conditions/parameters, documentation were developed. In most cases, companies just apply a cleaning process that they are familiar with no program for development of the cleaning process. In one occasion, a company was using mineral oil as a “cleaning agent”. When asked to dismantle the recirculation lines from the mixing tanks, various residues came out as the lines had never been dismantled for cleaning. Fortunately, as of late more companies are starting to understand the importance of such efforts, though likely after spending lots of time/resources trying to validate a cleaning procedure that was not well defined. Some critical decisions in defining the cleaning procedures are:
- Is the cleaning done manually? If so, the procedure needs to be reviewed with a focus to ensure people will follow the steps consistently.
- If the cleaning is executed by an automated system, such as a CIP skid or permanently installed system? In this case the procedure needs to be reviewed from a different perspective including the operation of the system and the data to be collected/reviewed. Sometimes this equipment includes on-line measurement of TIOC and/or conductivity which can be used to monitor the cleaning process continuously.
4. Cleaning Validation is executed as a product-specific challenge
Many companies still conduct a cleaning validation strategy by conducting a CV study/protocol for each product. This is feasible in cases where there are just a few products but, more often it can be rather impractical (and nearly impossible) to conduct a CV study for each product. This is one of the main reasons to work on a strategy/plan early (see step 1 above) before starting any activity. Ask the question: – do we have to conduct a cleaning validation protocol for each product? The answer is NO. As stated above, the strategy is defined by first selecting the equipment/cleaning procedure combinations to be challenged. Then, the product(s) can be selected based on a worst-case approach or just to test every product – those will be the options.
5. Cleaning and Sanitization are combined into one process
Combining cleaning and sanitation into one process is common mistake. Even though we can say both cleaning and sanitization are combined in one step, the purpose of both steps are totally different. Some companies mistakenly believe that by combining the steps combined but leaving the equipment idle for a prolonged period is sufficient. This is not an adequate approach. Cleaning is concerned with removing the residues from the previous product (and the cleaning agent if applicable) using a worst-case dirty hold time. Sanitization is concerned with the condition of the equipment before it is used next, particularly from a microbial consideration.
Once it has been demonstrated that the cleaning is effective after the CV protocol execution using a worst-case dirty hold time, the fact that you are keeping the equipment idle for some time brings a set of totally different questions:
- How long the equipment is kept idle?
- Under which conditions is the equipment kept?
- How does this combination of idle time and storage conditions affect the microbial bioburden on the equipment surface?
As a good option, many companies are establishing a sanitization process/step before using the equipment again and this step is validated separately from the cleaning validation. Or, separately they may test for the microbial bioburden in the equipment surface after the worst-case clean hold time has elapsed to see whether a sanitization step is necessary. If test fails, the option will be to apply a sanitization step which could be as simple as a high purity water rinse or other more sophisticated processes such as a hydrogen peroxide rinse/application. Of course, these considerations will be affected by the type of product/process being manufactured – from a topical drug, oral solid dosage to the more critical sterile products, specifically those aseptically filled.
6. The Only chemical residues of interest are the API residues
In some cases, the residue of interest within a product formula or in the case of an API production facility will be the API itself, but not always. Other components of the formula must also be considered, and those may be more difficult to clean, could represent a more toxic material or may just be present in higher concentrations when compared to the API. In these cases, it is recommended to test both the API and the worst-case formula component based on those criteria.
7. Application of LD50 directly into the Toxicity MACO calculation
The residue limit calculation for toxicity is much more complex than most companies realize. It is not adequate to just take the LD50 value from a reference source or MSDS and insert that value into the formula with an arbitrarily selected empirical factor. The fact that this formula includes at least one empirical factor requires a detailed consideration which may force some high-level scientific analysis from a qualified expert such as a toxicologist. I suggest involving an expert if any of their formula components is considered to be relatively high-risk in terms of their toxicity.
8. Application of a process train concept when calculating surface areas and residue limits for all drug processes
Some industry experts say that you “MUST” apply a process train concept for any CV effort. But that concept may not be applicable in every situation. Particularly when calculating the total surface area for the entire process equipment train with consideration for the total residues for the entire train. For example, the process train concept will make sense if the cleaning is actually conducted as a “process train” which is not the case in most operations. Oral solid dosage product manufacturing, due to the numerous steps, does not allow the material to necessarily flow as a train from one step to the other.– In this case, and because the cleaning of each equipment is different, it is recommended to validate the cleaning of each equipment separately. The same situation applies to most filling equipment. The filled product will not flow from one process to the next directly, so the cleaning of the filler should be a totally separate process
9. Rinse samples are enough to demonstrate cleaning process effectiveness
The decision of whether rinse samples will be enough to demonstrate effectiveness of the cleaning procedure and that the residue levels have been reduced to acceptable levels depends on several factors such as equipment design/physical characteristics and formula components. Are there difficult locations where a rinse sample will not have contact with the area and a swab sample must be taken? Are the selected formula components totally soluble under the rinse conditions and the solvent/water being used for the sample?
The final decision will consider these questions and the risk implied by the product itself (injectable versus topical drug products)
10. Analytical Methods must be specific for the particular entity being measured as residues
This question has been addressed extensively in the industry, and the consensus is – it depends. If you can develop/find a non-specific method that can measure/quantify the residue of interest under the sampling conditions applied, you may be able to use this method. This decision will reduce the time necessary for conducting your CV program by a considerable factor. Another reason to consider using a non-specific method is just the practicality for some operations where developing and validating a specific method for each residue will imply extensive time/resources which they may not have, and the value added by such efforts is not commensurate to the resources applied.