Over the last year, the BiocompCHATibility Podcast hosts have been compiling questions asked by our listeners and training series attendees. In this episode, we will answer your frequently asked questions about all things biocompatibility—and no, we did not answer why Don is funnier than Sheri (it is definitely a growth opportunity for her). Highlights include: The use of clinical data in the biological evaluation Completing chemistry testing before in vitro/in vivo studies Gathering historic data -and how much is useful to the evaluation U.S. FDA and DBT (dose base threshold) values The truth about “whole lifecycle” evaluation “I can certainly do a preliminary risk assessment and not have any extractables testing because part of my plan might be to go do extractables testing; but that doesn’t mean I always need it.” – Don Pohl “If you have clinical data and you are doing a preliminary risk assessment to evaluate the safety of this device, it is general information and cannot be ignored. But, if you are going to use the data to offset the need for a test, it better speak to the endpoint very specifically.” – Don Pohl “For manufacturing, I make sure to understand what was there and what wasn’t there. Mapping the process out is important for the reader of the assessment to understand I have performed the evaluation of the manufacturing and any impact it has on biological safety.” – Don Pohl

In this episode, our hosts are joined by APS’s Senior Director of Biocompatibility Services, Dr. Yan Chen, to discuss NAMSA’s acquisition of APS and the importance of preclinical studies in the biological evaluation of medical devices. This podcast discussion revolves around the many synergies of the combined companies, as well as a technical discussion regarding preclinical studies, preclinical study biocompatibility endpoints, and of course, an energetic game of ‘2 Truths and a Lie’ that will surely bring you a laugh. “We have expanded the possibilities of people who can join us now.”-Sheri Krajewski “We are very excited. We firmly believe that both companies share the same goals to provide high-quality, comprehensive services for medical device development.” – Dr. Chen “Companies are beginning to think about biocompatibility when they should early-on with studies like these. These [preclinical] studies can be so powerful in so many ways.” – Don Pohl “The local tissue response is the most commonly used (biocomp endpoint) in the preclinical study. Sometimes you want a clinically relevant implant site. That is something to keep in mind to combine (preclinical and biocomp) studies.” – Dr. Chen Discussion points include: The importance of preclinical testing to the biological evaluation Early-stage preclinical studies vs. GLP studies and the value they bring to medical device regulatory submissions The challenges of combining preclinical and biocomp studies

In this episode, our hosts answer listener questions regarding the new ISO 10993-23:2021 from NAMSA’s February 3, 2021 webinar. The standard recommends that In Vitro testing be completed prior to In Vivo testing, warranting many questions about how to deal with legacy data, regulatory acceptance and timelines. Our hosts will provide podcasters a full episode of responses, possible scenarios and potential recommendations. “This is an extraction-based evaluation and you will be creating and dosing extracts in most cases. There is not a direct contact equivalent for the In Vitro like there is In Vivo.” Don Pohl “In the past, you used the intracutaneous or primary skin appropriately, then this In Vitro test is for you.” Don Pohl “We have heard from one Notified Body that they are going to be giving a one-year grace period, [meaning the standard just issued in January 2021], they are giving folks until January 2022 to switch to the In Vitro method.” Sheri Krajewski-Bibins “Similar concept to Part 1, if you already have your data collected, it might be worth mentioning in your biological evaluation report. If you feel like you need to [mention] regarding the timing of events, that testing was already planned, executed and performed prior to -23 issuing, therefore, the In Vivo method was utilized.” Don Pohl “If you are having a pre-sub with the FDA, maybe have that conversation too that you would like to do the In Vitro method, and see what they tell you even though there is no official position.” Sheri Krajewski-Bibins “The standard has the one sentence that says In Vivo may be needed post In Vitro to clarify, but it doesn’t necessarily say because you failed or found an irritant….. I think you need to still be careful on your due diligence. Look at your failure in the In Vitro level, understand the materials, your manufacturing process, and confirm you didn’t miss anything.” Don Pohl Discussion points include:What is in the new 10993-23 and what is it not? How do you know if an In Vitro irritation test is right for an implant? Regulatory agency answers on when they will expect In Vitro irritation Limitations of the In Vitro assay What to do if you receive an irritant response in the In Vitro assay

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 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/accreditation-scheme-conformity-assessment-asca-pilot-program (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