Biocompatibility sampling requirements

Similarly, an experienced CRO may ask questions such as the quantities of sample that the manufacturer should provide and the deadline for the test results before they are needed to file the subnfission. The required amount of samples will depend on the nature of the material or device in conformance to the relevant regulations, on which the CRO will normally advise. The guidelines for biocompatibility testing usually have strict requirements on test samples, to which the medical device manufacturer should adhere. Alteration of the sample requirements should be approved by the regulators, and the manufacturer is usually required to present justifications for doing so. 

For several reasons, most applications of chemo- and biosensors require flow through devices, for example in allowing analysis of samples from multiple sources, removing flow sensitivities, avoiding sterilization and biocompatibility problems, enabling recalibration or performing bioanalytical assays. 

In this type of bioreactor, there is a compartment where cells remain attached to a surface or immobilized on or inside a biocompatible bed. Culture medium has to be pumped through this compartment for cells to have access to nutrients and dissolved oxygen. The main disadvantages of these bioreactors, developed for the cultivation of adherent cells that require a surface for proliferation, are the impossibility of obtaining homogeneous samples of the cell population and the limitations of scale-up. 

Magnetic biomaterials have different constraints than materials used for other applications. In vivo (in the body) applications require strict biocompatibility. In vitro (outside of the body) applications have less strict requirements, but techniques involving living cells still must consider the effect of the materials on the sample under study. In addition to biocompatibility, materials must be capable of being functionalized with one or more molecules, must retain their magnetic properties for a reasonable period of time in aqueous media with varying pH, must not be cleared too quickly from the bloodstream, and must form stable, non-aggregating dispersions [12, 13]. 

Many manufacturers can provide biocompatibility data either in their literature or as an FDA Master File. Often material manufacturers will advertise that a material meets class IV biocompatibility requirements. Class VI requirements are an old set of tests published in the U.S. Pharmacopeia that were developed for testing food packaging. They are similar to the cytotoxicity, acute toxicity, and subchronic toxicity tests. However, the data provided by a materials manufacturer are on samples that have not seen the processing and storage of the device. The data simply are an indication that the material can pass the initial set of biocompatibility tests if processed appropriately. 

Biodistribution and safety assessment during preclinical development requires both in vitro and in vivo studies. Biocompatibility of nanoparticles can be determined by in vitro cytotoxicity testing on cell lines. In vitro studies also facilitate the revelation of biochemical mechanisms under controlled conditions not achievable by in vivo studies. The rationale underlying the selection of in vitro assays to provide meaningful efficacy and safety data on nanoparticle is detailed in the literature. However, it is in vivo biodistribution and toxicity studies that determine safety for clinical trials, and all preclinical characterization studies must necessarily include in vivo determination of a nanoparticles biodistribution and toxicity in animal tests. FDA provides detailed guidelines for biodistribution and safety assessment of drug formulations in vivo using animal models and specific consideration for nanoparticle samples are reviewed elsewhere. ... 

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