The Bioburden samples should be tested in the media types and incubation conditions as defined in ISO 11737-1, Sterilization of Healthcare products–Microbiological methods Part 1: Determination of the population of microorganisms on product.

The conditions defining the different medias, incubation times, temperatures, are defined in Annex A, section A.6.1.3, all of which are different based upon the nature of raw materials, method of manufacture, and conditions under which manufacturing occurs. Also please note that the bioburden method must be validated as well. The validation method is described also in Annex A, section A.7.

The ISO 11737-1 document can be purchased at www.aami.org.

You can contact www.aami.org to see if they have, or know of, any training in that area. They do publish documents (standards) on hospital sterilization practices. If you would like industrial sterilization training, Sterigenics offers a course in September on radiation and EO sterilization that you can receive information on from our Web site: www.sterigenics.com. AAMI’s site will also have info on training for industrial sterilization.

If you are asking if there is a “quick and dirty” simple way to assure sterility of a clinical batch, unfortunately, the answer is “No.” One must still perform an EO Batch Release to assure the 10-6 SAL.  The details of such a batch release are detailed in AAMI TIR 16, Process development and performance qualification for ethylene oxide sterilization-Microbiological aspects.  The batch release includes the performance of the half cycle for microbiological validation and with the full cycle, the performance of EO residuals.  If you are not claiming “sterility” of the product, you may be able to use a generic overkill EO cycle, however, you should still be concerned with EO residuals and would need to perform those tests to ensure patient safety regarding the residuals.

The following AAMI standards can assist you in performing the proper testing to evaluate the validity of your sterile barrier: 

• ANSI/AAMI/ISO 11607-1:2006 - Packaging for terminally sterilized medical devices-Part 1: Requirements for materials, sterile barrier systems, and packaging.
• ANSI/AAMI/ISO 11607-2:2006 - Packaging for terminally sterilized medical devices-Part 2: Validation requirements for forming, sealing, and assembly processes.
• AAMI TIR22:2007 - Guidance for ANSI/AAMI/ISO 11607-Packaging for terminally sterilized medical devices-Part 1 and Part 2:2006. 

In addition, AAMI TIR 17:2008 provides guidance on performing accelerated aging studies, which you may also wish to perform while validating your packaging materials.

You can purchase all of these AAMI standards and TIRs at www.aami.org.

Heat is the oldest and possibly the most recognized agent of microbial destruction and is the most popular method of terminal sterilization used in the pharmaceutical industry. Costs for moist-heat sterilization, if contracted out, are similar to that of EO sterilization, in that you typically pay by the chamber where chamber sizes can range from 1 to 30 pallet sizes. Moist-heat sterilization is typically performed at 121 to 134 °C. A major concern is the degradation of materials by heat or moisture. Moist heat, however, can be successful with a range of products such as acetal,  glass, liquids, polypropylene , PTFE, fibers, and celluloses. 

Moist-heat sterilization, in that it is a terminal sterilization process, can be validated to an SAL of 10^-6. This, of course, provides a greater assurance of not producing a “non-sterile” product as compared to filtration.

AAMI TIR 17:2008, Compatibility of materials subject to sterilization, provides excellent information with regarding to Moist-Heat sterilization, as well as all other methods of terminal sterilization, and its effects on materials. You can purchase AAMI TIR 17:2008 at www.aami.org

The main advantage of terminal sterilization versus filtration is the reduced risk of a nonsterile product release to the end user.  There are a few different views on what the SAL is of product sterilized by the filtration method, the most common agreed upon being 10-4 SAL, and even that cannot be validated in the truest sense of the word.  However, sometimes the effect of terminal sterilization on a drug ingredient or API is detrimental and, therefore, terminal sterilization is not an option.

The main commercial terminal sterilization methods (EtO and Radiation)  do provide a validated SAL of 10-6.  And an ISO standard for each of these methods of terminal sterilization has been published for many years, both of which are listed as “accepted” standards by FDA.

It should be noted that for most pharmaceutical products, radiation provides the best method for delivering terminal sterilization, mainly owing to the high heat and introduction of moisture required of the EtO sterilization process.  Regarding costs, the costs associated with validating and maintaining the validation of a terminally sterilized process are also very inexpensive, as compared to filtration sterilization and the dreaded media fill testing. For example, a typical radiation sterilization validation costs at most $5000 initially and around $2000 quarterly for subsequent dose audits that are required to maintain the SAL validation (this includes cost of sterilization, bioburden testing, sterility testing.) There are also new methods of radiation validation that only use 10 to 30 product units, versus 100 - 200 units required of some of the methods used in the past. In addition, the latest ISO standard for radiation (ISO 11137-2) defines dose-setting methods designed specifically for low bioburden products, such as pharmaceuticals, so that a lower minimum dose can be used in order to obtain an SAL of 10-6.

Another suggestion, if one is still uncomfortable with the whole thought of terminal sterilization or your product is degraded by EtO or Radiation,  is not to exclude the use of terminal sterilization of the key components prior to filtration, e.g., packaging materials, vials, lyophilized ingredients, etc.).  Once again terminally sterilizing even just the key or some components prior to the filtration process can even further reduce the risk of producing a nonsterile product.

To gain more information about a respective terminal sterilization method, I suggest you obtain the ISO standard that addresses the type of sterilization.  Each of these standards can be purchased at www.aami.org, Radiation Sterilization (ISO 11137 parts 1 - 2), EO Sterilization (ISO 11135).

The quick answer to your question regarding when the term “may” or “possibly” is used in a standard is: These terms are indeed “suggestive” and are not listing a requirement but instead are providing the reader with a point or obstacle to be considered.

Here is the long answer. It is strongly suggested by irradiation providers that 2X the minimum sterilization dose be examined for setting the maximum allowable sterilization dose. In other words, when a minimum SAL dose of 25 kGy is selected, a maximum dose of 50 kGy should be examined regarding the effects of radiation on the product and its packaging components.  One would then set their dose range at 25 kGy to - 40 kGy for routine processing to ensure that if during routine irradiation the maximum dose is slightly exceeded then product can still be released.  And as someone that has been the irradiation business for 20 years, I can assure you an overdose will occur sometime during the life of the product.

The idea here is that you can add radiation to underdosed product,  but you cannot take radiation out of overdosed product.  However, if one chooses to only perform packaging tests with product exposed to only maximum allowable dose (in this example 40 kGy), then one is still adhering to the standards ISO 11607, ISO 11137 and associated TIRs.  Remember, a TIR is not a standard, and cannot be a normative reference in the world of ISO standards.

Another bit of information that may assist in packaging validation and dose selection is AAMI TIR 17:2008, Compatibility of materials subject to sterilization, which provides guidance on the radiation  effects, as well as other sterilization methods,  on different materials typically used in medical products.  AAMI TIR 17:2008 can be purchased at www.aami.org.

Not having specific information as to the type of product and the product description and packaging, I can only provide guidance on what should happen during the transition from clinical to commercial sterilization.

First, unless your two products are of a similar weight and can withstand the same amount of maximum dose delivered to the final product, the two products cannot be “sterilized at one time.” This is because if they are different weights, i.e., density, then a different cycle time in the irradiator would be necessary to deliver the same dose to the two products. In addition, it is not best practice to mix densities within the same irradiation container during routine production, in that certification of the final absorbed dose will not be accurate unless special monitoring and prior validation has occurred. However, if the two products are of similar density and minimum/maximum dose specification, then irradiating together is the best way to go.

Typically, when the manufacturer is producing clinical trial batches, the individual batches are submitted for release using a batch-release process, which is defined in AAMI/ANSI/ISO 11137-2 for both Method 1 and VDmax. The validation of the sterilization dose is only performed on 100 to 10 samples (depending on the method selected) so therefore a Process Validation Dose Map has not been performed, nor is the product subjected to the radiation source in a final carton package. It is typically a much smaller size in order to obtain the tight and low dose required of the dose validation. The product configuration during radiation-dose setting only applies to the dose-setting experiment, and not to routine processing loads. Now, if one is performing a batch release, the product configuration or loading configuration in the irradiator would be validated to that specific batch  if subsequent batches were in the same configuration. The data resulting from the dose-validation irradiation (certification of dose and dosimeter placement) will be expected to be submitted with your FDA submission as well as the loading configuration, dose received, and dose-map validation from irradiation of the clinical batch.

If after clinical trials, the final product carton is not changed, routine sterilization may continue with the dose-monitoring positions resulting from the dose-map validation performed during the clinical batch releases. If the product carton changes when the product goes to routine production, then the dose-mapping exercise at the irradiator would have to be repeated. Changing the final carton size, weight, etc., of the product does not require resubmission to FDA for your product. However, you must retain records of the product carton changes, subsequent dose-mapping results, and sterilization load configuration in your master file.

Yes, the current ANSI/AAMI/ISO 11137-2:2006 includes VDmax dose substantiation for both 25 kGy and 15 kGy. However, if you are using VDmax 15 kGy, bioburden is limited to no greater than 1.5 CFU. In addition, there is AAMI TIR 33:2005, Sterilization of health care products – Radiation- Substantiation of a selected sterilization dose – Method VDmax, which expands the VDmax method to several other doses, 15 kGy up to 35 kGy at approximately 2 kGy increments, where bioburden range is defined for each dose. AAMI TIR 33:2005 is available for purchase at www.aami.org.

Ability to control dose range in a gamma irradiator is directly related to the design of the irradiator. There are irradiator designs that specifically target a tight dose range delivery where a dose range as tight as +/- 10% of the target dose can be obtained. If a large scale irradiator is being used, dose ranges of +/-10 kGy can also be obtained by controlling the density of the product and how the product carton is presented to the irradiator, i.e., reduce the target width of the product carton when it is presented to the irradiation source. Personnel at the irradiation facility are experts in determining the best method of presenting the product to the irradiation source in order to achieve optimum control of the dose range. In addition to dose range, the dose rate too can be controlled in order to protect biological based products during the irradiation process.