Formulation development of novel drug entities may be considered a combination of science and ‘art’. The ‘art’ part being based on the formulator’s ability to apply prior knowledge and experiences from other drug entities with non-similar and similar physicochemical and biologic properties.
Toxicology formulations often require significantly higher dose strengths than clinical formulations. For toxicology studies, in general, drug formulations should be simple. They are usually developed based on the physical and chemical properties of the test article (i.e. drug substance) and specific to the animal species to which it is administered. The formulation needs to ensure accurate dosing, has suitable stability and is homogeneous.
The toxicology formulation may enhance bioavailability and maximize the systemic exposure of the drug in the animal model, even if it requires different excipients or dosage forms than the clinical formulation. This helps ensure that the animal models are exposed to potentially toxic levels, which is important because humans may be more sensitive to certain toxicities.
Non-clinical toxicology studies provide vital safety information that supports the design of clinical trials and the eventual development of a safe and effective drug product for human use. The goal for toxicology formulations should be to maximize exposure to achieve high enough drug concentrations in the animal to elicit potential toxic effects. Additionally, the formulation should be able to deliver a dose proportional to the intended exposure.
Careful consideration of formulation development early in the drug development process can help avoid costly and time-consuming issues later on, such as the need for reformulation during GLP non-clinical studies. Non-clinical dose formulation analysis is crucial in all non-clinical studies that assess drug safety. Also, the chosen vehicle or carrier, if any, should be safe for the animal species and compatible with the drug thereby avoiding interference with study results.
Formulation Development Considerations
Understanding the drug’s physicochemical properties, such as solubility, stability, and permeability is crucial for selecting the appropriate formulation approach. Excipients (inactive ingredients used in the formulation) should be well-tolerated and safe for the test animals. Their potential impact on toxicology study results must be considered, as some excipients can affect drug absorption, distribution, metabolism, and excretion (ADME), or even have their own toxic effects.
The formulation needs to be suitable for the specific animal species used in the study and the intended route of administration (e.g., oral, intravenous, subcutaneous, etc.). The route of administration (e.g., oral, intravenous, subcutaneous) will influence formulation choices. If needed, excipients should be carefully selected for their safety, compatibility with the drug, the animal species, and ability to enhance drug delivery.
The formulation must be stable enough to maintain drug concentration and integrity throughout the study duration. Ensuring the drug is evenly distributed in the formulation, especially for heterogeneous formulations like suspensions, is essential for accurate dosing. The formulation must support the study design, including the required dose levels, frequency, and duration of dosing. Toxicology studies often require delivering significantly higher doses than clinical studies to evaluate the drug’s safety profile at exaggerated exposure levels.
Non-clinical toxicology formulation approaches may include:
- Simple solutions or suspensions for use with drug substances having adequate solubility and stability.
- The use of particle size reduction, i.e. milling or micronization to enhance solubility and potentially increase dissolution rate.
- The use of co-solvents, cyclodextrins, surfactants, or self-emulsifying drug delivery systems depending on the specific properties of the drug substance and the study requirements.
- The use of lipid formulations to enhance bioavailability for compounds with solubility and permeability limitations.
- The use of amorphous dispersions which can enhance the drug substance’s solubility in the presence of a suitable carrier are a possibility for molecules with poor solubility due to their crystalline structure.
- Powder-in-capsule, tablets, etc., may be suitable for certain species dependent on the route of administration and study design.
Analytical Methods
For both toxicology and clinical studies, accurate and reliable analytical methods are crucial for determining drug concentration and stability in the formulation. Monitoring and quantifying impurities in the formulations are necessary for drug safety assessment.
Regulatory and GLP Compliance
Adhering to regulatory guidelines and GLP principles is essential for ensuring the quality and integrity of toxicology studies. Proper documentation of all formulation development and manufacturing steps is crucial.
Toxicology versus Clinical Formulation
Toxicity formulations are primarily designed to evaluate the potential safety and toxicity of a drug candidate, often at much higher doses than intended for clinical use. The goal is to achieve high systemic exposure to identify the No Observed Adverse Effect Level (NOAEL).
Clinical formulations, on the other hand, are designed to achieve the desired therapeutic effect with minimal side effects. Dosing is typically within the therapeutically relevant range.
Toxicology formulations may use simple or complex excipients to achieve sufficient exposure. Regulatory constraints regarding their safety for human use may be less stringent, particularly for shorter studies. Careful consideration should be given to the safety profile of excipients used in toxicology formulations, especially for longer duration studies that pave the way for human trials. Clinical formulations may have different excipients compared to the toxicology formulations, particularly if aggressive formulations were used to maximize exposure in animal models Excipients in clinical formulations must be safe for human use, and precedented excipients (e.g. FDA Excipient Database) are preferred over novel ones that would require extensive safety evaluations.
Toxicity formulations focus heavily on enhancing bioavailability and achieving the maximum feasible dose to maximize systemic exposure in animal models. While bioavailability is important for clinical formulations, the focus is on achieving the desired therapeutic effect and minimizing adverse effects within the intended dosage range.
Toxicity formulations may have less complex manufacturing requirements, especially for shorter studies. Clinical formulations usually require greater consideration for long-term stability and scalable manufacturing processes to ensure consistent quality and shelf life.
The choice of animal models and associated formulations needs to align with the proposed clinical dose route and the drug’s target. For instance, certain animal species might require modifications to accommodate higher administration volumes.
The route of administration can be varied to achieve sufficient exposure for safety assessment. For example, oral formulations in preclinical studies may be simple solutions, whereas clinical oral formulations are typically tablets or capsules.
The route of administration for a clinical formulation is generally determined by the physical and chemical properties of the drug substance and its intended use along with patient convenience. For parenteral and topical formulations, toxicology studies should ideally use formulations closely resembling the intended clinical formulation.
Table 1: Toxicology versus Clinical Formulation Comparison
| Toxicology Formulation | Clinical Formulation | |
| Primary Goal | Assess safety and toxicity at high doses | Achieve therapeutic effect with minimal side effects |
| Dosing | High doses, maximizing exposure | Therapeutically relevant doses |
| Excipients | May include less common excipients to enhance exposure | Excipients must be safe for human use |
| Exposure | Focus on achieving high systemic exposure | Focus on achieving the desired therapeutic effect and minimizing adverse effects |
| Manufacturing | Can be less complex, especially for shorter studies | Requires scalable manufacturing for long-term stability and quality |
| Route of Administration | Can vary to achieve high exposure | Determined by intended use and patient convenience |
In summary, the design of toxicology formulations is driven by the need to achieve high systemic exposure to assess safety, which may necessitate different approaches than the clinical formulation intended for human use. The decision to modify the toxicology formulation to maximize exposure must be balanced against the need for translatability to the clinical setting.
References
ICH Q3A (R2): Impurities in New Drug Substances, October 2006
ICH Q3B (R2): Impurities in New Drug Products, June 2006
ICH Q3C: Impurities: Guidelines for Residual Solvents, April 2021
ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, July2023
ICH Q8(R2): Pharmaceutical Development, August 2009
FDA Guidance for Industry: ANDAs: Impurities in Drug Products, November 2010
FDA Guidance for Industry: CGMPS for Phase 1 Investigational Drugs, July 2008
FDA Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well Characterized, Therapeutic, Biotechnology-derived Products, November 1995
FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information , May 2003
US Code of Federal Regulations, Title 21, Subpart F – Test and Control Articles, Part 58.105- Test and Control Article Characterization, Part 58.107 – Test and Control Article Handling, Part 58.113 Mixtures of Articles with Carriers