Drug Product Formulation & Process Development: The Must-Have Skills At A Glance

By Michelle Gischewski, KM Consulting-Pharma Intelligence

Drug product formulation and process development is an important and sometimes understated part of the development cycle of a new drug. Specialists in this area are known to 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 alignment with the specific needs of each phase of the development program requires a balance of scientific skills and multidisciplinary know-how.

As many reports indicate, biopharma investors have become more selective after the pandemic era, which naturally steered biotech companies to look for more efficient ways to execute their drug development plan. Drug product formulation and process development, when executed by the right group of professionals, can help mitigate risks and improve efficiency throughout the various stages of the drug life cycle. This article summarizes, at a high level, some important considerations in the drug product formulation and process development of a new chemical entity and aims to serve as a guide to small biopharma companies in identifying desired qualities to look for when hiring a drug product development professional for their team.

Inception Phase: Broad Scientific Knowledge and Multidisciplinary Skills

Investments are recently being directed to AI-driven technologies, precision oncology, and cell & gene therapies as well as target-centered small molecules. Whether the new chemical entity is a replacement gene carried by a vector, a monoclonal antibody, a living cell, or a small molecule, the following skills should be mastered by a drug product development professional during the very early phases of the development program:

• Good understanding of the disease pathway and the selected target for the proposed therapy. A skilled professional in drug product formulation and process development should be able to understand the main goals of the proposed therapy.
• Good general understanding of the molecular basis of pharmacology and drug delivery technologies. This general knowledge, associated with the ability to interact in a multidisciplinary way with the key stakeholders, opens the communication regarding potential routes of administration and dosage forms for the therapeutic. Sometimes, this is just a simple step with limited options to choose from, whereas sometimes there may be several options available. This is a multidisciplinary phase in which the drug product development professional can play an important role.
• Deep and up to date understanding of raw materials, processing equipment, and packaging materials for drug product use. Think of it like a chef who must have an understanding of food ingredients, cooking skills, and utensils to put together a successful dish. 

Pre-Clinical And Clinical Phases: Important Considerations

The experts in drug product formulation and process development should work collaboratively with the drug substance, preclinical, and clinical teams from the early phases of drug substance synthesis through all the various phases of preclinical and clinical trials. The knowledge around materials to be used to compose the most appropriate drug product formulation for a specific phase of the program should be combined with the understanding of the drug substance, the challenges to be overcome to enable the drug entity to reach its target, as well as the key objectives and timeline goals of each phase of the program. Below are some examples of questions that an experienced and well-versed drug product development expert should pose in different phases of the development program.

Drug Substance Synthesis

• What are the main characteristics of the drug substance that can affect the performance of the intended drug product?
• How are the characteristics monitored and how do we understand the impact of the critical drug substance attributes in the drug product performance in each phase of the program?
• Which characteristics need to be defined and “locked” for the specific development phase and which characteristics can be defined later?

Being able to understand these questions allows for a fruitful collaboration between the drug substance and the drug product teams. A pragmatic approach in this phase can significantly increase the efficiency of the development program, where key points are emphasized and secondary points to be tracked, monitored, and concluded are left to subsequent phases of the program. The understanding of the drug substance salt forms, co-crystals, and polymorph space is a good example of characteristics that need to be discussed amongst the key multidisciplinary teams to define what needs to be fully understood and “locked” at each phase of the program.

Preclinical Phases

• What is the main goal of each specific phase and what are the main characteristics of the drug product that need to be achieved to allow for a successful study?

Formulation and processes designed for in vitro trials may differ from trial to trial and from the ones designed for the in vivo phase. The experts in drug product should understand the study design, the in vitro and/or in vivo model used for the study, and the limitations regarding 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 trials, it is very common to modulate the formulation and process to maximize the exposure of the API in vivo. Often, the formulation used for animal studies is not the same as the one that will be used for human clinical trials. It’s common to see liquid dosage forms being developed for certain animal studies (involving rodents, for example), due to animal limitation and compatibility, whereas for other animal studies, involving bigger animals, a solid oral dosage form such as a tablet or capsule are normally desired. However, the drug product experts should always keep in mind the translational capabilities of the formulation and process along the various phases of the drug development to facilitate any necessary bridging equivalence study between phases.

Clinical Phases

• What are the findings of the preclinical phases and how do they contribute to defining the formulation and process for the first-in-human clinical study?
• What are the timelines involved?
• What are the target populations?
• What are the dose strengths to be used in each phase of the program?

The drug product experts understand that the formulation and process proposed for each phase may still differ. It’s common to see extemporaneous oral liquid dosage forms (solutions, suspensions, powder for reconstitution) being developed to support Phase 1 clinical trials, while subsequent Phase 2 trials are supported by oral solid dosage forms like tablets or capsules. The knowledge of material science, delivery technology, scale-up, and technology transfer needs to be blended with the knowledge acquired around the drug substance and the development program in a pragmatic approach that favors the achievement of the milestones inside the proposed timelines.

Late Phases: Important Considerations

As the development program moves toward its late phases, the drug product experts should be able to guide the team to the establishment of the final drug product formulation and process that will be used for commercialization, based on the accumulated knowledge acquired throughout the development phases. Although small adjustments post approval are still allowed under the SUPAC (scale-up and post approval changes) guidelines, the final drug product formulation and process are expected to be robust in meeting the characteristics defined in the regulatory quality target product profile (QTPP). In this phase, the drug product development experts should work collaboratively with the process validation team to establish the product critically, monitoring, and control.

In summary, drug product formulation and process development is an important piece of the drug development puzzle. Technical expertise should be combined with multidisciplinary skills and pragmatic approaches aimed at the achievement of the main goals of the development program.

About The Author:

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