Extractables and Leachables

SANDI SCHAIBLE, SENIOR DIRECTOR OF ANALYTICAL CHEMISTRY AT WUXI APPTEC, SHARES THE IMPORTANCE OF COMPLETE CHEMICAL CHARACTERISATION.

EXTRACTING THE TRUTH

Plastics are everywhere in medical device manufacturing. Whether we’re talking about a fi lter, bag, container, delivery system or implantable device, these days, chances are, plastic is part of the equation. While plastics and polymeric materials can enhance performance and pricing, these materials do carry risk of their own. Manufacturers need to understand these risks as they develop their products, plan for production and identify both materials and component suppliers as well as laboratory testing partners to support their submission and lifecycle management of their products. They need to understand the key tenet that not all plastics are created equally.

Plastic and polymeric products, parts and components can include signifi cant numbers of chemical constituents. Some of these constituents are expected, but many are unexpected and can be potentially harmful. Additives, excipients, and release agents along with impurities, can pose signifi cant diff erences in plastics that, at surface level, appear to be equivalent. It is these chemical constituents that can leach from the products and compromise patient safety. Extractables and leachables (E&L) testing is the most eff ective way to extract, detect and identify these potentially problematic compounds so that a thorough risk/safety assessment can be conducted to determine the risks.

Extractables testing challenges products using aggressive solvents under exaggerated conditions. The point of extractables testing is to generate “worst-case” data to create a conservative approach to safety. Leachables testing or simulated use extractions investigates compounds that have migrated from a plastic component under clinically relevant or “normal” conditions utilising drug products, placebos, or more clinically relevant extraction solutions.

Regulatory bodies are becoming more and more interested in understanding complete chemical characterisation, looking for extractables and leachables data. Because even common materials or those with a long history of clinical use can contain chemicals of concern. Per ISO 10993-1, most medical devices require extractables or exaggerated extractables studies and a toxicological risk assessment, with potentially additional chemistry to mitigate risks to fulfi l materials characterisation endpoints. For drug manufacturers, the release of USP <1665> and <665> signals a keen interest in the extractables and leachables in the plastic components of the biomanufacturing process in addition to the extractables and leachables work that has been conducted for years with regards to container closure and stability studies.

EXTRACTABLES LEACHABLES

The point of extractables testing is to generate “worst-case” data to create a conservative approach to safety. Leachables testing investigates compounds that have migrated from a plastic component under clinically relevant or “normal” conditions utilising drug products or more clinically relevant extraction solutions.

SHIFT YOUR MINDSET ON E&L TESTING The goal of an E&L study is to detect and identify all the chemical constituents above an analytical threshold, including chemicals that are unexpected. It takes a committed laboratory to do the work needed to identify compounds, a report with “unknowns” can cost delays and require retesting.

Robust, well conducted E&L studies require a commitment by the laboratories to provide complete characterisation; they must identify the unknowns. Many chemistry laboratories advertise E&L capabilities, but a lab designed specifi cally for them is diff erent. It means building an infrastructure that includes the instrumentation, cross-functional skill sets and staff to generate and interpret the data in meaningful ways.

For example, liquid chromatography-mass spectrometry (LC-MS) is a highly sensitive platform used to detect semi to non-volatile compounds. When it comes to plastic medical products, typically the most chemicals are found using LC-MS. And this is often when chemicals of concern are found. There are no commercial databases of LC-MS compounds, and even the most comprehensive private databases contain only a fraction of possible chemicals derived from E&L studies. So it takes the eff ort of expert chemists doing compound elucidation to get to identifi cation. But, without the identifi cation, an E&L programme is incomplete and often, unusable for a toxicologist doing a risk/safety assessment.

To reiterate, manufacturers need to know how committed their laboratory testing partners are to identifying all potential hazards. Complete identifi cation is complex and resource intensive. Working with a lab that specialises in complete chemical characterisation will yield the best results.

ASK THE RIGHT QUESTIONS Thoroughly vetting potential partners can save manufacturers from unexpected charges and unanticipated problems down the road. Understanding your lab testing partner’s method of identifying chemicals of concern and level of rigor is critical. To this end, manufacturers should dig deeply into any potential partner’s experience. Helpful questions include:

● How long has the laboratory been conducting E&L studies? How many programmes have you run? ● Can you commit to the elucidation and complete identifi cation of all components? ● Is complete identifi cation included in the price and timeline that you provided? Or is this extra? Successful partnerships require more than experienced practitioners, so it is essential to also ask about project management and communication. Helpful questions include:

● What is your on-time delivery record? And, when does the clock start? Upon receipt of the test article? ● E&L studies often yield unique situations. Can you commit to proactive communications when these arise? ● What support do you provide after analytical testing concludes?

What if regulators have questions?

Finally, manufacturers must understand the services they are purchasing—and those they are not. Some laboratories charge extra for identifi cation or identifi cation beyond what can be found in a commercial database. Other laboratories claim they have the capacity to take on a new E&L programme but fail to deliver on time when the process proves more complex than anticipated. Asking the right questions when vetting partners allows manufacturers to make informed decisions, achieve regulatory success and market safe products.

A FINAL WORD ON E&L TESTING Plastic and polymers have become the dominant materials in medical products, but several factors contribute to their safe use. Manufacturers cannot assume that just because a plastic or polymer has been used before or is commonly used that there will not be potential safety concerns. E&L testing helps manufacturers fi nd the unexpected chemicals that may, or may not, potentially impact safety. A robust E&L programme should detect and identify all chemical constituents and provide a clear picture to assess risk. Manufacturers are right to question any laboratory testing partner that cannot deliver complete data about their container, delivery system or device.

IT’S HEATING UP

ALAN WADE, OPERATIONS DIRECTOR AT SHAWPAK, SHARES HOW THE COMPANY PLANS TO KEEP AHEAD OF THE THERMOFORMING COMPETITION.

Shawpak is a UK manufacturer of a range of packaging equipment for medical devices, including rotary thermoforming machinery.

The start of Shawpak began in 2013 when David Shaw, CEO, thought that the size of a long linear thermoforming machine - which was six metres long - could be condensed into a smaller machine, but with the same input.

Alan Wade commented: “Our CEO, David Shaw had an idea at the end of 2013, to make a smaller rotary thermoforming machine.

“We started developing the fi rst machine and took it to the fi rst trade show, Medica, in Dusseldorf. The machine received such a great response that we knew we had to promote the machine commercially.’’

The shawpak thermoforming machine uses a rotary drum to form, fi ll and seal the medical devices unlike the traditional linear thermoformers. The benefi t of wrapping this around a drum reduces expensive clean room space, as it’s so compact, reduces waste on blister packs and also increases fl exibility to change tools over.

Riverside Medical Packaging has played a huge role in developing the shawpak machine. With their experience in packaging, they were able to assist in fi nding the advantages that the shawpak machine provides and overcoming many of the disadvantages that thermoforming machines generally have. While thermoforming is a huge industry, Shawpak intends to stay ahead of the game. Wade discussed several ideas that could benefi t the growth of the company, including making assemblies in advance to put into stock, so when a customer wants something, they can pull the assembly and build, rather than manufacture from new, which can reduce time signifi cantly.

A great way of staying ahead is being out there and meeting potential customers. Shawpak stays busy with medical expos around the globe; the company exhibited at Med-Tech Innovation Expo in 2022 and has signed up for 2023, as well as MD&M West, Compamed and more.

Not only do Shawpak exhibit at expos, but the company also held its own in-house expo over three days, in July, called Shawmed. The expo consisted of showcasing many of their own machines, a factory tour of Riverside and opportunities to speak to their related companies – Amaco Flexible Print Solutions, SP Automation and Robotics and Sterimed Infection Control.

Shawpak’s range also includes the Pouch Machine and the Pouch Sealer. The Shawpak Pouch Machine launched at the start of 2021, Shawpak says it represents the best solution for packaging fl at medical products.

Shawpak is now developing their own rigid blister making machine. Tony Crofts, sales director explained: ‘’To compliment our range of medical packaging machinery we are now developing a rigid blister making machine which forms the blister, die cuts the outer profi le and stacks them ready for use in production.

“This along with our pouch making machine gives our customer the full fl exibility in making their packaging on demand from roll stock rather than relying on their supply chain to deliver the packaging they require and keeping months of stock to ensure supply doesn’t run out. The tooling can be quickly changed to give the customer full fl exibility and control, it allows you to make the blisters and pouches you require just ahead of time and not keep pallets of stock taking up space and tying up cash.‘’

Shawpak’s newest addition to the range, the Shuttle Machine, is also coming soon.

BRIAN GOLDEN, SALES DIRECTOR, AMERICAS, GN THERMOFORMING EQUIPMENT, SHARES HOW THE MEDICAL PACKAGING INDUSTRY LEADS THE TREND TOWARDS THERMOFORMING AUTOMATION.

Automation of the thermoforming process has been embraced in the medical packaging industry more quickly than in other markets. Originally, this trend was driven by stringent quality requirements and the need for high levels of repeatability. Automation has also brought other benefi ts of strategic importance to medical packaging producers, including facilitating higher and more predictable throughput, as well as helping to address the challenges of attracting, training, and retaining a quality manufacturing workforce.

STRONG FLANGE AND COMPLEX GEOMETRIES The shape of the packaging typically diff ers for medical products. The entire package must withstand the temperature and pressure extremes of the sterilisation process. The fl ange must have the required thickness and rigidity, and smooth surface, to accept and maintain a hermetic seal to the Tyvek lid. The sidewalls must also have adequate and consistent strength and thickness to prevent cracking and leakage during transport and handling.

The most challenging aspect of medical packaging design is often the complex geometries required to isolate individual items into separate compartments and to lock each item in place. When properly designed and manufactured, undercuts allow each part to be snapped into place and held securely.

ELIMINATION OF AIRBORNE PARTICULATES Most medical packaging applications call for enclosing the thermoforming machinery in a protective enclosure to minimise exposure to airborne particulates that can cause gaps during the hermetic sealing process. It is imperative that measures are taken to eliminate static that will attract particulates and to ensure that the cutting process does not generate particulates that can migrate to the product.

Enclosing the machinery is important not only for protection against particulates but also for isolating the system from ambient air and temperature that cause fl uctuations in the heating of materials and in the air pressure of pneumatic components.

INCREASING AUTOMATION These various special requirements for medical packaging have led to the wide-scale adoption of Form/Cut/Stack thermoforming systems. Simpler and less costly Contact Heat systems are suitable for only a small fraction of medical packaging applications because they lack plug assist capabilities required for complex geometries and the higher clamping forces that Form/Cut/Stack systems off er.

Form/Cut/Stack systems are usually enclosed in a protective envelope protecting the process and the product from airborne particulates and ambient temperature and humidity, and they can be more fully automated and therefore more precisely monitored and controlled, especially machines with 100% servo motors and drives. Investment in automation off ers many advantages in medical packaging manufacturing - more precision and control result in much higher repeatability, which means higher quality products as well as fewer defects and less waste. The process improvements achieve faster cycle times and predictable output, for higher throughput and scalability.

Precise control and repeatability are also critical to the calibration and production consistency required by the strict standards and government regulations for medical packaging, such as ISO 11607:2019. Automation may also include vision systems and other inspection technology that provide automatic, continuous real-time quality control. In general, the more automation, the greater the opportunity to collect data for process improvement and for traceability.

EASE OF OPERATION Instead of requiring one or more operators per production line, a single operator can cover multiple lines. First of all, this requires that the machines autonomously perform the forming, cutting, and stacking processes with little or no hands-on engagement by the operator. For high volume production, robotics are increasingly employed to automatically perform downstream packaging and palletising functions. But the autonomous operation of these functions is only one element of automation.

The procedures for changing tooling between SKUs and for replacing roll stock also need to minimise human error and eff ort. The right tooling needs to be

installed in exactly the right way, for every production run, and roll stock can weigh 1500 lbs. Thermoforming equipment should be designed with procedures and tools for streamlining these processes and preventing errors and with ergonomic aids for lifting and correctly positioning heavy objects.

LOOKING FORWARD The whole concept of a Form/ Cut/Stack thermoforming machine is to integrate and automate these multiple functions in a single system. Medical packaging manufacturers have been at the forefront of the trend toward automation, initially driven by the need for high quality, repeatability, and traceability. Automation also increased scalability and throughput. The third driver of automation is the need to address labour shortages and high turnover by making processes more productive and less labourintensive, and easier to learn.

Form/Cut/Stack systems can be fully automated and therefore more precisely monitored and controlled, especially machines with 100% servo motors and drives.

Plastic Material Changes Require Latest Plastic Welding Technologies

Market pressures are driving medical device designers away from PVC and PC, yet replacements like PE and PP do not respond well to traditional plastic joining methods. Reliable assembly requires advanced BransonTM ultrasonic and laser welding systems from Emerson. They produce ultra-clean, aesthetically superior welds for today’s preferred materials while also delivering design flexibility, process efficiency, energy saving and sustainability advantages.

Learn more at: Emerson.com/Branson Come and speak with an expert at:

K-Show, Hall 11 Booth F55, 19-26th Oct 2022.

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