Sterilization: How to Validate Novel and Non-Traditional Processes

This article summarizes the process for validation of novel and non-traditional sterilization processes, and is intended for those who are already familiar with traditional sterilization methods, such as gamma irradiation and ethylene oxide sterilization.

Many devices are sensitive to the heat of steam sterilization and ethylene oxide sterilization, while gamma and e-beam sterilization cause degradation of certain plastics and adhesives. For example, when ultra-high molecular weight polyethylene (UHMWPE) is exposed to gamma irradiation in the presence of oxygen, super-oxides are formed and become trapped in the plastic. Superoxides are responsible for oxidative degradation of UHMWPE implants over time, and results in premature failure. This is why companies developed sterilization processes based upon hydrogen peroxide, nitrogen dioxide, peracetic acid combined with hydrogen peroxide and low-temperature steam combined with formaldehyde, pulsed light, UV light and microwaves. In addition to the development of new sterilization processes, the standards for sterilization process validation have been updated, as well. For example,

IS0 14937 was initially released in 2000 (current version is 2009) to provide guidance on:

  1. the characterization of sterilizing agents,
  2. sterilization process validation, and
  3. the control of the sterilization process.

Material Compatibility

Numerous material compatibility charts have been published for gamma and ethylene oxide sterilization, but new polymers present new challenges to sterilization validation. If a new polymer material meets the performance criteria for strength and biocompatibility, then evaluating compatibility with various sterilization processes is usually the next step. Some companies rule out certain plastics because the materials are not compatible with a preferred sterilization process (e.g., gamma sterilization). However, many new polymers outperform traditional selections, though these polymers are frequently ruled out due to a lack of compatibility with gamma sterilization, or the material may exhibit excessively high ethylene oxide residuals after sterilization. Evaluation of new materials for non-traditional sterilization processes should be considered prior to eliminating a material from the list of design options.

Most of the non-traditional processes involve gas sterilants. If gas sterilants cause deterioration, the material is not compatible. Other gases may be absorbed by the plastic. For example, nylon absorbs hydrogen peroxide gas. Gas absorption by nylon can also complicate the design of primary packaging, because nylon is often selected as a reinforcing layer. If the gas is absorbed by the polymer, this can have several different effects:

  1. Gas residuals may be excessively high and result in failed biocompatibility testing
  2. Amount of gas remaining after absorption may be insufficient to sterilize the device
  3. Variations in sterilizer loading density may create more pronounced variation in sterilization effectiveness

In the case of light sterilization processes, such as UV light, the material must either be transparent to the light, or all surfaces of the device must be in the direct line of sight for the light source(s). Transparency varies significantly based upon the wavelength(s) of light, the clarity of the plastic (e.g., air bubbles) and the surface finish of finished component. For a light sterilization process, fixture design is important as well. Usually conveyors are needed to pass the devices in front of the light source without compromising operator safety. You may also find that dyes and colorants may change color when exposed to certain light sources.

Microorganism Resistance & Process Challenge Devices

One of the tools you will need to conduct sterilization validation is Biological indicators (BIs). Spore test strips and ampules are examples of BIs used for sterilization validation. However, you are required to use an organism that is resistant to the method of sterilization. For example, steam sterilization processes use a species of Bacillus spores that is resistant to heat. The microorganisms that are naturally occurring should not exhibit resistance to the sterilization method, and therefore the BIs can be used as a process control to ensure that the process was effective in killing all of the naturally occurring population. These BIs are used as an extra safety measure—not as an alternative to cleaning product prior to sterilization.


In addition to using BIs, sterilization validation also makes use of a Process Challenge Device (PCD). The PCD is designed to protect BIs, so that it is more difficult to sterilize the BIs than the product. The design of PCDs is somewhat of an art, but some companies simply place the BIs in the same packaging that is used for the product and then place that packaging inside another layer of packaging (i.e., triple-layer packaging).

Another approach is to design small containers with a “torturous path” (e.g., a pouch within a pouch with openings facing in opposite directions) for gas sterilants to navigate. Often, these containers will have a cap that can be adjusted to have a larger or smaller opening for the gas sterilant to enter. The design of these containers may appear to be easy to copy, but the specifications for the materials and dimensions are critical to the proper function of a PCD. A microbiologist must also develop a validated incubation process for the BIs to ensure that BI testing does not result in “false negatives.”

Overkill & Half-Cycles

When you validate a sterilization process, you typically need to quantify and characterize the average bioburden present on the packaged devices. ISO 11737-1:2006 describes the method for determining the population of microorganisms on a product. You also need to verify that the sterilization process chosen is effective for the types of organisms present. After bioburden is counted and characterized, you need to determine the minimum amount of sterilant that is required to kill those organisms. BIs will have a known concentration of the resistant organism that exceeds one million cells—much higher than the native population. This serves to ensure that the resulting process has a Sterility Assurance Level (SAL) of 10-6 (i.e., the minimum requirement for “Sterile” products).

In order to determine the minimum dose required, a fractional cycle is typically performed. If the process is UV light, you want to determine the minimum length of exposure during your Operational Qualification (OQ). During the OQ, you also want to determine the impact of distance between the light source and the device, because the effectiveness of light diminishes rapidly as distance increases. If the process is a gas sterilant, you want to inject doses that are a fraction of the regular full-dose for a cycle. For fractional cycles, BIs will be placed with the product in the product packaging, and PCDs will be used.

The goal of this testing is to demonstrate that you have identified a fractional dose in which BIs packaged with product are killed, but BIs in the PCD survive the sterilization process. This testing demonstrates that you have identified a dose that results in a 6-log reduction in resistant organisms (i.e., a reduction from 106 to 100). The regular cycle must be sufficient to kill the BIs in the PCDs. The information gathered for fractional cycles is also valuable if you perform an incubation reduction study in order to reduce the incubation time for sterility testing from seven days to 48 hours.

A UV light process would simply increase the duration of exposure by two-fold, but gas processes are more complex. If the fractional cycle is one cycle of the maximum injection volume, and the regular cycle is three cycles of the maximum injection volume, then the required number of cycles for the production process will be two-times greater (i.e., six cycles).

The number of regular cycles is doubled because the half-cycle method is used for process validation. During half-cycle validation, companies will place BIs within product packaging and place PCDs throughout the same sterilization load. If none of the BIs are positive for growth, then three cycles provide greater than a 6-log reduction in the resistant organism and six cycles provide greater than a 12-log reduction (i.e., SAL of 10-6).


Preparing Your 510(k) Submission

For non-traditional sterilization validation processes, FDA has provided an updated draft guidance document for information that manufacturers are required to provide. FDA categorizes non-traditional sterilization processes into two categories: non-traditional and novel non-traditional. The non-traditional category includes hydrogen peroxide gas plasma and ozone, while the novel non-traditional category includes the following:

  1. Chlorine dioxide
  2. Ethylene oxide in a bag
  3. High-intensity light or pulse light
  4. Microwave radiation
  5. Sound waves
  6. Ultraviolet light
  7. Vaporized chemical sterilants

For 510(k) submissions using sterilization processes in the first category, consultation from the Infection Control Devices Branch (INCB) is not necessary, but these devices will be prioritized for post-clearance inspection. However, for 510(k) submissions using sterilization processes in the second category, a technical consultation by INCB with the CDRH Office of Compliance (OC) is recommended.

If the process has been used in a previously cleared 510(k) submission, then INCB notifies the OC that future submissions should be considered non-traditional—rather than “novel, non-traditional.” If the sterilization process you are using falls into this second group, it is recommended that you contact the INCB prior to submission to verify whether the method used will be considered novel. If INCB considers your process to be novel, the OC will be required to conduct a priority pre-clearance inspection to gather information prior to issuing a 510(k). Consultation with the INCB will help to minimize delays in the scheduling of the pre-clearance inspection.

Conclusion

Novel and non-traditional sterilization processes offer alternatives that enable manufacturers to consider new polymer materials that are not compatible with traditional sterilization methods. The technology is constantly evolving, but standards and regulations have matured to the point at which companies can confidently pursue product submissions using these novel sterilization methods. Validation methods require a person who is competent in process validation and microbiology, but the manufacturers that sell sterilizers, and the contract manufacturers that provide services using novel sterilizers, offer experienced sterilization validation experts who can help guide your company through this process. If your design team is considering this type of sterilization validation, make sure that the design plan is updated to reflect a longer sterilization validation process than traditional methods, and that the plan includes details of the major tasks in the process and specialized resources that will be required.


Robert Packard is a regulatory consultant with 20 years of experience in the medical device, pharmaceutical and biotechnology industries. Robert served in senior management at several medical device companies, including President and CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing and maintaining ISO 13485 and ISO 14971 certification. From 2009 to 2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE Marking applications, Canadian medical device applications and 510(k) submissions. The most favorite part of his job is training others. He can be reached by This email address is being protected from spambots. You need JavaScript enabled to view it..

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