Sterilization Process Validation

The FDA’s most acceptable sterilization methods

Established Category A

A long history of safe and effective use is demonstrated by:

1. ample literature,
2. clearances of 510(k)s or approvals of PMAs
3. satisfactory Quality Systems inspections
4. FDA-recognized standards for development, validation, and routine control Examples of this Established Category A Sterilization Methods:

• Dry heat
• Ethylene oxide (EO) in a fixed, rigid chamber
• Moist heat or steam • Radiation (e.g., gamma, electron beam)

Established Category B

• There are no FDA-recognized dedicated consensus standards
• There is published information on development, validation, and routine control
• FDA has previously evaluated sterilization development and validation data for specific sterilizers using discrete cycle parameters and determined the validation methods to be adequate Examples of Established Category
• Sterilization Methods:
• Hydrogen peroxide (H2O2)
• Ozone (O3)
• Flexible bag systems (e.g., EO)

Novel Methods

• little or no published information,
• no history of comprehensive FDA evaluation of sterilization development and validation data through an FDA-cleared 510(k) or approved PMA for devices sterilized with such methods
• no FDA-recognized dedicated consensus standards on development, validation, and routine control.
• FDA has not reviewed and determined to be adequate to effectively sterilize the device. Examples of Novel Sterilization Methods:
• Vaporized peracetic acid
• High-intensity light or pulse light
• Microwave radiation
• Sound waves
• Ultraviolet light

Explain individually for ETO, Gamma, Steam, and Moist Heat.

 

The following are documents need to be addressed in a 510(k) submission:

⊕    For the sterilization method:

1. sterilization method description
2. chamber description, if not rigid (i.e., bag)
3. For Established B:

• for a cleared sterilizer, 510(k) number, make, model, and cycle altered?
• if the sterilizer is not cleared, this should be stated;
• if the sterilization method has been reviewed: the 510(k)/PMA/HDE number or Device Master File containing the validation evaluation. In addition, have the cycles been altered?

1. the sterilization site;
2. the dose for radiation;
3. for chemical sterilants, the maximum residual levels and a justification.

 

⊕  Validation method, and relevant standards or a comprehensive description of process/validation protocol & maybe data

⊕  Sterility assurance level (SAL) of 10^-6 for devices labeled as sterile, 10-³ for devices that only contact intact skin.

⊕  Pyrogenicity Claim, if applicable: a description of the method, batch testing or sampling plan confirmation, the chosen testing limit and its justification, endotoxin units/device.

⊕  Packaging description and how it will maintain the device’s sterility, and a description of package test methods, but not package test data.

 

 

The following are documents need to be addressed in a 510(k) submission for Ethylene oxide:

⇒  sterilization method description

⇒ chamber description, if not rigid (i.e., bag)

⇒ the sterilization site;

⇒ For chemical Eto sterilants, the maximum residual levels and a justification.

⇒ Validation method, and relevant standards or a comprehensive description of process/validation protocol & maybe data

⇒ Sterility assurance level (SAL) of 10^-6 for devices labeled as sterile, 10-³ for devices that only contact intact skin.

⇒ Pyrogenicity Claim, if applicable: a description of the method, batch testing or sampling plan confirmation, the chosen testing limit and its justification, endotoxin units/device.

⇒ Packaging description and how it will maintain the device’s sterility, and a description of package test methods, but not package test data.

 

The following are documents need to be addressed in a 510(k) submission for Gamma radiation:

⇒ sterilization method description

⇒ chamber description, if not rigid (i.e., bag)

⇒ the sterilization site;

⇒ the dose for radiation;

⇒ Validation method, and relevant standards or a comprehensive description of process/validation protocol & maybe data

⇒ Sterility assurance level (SAL) of 10^-6 for devices labeled as sterile, 10-³ for devices that only contact intact skin.

 

The following are documents need to be addressed in a 510(k) submission for Moist Heat or steam sterilization:

⇒ sterilization method description

⇒ Validation method, and relevant standards or a comprehensive description of process/validation protocol & maybe data

⇒ Sterility assurance level (SAL) of 10^-6 for devices labeled as sterile, 10-³ for devices that only contact intact skin.

 

The following are documents need to be addressed in a 510(k) submission For Established B:

⇒ sterilization method description

⇒ chamber description, if not rigid (i.e., bag)

⇒ For a cleared sterilizer, 510(k) number, make, model, and cycle altered

⇒ if the sterilizer is not cleared, this should be stated;

⇒ if the sterilization method has been reviewed: the 510(k)/PMA/HDE number or Device Master File containing the validation evaluation. In addition, have the cycles been altered?

⇒ the sterilization site;

⇒ for chemical sterilant, the maximum residual levels and a justification.

⇒ Validation method, and relevant standards or a comprehensive description of process/validation protocol & maybe data.

⇒ Sterility assurance level (SAL) of 10^-6 for devices labeled as sterile, 10-³ for devices that only contact intact skin.

⇒ Pyrogenicity Claim, if applicable: a description of the method, batch testing or sampling plan confirmation, the chosen testing limit and its justification, endotoxin units/device.

⇒ Packaging description and how it will maintain the device’s sterility, and a description of package test methods, but not package test data.

Sterilization Process Validation is the methodology to determine that the sterilization process will consistently achieve sterility and that it won’t have an undesirable effect on the device or its packaging

The documentation must include:

• Device Type:
• Name of the Device
• Product code
• Regulation Number
• Common Name of the Device
• Standards
• Results and Discussion
• Conclusion

 

Annex:

Validation Protocol – Company Name; Common Name of the Device, Device Description Name, Methods/Process, Parameters considered, Sterilant, Dose, Acceptance Criteria

Complete Test Report – Method Employed, Parameters, D-value, F-Value, no, of cycles, Sterilant Used, Dose of radiation, VD _Max, SAL etc based on type of sterilization employed. Results and Discussion and conclusion

Validation Methods are the processes used to confirm that the procedure or technique employed for a specific test is suitable for its intended use. Results obtained can be utilized for the determination of the quality, reliability and consistency.

The validation methods used for sterilization are as follows:

EO and Steam – Overkill or Half-Cycle Method, most of the time

Half-Cycle Method:

• The method involves estimation of the minimum time of exposure to EO, along with other process parameters except time remaining constant, at which there are no debris.
• Two further experiments should be performed to confirm the minimum time. Both should show no growth from the BIs. The specified exposure time should be at least double this minimum time.
• Method 1: Dose setting using Bioburden
• Method 2: Dose setting using Fraction Positive information.

2A: General Applications

2B: For very low bioburden

• A cycle of short duration from which debris can be recovered should also be run to demonstrate the adequacy of the recovery technique.

 

Sterilization Method	Conesus Standard
Moist Heat (steam)	ANSI/AAMI/ISO 17665-series Sterilization of health care products: Moist Heat – Requirements for development, validation, and routine control of a sterilization process for medical devices
Ethylene Oxide (rigid chamber)	ANSI/AAMI/ISO 11135 Sterilization of Health-care Products: Ethylene Oxide – Requirements for the development, validation and routine control of a sterilization process for medical devices
Radiation	ANSI/AAMI/ISO 11137-series Sterilization of health care products – Radiation – Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices, and Parts-2 and -3.
Dry Heat	ANSI/AAMI/ISO 20857 Sterilization of health care products – Dry heat – Requirements for the development, validation and routine control of a sterilization process for medical devices (Almost) Everything Else ANSI/AAMI/ISO 14937
(Almost) Everything Else	ANSI/AAMI/ISO 14937 Sterilization of Health-care Products – General requirements for characterization of a sterilizing agent and the development, validation, and routine control of a sterilization process for medical devices

 

 

 

The technical operation is performed as part of development, validation, or requalification to determine the presence or absence of viable microorganisms on the product or portions thereof.

Sterility testing is performed for three reasons:

• Test for sterility (USP/EP)- Confirm requirements for sterility of a product following exposure to a sterilization process or aseptic manufacture
• Test of sterility (ISO11737-2)- Qualify the minimum irradiation dose needed to achieve a specified sterility assurance level (SAL)
• Test for Sterility of Sub-lethal EO validation samples (ISO11135) to establish and prove the relationship between the BI and the natural product bioburden.

Sterility tests are carried out by:

• Direct Transfer of the product in a suitable growth medium is the preferred method according to ISO 11737-2 as the device is in direct contact with test media throughout the entire incubation period.
• Membrane Filtration after extraction of microorganisms, which is applicable for products with antimicrobial activities.
• Addition of growth medium to the product. Depending on the product, additional preparation steps may be necessary, like disassembling the device, adding surfactants to the medium, or flushing the device.

Special attention should be given to the labelling of sterile devices.

• Devices that are not sterile entirely but certain parts to be sterilized must be labelled to adequately intended to be “sterile” in the package.

E.g., Caution: Only the fluid path of the set is sterile and nonpyrogenic. Do not use in a sterile or aseptic area without proper precautions.

• Devices are intended to be sterilized by the user before use. In this situation, the labelling should provide adequate information as to at least one suitable method of sterilization and any precautions or safeguards to be followed.

E.g., the labelling should describe any: unique cleaning methods required; changes in the physical characteristics of the device that may result from reprocessing, which affect its safety, effectiveness, or performance; and limit the number of times resterilization and reuse can be done without affecting the safety or effectiveness of the device.

• Single-use sterile devices, some manufacturers include labelling to advise against resterilization and reuse.

Devices are not designed or constructed to be recleaned and may not be capable of withstanding the necessary recleaning and resterilization procedures. However, where reuse is common practice, manufacturers are encouraged to provide the information.

• The label of multi-device kits or packages containing a combination of sterile and nonsterile products must not state or imply that all contents are sterile. The need for users to have instructions on how to open a sterile device package to avoid contamination of the device also needs to be evaluated. When necessary, such instructions should be included in the labelling.
• When a manufacturer modifies a device, the manufacturer must also review the labelling to ensure that it reflects current revisions and specifications.
• Some manufacturers identify labelling with a drawing number plus a revision code or date as an aid in identifying current labelling.
• The package insert or other labelling for in vitro diagnostic products is required to contain the revision date (21 CFR 809.10).

FDA puts established sterilization methods into two categories,

Category A:

These methods have a long history of safe and effective use as demonstrated through multiple sources of information such as ample literature, clearances of 510(k)s, or approvals of premarket approval (PMA) applications and satisfactory QS inspections. In addition, for established methods such as dry heat, EO, steam, and radiation, there are voluntary consensus standards for development, validation, and routine control that FDA recognizes.

Examples of this Established Category A Sterilization Methods:

Dry heat

Dry heart sterilization takes longer than steam sterilization due to the inefficiencies of heating air with shallow moisture content. Compared to steam sterilization, which requires a temperature of of around 121 degrees Celsius to be maintained for approximately 30 minutes, dry heat sterilization requires higher temperatures of around 180 degrees Celsius to be effective at neutralizing biological contaminants and their spores.

For this reason, dry heat sterilization is most appropriate for medical devices that are heat resistant but susceptible to water damage, making steam sterilization a poor choice. Hot air ovens are the most common setup for dry heat sterilization of tools composed of metal or glass.

 

EO with devices in a fixed, rigid chamber

Ethylene oxide sterilization is a chemical method that is popular among medical device manufacturers. Unlike steam sterilization and dry heat sterilization, which require that the medical device be heat stable, a variety of materials – like plastics and electronic components – can be exposed to ethylene oxide gas without distorting the medical device’s form or ability to function.

As an alkaline agent, ethylene oxide gas reacts with DNA, proteins, and enzymes to disrupt cell growth and division, thereby killing the microorganism. In addition to penetrating small spaces inside medical devices, ethylene oxide can also be used to sterilize medical devices that have already been packaged in plastic.

However, this medical device sterilization method has its drawbacks; for one, ethylene oxide gas is toxic to humans and highly reactive at low temperatures, making it imperative that the sterilization procedure take place in a leak-proof chamber. In addition, the method is more complex than other forms of sterilization as it requires three steps to complete. First, devices are prepared for sterilization through environmental controls, then, the operator sterilizes the device by adding the gas, and finally, the gas is thoroughly removed from the product.

 

Moist heat or steam

Characterized by high temperatures and pressures, steam sterilization is most appropriate for devices composed of stable, heat-resistant materials such as steel. In addition, reusable surgical tools are often steam sterilized in an autoclave to kill any microorganisms that may be present on the surface of the instruments, as well as bacterial spores, which can be resistant to other forms of disinfection.

Despite its ability to sterilize equipment quickly, steam sterilization is often not the decontamination method of choice for medical device manufacturers. While the steam sterilization process takes just three to 15 minutes, medical instruments must be allowed to cool and dry completely over several hours before being used.* The build-up of water droplets inside device components can impair their functioning and corrode materials that aren’t meant to come into contact with water. Of course, plastic and electronic components can also be damaged by exposure to steam, making this sterilization method unsuitable for most complex medical devices.

 

Radiation (e.g., gamma, electron beam)

Sterilization of medical devices using radiation does not leave any trace of radioactivity. Therefore, irradiating medical devices using gamma or electron beam (E-beam) radiation is a clean way to sterilize.

Like ethylene oxide sterilization, radiation can penetrate product packaging. However, the latter is a less time-consuming method. In addition, dense materials can also be irradiated quite efficiently.

This sterilization technique is best-suited to single-use devices like implants, catheters and syringes. When used to sterilize reusable devices, processors will need to perform quarterly dose audits to ensure that the level of radiation exposure is sufficient to destroy any microorganisms on the device.

This sterilization method causes slight fluctuation in temperature, making it appropriate for use on devices made from heat-sensitive plastics and other materials. For example, autoinjectors like the EpiPen, pre-filled syringes and other disposable medical devices can be sterilized using this method. However, care must be taken when using this method as it can cause cosmetic and functional issues such as discolouration and harmful effects on various materials used in the device.

Category B:

There are other established methods for which there are no FDA-recognized dedicated consensus standards but for which published information on development, validation, and routine control is available.

 Examples of these Established Category B Sterilization Methods:

Hydrogen peroxide (H2O2)

Hydrogen peroxide sterilization is a low-temperature sterilization process that utilizes hydrogen peroxide vapour. The vapour fills the sterilization chamber, penetrates the device, and sterilizes exposed surfaces. Hydrogen peroxide sterilization is one of the few commonly used low-temperature sterilization modalities, making it an option for sterilization of heat-sensitive devices. Hydrogen peroxide sterilization has cycle times typically running less than an hour. Hydrogen peroxide is compatible with a wide range of materials commonly used for medical devices. Hydrogen peroxide sterilizers must adhere to OSHA’s Permissible Exposure Limit (PEL), which is one ppm over 8 hours. Since these systems are self-contained, exposure to workers is limited. The only byproducts of the process are water and oxygen.

 Ozone (O3)

Ozone has been used for years as a drinking water disinfectant. Ozone is produced when O2 is energized and split into two monatomic (O1) molecules. The monatomic oxygen molecules then collide with O2 molecules to form ozone, which is O3. Thus, ozone consists of O2 with a loosely bonded third oxygen atom that is readily available to attach to and oxidize other molecules. This additional oxygen atom makes ozone a powerful oxidant that destroys microorganisms but is highly unstable (i.e., the half-life of 22 minutes at room temperature).

Flexible bag systems (e.g., EO in a flexible bag system, diffusion method, injection method)

The FDA 510k quality is important for quick approval and less review comments. The development of an FDA 510(k) file is difficult due to 17 different modules to satisfy each 510(k) need.  All pertinent procedures, test results, and other supporting documentation are offered in the designated annexures with the proper file numbering and titles.  The majority of 510(k)s have far more than 250 pages.  Write to us  or submit the online quote request form.

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