ISO 11607-01 FAQ
DDL Answers Your Questions
During the webinar you mentioned that testing should be conducted on a product produced at "worst case" parameters not at nominal - is this a recommendation or a requirement?
This will be a requirement. The thought process here is that if the sealing machines are operating within the control parameters established, but at the low end of the range, then there are many packages being produced that meet production quality requirements but may be somewhat weak relative to the dynamics that will occur during shipping and handling. These packages too must reach the final end use without breaches in the sterile barrier system.
Is it necessary to re-do previous validations to comply with the new standard?
NO! You will not have to re-do any validations that have already been completed or are in process. I would recommend that any future validation incorporate the provisions of the new standards.
Why is testing performed at every step of packaging? Current practice usually combines processes and only tests at certain points.
Performing seal strength and integrity testing at points at every step of the packaging validation process helps to determine the root cause of any failures. If these interval tests are not done and only left until the end, and a failure is found, it is very difficult to determine at what point and under what stress the failure actually occurred in order to take corrective action.
Why do you recommend the accelerated aging test separate from the distribution simulation test?
The order of testing has changed from what everybody is typically used to from the last ISO 11607 standard. The current ASTM F1980-02 is also under revision and is not released as of yet. The new proposed F1980 standard will hopefully have a new flowchart to depict the new ISO 11607 standard.
Can DDL perform a visual inspection on the boxes, shelf cartons and sealed pouches after the distribution simulation but before the leak/peel tests according to our protocol?
Of course! DDL is flexible in responding to customers' specific needs. Providing your criteria for DDL to follow regarding the inspections is always useful.
Why is yellowing after sterilization a potential problem?
Yellowing may occur to some plastic materials as a result of GAMMA or EtO sterilization. This is usually more of an aesthetic issue, as the quality of the packaging and product may be an issue if the package has yellowed. For some materials, the yellowing may indicate some possibility of extractables or additives migrating out onto the surface of the material. Most of these issues have been evaluated by the material manufacturers and are usually not a big issue for package design.
Does the end user have to do the microbial barrier testing of the material or can they use the material manufacturer's data?
This is most commonly done by the material manufacturer. You should ask them for their data.
Does the PQ testing for shelf life have to be done at the minimum and maximum setting for the heat sealer, or can it be at the nominal?
The revised standard emphasizes the fact that the PQ must be done on the worst-case packages. This would include the 'stability' testing as well as the performance testing. The 'worst-case' packages will most likely be produced at the upper and/or lower limits of the process; not at the nominal.
How do companies have to modify their current tests to meet the new standards.
There is probably little modification of your current practices in order to comply with the new standard. There are no additional requirements versus the old standard; only some re-emphasis of long standing provisions. The most significant change may be that you can do your stability (aging) studies as separate entities; that is, not in a sequence with dynamic (performance) testing.
How do you validate a test method?
Validating a test method entails running the method in your laboratory using control samples and with various operators to determine the precision of the data being obtained. If the method has a Precision and Bias statement such as in many ASTM Test Methods, then your precision can be compared with that ASTM statement to ensure that reliable and comparable data is being obtained in your laboratory, as that which was obtained during a Round Robin study. The bias of the test method cannot be determined unless you test the same control samples in other laboratories. Likewise, if you are developing a new method, then only the precision can be determined within your lab. Bias is not possible unless a control sample is tested in other laboratories.
Why do you need to include the IFU when testing?
The IFU is a component of the package system that is sometimes inserted into the carton (protective package). Many times it is loose and is allowed to move around. We've seen instances where the IFU causes damage to the sterile barrier system. In one instance, a staple caused a tear in the poly component of the pouch. The 'complete' package system should be evaluated under the dynamic conditions of shipping and handling.
What is a reasonable rational for selection of sample size?
The selection of sample size is a difficult question, as it depends upon the level of risk associated with the process. If the process of making a package causes many defects in itself, and the process cannot be refined to reduce the defects, then the sample size may need to be higher. Likewise, if the result of a defect causes significant harm to a patient, then more testing will be required to ensure that the defect is found before it can cause harm. For packaging, the process can usually be refined by compliance to standards like ISO 11607 to produce packages that have a high probability of withstanding the hazards and reaching their destination without failure. If the failure is obvious, the product will not be used. If the failure is a pinhole and undetected, the risk of a microbe entering the package and contaminating the product is also probably small. So, testing packages for seal failure using bubble leak testing with a sample size of 30 is probably a reasonable risk considering all of the probabilities and events that must occur for a microbe to contaminate the product.
Is environmental extremes testing now a requirement of ISO 11607-01?
It is not accurate to say that environmental extremes testing is a requirement; however, the standard indicates in several areas that the package design shall consider the effects of distribution, storage and handling. Environmental extremes should be considered a distribution and/or storage effect. The sections that imply that these environmental extremes shall be considered include:
6.2.3 (h)
6.2.3 (j)
6.3.4
6.4.4 (Note)
It should also be pointed out that this requirement is not a new provision of the standard, but is only being restated in this Part and is being given more emphasis than in previous editions of the standard.
In order to comply with this provision, as stated in section 6.3.4, you must produce packages specifically for the performance evaluation (final package validation), as opposed to taking packages from a normal production lot for the validation testing. So, a specific manufacturing 'run’ or ‘shift’ should be conducted with the machine set-up at the settings that produce the ‘worst case’, but acceptable, packages. This could include packages at the lower or upper limits of the process.
Isn't it true that for small parcels, the final drop should be done in the most damage prone orientation, not always the bottom?
You are correct that the drop test is performed on the most 'damage prone' orientation. In order to determine the most 'damage proven orientation,' a series of drop tests would need to be performed to determine that orientation. This could be onerous to determine for each different product, so common practice is to drop the package in the most probable orientation that would occur in transport. The most common orientation of impact is the bottom (not always flat) and a flat impact transmits the most energy into the product. This has been acceptable to the industry as a default.
How can you ensure that the pouch manufacturer is using their 'worst case' pouches for package validations? Do you need to request this from the pouch manufacturer?
You have to trust your manufacturer or obtain a certification that they have produced the packages at their worst case conditions. You should request that your packages for performance qualification testing are produced at the manufacturer's worst-case conditions, but within tolerances determined by the manufacturer.
What is the definition of 'worst case' in regards to package design?
Worst-case for a sterile barrier system is probably the seal strength. It could also be embitterment of materials due to over heating. It all depends. There is no definition of 'worst-case' in the standard. This is very nebulous.
Can microbial challenges be eliminated from package validation? If so, how can the results of physical testing be justified without correlation to microbial data?
For package validation, microbial challenge testing has not been performed for a number of years. The use of physical testing to prove the maintenance of package integrity; when a validated sterilization process has been demonstrated, is sufficient evidence to indicate that the product is sterile.
Is it true that dye penetration is unreliable for packages using Tyvek?
No, this is not true; however it takes special care and training to identify the difference between a true channel leak versus a permeation of dye fluid through the Tyvek. If a channel leak is present, the dye will migrate through in a matter of seconds. If the dye is allowed to be in contact with an area of Tyvek for too much time, it will permeate through. The usual length of time to allow the dye to be in contact with a seal is about 10 seconds.
In some medical devices, double pouch packing is used although these devices are light in weight. What is the specific reason of using a double pouch?
Usually when a dual (double) pouch is used it is for providing a dual sterile barrier because the delivery of the device to the sterile field requires that the inner package be dropped into or is handled in the sterile field. There is no requirement from FDA that all devices have a dual barrier. It depends on the application of the device.
A worst-case scenario would be to perform environmental conditioning and distribution simulation testing after accelerated aging, and then to perform the performance testing. Why does DDL recommend environmental conditioning and distribution simulation testing separate from the accelerated aging?
Following this type of testing regiment would be in compliance with ISO 11607-1:2006. ISO 11607 Subsection 6.4.4 “Note” – Stability testing (AA) and performance testing (4169) are separate entities. Performance testing evaluates the interaction between the packaging system and the products in response to the stress imposed by the manufacturing and sterilization processes and the handling, storage and shipping environment.
The selection of the representative hole size used for the bubble test should be carefully considered in relation to the size of a microorganism. It is expected that the protocol and results of the test method for the bubble test be provided along with the actual test results?
The bubble leak test procedure is widely utilized as a whole package integrity test to evaluate the integrity aspect of whole package. The main aspect why this is such a good procedure is that it is validated each time it is performed. With relationship to the whole size, DDL utilizes an .008 wire. Using anything smaller will typically result in the material closing back up on itself and nothing can be identified. The main reason for this procedure is to not only test the sealing area of a particular package, but also the field of the package for pinholes, cracks, tears, voids, holes.
Why is a sample size of 30 chosen?
The sample size of 30 is an industry norm. However, “No specified plans are mandated for accepting sterilized medical device packages; therefore, each manufacturer is responsible for setting its own risk”; “There is, in fact, nothing magical about the sample size 30”. Ultimately, the confidence intervals and allowable margin of error in the packaging process is determined by the Corporation’s policies and is based on risk analysis. One tool to use for risk analysis is HAACP (Hazard Analysis and Critical Control Points).
ASTM F2096: Standard Test Method for Detecting Gross Leaks in Medical Packaging by Internal Pressurization (Bubble Test), states in the Scope section that, "This test method covers the detection of gross leaks in medical packaging." In addition, the standard indicates that "the results of this analysis indicate that there is an 81 % probability of rejecting a package with a defect size of 250 µm. There is also an 11 % probability of rejecting a package with no defects." It is unclear whether or not the proposed Bubble Test is sensitive enough to identify breaches of the package sterile barrier.
Please can you provide a scientifically valid justification for the applicability of this test with regard to its use to validate sterile package integrity?
This test method has been used to determine the integrity of sterile medical device packages for close to 10 years. It is an FDA approved consensus standard, as it is included in the list of 'approved standards' in the FDA Guidance Document entitled "FDA Modernization Act of 1997: Guidance for the Recognition and Use of Consensus Standards; Availability". This ASTM test method has been fully accepted in submissions by former FDA personnel (Ms. Cathy Nutter); who has actively participated in ISO and ASTM standards writing activities and has been an advisor to the CDRH on packaging related issues.
Furthermore, the test method sensitivity has been established and the laboratory providing the testing can validate the method sensitivity prior to beginning a testing project. There is no guidance, regulation, specification, or other decrees by FDA or other regulatory bodies indicating what size hole must be detected in order to prove package sterile integrity.
Please can you provide method validation data that demonstrate the sensitivity of the sterile package integrity test? This should include, but not necessarily be limited to, appropriate control data.
The method can be validated in the laboratory by creating a hole in the package of the appropriate size or desired size to be detected (e.g. 0.005 to 0.008" are commonly used) and by establishing the internal pressure required to activate the a stream of bubbles emanating from the hole.
