Why early CMC–toxicology teamwork pays off

Close collaboration between toxicologists and experts in Chemistry, Manufacturing and Controls (CMC) can make a significant difference long before the first toxicology studies begin.

CMC experts provide a deep understanding of the substance’s quality, specifications, analytical methods, stability, manufacturing, and potential formulations. Toxicologists bring expertise in species selection, tolerability, regulatory expectations, and what is needed for a toxicology study to be meaningful. When these perspectives come together early, decisions improve, risks become clearer, and the development path becomes more efficient.

Here we look at the benefits of collaboration on material supply, formulation, and study design, factors that together help generate data that are relevant, interpretable, and useful for further development.

Getting the basics right: how much material is needed?

An early practical question is how much material should be manufactured for toxicology studies.

In addition to proposing a toxicological programme and study design that are aligned with the overall development plan, ethical considerations and regulatory requirements, the toxicologist may also recommend dividing the toxicological programme into relevant study packages. Such an approach will reduce the need for large upfront material investments and spread the costs over time, which gives teams the flexibility to adapt as new data comes in. It helps prevent costly waste if a drug candidate runs into issues that need to be solved before moving forward, or discontinue, the development program altogether. Taking such a stepwise approach could make a difference both for the budget and the success of the program.

Based on the type of studies included in the toxicology packages, toxicologists also estimate the required amount of substance based on study design, dose levels and dosing volumes, while taking into account foreseeable additional material needs. Additional material is required to compensate for unpreventable losses during formulation and administration, including losses during weighing, mixing, homogenisation, aliquoting and residual volumes left in containers and dosing equipment. Since it is not possible to recover 100% of the formulation, preparing only the exact calculated dose volume introduces a risk of material shortages and inaccurate dosing (e.g. drawing air instead of formulation for liquid formulations), particularly towards the end of dosing. Therefore, an overage of test substance is routinely included to ensure reliable dosing and study continuity.

Another important part included in the toxicology programme is development of the dose formulation. Here, the CMC expert can assess how much material is needed for formulation development, stability studies and development of analytical methods. Experience from multiple development programs will improve the accuracy in the estimations, and eventually you should not be surprised if the material need is twice the theoretical calculation based on the dosing schedule.

In practice, this means that more material than the theoretical minimum is always required; the key challenge is not whether to include an overage, but to define how much is sufficient to ensure robust study execution without unnecessary overproduction.

Choosing the appropriate vehicle and excipients

Another area where CMC and toxicology benefit from close collaboration, is the selection of vehicle and excipients.

CMC experts will propose technically feasible solutions to improve solubility, stability, or dosing flexibility. Toxicologists, however, assess whether these solutions are tolerable in the relevant animal species and at the intended dose levels.

Certain vehicles or excipients can affect the animals, limit achievable dose levels, or complicate interpretation of results. A formulation that works well from a pharmaceutical or chemical perspective is therefore not always optimal for a toxicity study.

Cyclodextrins are a typical example: they can be highly useful for increasing solubility of poorly soluble compounds, but they require careful consideration in terms of tolerability, dose levels, and, seen from a sponsor perspective, cost.

Development strategies and decisions are stronger with teamwork

At LINK Medical, we have seen that the best outcomes are achieved when toxicologists and CMC experts work together to define what the material and formulation need to demonstrate in order to support robust and reliable toxicology studies.

Early collaboration between CMC and toxicology helps the project teams make better decisions from the outset. By aligning material needs, formulation strategy, and study design at an early stage, development programmes can reduce waste, avoid unnecessary costs, and generate data that are more relevant for the next steps. In this context, material supply and formulation become more than a technical solution, they become an integral part of the overall development strategy.

In the next article, we turn to quality and impurities, and why early alignment on these questions is essential for regulatory confidence, development strategy, and patient safety.

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