After years of research and development, surveys and polls, functional device testing, and countless other preparatory actions, your medical device is almost ready to go to market. You have determined your optimal sterilization method and the end is now in sight. But there is one more step that is usually downplayed or forgotten, and it is key to bringing your product to market. Your package must demonstrate that it is effective in facilitating sterilization, maintaining sterile barrier properties for the claimed shelf life, physically protecting and containing the product, and facilitating easy removal and use in the field.
Design and subsequent testing to meet and prove these criteria can be a time-consuming and involved process. While all of these necessary functions are critical to the success of the packaging, facilitating sterilization and maintaining sterile barrier properties is probably the least understood. This article looks at some of the most commonly used forms of sterilization and identifies which tests are appropriate for determining optimal packaging.
The first step in the packaging design journey generally starts with choosing which sterilization method is appropriate for each device. This relies on knowledge of the geometry of the device, how it will be used in the field, and its material composition. For example, items with long lengths of tubing may have trouble allowing ethylene oxide (EO) to reach the center of lumens, or items with sensitive electronics may not fare well with gamma radiation or electron beam sterilization. While there are many sterilization methods to choose from, there are four very common methods that tend to dominate the medical device industry: EO, ionizing radiation also known as gamma irradiation, or electron beam, steam sterilization, and vaporized hydrogen peroxide.
EO is the most common sterilization method used in the industry today, accounting for more than half of all medical device sterilization performed. EO is a colorless, flammable, and carcinogenic gas that is primarily used in industry as a precursor to polymers and products like antifreeze. The process for sterilization includes preconditioning the products, exposing the products, and then allowing them to off-gas or aerate. Preconditioning involves exposing the product to a warm, humid environment until a uniform internal temperature and humidity is reached (~52 °C and 55–65 RH). Products are then loaded into a sealed chamber where they are exposed to EO gas. After a validated exposure time, the devices are removed and allowed to off-gas to remove residual EO.
This form of sterilization is known as a gas-in, gas-out process, because gas needs to be able to enter the packaging to come into contact with the device, and gas needs to be able to exit the packaging afterward to reduce toxicity levels. Because of this, one of the primary design considerations is the permeability or breathability of the packaging materials. The more breathable the materials are, the more easily EO enters and exits the package, reducing overall processing time and cost. One of the best standards for determining the breathability of packaging is ISO 5636-5, “Determination of Air Permeance.” In this test, a device known as a densometer uses a cylinder pulled downward by gravity to pass a known volume of air through a porous material. The more porous a material is, the more quickly the cylinder falls. Due to the porous nature of spunbond HDPE and medical-grade papers, these materials are commonly used for this test. A good example of packaging that fairs well in EO sterilization is shown in the photo.
The same principles that apply to EO also apply to vaporized hydrogen peroxide (VHP). To properly sterilize a device using VHP, the gases involved must come into contact with the device surface and therefore need a porous material to allow penetration. Again, testing for maximum permeability while maintaining a microbial barrier is the critical path for optimization of the sterilization process.
The next most prevalent form of sterilization is ionizing radiation, otherwise known as gamma radiation or electron beam. The process used for ionizing radiation sterilization is very much different from gas-based methods; however, it is also much simpler. In gamma radiation, packaged product is loaded onto totes that ride a conveyor system. The conveyor then transports the product around a radiation source of cobalt 60 until the appropriate dose of radiation has been applied. Electron beam is very similar to gamma, however, instead of energetic waves being projected at the test article, electrons are accelerated through an electric field and bombard the medical device.
One of the key characteristics of ionizing radiation is that it has a tendency to fundamentally change materials on a molecular level. One of the most common forms of change is known as scission (see Figure 1). Scission occurs when a long molecule chain is broken into smaller segments. If one imagines most polymers as a large knot of long molecules, and then the molecules are cut short, the physical characteristics of the knot are going to change. Often this causes optical changes (color change, opacity, and gloss) as well as physical changes (becoming more brittle).
Because ionizing radiation can cause materials to become more brittle, the packaging designer should choose tests that challenge the materials for its strength characteristics. For example, imagine trying to open a medical device in an operating room environment. Rather than having the package open at the seal as it was designed, the packaging experiences material failure and opens by rupturing the film itself. This could cause the medical device to fall onto nonsterile surfaces like the ground and become unusable.
Preliminary testing should include ASTM D4169, Standard Practice for Performance Testing of Shipping Containers and Systems, or ISTA 3A. In these test regimes, the packaging is subjected to a series of mechanical stressors such as environmental conditioning, drop tests, vibration tests, etc., which simulate the distribution environment. Once these tests have been completed, designers should consider using several strength tests to gain a better understanding of how the sterilization and distribution simulation affected the material properties. The seal peel test, ASTM F88 Standard Test Method for Seal Strength of Flexible Barrier Materials, would be an appropriate first choice. This test essentially pulls a section of packaging apart at the seal. If the package has material breakage in a location other than at the seal, it would indicate poor material strength or an oversealed package.
Performing this test prior to and post sterilization allows the packaging designer to understand the effect that the sterilization has on the material, and helps determine whether it will meet performance needs. A similar approach could be the burst test method, ASTM F1140, “Standard Test Method for Internal Pressurization Failure Resistance of Unrestrained Packages for Medical Applications.” Testing packaging prior to and post sterilization yields comparative results whereby the designer is able to determine any detrimental changes to the packaging.
The next most prevalent form of sterilization is what is known as wet heat, or steam sterilization. In this process, the medical device and packaging are placed within a chamber, and the chamber is filled under pressure with steam commonly at 121° or 132 °C. Because this is similar to the gas-based processes, packaging for steam sterilization must also be porous to allow free passage of the steam. Air permeance testing (ISO 5636-5) would once again be appropriate for this sterilization method.
Adhesives that are sometimes used to bond trays to their lid materials must also be taken into consideration. If the adhesive is not designed to withstand high temperature and moisture, the sterile barrier could be compromised. To test the integrity of adhesives, bubble emission testing (ASTM 2096) might be an appropriate choice. Premature bursting of the packaging or streams of bubbles emanating from the seals of the packaging may indicate a compromised adhesive layer. Seal peel testing may also be appropriate prior to and post sterilization to determine whether acceptance criteria is met and to determine whether detrimental changes to the seal strength have occurred.
This information, although not all encompassing, should provide a starting place when determining which testing should be performed to aid in design and engineering of packaging. Using the appropriate tests should illuminate possible modes of failure and should ensure that detection is made to assist with redesign if needed. Any process will affect materials and packaging to some degree. The goal is to understand how detrimental these changes are and how to successfully mitigate them.
More often than not, packaging design for the medical industry is a cross-disciplinary exercise involving engineering, material science, sterilization (microbiology), and regulatory understanding. Gaining insight into these areas will greatly assist in a timely packaging validation and approval. When navigating this process, it can be helpful to consult with outside experts to understand and determine the best test methods for the application.
This article was written by Andrew Manrique, Packaging Design Engineer and Sterilization Specialist at Nelson Laboratories, Salt Lake City, UT. For more information, visit here.