The Eto Sterilization Industry has long been predicated on the premise that larger is better. The industry as it is today is based on chamber capacities based on pallets of product, not units of product. As a result, with recent Eto Plant closures, large amounts of capacity have quickly disappeared and placed in jeopardy the overall ability of the current Eto Facilities to handle the needed market volume of product.
These large chambers that handle pallet loads of medical products are largely inefficient. While the goal of performing the Eto Sterilization is to sterilize the sterile barrier system and contained medical product, the pallet load scenario requires that folding cartons, corrugated cases and even the pallets themselves to be included in the sterilization load, creating unnecessary density that requires a longer overall cycle and more Eto Sterilant Gas to effect sterile processing.
Additionally, and especially in the current capacity constrained market, medical device companies seeking capacity will access any available chamber size in order to get needed products to market. This can result in small amounts of product being processed through chambers that are oversized for the load, requiring longer sterilization times and greater use of Eto Sterilant than should be required. This scenario is common with routinely sterilized smaller volume products, as well as new products.
Recent events have given rise to a need to complete medical device sterilization using appropriately sized chambers and a minimum of Eto Sterilant Gas in the process. Removal of unnecessary density from the load, and right sizing the load to the chamber are easily accomplished with some rethinking of historical preconditions.
A relatively new approach to meeting these objectives is available through the use of smaller chamber Eto Sterilizers. These sterilizers have been used for years in hospitals to sterilize devices and equipment on demand, and most recently are being used by OEM’s and Contract Service Houses to provide terminally sterilized sterile, disposable medical products. The use of these units is especially beneficial with small to mid-volume products where the sterilization can be performed in-process immediately following creation of the sterile barrier system, as opposed to at finished goods. With only the sterile barrier system and medical product being included in the sterilization cycle, the following benefits result:
Loads are a higher density containing only target materials (no folding cartons, IFU’s Corrugated Shippers or Pallets).
Cycles are shorter because of the reduced chamber size and focused density.
Eto Sterilant Density may be run at a lower level compared to the traditional finished goods sterilization approach.
In-process sterilization precludes the need for shipment of “non-sterile product that is labelled as sterile” to and from a contract facility.
Improved usage of sterilization capacity.
These small chamber sterilizers may not meet the needs for all products, but definitely offer advantages where product size and volumes avail themselves to the approach. Cycles typically range from 8-12 hours, and can easily be accommodated within a product as an intermediate step prior to secondary packaging. The production planning inclusive of sterilization becomes one focused on internal flow rather than building larger volumes of products to finished goods that are subsequently shipped off site for sterilization processing.
This scenario is especially advantageous in the processing of resorbable polymer products requiring barrier packaging post Eto processing. The “Open Time” between Eto Exposure and creation of the barrier package can be greatly reduced with in-process in-house sterilization compared to remote processing. The scenario also lends itself to the incorporation of past-Eto vacuum drying of the product followed in rapid succession by barrier packaging, an optimal approach to this type of packaging.
This is a different thought process than is typical for Eto Sterilization today, but one that can bring benefits in the capacity constrained Eto Market that we are dealing with today.
Designing, developing and validatingpoint-of-care diagnostic reagent blisters is so complex because medical device manufacturers must have their sights set on several different targets at once.
They need to know:
If their reagent is compatible with specified blister materials
Whether the chosen actuation method is compatible with blister shape and seal characteristics
Whether filled blisters will collapse and dispense the appropriate reagent volume to the test card reservoir
Whether extant testing methodologies are adequate to assess the quality of new blisters or if new tests must be devised
If their blister manufacturing and consumable assembly process is capable of ramping up from initial engineering builds through full-scale manufacturing runs to meet aggressive commercialization timelines
Owing to this complexity, medical device manufacturers risk underestimating or overlooking the critical technical aspects of delivering reagents to blisters and then attaching those blisters to test cartridges or other consumables.
The ways those complexities impact the onboarding of blisters to an associated consumable adds to the challenges.
These reagent-filled blisters must interact with the entire test system. They are a critical component to the efficacy and repeatable performance of a given point-of-care diagnostic test.
Use this white paper to learn:
Blister design, material selection and feasibility testing considerations
More detail on the qualification and validation considerations related to diagnostic reagent blister development
How program guidance from a turnkey point-of-care blister manufacturer can strengthen your processes and help commercialize your product faster
For a more concise summary of what to consider when designing reagent blisters, read this article.
Know what contributes to good blister design
Understanding the mechanics of a point-of-care test utilizing reagent blisters is essential to developing the most effective blister design.
The design of the consumable test card is contingent on test chemistry and defined instrument functionality that drives performance of the test. Developers must define reagent chemistries and know the associated dose volumes required to perform the test.
The instrument activates the test card in a manner that introduces the appropriate volume of reagent at the correct time and in a given order to drive a successful test. This activation method — along with the associated activation force — is a critical contributor to blister design.
Blister material selection
Blister material selection can begin once reagents and their formulations established. Selected materials should provide optimized chemical resistance to the contained reagent and display barrier performance characteristics to meet shelf life requirements.
A typical reagent blister is made from two unique foil laminates. The formed bottom stock is typically a heavier foil gauge that allows the blister reservoir to be cold-formed without fracturing the material and compromising barrier properties. The lidstock generally is a lighter and more flexible foil suitable for needed barrier properties but which also enables piercing — the most typical method to drive dispensing of the contained reagent.
These two substrates are heat sealed together to form the reagent blister.
Blister geometry
Two variables impact the overall shape of a blister: the space available within both the instrument and on the microfluidics consumable and the desired overall volume of the blister reservoir.
Blisters can accommodate several shapes, but the most typical is a dome reservoir shape. These perform most reliably and are the most economical to manufacture. (In general, complex blister shapes should be avoided because it’s more difficult to design a workable actuation method. This creates opportunities for leaks and increases overall costs.)
Blister volume includes a 20% headspace above the target reagent fill volume. This headspace provides some clearance for the placement of lidstock over the reagents. This minimizes the risk that reagents with varying meniscus types will interfere with heat sealing, ensuring more reliable, consistent heat sealing.
For any given blister bottom stock, the depth of draw that will be required to gain a needed volume within an available space must be carefully considered. As we noted above, formation of the reservoir must be accomplished without fracturing the foil or laminate layers to provide optimal stability performance.
A validated flat flange around the reservoir enables a high-quality barrier heat seal between the top and bottom blister stocks while also providing a flat surface to allow solid mounting of the blister to the microfluidics card via a two-sided pressure-sensitive adhesive.
Different sizes of flanges may be necessary depending on space restrictions on the card. If this is the case, consider:
Some additional engineering and process tweaks might be needed to ensure the sealed barrier is sufficient and provide for adequate adhesion to the card
Alternatively, you may decide the effort of redesigning the card itself to accommodate a more typical flange size outweighs the difficulties of sticking to a more unconventional shape
If you feel you may confront these alternatives and aren’t sure which makes the most sense, engage a blister manufacturing and assembly provider as soon as you can.
It’s an exercise in trade-offs. Engineers at J-Pac Medical excel in pointing medical device developers toward blister designs that (a) will result in the most consistent performance and (b) are the simplest and most effective to manufacture.
Blister fill volume
As mentioned previously, the blister design must include a reservoir volume calculation based on the available target fill volume and related headspace. Developers need to establish via testing that a given reagent volume within the reservoir will provide the necessary dose to the microfluidic card when activated and pierced.
Typically, the blister and/or reagent volume will require some adjusting to ensure repeatable reagent delivery. There will be some loss as reagents travel from their blister reservoirs through microfluidic channels and ultimately to the testing site.
The amount of reagent lost will depend on:
The console’s activation and piercing methodology including actuation force
The crush characteristics of the blister materials
The design characteristics of the microfluidic channels
It’s essential that blister design is not finalized until a blister fill volume reliably delivers enough reagent for a test to be successful.
Headspace management
While the blister reservoir size is established assuming headspace over the filled reagent, various headspace management methods can eliminate ambient gases in this headspace that may negatively affect test performance.
Developers must thoroughly assess reagent and process sensitivities to gases present in the blister headspace to determine what (if any) mitigating steps must be incorporated in the blister production flow.
One option is to replace ambient gases with inert gases. Alternatively, the gas and headspace can be eliminated entirely via vacuum sealing. Bear in mind that vacuum sealing is a more intensive process requiring advanced equipment. Consult a blister manufacturing provider to determine whether this is necessary or if the requirement can be side-stepped by changing other aspects of your product.
Preliminary shelf life study
At this point, developers should perform an initial shelf life evaluation to gain additional confidence that the chosen blister materials and format will accommodate reagents for the targeted shelf life duration.
This preliminary stability study is meant only to provide an early indicator of blister performance. If quality inconsistencies are observed, adjustments to blister design, materials or manufacturing processes may be necessary.
Even though it “doesn’t count,” don’t skip performing a stability study early! In our experience, medical device developers who overlook a preliminary investigation learn of quality problems upon formal testing which occurs much later in the development process.
This can cause significant, costly delays.
Blister design freeze and initiating process development
With feasibility testing completed, developers can claim a blister design freeze and initiate process development.
To support these activities, developers must fabricate production tooling and then develop the process the tooling will execute. To validate the processes, the typical IQ (installation qualification), OQ (operational qualification) and PQ (production qualification) methodologies must be employed.
Test runs conducted during process validation will yield usable blister samples you can use to validate your blisters and the diagnostic test.
The ultimate test for any reagent blister is the demonstrated integration to the test card, so buildouts and test performance of assembled consumables are always a concluding step in the various development phases.
Blister design is an iterative process sometimes requiring sample runs to determine the ideal design, material, forming, filling, sealing and die cutting specifications. Learn more or order blister samples from J-Pac Medical here.
Blister forming method
By this stage, developers should have concluded the design activities that establish final blister format. Now, they must analyze the chosen forming tools to ensure that formed blisters will meet all specified dimensional requirements. This step must be performed for each tool and each blister geometry that is incorporated to the test consumable.
Test runs demonstrate the capability of new tooling. Once those are complete, teams conduct visual assessments and take measurements to assess the quality of formed test blisters. These data must be documented.
As a turnkey contract manufacturing partner, J-Pac Medical supports in-house development of custom tooling. The process of designing and integrating custom tooling, verifying that it will perform to your requirements and ensuring it is adequately documented contributes to a faster overall development timeline.
Reagent dispensing method
Reagent filling is typically accomplished using a multi-up array of fill stations. Developers must qualify and validate each position.
A design of experiments (DOE) and a subsequent short sample run are critical to determining pump settings for each position. Through DOE and sample runs, you’ll be able to establish minimum and maximum fill volumes that will inform the ultimate target fill volume required for a successful test.
You must perform this step for each reagent and fill volume that will be incorporated to the test consumable. To assure quality, conduct weight checks of filled blisters and compare observed weights to the weight associated with minimum and maximum volumes.
Heat sealing method
The blister materials discussed in this white paper are typically heat sealed to form a permanent bond. Again, performing a DOE will provide critical data you’ll need to establish:
Heat seal tool temperature
Nip pressure
Contact time
Start by determining the parameter sets for the low and high burst strengths that meet specification. Visual assessments and burst tests will show whether those parameter sets will work.
Be aware of the following potential complication: Developers might not always know how much force a specified burst-type testing console can deliver. Or, if they are aware, they may yet assume that the blister materials and heat sealing methods they’ve specified are capable of achieving seal characteristics necessary to work reliably with that chosen console.
It’s not always a given, especially when blisters feature uncommon cross sections or flange sizes. In these cases, manufacturers must take special care to develop heat sealing methods and process parameters that create adequate seals without corrupting the reagents inside the blisters.
Uncertainty here may lead to product quality, shelf life and end use challenges that force developers back to the drawing board. For more, read about how contract manufacturing partners can help develop blister seal strength specifications.
Prototype build
With processes developed for the form, fill and seal components of the overall production flow, you can generate samples to use for benchtop testing that demonstrates performance feasibility.
As with the preliminary shelf life testing, these data are not submission quality but nonetheless are essential supporting information for process refinement and verification.
Test methods
The testing conducted to show whether a diagnostic reagent blister process will result in reliable quality manufacturing is one of the most crucial stages in program development.
Depending on the nature of the blister you’ve designed or the manufacturing process chosen to produce it, you may need to establish new testing methods to assess in-process or finished components.
If a new method is needed, test method development and validation is required such that the method can be utilized to support the upcoming OQs, PQs and ongoing production. However, note that new test methods are required only if existing test methods are not able to adequately measure critical-to-quality attributes or performance.
Obviously, using existing test methods is preferable to inventing new ones if the option is available. A blister manufacturing partner familiar with testing methods can help you quickly determine whether new methods are required or not.
J-Pac Medical’s extensive experience developing new testing methods (and our library of available existing testing methods we can pull from) is another contributing factor to an overall speedier product launch.
Process OQ
Process OQ is an overall process challenge that demonstrates the low and high parameter sets that result in blisters that will meet specification. This run is performed under protocol and is typically completed as a single end-to-end process challenge that will include forming, filling and sealing. An end-to-end assessment is recommended to capture the interactions between each of these processes at their process extremes.
Runs typically consist of 30 blisters per blister size/reagent combination from each tooling position. As above, you’ll need to test the critical-to-quality attributes (and document the results) of the sample runs to determine whether your process is capable of achieving in practice its intended performance in theory.
Engineering Build
Next, developers perform an engineering build using OQ nominal parameters. Data generated from blister samples run at these parameters apply to downstream PQ blisters so long as the OQ parameters used for the run remain within the validated parameters that are established through PQ.
Samples from this run can be used for activities that include:
Transit testing
Formal shelf life studies to establish expiry claims for the consumable (typically includes both accelerated and real-time studies)
Clinical trials
Process PQ
This is the process validation which consists of three lots of blisters that are ultimately saleable. Associates execute these runs under protocol using multiple crews and raw material lots to ensure the process as designed is capable in real-world production.
Developers must run PQs for each reagent/fill volume/blister geometry combination incorporated in the test consumable.
From there, developers can use these PQ blisters to aid the fabrication of consumables that will be used to validate the performance of the overall diagnostic test.
Provided that standalone blister performance data gathered during overall system validation was satisfactory, “development” is complete and commercial production can launch.
Good guidance can make the difference
If the process described in this white paper is any indication, point-of-care test developers have their work cut out for them.
It doesn’t help that developers face the added pressure to meet key development milestones and stay on-track under aggressive launch timelines.
If this is the case and you feel you need a partner who can provide critical technical guidance, reduce project risk and ultimately help launch your point-of-care test faster, contact the team at J-Pac Medical today.
Medical-grade textiles have been proven to deliver the high degree of versatility and performance that OEMs need to create implantable devices that best meet the needs of today’s surgeons – and patients. As a result, the market for medical textiles is rapidly growing.
Although textile structures have been utilized in certain surgical procedures for decades, recent technology innovations are allowing textile devices to serve greater purposes and be a successful option for a broader range of medical applications.
Understanding the most important factors that go into textile implant manufacturing can help OEMs ensure that the best final product is designed to meet the needs of their end-user. Selecting a single source partner such as J-Pac Medical to oversee devices from inception to manufacturing, through packaging and sterilization, reduces the complexity and likelihood of human error from having multiple partners involved in development and across the supply chain.
Enabling Better Medical Implants Using Medical Textiles
Surgical implant optimization is being pushed out of the operating room and into the device manufacturing process, with heavy reliance now being placed on the device manufacturer to provide a product that is ready to implant with little or no revision needed by the surgeon.
Medical textiles are emerging as an ideal option for creating more “active” device forms like resorbable or drug / device combination products. Resorbable textiles will break down naturally in the body post-implantation, which supports improved clinical outcomes by eliminating foreign material in the body and any need for additional implant removal procedures. These implants can be customized into unique anatomical shapes and incorporate various chemistries that can help direct the healing process and reduce potential complications, such as infection. Additionally, resorbable textile implants don’t interfere with imaging and radiotherapy like other permanent implants may.
Resorbable textile implants have already gained a foothold in the orthopedics market as an ideal option to aid in tissue regeneration and strength building at the surgical site. Textiles are also frequently used in sports medicine, trauma, wound management, tissue replacement, plastic surgery, women’s health, and neural and endoscopy applications.
Critical Medical Textile Implant Considerations
Taking a raw textile material and transforming it into an optimal medical implant is a complex process. There are many important considerations that must go in to medical textile implant manufacturing in order to ultimately create devices that are effective and fit for purpose. Choosing a qualified partner like J-Pac Medical early in the development process that understands and brings expertise in critical areas such as manufacturing, packaging and sterilization for textile-based implants ultimately saves OEMs time and money by reducing unexpected issues later on.
Correctness of the Shape
Resorbable and non-resorbable polymers can be used to create implantable textile devices that are custom-shaped to meet specific anatomical and biological requirements, as well as facilitate shape transformation in situ. Customization of an implant’s shape by the manufacturer can also reduce surgical procedure time by minimizing or eliminating currently needed intraoperative adjustments, and can also provide surgical repairs with reductions in tension inherent with noncustomized implants. The value of a pre-shaped textile implant has been most notably demonstrated in the area of hernia repair, but potential applications exist across general, cardiovascular and orthopedic surgical applications.
J-Pac Medical can develop textiles in two-dimensional and three-dimensional implantable forms in any number of configurations. The company further understands the unique needs of different surgical applications and can offer strategic counsel in the product development phase – coupled with the necessary process capabilities including precision cutting, shaping, forming and assembly capabilities during manufacturing which can optimize implant performance for purpose.
Specialized textile engineering techniques enable J-Pac Medical to capitalize on the unique properties of different materials. Braiding, weaving, knitting and non-woven textile manufacturing processes help to significantly enhance strength, texture, flexibility, and other performance characteristics for customized device requirements. For engineers, the possibilities for improved mechanical performance and anatomical accuracy are limitless, which will ultimately benefit the patient.
Interface to instrumentation to support minimally invasive methodologies
A textile-based implant is only completed when it is coupled with a methodology to place the device properly in-situ in the most minimally invasive manner possible. In meeting this objective, it is sometimes necessary to add attachments to what will be the final implant that will interface effectively with needed instrumentation. These attachments to the implant are removed post-implantation, but nonetheless are critical to an optimized implantation procedure.
The same cutting, shaping and forming capabilities that drive the manufacture of an anatomically correct textile implant can also support this critical instrument integration and needed deployment features that can minimize the invasiveness of any given implantation method.
Integration of different materials
One of the greatest benefits of implantable textile devices is that they can be patient-specific and developed for specialized end-user needs. Devices can be made entirely of absorbable components or of a combination of resorbable and nonresorbable parts. They can even be used for controlled delivery of drug or biological agents directly at the site of implantation.
It is important to choose the right textile materials and manufacturing partner to optimize the performance of the finished device for its intended purpose. J-Pac Medical’s team has the expertise to work with different types of materials – even hard to handle materials – and incorporate multiple materials into a device when beneficial for more optimized implants. Using thermal processing capabilities as a foundation for material manipulation, supported by a blend of tooling, materials, automation, and process expertise will result in more innovative solutions to complex customer challenges.
In instances where resorbable and/or lyophilized materials are included in the implant, the manufacturer should utilize low humidity clean room manufacturing environments (dry rooms) to extend the WIP Time (Open Exposure Time) for materials and components that are moisture sensitive, and also to drive product consistency that can be impacted by uncontrolled humidity. J-Pac has production controls in place to negate any product impact that can be brought on by overexposure to humidity.
Customized Edge Treatments
Most textiles are produced in a bulk form as rolls, sheets, or reels of all sorts of multi-filament woven, knitted or braided textiles. Traditional cutting processes are capable of providing a unit/part with the proper length or outline but in a manner that allows the ends of textiles to fray, making the edges of the implant rough, and potentially generating particulate or degrading the textile’s structural integrity.
J-Pac Medical has cutting methods that will create semi-sealed edges on cut parts that drastically reduce the amount of particulate, and greatly enhance the “surgical hand” of the implant by creating smoother, more flexible, cleaner and more structurally stable implants with improved tissue passage characteristics that significantly benefit both the patient and the surgical team.
Optimized edge treatment processes during manufacturing can offer broader benefits that may include:
Enhanced edge quality of implantable medical textiles, which may minimizes tissue inflammation and scar tissue formation
Reinforced edge feature that can enhance stability and suture pull-out
Integrated deployment feature that can enable device delivery through cannula
Smoother edge to enhance tissue passage
Advance manufacturability of the finished device, which reduces component preparation time within the overall device assembly process.
Packaging and Sterilization
For implants that incorporate resorbable materials, the packaging must provide the necessary barrier to ensure efficacy over the claimed shelf life. These barrier put-ups may also incorporate modified atmosphere (gas-flushed) packaging in order to extend shelf life, and/or can include desiccants and scavengers to gain the same outcome.
For implants that incorporate a three-dimensional shape, the package must protect and maintain the desired anatomical shape. The package not only must protect the implant through distribution and while on the shelf, but also must provide an intuitive and convenient platform to support sterile delivery technique in surgery.
If the implant is provided with instruments to be used during implantation, the packaging also needs to support the intended use of these instruments and aid the nursing staff and surgical team to gain easy access in the order the items are needed.
Regarding sterilization, in instances where actives (drug/device combinations) and/or a combination of resorbable and nonresorbable polymers are in use in a single device, a package format and flow may need to be developed to accommodate multiple sterilization flows such that each polymer chemistry present is sterilized in a manner not detrimental to its ultimate performance. In some cases, it may be necessary to perform separate sterilization flows for various components of the implant that are mated downstream in the supply chain to assemble the final kit. While these instances are not common, they will become more relevant as actives are incorporated into that textile implants.
J-Pac Medical’s sterilization services are conducted and validated in close collaboration with our trusted strategic partners to deliver market-ready products to customers. Sterilization methods include Eto, Gamma, VHP, and autoclave and among others.
J-Pac Medical: The Right Medical Textile Manufacturing Partner for OEMS
There are a broad set of requirements to be considered in the effort to develop and implement an optimized textile implant. As OEMs consider a manufacturer for medical textile implants, all the aspects that have been presented here must be considered. With the large number of integrated potential issues, partnering with a supplier like J-Pac Medical that has experience with all aspects of medical textile device manufacturing, including packaging and sterilization, can pay dividends through the entire product lifecycle.
With more than a decade of expertise in the manipulation of rolls and sheets of medical grade polymers and a reputation for excellence in manufacturing with difficult to handle materials, J-Pac Medical is able to produce the highest quality two-dimensional or three-dimensional implantable textile devices custom-shaped to meet specific anatomical and biological requirements.
J-Pac Medical provides forming, cutting and assembly capabilities for biomedical textiles and films backed by the extensive expertise needed to create two- or three- dimensional shapes with woven, knitted, braided or non-woven textiles, films, and more.
With efficient processing capabilities for delicate, brittle films and materials that meet industry standards, J-Pac Medical is able to achieve material utilization of 85% or better, which increases the efficiency of production, reduces waste, and decreases cost to the customer.
The benefits of partnering with J-Pac Medical to manufacture implantable textile devices include:
Reducing overhead for legacy products
Freeing-up internal capacity
Working with a single point of contact from start to finish, allowing potential obstacles to be identified and over come before delivery schedules are delayed
Ability to form complex two-dimensional and three-dimensional shapes
Cutting overall costs
Proven Class II/III compliance and adherence to stringent quality and validation standards at every step of the supply chain.
J-Pac Medical has experience including, but not limited to, developing:
Hernia repair products
Nerve conduits
Cardiovascular plugs
Heart valve sewing cuffs
Collapsible orthopedic anchors
Diabetic wound care tissue scaffolds
Osteoconductive bone grafts
Scoliosis correction devices
Suture loops
Sternal closure devices
Partially to fully resorbable soft tissue repair products
Drug and device combination products
By working with J-Pac Medical from start to finish, consistent quality management, validation, tracking and reporting processes can be applied at every stage from development to manufacturing. The packaging of implantable textiles devices will also provide assurance of a high quality end product fit for the stringent demands of the medical market.
About J-Pac Medical
J-Pac Medical is a trusted manufacturing and packaging outsourcing partner to medical device and diagnostic companies seeking to deliver superior quality, improve time-to-market and simplify the supply chain for single-use medical devices. With more than 30 years of experience in complex thermoplastic devices and packaging, J-Pac Medical has the unique technology that allows it to manufacture anatomically correct, class III implantable textile assemblies, lab-on-chip reagent blisters, and complex thermoformed packaging. Additionally, the company offers full-service supply chain management, packaging and sterilization.
The largest medical device companies in the world rely on J-Pac Medical to help meet the most difficult development, manufacturing, and logistics and supply chain challenges.
J-Pac Medical is FDA Registered (#1221051) as a Medical Device Manufacturer and a Device Labeller/Relabeller; and Certified to ISO 13485 standards through BSI.
This white paper is meant to identify critical considerations related to WIP Exposure vulnerabilities of resorbable polymers. A structured and disciplined assessment of the different contributors to the Overall Exposure Risk will enable a fact based decision pathway that will result in the establishment of a repeatable and capable manufacturing, packaging and sterilization processes that reduce device degradation. The result will be a consistently performing, efficacious product with optimized shelf life.
Background and Challenges
Implants that are made from resorbable polymers offer the ideal scenario for surgical repair. The device provides support to a surgically repaired site to enable critical wound healing of the affected tissues, and then the implant is absorbed by the body through routine body functions. No mass from the implant remains once it is totally absorbed.
The challenging part is that the same sensitivity of the polymer to breakdown in the human body is also taking place during the fabrication, packaging and sterilization of the device. This degradation occurs during manufacturing processing time (Work-In-Process) and needs to be assessed and controlled in order to provide a consistently performing resorbable polymer implant with an optimized expiry dating claim.
A broad range of resorbable polymers are available that display total absorption profiles from roughly 2 weeks up to 2 years. These polymers include Polyglycolide (PGA), Polylactide (PLA), and Polydioxanone (PDO) just to name a few. The decomposition of these materials can be driven most notably by moisture and/or Oxygen, but also can include sensitivities to light, heat, and other factors. The shorter the critical wound healing time the polymer is designed to accommodate, the more critical WIP Exposure control will be to the overall performance of the resorbable implant.
Manufacturing Requirements
The manufacturing and supply chain of a typical resorbable implant will include polymerization, extrusion or injection molding, kitting with other components, packaging, sterilization, and distribution. All these areas of production can negatively affect the ultimate performance of the device if exposure to environmental elements is not limited. A systematic understanding of the link between WIP Exposure and Product Performance/Shelf Life can be established, and controls put in place to ensure identified WIP Exposure limits are not exceeded.
As part of polymer and product development, a WIP exposure study should be performed to establish data that links WIP exposure to implant performance and Shelf Life. The goal is to set acceptable “WIP Exposure” windows for each critical assembly process step such that a documented overall exposure time will be established that will ensure finished product that is compliant to performance and shelf life claims. These WIP exposure windows should be challenged individually and sequentially through the supply chain (low and high exposure at each step), and implant efficacy measured as determined to set viable limits. Once limits are established, a WIP Exposure Log should be maintained for each processing step such that overall exposure is known for each lot/sub-lot of resorbable product. This exposure log can identify lots that may be at risk towards the end of the supply chain such that special handling may be instituted to ensure the Overall Exposure Limit is not exceeded. The WIP Exposure Log should be maintained as part of the Device History Record (DHR).
In establishing and controlling WIP exposure, there are a number of methods that can be utilized that will minimize polymer degradation:
A manufacturing dry clean room that maintains low humidity as an ambient condition will help to limit WIP Exposure Degradation.
For most resorbable polymer products, a dry nitrogen environment will stop or significantly slow any ongoing degradation. A nitrogen storage chamber should be available to store exposed product in case of unanticipated delays/stoppages in processing. In addition, flowing nitrogen over any exposed resorbable product can inhibit the impact of moisture and oxygen in the ambient environment.
In most cases, Nitrogen-flushed foil pouches provide an effective storage and shipping format for the in-process resorbable implants.
The resorbable components should be packaged in small quantities within a larger processing lot such that only a small number of components are exposed at any one time. The key to a successful flow is the rapid processing of product once opened to the environment, and the rapid return of product to barrier packaging that will slow or stop the degradation clock.
Minimize handoffs where at all possible. It is more desirable to perform all functions in a single facility than it is to be shipping these sensitive products from site to site.
Refrigeration of packaged, in-process resorbable components can also help to maintain implant efficacy.
Sterilization Optimization
Most of the resorbable polymer implants are sterilized via Ethylene Oxide (Eto). This presents the challenge of providing a breathable packaging format that performs through the sterilization cycle, but the need remains for a high barrier final format that will maintain a dry, and possibly alternate gas (like Nitrogen) environment that will maintain implant efficacy. Additionally, the packaged product must perform through transit and distribution, and provide easy aseptic transfer in the OR.
Additionally, the Eto Process itself will impact resorbable polymers. The Eto process utilizes steam to raise the load temperature and create the most advantageous environment for Eto sterilization to take place. With this introduced steam entering the package and impacting the resorbable implant, it is important that the overall cycle be developed to minimize any latent moisture that might remain in the package post processing. This can be accommodated through extended aeration, or with the addition of some sort of drying/vacuum drying cycle.
Unique Packaging Requirements
Historically, a Foil to Foil Pouch with Tyvek Header has been the preferred package format for resorbable products. This format can provide the needed barrier properties discussed above, but typically requires intricate inner packaging components to provide protection to the product and enable aseptic transfer. This format is especially complex when the resorbable implant is packaged with an inserter and/or other instrumentation that requires a 3-Dimensional infrastructure within the pouch.
Most recently, vented tray concepts are in development that provide the protection and handling simplicity of a tray that incorporates an easily placed barrier patch over vent to complete the barrier package post sterilization. This format incorporates all the performance advantages of a rigid tray/lid package while providing the final barrier packaging seal convenience of the header bag.
Process Controls to Reduce Degradation
With packaging identified, the logistics of integrating WIP Exposure Controls to the Eto Flow becomes a critical concern. With any product destined for Eto Processing, the package feature that allows for the Eto Sterilant to enter and exit the package will also allow for moisture and oxygen to enter the package and potentially impact the resorbable implant. If the Eto Sterilization is not on site, then shipping to the sterilizer must be orchestrated such that a minimum amount of time is spent in transit and in queue at the sterilizer so as to minimize this portion of WIP Exposure. As most sterilizers will not create the final barrier seal in any package format, the product will also need to be returned post-processing in an expedient manner again to minimize WIP Exposure.
About the Author
Rick Crane has more than 30 years of experience in the healthcare products industry. He brings strong general management skills demonstrated across operations, R&D, program management, technical sales, and marketing organizations. Crane is an Ameristar Packaging Competition Gold Star Award Winner for Medical Device Package of the Year, and is a patent holder. He has a Bachelor of Science from Ursinus College.
About J-Pac Medical
J-Pac Medical is a manufacturing outsourcing partner to medical device OEM’s seeking a faster time-to-market and dependable long-term supply. We specialize in single-use medical devices, biomaterial implants, and lab-on-chip diagnostic consumables. J-Pac delivers a validated end-of-line solution for package design, cleanroom assembly, sterilization, and supply chain management. We are FDA registered and certified to ISO 13485:2016.
There is a lot of excitement in the medical device packaging industry about pre-validated packaging.
Using pre-validated packaging may reduce time to market and minimize package development and validation expenses. However, international standards defining medical device validation requirements are complex, involving materials selection, design qualification, process validation, and design controls. Pre-validated packaging may not comply with all the requirements depending on the specific device involved. Nevertheless, pre-validated packaging can be a helpful strategy if adequately implemented by the device packager within the framework of these standards. This paper aims to clarify when pre-validated packaging makes sense and how its cost and lead time compare to a custom-designed package.
Packaging Standards for Terminally Sterilized Devices
Sterile packaging systems need to ensure the sterility of their contents until they are opened for use. The sterile barrier system (SBS) must also be designed to ensure aseptic presentation at the point of use. ISO 11607 (part 1 and part 2) is the global standard governing packaging for terminally sterilized medical devices. ISO 11607-1 defines requirements for SBS materials selection, and their design and testing. ISO Sterile packaging systems need to ensure the sterility of their contents from shipping through the point of use. The sterile barrier system (SBS) must allow aseptic presentation into the sterile field. ISO 11607 (part 1 and part 2) is the global standard governing packaging for terminally sterilized medical devices. Part 1 of the standard defines requirements for SBS materials selection and their design and testing. Part 2 defines manufacturing critical process validation requirements for forming, sealing, and assembly processes.
Key Definitions
ISO 11607 provides precise terminology used for medical device and healthcare packaging.
Sterile Barrier System (SBS):The minimum package that minimizes the risk of ingress of microorganisms and allows aseptic presentation of the sterile contents at the point of use. For example, a thermoformed tray with a Tyvek lid can be an SBS. Header bags and Chevron pouches are standard sterile barrier systems.
Protective Packaging:The configuration of materials designed to prevent damage to the sterile barrier system and its contents from the time of their assembly until the point of use. These include shelf cartons and shipping boxes.
Preformed Sterile Barrier System:A sterile barrier system that is supplied partially assembled for filling and final closure or sealing. Examples of these include porous and nonporous chevron pouches, header and patch bags. These are typically purchased from packaging suppliers partially assembled and used during final packaging by making a final closure seal. A thermoformed tray also falls within this definition.
Packaging System:The combination of the sterile barrier system and protective packaging. Both work in tandem to protect the product and the sterile barrier.
How is Sterile Packaging Validated?
ISO 11607 and ISO 11135 define the requirements for validating terminally sterilized medical device packaging.
Design Qualification. Packaging materials must be selected and documented within a quality system based on the requirements of the device and sterilization method used. These include the adequacy of the microbial barrier, biocompatibility and toxicity attributes, sterilization effects, sealing effectiveness, compatibility of the device and SBS materials that contact each other, and compatibility with labeling.
Stability Tests. The sterile barrier seals must be proven to maintain sterility over time. Validation involves a post-sterilization stability study. The sealing and sterilization parameters for this test must be under worst-case conditions. The FDA allows accelerated stability testing if real-time testing occurs in parallel.
Sealing Validation. The sterile barrier system’s sealing process must be validated. This requires a critical manufacturing process validation, which includes an IQ, OQ, and PQ on the sealing equipment performed at the manufacturing location.
Transit Simulation. Transit testing must reflect how the product will be shipped
Sterilization Validation. Sterilization results in a 10-6probability of any infecting microbes surviving the sterilization process.
What is pre-validated packaging?
A pre-validated package eliminates the need for design qualification (1), stability testing (2), and sealing validation (3). It does not negate the need for transit testing because each packaged product may impact the seal differently. Likewise, sterilization validation is still required because it is unique to the product – not the package.
When is pre-validated packaging preferred?
Pre-validated sterile packaging is a novel concept that, if properly executed, can help MDM’s reduce
Pre-Validated Packaging
High probability package will change
A clinical trial is the next step
Custom Packaging
Low probability package will change
Commercial launch is the next step
What sterilization validation methods are typical?
The available sterilization validation methods are “full validation” and “single batch release.” A full validation validates the cycle parameters and the specific equipment. The single batch release verifies each lot separately. Three single batch releases performed in twelve months may equate to a full validation after a retrospective analysis.
Batch Release Sterilization
High probability package will change
Commercial launch in <16 weeks
Higher Cost
Sterilization Validation
Low probability package will change
Commercial launch >16 weeks
Time and cost savings
Typical project plan for pre-validated packaging
Conclusion
Pre-validated sterile packaging is a novel concept that, if properly executed, can help MDMs reduce expenses and improve time to market. However, the ISO 11607 standard (Parts 1 and 2) is complex and cites three critical components of a “validated” packaging system. (A) The design and development of the packaging system include material selection, design, and packaging qualification testing, (B) qualifying or validating or providing proof of the stability of the SBS materials and seals, and (C) sealing process validation.
The MDM’s unique devices, sterilization cycle, distribution environment, and manufacturing processes often require pre-validated packaging solutions to undergo additional qualification and validation testing to satisfy regulatory requirements. MDMs should ask specific questions to understand how pre-validated packaging meets these requirements and identify any further testing that may be required. Finally, MDMs must ensure that all validation data is maintained in their design history files, as they are ultimately responsible.
Additional Resources
ISO 11607-1:2006/(R) 2010Packaging for terminally sterilized medical devices—Part 1: Requirements for materials, sterile barrier systems, and packaging systems and ISO 11607-1: 2006/A1: 2014Packaging for terminally sterilized medical devices – Part 1: Requirements for materials, sterile barrier systems, and packaging, Amendment 1
ISO 11607-2:2006/(R) 2010Packaging for terminally sterilized medical devices—Part 2: Validation requirements for forming, sealing and assembly processes and ISO 11607-2: 2006/A1: 2014Packaging for terminally sterilized medical devices – Part 2: Validation requirements for forming, sealing, and assembly processes, Amendment 1
ANSI/AAMI/ISO TIR16775: 2014, Technical Information Report, Packaging for terminally sterilized medical devices-Guidance on the application of ISO 11607-1 and ISO 11607-2.
