The Changing Landscape of Cleaning Validation—A Medtech Makers Q&A

By Sean Fenske, Editor-in-Chief

There are a variety of rules and regulations that must be followed for any country or region in which a device maker wishes to market a product. While a cleaning validation is just one aspect of the process, it can directly impact patient safety and, therefore, must be addressed vigorously. Further complicating the matter is potential changes to ISO 19227, which is going through an update.

As this complicated process is so critical to the success of a medical device, manufacturers need to partner with companies that have a thorough understanding of the ISO standard and have established best practices for its implementation. In addition, keeping track of all aspects of the touchpoints that can impact a cleaning validation presents further challenges. Again, with close interaction with a company maintaining this expertise will help ensure a smooth pathway to compliance.

Fortunately, a representative from one such company—Matthew Homuth, Sr. Validation Engineer at Cretex Medical | QTS—took time to answer a number of questions around cleaning validation. In the following Q&A, Homuth explains what a cleaning validation is, the impact ISO 19227 has, and where companies often come up short on their own cleaning validations.

Sean Fenske: Can you please explain what a cleaning validation is and what the difference is between cleaning and sterilization?

Matthew Homuth: Cleaning validation (CV) is a data-driven process validation with the final intent of ensuring consistent final residues prior to final packaging and sterilization. Cleaning validation is also a critical input to the biocompatibility evaluation. Assurance of biocompatibility is only possible if device residues are consistent.

While final cleaning is often the focus, design and validation of in-process cleaning is equally critical. Unvalidated in-process cleaning can result in highly variable residues leading into the final clean, which can then lead to increased variability in the device prior to final packaging. Thus, the capability of all critical cleaning processes directly impacts the assurance of patient safety.

Sterilization and cleaning are related but have different outputs. Cleaning is focused on the removal of contamination. Sterilization, however, aims to inactivate infectious microorganisms. While the focus of cleaning validation is typically material-related residues, the effectiveness of cleaning processes to control microbial contaminants is also important. Microbial reduction is typically accounted for during the sterilization validation. Devices used to evaluate the sterilization process must be manufactured using the validated cleaning process(es). Consistency of post-clean microbial residues is essential for sterility assurance. Only with consistent microbial residues as an input can the sterilization process be effectively designed and validated.

Fenske: What ISO standard should be used when developing a cleaning validation for a medical device? What’s covered in this standard?

Homuth: Newly developed consensus standards such as ISO 19227:2018 and ASTM F3127-22 (initially published in 2016) establish the current principles for cleaning process validation and continued process monitoring. Some of these principles are guided by good manufacturing practices, and others are based on risk analysis (see ISO 14971).

Per ISO 19227: “As part of the risk management, the cleaning process shall be evaluated for the measures that are necessary to achieve an intended level of cleanliness…”

This means that as part of the cleaning validation, we must demonstrate that we have considered all variables that can impact the capability of the process. For example, as part of the design phase, there should be documented justification as to why the cleaning process is expected to be effective at removing all residues that have been identified as potential hazards. If we simply use our “standard” cleaning process (i.e., put parts in a basket and clean with detergent), we may miss documenting that the devices need to be fixtured in a certain orientation to be effectively cleaned.

The standard goes on to discuss:

• Device design: Consideration of features that are a challenge to the cleaning process or that may be adversely impacted by the cleaning process itself.
• Sampling: Historically, process capability was not as widely scrutinized for CVs, which set the bar low for sample size expectations. ISO 19227 hints at statistical sample sizes, but in our experience, capability analysis is expected unless otherwise justified.
• Sample manufacturing: Sample devices should be manufactured, cleaned, and packaged in a manner that represents the expected manufacturing process, including environmental conditions.
• Test methods: Based on the evaluation of contact materials, test methods are provided that will quantify target residues. Analytical considerations such as extraction qualification and detection limits are also discussed.
• Acceptance criteria: Although very limited, there are suggested starting points for residue limits. ISO 19227 points to NF S94-091 as the source of the specified limits. To date, there are no clear expectations for residue limits for cleaning validation. Both ASTM and ISO are developing additional guidance for residue limits in cleaning validation, although any such publication is likely to rely heavily on toxicological assessment.
• Process monitoring: Cleaning directly impacts the clinical safety and efficacy of a device. Thus, the process must be monitored.

Fenske: What methods are used to test whether the validation accomplishes what’s required?

Homuth: Test method selection is dependent on the expected types of residues and the established acceptance criteria. Expected residues are determined as part of the contact material assessment; we need to determine which residues are most likely to remain on the device prior to going through the final cleaning process. Detection capability is another factor for method selection; test methods need to have enough sensitivity to report data that is below the established residue limit.

A factor that is not talked about (much) as part of method selection is the capability to use the data for the determination of process capability. Using test semi-specific methods that target certain residues, such as total organic carbon and total hydrocarbons, often results in data that is below the limit of detection (LOD). While an LOD result shows that the process is effective in removing the targeted material type, it misses other residues that are outside the method’s detection capability. Performing statistical analysis on a stacked data set is not value-added.

For this reason, we suggest using non-specific tests like gravimetric analysis, which quantify all extracted materials. With this approach, data is much more likely to produce variable data that is quantifiable, which allows for more meaningful evaluation of process capability. The residue limits for these types of analyses will generally be higher as they represent a total residue mass rather than a fractional mass that would be associated with a targeted analysis.

ISO 19227 suggests the following (targeted) test methods:

• Bioburden
• Endotoxin
• Total Orgain Carbon
• Total Hydrocarbons
• Inorganics
• Particulates
• Cytotoxicity

Fenske: What’s the impact on regulatory oversight from ISO 19227? Does following it ensure compliance with regulatory guidance worldwide?

Homuth: In general, ISO 19227 requirements are what medical device manufacturers will be held to for cleaning validation. Other standards, such as ASTM F3127—Standard Guide for Validating Cleaning Processes Used During the Manufacture of Medical Devices—provide valuable information not incorporated in ISO 19227. From my view, the ASTM document, being a guide, is less prescriptive and provides greater detail to help the user during process development. ISO dives deep into how to make risk-based decisions, so the user can interpret the minimum requirements for CV. The ISO standard is more widely used as it is the result of international collaboration. Keep in mind that the documents aren’t mutually exclusive. Guidance from ASTM F3127 may be used to comply with ISO 19227.

Fenske: ISO 19227 is currently under revision, and the new edition will replace the current 2018 version. What aspects need to be revised, and/or where is the standard lacking?

Homuth: The current version of 19227 provides a decision-making blueprint for designing a cleaning validation. It is heavily based on risk-related decisions since there are limitless different combinations of residues that can end up on a device. 19227 exemplifies how difficult it is to template the design of cleaning validation.

I would like to see a few changes to the standard:

• Provide greater detail on the expectations for process capability analysis. The current wording seems to be an artifact of old CV assumptions (test a few parts and compare each to the residue limit).  We need to establish that CV is a process validation that should include standard statistical capability evaluation.
• Broaden the test method tool bucket. The current list of methods is heavily focused on mitigating the risk of known contaminants. I suspect biocompatibility was the primary factor in the development of the first version. We need some tests that are better tools to assess process capability, like gravimetric analysis.
• Provide more information on the development of residue limits. In the absence of clinical data (i.e., smaller or start-up firms), establishing limits can be very difficult. Access to toxicology data and evaluation thereof can be prohibitive.

Fenske: Where do companies fall short when it comes to a cleaning validation? What steps are missed or overlooked? What are the most common omissions or mistakes based on your observations and experience in assisting manufacturers in performing cleaning validations?

Homuth: We see a lot of instances where the design of the cleaning process is overlooked. Assuming that the “standard” process will work can end up in a lot of additional effort. Some things to consider:

• Process Controls: This is the number one failure in most regulatory reviews. Failure to establish these as minimum process controls will likely result in an audit finding.
  • Bath Life: A set limit of devices or surface area that can be cleaned before solutions need to be refreshed.
  • Fixture Loading: Define fixture, loading instructions, and maximum allowable load per fixture.
  • Routine Monitoring: Testing to verify ongoing process capability.
• Contact Material Assessment: All contact materials should be identified and assessed for risk as part of the CV design. This should be documented in the CV.
• Ultrasonic Agitation: This method is great in some situations, but is not universally effective. Time, total energy, form, and wavelength all greatly impact the effectiveness of agitation. Too much energy and you may shake off the good stuff; too little and you may not reach all surfaces. If there is a void in the device, a pulse form may be needed to allow for solutions to move in and out.
• Lack of Justification for Design Decisions: In other areas, such as sterilization and packaging, there are defined validation requirements. With that, the rules for setting acceptance criteria and sample size are clearer. Due to the complexity of the risk assessment associated with CV, the process owner needs to justify decisions in the CV protocol rather than just citing a standard.

Fenske: Do you have any additional comments you’d like to share based on any of the topics we discussed or something you’d like to tell medical device manufacturers?

Homuth: Cretex Medical | QTS actively participates in the development of industry standards. This allows us to understand where the industry is headed. We can help OEMs make decisions not only based on current expectations, but also on where the industry will be.

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