The preclinical stage of device development is a vital one for medical device manufacturers. This is the stage in which the design of the product is set, including functionality and safety aspects, and validation of the selected materials and processes begins. Common questions medical device manufacturers ask are “When should we start planning the preclinical stage of our device’s development?” and “What aspects should be considered?”
The first step is to review the current industry standards, including ISO 10993. The ISO 10993-1 standard contains a lot of useful information that can aid in planning. When starting the preclinical planning of a device, all aspects of the device (e.g., composition, manufacturing, packaging, etc.) will need to be addressed. Items to consider include material selection, manufacturing methods, safety testing, functional study design, packaging, sterilization validation, and submission preparation. These aspects of the planning process are intertwined and interdependent. The level of focus each aspect requires can be affected by history of use of the materials, the target population, and intended use of the device.
Material selection. After review of the relevant industry standards, the next step is to carefully select the material used in the device. This can play a crucial role in the timing of the preclinical stage. The material should fit the purpose of the device, including areas such as mechanical, physical, chemical, and toxicological. When considering materials, a review of current literature and available information should be conducted in order to determine what standard testing, purity data, or biocompatibility studies associated with a raw material already exist.
Gathering information that is already available on materials is important. Even though this information may be difficult to obtain, without this information, additional time and testing or assessment may be needed to fully address a given regulatory body’s requirements. While new or novel materials and additives are continually marketed, the use of these can impact timelines due to the additional preclinical assessment or testing that may be required.
Manufacturing methods. It is also important to note that manufacturing processes play a key role in the safety and performance of a device. While many of these aspects will be evaluated as part of the final device testing, it is best to ensure that effects of the manufacturing process are included in the evaluation. Device manufacturers are encouraged to obtain as much information as possible on both raw materials and manufacturing processes.
Changes to manufacturing methods made during the preclinical phase will also need to be evaluated. Although some changes do not cause a large impact on the timing of the assessment or testing of a device (e.g., a manufacturing location change), other changes may cause additional testing to be required (e.g., a change in polymer additive). A review of such background information can help gauge what steps will be needed to address these changes. Changes to manufacturing methods may also occur during the post-market phase of the device development. It is imperative the possibility of these changes is taken into consideration during the preclinical phase.
Additionally, indirect components and processing of a medical device should be considered in the planning stages. This includes packaging/sterilization, manufacturing storage instructions, shelf life, transport, intended use or target population. While these areas don’t typically show up until the post-market phase, they play an important role in the safety and efficacy of a medical device.
Biocompatibility testing. If existing information is not sufficient to address concerns about a product’s safety, preclinical biocompatibility testing may be needed. ISO 10993-1 addresses the different categories that should be considered. If the product is an implant and no data exists on whether it causes mutagenicity, genotoxicity testing may be in order. If the product is made of a new material that hasn’t been used in healthcare applications before, a full suite of testing may be required. Some of these tests are lengthy and may take considerable numbers of devices to run, so proper planning for this segment is essential to meeting timelines.
Preclinical study design. After consideration of how materials and processing will affect the safety of a device, the manufacturer must also evaluate its performance. Firstly, it is important to determine the purpose, objective, and endpoints of the study. Will functionality be the only endpoint evaluated, or does it make sense to include some safety assessment endpoints as well? Often, data gained in a preclinical functional GLP study can be leveraged to help demonstrate biocompatibility. To design a study that can be used as evidence of biocompatibility, the appropriate type and number of test and control subjects must be utilized. These groups should be balanced and may include members of both sexes.
The duration of the study is another important consideration. The duration of intended patient contact will determine whether single or multiple termination intervals are needed; which can range from a couple of weeks to several months. Finally, what types of evaluations will be needed? If you are only looking at functionality, histopathology of the implant site may be sufficient. If the data is going to be used to prove safety, oftentimes body and organ weights, target organ pathology and a statistical analysis of the information may be useful.
Keep an eye out for the next blog in this series, Medical Device Development: Design Validation and Preclinical, Part 2.
If you missed the previous post, Medical Device Development: Concept and Feasibility, Part 2, you can view it here.
Additional contribution from Mike Bravo.