Sterilization Notes

Introduction to Sterilization

• Medical devices are sold in various formats:
  • Non-sterile but microbiologically controlled.
  • Non-sterile, intended for sterilization by healthcare facilities (single or multiple uses).
  • Sterile for single use.
  • Sterile for repeated use (reused single-use devices).
• Sterilization prevents serious illness or death by eliminating microorganisms.
• Most microorganisms in medical device bioburden post-manufacturing are non-pathogenic but can be opportunistic pathogens in immunocompromised patients.
• Critical and invasive devices pose a greater risk.
• Reusing devices increases the likelihood of pathogenic microorganisms, heightening patient risk.
• Sterilization is vital for ensuring patient safety for both reusable and single-use medical devices.
• This chapter covers sterilization methods for single-use and reusable medical devices.
• Two primary sterilization modalities for single-use devices:
  • Ethylene Oxide (EO): Sterilizes approximately half of all single-use medical devices globally. About 20 billion devices annually in the US.
  • Ionizing Radiation: Accounts for about 45% of medical device sterilization, including gamma, electron beam, and X-ray technologies.
• Other sterilization methods include moist heat, dry heat, gaseous/vapor methods (chlorine dioxide, nitrogen dioxide, supercritical $\text{CO}_2$, vaporized hydrogen peroxide), and liquid chemical sterilization.
• Reusable devices' sterilization methods vary, with moist heat being most common in hospitals and surgical centers, followed by vaporized hydrogen peroxide or EO. Dental practices primarily use moist and dry heat.

Factors Influencing Sterilization Method Choice

• Reasons for choosing a sterilization method for single-use devices:
  • Cost.
  • In-house or contract sterilization.
  • Proximity of contract sterilization.
  • Simplicity/speed of qualification process.
  • Functional compatibility.
• Functional compatibility is the most critical factor: the device must meet all functional requirements after sterilization throughout its lifetime.
• If multiple methods are functionally compatible, other factors determine the final choice.
• Historically, EO sterilization is preferred for single-use devices due to its material compatibility.
• For reusable devices:
  • Functionality is primary.
  • Availability of the method in healthcare facilities drives selection.
  • Radiation sterilization isn't used in healthcare settings.
  • Moist heat is preferred unless the device can't withstand it.

Radiation Sterilization

• Consists of gamma rays, electron beams, and X-rays which disrupt nucleic acids to prevent reproduction and effectively kill microorganisms.
• Dose is measured using dosimeters in Gray (Gy), with measurements in kilograys (kGy) where $1 \text{kGy} = 1000 \text{Gy}$.
• Common dosimeters include alanine and radiochromic dye film, calibrated for qualification and routine processing.

Gamma Radiation

• Predominant form of radiation sterilization since the early 1960s, using Cobalt-60 as the gamma-ray source.
• Cobalt-60 is produced by bombarding Cobalt-59 with neutrons in a nuclear power reactor.
• Cobalt-60 has a half-life of 5.27 years.
• Downsides of using radioactive material:
  • Difficult radioactive material procurement (2-3 years).
  • Limited raw material supply.
  • Inability to turn the process off.
• Products are transported into the irradiation room via a conveyor system.
• Two types of gamma irradiators:
  • Batch: Containers are moved into the irradiation room for exposure.
  • Continuous: Containers move around the radiation source in a shuffle-dwell pattern.
• The exposure time depends on the dose, source radioactivity, and product density.
• Facilities continually adjust for source decay, typically increasing processing time by about 1% per month.
• Continuous irradiators require balancing dose and product density to avoid under or overdosing.

Electron Beam

• Second most used radiation sterilization method, developed before gamma sterilization.
• Uses machine-generated electrons to disrupt microorganism lifecycles.
• Faster than gamma radiation, taking seconds or minutes to deliver the same dose.
• Faster dose rate reduces oxidation and damage to polymeric materials.
• Electrons have lower penetration than gamma photons, resulting in higher maximum to minimum dose ratios.
• Best suited for low-density products (less than $0.2 \frac{\text{g}}{\text{cm}^3}$), evenly distributed packaging, and thickness no more than 30 cm in the beam direction.
• Similar conveyor systems to gamma radiation, but often transport individual boxes.
• No batch processes; all operate continuously.
• Easy to customize the radiation for particular boxes.
• No need to compensate for radioactive decay; radiation is controlled by beam current and power.

X-Ray

• First radiation form found to kill microorganisms but least common due to cost.
• Machine-generated like electron beams, using the same equipment with an addition.
• Electrons interact with materials like tantalum or tungsten, decelerating and releasing X-rays (Bremsstrahlung).
• Bremsstrahlung is an inefficient process; only about 12% of electrons are converted, with the rest expended as heat.
• Advantages:
  • X-rays penetrate better than electrons and often better than gamma rays.
  • Whole pallets can be irradiated.
  • Dose uniformity ratio comparable to gamma irradiation with smaller containers.
  • Less product handling.
  • Easier processing for products with tight dose ranges.
  • Dose rate between electron beam and gamma, reducing material degradation.
  • No radioactive source or decay to manage.

Validation of Radiation Sterilization

• Standards: ISO 11137 series applies to all modalities.
• ISO 11137-1: Requirements for development, validation, and routine control of radiation sterilization, FDA-recognized consensus standard since 2006, revision expected in 2024.
• ISO 11137-2: Establishing the sterilization dose, FDA-recognized, revision likely in late 2025 or early 2026.
• ISO 13004: Substantiation of selected sterilization dose using Method $\text{VD}_{\text{max}}$SD, specific to sterilization doses of 17.5, 20.0, 22.5, 27.5, 30.0, 32.5, and 35 kGy, FDA-recognized consensus standard.

Bioburden in Radiation Sterilization

• Bioburden plays a significant role because the means to establish sterilization dose are only bioburden-based.
• Factors include bioburden population and microorganism resistance to ionizing radiation.
• Finding a sterilization dose is possible even with high population or resistance, but it may cause material degradation.
• Recourse involves reducing bioburden population or eliminating resistant microorganisms.
• Multiple methods for sterilization dose establishment are described in ISO 11137-2 with advantages and disadvantages.
• Additional test units are required to validate the bioburden method and demonstrate that the sterility test method isn't inhibitory.
• Sample Item Portion (SIP) validity must also be demonstrated if used.
• Method 1 and the $\text{VD}_{\text{max}}$ Method have bioburden population limitations that dictate the ability to achieve the lowest sterilization doses.
• Demonstrating that the sterilization process will not affect the product's functionality over its intended lifetime is necessary.
• Radiation degradation can be ongoing.
• The maximum acceptable dose becomes part of the processing specification.

Routine Processing

• Defined specification consists of the sterilization dose (minimum dose) and the maximum acceptable dose.
• Example: A product's dose specification could be 25 to 45 kGy.
• The sterilization facility will also have a specification that defines the loading configuration.
• No microbiological monitors are used, only parameter specifications and dosimeter readings.

Comparison of Dose Establishment Methods

• Method 1:
  • Minimum Number of Product Units or Sample Item Portions: 130
  • Minimum Sterilization Dose That Can Be Established: 11kGy
  • Advantages: Can result in lower doses
  • Disadvantages: Higher levels of resistance can make a sterilization dose difficult to attain
• Method 2A:
  • Minimum Number of Product Units or Sample Item Portions: 640
  • Minimum Sterilization Dose That Can Be Established: ~11kGy
  • Advantages: A dose will always be able to be established
  • Disadvantages: Requires large quantities of product samples* (*AAMI TIR 40 describes a method to reduce the number of samples required for Methods 2A and 2B)
• Method 2B:
  • Minimum Number of Product Units or Sample Item Portions: 580
  • Minimum Sterilization Dose That Can Be Established: 8.2 kGy
  • Advantages: Achieves the lowest dose level
  • Disadvantages: Requires large quantities of product samples*
• VDmax Method:
  • Minimum Number of Product Units or Sample Item Portions: 40
  • Minimum Sterilization Dose That Can Be Established: 15 kGy
  • Advantages: Used the fewest number of samples
  • Disadvantages: There are restrictions for the bioburden levels for each sterilization dose

Ethylene Oxide (EO) Sterilization

• Under scrutiny in the US due to emissions.
• Medical device manufacturers are exploring alternative sterilization methods or means to reduce EO use.
• Still the most predominant method for single-use devices.
• The EO sterilization process can consist of three phases:
  • preconditioning
  • the sterilization cycle
  • aeration
• Only required phase is the sterilization cycle.
• Preconditioning prepares the product and microorganisms for sterilization via elevated temperatures and humidity.
• Aeration dissipates EO residuals for product release, usually without humidity control.
• The EO sterilization cycle typically occurs in batch chambers ranging from $0.2 \text{m}^3$ to over $75 \text{m}^3$ (30 US pallets).
• Small chambers (or flexible bags) sterilize products only in the sterile barrier system.
• Large chambers sterilize products on pallets moved manually or automatically.
• The direct action of EO to accomplish sterilization is alkylation of proteins and the nucleic acids present in the microorganism cell which eliminates the microorganisms' ability to reproduce.
• Factors that directly affect EO sterilization:
  • EO Concentration
  • Temperature
  • Humidity

EO Concentration

• Increased concentration enhances lethality, but with diminishing returns.
• Historical concentrations: 800–1200 mg/L; recent concentrations: 500–700 mg/L; current targets: 300–400 mg/L to reduce consumption and emissions.
• Lower concentrations may require longer EO dwell times.
• Lower concentrations reduce residuals in the product, which is governed by ISO 10993-7.
• This standard also provides limits for ethylene chlorohydrin (ECH), a toxic byproduct formed when EO reacts with chloride ions (e.g., from bleached products or PVC).

Temperature

• EO sterilization is considered a cold sterilization process.
• Effectiveness is improved by raising the temperature.
• Assess the load temperature; influential factors include chamber temperature, load density, pallet configuration, and recirculation.
• Insufficient temperature, especially with lower EO concentrations, can lead to long EO dwell times or inadequate sterilization.
• The goal is to reach adequate temperature for effective sterilization without exceeding the product's maximum acceptable temperature.
• Higher temperatures increase lethality and improve residual dissipation.
• Temperatures in large chambers are typically 40°C-55°C; in smaller chambers, temperatures tend to run around 55°C.
• Lower temperature cycles are used for products with temperature limitations.

Humidity

• Moisture influences sterilization by softening cell walls/spore coats and facilitating EO movement.
• Relative humidity is typically measured, with a historical minimum of 30%.
• Maximum humidity is variable, aiming to prevent condensation, usually in the range of 90%-99%.
• Typical relative humidity levels are between 30%-90% RH.
• Moisture is introduced during conditioning/humidification to raise the temperature and moisture level of the load.
• Conditioning can use static or dynamic steam introduction.
• Static steam introduction involves steam injection for 60-90 minutes, with additional steam if pressure drops.
• Dynamic conditioning (DEC) uses steam injections/evacuations or continuous steam flow to improve temperature, but can cause condensation if not controlled.

EO Sterilization Process

• Established through process definition/cycle development.
• Consists of preconditioning, sterilization cycle, and heated aeration.
• Phases are dictated by the facility performing sterilization.
• Some facilities lack preconditioning areas and use dynamic conditioning or are located in climates where the product doesn't experience cold conditions.
• Heated aeration may be limited, with most EO removal occurring in the chamber (all-in-one process).

Validation of EO Sterilization

• Requirements are in ISO 11135, FDA-recognized consensus standard since 2014, Revision is due late 2026.
• validation consists of equipment installation qualification (IQ) and operational qualification (OQ) and the performance qualification (PQ).
• PQ consists of a microbiological PQ (MPQ) and physical PQ (PPQ).
• MPQ demonstrates that the sterilization process will achieve the defined sterility assurance level (SAL).
  *Biological indicator (BI) is used to act as surrogate for the bioburden.
  *Biological indicator (BI) selected for EO sterilization uses Bacillus atrophaeus spores as the reference microorganism
• Approches described in the standard are the BI/Bioburden Approach and the Overkill Approach.
• Overkill Approach can be performed using two different methods with the most common method that has been used being the Half Cycle Method and the other method the Cycle Calculation Method.
• The approach involves the use of a process challenge device (PCD).
• Overkill Half Cycle Method, at least three (3) cycles are performed that must demonstrate complete kill of the BI within the PCD and the EO dwell time is doubled for the routine sterilization process.
  *In the Overkill Cycle Calculation Method, the decimal reduction value or D value is determined for the PCD, and the routine sterilization process is based on the delivery of 12 logs of reduction (required for an overkill process), so the EO dwell time is determined by multiplying the D value by 12.
• the MPQ will consist of performing sterilization processes s that are designed to deliver less lethality than the routine sterilization process.
• The PPQ is performed to demonstrate that the process is reproducible and that that the parameters for sterilization are achieved throughout the load, so an integral part of the PPQ is the use of temperature and humidity sensors throughout the load to demonstrate the levels that are achieved.

Routine Processing

• Once the EO process has been validated, the routine sterilization process will be performed using the product within the product family or processing category and the mode of release is either BI release or parametric release.
• Both release methods require that the sterilization process be performed according to the specification, however, BI release requires BIs from PCDs.
• Parametric release also requires monitorization of:
  • Temperature monitoring in at least two locations throughout the sterilization cycle;
  • Chamber humidity during conditioning by direct measurement;
  • EO concentration during EO dwell by direct measurement.
• parametric release is an industry trend.

Typical Sterilization Process

• Preconditioning:
  • Product temperature prior to entry: $\geq 40$ °F
  • Chamber temperature: 90-130 °F
  • Room temperature: 95-113 °F
  • Room humidity: 45-80 %RH
  • Duration: 24-48 hours
  • Transfer time to sterilizer: $\leq 60$ minutes
• Sterilization Cycle:
  • Dynamic conditioning time: 120 - 240 minutes
  • Chamber temperature: 120-130 °F
  • Initial evacuation: 1.5-2.5 "HgA
  • Time: 5-60 minutes
  • Steam inject to: 2.5-3.0 "HgA
  • Steam inject time: 5-60 minutes
  • Eo gas inject to: 10.2 - 11.2 "HgA
  • Eo gas inject time: 5-60 minutes
  • N2 inject to: 27-28 "HgA
  • N2 inject time: 560 minutes
  • Chamber temperature: 105-130 °F
  • Eo concentration: 300 - 578 mg/L
  • Eo dwell time: 240-270 minutes
  • Gas make-ups: Yes-Inert
  • Vacuum: 1.5 -2.5 "HgA
  • Time: 5-90 minutes
  • Humidification Sp: 1.0-1.5 "HgA
  • Steam inject to: 2.6-3.5 "HgA
  • Steam inject time: 2-30 minutes
  • Maintain pressure at: 2.2-3.8 "HgA
  • N2 inject to: 6.0 - 7.0 "HgA
  • N2 inject time: 2-30 minutes
  • Evacuation to: 1.8-2.4 "HgA
  • Evacuation time: 1-60 minutes
  • Total number of wash cycles: 15
  • Exposure duration: 240-250 minutes
• Heated Aeration
  • Room temperature: 95 - 113 °F
  • Duration load: 24-72 hours

All-In-One Sterilization Process

• Product temperature prior to entry: $\geq 40$ °F
• Chamber temperature: $\geq 40$ °F
• Initial evacuation: 1.5-2.5 "HgA
• Time: 5-60 minutes
• Steam inject to: 2.5 3.0 "HgA
• Steam inject time: 5-60 minutes
• N2 inject to: 27-28 "HgA
• N2 inject time: 560 minutes
• Chamber temperature: 105-130 °F
• Eo concentration: 300 - 578 mg/L
• Eo dwell time: 240-270 minutes
• Gas make-ups: Yes-Inert
• Vacuum: 1.5 -2.5 "HgA
• Time: 5-90 minutes
• Humidification Sp: 1.0-1.5 "HgA
• Steam inject to: 2.6-3.5 "HgA
• Steam inject time: 2-30 minutes
• Maintain pressure at: 2.2-3.8 "HgA
• N2 inject to: 6.0 - 7.0 "HgA
• N2 inject time: 2-30 minutes
• Evacuation to: 1.8-2.4 "HgA
• Evacuation time: 1-60 minutes
• Total number of wash cycles: 15
• release time:
  • nitrogen inject/ evacuation to/ Air inject/ release to vacuum, total number of wash cycles, Approx rate of nitrogen injection evacuation and air and release injection

Moist Heat Sterilization

• One of the oldest and highly effective methods, but less used by medical device manufacturers for single-use devices due to high temperatures.
• Low temperature moist heat processes exist but the temperatures still exceed 70°C, while most common methods take place in 121°C-135°C.
• Kills microorganisms by coagulating and denaturing proteins and enzymes.
• Can be achieved by direct contact with steam or heat in a contained liquid product; steam contact is more common with medical devices.
• Multiple processes include:
  • Saturated steam sterilization using gravity displacement.
  • Saturated steam sterilization using dynamic air removal.
  • Contained product sterilization using steam or steam-air mixtures.
  • Contained product sterilization using water sprays.
  • Contained product sterilization using water immersion.
• All methods are addressed in ISO 17665, an FDA-recognized standard.
• Moist heat sterilizers (autoclaves) range from small table-top versions to large industrial units.
• The saturated steam sterilization processes consist of the following phases or stages:
  *Conditioning: air is removed from the sterilizer and load.
  *Plateau period: conditions (temperature) for sterilization have been met.
  *Steam Exhaust: steam is removed either by venting or by vacuum removal. It can also include a drying phase to ensure that when the product is removed that it is dry.

Validation of Moist Heat Sterilization

• Most moist heat sterilization is performed by the medical device manufacturer.
• The moist heat sterilization process validation consists of the equipment IQ and OQ (or assessment of the existing IQ and OQ, followed by the PQ for the sterilization process with the load.
• The PQ for moist heat sterilization processes can be performed with or without microbiological testing.
• In the US, microbiological inactivation must be demonstrated, as described in Annex B in ISO 17665.

Microbiological Inactivation

• The methods prescribed in the standard allow for the use of one of three different approaches:
  • Bioburden-based
  • Bioburden/Biological Indicator-based
  • Overkill
• In the bioburden-based approach, the product bioburden is used to establish the sterilization process parameters making this approach similar to how the radiation sterilization dose is determined.
• However, for moist heat sterilization, testing includes determination of thermophilic microorganisms in the bioburden.
• The bioburden/biological indicator-based approach is like the BI/bioburden approach used in EO sterilization, with the main difference being the reference microorganism used.
• For moist heat sterilization, the commercially available BI uses the spores of Geobacillus stearothermophilus.
• In the overkill method, which is often the most common approach used, the lethality of the process is based on the BI's resistance. This approach can be applied in two different ways. The first being a partial cycle approach using either a half cycle or cycle calculation and the second a full-cycle approach.
• The half cycle or cycle calculation methods would be applied as they are in EO sterilization, i.e., in the half cycle, the BIs must demonstrate no growth while with cycle calculation the determined D value is multiplied by 12 to calculate the exposure time for the product.
• The full cycle approach can be used for moist heat sterilization since there is only the parameter of temperature that needs to be factored in to determine lethality.
• Temperature measurements within the load are performed during these cycles but additional cycles to demonstrate that the load attains the defined parameters are not typically required in moist heat sterilization.

Routine Processing

• Once the moist heat sterilization process has been validated, the routine sterilization process will be performed using the product within the product family or processing category.
• The mode of release that is used is either BI release or parametric release.
• Both release methods require that the sterilization process be performed according to the specification, however, BI release requires BIs to be evaluated and demonstrate no growth for the load to be released.
• With parametric release, it is necessary that the temperature of the load in the worst-case location is demonstrated to have achieved the defined level of lethality.
• The scale of cyle robustness: overkill half cycle> overkill cycle calculation > overkill full cycle > Bioburden/BI -based> Bioburden - based

Dry Heat Sterilization

• Temperature-dependent like moist heat, with typical temperatures around 160°C.
• Temperatures lower of higher than 160°C can be used depending on time.
• Destroys cells via protein and enzyme destruction.
• Usually performed via static heating or forced-air convection.
• Also uses conveyor systems.
• Often used for depyrogenation.

Validation of Dry Heat Sterilization

• Medical device manufacturer is responsible.
• Only a review of the prior qualifications will be needed before the PQ is completed.
• PQ combines aspects of EO and moist heat sterilization.
• Microbiological approaches are identical to moist heat sterilization.
• Also, that the BI used in dry heat sterilization contains Bacillus atrophaeus spores which is the same reference microorganism that is used for EO sterilization.
• ISO 20857 provides requirements and guidance.

Routine Processing

• Either BI release or parametric release can be used.
• Both release methods require that the sterilization process be performed according to the specification.
• With parametric release, it is necessary that the temperature of the load in the worst-case location is demonstrated to have achieved the defined level of lethality.

Low Temperature Vaporized Hydrogen Peroxide

• Addressed in ISO 22441, published in 2022, FDA recognized in early 2024.
• Covers all VH2O2 processes.
• Liquid hydrogen peroxide is converted to a vapor for sterilization purposes.
• Smaller chambers are used, ranging from 14 liters to 10 m³.
• Product is placed on racks or shelves in sterile barrier systems.
• The sterilization process usually takes less than an hour up to several hours but has the advantage over EO in that additional time for residual dissipation is not required.
• Temperatures are similar to EO, with lower vacuum levels.
• Does not penetrate as well as EO.

Sterilization Process

• Involves converting liquid $\text{H}<em>2\text{O}</em>2$ to vapor.
• Introducing the vapor into the chamber so that all surfaces are exposed to the vapor.
• Removal of the vapor is performed by converting the $\text{H}<em>2\text{O}</em>2$ to oxygen and water.
• Hydrogen peroxide's lethality results from it being an oxidizing agent, reacting with microorganisms' enzymes, proteins, DNA, and the cell membrane.

Validation of Low Temperature Vaporized Hydrogen Peroxide

• The approaches described in ISO 22441 for establishing and qualifying the microbiological aspects of the sterilization process include:
  • A bioburden method
  • A BI/bioburden method
  • Overkill methods
    *It is only required to review the IQ and OQ if the equipment has been previously installed and qualified.
• Critical parameters that need to be assessed during the PQ include sterilization chamber pressure, temperature, and $\text{H}<em>2\text{O}</em>2$ concentration.
• The BI used for $\text{VH}<em>2\text{O}</em>2$ sterilization used Geobacillus stearothermophilus spores which are placed on either stainless steel or fiberglass rather than the standard filter paper that is used for moist heat sterilization.

Routine Processing

• The release methods for $\text{VH}<em>2\text{O}</em>2$ sterilization processes are also BI and parametric release.
• it is unlikely that parametric release will be used based on the relatively new standard and less experience with the process on a large scale, industrially.

Other Sterilization Modalities

• Nitrogen dioxide ($\text{NO}<em>2$), chlorine dioxide ($\text{ClO}</em>2$), supercritical carbon dioxide, and vaporized peracetic acid (VPA).
• These methods are batch processes similar to EO and $\text{VH}<em>2\text{O}</em>2$.
• Typically performed at close to room temperature and have vacuum levels comparable to EO or $\text{VH}<em>2\text{O}</em>2$.
• AAMI TIR 17 provides guidance related to material compatibility with the different sterilization methods.

Annual Review and Requalification

• All sterilization methods require some level of review and requalification on a periodic basis.

Radiation Sterilization

• Requires annual review to determine if product families and processing categories remain appropriate.
• They also require periodic bioburden testing and dose auditing on an every three-month basis.
• Bioburden testing and a dose audit need to be performed to ensure that the sterilization dose remains adequate.

All Other Sterilization Methods

• with requalification, repetition of a portion of the validation is performed on a periodic basis.
• The period of time that is defined is based on each medical device manufacturer's own quality system, but the frequency needs to have a rationale.
• While for EO the frequency is often every two to three years , typical time frames used for moist heat sterilization requalification tend to be annual.
• when a change occurs or is planned, it should be assessed prior to acceptance, but the purpose of the annual review is to look at the process holistically to determine if additional review or requalification is needed.
• If there are changes to the product or how it is presented Periodic requalification is not required for reusable medical devices.reusable medical devices, a medical device manufacturerwill initially perform a PQ initially performance. requalification of a new PQ is only necessary to the sterilization process that warrants new testing.

Table 13-5: Guidance Documents

• AAMI TIR 14:2016, Contract sterilization using ethylene oxide 16
• AAMI TIR 15:2016, Physical aspects of ethylene oxide sterilization 17
• AAMI TIR 16:2023, Microbiological aspects of ethylene oxide sterilization 18
• AAMI TIR 28:2016, Product adoption and process equivalence for ethylene oxide sterilization 19
• AAMI TIR 35:2016, Sterilization of health care products-Radiation sterilization-Product adoption and alternative sampling plans for verification dose experiments and sterilization dose audits 20
• AAMI TIR 56:2013, Guidance for the development, validation, and routine control of an ethylene oxide sterilization process utilizing flexible bag systems for the sterilization of medical devices21
• AAMI TIR 76:2021, Sterilization of health care products-Radiation-Substantiation of a selected sterilization dose at a specified sterility assurance level: Method VDmax SD-S22
• ISO 11137-3:2017, Sterilization of health care products-Radiation-Part 3: Guidance on dosimetric aspects of development, validation and routine control 23
• ISO/TS 11137-4:2020, Sterilization of health care products-Radiation-Part 4: Guidance on process control 24
• ISO/TS 21387:2020, Sterilization of medical devices-Guidance on the requirements for the validation and routine processing of ethylene oxide sterilization processes using parametric release25
• ISO/TS 22456:2021, Sterilization of health care products-Microbiological methods-Guidance on conducting bioburden determinations and tests of sterility for biologics and tissue-based products26