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Developing a Robust Cleaning Validation Process

A proper cleaning validation lifecycle minimizes risks to product quality and ensures regulatory compliance

TJ Woody

TJ Woody is the director of cleaning validation at Azzur Group

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Equipment cleaning in pharmaceutical manufacturing is essential for preventing cross-contamination on equipment surfaces. Product, cleaning agent, and microbial residues above acceptable limits can impact patient safety and cause critical equipment downtime. Although it is not a consistently used process, given the additional cost and labor involved, embracing a standardized cleaning methodology puts companies on the trajectory for a successful cleaning validation program.

Companies that struggle with poor cleaning processes face visual, chemical, and microbiological failures that may compromise product quality, potentially harming those who take the medications, and threaten regulatory compliance, putting the company's reputation on the line. Failure also results in additional labor costs, effort, and time to investigate the cleaning issues and reclean the equipment, as well as product losses. 

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While many companies jump right into validating a cleaning process, the proper route to success is to develop the cleaning validation lifecycle. In doing so, companies take a science-based, data-driven process to develop and optimize the cleaning. Investing in the development of the cleaning process from the very beginning will save time, money, and labor.

Trust the TACTful approach

Some pharma companies do not fully understand cleaning validation. There is a method to the process, however. Cleaning validation can be broken down into two main pillars: determining the carryover acceptance criteria and cleaning the manufacturing equipment.

When looking at the acceptance criteria established by the industry and regulatory bodies, it is critical to determine the basis for the product, cleaning agent(s), and microbial carryover limits. The industry and regulatory agencies expect that safety-based parameters, which consist of Acceptable Daily Exposure (ADE) and Permitted Daily Exposure (PDE) values, must be determined by the company when evaluating product and cleaning agent carryover limits. If these measurements are not used, there has to be a reasonable rationale for not being used in the carryover limits.

As soon as the carryover limits are established, targets for the cleaning process should begin in the lab on representative equipment materials of construction (MOCs), otherwise known as coupons. It is crucial that the cleaning focuses on critical cleaning parameters (CCPs), which are identified by the acronym TACT (Time, Action, Chemistry, and Temperature).

Time includes durations for the hold (dirty and clean), rinse, and wash times. Action refers to the type of cleaning process, which can consist of impingement, soaking, rinsing, ultrasonics, and manual cleaning. Chemistry refers to the cleaning agent(s) and concentration used during the process. The final aspect to consider is the temperature of both rinse and wash steps.

Test runs in the labs—cleaning development

In the lab, representative products are used to soil the coupons in a defined manner and held for a set time. This period represents the dirty hold time (DHT).

Once the DHT has ended, a cleaning process is performed that represents the targeted manufacturing equipment cleaning process. The results of the coupon cleaning can be evaluated in a number of ways including visual inspections and through water break free testing. A water break free test is used to check that a surface is clean when rinsing the coupon’s surface with water after cleaning. If the surface is not clean, the flow of water across the surface will be disrupted by any contaminants.

If a product analytical method has validated sampling techniques including swab or rinse recovery, the coupons can be sampled using these techniques after cleaning to obtain actual test results. This data can be correlated to the targeted product carryover limit to determine the level of cleaning effectiveness. 

It is important to note that these lab studies can be repeated quickly to develop the preliminary CCPs. Multiple lab cleaning tests should be done to evaluate and detect the different parameters for the cleaning process. Additionally, different cleaning agents can be trialed in various concentrations to the type of product residue being cleaned. One rule of thumb is to start simple and add complexity only when the data calls for it. The generally preferred method is that if water alone cleans the product residue, then the process should use only water. When it comes to developing cleaning processes, more complexity doesn’t equal more compliance.

Documentation is key in the cleaning validation process including the manufacturing equipment MOCs. All equipment surfaces coming into contact with product or cleaning agents should be documented. These surfaces include unique elastomers that may be on tanks and vessels. During the development phase, all cleaning agents and materials of construction (MOCs) need to be researched/tested, to ensure compatibility and that there are no unforeseen issues.

Once the lab trials are complete, the identified preliminary CCPs are then tested on actual manufacturing equipment. This implementation will further develop and optimize the cleaning processes.

Test runs on manufacturing equipment—cleaning verification

Cleaning verification follows in the same footsteps as cleaning validation, in that it has the same product, cleaning agent, microbial acceptance criteria, validated analytical methods, and release criteria. What differs is that each cleaning verification trial or process needs to be sampled and tested to ensure it meets the acceptance criteria along with visual inspections of equipment surfaces. The results from the tests enable alterations to be made to the process, to further optimize the cleaning to meet the targeted acceptance criteria. Targeting and optimizing specific aspects of a cleaning process is key to cleaning verification methodology.

The cleaning verification process is dependent on the results and how they relate to the carryover limits.  The number of trials or cleaning events will vary on these factors. Once the results are well below the limits needed, optimization of the cleaning process comes into clear view as the next question.

A general rule of thumb is that an optimized cleaning process entails the shortest cleaning and drying times to achieve acceptance on visual, product, cleaning agent, and microbial test results. Additional time can be allotted to optimize cleaning steps if variability is expected in the cleaning process. This is common when manual cleaning processes steps are used during the process. Once a cleaning process has been optimized, a report is generated outlining the CCPs that will be validated in the next stage. Validation is completed using defined cleaning processes outlined in cleaning recipes or standard operating procedures (SOPs) derived from the developmental cleaning trials. This type of methodology ensures that cleaning validation and the cleaning processes will be robust based on the successful developmental efforts.                             

The end goal

Cleaning development is the most essential phase in the cleaning validation lifecycle (see Figure 1), as it accounts for the majority of the time sunk into the process—yet companies often give this phase the least amount of attention.

Chart illustrating breakdown of cleaning validation efforts
Figure 1: A typical breakdown of cleaning validation efforts
Credit: TJ Woody, Azzur Group

Proper development of a successful cleaning validation lifecycle takes time. Companies must step back and invest in proper cleaning development both in the lab and manufacturing floor to develop and optimize cleaning processes. By making the investment in developing the cleaning process, its validation will be robust and, more importantly, the process will be optimized for manufacturing ultimately saving companies time, money, and labor. These actions will also provide assurance of safety for the patients using these products.