Practice makes perfect

WEB CONTENT EDITOR, IAN BOLLAND WRITES ABOUT HIS RECENT VISIT TO ST HELENS TO LEARN HOW MANUFACTURER INOVUS MEDICAL CREATES USEFUL TOOLS TO AID SURGICAL TRAINING.

Beginning with simply a sheet of plastic and a heat gun, the team at Inovus Medical has come a long way since the development of its first laparoscopic simulator.

The St Helens-based team is expanding, with much of its manufacturing done in house. While it builds its own simulators to allow junior doctors and surgeons to practice procedures using digital aspects, augmented reality and virtual reality, it has also started to develop its own electronics and materials behind the use of medical devices. This year alone has seen £1 million investment going towards another augmented reality system.

Elliot Street, Inovus CEO and cofounder, worked as a junior doctor in the early years of the business. His co-founder, Jordan Van Flute, had only just graduated. Addressing how the company began, Street said: “What we wanted to do first was answer an unmet need which needed to be answered. We wanted to answer it affordably and we set up a company where we had to really hustle, and noone would hear of us apart from the exact end users using the kit.

“All we were going to do in those first five years was developing really good kit in front of the people who need to buy it.” The “kit” Street refers to was at first just a plaster box with a webcam in. Street realised when he began his surgical training how there was a “real lack of access to good quality, affordable laparoscopic trainers,” and this is how the idea was created.

Inovus’ first device was made by bending a piece of plastic with a heat gun around the side of a fridge, and then drilling some holes in to it. Street and Van Flute took photos of the product and shared the images on their self-coded website. Every time they sold something, they constantly reinvested the money, using it to initially buy a safer method of bending plastic and later, more kit. Talking about the industry, Street said: “We’re vertically integrated in the processes of manufacturing, we’re vertically integrated in the process of design and product development, but we’re also vertically integrated in the actual products themselves and the portfolios.”

As well as the digital simulators, Inovus also manufactures original materials in-house. “Our haptics are real haptics, you don’t need sensors because we’re putting in models that feel like real tissue,” Street added. “The thing that’s giving you all that haptic feedback is a real, tangible model and then we build a digital environment around that.”

Street explained that a major driver of the idea was the desire to allow trainees to perform a virtual procedure in the most realistic way – repeatedly stating his desire for products to be affordable, accessible and functional. Simulators have been developed for multiple purposes including those that can be taken home, and those that are designed for use in an institutional setting.

The materials developed in-house allow Inovus to try and make procedures like appendix surgery and ectopic pregnancies as realistic as possible – the latter specifically having its own mass that can be removed from the model. Polyps and lesions are among the ‘dummy scenarios’ that have been manufactured for surgical practice from silicone material.

The simulators therefore conjure up a mixture of the digital environment and reality. To take it as close to reality as possible, with some of them 3D printed in their entirety like the Bozzini Hysteroscopy Simulators and Sellick Cricoid Pressure Trainers.

Talking about the materials Inovus is developing in-house, Street commented: “Some materials we have are proprietary to us and we spent a long time developing those materials, which allow us to perform electric surgery, use energy devices in theatre on them and they react like real tissue.”

Elliot Street, CEO and co-founder, Inovus

Inovus is putting newly developed materials into its first products to be used – where it looks as if surgeons are cutting through real tissue, attached to an energy device. Street explained: “The first time I put the energy device through it’s probably the most excited I’ve been and there’s lots of exciting stuff that goes on under this roof.

“For me, that’s a game changer. I don’t say these things lightly because prior to this I wouldn’t say that. I’d say that’s a really sensible solution for an unmet need but now we’re developing technologies on the material side, on the way we utilise other technologies like 3D printing, and on the software side which are truly game-changing for the industry.”

Street explained using the company’s own blend of materials has allowed them to manufacture tissue which can be of real benefit to surgeons. He commented: “The materials we use range right through from a whole myriad from different types of silicones – our proprietary soft tissues to our acrylic plastics which we heat and fabricate here right through to the stuff we 3D print such as nylon.

“Everyone uses silicone for soft tissue. The great thing about silicones is when you get your mix right you can create tissues which give you tension when you’re holding them in a medical device or instrument which actually feels like a real tissue.

“With our appendix model, one surgeon I trained with said, ‘how on earth have you managed to make that feel like an appendix?’ Imagine his surprise the next time I see him when he’s cutting through this tissue, he can use an energy device and it behaves like real tissue. That for me is not only a value added to training surgeons, but also they’re now able to perform procedures super-realistically and they can use the real instruments.”

However, it’s not just surgeons who can benefit from this technology. Street concluded: “For medical device companies as well, we’re offering them a product that shows their product in the best light so when they want to go and demo their product, they’re able to use non-animal by-products so they don’t sully their kit.

“Training surgeons are also able to practice in a safe, controlled environment away from the patients but on a material that’s behaving like a real tissue behaves.” SURGERY

For medical device companies as well, we’re offering them a product that shows their product in the best light.

How clean is your cleanroom?

Many facilities choose to install facility monitoring systems to monitor particle counts and other environmental parameters. There are multiple benefits associated with use, and it makes great business sense, however, the advantages to a business are not always fully understood. These benefits include: • Reduced waste • Improved yield • Improved quality • Increased profits While there are some organisations that choose to install a facility monitoring system just because regulatory guidance states one should be installed and used, many, given the choice, would choose not to. Initial capital and ongoing maintenance costs seem expensive, the mountains of data that will require analysis seems daunting, and alert and action level excursions often leads to time consuming root cause investigations. Plus, there are also necessary considerations around the maintenance, calibration and validation overhead involved. and a better understanding of the manufacturing process. This increased knowledge leads to recognising when the process is drifting out of control before it’s too late and means a less segregated product, less product waste and fewer interruptions during manufacturing without compromising patient safety. 2. Monitoring makes great business sense Today, monitoring systems are already being used to support energy saving initiatives. There are significant energy savings to be made when setting back air change rates and air velocities whilst being safe in the knowledge that environmental conditions have not been compromised. Continuous particle monitoring in a facility means the exact time of a particle excursion is known and immediately notified to end users. This supports timely root cause investigations and minimises how much of the batch is segregated – saving a significant amount of money. The availability of Alternative Microbiological Methods (AMMs), such as continuous laser induced florescence particle counting, means there is also an option for immediate understanding of the microbiological quality of the air surrounding the process. This could possibly lead to intervention free manufacturing and supports Real Time Release Testing (RTRT). Smart factories of the future will have fully interoperable systems where data is seamlessly exchanged between multiple platforms. Sharing and centralising facility monitoring system data transforms it into holistic information that aids decision making. This holistic information could predict that an excursion is likely, enabling proactive steps to be taken to positively impact yield and significantly save on manufacturing costs. TIM RUSSELL, BUSINESS DIRECTOR-CONTROLLED ENVIRONMENTS AT TSI INCORPORATED IN CONJUNCTION WITH PMT (GB) EXPLAINS THE CASE FOR A FACILITY MONITORING SYSTEM IN A CLEANROOM ENVIRONMENT.

WHY DO REGULATIONS EXPECT A MONITORING SYSTEM TO BE INSTALLED? 1. Risk reduction A facility monitoring system improves probability of hazard detection, leading to a reduction in risk. Product quality is impacted if too many airborne particles find their way into the product, compromising patient safety. Only when deploying and correctly positioning monitoring probes to frequently collect data, is there a chance of detecting particles. If there are no particle monitoring probes installed close to critical processing locations, the probability of detecting particles entering the process is zero.

Turning critical data into information is key. This can be conducted through real-time data presentation, reports and alarm notifications. The ability to do this results in increased knowledge

Smart factories of the future will have fully interoperable systems where data is seamlessly exchanged between multiple platforms.

Patient-focused drug delivery devices

Drug Delivery Devices Innovative developments Customized solutions GMP customer IP manufacturing

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Spick & span E urope’s current Medical Device Directive (MDD, 90/385/EEC) on active implantable medical devices states that, “devices must be designed and manufactured in such a way that, when implanted under the conditions and for the purposes laid down, their use does not compromise the clinical condition or the safety of patients.” The clear message here is on patient safety; however medical device manufacturers often struggle with the fact that the directive is not prescriptive enough in terms of the environment. Instead, some feel it leaves ambiguity over which clean manufacturing standard is applicable to their production environment specification and which guideline they should follow to mitigate risk. LIMITATIONS OF APPLICABLE GUIDELINES Typically, medical device manufacturing is conducted in ISO 14644-1:2015 classified cleanrooms, ranging from ISO 5 to 8, with final packaging usually conducted in an ISO 7 or 8 environment. This cleanroom standard however, does not provide specific instructions for medical device processes, and even ISO 13485 focuses mainly on the quality management systems throughout the life cycle of a medical device. This leaves manufacturers with quite a few questions to answer. What part of the product do we need to protect at what stage of manufacturing? Does it need post-processing and will the material or object withstand the conditions required? Does it need to be manufactured aseptically? How should it be packed and under which conditions? instance, if the implant is made of one solid polymer and can be autoclaved or gamma-sterilised, the required manufacturing conditions are relatively easy to specify. But what if your active medical device is a polylactic acid-based absorbable implant? Sensitivity to hydrolysis and molecular weight reduction may not permit autoclaving or radiating. Post-sterilising the outer surface would also not be effective as, over time, the human body will be exposed to the core and the 3D printed inner layers of the object, including any potential contamination trapped in there during the manufacturing process. Trapped organisms could potentially be pathogenic or the core could be sterile, but still endotoxin-laden. So is ISO 5 sufficient, or should the manufacturing environment be scaled up to EU GMP A or B? EXPLORING NEW STERILE TECHNIQUES The question over sterile production and techniques has triggered researchers to start experimenting and exploring emerging technologies. It has recently been documented that 3D printing could be intrinsically sterile because of the temperature and pressure applied during manufacturing, such as in the article titled, ‘On the intrinsic sterility of 3D printing’ by Neches et al., 2016. In more than twenty incubations, the researchers found only two contaminated parts. Although the experiment was based on a limited amount of incubations and a rather wide spectrum of manufacturing conditions was applied, the researchers suggest that the printing process does indeed produce functionally sterile parts. Most of their experimental manufacturing conditions included the use of biosafety cabinets, including ultraviolet light, and aseptic preparation and decontamination of the printing area and substrate, and therefore, in essence, they were set up in line with EU GMP A particle and microbial manufacturing guidelines. From a clean manufacturing perspective, it was interesting to observe that the contamination on the parts was found to be common skin associated microflora, potentially indicating a post-processing handling error. Considering the latter, the results indicate that not only the technical (particulate) aspects of ISO 5 should be considered, but rather the whole chain of processing and handling activities should be defined in Standard Operating Procedures (SOPs) according to EU GMP aseptic processing. ROWIN VOS, GENERAL MANAGER BV AT CONNECT 2 CLEANROOMS, A CLEANROOM DESIGN AND MANUFACTURE SPECIALIST, EXPLORES THE CLEAN MANUFACTURING GUIDELINES, TRENDS AND EMERGING TECHNOLOGIES TO PROVIDE CLARITY TO MANUFACTURERS.

What is needed in practice requires a thorough evaluation through risk assessments of the intended use, the class of the medical device, and its manufacturing materials. For

Q&A

ROWIN VOS, GENERAL MANAGER BV, CONNECT 2 CLEANROOMS PROVIDED MEDICAL PLASTICS NEWS EDITOR LAURA HUGHES WITH HIS EXPERT OPINION ON CLEANROOMS REGULATIONS.

WHAT IS THE DIFFERENCE BETWEEN ISO AND GMP? In both guidelines, particle contamination is used for the classification of the environment, both at rest and in operation. One of the main differences between the ISO classification and the EU GMP grades is the addition of microbiological limits of the room in operation. When following EU GMP guidelines, the principles of Quality Risk Management (QRM) should be applied to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final product, or at least reduced as far as possible. In practice that also means that the facility, equipment and process design must be optimised, qualified and validated according to Annex 15 of the EU GMP.

IS IT THEN SUFFICIENT TO BUILD AN ENVELOPE WHERE ALL EXPOSED SURFACES ARE SMOOTH AND IMPERVIOUS, WITHOUT UNCLEANABLE RECESSES, AS DETAILED IN EU GMP ANNEX 1? No, that is not sufficient to provide complete product protection, as the case studies by Neches have shown. Personnel must have appropriate skills, training and attitudes, with a specific focus on the principles involved in the protection of the product during the aseptic manufacturing and packaging process. Also, the processes and monitoring systems must be designed, commissioned, qualified and monitored by personnel with appropriate process, engineering and microbiological knowledge. In essence, all activities should be managed in accordance with QRM principles that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality (GMP draft Annex 1, December 2017).

YOU MENTIONED THE DIFFICULTIES THAT APPLY TO TERMINAL STERILISATION OF POLYLACTIC ACID, POLYGLYCOLIC ACID AND POLY(LACTIC-CO-GLYCOLIC ACID) IMPLANTS, BUT UNDER STRICTLY CONTROLLED CONDITIONS IT CAN BE DONE. HOW DOES THAT AFFECT THE MANUFACTURING CONDITIONS? In general, there are two primary routes of manufacturing sterile products: • One leads to terminal sterilisation • The other is based on pure aseptic manufacturing to completely prevent contamination and maintain sterility from start to finish. • In fact, a third hybrid option could be to apply a minimum level of thermal or radiation post-processing to improve the sterility assurance level of an aseptically manufactured device.

But even in the case of terminal sterilisation, the manufacturing objectives are to control and minimise the particulates and bioburden in the product throughout the non-sterile processing stages. That’s why we refer to a “controlled” environment. The envelope, equipment and pre and postmanufacturing processes all need to be governed by Standard Operating Procedures (SOPs) in order to create that “controlled” environment.

SOME MANUFACTURERS MAY ARGUE THAT THE CONTAMINATION RISK IS FAR-FETCHED. WOULD YOU AGREE? Yes, to some extent I tend to agree, but it is still up to them to assess their risks, based on their materials, process and intended use. Another way of looking at it would be to develop a process of minimal measures and to validate the outcome to a sterility assurance Level of 106. Although in practice, that is not very likely to work, as that case would be hard to validate. Validation depends on repeatable results, time after time, which is difficult to do without strict process control.

Industrial pharmaceutical manufacturing sets out new sets of rules. Compare that to a situation where a patient could be expected to freshly prepare and reconstitute lyophilised drugs by aspirating saline from a pre-sterilised container, breaking an ampoule, adding the water, aspirating the solution in the syringe again and injecting intramuscularly. All of that would usually be done standing at the kitchen worktop. The manufacturer who delivers that same syringe in a “ready to use” format will have to build a full EU GMP suite from grade D, cascading all the way down to grade A for sterile filling the syringes.

We have to bear in mind that the Medical Device Directive stipulates that devices must be manufactured in such a way that their use does not compromise the safety of patients. That is all encompassing.

Connect 2 Cleanrooms ©

The next generation

JOHN DEVINE, MEDICAL BUSINESS DIRECTOR AT INVIBIO BIOMATERIAL SOLUTIONS, A SUBSIDIARY OF VICTREX, SPOKE WITH MPN TO EXPLAIN THE ACCELERATING ROLE OF BOTH NON-IMPLANTABLE AND IMPLANTABLE GRADES OF POLYETHER ETHER KETONE (PEEK) POLYMERS.

What are the major trends you anticipate for drug-delivery devices within the future? We see a key trend towards connected drug-delivery devices or e-devices, such as insulin pumps which are used in the treatment of diabetes. E-devices have smaller dimensions compared to non-e-devices and are miniaturised to precise tolerances, resulting in reduced weight and easier use. When complex electronic components must be embedded, they too are designed to be compact with the lowest possible wall thickness.

Is there a place for PEEK within the future of the medical sector? Based on properties such as PEEK’s low moisture absorption and stability as a dielectric, PEEK has a long history of use in numerous applications. Polymer solutions provider, Victrex Group has acquired knowledge in design synergies and cross-applications, which allows us to address both the design and manufacturing challenges of these devices.

Can you expand on the properties of implantable PEEK and how these can benefit applications? Invibio’s PEEK-OPTIMA is biocompatible, which is an absolute requirement for implantable applications. PEEK is inherently radiolucent, so medical imaging by X-ray, computerised tomography scan and magnetic resonance imaging, are artefact-free and therefore facilitate analysis and diagnosis with unobstructed views. Furthermore, it can be sterilised using standard processes such as gamma and e-beam radiation and steam sterilisation.

In terms of mechanics, given that the polymer can be processed by injection moulding or machining, very small parts with accurate dimensions and tight tolerances can be produced and assembled, making it a competitive option for drug-delivery applications. PEEK is also chemically inert, and this stability allows it to be in contact with aggressive chemicals or drugs without interactions, whether PEEK is present in the form of packaging or as a conduit. If mechanical strength is required, then PEEK parts can be designed to meet this key engineering requirement. Some companies are focused on subcutaneous drug delivery devices to make it easier for patients and this trend may require materials which are known to be safe for long-term implantation. (1)

PEEK polymer is available in a wide range of forms for use in different manufacturing processes in order to deliver patient value. Victrex ©

PEEK has the potential to drive cost savings for the manufacturer.

What are the main benefits of using PEEK for non-implantable applications? For non-implantable Victrex PEEK, the potential range of applications is quite broad and includes injection-pen/autoinjector and wearable segments. For these devices, the solutions must be reliable and safe as well as accurately dispense the right amount of drug at the right location at the right time. The requirement to be patient-friendly and low cost is important for these types of applications in order to address any treatment adherence challenges.

PEEK can play a key role thanks to its high mechanical strength, where it exhibits stiffness, along with impact and fatigue resistance, and a low frictional ratio. Additionally, it is chemically stable at both high and low temperatures, remaining non-leachable and non-extractable. In terms of processability, it can be machined and injected to precisely accurate dimensions and tolerances. One beneficial consequence could be the opportunity to reduce the number of parts and components that comprise the device.

Conclusion PEEK has many attractive properties for the medical sector, and the choice of PEEK can help to reduce the number of parts by integrating functionality, reducing the size and weight of devices, and streamlining the manufacturing processes. As a result, PEEK has the potential to drive cost savings for the manufacturer.

References 1) Sci Transl Med. 2017 Aug 30;9(405). pii: eaaf9166. doi: 10.1126/ scitranslmed.aaf9166.Subcutaneous drug delivery: An evolving enterprise

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