According to the World Health Organization (WHO), healthcare-associated infections (HAIs) are the most frequent adverse event in the delivery of healthcare services worldwide. Ensuring the sterility of medical devices is a critical step in the overall effort to reduce the rate of infections in hospitals and other healthcare settings.

Medical device packaging and sterilization validation are required for FDA 510(k) submissions yet are often causes of delay. Sterile packaging validation is a vastly misunderstood topic in its own right but becomes even more complicated when considering it involves the additional coordination of manufacturing, product shelf life, and sterilization validations all under a complicated array of regulations. This white paper explains how these validation requirements must be coordinated for medical device manufacturers to get their single-use medical devices to market faster.

Key Regulations

Medical device OEMs typically work with three separate entities for the back-end stages of product realization: medical device outsourcing companies, testing labs, and sterilization companies. It is common for these entities to focus on their particular expertise without helping the OEM navigate the process as a whole.

The best way to think about the market launch requirements of sterilized, single-use medical devices is to think in terms of how these requirements work together.

1. Package Design

Package design is regulated by ISO 11607 (Part 1 and Part 2), and these standards are universally required by the FDA and the EU Medical Device Regulations. ISO 11607 is one of the most misunderstood standards in device development, requiring the execution of more than 25 specifications, protocols, and test reports.

The regulations require that sterile packaging be treated holistically as a Sterile Packaging System. A sterile packaging system is much more than a sterile barrier package; it is the combination of the sterile barrier system and external protective packaging required to deliver the device from manufacturing through sterilization, storage, distribution, and aseptic delivery to the sterile field. This requires a significant amount of design activities, verification, and validation. Most importantly, it requires a complete understanding of the stresses the package will endure throughout the distribution cycle.

ISO 11607-1 defines requirements for sterile barrier system materials selection and their design and testing. ISO 11607-2 defines manufacturing packaging process validation requirements for forming, sealing, and assembly processes. Too frequently, medical device manufacturers do not include assembly process validation as part of the equation.

Some of the critical steps of this standard include:

• Developing packaging system requirements that specify the customer’s design needs for the sterile barrier and the protective packaging system. Medical device manufacturers must obtain customer feedback on the package ease-ofuse and gain a solid understanding of the storage, transportation, and shelf life requirements of the device. Other considerations include the requirements for the microbial barrier and evaluating possible interactions with the sterilization method on both the sterile barrier as well as the device itself.
• Designing a sterile barrier . Examples of these include porous and nonporous pouches, header, patch bags, and thermoformed trays. The packaging solution is a direct result of the system requirements.
• Designing protective packaging to ensure the device can survive transportation stresses from the point of manufacture to the customer. One of the most common causes of packaging failures is not considering how products are shipped to customers. For example, palletized products from the manufacturer must be tested to ensure they can be delivered through sterilization, but further testing is required if those pallets are broken down and the product is shipped to customers through common carriers. Having a box thrown into a UPS truck is not the same as shipping a skid from the manufacturer. One of the most common mistakes we see is not considering consolidated shipping configurations that are used for sterilization. Orthopedic implants, in particular, generate significant stresses on packaging and are highly sensitive to shipping configurations.
• Package prototyping is recommended to ensure the final package will meet the needs of the customer and will be manufacturable and optimized for final assembly of the device. Selecting a contract manufacturer with internal thermoforming and a broad array of packaging technologies can provide companies with a realistic sample of the final package much faster than having to coordinate multiple suppliers.
• Package verification testing is a critical step and is often overlooked, which increases the chance that the package fails the final transit test. In this step, the final version of the product is packaged and undergoes preliminary package testing to ensure it has a high probability of passing the final transit testing. Some labs report up to 30% of their medical device packages fail the ASTM or ISTA transit tests. A preliminary transit test greatly reduces this risk. Typical sterile package verification tests include peel testing and bubble leak testing. These tests must be validated in advance.
• A sterile presentation test must be conducted with actual end-users to ensure the medical device can be aseptically presented. Scrub nurse and doctor interaction with the package is critical. Some packages can be designed to deliver the device to the sterile field by allowing the device to gently “fall” out of the package onto a sterile table. Other devices require the product to be held over the sterile field while the scrub nurse manually removes the device from the package. Each of these scenarios impacts the design of the package regarding ease of opening and, for thermoformed trays, how the package is designed to be held with one hand while peeling the lid with the other.

2. Validation of Forming, Sealing, and Package Assembly

The process used to assemble the package and seal the sterile barrier must be validated. Key steps include:

• Developing a sampling plan that applies to the process being validated, based on a statistically valid rationale. ISO 2859-1 or ISO 186 are common references.
• Using a validated test method and defining the criteria for acceptance.
• Tooling design and fabrication. IQ (Installation Qualification) for forming and sealing equipment.
• OQ (Operational Qualification) of the sealing process. This involves challenging the sealing process parameters to create windows of variability that the process must maintain to provide an acceptable seal. It is imperative that products produced for subsequent sterilization and transit testing be produced at OQ-Low to simulate worst-case manufacturing conditions. This is often overlooked and can yield compromised packaging during ongoing production when sealing parameters drift to the low end of their specification. This requirement ensures that a seal made under the worst-case process variation will stay intact.
• PQ (Process Qualification). This step involves producing product under realworld manufacturing conditions including multiple shifts and operators. The fastest path of validation involves using OQ-Low to validate post-sterilization transit and seal stability testing and PQ for final sterilization validation

3. Manufacturing Process Validation

Validating the sealing process is just one element of the manufacturing validation, which must include all the cleanroom assembly steps to produce the device. A separate IQ, OQ, and PQ must be performed for the assembly process prior to sterilization validation. Conducting the production and assembly process validation in conjunction with package validation saves significant time.

4. Worst-Case Sterilization

Sterilization can put significant stresses on a package and also can impact the shelf life of the device. To reduce the risk of failure the medical device package must be exposed to worst-case sterilization prior to transit testing. “Worst-case” needs to be justified. A double (2X) sterilization is often used to simulate worst-case. A 2X sterilization cycle may occur when there is a sterilization cycle that needs to be aborted due to mechanical failure, or there is a need to re-label a previously sterilized product. Your contract manufacturer should coordinate a discussion with the sterilizer to determine the best assumptions.

5. Transit Testing

Transit testing has two objectives. The first is to evaluate if the product and package interaction during shipping will compromise either the sterile barrier or the product itself. The second is to determine if sterilization will impact the sterile barrier irrespective of the product interaction.

An ISTA or ASTM transit test should be selected that best reflects the actual transportation and storage environment that the package will experience. There are a variety of possible distribution cycles for transit simulation including air and motor freight. Test conditions include atmospheric conditioning (e.g., humidity, temperature), compression, vibration, and shock. Testing for both palletized movement and individual shipper handling are crucial considerations.

ISO 11607 requires proper documentation and a rationale for the use of a particular test along with detailed conditions under which the sterile barrier must be maintained.

6. Seal Testing

Always conduct seal tests with empty packages. This allows the sterilization effect on the package seal to be independently evaluated. There are many reported cases where package design has been changed unnecessarily because there was not independent testing of the seal. In essence, if the seal is not tested independently and the transit test fails, the customer will not know if the failure was caused by the seal design or the impact of the product. Costs are increased because tests must be repeated, and product is wasted. Similarly, testing full packages increases the volume of product that needs to be manufactured for the test.

Seal tests can involve several ASTM test methods with the most popular being the bubble leak test, visual seal inspection, and peel strength testing. These tests are performed after both accelerated and real-time stability testing. The FDA will accept accelerated shelf life testing as long as real-time testing is completed in parallel. The desired shelf life dramatically impacts the cost of the test due to the sample size and test time required.

Accelerated shelf life testing allows the product to be launched more quickly and can be critical to supporting clinical trials. A one-year shelf life label can be accomplished in just 46 days of accelerated aging; this is adequate for clinical testing. Two types of stability tests must occur: tests on the seal design and tests to ensure the packaged device does not negatively impact the seal. The medical device must also be tested to ensure its functionality is acceptable for each point of shelf life testing (1 yr., 2 yr., etc.).

7. Sterilization Validation

There are two main methods of validating medical device sterilization.

First is validating the desired load size for ongoing production. This method requires that the planned batch size be validated as a group. For example, a four-pallet Eto chamber process can be validated with four pallets of packaged product or a smaller amount of packaged product with dunnage that simulates the density of the larger load. This can be an impractical method for new product launches because it often requires more product to be produced than needed for initial market launch.

The second popular method is “single lot release.” This is accomplished by sterilizing three separate smaller lots of product and then performing a retrospective study to create a validated sterilization process. All three lots must be processed within one year. The single-lot release is a sterilization verification method — not a validation method — because each lot is tested to verify its sterility. This is often more expensive than validating a larger load but is often the most practical approach.

Sterilization validation should use manufactured product out of PQ so that it represents product produced under a validated manufacturing process. So, while package transit testing should use OQ-low to ensure the package protects under worst-case conditions, product from the sterilization validation should be validated using PQ production. This way customers can use the product undergoing sterilization validation.

Timing of the Complete Validation Process

Timing and costs can vary greatly depending on the medical device validation strategy deployed as well as how coordinated the individual processes are managed. Your medical device outsourcing partner should provide a detailed schedule of timing and costs for various scenarios. This timing must also be integrated into the higher-level product development plan. It is very typical for customers to be surprised by the length of this process which often delays 510(k) submissions.

Package Design (#1): 13 Weeks

• Package System Requirements
• Sterile Barrier Design
• Protective Package Design
• Prototyping
• Verification Testing
• Sterile Presentation Test

Sealing and Manufacturing Process Dev. (#2/3) 16 Weeks

• Thermoforming & Sealing Tooling
• Thermoforming IQ/OQ
• Sealing IQ/OQ
• Device Assembly IQ/OQ
• Label Development
• Build OQ-Low for Transit Test

Transit Testing and Seal Testing (#4/5/6) 13 Weeks

• Expose to Worst-Case Sterilization
• Transit Simulation
• Accelerated Aging Testing
• Real-Time Aging Testing
  • Seal Integrity Test
  • Seal Strength Test
  • Product Stability Test
• Seal Testing
  • Accelerated Aging
  • Real-Time Aging
  • Seal Integrity Test
  • Seal Strength Test

Sterilization Validation (Assume Lot #1) 8 Weeks

• Manufacturing PQ
• Single Lot Verification 1
• Single Lot Verification 2/3 (Additional 16 Weeks)

These are typical lead times, but they can be significantly reduced by selecting an outsourcing partner well versed in all aspects of the process as well as having vertically integrated packaging and manufacturing processes.

Conclusion

The requirements for validating the back-end processes for medical device package design, manufacturing, sterilization and shelf life of a sterile medical device is often misunderstood. Errors and oversights can result in failed validation tests and longer-term sterile barrier reliability. It can take nearly a year to get a validated sterile package to market, and many medical device manufacturers fail to plan for this time and expense. While there are regulations that govern package design and validation, additional regulations for manufacturing, sterilization, and shelf life validation must also be coordinated to reduce lead-time, improve quality, and reduce costs. Using an integrated approach to treat all these processes as a system, achieves a faster and less expensive approach. OEMs should ensure that their medical device contract manufacturing partners are well versed in this area and can offer comprehensive schedules and cost estimates that reflect the entire process.