Medical Device Link.

The Sterilization Packaging Manufacturers Council (SPMC) is addressing a number of questions presented to them during their February 2008 Webcast, “Understanding the Nuances of ISO 11607.” The speakers were among the SPMC members who had previously authored "Complying with ISO 11607: What Will TIR 22 Do for You?, Parts 1 and 2," in PMP News's October 2007 and November 2007 issues.

You may also find a complete list of questions and answers at the SPMC Web site at www.sterilizationpackaging.org.

And if you think of another question, please feel free to submit it to PMP News through Editor Daphne Allen at daphne.allen@cancom.com .

General Questions on Validation

Can a packaging machinery manufacturer successfully offer a template for validating its machine?

The machinery manufacturer is in the best position to provide the critical parameters for successful machine operation. Whether or not the machine manufacturer would provide a true validation template probably depends on how familiar the manufacturer is with the medical device packaging market. In any case, it is important to get information from the machine manufacturer to successfully plan the installation qualification (IQ) and operational qualification (OQ) portions of a package manufacturing process validation.

When performing process validation for a new preformed sterile barrier system across multiple sealers (e.g., nine sealers) with little rationale for equivalence, how do I reduce sample size for performance qualification (PQ) lot runs?

The different sealers need to be evaluated for similarities, but not necessarily absolute equivalence. For example, it may be possible to group heated bar sealers together, impulse sealers together, and/or band sealers together. It is likely that the IQ and OQ work will demonstrate that there are significant similarities between some of the sealers that could be used to rationalize grouping them together for validation runs. Depending on the sealers involved, you should be able to reduce the number of groups tested to something much less than nine. Just remember to document your rationalization for doing so.

For conditioning methods (such as ISTA methods), doesn't one need to validate that it is somehow representative of the dis­tribution environment your package will see?

First, it is important to understand that the ISTA methods are conditioning methods or protocols rather than test methods. As such, there is no ISO 11607 requirement that they be validated. Instead, a rationale must be developed that demonstrates the applicability and appropriateness of the protocol. You need to understand the distribution environment that your packages will likely see. This is important in setting up the distribution testing of finished packages, which is required by ISO 11607. If you understand the distribution environment and can find a conditioning method or protocol that closely simulates that environment, then you could rationalize using that method as part of the distribution testing. If the distribution environment is not well understood, then it is necessary to do actual shipping tests to complete the distribution testing requirement, or, with appropriate rationale, use published data that provide information about storage and distribution environments that have been measured.

When you refer to validating the seal area, do you mean manufacturer or end-user made seals?

ISO 11607 requires that you validate the sealing process on the seals that you produce. In the case of form-fill-seal packages, the medical device manufacturer is responsible for validating all of the seals. In the case of premade sterile barrier packages, the sterile packaging manufacturer is responsible for validating the seals that it makes and the medical device manufacturer would be responsible for validating the final seal.

Can parts of this presentation be used in justifications?

Many rationales are built around published information. In consensus standard documents like ASTM F2097, Standard Guide for Design and Evaluation of Primary Packaging for Medical Products, for example, there are applicability statements for use of each method that have been reviewed and approved through ballots to a broader community. Other sources for reference can be found in articles published in peer review or recognized trade publications. While our presentations are here to serve as guidance for decision making, it is still up to the individual or company to demonstrate that such rationale can be supported through testing.

Can't I just get a package that is already validated?

You may be able to get close to that if you have other very similar products. You can use a product family validation and that would make life relatively simple. You really can't get a package that is fully prevalidated, though, because it's not just the package that is being validated. It is a package and product combination and that combination is designed for a specific sterilization procedure and a specific set of distribution requirements. All of those requirements together make up the total validation.

General Questions

I have a product in development that is still in the concept phase. Right now it seems too early to include a packaging manufacturer. Wouldn't it make better sense to do this after we have the product designed?

No, it is definitely not too early. In many cases, it is a perfect time to start working with your packaging supplier. Ideally, the two paths of developing the device and the package with the device should run concurrent to one another. You can evaluate the material compatibility with the device and any special requirements for shielding and sterilization in the development phase. You can also discuss options regarding the best type of package for this product, the ramifications of cost, how the end-use customer perceives the packaging materials, and many other features more easily designed into the package if known early during the product design phase. The bottom line is that the earlier the sterile packaging manufacturer (SPM) gets involved, the more likely you are to optimize package performance as well as cost.

If you have a sterile fluid pathway, is this considered your sterile barrier system (SBS)? What would you suggest for validation of this SBS? Is outer packaging considered protective?

The following response was provided by Mike Scholla of DuPont, Convener ISO TC198 WG7 group, which wrote and maintains responsibility for revising ISO 11607.

A sterile fluid path is a special case when it comes to a sterile barrier system, which is why there is a specific definition in ISO 11607. In a sterile fluid path system, fluids flow through a lumen; the critical characteristic is that the inside of the tube is sterile. This is in contrast to a typical medical device, where is it critical that the outside of the instrument is sterile. The sterility of the sterile fluid path system is maintained by the closure system of the fluid path, and it must be demonstrated that the closure system maintains sterility until point of use. Sterilization validation is usually conducted by exposure to an aerosol of spores followed by sterility testing of the lumen.

As many sterile fluid path systems are packaged in pouches, a common sterile barrier system, it is important to determine in each case what is providing the sterile barrier and to make sure that the package is labeled accordingly. Without such labeling, a user may assume that the pouch is providing the sterile barrier. If the sterile fluid pathway is labeled as such, then the pouch enclosing may be considered protective packaging and validated as part of the packaging system.

Are the ISO 11607, AAMI, and ASTM International standards equally recognized and applied globally? If not, what are the validation standards in these other parts of the world?

ISO 11607, also referred to as ISO/EN 11607, is a European norm, as it supports the European Device Directive, and conformance to it is required in the EU. Outside of the EU, the ISO standards take a number of different roles. Within the United States, FDA has a standard recognition process that acknowledges standards and publishes them as such in the Federal Register. Once a standard has undergone this process, it becomes official guidance of FDA.

ANSI/AAMI/ISO 11607–1:2006 and ANSI/AAMI/ISO 11607–2:2006, for instance, are recognized standards and were included on FDA's Recognition List published in the September 12, 2007, Federal Register.

The ISO standards outside of the EU and the United States can be recognized in one of three ways:

• completely as a guidance document, with no official recognition.
• as official guidance from a regulatory body within a country.
• can be adopted as a requirement just like ISO 11607 in the EU.

This depends on the individual country, and there is no established pattern. For further information on the regulatory agencies in a specific country, please see Annex A of TIR 22:2007. ASTM and AAMI documents are referenced in and support the work to be accomplished in complying with ISO 11607.

Questions on Worst Case

What is the difference between process windows and specifications?

A process window defines the manufacturing parameters (machine settings) under which the sterile barrier system will be produced. Specifications, on the other hand, detail the various properties and characteristics of the sterile barrier system, establishing limits where appropriate. Examples of properties that may be included in a specification are dimensional requirements, seal strength, and seal integrity to name a few. ASTM F99 and F2559 are excellent references when developing specifications. Sterile barrier systems that are produced within a validated process window should yield product that falls within the specification.

To meet 6.3.4 performance testing on the worst case sterile barrier system, should I make packages at the extremes of the specification?

Clause 6.3.4 requires that sterile barrier systems that represent the range of the process window (“the specified limits of forming and sealing”) be evaluated. Because the validated process window is designed to yield product that falls comfortably within the specification, to produce product at the limits of the specification can generally only be achieved by moving outside of the validated window. Often significant modifications to the process are required to produce sterile barrier systems that fall consistently at the limits of the specification. If this is attempted, it should be realized that:

• The modified process may create issues that would not be seen within the validated window; and
• Because of normal variation that exists in any process, some of the sterile barrier systems evaluated will actually be outside of the specification.

To meet 6.3.4 the medical device manufacturer may choose to source from a fully validated process selecting an appropriate sample size from multiple lots to represent the range of package characteristics. For further assurance, the final closure seal can be made at the specified process limits of sealing. Alternatively, the medical device manufacturer may utilize sterile barrier systems where all seals are made at the worst-case conditions of manufacture within the validated window. With either approach, it is not necessary to make packages at the extremes of the specification.

Can you please give some more examples for worst case sterile barrier systems?

As each of the three clauses in ISO 11607 that references worst-case mean something slightly different, there are three different types of “worst-case systems” that have to be considered. We will attempt to provide more examples of each:

Clause 6.1.6 of ISO 11607-1 applies to worst-case configuration of devices using a common sterile barrier system. In general, the device(s) that apply the most stress to the packaging system would be considered the “worst case”. Examples of what may represent the worst case device configurations follow:

• For IV sets, the worst case configuration may be the set with the most fitments.
• For implantable joints, the worst case configuration may be the heaviest joint.
• For bulk or kit packaging, the configuration with the most individual pieces may be the worst case.

Clause 5.1.5 of ISO 11607-2 applies to the worst-case configuration of the sterile barrier system family that is being validated. In general, the sterile barrier system family will be made with common materials using a common process but be of different sizes. Examples of worst-case sterile barrier system configurations include:

• For a chevron pouch family, the worst case may be the largest and smallest pouch.
• For rigid trays with a flexible lidding material, the worst could be the largest and smallest seal perimeters.
• For a form-fill-seal application using a sealing platen, the worst case may be the configuration (array) with the greatest and least sealing area.

Clause 6.3.4 of ISO 11607 -1 refers to the sterile barrier system itself. The goal is to ensure the performance testing has been conducted on sterile barrier systems that represent the range of variation that will be seen in the sterile barrier system. There are two common approaches to creating worst-case sterile barrier systems to be used for performance testing:

• The first and most common approach is to source from a fully validated process selecting an appropriate sample size from multiple lots to represent the range of package characteristics. For further assurance, the final closure seal can be made at the specified process limits of sealing.
• The second approach is to utilize sterile barrier systems where all seals are made at the worst-case conditions of manufacture within the validated window.

Any comments to using a supplier's “process validated” product (pouches) and then having the device manufacturer use their worst case production process for performance validation?

This approach is by far the most common method for satisfying the requirement of ISO 11607-1 clause 6.3.4 and is the method that the authors' of ISO 11607 had in mind when drafting the documents. Because it does not require specific and separate production runs by the sterile packaging manufacturer, it is economical while still creating packages that are known to represent the limits of the process (the closure seal).

For final package performance testing could you submit packages produced at the nominal process parameters if the process has been validated? If the process has not been validated then packages for final package performance testing must be produced at worst case process limits?

To address the first question, if the sample size was appropriate to ensure that the range of package characteristics was represented (ideally from multiple lots) then packages produced at the nominal process parameters could be used for final package performance testing. Often the medical device manufacturer chooses to make the final closure seal at the specified process limits of sealing.

As for the second question, the process must be validated in order to meet ISO 11607. That is the only way to establish the worst-case process limits. However, packages can be produced at the worst-case validated process limits to create sterile barrier systems for final package performance testing. This approach can be quite costly because it requires specific and separate production runs.

Test Method Validation Questions

Can I have someone else validate my test methods?

You can hire someone to assist you in validating your test methods. However, the validation must be done on the actual equipment with appropriately trained personnel in the facility that the testing will occur.

How do you validate a test method when there's only one person in the lab?

There are a couple of options to consider. First, you can have another non-lab person take part in a gauge (repeatability and reproducibility ) R&R study. The person does not have to be a trained technician; however, they should have a basic understanding of the test to be performed. It is important to remember that a validation of this type is a test for the application of the method, and using a person unfamiliar with the test method will assess the robustness of the method. If there are issues with variation owing to this person's inexperience, it can be overcome with training.

Secondly, you can compare your data with those from a round-robin study, such as that typically found in an ASTM test method, and you can see how close or relatively close you are to that data. If you do this, Annex B in AAMI TIR 22:2007 states that the repeatability data from your lab should be compared to the reproducibility results from the interlaboratory study in the existing standard.

How do we know which standards to validate and which ones not to?

Test methods are standards that have a result and are used to determine product performance or conformance. Test methods must be validated in order to meet the requirements of ISO 11607. It is important to remember that accelerated aging and distribution are conditioning methods and are not test methods. For example, accelerated aging is a way to condition your samples for use with a test method such as dye penetration.

Do you have any experience or recommendations for successfully creating channels in a tray-and-lidstock sterile barrier system for the purposes of the dye-penetration integrity test method validation?

In validating ASTM F1929, a 0.002-in. tungsten wire was used to create the channels. The wire was sealed within a seal and then pulled out after cooling. To facilitate removal, one end of the wire may be left spooled or wrapped around a cylinder.

Are you aware of any medical device manufacturer that has validated visual inspection for part 2 compliance without identifying it as a special process?

A “special process” is one for which the product cannot be fully verified (for example, the ability of a heat-sealing process to meet a seal-strength specification cannot be fully tested without destroying the seal). This is why that process must be validated. Visual inspection is a test method (not a process) and should be validated as such.

When doing a test method validation, how do you know what the acceptable results are?

The acceptable results are relative to your test method and your specifications. For variable data, the results would be gauge R&R percentages per testing equipment. For attribute data, this could be based on confidence limits set by your company's risk policy.

Percent R&R are common statistical references with the following ranges:

• 0-10% of tolerance – typically acceptable.
• 10-30% of tolerance – can be acceptable with rationale or justification.
• >30% of tolerance – typically unacceptable.

Other acceptance criteria should be based on your company's risk policy and the relationship to specifications, if not already defined in a standard test method.

If a test method is validated (accuracy, precision, repeatability defined), does it need to be verified every time the test is run? For example, for the dye-penetration test, I validated it for a 0.002-in. channel leak, Do I need to prove it again every time I run the test?

No, you do not have to perform a test method validation every time a test is run. You would consider redoing a test method validation if you have a significant change in the method.

In the case of the dye test, while it is not required to prove it again every time, you may want to verify the sensitivity of the dye solution with every new batch by testing it with a known 0.002-in. channel leak or by controlling the production of the solution to maintain a high level of assurance of repeatability.

If a standard is already validated (for example, ASTM F2096, Standard Test Method for Detecting Gross Leaks in Medical Packaging by Internal Pressurization ), what else are we supposed to do in-house to validate the procedure, other than validating the equipment?

You should verify with your test method and equipment that you can detect to the same sensitivity as the standard. This can be done by creating a hole or channel the size designated in the test method and testing accordingly. The point of test method validation is to ensure that you understand the anticipated variation in your testing.

Material and Sterile Barrier System Questions

Can a water-based coated paper web be used for EtTO packaging?

There are water based coatings that are stable for EtO sterilization applications. The same is true for adhesives and inks. The best course of action is to verify stability with your SPM and to validate the stability of the coating through appropriate qualification efforts. Verification can be confirmed through visual inspection, IR (verify no migration of the coating to the instrument), and through coating adhesion testing.

Are there any adhesives that facilitate or accommodate for the rapid EtO cycle?

Yes, there are adhesives available that perform very reliably in rapid Ethylene Oxide cycles.  Overall, porosity of the package is critical for success in rapid EtO cycles as there are more pressure changes. As a result, packages with a very small ratio of breathable material to non breathable material – small headers or patches of breathable material related to the overall size of the package – will see the greatest stress.  Keep in mind that in rapid EtO processing, there are more pressure changes often accompanied by increased levels of relative humidity.  Adhesives need to be able to withstand the increased number of pressure changes and the materials themselves need to be able to withstand the increased levels of relative humidity.  Your packaging supplier can guide you with material recommendations for your specific package (pouch, header bag, vented bag etc) and your specific EtO processing conditions.

Do I need to check the porosity of the Tyvek during incoming inspection?

Typically, incoming inspection is required to verify the identification and the performance of the purchased product. This can be accomplished through physical inspection and/or by Certificate of Analysis or Certificate of Conformance provided by the supplier. Through historical performance, a rationale may be provided that would allow for reduced or skip lot inspection or auditing of porosity, or other variable measures at incoming inspection. The amount of risk one is willing to accept predicates the degree to which inspection is performed.

How much porous area do I need for EtO sterilization?

The amount of porous area required can only be determined through validation efforts utilizing your unique sterilization process, and your medical device. The density of the product to be sterilized, the pack out configuration, and the sterilization cycle are all unique factors that determine the amount of porous area required for a package.

For example, typically you start with some package that is known to go through the process successfully. Determine how different the package being designed is from that package and make a judgment on where to start sizing the porous area. Adjusting the porous area to larger and smaller sizes run them through the ETO cycle and determine if the package remains intact and the product gets adequate sterilization. This occurs in the design phase of the package, not in the validation stage of the package. Also make sure you are not masking the porous area of your package with a label or excessive shipping materials or dunnage.

Is delamination of the substrate considered to be a breach in sterile barrier? If not, what other methods are available to confirm the potential breach?

During a qualification effort, delamination is generally considered a design failure, and a root cause / CAPA effort should be pursued to identify and correct the source of the delamination. In many cases, however, delamination does not result in a breach of the barrier.

Other methods to confirm breach of sterile barrier are: dye leak testing, gas leak testing, and bubble emission testing. See ASTM F2097, Standard Guide for Design and Evaluation of Primary Packaging for Medical Products, for other applicable test methods.

What is sheet separation?

Sheet separation is another term for delamination – this is applicable to laminated structures, where numerous folds in the laminated material may cause layers of the sheet to separate, or delaminate. Thie can also occur in non laminated materials such as spunbonded polyolefins, for further information you may consult Curt Larsen's article, “Porous Sterile Barrier Integrity Testing: Failure Anomalies,” in the January 2006 issue of MD&DI.

We use Tyvek pouches for our gamma-sterilized medical devices. I need to know the environmental condition or parameters at which these sterilized products should be stored i.e., in a warehouse to prevent the deterioration of the packaging.

The best course of action is to verify the appropriate storage conditions with your SPM; however a good rule is to maintain storage between 60º to 80º F, with ambient humidity of less then 50% Rh. In general, a standard Tyvek to PET/PE pouch is stable over a range of storage conditions, as long as they are not exposed to extreme conditions for a long period of time. Tyvek and polyethylene can be subject to phenolic yellowing due to prolonged exposure to UV light, or the exhaust from propane driven fork trucks. Primary packaging should remain in its original containers until time of use.

Do any types of devices or implants require double barrier packaging?

The use of a double barrier system is influenced by the situation in which the product will be presented for use. Thus, the decision to utilize a double barrier system is highly dependent on input from other areas such as marketing and product development.

For example, t here are double barriers that are required because the outside of the package needs to remain sterile - as the whole package is introduced into the sterile field, not the contents of the package.  An example of this may be an absorbable suture pouch which would be used in an operating room.  The whole package may be required to be packaged in a second barrier - such as a Tyvek/film pouch that would allow the outside of the inner pouch to be sterile as it is introduced into the sterile field.

How do we establish the minimum seal strength for a given product? Is there a standard that explicitly states the minimum seal strength for a given type of product?

There is no current US regulatory standard that states the minimum seal strength for a given type of product.  This is because the type of product is not the only determining factor in assessing seal strength requirements.  The mass and shape of the product may be the same but there can be dramatic differences based on the sterilization protocol, protective packaging, distribution environment and other factors that would render a guideline difficult if not impossible to create.

The seal strength requirements can be determined through the design process for the packaging system.  The first step in the design process is to determine the design inputs- these are the requirements and constraints that will guide the development process. Design inputs include the product design itself as well as, package development, manufacturing, regulatory, marketing, sales, and the customer or end user.

In this process, you should be using the nine drivers that are listed in Annex D of AAMI TIR 22:2007: As always – the earlier you involve your packaging supplier in discussions, the greater your likelihood for success and the more efficient the material and package selection process will be.  With the right inputs your supplier should be able to guide you towards the right seal strength requirements for your product.