The requirements for validating the back-end processes for packaging, manufacturing, sterilization and shelf life of a sterile medical device are often misunderstood. Errors and oversights can result in failed validation tests and longer-term sterile barrier reliability.
Jeff Barrett, J-Pac Medical
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 regulations govern package design and validation, manufacturers must also coordinate compliance with additional regulations for manufacturing, sterilization, and shelf-life validation to reduce lead time, improve quality and reduce costs. Here’s an explanation of how to coordinate these validation requirements to get single-use medical devices to market faster and less expensively.
Key regulations
Medical device OEMs typically work with three separate entities for the back-end stages of product realization: contract manufacturers, testing labs and sterilization companies. These entities often focus on their particular expertise without helping the OEM navigate the entire process. 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.
Package design
Package design is regulated by ISO 11607 (Parts 1 and 2), which requires that sterile packaging be treated as a system that combines the sterile barrier and external protective packaging to deliver the device from manufacturing to the sterile field. This requires a significant amount of design, verification and validation as well as an understanding of the stresses the package will endure throughout the distribution cycle.
This standard includes some critical steps, including:
• Developing packaging system requirements that specify the customer’s design needs. Requirements include the sterile barrier and the protective packaging system. Medtech manufacturers must obtain customer feedback on package ease-of-use and understand the device’s storage, transportation and shelf-life requirements. Other considerations include the requirements for the microbial barrier and possible interactions of the sterilization method with the sterile barrier and the device itself.
• Designing a sterile barrier. These may include porous and nonporous pouches, headers, patch bags and thermoformed trays. The packaging solution is a direct result of the system requirements.
• Designing protective packaging. Packages often fail when manufacturers don’t consider shipping methods. For example, products shipped on pallets must be tested to ensure they can be delivered through sterilization, but further testing is required if those pallets are broken down and the products are shipped on common carriers. Consolidated shipping configurations must also be considered. Orthopedic implants, in particular, generate significant stresses on packaging and are highly sensitive to shipping configurations.
• Package prototyping is recommended. It ensures the final package will meet customer needs and work for the product. Contract manufacturers with internal thermoforming and an array of packaging technologies can provide a realistic sample of the final package much faster than having to coordinate multiple suppliers.
• Package verification testing typically includes peel testing and bubble-leak testing. It’s important to validate such tests in advance. Some labs report up to 30% of their medical device packages fail the ASTM or ISTA transit tests.
• It’s important to conduct a sterile presentation test with end-users. The test ensures the device can be aseptically presented. Some packages allow the device to gently fall onto a sterile table while others require manual removal. Each scenario affects design for ease of opening.
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.
• Installation Qualification (IQ) of tooling design and fabrication for forming and sealing equipment.
• Operational Qualification (OQ) of the sealing process to ensure that a seal made under the worst-case process variation will stay intact. Packaging produced for subsequent sterilization and transit testing must be produced at OQ-low to simulate worst-case manufacturing conditions.
• Process Qualification (PQ), which involves producing packaging under real-world manufacturing conditions, including multiple shifts and operators.
Manufacturing process validation
A separate IQ, OQ, and PQ must be performed for the assembly process before sterilization validation. Conducting the production and assembly process validation in conjunction with package validation saves significant time.
Worst-case sterilization
Because sterilization can harm a medical device package and reduce device shelf life, the package must be exposed to justified worst-case sterilization before transit testing. A double sterilization cycle can simulate worst-case. The contract manufacturer should work with the sterilizer to determine the best assumptions.
Transit testing
Transit testing has two goals: to evaluate whether device interaction with the package during shipping will compromise the sterile barrier or the product itself, and if sterilization will affect the sterile barrier regardless of the product interaction.
Select the ISTA or ASTM transit test that best reflects the actual transportation and storage environment that the package will undergo, including humidity, temperature, compression, vibration and shock. Testing for both palletized movement and individual shipper handling is crucial.
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.
Seal testing
Always conduct seal tests with empty packages to evaluate the effects of sterilization alone — and not the device — on the package. Seal 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 affects 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.
Sterilization validation
There are two main methods to validate sterilization. First is validating the desired load size for ongoing production. This method requires that the planned batch size be validated as a whole. For example, a four-pallet ethylene oxide 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 market launch.
The second popular method is “single lot release,” in which three separate smaller lots of product are sterilized, followed by a retrospective study to create a validated sterilization process. All three lots must be processed within one year’s time. 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.
Timing of the complete validation process
Timing and costs can vary greatly, depending on the validation strategy and the coordination of individual processes. A 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. Customers are typically surprised by the length of this process, which often delays 510(k) submissions.
Package design (13 weeks):
- Package system requirements
- Sterile barrier design
- Protective package design
- Prototyping
- Verification testing
- Sterile presentation test
Sealing and manufacturing process development (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 (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, including accelerated aging, real-time aging, seal integrity test and seal strength test
Sterilization validation (Assume lot No. 1) (8 weeks):
- Manufacturing PQ
- Single lot verification 1
- Single lot verification 2/3 (additional 16 weeks)
These typical lead times 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.
Jeff Barrett is president & CEO of J-Pac Medical, a commercial packaging provider to medical device companies. He has more than 20 years of experience building high-growth medical device companies, including as CEO of GI Supply and Optim LLC and VP of operations at Haemonetics and Aspect Medical Systems (acquired by Covidien).
The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of Medical Design and Outsourcing or its employees.
