Medical Device Link.

FEATURE

Towards worldwide adoption

The new globally harmonised standard for packaging terminally sterilised medical devices was ratified as an ISO and European standard in April 2006. The standard has two parts:

• ISO EN 11607-1:2006, “Packaging for Terminally Sterilised Medical Devices, Part 1: Requirements for Materials, Sterile Barrier Systems and Packaging Systems,” sets out the obligations for materials, sterile barrier systems and package design.
• ISO EN 11607-2:2006 “Packaging for Terminally Sterilised Medical Devices, Part 2: Validation Requirements for Forming, Sealing and Assembly Processes,” addresses requirements for validation of the packaging process.

This standard replaces the previous European standard EN 868-1. From May 2007, new terminally sterilised medical devices placed on the European Union (EU) market place must comply with ISO EN 11607 Parts 1 and 2. These two standards have also been officially “recognised” by the United States (US) Food and Drug Administration (FDA) via the standards recognition process and published in the Federal Register. Several countries outside the EU, including China and Japan, are also considering adopting the standard as official guidance or regulatory requirements.

Help with compliance

To comply with the new regulation, a medical device manufacturer must meet the requirements of each “shall” statement in the standard. There are one hundred and nineteen unique “shall” statements in ISO EN 11607 Parts 1 and 2. The question is how can this be achieved? Several articles, seminars and webinars designed to describe the standard and strategies for compliance have been presented over the past eighteen months. The Association for the Advancement of Medical Instrumentation (AAMI) has revised Technical Information Report (TIR) 22: “Guidance for ANSI/AAMI/ISO 11607, Packaging for Terminally Sterilized Medical Devices Part 1 and Part 2: 2006.” This guidance was specifically written to address compliance with ISO EN 11607 under the US FDA Quality System Regulation and is available at www.aami.org. However, much of the content of TIR 22 is applicable to ISO EN 13485, Medical Devices, Quality Management Systems, Requirements For Regulatory Purposes, and it may be offered for use as a draft for a new ISO guidance document in 2008.

There are several areas that seem to raise questions when interested parties review ISO EN 11607. These are explored below and guidance is given on how to fulfill the requirements.

Test method validation

The requirement for test method validation (Parts 1 and 2, Section 4.3) is one area that raises questions, specifically: is a standardised test method validated or do companies need to perform additional testing in their own laboratories to satisfy the requirement?

Test methods that have been subjected to formal inter-laboratory studies (ILS) usually provide the user with a statement that indicates the repeatability and reproducibility of the test method. Repeatability is a measure of the variation within a laboratory, which can result from several variables including operators, test equipment and variation over time. Reproducibility is a measure of the variation between laboratories. An ILS will also usually provide the user with an indication of the sensitivity of the test method, which is a measure of the limits of the test method. In addition, an ILS provides an indication of the robustness of the test method when repeatability and reproducibility are good. The ILS signifies that the test method can be validated in a company’s own laboratory and that additional steps are necessary. The company needs to perform its own internal testing. It is important to conduct tests to determine the contribution of variables such as operators and/or equipment, and to determine that the results from the company’s laboratory are comparable with those produced in the ILS.

There are many acceptable test methods that have not been subjected to an ILS. These may be from scientific literature, national standard methods or developed internally. The most important issues with these tests are

• demonstrating that the test is actually measuring the property intended to be measured
• determining the sensitivity and accuracy are sufficient to measure the intended property over the specified range of values
• determining the repeatability of the test method.

These can be established by application of the scientific process through carefully designed experiments. However, there is one caution that must be noted. If a company uses an internal test method when another test method already exists to measure the same attribute, and that test method has been subjected to an ILS, then the US FDA states that it would expect to see a direct comparison of the two methods as part of the validation process.

Worst case configuration

Another area that raises questions is the concept of “worst case” configuration, which appears in Part 1, sections 6.1.6 and 6.3.4, and Part 2, section 5.1.5. Although the same term is used in all these sections, it is important to examine the context in which it appears to understand the nuances.

Part 1 section 6.1.6. Here the term appears in the context of design requirements and it states:

“When similar medical devices use the same packaging system, a rationale for establishing similarities and identifying the worst case configuration shall be documented. As a minimum, the worst case configuration shall be used to demonstrate compliance with this part of ISO 11607.”

The concept of similar devices in the same packaging system is commonly referred to as a product family. A good example is intravenous (IV) tubing sets, which can come in a multitude of configurations with differing lengths of tubing and various ports and valves. Many companies use the same header bag or pouch as the sterile barrier system on all of their IV sets. Perhaps one of these sets has more tubing, ports and valves than any other and represents the worst case configuration. Section 6.1.6 indicates that the company must develop a written rationale for the establishment of the product family, the worst case configuration and, at a minimum, use the worst case configuration to fulfill the design and development requirements contained in section 6. Many times, two worst case configurations are used: one represents the maximum and one represents the minimum to formally bracket the bounds of the product family.

Part 1 section 6.3.4.The next time the term “worst case” appears is in the context of package system performance testing and section 6.3.4 states:

“Performance testing shall be conducted on the worst case sterile barrier system produced at the specified process limits for forming and sealing and after exposure to all the specified sterilisation processes.”

Using the IV tubing example again, this simply means that the company must use the documented worst case described above. It must also conduct performance testing when that product has been packaged using the process limits of the company’s equipment that produces the least acceptable sterile barrier system. These process limits should have been developed when conducting the validation of the packaging process. If multiple sterilisation cycles or processes are to be qualified, the performance testing must be conducted on those samples after they have been subjected to all specified cycles or processes. Package performance testing is done to determine whether the chosen materials, design and sterilisation processes result in a packaging system that protects the device and maintains integrity through to the point of use. Some companies simply produce samples for performance testing using nominal configurations; however, this approach will not identify if worst case configuration(s) will meet the specified requirements after performance testing.

Part 2 section 5.1.5. The third time “worst case” appears is in Part 2, section 5.1.5 where it states: “When similar preformed sterile barrier systems and sterile barrier systems manufacturing processes are validated, a rationale for establishing similarities and identifying the worst case configuration shall be documented. As a minimum, the worst case configuration shall be validated to determine compliance with this part of ISO 11607.”

A useful example to explain this point is the manufacture of pouches using the same top, bottom and adhesive. Pouch manufacturers produce a multitude of sizes to meet the specific needs of all of their customers. Is it necessary for them to validate the process they use for all the sizes when the process is exactly the same? If this is the expectation, they would be performing process validations for several years. Instead, the concept of a product family can be applied here; a rationale must be documented and, as a minimum, the process used to manufacture the worst case must be validated. Perhaps the worst case is the longest pouch they manufacture or it could be the smallest.

Stability studies

Another area that raises questions is stability studies and package performance testing. Stability studies are commonly known as accelerated ageing tests. The requirement in the standard is to perform real-time studies, but accelerated ageing is acceptable for claimed expiry dates pending results of the real-time study. The real issue here is that accelerated ageing is based on the Arrhenius equation that describes the effects of temperature on first-order reaction rate; that is, when the temperature is increased by 10 ºC, the rate of the reaction doubles (Q10=2). Typically, that is the value that is used. This means that 45 days at 55 ºC is equivalent to one year at 25 ºC. Many times during ageing studies, package performance protocols involving temperature are incorporated into the ageing studies such as freeze and thaw cycles or high temperature and high humidity exposures. The standard and the TIR 22 document encourage the separation of performance protocols from ageing because if the sterile barrier system fails, the reason for the failure is not known. Was it the ageing or the freeze and thaw cycle? If the company runs a complicated multi-temperature multi-humidity protocol and passes, that is good, but when sterile barrier system fails, the company will have to go back and separate the test protocols to determine the source of failure. In addition, the accelerated ageing study has to be restarted.

Packaging system performance testing must be based on the environmental exposures that the package is expected to be subjected to during distribution prior to use. This means that it is important to understand the distribution system to identify and test for these exposures. There is really no reason to conduct freeze and thaw cycle testing for a device manufactured in Bangkok, Thailand, and distributed only in South East Asia. However, exposures to high temperature and humidity would be prudent.

Materials

The last area that raises queries relates to the requirements described in Part 1 section 5 on materials and preformed barrier systems. This section outlines the physical, chemical and toxicological requirements of material to be used in medical packaging. This information may be available from the converter or material manufacturer. The decision for a supplier to provide all or part of this information is a business decision and not a requirement of the standard. The Scope of the standard states that this information is applicable, “wherever medical devices are placed in sterile barrier systems and sterilised.”

For users of Tyvek (DuPont Medical Packaging), the document, “DuPont Tyvek Compliance to ISO EN 11607-1:2006,” is available at www2.dupont.com/medical_packaging This publication addresses all of the clauses in sections 4 and 5 of Part 1 of the standard and provides information on how Tyvek products meet those requirements.

Working with it

In summary, ISO EN 11607 is here.

Everyone must address this standard because it is a truly global standard and therein lies some of its value. Now medical device companies need to meet the requirements of just one standard regardless of where they are in the world. If companies follow ISO EN 11607, Parts 1 and 2, it will be highly probable that they will have products that are safe and efficacious. The next revision of the standard is scheduled for 2011.

Michael H. Scholla, Ph.D. is Senior Consultant at DuPont Non-wovens, Chestnut Run Plaza, Building 728, Room 3419, Wilmington, Delaware 19880, USA, tel. +1 302 999 6744, e-mail: michael.h.scholla@us.dupont.com, www.medicalpackaging.com. Dr Scholla is also Convener of ISO Technical Committee 198, Sterilisation, Working Group 7, Medical Packaging.