One of the cornerstones of biocompatibility evaluations is the use of toxicological risk assessment to screen for potential hazards and safeguard against long-onset risks like cancer. While there is an abundance of toxicological literature available, and the techniques of toxicological risk assessment are generally accepted, the process for conducting the underlying chemistry studies is less mature. FDA has been building finesse in reviewing chemistry studies, helping the testing facilities to be more aware of the nuances in chemistry. New internal awareness and recent reports with poorly conducted studies used for regulatory submissions have raised anxiety regarding the extent of use of chemistry for toxicology (“ChemTox”) within the agency over the last year and motivated changes in expectations.
A key change in ChemTox is the amount and type of information expected for submission. Regulators are asking for details regarding the methods used in identification of compounds and providing suggestions on when a compound should be considered an unknown. Part of this scrutiny is arising due to recent publications that focus on the shortcomings of external databases and automatic compound matching algorithms. Another focus is on detailed information regarding the type and quality of concentration quantification. FDA has been asking for details regarding the number and type of internal standards used and how this extrapolates to uncertainty in the concentration. Scrutiny of identification and quantification, while justified, has proven to produce challenges for labs that have built ChemTox programs over several years absent of 3rd-party questioning. Many of FDA’s new requests regarding chemistry, like its preference of liquid chromatography/mass spectrometry (LC/MS) ionization modality, are easily achievable. However, other requests may present serious challenges that for some device categories are preventing chemistry from being useful at all.
One of the biggest pain points is related to the specific identification and quantification standards. For plastic devices, or devices that are derived from biological materials, there are often hundreds of compounds detected above a threshold of toxicological concern. Each of these compounds must be identified, and even with expert review and the use of multiple internal and external databases, a confirmed identification isn’t possible for all compounds. Therefore, if a hard line is drawn regarding the tolerable amount of uncertainty in identification, some compounds will be considered unknowns and therefore not assessable. Even a single compound that is not assessable leaves risks like chronic toxicity and carcinogenicity unevaluated. In these situations, passing some limited biological testing like genotoxicity can help by raising the acceptable threshold of toxicological concern. To cope with the reality of some uncertainty in identifications, it is important to set expectations appropriately with regulators and toxicologists. It should, however, be recognized that ChemTox can provide actionable information, much more detailed and sensitive than biological testing, even if some limitations are acknowledged.
Specific FDA feedback regarding expectations for ChemTox will be discussed during the upcoming MD&M West 2020 presentation, "Chemistry for Toxicological Risk Assessment – Transitions in Expected Approach," held during the day-long Feb. 12 sponsored session, "Medical Device Validation – Biocompatibility Testing, Cleaning, Sterilization and Packaging." (The session is free to all expo badge holders.) Attendees planning out or currently executing their biocompatibility studies should consider FDA’s position on study details so that they can avoid surprises when starting discussions with them regarding submissions.