BiocompCHATibility Archiv

In this episode, our guests are joined by Syntactx’s Dr. Valerie Merkle, Associate Director – Regulatory Strategy, to discuss NAMSA’s recent acquisition of Syntactx.

During this one-hour installment, Dr. Merkle discusses her deep-rooted experience at the FDA and the importance of proper biological safety planning to achieve biomechanical efficiency and successful clinical trial execution. Examples will be provided regarding how and when biocompatibility programs go wrong, which often result in derailment of development efforts. How can manufacturers create biocompatibility programs that are observed favorably by the FDA? Learn helpful tips and strategies to help ensure a successful FDA submission.

“We really wanted to mirror what we were doing at the FDA.” – Valerie Merkle

“You just never know what is going to come in next. It keeps you on your toes for sure.” – Don Pohl

“People think biocomp is just a checklist, but there are a lot of rabbit holes you can go down—a lot of ways you can stray off the path unnecessarily. Definitely not a checklist item.” – Valerie Merkle

“Make good decisions early-on to not derail yourself later.” – Sheri Krajewski-Bibins

“A lot of companies don’t want to provide their thought process. They spend years and years developing and making decisions, FDA only sees what is in front of them and if the background is not there, we see lots of questions.” – Valerie Merkle

Discussion points include:

Syntactx company overview and strengths they bring to NAMSA

Material selection and its importance in avoiding derailment of biocompatibility projects

FDA experiences with manufacturers overlooking material testing

FDA biocompatibility guidance and its role in regulatory submissions

In this episode, our guests are joined my NAMSA’s Melissa Cadaret to discuss the ever-confusing cytotoxicity failure.  Manufacturers can have more questions created when encountering an unexpected cytotoxicity result and these podcast experts have seen thousands of various cytotoxicity results.  The information provided from a cytotoxicity test can be useful and stressful, so what do manufacturers need to know to navigate the cyto failure, whether expected or unexpected.

“I would say we generally see some type of cytotoxicity failure weekly.” –Melissa Cadaret

 “Cytotoxicity is not really an end point. It’s a screen.” – Sheri Krajewski-Bibins

“It is what it is and it is what it’s not.” – Don Pohl

“It’s the only biological effect listed as an overall screen for biocompatibility.” – Don Pohl

“Things like copper, and antimicrobials really wreak havoc and contribute to a lot of cytotoxicity failures.  Some of your residues from your cleaning and in processing aspect are also a huge culprit.”  Melissa Cadaret 

“It might have been expected.  You can get pretty good at predicting cytotoxicity.” – Don Pohl

Discussion points include: 

What does it mean when one receives a failed cyto result 

What is the useful information you can gather from a cytotoxicity test

What typical materials and devices may have problems with a cytotoxicity test

What to do if you know your material is going to fail cyto

In this episode, our hosts are joined by Allison C. Komiyama, Ph.D., R.A.C., Owner and Consultant at AcKnowledge Regulatory Strategies and former U.S. FDA reviewer, to discuss the U.S. FDA’s latest draft guidance, “Select Updates for Biocompatibility of Certain Devices in Contact with Intact Skin.”  The FDA has determined the biocompatibility risk of various polymers and fabrics to be low based upon a safe history of use in medical devices for this categorization. Our hosts dive into the list of materials as well as the nuances of this guidance that will ideally help manufacturers with these types of devices receive market access with fewer questions.  

“There might be some unnecessary testing going on in some cases.” –Don Pohl

“The long history of safe use. U.S. FDA uses a lot of resources to not only review the tests themselves, but they mention they spend resources on review of rationale and justifications; and I think that may be harder than reviewing test reports.” – Allison Komiyama

“It was very exciting when we saw this guidance document. We all felt like this was a long time coming.” – Allison Komiyama

“Class VI testing might become useful again.” – Sheri Krajewski-Bibins

“People are going to be googling Type 4 Sensitivity to figure out what that is because its sitting on a label.” – Don Pohl

“I commend the biocomp group on this document.” – Allison Komiyama

“I was thinking about a device I’m reviewing right now. I look back at that device and it has stainless steel and aluminum, and if I look at all those polymers, I have co-polymers as well. If I look at this guidance now, I would be left wondering if I can apply everything here or am I going to have to do cyto, sensitization and irritation because I have metals and some co-polymers that aren’t necessarily defined.” – Don Pohl

“Guidance is U.S. FDA’s current thinking, and even if it is a draft, we’ve had many reviewers say “there’s a new draft guidance, look at that”.” –Allison Komiyama

Discussion points include: 

Complete overview of the guidance and implementation

Inclusions and exclusions for materials and devices

Submission guidelines when applying this guidance

Information needed to submit for these types of devices immediately

Precautionary labeling instructions that may be necessary

In this episode, our hosts are joined by Lisa Olson (NAMSA’s Vice President, North American Lab Services) to discuss the U.S. FDA’s new Accreditation Scheme for Conformity Assessment (ASCA). This pilot program, launched September 24, 2020 with a new guidance document, is designed to accredit laboratories for certain biocompatibility tests, allowing for decreased paperwork and time for certain regulatory submissions, among other things. Although this is not specific to the device manufacturer unless they have an in-house laboratory, it is important for manufacturers to understand what ASCA is, how it is implemented and how important it may be when selecting a laboratory testing facility in the future.

“For the first time in medical device regulation history in the U.S., the U.S. FDA is going to accredit laboratories.” – Sheri Krajewski-Bibins

“If things were inconsistently reported by different laboratories, they [the U.S. FDA] had the responsibility to ask things. So if you can imagine them having to ask the same type of question on a basic cytotox assay for example, how much extra work that created because they [the U.S. FDA] can’t just assume it was done correctly.” – Lisa Olson

“They [the U.S. FDA] certainly won’t have to in all cases, review the complete testing report anymore.” – Don Pohl

“There’s the founding basis that you have a robust quality system, and that is the basis of the whole 17025 certification, but now the ASCA program allows or requires, however you want to look at, to allow you to get yourself [a lab] accredited to a certain test.” – Lisa Olson

“I could certainly see the benefit in trying to normalize that [training] across the industry.” – Don Pohl

“It’s an easier button, not an easy button, and manufacturers need to think about then do they go with labs that have no exposure to this program, simply because I think the Agency is going to use that [ASCA] in the background in how they are looking at data, no matter what it is.” – Lisa Olson

Discussion points include:

When will the program be implemented?

How does a laboratory qualify for the accreditation?

How can manufactures capitalize on utilizing an ASCA laboratory for their biocompatibility testing?

What are the challenges with implementing ASCA?

In this episode, our hosts are joined by Dr. Joe Carraway, co-author of the new research paper, “The suitability of reconstructed human epidermis models for medical device irritation assessment: A comparison of In Vitro and In Vivo testing results,” which discusses in vitro irritation assays and their viability for medical device testing. The three Rs in this type of experimentation, which stand for Replacement, Reduction and Refinement, are a concept always considered for new test development. In vitro irritation is one of the latest to reach the normative text of the ISO standards and manufactures and laboratories will need to be prepared to evaluate and utilize this test method. This episode provides in-depth  details regarding the timing of the standard, the viability and accuracy of the test method and opportunities and challenges for laboratories and manufacturers related to the standard.

 “The standards were written in such a way that it was still an option, and with the release of this new part 23… it essentially mandates what you really need to be doing, if you need to test for irritation {…} if you’ve determined that the next step says you do an in vitro model before going into an in vivo model.” Dr. Carraway

“The concern with predictive assays is you don’t want to have false negatives. You can live with false positives because you are typically going to do further testing to confirm those.” Dr. Carraway

“If you have a positive response, one of the approaches is to look at in vivo testing. Here, it’s a point to point comparison of irritation.” Don Pohl

Discussion points include:

When will an in vitro method be expected for irritation?

What was the methodology of this comparison study?

How does the in vitro method compare against the primary skin and intracutaneous study?

What are some challenges of the in vitro study?

What should manufacturers be doing now to prepare for the new ISO 10993-23

In this episode, two esteemed colleagues from Abbott, Tim Schatz and Ken Grove, join our hosts discuss ISO 10993-4:2017 Biological Evaluation Of Medical Devices - Part 4: Selection Of Tests For Interactions With Blood. Our experts highlight the general requirements of this very important and sometimes misunderstood segment of biological evaluations, including how to classify products requiring this test and how various products and scenarios may call testing evaluations. 

 “We are discussing specifically contact with circulating blood directly or contact with circulating blood indirectly at its most basic element.” –Don Pohl

“When assessing blood damage, we really use a battery approach to assess the overall interaction of the medical device with blood.” -Tim Schatz

“In the event with the thrombosis NAVI model, you do end seeing thrombosis, you are allowed to go into using anticoagulation model.” -Kent Grove

“(for platelets and leukocytes) You are trying to make sure that your new device or iteration performs at least as well as your marketed device – it’s a pretty quick test and definitely more sensitive than it used to be.” -Tim Schatz

“Now we have the ability to assess the variability in blood that can come in from one donor vs. the next and what’s interesting is that we have a true positive and true control – it helps us understand how the blood is behaving specifically from a thrombosis aspect.” -Kent Grove

Discussion points include:

General overview of the standard and applicability to various medical devices

Strategies for new devices and design iterations

U.S. and EU approaches, and where they may differ

Challenges with Non-Anticoagulation Venous Implant (NAVI) studies, including possible improvements for future evaluations

The blood loop model and the future state of this evaluation

In this bonus episode, our hosts discuss the new FDA Supplementary Information Sheet (SIS) on ISO 10993-18:2020 and their extent of recognition. On July 6, 2020 the FDA released this document to help clarify how manufacturer’s should utilize ISO 10993-18:2020 for US submissions. With this release, may come more questions than answers, so we decided to try to clarify this document and highlight the items that have the most impact to manufacturers and their upcoming submissions.

“There’s certainly a lot to recognize or not recognize when it comes to part 18.” – Don Pohl

“What you’re hoping to see there is something that states complete standard {..} in this instance that is not the case.” -Don Pohl

“Myself and some of our colleagues were pretty much, if we were betting people, we were betting this would not be recognized by the FDA.” – Don Pohl

“Overall, I don’t see these {extent of recognition} as being huge show stoppers for anyone.” – Don Pohl

Discussion points include:

What is an SIS and how is it helpful

What does partial recognition really mean

How do these changes impact the chemical testing we have ongoing

What are the 5 main parts not recognized and what does that mean to manufacturers

In this episode, our hosts answer your questions about biocompatibility. After 15 episodes of discussing what we think is important surrounding this topic, we asked for your questions and created this special episode to answer them.

“A toxicological risk assessment is the process of focusing on the risk associated with the chemicals that are in or may come out of a device, that’s your primary focus.” –Don Pohl

“The first step to investigation is trying to understand root cause […] what went into to my device that might cause this response.” - Don Pohl

“I love the ever changing environment, and I’m excited about us (the industry) getting better at performing evaluations that minimize unnecessary testing,” – Sheri Krajewski-Bibins

“The reality is, if you look at the grand scheme of things, it (biological evaluation of medical devices) is relatively new in terms of what we are doing – it’s constantly evolving and changing.” - Don Pohl

Discussion points include:

Updates on In Vitro alternative testing

How to handle unexpected biocompatibility results

What genotoxicity methods are preferred by the FDA

Alternative extraction temperatures accepted by the FDA

Differences between a toxicological risk assessment and a biological risk assessment

The future of biological safety evaluations – an exciting outlook

In this episode, our hosts are joined by Nicole Soucy, PhD, DABT from Boston Scientific to discuss qualifications of expert assessors and other personnel qualified to make biological evaluation decisions for medical devices. Documents including ISO 10993-1, Medical Device Regulation (MDR) documentation submissions and BSI best practice guidelines recommend having a qualified individual make decisions for the biocompatibility of medical devices.

While many testing organizations claim to perform this work, what does “qualified” really mean and how do companies determine this qualification?

In this episode, our experts discuss hiring and training processes utilized to identify and grow qualified individuals within their organizations.

“What are the qualifications that a person needs to have to evaluate the biocompatibility of a device? We get questioned about it all the time.” –Don Pohl

“Anytime you have a position open…you’re looking for that needle in a haystack to find someone who is appropriately qualified and has a good, strong background.” -Nicole Soucy

“You are not going to go out and find someone who has a Bachelor’s or Master’s degree—or even a PhD—in medical device biocompatibility; those people don’t exist. There is definitely an on-the-job training component to growing and developing this skill set.” -Nicole Soucy

“A really critical partner in all of this is your analytical chemist. They need to be integrated into you team. You need to have strong chemistry support all the way through your project.” -Nicole Soucy

Discussion points include:

How this role is the “famed unicorn” of medical device development

How on-the-job training is a critical component to successful assessors

How long until an assessor is able to work independently on a plan and assessment

Challenges with regulators utilizing an assessment properly

What someone looks for when choosing a qualified individual to perform this work

*Please note that the opinions discussed throughout the podcast are their own and do not reflect that of their current or former employers.

In this episode our hosts are joined by 2 esteemed colleagues from Abbott: Deanna Porter, Kent Grove to discuss the US FDA pre-sub meeting process as it pertains to the biocompatibility of Medical devices.

The group will review the current procedure for a pre-sub meeting and how this opportunity to obtain FDA feedback prior to an intended submission can be very useful, especially for programs containing chemical characterization or other complex testing protocols.

It’s a great opportunity to receive feedback and responses to specific questions, although not guaranteeing approval, the guests show today how using this process saves them valuable time in their biological evaluation.

“When you see 3 responses in a week with 15-17 questions about biocomp, it makes you wonder if there’s a way to make this process more effective.” – Don Pohl

“We focus the presubs and take advantage of this meeting with the FDA” – Kent Grove

“We like to focus the meeting on a specific need, so that we can really zero in on the responses and the guidance that we specifically need.” -Deanna Porter

“Little things can make a difference in profile.” -Kent Grove

“The key to a successful presub is knowing what you know and what you don’t know so you put the right detail into the presub.” -Don Pohl

 

“Have very pointed questions, not presenting a lot of ambiguity, making sure you understand what you want to get out of them, what answer you are seeking, so that it speaks specifically to the input that you are requiring them to provide.” -Deanna Porter

Discussion points include:

How is a presub meeting useful in evaluating the biological safety of medical devices

What types of questions are useful to include in a presub 

What can you expect the FDA to provide to you in a presub

How can you insure the data you are getting from extractables/leachables program will be most useful

What can you do to insure the proper FDA personnel is present to answer the questions you have in a Presub meeting

Opinions are their own and do not reflect that of their current or former employers.

In this episode our hosts are joined by Jeremy Koehler, Director of R&D for Prescient Surgical. Prescient Surgical is a small medical device company in the San Francisco area, with a biocompatibility story to tell.

Their first product submitted to the FDA, although not a high risk device, encountered delays directly related to some biocompatibility testing and the program. As a young start-up this can be very time consuming and most of all expensive.

“As a small company, speed is everything and time is a precious commodity.” Jeremy Koehler

“Externally communicating, limited contact. What more is there to talk about? What gives? As it played out it got a little bit more interesting.” Don Pohl

“The challenge came when we didn’t really have a good scientific justification for what we’d done and why we did it and why it was appropriate and sufficient.” – Jeremy Koehler

“Kind of the moral here is to have a solid scientific plan to help you down the road.” Sheri Krajewski-Bibins

“It’s important to mention that not every change triggers new testing.” Jeremy Koehler

“There’s plenty of projects that I’m involved in where I tell people; You don’t have to do testing, you have to address biocomp but that doesn’t always mean testing.” Don Pohl

Discussion points include:

When to perform a biological evaluation strategy in the product development process

Material selection and biocompatibility

How a “passing” test does not mean there won’t be reviewer questions

How the scope of biocompatibility reaches into the development cycle and planning for biocomp can alleviate challenges down the road

It’s never too early to start planning for the biological safety of the device

Opinions are their own and do not reflect that of their current or former employers.

In this special release episode, our hosts are joined by Dr. Phil Smiraldo, Toxicologist at NAMSA.

During this episode the team discusses the current pandemic situation of Covid 19 and the production of ventilators and respirators to help treat and prevent spread of this virus. With companies like Dyson, Ford, GMC and others discussing the design and/or manufacture of ventilators to meet the growing need of infected patients, how do we insure biological safety on a very short term?

Hosts will discuss some guidance put in place by the UK and USFDA alike that address these needs and offer some guidance and solutions.

This is a great example of the evaluation of risk/benefit and how using risk as your guide for biological safety is so critical. These documents go through risk mitigation through various means, which may address evaluation endpoints outlined in ISO 18562, the document that guides the evaluation of air pathway devices.

“Respirator is a protection piece of equipment… technically in the US may not even be a medical device – although a surgical mask is a medical device,” – Don Pohl

“This (ventilator) is an actual instrument that is helping you breathe - whether it’s provided a positive pressure situation or its doing your inhaling and exhaling for you. So these are very different than respirators.” -Dr. Phil Smiraldo

“Biocompatibility associated with all these different guidance (documents) as they pertain to ventilators, masks, respirators - it’s certainly interesting to at least ponder where biocompatibility falls in the grand scheme of things.” – Don Pohl

“The lungs are quite efficient at absorbing chemicals and putting those chemicals into systemic circulation.” – Dr. Phil Smiraldo

“It’s a risk evaluation. Is the short term solution more critical than any long term risks of exposure?” - Sheri Krajewski-Bibins

Discussion points include:

Difference between respirators and ventilators and their evaluation process

Overview of the US and UK guidance documents for ventilators

Selecting materials to help control the chemical possibly released

Particles – and how to produce in a “relatively clean” environment

The use of these short term ventilators for acute, life-saving care until a CE Mark device could be used

Opinions are their own and do not reflect that of their current or former employers.

Our hosts are joined this week by Stephanie Taylor, Staff Scientist - Toxicology and Biocompatibility at DePuy Synthes Companies. During this episode the team discusses the reprocessing of reusable devices and the challenges of the ever- changing landscape of the biological evaluation of such devices.

There is activity requested both by the USDA and the EU that greatly impacts the timelines and costs of evaluating these devices for biological safety, so the team shares some strategies and practices used by manufacturers today to meet high regulatory expectations.

“The end goal is a defensible position.” -Stephanie Taylor

“The magic number 6? I don’t know if that’s justifiable.” - Don Pohl

“What’s your biocomp at the end of life – you have to be able to figure that out.” - Stephanie Taylor

“Biocomp is interesting, challenging and a little bit magical at times.” – Stephanie Taylor

Discussion points include:

Why the great concern with such devices?

The differentiation between an end of life evaluation and what might be expected currently by the USFDA.

The great cost and time involved in such evaluations and burdens on manufacturers.

Opinions are their own and do not reflect that of their current or former employers.

During this episode, our hosts are joined by Andy Wyen, Toxicologist at NAMSA, to answer questions received during NAMSA’s live Webinar on the new ISO 10993-18:2020. As this new standard is a complete re-write from the 2005 version, it is stirring up industry and leaving many manufacturers confused and searching for the most efficient adoption methods.

Topics include:

Triplicate testing and how to determine if there is low variability in a sample before extraction has occurred

AET: How to calculate the number of devices used in clinical use for a chronic device that can be used during someone’s lifetime

Whether NVR used to establish exhaustive conditions affect the AET calculation for analysis

Whether the same replicates (single, duplicate, and triplicate) apply to NVR

With the release of 10993-18:2020 on January 15, 2020, it is crucial for professionals involved with the Biological Evaluation of medical devices to understand the standard’s use, interpretation and requirements, as well as how an effective link now exists to the overall Biocompatibility Evaluation as described in ISO 10993-1.

Connect with Andy: https://www.linkedin.com/in/andy-wyen-3448486/

Opinions are their own and do not reflect that of their current or former employers.