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Can investing in early formulation studies drive a new therapy successfully across the commercialization finish line?
In an automobile race, a vehicle must be well designed, highly tuned, and have the proper fuel to outperform the other competitors. If corners are cut on any of these elements, the car may stall or be forced out of the race.
In the traditional drug development race to get a molecule to clinic, drug companies sometimes look for shortcuts. Questions about manufacturability and drug performance may not be answered until formulation steps are initiated after the filing of the investigational new drug application. As a result, the commercialization finish line may be farther away, or never reached.
The traditional approach works if APIs that are easy-to-formulate, are water-soluble, and have a conventional route of administration (e.g., oral dosage forms) are used, says Robert W. Lee, president, Lubrizol Life Science Health’s CDMO division, “but this level of ease is no longer the reality in drug development.” The complex and poorly soluble molecules that are typical of many novel drug candidates in research phases are prompting drug developers to consider more factors about a drug earlier in in the development cycle.
The drug formulation process requires time, money, specialized expertise, and resources that may not be available to small drug companies in early research phases. Development-phase companies anxious to get to clinic may seek to gain an advantage by postponing early stage formulation development. Instead, they place priority on activities traditionally considered to have the largest impact, such as optimizing potency and determining efficacy determination, says Darren Matthews, research leader, pharmaceutical sciences at Charles River.
“The biggest disadvantage to delaying formulation activities is that the inherent risk is significantly increased, resulting in a potentially poor candidate being nominated,” Matthews explains. “Consequently, any challenges relating to bioavailability post-candidate nomination must be solved using formulation strategies alone, whereas prior to candidate nomination a different molecule could have been selected or the medicinal chemistry optimized further.”
“For Developability Classification System (DCS) I compounds (1), this is a low-risk approach, because the formulation is not likely to have much impact on drug performance,” says Meredith Perry, director of pharmaceutics, Catalent Pharma Solutions, San Diego. “But for all other DCS class compounds, understanding the bioavailability in various preclinical species is critical.”
Unfortunately, most new molecular entities have low aqueous solubility; if preformulation or formulation studies are not conducted to solve this issue, it may not be possible to deliver the drug to its target. “Without investigating advanced drug delivery technologies at this early stage, you’re not creating the best chance of success and may end up eliminating a good molecule. Formulation groundwork should be done up front to at the very least identify a viable candidate,” says Lee.
“Not addressing solubility challenges through formulation prior to conducting clinical studies can render the clinical data meaningless and potentially ‘kill’ good molecules that would become good drugs if formulated correctly,” states Lisa Caralli, director of science and technology, pharmaceutics, Catalent Pharma Solutions, San Diego. Physicochemical characterization, preformulation, and drug metabolism and pharmacokinetics (DMPK) analyses are needed to identify hurdles to bioavailability that an enabled formulation can overcome, she says.
An understanding of how a drug may behave in vivo is predicated on initial in-vitro studies, as well as an understanding of basic drug substance physicochemical characteristics, says Stuart Madden, vice-president, drug development and consulting, ICON. “Lacking knowledge of key aspects of a drug product’s characteristics may hinder an understanding of in-vivo data related to the product’s performance,” he explains. “So, although initiation of a clinical program may be quicker and cheaper, in the longer term it may be more difficult to make rationale choices for formulation and process development for any follow-on clinical program.”
Using a drug substance for dosing patients in small, early-phase clinical trials saves the cost of developing, manufacturing, and testing a product for a compound that may be discontinued, says Eugene McNally, vice president, consulting, PPD. “The disadvantage is, not all drugs are candidates for such ‘powder in bottle’ dosing.”
Getting quickly to clinical studies using API in capsule or powder in a bottle is an advantage, agrees Sanjay Konagurthu, senior director, Thermo Fisher Scientific–Pharma Services Group. “Based on outcomes, a formulated drug product might have to be developed in a short time,” he explains. For fast track and breakthrough therapies, developing a formulated, commercial dosage form is advantageous, he says.
Managing expectations and the amount of available API also must be considered. “Companies desiring to sell early stage assets should consider that buyers expect to see formulation and manufacturing process development results that demonstrate the product can be commercialized,” says McNally. And, Perry notes, “Determining whether formulation enhancement is feasible can decrease the doses needed for efficacy, which decreases the risk of side effects and reduces the quantity of API needed throughout the program.”
Formulation and manufacturing process development is driven by the route of delivery and the anticipated human dose, says McNally. For small-molecule drugs-typically oral doses-knowledge about a compound’s solubility and permeability is crucial.
For oral solid-dosage drugs, the DCS can be an effective predictive tool to determine risks associated with a compound’s bioavailability by classifying a drug into one of five different categories. “Classifying a potential drug using the DCS provides the formulator with an appropriate strategy for maximizing bioavailability, especially for sparingly soluble drugs,” Matthews says. “The DCS provides a simple approach, by using solubility and permeability data, to understand and predict a complicated subject (e.g., bioavailability of a potential drug).”
Charles River uses DCS for hit-to-lead and lead optimization stages, and Matthews sees the hit-to-lead stage as an early opportunity to understand potential development risks associated with a chemical series. “Determination of the DCS risk number at this stage empowers the medicinal chemists to choose an appropriate series to take forward to determine a suitable development pathway during lead optimization,” he says.
Understanding the molecular properties of the drug is crucial. “Bioavailability can be impacted by the fraction absorbed, which is dependent on the drug’s solubility and permeability,” says Caralli. “But it can also be impacted by gut wall and hepatic metabolism. If the source is the former, it can be addressed through formulation. If the issue is metabolism, the basic molecular structure of the candidate may need to be reconsidered.”
Detailed preformulation studies can help drug developers understand a molecule’s physicochemical characteristics, solid-state characteristics, and dissolution rate, says Lee. “This will indicate whether the use of enabling technologies like nanomilling will be needed to help formulate the molecule.” Other factors to consider include the molecule’s stability in water, acid/base, oxidation, heat, and light; excipient compatibility; potential for polymorphic transformation; particle size distribution powder flow; and hygroscopicity.
Typically, biologic drugs require extensive preformulation studies because they are more complex with aggregation and degradation of special concern as they are much more sensitive to stresses from manufacturing and environmental conditions, says Madden.
“For large molecules, it’s not just the sequence of the monomers (i.e., amino acids or nucleotides) that is a concern but also the three-dimensional structure,” says Lee. “During formulation development, it’s important to track this 3D structure as this may be key to its biological activity, and this may very well be impacted by the formulation.”
An indication of solution stability, and whether a lyophilized, or dried, formulation will be needed to maintain stability, is typically the starting point for development of large molecules, adds McNally.
Advances in screening and characterization have enabled more rapid and accurate analysis of molecules, providing support for formulation steps. “Materials science-based characterization of the drug substance using modern compaction simulators, Raman spectroscopy, electron microscopy, chromatography, crystallography, thermal characterization, and dissolution and absorption technologies can help in the characterization,” explains Konagurthu.
“Physical characterization of each API lot requires very small amounts of API (milligram quantities),” says Perry. “It is worthwhile to use the sensitive, API-sparing tools that are now available, such as differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction, and scanning electron microscopy.” In addition, she notes, the use of software modeling, in addition to actual characterization, can help expedite the process. “Predictions for solubility, permeability, and DMPK performance are all helpful tools,” she says.
Tools developed in the past 20 years are allowing formulation scientists to do more, says Matthews. For example, biorelevant dissolution media allow the formulation scientist to predict the solubility and dissolution behavior of sparingly soluble drugs in vivo. When coupled with small-scale dissolution equipment with in-situ measurement by fiber optics, automated pH adjustment, or automated media addition, these systems can mimic the in-vivo environment. And, in-silico prediction tools that consider formulation, polymorphic, and particle sizes effects on in-vivo performance can be powerful tools for the formulator. “Such a method can be used to triage potential approaches to enhancing bioavailability without the need for expensive animal studies,” he says.
Madden also notes the importance of software to aid development, ranging from programs to calculate basic physicochemical parameters for drug substances to bioavailability development toolkits and excipient interactions software. “There are also strategies developed by contract research organizations that allow the rapid in-vivo screening of numerous formulation prototypes to aid rapid formulation selection prior to the start of any formal clinical program,” he states.
Physiologically based pharmacokinetic modeling is essential to ensure that the correct delivery route and dosage form is pursued for a molecule, says Caralli. “These in-silico models can incorporate both in-vivo data from animal models, and in-vitro data from biphasic dissolution studies, to predict the performance of a formulated API in human clinical studies.”
Konagurthu notes that predictive models are of great benefit in early development, citing Thermo Fisher’s Quadrant 2 platform as an example. “Implementation of in-silico predictive models are being used to guide formulation,” he says, citing materials science and characterization (e.g., compaction simulation), accelerated stability assessment, discrete element modeling, computational fluid dynamics, and pharmacokinetics and pharmacodynamics models. “An ensemble approach can help developing quantitative models that relates product structure to performance,” he says.
Predictive pharmacokinetic and pharmacodynamic modeling certainly helps to inform the ‘best’ dose and dose frequency, formulation, and route of administration to take forward into clinical trials, says Scott Dove, vice president, early development, PPD.
While models can help direct studies, they do not necessarily replace laboratory analysis. “Computational models can give you an idea of the molecular characteristics in silico and predict solubility and a host of other properties. Some are particularly effective and can guide your lab work, but they are not a substitute for actual lab work-this must still be carried out,” Lee says. “If you are looking at several different molecules to synthesize in early development, then using predictive models to do a computer screen of potential structures can help direct your work and narrow your choices.”
Using predictive models as a substitute for experimental data in the early stages of drug development can save time and money, allowing the development program to move to wet chemistry more quickly, says Madden. “For example, screening a series of analogues to determine bioavailability, solubility, or even potential genotoxicity signals by quantitative structure-activity relationship can be of tremendous value in early development and accelerate lead optimization efforts enabling faster development.”
A decision to divert limited resources from early formulation studies may come back to haunt many drug developers, especially when the solubility or other issues associated with a compound are revealed in clinical trial stages. However, notes Perry, “Formulation screening at small scale is significantly less expensive than a failed clinical trial.”
The consequence of not gaining insight early in development can result in batch failures that lead to delays or cancellations of trials due to a lack of understanding of the
“It is critical for companies to understand that investing in formulation and process development during the early phases can yield dividends in the long run,” says Konagurthu. “The company should obtain a mechanistic understanding of the formulation and process.”
“Companies must have a viable formulation for in-vitro studies and beyond, so it’s important to invest effort and resources in the most effective formulation,” says Lee. “At the same time, it’s a balancing act, and it’s not cost effective to waste resources on the wrong technologies.”
“Scientists must often justify their chosen scientific path to management, who may have limited understanding of the underlying science. For low-solubility molecules, this inability to translate the ‘why’ can lead to decisions being made for purely financial reasons,” says Caralli. “Using a visual tool like the DCS, solubility, permeability, and dose can be plotted to demonstrate the need for an enabled formulation to ensure a successful clinical trial outcome.”
1. J. M. Butler and J. B. Dressman, J. Pharm. Sci. 99 (12) 4940–4954 (2010).
Vol. 44, No. 3â¨
When referring to this article, please cite it as R. Peters, “Fast vs. Formulated? " Pharmaceutical Technology 44 (3) 2020.