Validating Radiation Sterilization in a Global Marketplace

A review of current standards and their implementation and validation and how they affect product release times to the marketplace.

Ed Arscott, Susanne Anderson, John J. Broad, and Dave Parente

When choosing irradiation to sterilize medical devices, U.S. manufacturers have historically relied on FDA guidance and generally followed validation methods prepared by AAMI. Although this is still true, manufacturers must now also consider the European Medical Devices Directive (MDD). AAMI members have been working with ISO and the American National Standards Institute (ANSI) to produce voluntary, harmonized guidance for validation and testing methods. The European Union (EU) has also enacted mandatory standards for its members. Although efforts toward harmonization are still ongoing, there have been sufficient changes in the regulatory guidance to generate questions as to how to achieve simultaneous compliance with these various standards.

GUIDANCE STANDARDS

Section 820.752 of FDA's quality system regulation (QSR) requires that "all processes used to produce medical devices be validated."1 Manufacturers may follow accepted sterilization validation guidelines or develop their own. For companies selling solely within the U.S. marketplace, compliance with ANSI/AAMI/ISO sterilization standards is sufficient.

Any medical devices sold into EU-member countries are required to meet relevant EN sterilization standards. Fortunately, there is a good deal of congruence between ANSI/AAMI/ISO and European standards for radiation sterilization (Table I).

Document Europe ISO United States
Estimation of population EN 1174 11737-1:
1995
AAMI TIR
No. 8: 1991
Microbiological sterility * 11737-2:
1996
AAMI TIR
No. 8: 1991
Validation
sterilization
methods 1 and 2
EN 552:
1994
11137:
1994
AAMI
ST 31: 1990
ST 32: 1991
Validation sterilization
small lots and
single batch
** AAMI/ISO TIR
13409: 1996
15844: 1998


Table I. A comparison of the various guidance documents being used for radiation sterilization process validation. (* signifies that guidance is currently unavailable.)

The current primary ISO standard regarding irradiation of medical devices is ANSI/AAMI/ISO 11137, "Sterilization of Healthcare Products—Requirements for Validation and Routine Control—Radiation Sterilization."2 Some techniques developed in previous AAMI guidelines ST 31 and ST 32 were adopted into ANSI/AAMI/ISO 11137.3,4 The validation methods in ANSI/AAMI/ISO 11137 have been referenced in European Standard EN 552, "Sterilization of Medical Devices—Validation and Routine Control of Sterilization by Irradiation."5

Additional approved ISO and European standards focus on test methods to support validation programs. These documents address bioburden enumeration (ISO 11737-1; EN 1174-1) and sterility testing (ISO 11737-2).6–8 Three segments under development—EN 1174-2, EN 1174-3, and EN 1174-4—will provide specifics on sampling methods, validation of test methods, and test methodology.9 Technical comparison of these documents shows great uniformity in testing methods, including incubation times, media selection, and temperature conditions used during validation and routine-audit bioburden and sterility testing.

The procedure for establishing a 25-kGy minimum sterilization dose for small or infrequent production batches is not fully harmonized. Validation was previously addressed in AAMI ST 32 as method 3. In 1997, this document was superseded by an enhanced method in AAMI 13409, "AAMI/ISO Technical Information Report (TIR) 13409 Substantiation of 25 kGy."10 At present, AAMI 13409 has been approved in the United States, but it has not been adopted internationally.

CHOOSING A STERILITY ASSURANCE LEVEL

The first step in ensuring medical device sterility is determining the appropriate sterility assurance level (SAL), a measure of the probability that one unit in a batch will remain nonsterile after being exposed to the sterilant. Product lot sterility can only be expressed in terms of probability. For example, an SAL of 10-3 means that one device in a thousand might be nonsterile. Selecting the SAL occurs during the dose-setting phase of radiation sterilization validation. In many cases, the intended use of the device will dictate the need for a particular SAL. The commonly accepted SAL for invasive medical devices is 10-6.

Some European countries, however, recognize only 10-6 SAL for a "sterile" label claim. The European Pharmacopoeia Commission concurs. Therefore, the minimum SAL may be based on the regulatory requirements of the country in which the device will be sold as much as on the device's intended use.

LOT RELEASE CRITERIA—DOSIMETRIC RELEASE

The desired goal for radiation sterilization validation is determining the minimum exposure dose that can routinely be used to meet the preselected SAL requirements and allow dosimetric release, which is the determination that a product is sterile based on physical irradiation process data rather than sterility testing. Dosimeters measure the absorbed radiation dose (physical data) delivered to the product at given locations. These data can verify that the dose absorbed by the product meets validated specifications.

Sterilization using 25 kGy did not require validation prior to implementation of the QSR. However, tests have evidenced microbiological issues that indicate that 25 kGy may not always yield the desired product SAL.

The model microorganism population used in ANSI/AAMI/ISO dose-setting validation procedures is designed so that a 25-kGy dose is expected to sterilize a device to an SAL of 10-6 when its bioburden—the sum population of viable microorganisms on the device—is less than 1000. Many devices, however, have a bioburden greater than 1000 microorganisms, and some microorganisms have sterilant-resistant characteristics that make them harder to kill than the model population. In such cases, 25 kGy may be insufficient to achieve an SAL of 10-6.

ANSI/AAMI/ISO VALIDATION METHODS AND SUBSTANTIATION OF 25 kGy

Methods 1 and 2 of the ANSI/AAMI/ISO 11137 guideline involve establishing a sterilizing dose using a bioburden resistance model. Method 1 is preferred because of its reasonable cost and study time. Because it employs model population data from Whitby and Gelda that is based on historical data received from manufacturers, it provides a greater challenge than the natural bioburden on a device.11 With method 2, the dose is determined experimentally based upon the resistance of the device under study.

The substantiation of 25 kGy as a sterilization dose (AAMI/ISO 13409) uses bioburden to establish a minimum acceptable product release dose of 25 kGy. Although the three methods require different numbers of samples to complete the validation, they all specify quarterly dose audits to confirm the continued validity of the sterilization dose (Table II).

Validation
Method
Samples Required
Initial
Validation
Dose
Audits
Method 1136110
Method 2643110
25 kGy66–30620–100


Table II. A comparison of the various requirements that different sterilization modes have to verify the continued validity of their doses.

The applicability of methods 1, 2, or 25 kGy to a specific product is based on a combination of factors. Table III illustrates some of the issues to be considered when choosing which method is most appropriate for a given situation. Note that this table factors in both technical and financially based considerations.

Sterilization Methods 1 2 25 kGy
Bioburden <1000 CFU
>1000 CFU
X
X
X
X
X
Radiation
tolerance
<25kGy
25kGy
X
X
X
X

X
Lot size500
>500

X

X
X
Production
frequency
Routine
Infrequent
X X
X
Bioburden
resistance
Resistant
Nonresistant

X
X
X


Table III. Practical considerations when selecting which sterilization method to use for a particular application. CFUs are colony-forming units.

Method 1. This method is commonly called the bioburden method because the number of organisms on the product must be determined prior to sterilization. Ten samples from each of three lots are tested for a total of 30 samples. The bioburden results are used to calculate an experimental radiation dose called the verification dose, which is anticipated to yield an SAL of 10-2. An additional 100 samples from a single production lot are exposed to this dose and sterility tested. A bacteriostasis/fungistasis test also is conducted with selected microorganisms to examine whether the presence or absence of various other substances inhibits their growth. Additional samples are required for this test. If there are no more than two positive (nonsterile) cultures in the 100 sterility test samples, the validation is considered successful, and a routine SAL sterilization dose is calculated based upon the original bioburden data. Method 1 generally requires 136–146 samples and is usually considered the method of choice because method 2 requires a much larger number of test samples.

When using method 1 on a large or costly device, the manufacturer may not have to use the full number of samples noted above. For example, instead of using a full complement of complete finished devices, a large device might be divided into five portions equal in anticipated bioburden makeup, both in overall number of organisms and number of types. Twenty such devices would be cut into five pieces, yielding 100 portions with a sample item portion (SIP) equal to 0.2% of the original device.

If a large device consists of several dissimilar components, each with a different level or mix of bioburden organisms, this practice will not work. There are, however, often other ways to reduce the total number of devices needed to fulfill method 1 requirements. If an SIP of less than 1.0 is chosen, it must be validated to document the bioburden equivalency by performing a sterility adequacy test with 20 nonsterilized units that yield at least 80% positives.

Method 2. This bioburden resistance method requires the manufacturer to determine the radiation resistance of the organisms actually resident on a product. In method 2, device units from each of three production lots are exposed to incremental radiation doses (e.g., groups exposed to 2, 4, and 6 kGy, etc.) and then sterility tested. The results are used to determine a verification dose expected to yield an SAL of 10-2. A group of 100 devices is then exposed to this verification dose. If fewer than 2 of the 100 units are nonsterile, the data are used to calculate a routine SAL sterilization dose.

Method 2 is composed of two protocols. Both require a greater number of samples during validation than the other methods. For protocol 2A—validation for normal product bioburden distribution with an SIP of 1.0 or less—the minimum number of samples used is 640; 540 are used for the incremental dose series and 100 for the verification dose experiment. For protocol 2B—validation for product with consistent and low bioburden and an SIP of 1.0 (i.e., the entire device)—approximately 580 are generally tested. In each method—2A and 2B—an extra 200 samples (100 from each of the lots not used for the verification dose experiment) must be available. It they are not consumed in the study, they will be discarded if the SIP is <1.0,>

A good reason to choose method 2 is its ability to validate a lower dose than method 1. Method 2 is based on a device microorganisms' average resistance to radiation, whereas method 1 is based on a theoretical model population that may or may not be similarly resistant to radiation as the organisms under study. Based on the ability of DNA ligase to repair radiation-caused DNA damage, it could conceivably take a smaller dose of radiation to destroy the less-sensitive organisms on the actual device than it would to inactivate the model population used to establish the method 1 doses. Thus, a method 2 study on such a device would allow a lower minimum routine sterilization dose.9 Conversely, if the ambient bioburden organisms would require more radiation than that indicated by the method 1 chart, method 2 can be an alternative method for validation. Another tactic involves identifying ways to lower bioburden levels and revalidating using method 1.

TIR 13409 SUBSTANTIATION OF 25-kGy MINIMUM STERILIZATION DOSE

Methods 1 and 2 are not practical when there is limited test sample availability. The substantiation protocol for 25-kGy radiation sterilization was designed for use with small-volume production of fewer than 1000 units per lot, for single special-order lots and lots used in clinical trials and field studies, and for release of the first lot produced by a manufacturer. Given problems of failures associated with its use, the historical AAMI method 3 was not included in ANSI/AAMI/ISO 11137 and will not be discussed here except as a counterpoint to method 13409. The industry has had only limited experience in application of the latter method. Both methods use data developed from the inactivation of the microbial population in its natural state and are based on the probability model for inactivation of microbial populations provided in ANSI/AAMI/ISO 11137.

Method 13409 targets substantiation of 25 kGy for a single batch of products or for routine production of small batches of fewer than 1000 devices. Bioburden testing and dose-verification experiments are conducted on samples from each of three production lots.

Method 3 allowed test sample sizes to be selected based on production lot sizes from 7 to 1000 units. AAMI 13409 takes into account the pitfalls associated with taking samples from small batches and requires a minimum sample size of 10 devices for each of the bioburden and sterility experiments. The rationale for this change is that the distribution of the natural bioburden on products in batches of less than 20 may vary and not be sufficiently represented if fewer than 10 units are tested, potentially leading to validation failures.

Another significant difference between method 13409 and method 3 is the acceptance criteria when testing 30 or more samples in the verification experiment. Method 3 had allowed only one positive culture; method 13409 allows two. The acceptance limit in method 13409 is more in line with the acceptance criterion established in method 1.

Method 13409 requires only three successful verifications, as long as product batches are produced more frequently than one batch every 3 months. The verification dose is recalculated and tested for each subsequent dose audit after validation completion.

For method 13049, the average adjusted bioburden of each device may not exceed 1000 colony-forming units (CFU) per device. When working with a device with a high bioburden, it is important to consider that the 1000-CFU limit applies to average device bioburden, not to each individual sample result. Bioburden spikes—individual device unit values that are significantly higher than the average bioburden of the tested sample group—can potentially lead to a validation failure. If false spikes are used in calculating the verification and sterilizing doses, prohibitively high irradiation doses might be set. It is also possible that doses could be set too low if spikes exist but not in sufficient numbers to be factored into the dose-setting calculations. Spikes within the 100 sterility test sample lot can cause a verification dose failure.

Manufacturers should investigate bioburden spikes and determine their source. Spikes can result from the following causes: lack of environmental control in manufacturing, faulty handling during or after sampling, packaging problems, or lab contamination. For additional information regarding controlling manufacturing environments, see USP Supplement 8, 1998.12 The destruction of microorganisms can be characterized by their survival curves, and resistance data in the literature can guide a course of action during a failure investigation.13 A detailed review of source-specific factors known to be associated with the product—e.g., human handling or contact with air, equipment, or water—should occur. If the organisms associated with product bioburden can be identified or characterized, it is possible to determine their resistance to irradiation. High levels of resistant microorganisms may reduce the SAL to less than 10-6.

Manufacturers that have used method 3 should review their data in light of the AAMI 13409 substantiation method requirements. Rather than invalidating the previous results, it is possible to simply adopt the AAMI 13409 audit procedure based on the testing that has been performed, although manufacturers that use fewer than 10 samples should be aware of the increased probability of failure. For example, products composed of stainless steel/titanium are manufactured under harsh conditions that reduce the microbial populations to such low levels that the population may have a resistance probability greater than that assigned to the model population. The manufacturer should increase the test sample size whenever possible to avoid validation failures. If revalidation is required, it is acceptable to continue sterilization based on the method 3 data until the revalidation process is complete.

STERILIZATION VALIDATION COMPARED WITH USP STERILITY TESTING

Although still used for some materials produced in sterile fill operations that are not subjected to terminal sterilization, or to determine sterility of products selected from field sampling, USP sterility testing is not acceptable as a lot-release criterion for irradiated devices.

Many factors support the release of devices, and there are five steps to achieving a successful validation. They are:

  • Product qualification.

  • Installation qualification.

  • Process qualification.

  • Certification.

  • Maintenance of validation.

The product qualification phase addresses product and packaging materials evaluation, as well as sterilization dose determination. The installation phase deals with equipment testing calibration, mapping, and documentation by the sterilization facility. The manufacturer and sterilization facility should then address process qualification, which includes establishing a product loading pattern, followed by dose mapping for the identification of minimum and maximum dose within the product load. Once the data have been collected for the first three phases of validation, the documentation is certified in accordance with ISO 9001 or ISO 9002. Routine validation maintenance ensures the validity of the sterilization dose, equipment, and dosimetry systems. (For more details, refer to ANSI/AAMI/ISO 11137.) After validation is successfully completed, each product lot is released by dosimetry.

The validation process covers the product sterility assurance requirement. USP testing cannot achieve this level of assurance because it is only conducted on a subset of the total sterilant-exposed samples. While the results are accurate for the samples tested, they cannot be extrapolated to determine the sterility assurance level of the remainder of that lot. Since the test results do not demonstrate the desired SAL characteristic, product sterility testing cannot be used in lieu of validation.

Once a validation is conducted, product lot-release sterility testing is not required as long as the manufacturer periodically conducts audits to verify continued validity of the minimum sterilization dose. Barring the need for other release tests, such as pyrogen testing, the product is ready for release if the dosimeters indicate that the required minimum sterilization dose has been achieved. Although there is no rule that says that validation can't be augmented with USP sterility testing, there are issues that render this impractical. Because a USP sterility test requires a 14-day test period, its use can create a 2-week delay for a product otherwise ready for release. Also, devices used in a USP sterility test cannot be sold, and are thus a sunk cost. If the product is expensive to manufacture, product sterility testing adds significant unnecessary expense to lot release.

BIOBURDEN AND STERILITY METHODS VALIDATION

The validation methods discussed in this article require methods developments testing to ensure the reliability of bioburden and sterility test results. These tests include bioburden recovery bacteriostasis/fungistasis and SIP adequacy (discussed previously).

Questions concerning bioburden recovery validation are becoming more frequent as manufacturers and contract sterilizers realize the importance of this test in establishing a routine sterilizing dose. Although bioburden recovery validation is not a new concept, it has become a specified part of ANSI/AAMI/ISO TIR 11737-1 and EU Standard EN 1174-1. Understanding the purpose of the recovery test is critical to understanding its use.

A bioburden recovery validation generally involves three to six samples and determines the efficiency of the bioburden testing method. Based upon the materials used for manufacturing the device and the complexity of its design, there is a possibility that a specific bioburden test can only remove a fraction of the existing microorganisms from the device for bioburden counting. The recovery test makes allowance for the residual organisms remaining on the device after the assessment, yielding either a percent recovery or a recovery factor used to adjust the bioburden counts. Because the results gained from both AAMI 11137 method 1 and AAMI 13409 rely on mathematical calculations based on the device bioburden, using the correct bioburden number is critical. An underestimated bioburden results in a lower verification dose, risking validation failure and product recall.

For example, if bioburden test results yield 750 CFU per device, knowledge of the method's efficiency may be critical to the selection of the validation test method. If the 750-CFU total is a nonadjusted figure, and a subsequent recovery study of the device indicates that the bioburden test method recovers only 40% of the organisms on the device, then the assayed bioburden must be divided by 0.4, resulting in an adjusted bioburden of 1875 CFU, well over the method 13409 maximum limit of 1000.

Average Device Bioburden LevelMaterial or Assembly CategoryFinished Devices
1–10 MetalDental or orthopedic implants
Extruded polymersExtracoporeal tubing, light handle
Automated assemblyNeedles
Sterile fill syringes
10–100Plastic assembled with cleaningCatheters
Partially automated with assemblySuture collection devices
100–500Natural materials, treatedLatex gloves
Plastics assembled without cleaningDiagnostic probes
>500Natural material, untreatedCotton stockinette
Tissue grafts


Table IV. The material used in a device and its assembly process greatly affect the expected average bioburden results.

When there is a significant increase in the bioburden for a device that has already undergone a validation study, the manufacturer should review the original validation program and, if necessary, conduct a new dose-setting validation. Bioburden levels vary depending on the manufacturing processes and operator control. Highly automated assembly with minimal operator contact produces products with low bioburden. However, if the assembly process requires multiple assembly steps and operator contact, a lack of cleaning, for example, will yield significantly higher bioburden levels (Table IV). Although the established dose may achieve a certain level of product sterility, it may not consistently meet the prescribed SAL. Moreover, although an increase in bioburden numbers does not necessarily represent an increased resistance to irradiation, such a result is common enough that the ANSI/AAMI/ISO 11137 guideline sections covering method 1 contain a table that indicates a direct relationship.

If routine quarterly audits are conducted using the 1994 AAMI audit procedures and result in acceptable numbers according to the AAMI criteria, both the audit dose and the sterilization dose can be considered adequate, and no action is required to comply with the doses listed in the table. If, however, periodic failures occurred in audits or the dose has required augmentation, it is likely that the sterilization dose needs to be reestablished using bioburden studies that include bioburden recovery data. The manufacturer might also need to investigate the facility's environmental controls that could affect device bioburden. An investigation checklist should include facilities, equipment, personnel practices, process changes, and material control.

Manufacturers can choose to continue using their bioburden recovery validation programs established before 1994, and they are not required to use the new procedures in ANSI/AAMI/ISO TIR 11737-1. The 1991 AAMI ST 32 radiation sterilization guideline refers to AAMI TIR No. 8, developed by the radiation sterilization subcommittee to outline microbiological procedures for use in validating radiation sterilization.14 However, the 1994 radiation sterilization guideline is considered an improvement over the 1991 version because it incorporates internationally harmonized test methods. If using the 1991 method, a manufacturer must be prepared to justify its continued use of the older method—for example, consistency of the information and data generated using those guidelines.

Validation can be significantly affected when a device manufacturer designs a product that may support microbiological growth, such as gel products or burn dressings. The temperature and the length of time between the final packaging and the processing for sterilization, including any process interruptions, must be considered when determining a sterilization dose. The validation of this phase of the presterilization control can be performed by conducting bioburden tests at multiple time increments. For example, if the product is processed within 3 days of being manufactured, testing may be performed at 0, 24, 48, 72, and 96 hours. The sampling at 96 hours gives an understanding of the bioburden growth characteristics in the event that processing exceeds 3 days. Once validation of growth-supporting products is complete, the samples for dose verification and audits should be irradiated at the maximum time validated—3 days in this example—so that the schedule is maintained.

Manufacturers have questioned whether the sterilization process can be validated by identifying all of the bioburden isolates, determining each one's resistance, and establishing a sterilization dose based on the most resistant one. In most cases, the bioburden fluctuates with raw material shipments, personnel changes, climate changes, and manufacturing conditions. It is unlikely that the exact same group of organisms would always be on a product. Even if they were, to prove so would require constant monitoring, and the expense associated with ongoing identification and resistance studies would probably be prohibitive. In addition, these studies are somewhat controversial because of resistance changes that may occur during laboratory propagation techniques.

BACTERIOSTASIS/FUNGISTASIS TESTING

The USP bacteriostasis/fungistasis (B/F) test is an important step in ensuring the successful completion of a sterilization validation program. The B/F test is used to demonstrate whether the product under investigation could inhibit microorganism growth—and thus the observation of a true result—in the dose verification sterility test. In the presence of an inhibitory substance, existing microorganisms might not be observable, leading to a false negative (sterile) test conclusion. The B/F test is usually run prior to or along with the initial verification sterility test for a particular combination of sterilization process and product. The procedure consists of performing the proposed standard sterility test, adding a low level (100 CFU) of selected microorganisms on the device cultured. The results should show positive growth within no more than 7 days. This growth indicates that there are no inhibitory substances in or on the test article that would cause a false negative reading in the sterility test. It is important that the B/F test method mimics the sterility test method by duplicating the proper media type, media volume, and temperatures (for example, 100 ml of soybean casein digest at 28°–32°C). The April 1998 USP Supplement No. 8 addressed a revised B/F test, and additional microorganisms were added.12

DESIGNATION OF PRODUCTION LOTS AND VALIDATION TIMING

Taking several weeks to prepare products for validation can affect the success of the results. If an elongated time frame is normal for lot production, it may be necessary to adjust the definition of a lot for the validation study. An extended amount of time between production and bioburden testing could change bioburden numbers, resulting in an artificially low or high assessment that does not reflect actual numbers at the time of production. Three lots are used for bioburden testing to avoid basing the validation on limited data from a single set of production circumstances. If a lot can be redefined in such a way as to obtain samples representing a broad range of production factors, this special lot definition can be used for the validation. For instance, different production shifts, use of materials, or packaging from different lots can influence the definition of a lot on a given day.

VALIDATION FAILURES

During the course of the initial validation or dose audit, a verification dose experiment may fail with several positive cultures. A complete failure investigation should be conducted to determine if the problem can be traced and corrected so that the study could be repeated. Among the questions that should be asked are:

  • Were there any process changes that could potentially affect bioburden population or resistance?

  • Were any of the samples old—i.e., had they been held for several weeks or months?

  • Was the recovery test done to ensure that the bioburden average was correct and not too low?

  • Was the verification dose calculated using the right SIP?

  • Was irradiation performed to correct specifications?

  • Were the dose verification samples handled and packaged the same way as the bioburden samples?

  • Were the samples handled correctly during culturing, or was there a chance of contamination?

  • Was an investigation performed to rule out the possibility of lab contamination?

  • Was an SIP less than what was originally validated?

  • Was the potential bioburden of molders and other packaging considered?

These and other factors should be investigated by both the laboratory and manufacturers before the decision is made to retest or use another validation technique or sterilization method.

DOSE AUDITS

Following each successful validation procedure, the manufacturer should plan an effective audit program. Quarterly dose audits provide a mechanism for reverifying the validated sterilization dose. This is necessary because several variables can change the device bioburden in the 3 months between quarterly dose audits. In some circumstances, such as infrequent production, a quarterly dose audit may not be practical. If an alternative auditing schedule is used, it should be documented in the validation protocol, indicating the reason and explaining the specifics.

The 1984 guideline, AAMI ST 32, states that "dose audits should be performed quarterly unless bioburden data indicate otherwise." Many manufacturers have interpreted this to mean that verification dose audits are not required if bioburden data are acceptable. The AAMI radiation working group is currently proposing guidelines that allow the audit frequency to decrease once a successful audit history has been established. Quarterly audits, however, help maintain a controlled manufacturing environment.

A dose audit failure does not automatically mean there are nonsterile products on the market. There is a possibility that all the lots until the one that failed the dose audit test were acceptable. It is possible that the SAL of the marketed products is lower than was intended. Depending on the number of samples that were positive in the audit, it might be permissible within the guideline to augment the verification and sterilizing dose. If three to six positives occurred in the sterility test, the dose should be augmented to match the bioburden audit results. For an audit failure of seven or more positives, the bioburden information can help determine a possible cause for the failure. Additionally, if there was known or suspected improper preparation or irradiation exposure, or incorrect testing of the dose audit samples, the audit can be invalidated and repeated. The key is determining whether the audit failure was related to a change in the device that warrants reestablishing the sterilizing dose. A thorough investigation of laboratory- and sterilization-related issues will help resolve this question.

SPECIAL SITUATIONS

When a device manufacturer produces many product lines, the validation program may be designed to categorize products by family groups depending on the type of manufacturing process used. Within each product family, a representative device is selected based on bioburden data and characterization of organism types used for the validation assessment. The results are used to determine the sterilization dose for the remainder of the product family. It is entirely possible, given a similarity of raw materials, manufacturing processes, and intended use, that all devices produced by a manufacturer might be considered as a single product family. This and any other assessment of product-family designation requires sound, documented justification. A standard for developing and monitoring product families is in preparation by the AAMI radiation committee working group.

Some devices are custom made in small lots, which can be manufactured in various sizes and designs. Validating the radiation sterilization process for these devices can be accomplished by using a test sample made of the same material that is as large as the largest current or planned device and that has been subjected to at least as much handling and processing as the actual device. The object is to represent the worst-case or most difficult situation so that all other custom devices can belong to the product family group represented by this dose-setter. Once validated, tight control over new or altered devices is required for ongoing proof that none of the actual devices poses a greater sterilization challenge than the dose-setter. Depending on the diversity of the devices, an alternative is to validate using a mix of all the products or components manufactured, keeping density issues in mind when considering a product mix.

Some device manufacturers choose to produce one or two lots per year with single-batch sizes greater than 1000 units. Since the lot size is greater than 1000 units, the 13409 substantiation method is not applicable, and the manufacturer must consider other options in order to validate and maintain requirements of ISO 11137. A validation of a single product lot that exceeds the small batch-size limits can be conducted via use of a modified method 1 approach. The validation employs bioburden testing of 10 samples and dose verification sterility testing using 100 samples from the single production batch. This technique is referenced in a new standard, ISO/AAMI TIR 15844, titled "Sterilization of Healthcare Product—Radiation Sterilization—Selection of a Sterilization Dose for a Single Batch."15 This document is intended for use in conjunction with ISO 11137.

CONCLUSION

The various harmonization committees are still working to improve current standards, as well as to add new areas to them. Just as the United States went from the megarad to the kilogray as a unit of measure for absorbed dosage levels and moved away from using biological indicators in validation methods, some of the standards detailed here will continue to advance in upcoming years.

However, some things do not change, such as the need for strict environmental controls, accurate documentation, and procedural completeness—for example, once a product is on the market, maintaining quarterly audits. Manufacturers that exercise attention to detail and keep abreast of regulatory changes will find the constant changes less daunting.

REFERENCES

1. Code of Federal Regulations, 21 CFR 820, 1996.

2. "Sterilization of Health Care Products—Requirements for Validation and Routine Control—Radiation Sterilization," ANSI/AAMI/ISO Standard 11137 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1994).

3. "Guideline for Electron Beam Radiation Sterilization of Medical Devices," ANSI/AAMI Standard 31 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1990).

4. "Guideline for Gamma Radiation Sterilization," ANSI/AAMI Standard 32 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1991).

5. "Sterilization of Medical Devices—Validation and Routine Control of Sterilization by Irradiation," BS/EN 552 (Brussels: European Committee for Standardization, 1994).

6. "Sterilization of Medical Devices—Microbiological Methods—Part 1: Estimation of Population of Microorganisms on Products," ANSI/AAMI/ISO Standard 11737-1 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1995).

7. "Sterilization of Medical Devices—Estimation of the Population of Microorganisms on Product—Part 1," Draft BS/EN 1174-1 (Brussels: European Committee for Standardization, 1994).

8. "Sterilization of Medical Devices—Microbiological Methods—Part 2: Tests of Sterility Performed in the Validation of a Sterilization Process," ANSI/AAMI/ISO Standard 11737-2 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1997).

9. "Sterilization of Medical Devices—Estimation of the Population of Microorganisms on Product—Parts 2–4," Draft BS/EN 1174-2—Guidance on Part; Draft BS/EN 1174-3—Guide to Methods of Validation of Microbiological Techniques" (Brussels: European Committee for Standardization, 1994).

10. "Sterilization of Health Care Products—Radiation Sterilization Substantiation of 25 kGy as a Sterilization Dose for Small or Infrequent Production Batches," AAMI TIR 13409 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1996).

11. JL Whitby and AK Gelda, "Use of Incremental Doses of Cobalt 60 Radiation as a Means to Determine Radiation Sterilization Dose," Journal of the Parenteral Drug Association 33 (1979): 144-155.

12. United States Pharmacopeia 23, 8th supp., monograph <116>, April 1998.

13. Seymour Block, Disinfection, Sterilization, and Preservation, 4th ed. (Philadelphia: Lea & Febiger, 1991).

14. "Microbiological Methods for Gamma Irradiation Sterilization of Medical Devices," AAMI TIR 8 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1991).

15. "Sterilization of Healthcare Products—Radiation Sterilization—Selection of a Sterilization Dose for a Single Production Batch," ISO/AAMI TIR 15844 (Arlington, VA: Association for the Advancement of Medical Instrumentation, 1998).

Ed Arscott is a manager of microbiology at NAMSA, Northwood, OH; Susanne Anderson is a technical specialist in marketing and John J. Broad is the director of microbiology at NAMSA, Irvine, CA; and Dave Parente is director of operations at NAMSA, Kennesaw, GA.

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