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Biocompatibility Testing: Are You Considering Interactions Between Packaging and Devices?

Biocompatibility Testing: Are You Considering Interactions Between Packaging and Devices?
Wei Zhang and Frank Bieganousky

The biocompatibility and toxicological attributes of medical device packaging materials and systems should be evaluated, according to the general requirements section of ISO 11607. But if this recommendation hasn’t been enough of a reason to consider biocompatibility requirements in your evaluation plan, revisions to ISO 10993 just might be.

At MD&M Minneapolis last month, Frank Bieganousky, director of package and medical device testing at Whitehouse Labs, a division of AMRI, told the audience that ISO 10993 revisions will speak about evaluating the biocompatibility of medical device packaging for the first time. He spoke November 9 in the Center Stage presentation, “How to Prepare Your Medical Device Packaging for a Regulatory Submission.”

When it comes to biocompatibility testing, work is already being done to evaluate potential risks to patient from medical devices, Bieganousky said. What is needed now is “to look at the interaction between packaging and the device,” he said.

“Packaging may impart leachables that may affect the safety of the device,” he explained. “You must consider what comes out of the package and into the product, as well as what comes out of the product and into the package.”

As an example of why such interactions need to be evaluated, Bieganousky showed pictures of a damaged tray. “Plasticizer from the tube attacked the tray material and ate through the tray,” he said.

Data is needed to characterize potential extractables and leachables, and ISO 10993 outlines how to perform the associated risk management process, explained cospeaker Wei Zhang, Ph.D., senior research scientist on AMRI’s Extractables & Leachables and Impurities (ELI) team. The revised standard presents chemical characterization as a potential substitute for some traditional biological testing.

Potential sources of extractables and leachables include “the way a material or product is made, including use of any catalysts, additives, manufacturing residues; storage conditions and/or sterilization; use conditions such as temperature, duration, etc.; and the contact environment,” he said.

Zhang said that he is often asked why studies must look at both extractables (what could come out) and leachables (what does come out) of a material. He says that because some leachables are in quantities of parts per million or even parts per billion, with the presence of sophisticated matrix interference, “detecting these leachables is worse than looking for a needle in a haystack as if you have no idea what a needle looks like. [The extractable study] will provides a scope of possible leachables, in other words, shows what the needle looks like.”

Some E&L potential sources Zhang listed include:

  • Polymer oligomers
  • Polymer degradation products
  • Polymer/Rubber Additives
        • Antioxidants
        • Photostabilizers
        • Plasticizers
        • Lubricants
        • Acid Scavangers
        • Pigments/Colorants
        • Carifying/Nucleating Agents
        • Cross Linking Agents (Rubbers)
        • Initiators (Rubbers)
        • Accelerators (Rubbers)
  • Polymer additive degradation products
  • Impurities in polymer additives
  • Catalysts
  • Polymer residues (e.g. monomers)
  • Adhesives
  • Manufacturing impurities/residuals

“Even in trace levels, these could cause detrimental effects to human health,” Zhang said. “You need to understand not only the additives itself, but also the degradation possibilities.”

ISO 10993 highlights several “analytical techniques bolted together to offer a comprehensive view,” added Zhang. He said that a program should consider the following:

  • Risk assessment and DOS (Design of Study).
  • Controlled extraction study using aggressive extraction conditions to be protective of clinical use conditions.
  • Simulation studies when applicable to the gap between extractables and leachable expectations.
  • Leachable studies to monitor leachates with validated quantitative methods when necessary to bridge any gaps in assessment. .

Zhang advises that such a program must be “adequate and sufficiently comprehensive” to ensure protection to the patient.

For more details,  contact the speakers at Wei.Zhang@amriglobal.com or Frank.Bieganousky@amriglobal.com. John Iannone, director at AMRI and U.S. Elected Expert to the ISO Technical Committee overseeing the development of the relevant ISO 10993 guidelines, can also be reached at John.Iannone@amriglobal.com.

AMRI will be exhibiting at Booth 351 at the upcoming MD&M West 2018 expo February 6-8 in Anaheim.

Edwards Buys Harpoon for up to $250 Million

Pixabay Edwards Buys Harpoon for up to $250 Million

Edwards Lifesciences may be best known for its leadership in transcatheter valve therapies, but the company appears to be turning to its surgical valve portfolio as part of its growth strategy for the coming year. The company's acquisition of Harpoon Medical, announced Wednesday afternoon, is the first major indicator of this shift.

Harpoon is developing beating-heart repair technology for degenerative mitral regurgitation (DMR). Edwards paid $100 million up front for Harpoon and agreed to pay up to $150 million more in milestone payments over the next 10 years. The company has had an eye on Harpoon since 2015 when it made a structured upfront investment in the company that included an exclusive acquisition option.

During an investor conference Thursday, Edwards said it expects growth in its surgical heart valve portfolio despite the continued strong adoption of transcatheter aortic valve replacement (TAVR) therapy in more developed regions. The company said CE mark for Harpoon's technology is expected soon, and that it plans to launch the device in Europe next year. Edwards also said it is pursuing new surgical valve products such as the Intuity Elite valve system and the Inspiris valve, which is expected to be introduced in the United States and Japan in 2018.

Harpoon's beating-heart repair procedure for mitral valve patients complements Edwards' portfolio of treatments for structural heart disease, according to Bernard Zovighian, the company's corporate vice president of surgical heart valve therapy. The deal also reinforces the company's commitment to innovation in cardiac surgery, he said.

The Harpoon system is designed to facilitate echo-guided repair of mitral valve regurgitation, by stabilizing the prolapsed mitral valve leaflet to restore proper coaptation and valve function.

"There are a significant number of patients currently undergoing mitral valve surgery that we believe can benefit from Harpoon's therapy during a minimally invasive, beating-heart procedure," said device inventor James Gammie, MD, chairman of Harpoon's scientific advisory board and professor and chief of cardiac surgery at the University of Maryland School of Medicine. "This therapy offers the potential for earlier treatment of degenerative mitral valve disease with faster recovery and less morbidity, while also providing the opportunity for more consistent procedures and outcomes for patients."

Gammie had an equity interest in Harpoon Medical, and will serve as a consultant to Edwards, the company noted.

OrbiMed Founder Sam Isaly Accused of Sexual Harassment

Pixabay/GERALT OrbiMed Founder Sam Isaly Accused of Sexual Harassment

Sexual harassment scandals are not limited to Hollywood, famous broadcasters, and politicians. This week STAT broke a sexual harassment story that touches medtech, as it involves the founder of one of the industry's largest hedge funds. According to the investigative report, OrbiMed founder and managing partner Sam Isaly harassed and demeaned female employees for years.

Former employees reportedly told STAT that Isaly routinely subjected young female assistants to pornography in the workplace, lewd jokes, and sexist comments. Five people who once worked at the firm described how Isaly would often handle a set of breast implants that he kept on his desk, palpating them during conversations with employees as though they were stress balls.

According to STAT, moments after publishing the story Tuesday evening OrbiMed issued a statement calling the alleged incidents "concerning" and said it has retained an independent law firm to investigate the matter. "OrbiMed takes gender equality seriously and wishes to encourage a supportive work environment and equal opportunity for all employees," the firm noted in the statement.

STAT also said that earlier on Tuesday, prior to publishing the story, OrbiMed partner Carter Neild said in an email to STAT that, "If this article proceeds I hope that you will be fair and focus on the person responsible, not the entire firm."

The article also states that Isaly denied the allegations during a 90-minute interview with STAT on Monday at OrbiMed's headquarters, during which he was surrounded by three colleagues and a crisis management consultant.

STAT said it spoke with five former OrbiMed employees, four women and one man, who worked at the firm between 2000 and 2015. All four women were executive assistants, and the man was an investment professional, the article noted. One of the women, Delilah Burke, spoke on the record, while the other four spoke on condition of anonymity, saying they had signed nondisclosure agreements and feared reprisals from Isaly.

It seems their concerns were validated. Burke reportedly received a courier-delivered copy of her nondisclosure agreement just last week, reminding her of its contents. She worked as Isaly's assistant for about 18 months beginning in 2009.

It has created a wave of awareness and brave confrontations over sexual harassment and assault, taking down powerful men in the process. And now the #MeToo movement has been named Time magazine's Person of the Year for 2017.

STAT's report on Isaly published just before Time published its choice for the Person of the Year. The magazine said the women who shared stories about sexual harassment and abuse through the #MeToo campaign are its Person of the Year and dubbed them collectively as "the silence breakers."

Finally – FDA Offers Guidance on 3-D Printed Products

Pixabay/SPLOTRAMIENNY Finally – FDA Offers Guidance on 3-D Printed Products

Not so long ago, the concept of 3-D printed medical devices seemed like something out of a science fiction movie. But the technology is very much a reality, and FDA Commissioner Scott Gottlieb, MD, said the agency is preparing for a significant wave of new technologies that are "nearly certain to transform medical practice."

As part of that preparation, the agency released a comprehensive technical framework this week to advise manufacturers creating medical products on 3-D printers. FDA is the first regulatory agency in the world to do so.

The agency said it reviewed more than 100 3-D printed devices currently on the market, including devices tailored to fit a patient’s anatomy. "Examples include knee replacements and implants designed to fit like a missing puzzle piece into a patient’s skull for facial reconstruction," Gottlieb said.

Even medicine can be manufactured on a 3-D printer, and FDA has already approved a 3-D printed drug that is used to treat seizures and has a more porous matrix than the drug manufactured in the traditional way, enabling the drug to dissolve more quickly in the mouth to work faster, Gottlieb said.

"This is likely just the tip of the iceberg given the exponential growth of innovative research in this field," he said. "We envision that burn patients in the near future will be treated with their own new skin cells that are 3-D printed directly onto their burn wounds. Further down the road, there is the potential for this same technology to eventually be used to develop replacement organs."

3-D printing is even advancing the field of regulatory science, and Gottlieb said FDA has 3-D printing facilities on its campus for agency scientists and engineers to use. The Center for Drug Evaluation and Research's facility, for example, helps FDA scientists to determine how the 3-D printing of drugs impacts inactive ingredients and other drug components as well as the quality control process of manufacturing. FDA engineers in the Center for Devices and Radiological Health have their own 3-D printing facility to investigate the effect of design changes on the safety and performance of devices, and to determine how iterative changes alter the device's fit and functionality. 

"Such answers could, for example, help improve the effectiveness and comfort of prosthetic devices," Gottlieb said. "This research also helps inform us as regulators to help us understand the policy framework needed to ensure the quality and safety of 3D printed products."

The newly issued guidance was created to help advise device manufacturers on technical aspects of 3-D printing, also known as additive manufacturing, and clarifies what the agency wants manufacturers to include on submissions for 3-D printed devices.

"It includes our thinking on various approaches to 3-D printing, including device design, testing of products for function and durability, and quality system requirements," Gottlieb said. "Overall, it will help manufacturers bring their innovations to market more efficiently by providing a transparent process for future submissions and making sure our regulatory approach is properly tailored to the unique opportunities and challenges posed by this promising new technology."

The technical guidance is only intended to provide FDA’s initial thoughts on the emerging technology, and Gottlieb said the agency's recommendations are likely to evolve as the technology does.

"We are already seeing the beginning of this evolution as hospitals and academic centers use their own 3-D printers to create innovative dental implants, replacement knee joints, and experimental heart valves and bone implants for use in clinical studies," he said. "An increasing number of surgeons across the country have been saving infants born with a life-threatening breathing condition by creating patient-matched 3D-printed splints to install in their patients’ tiny airways, which expand and degrade as the babies grow."

FDA plans to explore the role of nontraditional manufacturing facilities like a hospital operating room or university laboratory, Gottlieb said. The agency also plans to review the regulatory issues related to the bioprinting of biological, cellular, and tissue-based products to determine if additional guidance is needed beyond the recently released regulatory framework on regenerative medicine medical products.

Is This the Deal LivaNova has Been Waiting For?

Pixabay Is This the Deal LivaNova has Been Waiting For?

LivaNova isn't one to waste time. Just two weeks ago the London-based company unveiled plans to divest its cardiac rhythm management business (CRM) to MicroPort for $190 million in cash, a move that would allow the company to shift more focus to its areas of strength, including neuromodulation. This week, the company said it has agreed to pay up to $225 million to acquire San Diego, CA-based ImThera Medical.

ImThera develops neurostimulation technology for the treatment of obstructive sleep apnea (OSA). The company's implantable device is designed to stimulate multiple tongue muscles via the hypoglossal nerve, which opens the airway while a patient is sleeping.

LivaNova has been an investor in ImThera since 2011. To acquire the remaining outstanding interests of ImThera, LivaNova has agreed to pay about $78 million up front, plus regulatory and sales-based milestone payments up to a total of roughly $225 million. The company expects the deal to close in early 2018 and be near-term accretive.

"The ImThera device is highly aligned with our existing neuromodulation business, and we are extremely excited about the opportunity to optimize the technology and fold it into our universal platform," said LivaNova CEO Damien McDonald.

He said that in the near term the company will focus on expanding ImThera's commercial presence in Europe, while advancing enrollment in an FDA pivotal trial for the OSA implant.

“The OSA market is large and growing, with many unmet needs. With our strong commercial capabilities and robust manufacturing, we look forward to bringing this innovative technology to the large patient population that has been unsuccessful with other treatments, allowing them to improve their quality of life,” McDonald said.

Patients with OSA can experience impaired daytime functionality, along with severe comorbidities such as heart failure and stroke. ImThera’s implantable device received CE mark in 2012 and is indicated for patients with moderate to severe OSA who are unable or unwilling to use continuous positive airway pressure (CPAP) therapy. For these patients, the device is designed to reduce or eliminate sleep apnea, as demonstrated through clinical studies and its initial commercial use in Europe. Enrollment in a pivotal study is currently underway to obtain FDA premarket approval for the OSA implant.

“Adding ImThera and its obstructive sleep apnea device to our portfolio will strengthen our position as a leader in the field of neuromodulation,” said Jason Richey, LivaNova's president of North America and general manager of the neuromodulation business.

Can a High-Tech Chip Conquer Global Health Challenges?

Nano Global Can a High-Tech Chip Conquer Global Health Challenges?

An Austin, TX-based molecular data company is out to prove that big things can come in small packages. Nano Global is developing a chip in partnership with Arm, a leading semiconductor IP company.

According to Nano, the technology will help redefine how global health challenges such as superbugs, infectious diseases, and cancer are conquered. The system-on-chip (SoC) will yield secure molecular data that can be used in the recognition and analysis of health threats caused by pathogens and other living organisms.

Combined with the company's scientific technology platform, the chip leverages advances in nanotechnology, optics, artificial intelligence (AI), blockchain authentication, and edge computing to access and analyze molecular-level data in real time.

“In partnership with Arm, we’re tackling the vast frontier of molecular data to unlock the unlimited potential of this universe,” said Steve Papermaster, chairman and CEO of Nano Global. “The data our technology can acquire and process will enable us to create a safer and healthier world.”

Papermaster told MD+DI  that the chip will present a way to turn the world into the laboratory, rather than taking samples of the world and sending them to the lab. "And that really is a fundamentally different approach to being able to access, monitor, analyze and even impact every form of life function from detecting and controlling infectious disease to chronic conditions and diseases like cancer ... but even into, eventually, areas like agriculture, crop management, and the basic environmental wellness of air and water," he said. "That's obviously a very broad reach, and it doesn't happen overnight."

Because the scope of this technology is so broad, Papermaster said AI is a necessary component of the chip. Training an AI engine on the chip is the only realistic way to be able to process and analyze what's happening at the point of contact with reality, he said. Over time, Papermaster envisions that the chip will be embedded into everyday objects like clothing, toys, and medical devices. Everything that today is still "dumb," he said, meaning anything that exists on its own and is not yet a connected device.

"Over time our chip will light these things up and enable them to be smart," Papermaster said.

For example, he said a product that comes into contact with a patient's skin could be enabled to detect an infection, identify what kind of infection it is, and determine how it should be treated. Perhaps, he said, there would be something embedded into a wound bandage that could be released based on the information the chip interprets. Such a product could be particularly useful in remote areas where healthcare resources are limited, he said.

"This combination platform is really taking it to the world directly instead of sampling the world to bring it inside a lab," Papermaster said.

Partnerships with organizations like Arm are a fundamental part of Nano's business model. Arm's IP is the basis for Nano to build on top of, according to Papermaster. 

“We believe the technology Nano Global is delivering will be an important step forward in the collective pursuit of care that improves lives through the application of technology,” said Rene Haas, executive vice president and president of IPG at Arm. “By collaborating with Nano Global, Arm is taking an active role in developing and deploying the technologies that will move us one step closer to solving complex health challenges.”

Additionally, Nano will be partnering with several institutions, including Baylor College of Medicine, and the National University of Singapore, on broad research initiatives in clinical, laboratory, and population health environments to accelerate data collection, analysis, and product development.

The initial development of the chip is in process with first delivery expected by 2020.

Despite a number of impressive developments being made to address antibiotic-resistant bugs and other major health challenges of our time, Papermaster said, "the reality is we're not winning."

That's why, he said, Nano is trying to take a step back and think about new approaches and tools that could fight these large-scale problems.

Medtech Company of the Year 2017 Finalists

Each year, MD+DI's editors take a long, hard look at the medical device and diagnostics companies that rose above the ranks over the past 12 months. It can be savvy business strategies, breakthrough products, or operational execution that set the best of the best apart. The following are our nominees for the 2017 medtech company of the year. Check them out, then let us know your choice at the end. We'll announce our pick the week of December 11, 2017.

Supplier Stories for the Week of December 3

This is a compilation of the latest news from suppliers in the medical device industry. If you have news you’d like to submit for potential inclusion in this weekly roundup, please send a press release and any related images to daphne.allen@ubm.com with the subject line “Supplier Stories.”[Image courtesy of STUART MILES/FREEDIGITALPHOTOS.NET]

Coordinating Requirements and Objectives Across Silos During Development

3dman_eu/Pixabay.com Coordinating Requirements and Objectives Across Silos During Development

It is no secret that an ideal medical device development team structure includes being co-located and multi-disciplined, with every product development lifecycle role included within that team.

The reality, however, is quite different: we are often a mix of integrated teams and silos in collaboration, striving to achieve the best product for our clients.

Silos can take many forms. They can be comprised of organizationally structured groups, product line divisions, contract workers, and even external partners. The challenges with these silos—including the burden of orchestration, disjointed traceability, and unaligned cadences—add up to a chaotic process with too many moving parts.


Some practices that have helped address the silo issue are tried and true, such as improving visibility to requirements and traceability, where the team agrees on traceability strategy early. Providing shared access to working and released documents as well as maintaining an up-to-date trace matrix throughout the life cycle are essential. Using an enterprise product life cycle management tool can also be helpful.

Creating cross-functional teams that include representatives from the various functions is key. These representatives have a dual purpose: They are ambassadors for their functional area, bringing information from their department or group to the product team, and serve as representatives of the product, communicating back to their department.

Be sure to choose representatives that are knowledgeable about the product and/or market, passionate about what the company does, and have influence within their own department. The members can then coordinate with the product team and their functional groups so that every member is involved in all requirement and design reviews. Combined with the use of collaboration tools, this critical step helps with the orchestration process and allows the systems engineering role to have ultimate oversight and authority.

As we synchronize across silos, cross-team planning cannot be emphasized enough. Key milestones and dependencies must be defined between teams and planning how teams will address dependencies requires frequent integration and cadence alignment. Also, consider an Agile framework for the system and use web-based productivity tools like Jira or Asana.

Team coordination and collaboration is not only desirable, but essential for the successful development of medical device products. Consistently giving this important issue the appropriate amount of foresight will ensure this goal is attained.

Mazor CEO Under Investigation for Insider Trading

Pixabay Mazor CEO Under Investigation for Insider Trading

The Israel Securities Authority is investigating the CEO of Mazor Robotics concerning accusations of insider trading, according to a report in Calcalist, an Israel-based publication. The probe is connected to a May 2016 distribution agreement with Medtronic, according to the report, which cites documents reviewed by Calcalist.

Caesarea, Israel-based Mazor gave Medtronic U.S. distribution rights for its spinal surgery systems. Earlier this year, Mazor gave Medtronic worldwide distribution of the systems and agreed to pay Mazor $40 million, bringing its overall investment to $74 million.

In August, after the companies entered the second phase of their partnership, Hadomi said the partnership had already resulted in 59 Mazor X orders since the system was launched in October 2016, which he said reflected an accelerated sales cycle due to customers' eagerness to adopt the technology for the spine market.

The Israel Securities Authority reportedly raided Mazor's offices in May and questioned senior executives following a suspicion that information regarding the deal was leaked to close associates before it was made public. That prompted those associates to buy Mazor securities, and in June Mazor disclosed the investigation to investors. Now it is reported that Hadomi is among the executives being considered as a suspect. The report said Hadomi's home was searched and his cell phone was confiscated.

The investigation could be at least partially responsible for a 3.63% ($2.10) drop in Mazor's stock on Monday.

MDDI reached out to Mazor for comment on this matter and will update the story when the company responds.