Drug formulation and process development: The most important skills at a glance

By Michelle Gischewski, KM Consulting-Pharma Intelligence

Drug formulation and process development is an important and sometimes underestimated part of the development cycle of a new drug. Specialists in this field master multidisciplinary skills that include, but are not limited to: organic chemistry, analytical development, solid state characterization, pharmaceutical excipients, manufacturing processes, scale-up, technology transfer and continuous improvement. However, the use of scientific skills in accordance with the specific requirements of each phase of the development program requires a balance between scientific skills and multidisciplinary expertise.

As many reports show, biopharma investors have become more selective after the pandemic, which naturally led biotech companies to look for more efficient ways to execute their drug development plan. Drug formulation and process development, when performed by the right group of professionals, can help mitigate risks and improve efficiency at the various stages of the drug lifecycle. This article summarizes at a high level some key considerations in drug formulation and process development of a new chemical entity and is intended to serve as a guide for small biopharma companies to identify the desired qualities they should look for when hiring a drug development professional for their team.

Initial phase: Broad scientific knowledge and interdisciplinary skills

Investments have recently been pouring into AI-driven technologies, precision oncology, cell and gene therapies, and targeted small molecules. Whether the new chemical entity is a vector-borne replacement gene, a monoclonal antibody, a living cell, or a small molecule, a drug development professional should master the following skills in the very early stages of the development program:

• Good understanding of the disease process and the selected target for the proposed therapy. An experienced drug formulation and process development professional should be able to understand the key targets of the proposed therapy.
• Good general understanding of the molecular basis of pharmacology and drug delivery technologies. This general knowledge, coupled with the ability to interact with key stakeholders in a multidisciplinary manner, opens up communication about potential routes of administration and dosage forms for the therapeutic. Sometimes this is just a simple step with limited choices, while other times multiple options are available. This is a multidisciplinary phase where the drug development professional can play an important role.
• Comprehensive and up-to-date knowledge of raw materials, processing equipment and packaging materials for the use of medicines. Think of it like a chef who needs to know about food ingredients, cooking skills and utensils to prepare a successful dish.

Preclinical and clinical phases: important considerations

Drug formulation and process development experts should work with the drug substance, preclinical and clinical teams from the early stages of drug synthesis through all the various phases of preclinical and clinical trials. Knowledge of the materials to be used to assemble the most appropriate drug formulation for a particular phase of the program should be combined with an understanding of the drug substance, the challenges to be overcome for the drug to achieve its goal, and the key objectives and timelines of each phase of the program. Below are some examples of questions that an experienced and accomplished drug development expert should ask at various stages of the development program.

Active ingredient synthesis

• What are the main properties of the drug substance that can affect the performance of the intended drug?
• How are the properties monitored and how do we understand the impact of the critical drug substance attributes on the drug product’s performance at each stage of the program?
• Which features need to be defined and “fixed” for each development phase and which features can be defined later?

Understanding these questions enables fruitful collaboration between the API and drug product teams. A pragmatic approach at this stage can greatly increase the efficiency of the development program by highlighting key points and leaving secondary points that need to be tracked, monitored and completed to subsequent phases of the program. Understanding the API's salt forms, co-crystals and polymorphic space is a good example of features that need to be discussed in key multidisciplinary teams to define what needs to be fully understood and “locked in” at each stage of the program.

Preclinical phases

• What is the main objective of each specific phase and what are the main properties of the drug that need to be achieved for the study to be successful?

Formulations and processes for in vitro studies may vary from study to study and from those for the in vivo phase. Drug product experts should understand the study design, the in vitro and/or in vivo model used for the study, and the limitations on the use of some excipients in each specific study, and be able to propose a phase-appropriate formulation and process for each phase. During preclinical studies, it is very common to modulate the formulation and process to maximize in vivo exposure of the API. Often, the formulation used for animal studies is not the same as that used for human clinical trials. It is common for liquid dosage forms to be developed for certain animal studies (e.g., with rodents) due to animal limitations and tolerance, while for other animal studies with larger animals, a solid oral dosage form such as a tablet or capsule is usually desired. However, drug product experts should always keep in mind the translational capabilities of the formulation and process at different stages of drug development to facilitate any necessary bridging equivalence studies between phases.

Clinical phases

• What are the results of the preclinical phases and how do they contribute to defining the formulation and process for the first-in-human clinical trial?
• What timelines are involved?
• Who are the target groups?
• What dosage strengths should be used in each phase of the program?

The drug experts are aware that the formulation and process proposed for each phase may still be different. It is common that ad-hoc liquid dosage forms (solutions, suspensions, powders for reconstitution) are developed to support Phase 1 clinical trials, while subsequent Phase 2 trials are supported by oral solid dosage forms such as tablets or capsules. The knowledge of materials science, delivery technology, scale-up and technology transfer must be combined with the acquired knowledge of the drug substance and the development program in a pragmatic approach that favors the achievement of the milestones within the proposed timelines.

Late Stages: Important Considerations

As the development program approaches its later stages, drug development experts should be able to assist the team in determining the final drug formulation and process that will be used for commercialization, based on the knowledge acquired during the development phases. Although small post-approval adjustments are still permitted under the SUPAC (Scale-up and Post-Approval Changes) guidelines, the final drug formulation and process are expected to robustly meet the characteristics defined in the regulatory Quality Target Product Profile (QTPP). During this phase, drug development experts should work with the process validation team to critically establish, monitor and control the product.

In summary, drug formulation and process development are an important part of the drug development puzzle. Technical expertise should be combined with multidisciplinary skills and pragmatic approaches to achieve the key objectives of the development program.

About the author:

Michelle Gischewski is the founder and principal consultant of KM Consulting-Pharma Intelligence LLC. She is a pharmacist with over 20 years of experience, trained in Brazil and Canada. Her career has been dedicated to addressing the challenges and nuances of formulation and process development, from strategic proof-of-concept projects in late-stage discovery, to scaling and optimization in clinical trials, to continuous improvement post-commercialization. Gischewski has led scientific teams in large organizations such as Eurofins CDMO, Apotex, and Teva. She helps clients navigate the complexities of drug development by combining scientific rigor with practical approaches.