By Michael Song, Ph.D.
Biocompatibility assessment is an essential development activity for all medical devices. The ISO 10993 series is the internationally recognized standard for conducting biocompatibility endpoint testing for various medical devices. It is comprehensive and covers a broad range of device types.
Since 1995, ISO 10993 has been referenced by numerous FDA guidance documents. For those working on drug delivery devices, the 2013 technical guidance for pen, jet, and related injectors references biocompatibility as an essential element in device development.
The intended purpose of biocompatibility testing and/or assessment is to demonstrate that the device will not pose risk of physiological harm to the user/patient. As there are numerous medical devices with broad designs, unique technologies, and use conditions, there cannot be a one-size-fits-all approach to biocompatibility testing. There are numerous situations to consider depending on your device, device design, device interaction with the user/patient, and duration of contact. To this end, there are a number of normative references to ISO 10993, from -1, which provides a general framework on how to apply biocompatibility assessment based on a generalized classification/categorization and overview of the device use condition, what part of the body it makes contact with, and duration of contact, to a subsequent sub-standard that touches on various aspects that go into performing biocompatibility studies, to -2 on animal welfare, to -10 on irritation and skin sensitization testing approaches, to -7 on EO sterilization and EO residual, to -22 on nanomaterials (a novel technology that is beginning to be used more often and also a new addition to ISO 10993 in 2017).
As such, there are a number of factors to consider when evaluating biocompatibility ranging from how the medical device is sterilized, to how the device is used and what bodily parts it makes contact with, to selecting testing approaches. As early as 1995, the FDA saw the need to provide industry with guidance on how to apply ISO 10993 for biocompatibility. This has been done through the FDA 1995 Blue Book Memorandum G95-1 through to the more recent release of a 68-page guidance on applying ISO 10993-1.
Conducting Biocompatibility Studies
ISO 10993-1 is typically the starting point for biocompatibility study planning as it provides a general overview and recommendation on testing endpoints. While this may seem straightforward, there are intricacies when conducting biocompatibility studies. First, the new ISO 10993-1 guidance now explicitly asks the user to assess their device’s material of construct as part of initial assessment, prior to determining if testing is necessary. What approach should be taken when assessing materials? If the material is used in a similar product on the market, that makes things easier, but what if it is not — or if it is used in a different way in marketed product? How different or similar do materials need for them to be considered comparable?
There are a number of additional intricacies to consider. Take, for example, standard cytotoxicity testing. There are a number of ways this test can be performed, ranging from agar overlay to MEM elution. Depending on how your device interacts with the user/patient, it is important to select the appropriate cytotoxicity testing, rather than one that may be more constricting and less relevant.
Biocompatibility testing assesses the surface area of the device that makes contact with the user/patient and determines whether it can cause harm to the user/patient under normal use conditions. As such, biocompatibility testing should not be done on every component of the device; it should only be done on the parts/surface areas that contact the user/patient, unless there is a reason to expand the scope.
ISO 10993-16 and -17 touch on leachables. It should be noted that these referenced leachables are more related to the leachables from implants or devices with prolonged contact with body parts, fluid, or serum. ISO 10993-16 and -17 should not be confused with the FDA’s requirement for extractable and leachable studies on drug product containers. Extractables and leachables for drug product containers follows the Product Quality Research Institute (PQRI) guidance and is intended to assess what leachables from the primary container components and surrounding materials can be drawn into the drug product solution and injected into the patient’s body.
For those who terminally sterilize a device with ethylene oxide (EO), because EO is a known toxin and carcinogen, ISO 10993-7 should be referenced and followed to determine residual EO levels after sterilization as part of design verification/sterilization validation. This is an expected test, but it is only briefly referenced in the body of ISO 10993-1 and not listed on Table A1 Biological Assessment Endpoint charted in ISO 10993-1 and FDA guidance. Often, it is more prudent to perform this study with worst-case EO outgassing parameters.
Before we dive deeper into biocompatibility for pharmaceutical devices, it is important to touch on the fact that the core of ISO 10993 is about user/patient physiological safety risk associated with the medical device contact material. To this end, along with the fact that biological safety evaluation can be achieved through multiple means, ISO 10993 provides those with the appropriate training, and experience flexibility to deviate from recommended testing endpoints such as cytotoxicity, irritation, systemic toxicity, etc., and perform assessments in lieu of certain tests (i.e., sensitization, systematic toxicity, etc.). in fact, this is one of the few ISO standards that emphasizes this (for reference, see paragraph 6 of the introduction to ISO 10993-1:2018). Assessments can be completely paper-based if sufficient data is available to support the medical device biocompatibility, or it can be a combined paper exercise supplemented with select testing.
Often, companies are looking to save time, cost, and testing and seek to find alternatives to traditional biocompatibility testing, while at the same time meeting the endpoints demonstrating their products’ biocompatibility. This can be achieved through the use of the biological safety assessment that was alluded to few paragraphs prior. Biological safety assessment is basically a toxicological assessment/justification for why the medical device is safe for use from a physiological interaction / biocompatibility standpoint.
When performing a biological safety assessment, it is important that the individual performing the assessment knows how to apply toxicological principles to demonstrate scientifically that the medical device material pose a low risk to user/patient health. I have often reviewed biological safety evaluations that are very loose and easily taken apart by a medical device toxicologist/biocompatibility expert, whose ranks are increasing within the FDA. A good toxicologist/biocompatibility expert should leverage a multitude of information sources, such as your manufacturing process, materials, and other prior work as a whole, to provide a justification backed by scientific risk assessment.
Biocompatibility For Pharmaceutical Drug Delivery Devices
In the pharmaceutical industry, combination products are typically made up of a device and a primary container element. Oftentimes, especially with a prefilled syringe in a needle safety device, the question comes up as to whether the prefilled syringe itself needs to undergo biocompatibility. In such a case, one should assess whether the user/patient will, in the course of normal use, come into contact with the prefilled syringe. If the answer is yes, then the prefilled syringe should be a part of the biocompatibility assessment. This also applies to the label on the syringe barrel. Some needle safety devices have an open window to directly view the prefilled syringe in order to allow the user to examine the drug. In such a case, one should always look at the size of the viewing window and determine whether it is big enough that, under normal conditions, a user/patient could come into contact with the prefilled syringe. This is easier said than done. One approach is to leverage ISO 23908 testing criteria for sharps injury prevention on the opening in question. If it fails to meet the requirement of that standard, then it is user/patient-contacting. Of course, there are always exceptions.
With an injectable combination product, selecting the device category for ISO 10993 can also become somewhat tricky. Based on the drug delivery device itself, the device element can be categorized in the “surface medical device” category. On the other hand, with a prefilled syringe or drug delivery container that breaches the skin via the needle, if one considers the primary container as a part of the device, the combined device can also be considered an “externally communicating medical device.” Because ISO 10993 follows a risk-based approach, however you categorize your device, the biocompatibility testing or endpoints that need to be assessed are most likely be the same. So “who cares?” you might ask. How you categorize your device will determine how you will need to write up your protocol and report. With one approach, you are rationalizing why you are adding more biocompatibility testing, while with the other, you are justifying why a certain test does not apply.
Leveraging Vendor Assessments
With parental drug delivery, the device often comes from a vendor. In such cases, device vendors may have performed the biocompatibility assessment or testing and have data they can share with you. The proper adoption and leveraging of vendor biocompatibility data can save a lot of resources, time, and cost, but it can also be tricky.
For one, the vendor may have performed certain tests and justified others using prior or leveraged data themselves. These documents, as well as their rationales, should be examined thoroughly. If the vendor has conducted biocompatibility testing, the testing approach should be looked at and checked. It should also be noted that some devices or components are used in multiple circumstances, and some of the circumstances may require more biocompatibility endpoint assessments than for your situation. In such cases, vendors may provide that additional data. While it may be tempting to include all provided data in your biocompatibility assessment report, sometimes more may not be better. It is recommended you leverage and use only the information that is relevant to you.
In other situations, device vendors may themselves be leveraging their suppliers’ biocompatibility data and/or data from a predicate device. In such cases, you are dealing with third-hand+ data, and special attention should be paid to how strong and/or relevant the leveraged data are. If the primary vendor is leveraging its vendor’s data, one of the questions that should be asked is how applicable the tier-2 (and beyond) vendor’s biocompatibility data is after the device/component has undergone your vendor’s manufacturing process. Other questions include how your device vendor is managing its suppliers’ quality and whether there is sufficient quality oversight between your vendor and its vendors to ensure materials and processes are not changed without their knowledge and, subsequently, your knowledge and agreement.
On the other hand, If the device vendor is leveraging a predicate device, you should ask how relevant the predicate device and its manufacturing process are to the current device and its manufacturing process. Sometimes, different devices may use the same plastic materials. In such a case, it is not just about the same materials but also about whether the manufacturing processes, from part molding to assembly, are comparable. For example, two device housings may be made from the same material, let’s say polycarbonate. If the releasing agent used on one housing’s injection molding die is different from the other, then residual on the two housings will be different. This is just one example; other things, such as molding parameters, mold die material construct, colorants, etc., need to be factored into the consideration, as well.
Keep in mind, leveraging vendor biocompatibility data only covers up to the point you receive the parts. For a complete biological assessment, you must also assess your own manufacturing processes to determine whether any steps can introduce residue or material changes to the device that can pose a biological safety risk to the end user/patient. If risk is identified, you may still need to perform some or all biocompatibility endpoint testing with the finished product even though your vendor has already performed biocompatibility testing on the components/semi-finished products. This is because in order to leverage vendor data, you must demonstrate that your finished product is comparable to the vendor-supplied component or subassemblies from a material safety standpoint.
When leveraging biocompatibility data, in addition to vendor biocompatibility data, one should also examine peripheral information such as materials, agents, and tools used during the manufacturing process. This includes whether any of the materials, agents, and tools are of animal origin or can contribute chemical residue onto the finished device/product.
For those working with inhaled product, in addition to ISO 10993, ISO 18562, “biocompatibility evaluation of breathing gas pathways in healthcare applications,” will also apply. We will dive into ISO 18562 another time.
Biocompatibility is an essential element for any pharmaceutical combination product. ISO 10993 is the standard for biocompatibility, and it is broken into various normative sub-standards from ISO10993-1 to -22 that focus on various assessments, considerations, recommendations, and approaches. While the number of sub-standards is large and they have multiple references, ISO10993 at its heart follows a risk-based approach to evaluate and ensure that the finished device material is safe for users/patients to use. One should also remember that standards like ISO 10993 are intended to cover a broad spectrum of current and future medical device variants and technologies; as such, it leaves room for flexibility. While following the recommended testing endpoints for your device may be the safe route, doing so still requires thought and consideration of the specifics of each test, in addition to the necessary time and cost to plan and execute those tests/studies. Sometimes, it is advantageous for companies to leverage vendor data/justifications as well as their own prior data and information to help expedite biocompatibility assessment, accelerate programs, and keep cost down by using biological safety assessments/toxicological justifications to demonstrate safety and minimize the need for testing. Biological safety evaluation/justification requires a thorough assessment and should be done carefully, as it requires well thought-out rationale and appropriate linkage to and between internal and external data sources. Leveraged toxicological data may oftentimes come from different situations, and appropriate toxicology safety factors, such as animal to human and population variance, need to be defined and applied to the data before it can be used.
In summary, as the new EU Medical Device Regulation (MDR) takes effect, many are worried about biocompatibility, but biocompatibility is not to be feared. The updated ISO standard is still a risk-based approach and provides flexibility demonstrating biocompatibility. This article has provided a high-level look at approaches to and considerations for biocompatibility and biological safety evaluation.
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Opinions expressed in this article are those of the author and do not necessarily represent those of the author’s employer.
About The Author:
Michael Song, Ph.D., leads the biological device functionality, safety, and digital connectivity group within AstraZeneca’s biologic device development. In his current role, he oversees device functionality and safety, primary container science and technology, biocompatibility, container closure integrity strategy and testing, and digital connectivity development. Prior to his current role, Song was head of the Device, Packaging, and Process Engineering Department at Adello Biologics. He has held key technical positions at Stryker, Amgen, and Kavlico Corporation and has led the development of both combination products as well as 510(k) medical devices. He received his postdoctoral training at Barrow Neurological Institute / St. Joseph Hospital and Medical Center (part of Dignity Health) and holds a B.S. in electrical engineering from Purdue University and a Ph.D. in neuroscience and toxicology from Iowa State University.