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First-in-Human Drug Substance and Formulation: The Challenge of Achieving Flexibility and Quality

For nonclinical studies that precede Phase I, a drug formulation in high doses and concentrations is required. While entering Phase I, high flexibility is needed, often covering a wide dose range. In addition, the quality and stability of the drug formulation should be adequate for the purpose.

  • Are there differences in what level of quality is expected for the active drug substance in each phase?
  • What are the requirements of the drug formulation for non-clinical studies and Phase I studies?
  • Do you need a placebo corresponding to the active drug product?

Let’s look at how to handle some of these questions.

Formulating a drug substance for nonclinical toxicology studies

Before a drug can reach a Phase I trial in humans, nonclinical studies (i.e., toxicological studies) are needed to ensure a certain level of safety. The drug substance should be adequately developed and characterized, and the drug formulations (suitable for selected animal species and administration routes) must be developed in the required doses or concentrations.

The drug formulation used in the Good Laboratory Practice (GLP) toxicology study should, if possible, be similar to the formulation intended to be used in the clinic trial, and it should be administered by the same administration route but at a higher dose than will be given to human subjects.

An important objective in achieving the maximum pharmacological efficacy of a new drug is to optimize the physicochemical properties of the drug substance and the formulations to ensure sufficient exposure in clinical studies. Comprehensive pre-formulation data — i.e., understanding the drug molecule’s physical characteristics, solid state stability, solubility, and solution stability across the biological pH range, and permeability through biological barriers — is essential during formulation development.


Drug formulations for Phase I clinical trials: Quality for the purpose and the importance of stability

Phase I clinical trials primarily aim to determine the investigational product’s safety, tolerability, and pharmacokinetics (PK). When entering Phase I, high flexibility is often needed to cover a wide dose range. The studies are performed starting at a very low dose. Then, the dose is escalated until the maximum dose is attained as per protocol unless a predefined maximum exposure is reached, or unacceptable side effects appear.

The drug formulation used for Phase I does not have to be the final drug product intended for market. However, it must have the properties and the stability to ensure the required drug exposure and limited amount of potential pharmacologically active impurities. In addition, it must be manufactured according to Good Manufacturing Practice (GMP).

The practical work to develop and finally manufacture the Investigational Medical Product (IMP) according to GMP is usually done by a Contract Development and Manufacturing Organization (CDMO).

Stability data covering the entire Phase I study length needs to be generated. This means that supportive technical stability studies are required to evaluate and estimate the stability of the potential drug formulations developed. The final drug formulation for Phase I should not only be chemically stable with respect to assay of active drug substance during storage, but also stable when it comes to, e.g., appearance, texture (for topical or viscous formulations), and microbiological quality. Ideally, the storage condition of the drug formulation is room temperature, but often solutions or suspensions used in the early phase require cold or frozen storage, and the effect of storage conditions on physical attributes of the drug formulations, such as re-suspendability for suspensions, must then be considered.

Practical considerations to obtain flexibility

To achieve flexibility in dosing and overcome stability issues, sometimes it is beneficial to manufacture a stock formulation or preparation that may be finally prepared — diluted, thawed, or mixed with additional excipients at the clinic in close connection to administration to the patient. The stock formulation may be in the form of a bulk powder, powder in bottle, a concentrated solution, or others. However, this requires in-use stability studies to show that the final formulation is stable from preparation until administered to the patient.

Is a placebo required?

It is often recommended to include a placebo in first-in-human studies. The development work to obtain a suitable placebo should not be underestimated; masking the taste, smell, or visual appearance of the active drug substance can sometimes be very challenging and must be handled with care to not de-blind the study.


Interested in learning more? Bengt recently presented “The Road to First-in-Human Trials: Insights from a Real-World Example.” Click below to watch the webinar:


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