POINTS FOR DISCUSSION
When presenting your comments regarding the technical considerations related to manufacturing, QC, characterization, and biocompatibility presented below, please describe what you consider to be a "nanomaterial" or "nanostructure" as applicable to medical devices.
CDRH has an interest in providing consistent recommendations for the characterization of nanotechnology products. For instance, how many characterization studies are needed? It is CDRH’s current thinking that more than one technique is required to characterize a single endpoint [i.e., size, size distribution, shape (aspect ratio), purity, composition, surface composition (reactivity), surface charge, surface area, agglomeration/aggregation state, and degradation].
- Discuss whether there is a specific set (more than one) of distinct measurement modalities that should be used with the majority of nanomaterials (e.g., two microscopy methods versus a light scattering method and a microscopy technique).
- Discuss whether requiring physiological characterization of a nanomaterial or structure in its final finished form would be likely to preclude certain common characterization techniques from use (e.g., it may not be possible to characterize a nanomaterial incorporated into a solid device by using some spectral methods).
- Discuss the characterization considerations when developing and/or reviewing diagnostic and other medical devices, (e.g., interference effects).
- Discuss other physical/chemical characteristics that are important for an assessment of safety and effectiveness that have not been identified as endpoints, above.
- In the case of nanomaterials or structures with additional surface ligands attached, please discuss what additional characterization parameters are important to evaluate (e.g., stability of ligand, completeness and consistency of surface coating, etc.).
In terms of manufacturing and quality control for nanotechnology products, small changes in input parameters can have a large impact on the final product.
- Please discuss the impact of accelerated versus real-time aging on the characteristics of the final nanotechnology based product.
- Please discuss how shelf life, stability, and lot to lot reproducibility should be tested and evaluated, taking into account different considerations for various medical devices. For example, nano-coated devices versus in vitro diagnostic assays containing nanoscale reagents.
- Please discuss whether there are unique quality control issues (e.g. segregation of materials) when multiple types of nanomaterials are used in a single facility or when there is the possibility of contaminating other products.
- Please discuss the effects of sterilization and sterilization methods on final nanotechnology based products.
CDRH has an interest in the development and utilization of reference materials in the assessment and quality control of nanotechnology products.
- Please discuss how reference materials should be utilized when there are very few standard reference materials available.
- Please discuss whether there are appropriate positive and negative control standard materials against which various in vitro characterization and toxicity methods can be measured and how nanomaterial controls should be used.
Endotoxin contaminated health care products can have adverse health effects in humans. Thus, CDRH has established endotoxin limits for health care products including certain devices, such as those in contact with blood and spinal/cerebral fluids. Endotoxin determination and decontamination for devices containing nanoscaled materials can be very challenging. Studies have shown classic methods of determining endotoxin levels may not be suitable for nanomaterials due to, among others, interference effects with classic test methods.
- Please discuss how one can control endotoxin contamination during the manufacturing of nanoscaled materials for medical device applications and whether there are certain techniques specific for use with nanomaterials that can be used to depyrogenate the materials without compromising the integrity of the nanomaterials or structures.
- Please discuss the validity of using the various CDRH recognized standards, regarding the measurement and limits for endotoxin, when dealing with products containing nanoscaled materials or structures.
- Due to potential/known interference issues with some of these tests, please discuss the need to account for this when evaluating the amount of endotoxin present for these products and how best to quantify the levels of endotoxin present in the final sterilized medical device.
Biocompatibility tests described in ISO 10993-1 Table “Evaluation tests for consideration” for different tissues/contact durations alone may not be sufficient to completely evaluate the biocompatibility/toxicity of devices with nanotechnology.
- Please discuss how the potential release of nanomaterials from a device should be determined. Please discuss when it is necessary or appropriate to collect information on degradation, metabolism, absorption, distribution, and excretion of released or free nanomaterials for a device which incorporates nanotechnology. Please also discuss whether there are unique testing considerations that would apply to collection of this information for devices with nanotechnology.
- Please discuss the use of in vitro testing in clinically relevant cellular/biological models versus standard cell-lines when assessing cyto- and genotoxicity for devices with nanotechnology.
- There are many mechanisms by which genotoxicity may occur and some of these might be triggered by nanomaterials, regardless of whether the nanomaterials remain in the tissue or not. Current genotoxicity testing may not be optimal for detecting genotoxic effects caused by nanomaterials. For example, the production of reactive oxygen species (ROS) seems to be an important endpoint related to DNA damage (DNA strand breaks) and this type of damage may not be optimally detected in standard genotoxicity tests. Please discuss what additional tests (both traditional and non-traditional) might be useful to more optimally assess the genotoxicity of devices which incorporate nanotechnology, and discuss both the benefits and limitations of each test for evaluating nanomaterials or structures.
- Even without the release of nanomaterials, the unique properties of surfaces with nanoscale features can alter the biological response to a device. Please discuss the benefits and limitations of specific standardized and non-standardized biocompatibility tests for the assessment of devices with these surfaces.
- Nanomaterials have been shown to respond differently in different tests which assess the same endpoint. Please discuss whether at least two distinct assays should be used to assess a given biological endpoint, e.g., cytotoxicity.
In an assessment of biocompatibility, the traditional mass-based dosimetric may not be suitable for nanomaterials. More appropriate parameters for dose assessment may include surface area, particle number, and surface reactivity.
- Please discuss whether CDRH should recommend the characterization of nanomaterials that includes size, surface area, surface reactivity, and particle number to define the dose of the nanomaterial incorporated into the final, sterilized device.