Modalities, Timelines & Tips: What Manufacturers Need to Know About Tissue Sterilization Validation

By John Neville, Ph.D.

The FDA requires medical device manufacturers to demonstrate the sterility of their products. Whether a device functions in vivo or in vitro, sterility is crucial to ensuring patient safety and maximizing device functionality.

No product or process can prove that all potentially harmful organisms have been removed or destroyed. That is why sterilization validation experts try to achieve a sterility assurance level (SAL). A device’s SAL is the probability of a single viable microorganism occurring on an item after sterilization. The most common SAL of 106 denotes the chance of a viable microorganism being present on the sterilized device is less than one in a million.

The sterilization validation process for most medical devices is the same—conduct bioburden testing, establish verification dose and validate with sterility testing. But when the product is tissue, fully understanding the bioburden becomes even more paramount. Eliminating bioburden can literally mean the difference between life and death.

It’s critical to remember that the products the tissue processors receive are gifts and not always available when needed or in the quantities required. Somebody’s loved one donates a part of themself to help recipients who have suffered a profound injury or disease. That’s why the bonds made in the tissue community—from donors and recipients to processors, researchers and regulators—are often powerful. And it’s what makes the work so rewarding.

From the nuanced work to the limited samples to the sensitivity of the process, it is essential manufacturers ensure their partners share the same mindset before starting tissue sterilization validation.

Tissue Sterilization Validation Modalities

Several modalities are used to sterilize tissue—i.e., heat, chemicals, irradiation or other novel means—each with its own mechanism, post-sterilization effects and efficiency. Gamma radiation is the most common for medical uses and has the longest track record of success. It is a particularly effective modality because it addresses a wide variety of bioburden.

Establishing and validating the radiation dosage according to standards outlined in guidelines from the Association for the Advancement of Medical Instrumentation (AAMI) is critical to achieving the lowest possible bioburden. Matching a tissue allograft with the appropriate sterilization modality typically comes down to material compatibility—essentially the modality’s impact on the tissue, while still eliminating the bioburden.

A noteworthy alternative to gamma sterilization is electron beam (e-beam) irradiation. E-beam sterilization requires placing products on a conveyor belt and exposing them to a field of machine-generated accelerated electrons. Technicians then calibrate the conveyor belt to achieve the desired sterility assurance level.

E-beam has been used for several decades to sterilize sutures, gloves, gowns, masks, etc., but has only recently gained momentum in tissue sterilization. E-beam doesn’t allow for the same volume of products as gamma does, but e-beam’s advantages include reduced cost, quicker turnaround times and fewer environmental concerns. Gamma irradiation has proven effective for decades, but e-beam is gaining traction as an alternative.

Understanding Timeline Sensitivity in Tissue Sterilization Validation

The number of sources that may add to the bioburden of the donor’s microflora is endless. Contributing factors may include the raw materials used to clean or package the product, the environment in which the product was processed or collected, and the geography or seasonal differences between locations.

Understanding the bioburden level is one of the most important steps in tissue sterilization validation. Establishing bioburden includes microbial identification and characterization, i.e., aerobes, anaerobes, fungi, spore formers, etc. Once the bioburden level is determined, the dose level is substantiated and becomes the cornerstone of the subsequent dose audits. Dose audits are like miniature validations and are initially required every quarter.

Measuring bioburden levels can often include dilution factors and/or correction factors that may add steps and increase the likelihood of confusion. These steps could potentially reduce the limit of detection of the bioburden tests, causing a slight increase in bioburden to result in a failure. Bioburden methodology, dose level and sterility methods each become part of the protocol written to ensure proper dosing. The less ambiguous or confusing the protocol, the easier it is to monitor the methods and processes, and the safer the product is for patients.

A lengthy but crucial component in tissue sterilization validation is the dose substantiation study. This step attempts to determine the minimum level of radiation needed to achieve the desired SAL.

The study can take up to three months, but it helps set the roadmap for validating sterilization dosage. Tissue sterilization validation usually includes writing a customized protocol for each product, working with a testing laboratory and establishing a place in line at the irradiator. The overall timeline might be fluid if there are new tissue products in the process for which bioburden has not been previously established. Manufacturers can begin lot testing once the dose substantiation study is complete and the sterility assurance level is established. For a tissue manufacturer, that might mean working with several donors and conducting multiple recoveries.

Once a specific product is validated, it is monitored through quarterly dose audits, which rarely leave room for error. A single failed audit can be an anomaly, but failing two of them could require revalidation. That could mean dissecting and rebuilding a validation process from the ground up. Failing two dose audits can add significant delays to any product release date.

Between writing custom protocols, weaving together laboratory, donor and irradiator schedules, and navigating dose audits, tissue sterilization validation requires time and patience. Manufacturers cannot overlook the importance of planning carefully and budgeting for delays.

Pain Points in Tissue Sterilization Validation

Effective time management is crucial during tissue sterilization validation. If timelines are too tight or, potential delays are ignored, managing the timeline will quickly become the most significant pain point any manufacturer faces. Period.

Even if manufacturers give themselves plenty of time to complete all the necessary steps, there are still a few things to consider to keep the validation running smoothly.

  • Sample availability. This should be every manufacturer’s primary concern. Tissue samples are very limited, and the length of time it might take to replace a tissue product if lost or wasted is uncertain. It’s best to handle all tissue products with extreme care and budget resources, assuming a level of attrition.
  • Know the product. Different types of tissue can have different bioburden levels. Certain genus of microorganisms can be more or less resistant to radiation. Tissue recovery and quantification can add unforeseen bioburdens. Certain tissue types may have shorter expiration dates after processing. Knowing these details before beginning will provide the best opportunity to eliminate problematic microorganisms.
  • Transportation & timeliness. Within the contiguous United States, transportation is typically not a concern. Stringent measures are in place to ensure any recovered tissue products arrive at their destinations intact. That said, working with a laboratory partner that is prepared to receive and process material quickly and appropriately will help safeguard delicate products.

The Bottom Line

The numerous requirements and nuances to tissue sterilization validation mean manufacturers can’t afford to wait. Validating tissue sterilization can have dramatic downstream impacts, especially if product revalidation is necessary. Planning for unforeseen delays will be the most valuable step manufacturers take in their validation journey.

For these reasons, tissue sterilization validation is an incredibly unique and rewarding process. Given the personal nature of tissue donation, sterilization professionals who recognize the volatility of the work and respect its sensitivity will be valuable assets. Overall, manufacturers need a conservative mindset and skilled partners who draw from past experiences to ensure a successful tissue validation program.

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