Creating a Biological Evaluation Plan Your Notified Body Will Appreciate

Evaluating biological safety (biocompatibility) is an essential requirement for all medical devices. To meet this requirement the medical device industry typically follows guidance from international standards like ISO 14971 and ISO 10993-1. In some cases, depending on the intended use of the device, additional guidance documents, or vertical ISO standards, may enter into the picture (for example, ISO 7405 for devices used in dentistry, the ISO 11979 series for intraocular lenses, the ISO 18562 series for devices in breathing gas pathways, etc.).

Regardless, one common theme amongst the ISO standards is the need for a Biological Evaluation Plan (BEP). Clause 4.1 of ISO 10993-1:2018 states, “The biological evaluation of any material or medical device intended for use in humans shall form part of a structured biological evaluation plan within a risk management process in accordance with ISO 14971:2007, Annex I, as given in Figure 1 of this document. This risk management process involves identification of biological hazards, estimation of the associated biological risks, and determination of their acceptability. Annex B provides guidance on this process. The biological evaluation shall be planned, carried out, and documented by knowledgeable and experienced professionals.”

In the past, some medical device manufacturers would simply follow the below steps:

1. Determine the device categorization (based on nature and duration of contact)
2. Find that category in Table A.1 of ISO 10993-1
3. Request a testing proposal for each biological endpoint that was ‘marked’.

In this situation (again, from years past), the testing proposal essentially became the biological evaluation plan. In present times, however, this type of approach would not be accepted (an approach your Notified Body will not appreciate). For example, Annex B of ISO 10993-1:2018 states, “Since biological evaluation is a risk management activity, a Biological Evaluation Plan is required, and this forms part of the Risk Management Plan. It is emphasized that simply planning to conduct testing against all of the aspects of biocompatibility identified in Annex A does not meet the requirements of ISO 14971 or this document.”

What is a Biological Evaluation Plan?

A Biological Evaluation Plan is a document that explains a strategy that will be followed to establish the biological safety of the device. It is intended to help us identify biological hazards, mitigate identified biological risks (if possible), and provide predictive evidence of biological safety. If gaps in knowledge are detected (for example, not knowing the complete composition of a patient-contacting polymer that is used in the device) or biological hazards have been identified that cannot be mitigated, the biological evaluation plan should describe a program of chemical and/or biological testing.

A BEP should be developed when a new device is to be submitted for clinical trial or marketing approval. Additionally, if changes occur to an already-marketed device (e.g., change of raw material, supplier of raw material, manufacturing steps or processes, subcontractors or manufacturing facilities, intended use, etc.), a Biological Evaluation Plan would be needed. When evaluating a change to a device, some may refer to this as a Change Control Assessment, the document is still intended to evaluate ‘something’ and determine if a program of testing is needed.

What is a Notified Body?

To obtain approval to market a medical device in the European Union (EU), medical device manufacturers submit through a Notified Body, which is an organization designated by an EU country to assess the conformity of certain products before being placed on the market. In the case of evaluating a medical device for safety, the Notified Body will expect conformity to ISO 14971, ISO 10993-1, and other vertical ISO standards (as applicable).

Creating a Biological Evaluation Plan will make both you and your Notified Body happy. While we will be discussing some of the desired contents of a plan later, simply having a documented plan is a great first step.

Creating a Biological Evaluation Plan

Creating a Biological Evaluation Plan is not a simple task (in some cases, performing a toxicological evaluation of 500+ extractables can feel less tedious). It goes far beyond simply checking a box. Each medical device is unique and, therefore, requires an individualized approach (for example, a BEP for a cardiovascular stent and associated delivery system will not look the same as the BEP for a blood pressure cuff).

Many factors come into play when developing a biological evaluation plan for a medical device, such as:

• Device type
• Patient contact
• Contact duration
• Materials used to construct and manufacture the device
• Sterilization technique
• Available clinical and biocompatibility data (if any), etc.

One additional item that sometimes gets overlooked–do not lose sight of what you are submitting for. For example, let’s say we have created a device that will, ultimately, be used for a long-term duration. However, currently, we are only preparing to submit for a five-day early feasibility study in humans. In this situation, a BEP that focuses on patient safety for the five-day human study should be prepared. For longer duration trials or marketing approval in the future, corresponding BEP documents/versions should be created.

In our experience, the Notified Body groups tend to follow each set of standards very closely and, oftentimes, literally. If the standard states, “the following shall be evaluated…”, then that item needs to be evaluated (note, in some of the recent ISO standards, the term “shall” is explicitly defined as a requirement). As an example, let’s say that we have an orthopedic pin that is composed of implantable-grade titanium. ISO 10993-1:2018 (Clause 4.3 e) states that degradation products need to be taken into account as part of the biological evaluation of the medical device. One author may think to themselves, “By virtue of using an implantable-grade titanium, it is understood (without the need to write anything) that degradation is not an issue.” A separate author may use a different approach, writing something like, “An assessment of degradation products was performed following guidance from Figure A.1 of ISO 10993-9:2019; implantable-grade titanium is not intended to degrade and toxic degradation products are not released.” Neither author is wrong. However, a Notified Body will certainly prefer the latter approach, since the evaluation was 1) documented and 2) performed in a manner that, literally, conforms to the standards.

Generally, when starting the process of creating a Biological Evaluation Plan, the team begins by “setting the stage”. This involves identifying the primary purpose: Is the plan intended to satisfy EU, US, Japan, China, and/or other geographical locations? Is the plan being used to support an early feasibility study in humans or a full marketing approval? Once that is established, the team moves on to providing a description of the device (including an image), summarizing the intended use of the device (type of patient contact, duration of patient contact, repeated-use frequency, defining the intended patient populations, etc.), listing the materials used to construct and manufacture the device (specifying those materials that have patient contact), and identifying any contraindications for use. The goal of this section is not to write a full dissertation or thesis about the device. Rather, it is intended to provide the reader with a succinct background so that the remainder of the document (device categorization, ISO standards that are being followed, evaluations of scenarios that may be unique to the subject device, etc.) makes sense. It also proves to the reader that the author “knows” the device they are evaluating (something your Notified Body will appreciate).

In an ideal world, we would know the full composition of every material (including all additives) and manufacturing agents used to construct a medical device. If this is the case, your Notified Body will be thrilled. However, from our experience, this is an extremely rare situation. Oftentimes, we are provided with material Safety Data Sheets (SDS), which contain varying levels of detail (wide ranges of disclosed additives, notification of ‘proprietary’ additives, etc.). This is an obvious source of frustration for those authoring BEP documents, as it prevents us from completing some of the compositional profiling activities described in ISO 10993-18:2020. Some material suppliers have created region-specific SDS documents (e.g., one version is specific to European countries while others are specific to different regions of the world). Sometimes, reviewing multiple SDS documents for the same material can fill compositional gaps. Regardless, if a material supplier is unwilling to provide you with additional details, there are a couple of avenues to pursue. You could enter into a non-disclosure agreement with them (in this manner, information can be shared between parties). You could request a current Regulatory Data Sheet (RDS) for the material, which would summarize the level of compliance with REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals), RoHS (Restriction of Hazardous Substances) and/or other regulations. If the supplier will not tell you what additives are used, an RDS would tell you what additives are not used. The goal is to acquire as much information as possible about the materials and chemicals that are present in (or on) the medical device (efforts that your Notified Body will appreciate). You should also request a summary of any biocompatibility testing that may have been performed on the material (e.g., cytotoxicity, sensitization, irritation, etc.). If available, it would support that certain biological effects, at a material level, have already been tested.

Once the composition of the materials (including all additives) and manufacturing agents used to construct a medical device are known, the next step is to review them for potential adverse biological effects. Especially when evaluating chemicals, we are trying to find information in the literature about acute and repeat-dose toxicities, irritation, sensitization, reproductive and developmental toxicities, genotoxicity, carcinogenicity, and any other potential biological effects. In addition to these analyses, the materials and manufacturing agents (including all additives) are typically screened to determine if any are Substances of Very High Concern (SVHC), Carcinogenic, Mutagenic or Reprotoxic (CMR) 1A/1B substances, or human endocrine disruptors. Based on the results of these analyses, consider these questions:

• Are there chemicals in the device that might cause adverse effects?
• If so, can the concern be mitigated based on the current information?
• Will testing of the device be needed?
• Are there gaps in our knowledge about the device composition?

It is this information that guides us into which tests are needed (under the assumption that the concern(s) cannot be mitigated with the currently available information) and forms the basis for the testing program.

Note that the activities described above would also, optimally, be performed at the material selection stage (before a device has ever been produced). For example, in the early stages of device design you are given the option of selecting a particular polymer from three different suppliers. Supplier 1 is willing to provide you with a lot of information about their material; upon review, there are no obvious hazards identified. Supplier 2 is willing to provide you with a lot of information about their material; upon review, it is discovered that a potential carcinogen might be present. Supplier 3 is not willing to provide you with much information and is, generally, uncooperative. In this case, the choice is fairly obvious. The point is, an assessment of risk is not reserved for the BEP. Rather, it is something that is (or should be) performed at many stages of device design. Again, this is something that your Notified Body will appreciate.

Testing Recommendation or Justification

If testing has already been performed (e.g., on a prototype version of the device or a predicate device), this information could certainly be incorporated into the BEP. But, before doing so, it must be confirmed and documented that the data are applicable and relevant:

• Are the materials of construction the same?
• Are the manufacturing processes the same?
• Due to the age of testing, are gap analyses of the methods needed?
• Are the devices used in a similar manner?
• Is there clinical history information for a predicate device that could be helpful?

It is still necessary to confirm and document that the data are applicable and relevant. Ultimately, this data may fill gaps in our knowledge and could be used to mitigate hazards that were identified from the evaluations of the materials used to construct and manufacture the device.

Upon completing the evaluations described above, you might conclude that no additional testing is needed. If this is the case, the logic should be summarized and documented in a clear, logical manner. If it is determined testing may be needed, a brief description of the study should be provided. For example, if extractables testing is being recommended, describe “why?” by considering the questions below:

• What is the purpose (compositional profiling or trying to determine patient exposure to chemicals)?
• What type of extractions will be used (simulated use, exaggerated, or exhaustive)?
• Are polar, semi-polar, and non-polar extraction vehicles needed?
• Are there specific chemicals that need to be targeted (e.g., a CMR substance that was identified from the material analyses) and, if so, what dose-based threshold (DBT) is needed for in the analytical evaluation threshold (AET) calculation?
• If there are no target chemicals and the study will be a screen, what DBT is needed for the AET calculation?
• What will the data be used for?
  • The goal is not to write an analytical chemistry protocol in the BEP. Rather, the goal is to provide the basics so that the reader understands what you are trying to accomplish and why (your Notified Body and laboratory will appreciate this).
• When outlining your biological testing, what methods will be used?
  • For example, if testing for the biological endpoint of irritation is warranted, ISO 10993-23:2021 gives preference to in vitro methods over in vivo methods. Which are you selecting? If you select an in vivo method, you will need to provide a reason why. It could be a very simple, one-sentence explanation that other geographies that are in-scope do not currently recognize the in vitro methods (this exemplifies why it is important to establish the intended geographies early in the BEP, as recommended previously).
  • Again, the goal is not to write a protocol in the BEP. Rather, the goal is to provide the basics so that the reader understands what you are trying to accomplish and why (your Notified Body and laboratory will appreciate this).

Who Develops a Biological Evaluation Plan

Lastly, as quoted earlier, ISO 10993-1:2018 states that the evaluation shall be planned, carried out, and documented by “knowledgeable and experienced professionals.” A good laboratory team will include a 1- or 2-page curriculum vitae for each Associate that is signing the BEP, confirming the qualifications of training and experience. This is helpful for both you and your Notified Body.

Conclusion

In summary, when evaluating the safety of medical devices, the ISO standards instruct that a biological evaluation plan shall be created. Therefore, to ensure conformity with the standards, your Notified Body will expect to see one. Here, we have highlighted multiple items that should be included in the BEP that your Notified Body will appreciate.