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Why you don’t need a GMP-compound to start your first-in-human study

Maarten Brom, PhD

Often a GLP-compound is enough to start your first-in-human clinical trial. This is in sheer contrast with classical Phase 1 studies that require large amounts of a clinical grade quality compound.

To obtain a clinical grade compound for your trial you need to manufacture the compound in a facility that complies with Good Manufacturing Practices (GMP). This is a lengthy and costly procedure. As many potential compounds fail after Phase 2 or 3 trials, the manufacturing of your compound in GMP grade in early trials could very well be a loss of time and resources. By labeling your compound for a microdosing Proof-of-Concept (PoC) clinical trial you can avoid the manufacturing of GMP-grade material in many cases.

Label your compound in a GMP facility.

To produce a radiolabeled compound (a tracer) for clinical use, you label your compound in a GMP facility for radiolabeling. This is also referred to as a hot lab. The manufacturing of the radiotracer is thus GMP-compliant.

You can produce your compound, that will be used for radiolabeling, as a precursor. The precursor does not need to be fully GMP compliant. Instead it is often sufficient to produce your compound under controlled circumstances under Good Laboratory Practice (GLP).

When you then label your precursor with a radionuclide in a hotlab under GMP, the resulting radiotracer is considered “GMP-grade”. This means it can be used for first-in-human studies. However, it is good to realize that the non-GMP grade precursor cannot be used on its own (without labeling) for clinical use. Sometimes, the use of a non-GMP precursor requires additional quality control or analysis in the GMP manufacturing procedure to verify the purity and identity of the precursor.

Toxicity studies for microdosing Proof-of-Concept studies.

Often before you use your compound in a first-in-human trial you need to perform a toxicity study. When you perform a clinical trial with the microdosing principle you only need limited toxicity data. In most cases a single dose extended toxicity study is sufficient. This is a toxicity study with a single administration of the compound in a limited number of animals. You only need to perform the toxicity study in one species. Rats and mice are the most used species and large animals are not needed.

For proteins and peptides, a toxicity study with the precursor can be performed. The compounds do not have to be labeled. For smaller molecules labeling can have a large effect on the chemical and pharmacological properties of the molecule. Therefore, it is important to perform the toxicity studies with the labeled compound. For this, you can use a non-radioactive isotope for the labeling to avoid radiation safety issues. You can also perform toxicity studies with labeled large molecules, but this is not common.

Benefits of microdosing studies with a GLP compound.

The main benefit is that you do not necessarily need a GMP-grade product of your compound for a microdosing first-in-human study with a radiolabeled compound. As a result, this saves valuable time and resources in the first stage of clinical development. Also, the limited amount of compound that needs to be produced for the clinical trial and toxicity studies is much lower compared to classical Phase 1 and 2 trials. Lastly, the single dose extended toxicity study requires less time and is cheaper than a full toxicity study. Usually, 10% of the costs of a full toxicity study. So, in general microdosing studies are a more time and cost-efficient option for the development of your compound.

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