Why quality and impurities need early CMC–toxicology alignment

When CMC (Chemistry, Manufacturing and Controls) and toxicology collaborate early, drug development becomes smoother, smarter, and less likely to run into late-stage surprises. Here we will look at the benefits of collaboration on quality and impurities – areas that are crucial for the drug development programme, regulatory confidence and patient safety.

CMC experts define quality requirements in line with regulatory expectations for manufacturing and control of the drug substance and the drug product, covering parameters such as purity, impurity profiles, limits for known and unknown impurities, analytical methods, and stability.

For each nonclinical study including toxicology studies, clear information is needed about the specific batch used including its impurity profile and the purity basis used for dose calculations. This information is typically documented in a Certificate of Analysis (CoA), which summarises the analytical results for a specific batch.

A CoA may contain parameters that appear similar at first glance, but which answer different questions:

• Assay indicates the amount of intended active substance and is often critical for dose calculations.
• Purity describes the presence of other components, such as related impurities or degradation products, and is essential for understanding what the test system is exposed to beyond the main compound.
• Potency is particularly relevant for biological products, vaccines, or enzymes, where it is not enough to know how much material is present – the biological activity also needs to be understood.

Impurities: A shared responsibility

Purity and impurity profiles should be addressed jointly.

One might think that “the cleaner the batch the better”. In the toxicology studies, however, this is not always the case. If the clinical material later contains impurities that were not present in the toxicology batch, the use of an overly “clean” material may raise regulatory concerns during the Clinical Trial application, as patients could be exposed to components that have not been toxicologically qualified.

With this in mind, selecting a less pure test material for toxicology studies should be a deliberate and well-justified decision rather than a coincidence, as high impurity levels can create challenges of their own. Potentially genotoxic impurities, acceptable limits, and specifications should therefore be discussed early between CMC, toxicology, and manufacturing teams.

A more efficient and robust development strategy

At LINK Medical, we repeatedly see the value of bringing together toxicology and CMC expertise early in development programs.

When questions related to material, formulation, impurities, dosing, and regulatory strategy are addressed jointly, the risk of late-stage surprises and unnecessary detours is reduced. The result is more robust toxicology studies, better-informed decision-making, and a smoother path toward clinical development.

In short, close collaboration between CMC and toxicology on quality and impurities helps make the drug development become not only more efficient, but also better positioned to support regulatory confidence.

Keep your eyes open for upcoming discussions regarding dose selection and how it is related to the drug´s toxicology, pharmacokinetics (PK) and pharmacodynamics (PD).

Anita Annas, Principal Consultant Toxicology
Ulrika Bergströ, Senior Consultant Toxicology
Bengt Hedin, Principal Consultant Pharmaceutical Development