Editor’s Note: This article was published in Pharmaceutical Technology Europe’s March 2022 print issue.
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Developers need to consider key challenges when approaching accelerated formulation strategies to ensure success.
Accelerated formulation strategies can aid with cost and time-efficiencies in drug development. However, there are key challenges of which developers must be aware to ensure success. To discuss the primary hurdles to accelerated formulation strategies and best practices for developers, Pharmaceutical Technology Europe spoke with a panel of experts. The panel included Paul Kippax, Pharmaceutical Sector director at Malvern Panalytical; Chris Roe, senior research fellow, and Vanessa Zann, senior drug development consultant, both at Quotient Sciences; Cornelius Pompe, vice-president R&D at Leukocare; and Alexander Faude, director Process Science, downstream processing, and Marvin Kadisch, director Process Science, upstream processing, both at Rentschler Biopharma.
Editor’s Note: This article was published in Pharmaceutical Technology Europe’s March 2022 print issue.
PTE: Could you run through the primary challenges facing developers when employing accelerated formulation strategies in drug development?
Zann (Quotient Sciences): The main challenge with accelerating formulation strategies is knowing which dosage form technology is the most appropriate to give optimum exposure in patients. There is widespread acknowledgement of the lack of predictability of preclinical data for formulation assessments. Improvements in in-vitro and in-silico tools are emerging; however, there are still significant risks for innovator companies, particularly given continued drug delivery challenges presented by molecule chemistry. This uncertainty is magnified when batch sizes and stability packages are needed for new formulations, for testing in the clinic to even be considered.
Roe (Quotient Sciences): Truly understanding the drivers of poor product performance is a key challenge to overcome. Using the correct techniques can provide meaningful improvements in in-vivo performance that can aid in rapidly progressing formulation efforts. At the same time, developers need to avoid the risk of trying to progress overly complex formulations, which may add unnecessary time or cost to the drug development process. While speed is critical, it shouldn’t come at the expense of sufficient product quality.
Kippax (Malvern Panalytical): No matter what type of drug product you are developing, the principal challenge—or opportunity—is to identify and deploy the techniques that are relevant to assessing your sample’s critical material attributes (CMAs). If you are not applying the right methods, you may not achieve the design space understanding that will ensure you’re tracking quality throughout development and into manufacturing—this could lead to expensive late-stage failures.
So, it’s vital to take a sample-centric approach to understand which CMAs define the performance of your formulation. For example, is it relevant to measure particle size for your API? If you’re working with a highly-soluble biopharmaceutical classification system (BCS) Class I product, then particle size may not be an important indicator, but for BCS Class II products, particle size is key.
It is also important to consider how changing conditions impact your drug substance. For example, are crystal polymorphs an issue when formulation conditions change? If so, how must the formulation adapt to maintain product stability and quality? Being able to answer such questions by accessing the right analytics at the right time is the fastest way to optimize the formulation design space for your product.
Pompe (Leukocare): Accelerated strategies are of paramount importance to reduce the time-to-market and to make innovative therapies accessible to patients in a timely manner. However, these strategies imply a certain risk profile, which has to be assessed on a case-by-case basis. Experienced service providers can be instrumental in tailoring such strategies to the specific project requirements and define measures for risk mitigation to accommodate the intended acceleration.
Kadisch (Rentschler Biopharma): The greatest challenge that developers face is the availability of early and representative material supply. This [challenge] can be a defining factor in the success of the project. Risks in such projects can be mitigated by employing an integrated approach, such as the one followed by the Rentschler Biopharma and Leukocare alliance.
Faude (Rentschler Biopharma): It is the experience and expertise that service providers (such as the strategic alliance of Rentschler Biopharma and Leukocare) bring to the table. The goal is to ultimately find a best-fit solution for accelerated strategies, while maintaining high quality.
PTE: Are the challenges more significant for large-molecule products versus small-molecule ones, in your opinion?
Pompe (Leukocare): The challenges associated with accelerated formulation strategies for small versus large-molecule products certainly differ, but developers may face a comparable degree of complexity for both product classes. Differences mainly arise from critical quality attributes (CQAs) specific to these products. In addition, the degradation pathways and kinetics may largely deviate from each other. The regulatory requirements that apply to these products are also specific in several aspects.
Zann (Quotient Sciences): The challenges for large molecules are still present but different. Large molecules will typically be administered parenterally via intravenous (IV) or subcutaneous (SC) routes, hence formulation options will be more limited compared to the likes of solubility enhancement or modified release development solutions for oral small molecules. There will be less dependency of the formulation composition on its clinical performance. The challenges still remain with regard to predictability from preclinical species and also manufacturing and stability for drug products.
Roe (Quotient Sciences): Arguably the most significant challenges for large molecules would be to achieve adequate exposure from the oral route to exert a systemic therapeutic effect, given this is often seen as the gold standard for convenience and compliance. Issues for large molecule oral formulation strategies include poor permeability and potential instability in the gastrointestinal tract, both of which need to be addressed via compound selection and/or formulation technologies. Success is possible, as evident from the recent [US Food and Drug Administration] FDA approval of Rybelsus (Novo Nordisk), an oral glucagon-like peptide (GLP)-1 agonist (1).
Kippax (Malvern Panalytical): Every product brings its own unique challenges, and there are certainly established hurdles to clear with both small- and large-molecule drug candidates. For example, if we consider drug substance stability, the complexity of establishing, maintaining, and indeed measuring this attribute for large molecules can be extremely challenging as the analytical landscape is quickly evolving, whereas the key analytical tools for small-molecule APIs are well-established and understood.
However, small molecules have their own challenges in terms of solubility issues and also their wide variety of administration routes and dosage forms. The analytical toolsets that are applied to ensure efficacy, quality, and safety must reflect these diverse requirements. For all dosage forms, the questions are the same, but the analytical approach applied will differ.
Again, taking a sample-centric approach to the application of analytics in your formulation design space will ensure these challenges are addressed in a way that accelerates your development programme.
PTE: What sort of activities can developers pursue to ensure their accelerated formulation strategies are successful?
Kippax (Malvern Panalytical): It’s vital to keep your end-goal in sight. Ask yourself upfront, ‘what are the critical quality attributes and which analytics should be applied throughout the workflow to ensure they’re achieved?’ With the focus firmly on your sample, you can quickly home-in on the best formulation for your product.
It may be useful to consider contracting-in consultancy, services, and/or instrumentation that meets your specific requirements. Partnering with a contract services provider allows you to access new analytics and expertise and develop relevant and accelerated approaches.
Whether the analytical workflow takes place in your own laboratory or in that of a contract research organization, applying an orthogonal approach provides the most thorough and detailed picture of your formulation and ensures nothing is missed that might cause issues later in development. A critical design workflow that uses robust datasets to inform decision‑making, together with an orthogonal approach to validate your findings, will ensure you find the ‘sweet spot’ formulation for your product, faster.
Pompe (Leukocare): In the very initial phase, developers are advised to define a holistic target product profile covering chemistry, manufacturing, and controls aspects beside non-clinical, clinical, and commercial features. Depending on the available prior knowledge about the specific molecule or other molecules of the same modality, a basic characterization should be performed. Thereby, predominant degradation pathways can be elucidated by applying stress modes, which reflect conditions encountered during manufacturing, storage, supply, and administration of the drug product. These activities inform the design of iterative formulation screening and optimization studies. The application of tailored designs of experiments generates insights into how formulation parameters impact CQAs and supports the generation of design spaces. Formulations with optimized stabilizing properties can then be identified by confirmatory stability studies under target and accelerated storage conditions.
Faude (Rentschler Biopharma): To elaborate on iterative formulation screening: This starts with explorative produced product, and the subsequent optimization studies lead to an incrementally maturated process for the generation of drug substance. Also, an appropriate panel of quality control methods is an absolute must to ensure the success of the accelerated formulation strategy.
Roe (Quotient Sciences): For oral small molecules, having a data driven formulation strategy based on the compounds’ biopharmaceutic properties is likely to result in a greater chance of success. Employing the developability classification system (DCS) to molecules will allow a targeted formulation strategy for poorly soluble compounds that is based on whether the absorption is either limited by dissolution rate (Class IIa) or solubility (Class IIb). Where there is uncertainty (border-line case) in the classification, Quotient Sciences would recommend assessing both a particle-size reduced formulation (a DSC IIa strategy) and a solubility-enhanced formulation (DCS Iib strategy) to cover both situations to maximize the potential for success.
The focus around solubility can begin in the candidate development stage. If good solubility properties can be built into the drug molecule at the compound selection stage, this can help avoid downstream formulation optimization requirements. At Quotient Sciences, fully integrated drug substance and drug product activities are offered in-house, allowing both preclinical and clinical development activities to be run in parallel on a single programme. This approach simplifies the supply chain, shortens time from discovery to clinic, and allows developers to assess a number of formulation strategies within first-in-human (FIH) studies or enter their FIH studies with an optimized dosage form. By the end of FIH studies in both situations, the sponsor has generated data not only on safety, tolerability, and pharmacokinetics (PK), but also has a formulation suitable for future patient studies. Additionally, druggability assessments can be performed alongside salt and polymorph screening to ensure that the best compound is selected for development. Lead compounds can be manufactured in sufficient quantities to support toxicology and preclinical studies. Formulation and solid-state investigations should provide clear and unambiguous data for optimizing drug substance form, leading to rapid drug substance, dosage form design, and drug product manufacturing.
Zann (Quotient Sciences): For large molecules where oral delivery is required, one optimizing strategy is to formulate with penetration enhancers to increase oral absorption either through modification of the tight junctions or membrane perturbation. There are in-vitro permeability assays that can be used to assess large-molecule permeability in the presence of various formulation components that are available to increase permeability, both early and relatively rapidly within the development programme. However, these models have limitations in terms of being able to test formulated drug products that do not damage the in-vitro cell-based system.
More complicated preclinical animal models are often required to assess the oral formulation performance of large molecules, for example whether oral dosing or a more complicated study with intraduodenal dosing is required, necessitating specialized surgery. Oral absorption may only need to be increased by a small amount to result in a viable oral product compared to an IV formulation, and hence this avenue is often pursued; however, assessing the levels of formulation enhancement required in an oral formulation can be challenging to optimize.
1. FDA, “FDA Approves First Oral GLP-1 Treatment for Type 2 Diabetes,” fda.gov, Press Release, 20 Sep. 2019.
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Pharmaceutical Technology Europe
Vol. 34, No. 3
When referring to this article, please cite it as F. Thomas, “Successfully Accelerating Formulation Strategies,” Pharmaceutical Technology Europe 34 (3) 2022.