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Don’t fail your Phase 1 study because of formulation

In this article, we discuss formulation considerations when preparing for Phase 1 studies. Regardless of whether you are working on an amorphous formulation, a lipid-based formulation, or an oral tablet, the in vivo performance of the formulation should not influence the study’s results.

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Don’t fail your Phase 1 study because of formulation

The narrative ‘it’s better to fail your Phase 1 study fast’ has been around for decades. Indeed, the success rate for clinical drug development[1] can seem discouraging. However, despite all the pressures on development teams to get to the clinic quickly with a material and resource sparing approach for drug product, there is no reason why poor formulation performance in vivo should ever be factor in determining the outcome from the study.

Amorphous materials

If you are developing an oral product and planning for a Phase 1 study with a solid oral dosage form, there are several factors which may contribute to the success of the study. First, the physicochemical properties of the compound and the selection of the solid form can be critical for bioavailability. Over the last few decades with increasing number of poorly soluble lipophilic compounds moving through company pipelines, the interest in employing technologies to enable the formulation and delivery of amorphous materials has increased. This approach can provide a significant solubility enhancement but also poses the risk of precipitation. Hence, sufficient understanding of dissolution, solubility/supersaturation and precipitation kinetics is necessary. The differences between in vitro testing conditions and the physiological environment also should not be underestimated, as the dynamic environment in the gastrointestinal tract may lead to a very different outcome compared to a standard dissolution test. As a part of a drug product performance risk assessment for an enabled amorphous formulation, phenomena which are relevant for bioperformance such as supersaturation, formation of liquid-liquid phase separated nanodroplets, precipitation, re-crystallisation and re-dissolution should all be thoroughly evaluated to gain an understanding of the formulations.

Lipid-based formulations

In addition, if species other than API monomers are formed in the media following drug product dissolution, it is important to characterise these species and to assess any potential impact on absorption. For example, lipid-based formulations are often used to enhance dissolution rate and address solubility limitations, however, the digestion of these formulations in the gastrointestinal tract can be key to their performance. Bile salt mediated solubilisation is also critical for many poorly soluble molecules but biological variability and the impact of micellar solubilisation on permeability across the gut wall need to be considered. The design of any bioenhanced phase 1 formulation needs to be based on a thorough understanding of compound and drug product properties, and the appropriateness of a dissolution test method which accounts for the critical performance attributes and their interplay with relevant physiological parameters in the gastrointestinal tract.

Critical dissolution attributes

Even for relatively simple drug products, such as tablets of soluble compounds, mishaps are possible ranging from particle size related dissolution rate issues, interactions of the API with excipients during dissolution process to impaired disintegration of the drug product. These scenarios can lead to lower-than-expected exposures in study participants and high variability. To mitigate these risks, they first must be recognized through a biopharmaceutical risk assessment which enables identification of critical dissolution attributes. Once the critical dissolution attributes are understood, they can be used to inform dissolution workflow and the design of experiments. Through a combination of results from in vitro studies including biorelevant dissolution tests with modelling approaches it is possible to identify formulation related risks ahead of Phase 1 studies and develop a formulation designed for robust performance in study volunteers and patients.

Please see The Biowaived Process – Biowaived – Biopharmaceutics Experts to learn about our approach to reducing performance risks during drug product development.

[1]Why 90% of clinical drug development fails and how to improve it? – ScienceDirect

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Aaron brings a solid foundation of analytical expertise from academia and industry to his position at Biowaived.

He earned his master’s degree in biotechnology from the University of Kent in 2016. His professional career began at Eurofins Lancaster Laboratories, where he was responsible for assessing solid dosage form characteristics in support of formulation development.

Aaron later joined Pfizer Analytical Research and Development in Sandwich where he specialised in dissolution design and analytical method development. He had leading roles in implementing initiatives to enhance operational efficiency to reduce overall work-in-progress during formulation development and in supporting project teams with regulatory filings. In this role, he gained valuable experience of in vitro drug product performance in relation to pharmaceutical quality.

As Chief Compliance Officer, Aaron is dedicated to positioning Biowaived as a trustworthy entity in its field, ensuring that the organization not only meets regulatory standards but also builds a reputation for integrity and reliability in its operations.

Mike is set to become the Chief Technology Officer at Biowaived. He holds a degree in Chemical and Pharmaceutical Sciences from the University of Sunderland and is an RSC Chartered Chemist, bringing with him 28 years of experience from GSK and Pfizer, where he developed a keen interest in advanced analytical technologies.

During his early career, Mike spent 14 years in Research Formulation at Pfizer, where he not only assisted with pre-formulation and physicochemical profiling activities, but also led the execution of multiple fully integrated automation projects, encompassing kinetic, thermodynamic, and BCS solubility as well as Caco-2 absorption screens.

He subsequently joined Drug Product Design at Pfizer where he spent several years leading cross functional teams during the late-stage development of two novel parenteral projects.

Over the past decade, Mike has dedicated himself to the field of Materials Science at Pfizer, displaying an elevated level of technical expertise and a strong analytical approach to problem solving. This combination has empowered him to effectively lead multidisciplinary teams, both within the organisation and externally, in the investigation of intrinsic and extrinsic particulates identified during drug product development.

Kieran brings over a decade of experience in pharmaceutical analysis to his role as Chief Operating Officer at Biowaived.

He holds a Master’s degree in Chemistry from the University of Surrey and began his career at the British Pharmacopeia Commission Laboratory, where he developed his analytical skillset, testing a vast array of products and developing pharmaceutical monographs.

Following this, Kieran joined Pfizer and gained considerable experience in pharmaceutical development from early product design stages through to regulatory submission. Through a focused commitment to studying dissolution, he developed a deep understanding of drug product performance and the importance of dissolution testing; not only to ensure the quality of medicines but also to predict in vivo performance.

Kieran advocates for continuous improvement and adaptability, believing that focus on mentorship, collaboration and productivity can create a dynamic and responsive work environment. He enjoys new challenges and implementing strategies to streamline processes.

Inese joins Biowaived as the Chief Executive Officer, bringing with her experience from both academic and industrial settings.

During her Master’s and PhD studies in physical chemistry at the University of Latvia, she developed a strong fascination with molecular processes. This foundation has proven helpful in her subsequent work within the biopharmaceutics field, where understanding the physicochemical properties of drug compounds is crucial for drug product bioperformance.

Over the course of her career in the pharmaceutical industry, Inese has worked on modelling techniques that extract insights from experimental data, thereby facilitating drug product development. While at Pfizer’s Drug Product Development group, she worked on integrating the knowledge of material properties with in vitro study outcomes to forecast the performance of drug products. Inese aims to harness her passion for innovative solutions to position Biowaived as a trusted partner for pharmaceutical companies in need of biopharmaceutical expertise.

Dr Mark McAllister is a Pharmacy graduate from Queen’s University Belfast and has a pharmaceutics PhD from Aston University which focused on liposomal delivery to the lung for the treatment of cystic fibrosis infections. 

Mark has 30 years industrial development experience and has specialised in oral delivery systems and biopharmaceutics through roles with Hoechst-Roussel, GlaxoSmithKline and most recently as a Senior Director and Head of Global Biopharmaceutics, part of the Drug Product Design group at Pfizer in Sandwich, Kent. 

Mark was the Pfizer drug product lead for Lorlatinib, an accelerated small molecule treatment for NSCLC, commercialised as Lorviqua in the EU and Lorbrena in USA/Canada/Japan. He is a former chair of the Academy of Pharmaceutical Sciences and is currently a visiting lecturer at King’s College London. 

Mark co-led the IMI ‘OrBiTo’ biopharmaceutics project, an academic/industrial collaboration, focused on the development of the next generation of models to predict oral absorption and he currently participates in a number of pre-competitive research programmes including COLOTAN, AGePOP and InPharma Marie Skłodowska-Curie innovative training networks. 

Mark is a Fellow of the Royal Pharmaceutical Society and the Academy of Pharmaceutical Sciences. Mark is a co-author on more than 60 peer-reviewed publications and book chapter contributions, multiple patents and invited presentations and 50 poster presentations.

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