Shelley Zimmerman and Cathy Leckwart, WuXi AppTec06.01.22
The use of ionizing radiation (i.e., X-rays, gamma rays, or electron beam) to sterilize medical devices has significantly increased in recent years. About 12 million cubic meters of medical devices are irradiated every year, and more than 40 percent of that total is sterilized via gamma irradiation. Irradiation can be a highly efficient way to kill microorganisms and is performed on devices that have already been packaged.
Radiation sterilization studies are performed to substantiate the radiation dose to be used for sterilization of a medical device to a specific Sterility Assurance Level (SAL). The SAL is measured in 10-n, with 10-3 or 10-6 being the most common SAL levels. A 10-3 SAL means there is a 1 in 1,000 probability, after sterilization, of a single viable microorganism occurring on a product (i.e., non-sterile). A 10-6 would mean a one in 1,000,000 probability that a device is non-sterile. Regulators will expect to see manufacturers’ sterilization validation data that confirms their labeling claims.
Bioburden can be introduced at several stages throughout the manufacturing process—from raw materials, the workforce, or the manufacturing environment—so routine testing is essential. Understanding the bioburden level is one of the most critical steps in sterilization validation. Once scientists determine bioburden level through microbial identification and characterization, the dose level is substantiated and becomes the basis for dose audits.
ISO 11137-2 includes specific requirements regarding the number of samples required for a radiation validation and dose audit testing. The testing lab will comply with the necessary instructions per the standard.
As the ISO standard states: “Consideration shall include all product-related variables that affect bioburden, including, but not limited to: a) nature and sources of raw materials, including the effect, if any, of raw materials that might be sourced from more than one location; b) components; c) product design and size; d) manufacturing processes; e) manufacturing equipment; f) manufacturing environment; g) manufacturing location.”
When testing sterilization dosage for a product family, device manufacturers are often inclined to select the “worst-case” products in terms of size and complexity. At first glance, this may seem logical and even intuitive. But your lab testing partner may recommend a more effective testing strategy.
Sterilization dose audits typically occur every quarter and must be documented. By limiting validation test samples to only the worst-case products, manufacturers risk running out of suitable representatives. There are advantages to bioburden screening that manufacturers may not realize.
When bioburden screening is performed as a part of the sterilization validation, the screening is being used to assess the microbiological equivalence or difference of family members to select either a “master” or “equivalent” product. If a product family member exhibits bioburden that is significantly higher than other family members, it is considered a master product. The master product would be the member chosen to represent the family for dose substantiation and verification dose experiments. However, submitting the master product for validation studies can lead to availability and cost challenges previously mentioned. But, when all family members exhibit microbiological equivalency, they are considered an equivalent product. And equivalent products selected to represent the family can be chosen at random or according to a rotating schedule, freeing up valuable samples for quarterly dose audits and keeping timelines and budgets intact.
In addition, experienced testing partners will be able to demonstrate regulatory compliance and success. They should be able to supply references to confirm a track record of setting realistic milestones and achieving project goals. An oft-overlooked advantage to establishing a strong relationship with a lab testing partner is data accessibility. Lab partners will store relevant data and in-process test results to ensure manufacturers have the answers they need for the next dose audit or regulatory submission. Keeping these data in-house can cause organizational confusion and unnecessary delays.
Shelley Zimmerman is a manager of Laboratory Services with WuXi AppTec. Shelley specializes in medical device testing for radiation sterilization studies and dose audits.
Cathy Leckwart is a senior technical specialist at WuXi AppTec. Cathy specializes in sterilization management, microbiology testing, and quality assurance.
Radiation sterilization studies are performed to substantiate the radiation dose to be used for sterilization of a medical device to a specific Sterility Assurance Level (SAL). The SAL is measured in 10-n, with 10-3 or 10-6 being the most common SAL levels. A 10-3 SAL means there is a 1 in 1,000 probability, after sterilization, of a single viable microorganism occurring on a product (i.e., non-sterile). A 10-6 would mean a one in 1,000,000 probability that a device is non-sterile. Regulators will expect to see manufacturers’ sterilization validation data that confirms their labeling claims.
Bioburden can be introduced at several stages throughout the manufacturing process—from raw materials, the workforce, or the manufacturing environment—so routine testing is essential. Understanding the bioburden level is one of the most critical steps in sterilization validation. Once scientists determine bioburden level through microbial identification and characterization, the dose level is substantiated and becomes the basis for dose audits.
The Regulatory Landscape for Bioburden Screening
Radiation sterilization studies are based on sterilization guidelines specified in ISO 11137-2. According to ISO guidance, dose audit procedures test the sterility of products that have received doses of radiation lower than the terminal sterilization dose. In short, a validation study helps evaluate the effectiveness of the sterilization dose that was calculated to eliminate bioburden.ISO 11137-2 includes specific requirements regarding the number of samples required for a radiation validation and dose audit testing. The testing lab will comply with the necessary instructions per the standard.
Selecting the Right Product for Studies
Choosing the right product as a representative in radiation sterilization studies is key to testing success. Guidance documents provide direction on the assessment needed to select a representative product for dose substantiation and verification testing (sterilization dose audits).As the ISO standard states: “Consideration shall include all product-related variables that affect bioburden, including, but not limited to: a) nature and sources of raw materials, including the effect, if any, of raw materials that might be sourced from more than one location; b) components; c) product design and size; d) manufacturing processes; e) manufacturing equipment; f) manufacturing environment; g) manufacturing location.”
When testing sterilization dosage for a product family, device manufacturers are often inclined to select the “worst-case” products in terms of size and complexity. At first glance, this may seem logical and even intuitive. But your lab testing partner may recommend a more effective testing strategy.
Sterilization dose audits typically occur every quarter and must be documented. By limiting validation test samples to only the worst-case products, manufacturers risk running out of suitable representatives. There are advantages to bioburden screening that manufacturers may not realize.
Advantages of Bioburden Screening
Bioburden screening can be an effective assessment tool to ensure the most suitable representative product is selected for radiation sterilization studies and dose audits, which manufacturers do not always understand. Some manufacturers may consider it an additional expense without clear benefits. Accurately understanding bioburden minimizes patient risk and is paramount for regulatory success.When bioburden screening is performed as a part of the sterilization validation, the screening is being used to assess the microbiological equivalence or difference of family members to select either a “master” or “equivalent” product. If a product family member exhibits bioburden that is significantly higher than other family members, it is considered a master product. The master product would be the member chosen to represent the family for dose substantiation and verification dose experiments. However, submitting the master product for validation studies can lead to availability and cost challenges previously mentioned. But, when all family members exhibit microbiological equivalency, they are considered an equivalent product. And equivalent products selected to represent the family can be chosen at random or according to a rotating schedule, freeing up valuable samples for quarterly dose audits and keeping timelines and budgets intact.
Consult With a Lab Testing Partner
Understanding the complexities and nuances of bioburden screening can significantly reduce time and costs during medical device testing. Strong connections and open dialogue with experienced laboratory testing partners can make a big difference. Lab partners often have access to industry norms and testing strategies that manufacturers may not have in-house. This leads to accurate and reproducible results and, ultimately, greater patient safety.In addition, experienced testing partners will be able to demonstrate regulatory compliance and success. They should be able to supply references to confirm a track record of setting realistic milestones and achieving project goals. An oft-overlooked advantage to establishing a strong relationship with a lab testing partner is data accessibility. Lab partners will store relevant data and in-process test results to ensure manufacturers have the answers they need for the next dose audit or regulatory submission. Keeping these data in-house can cause organizational confusion and unnecessary delays.
A Final Word
The benefits of achieving product equivalency during sterilization validation can be misunderstood or overlooked, but it can help manufacturers curb costs and alleviate product availability issues. Collaborating with a proven laboratory testing partner can help manufacturers navigate the regulatory landscape and help companies achieve regulatory compliance.Shelley Zimmerman is a manager of Laboratory Services with WuXi AppTec. Shelley specializes in medical device testing for radiation sterilization studies and dose audits.
Cathy Leckwart is a senior technical specialist at WuXi AppTec. Cathy specializes in sterilization management, microbiology testing, and quality assurance.
