With the release of ISO 10993-1:2018, biocompatibility evaluation has once again become a hot topic of discussion in the industry, especially the overall update of Appendix A of the well-known reference list for biocompatibility testing, and the overall introduction of Appendix B biorisk management The update of ISO TR 15499 will have a structural impact on medical device manufacturers, registrants and inspection agencies.

  ISO10993-1:2018 supersedes ISO 10993-1:2009, which subsequently lapses. The new version of the standard has a total of 41 pages. Compared with the 21 pages of the previous version, there is a considerable increase in the text content.

   First of all, let's feel the biocompatibility changes of the new version through a brief table:

Figure 1 List of biocompatibility test items

  Note: Red is the new test item

   For the added or changed parts of the new version of the standard, according to the layout order of ISO 10993-1:2018, we will guide you from the standard text, that is, Clause 4 Generalprinciples:

  4General principles

4.1 The new concept of physical/chemical information (physical/chemical information) is introduced. The priority of obtaining this product information is in the front of all biocompatibility tests. Additional biocompatibility testing provides the basis for product information.

  New Standard The physical/chemical information is also updated in the biological risk management flowchart in Figure 1, and a new diamond-shaped grid geometry and physical properties has been added to the first row of the flowchart. At the same time, clinical use is also added to the flow chart as an evaluation item for risk management, as shown in Figure 2.

Figure 2 is taken from ISO 10993-1:2018 Figure 1

  4.3 c) packaging materials that directly or indirectly contact the medical device can transfer chemicals to the medical device and then indirectly to the patient or clinician;

  The biological evaluation factor adds a new consideration for packaging materials.

   According to the new version of the standard, it is necessary to consider whether the packaging materials will produce harmful chemical substances during the shelf life and affect the safety of medical devices. For example, the biological heart valve needs to be immersed in aldehyde solution, and the material of the storage tank containing the solution is often engineering plastics. Therefore, it is necessary to consider whether the storage tank containing the solution has chemical substances dissolved during its shelf life, which will affect the to the safety of heart valves.

  4.7 The biological safety of a medical device shall be evaluated by the manufacturer over the whole life-cycle of a medical device.

   A new clause is added, the biosafety evaluation of the medical device by the manufacturer shall cover the whole life cycle of the medical device.

This clause introduces the biological evaluation of the whole life cycle, that is to say, the biological evaluation no longer stops at the biocompatibility test, and all the data generated from the subsequent clinical trials until the product de-marketing stage will become necessary to update the biological evaluation report. enter.

  4.8 For re-usable medical devices, biological safety shall be evaluated for the maximum number of validated processing cycles by the manufacturer.

   A new clause has been added. For reusable medical devices, manufacturers should conduct biosafety evaluations for medical devices that have confirmed the maximum handling limit.

  4.11 A supplementary note to the basic rules of the new version of the standard:

  1) It is clarified that before the release of the new version, medical devices that have been evaluated do not need to add new biocompatibility tests;

  2) According to the new version of the standard, any exemption of biocompatibility test items needs to provide a reasonable explanation;

  3) Historical clinical data can be used as evidence of compliance with biocompatibility requirements to exempt from testing;

  4) Any medical device involving biocompatibility re-evaluation must be re-evaluated in accordance with the new version of the standard.

  5Categorization of medical devices

  5.1 General

   It is clarified that the classification of airway medical devices refers to the ISO 18562 series of standards.

  5.2.1 Non-contacting medical devices

  The new version of the standard covers non-contact medical devices and clarifies that non-contact medical devices do not require biocompatibility testing, such as medical diagnostic software, in vitro diagnostic equipment, and blood collection tubes.

  5.2.2 Surface-contacting medical devices

  a) Skin

   The new version of the standard adds a NOTE explanation to clarify that skin contact devices using conventional raw materials do not require more biological evaluation. Including glove-free contact devices (such as keyboards, buttons, touch screens, SD cards, USB sticks, etc.) and glove-contact devices (such as catheter handles).

  5.2.3 Externally communicating medical devices

  b) Tissue/bone/dentin

  Medical devices or components that do not necessarily directly contact tissue or bone but serve as conduits to deliver fluids to the tissue or bone.

   Catheter-like devices used to deliver fluids to tissue or bone, the new version of the standard is classified as external access devices.

  5.3 Categorization by duration of contact

  5.3.1 Contact duration categories

  c) Long-term exposure (C) – medical devices whose cumulative sum of single, multiple or repeated contact time exceeds 30 d.

  In the new version of the standard, long-term is used to replace permanent for medical devices that have been in contact for more than 30 days, which is more rigorous in expression. For example, a pacemaker is a long-term implantable medical device, but due to the limited battery capacity, even a single-chamber pacemaker can only last for 7-8 years, and cannot be regarded as a permanent implant.

  5.3.2 Transitory-contacting medical devices

   Added the definition of short-term exposure to medical devices, and devices with a specified contact time of less than 1 minute are classified as short-term exposure, such as lancets, hypodermic needles, capillaries, etc. Brief exposure medical devices generally do not require biocompatibility testing and are not listed in Appendix A, but such devices require additional evaluation if they involve cumulative use.

  6Biological evaluation process

  6.1 Physical and chemical information

New clause, physical and chemical information is an important first step in biocompatibility evaluation. For specific implementation, please refer to ISO 10993-18. For nanomaterials, please refer to the new biocompatibility standard ISO/TR 10993-22 issued in 2017. .

  6.2 Gap analysis and selection of biological endpoints

   A new clause specifies the implementation process of the gap analysis, which should be determined by referring to Appendix A and in conjunction with Appendix CLiterature review. Based on the results of the gap analysis, the potential risks exist to determine the biocompatibility test items that need to be selected.

  6.3 Biological testing

The new test items in this new version of the standard mainly refer to the content of the FDA's Annex A of the 2016 edition of the ISO 10993-1 Guidelines for Use, which means that the ISO standard for biocompatibility testing as a whole is close to the FDA. For reference to ISO 10993-1 It is a big challenge for medical device manufacturers in Appendix A, especially the addition of long-term testing items such as chronic toxicity and carcinogenicity.

   ISO 10993-1 Annex A is updated as shown below:

Figure 3 is excerpted from ISO 10993-1:18 Annex A

  1) Use the symbol E to replace the X in the previous version to identify the biocompatibility test endpoint;

  2) The new version of the standard symbol X indicates the prerequisite information required for biological risk assessment, such as Physical and chemical information;

  3) Added new biocompatibility test items (as shown in the yellow mark in Figure 3): materials mediating heat, chronic toxicity, carcinogenicity, reproductive toxicity and degradability.

  6.3.2.5 Material-mediated pyrogenicity

  Appendix A Newly added test items, material dielectric heat. Pyrogens are divided into endotoxin-mediated heat-generating and material-mediated heat-generating heat-generating agents. Although material-mediated heat-generating heat-generating agents are relatively rare in general medical devices, they are more common in devices of biologically derived materials, and the test method is mostly the rabbit method.

  6.3.2.8 Chronic toxicity

  Appendix A New test item, chronic toxicity. Compared with sub-chronic toxicity, the test period of chronic toxicity will be longer. For example, 3-month sub-chronic toxicity in mice requires up to 6 months of chronic toxicity in mice. The lengthening of the inspection cycle will also be a challenge for the rapid launch of medical devices, especially the many potential compliance risks.

  6.3.2.9 Implantation effects

   For implantation trials, the new version of the standard has a major update, suggesting that the implantation trial protocol can be expanded to simultaneously evaluate local reactions and systemic toxicity to meet the needs of acute, subacute, subchronic and chronic toxicity testing. If possible, blood compatibility evaluation can also be included.

  6.3.2.11 Carcinogenicity

  Appendix A Newly added test item, carcinogenicity. For general medical devices, carcinogenicity testing is rarely covered, but needs to be considered for medical devices with exposure times greater than 30 days. The new version of the standard suggests that carcinogenicity can be combined with a chronic toxicity test. For details, please refer to OECD Guideline 453.

  6.3.2.12 Reproductive and developmental toxicity

  Appendix A New test item, reproductive toxicity. For general medical devices, reproductive toxicity testing is rarely involved, but it needs to be considered for medical devices intended to be used by pregnant women.

  6.3.2.13 Degradation

  Appendix A New test item, degradability. For degradable medical devices, in vitro methods are used to simulate clinical use for testing. When in vitro testing cannot obtain sufficient data to prove its biocompatibility, in vivo degradation testing needs to be considered. Degradation test can refer to ISO 10993-9, ISO 10993-13, ISO 10993-14, ISO 10993-15.

ISO 10993-1:2009, with the rapid development of medical devices in China, is familiar to those who are engaged in passive medical devices, and this update after nine years also shows from one side that passive medical devices will soon be Upgrading has begun, and regulatory requirements for biocompatibility testing have also begun to increase.