At the point of candidate selection, a chosen drug substance will typically have been prepared in only small quantities (up to a few grams) to support initial medicinal chemistry activities. The synthetic route used for this initial supply is rarely suitable for producing larger quantities of material for downstream development and will typically need to be modified, or sometimes redesigned entirely, to produce enough material for first-in-human (FIH) clinical trials.

There may be several challenges to address at this point:

• The existing route may rely on chemistry that is too hazardous to be performed at a large scale, with reagents that are highly toxic, difficult to handle, or even explosive.
• It may rely on the use of solvents or reagents that generate hazardous waste or are discouraged due to environmental concerns.
• The starting materials may be expensive or difficult to procure in large quantities.
• Process impurities may be generated that are difficult to remove from the drug substance, and the existing synthesis might use purification methods (e.g. chromatography) that are impractical at large scale.
• The quantity of solvent used for a given reaction might result in poor throughput, meaning that many batches would have to be performed.
   

We have a state-of-the-art facility in Alnwick, UK, where we work with our customers to address these challenges with recently increased capacity.

An experienced team of process chemists works alongside colleagues in analytical chemistry and material science to develop safe, scalable, and economical synthetic routes to achieve a suitable drug substance. Each cross-functional project team is overseen by a single project manager, who seamlessly manages the end-to-end process, provides regular status updates, and ensures timely project delivery for our customers. 

We work with clients of all sizes, from small biotech companies to large pharmaceutical companies, tailoring our services to meet their specific project goals.

We engage with our customers from the point of candidate selection and start by performing an initial analysis of the synthetic route.

This exercise allows our process chemists to highlight any potential red flags and identify possible alternatives.

To minimize risks further downstream, we then carry out a period of small-scale process research and development (PR&D) in the laboratory to determine the suitability of the route for scale-up, assess any potential improvements that could be introduced, and generate samples of process intermediates to support analytical method development.

We also generate data on the thermal safety of chemical processes in real-time, which allows us to make informed decisions on route selection at a very early stage in development. With access to differential scanning calorimetry (DSC), heat-flow calorimetry (HF-Cal), and online off-gassing measurements, any safety concerns can be rapidly assessed, and the necessary control measures can be introduced. This not only ensures that our chemical processes are carried out safely when scaling up, but it also reduces the risk of project delays caused by unexpected issues identified later in process development.

At this point, we may begin additional activities, such as salt screening and polymorph assessments of the drug substance, in parallel to support the synthetic route development, and to facilitate an easier transition into the formulation development phase.

The final stage of a synthetic route is typically a crystallization of the drug substance, either as a single component or as a salt. This is arguably the most important step of the entire synthesis as it controls not just the purity profile of the drug substance, but also the crystalline form or polymorph that is obtained. Different polymorphs can have significantly different physicochemical properties, and it is therefore important to make sure that a suitable solid form is identified as early as possible.

Our integrated material science team offers expert advice throughout the drug substance development process.

By performing these activities in parallel with synthetic route development, all within one organization, we can make informed decisions on the most suitable process, and make sure that we get it right on the first try for our customers.

This is part one of our three-part series focused on scaling drug substance.

Continue reading part 2: How do you streamline manufacturing of your drug substance?

Continue reading part 3: How do you successfully bridge into drug product development?

Learn more about our drug substance capabilities

In the previous blog post in this three-part series, we discussed how to design a safe and scalable synthetic route for your drug substance – Part 1: How do you design a safe and scalable synthetic route for your drug substance?

The next challenge is to develop a safe and efficient manufacturing process that is capable of consistently producing your drug substance at the intended quality on a larger scale. When developing a drug substance manufacturing process, considering the impurities that are produced is as important as the drug substance itself. You need to identify, quantitate, and ultimately control the impurities generated in the manufacturing process, as small differences in impurities can have a significant impact on the toxicological profile of the compound.

At Quotient Sciences, we have dedicated manufacturing suites in our state-of-the-art facility in Alnwick, UK, where an experienced team of process chemists works alongside colleagues in analytical chemistry and material science to support the manufacture of multi-kilogram quantities of Good Manufacturing Practice (GMP)-grade active pharmaceutical ingredient (API). Each cross-functional project team is overseen by a single project manager, who seamlessly manages the end-to-end process, provides regular status updates, and ensures timely project delivery for our customers. 

We work with clients of all sizes, from small biotech companies to large pharmaceutical companies, tailoring our services to meet their specific project goals.

Once a suitable synthetic route has been chosen, we focus on ensuring that the chemistry can be safely and reliably carried out at a large scale, with process parameters (temperature, addition rates, reaction concentration, and stoichiometry) optimized to maximize reaction yield and throughput and ensure that the process is robust and scalable.

At this point, we use analytical chemistry to identify key process impurities. Our state-of-the-art analytical chemistry department has expertise in high-resolution mass spectrometry, solution- and solid-state nuclear magnetic resonance (NMR) spectroscopy, trace metal analysis, and gas and liquid chromatography. Having all these technologies under one roof allows us to gather important process information in real-time. By identifying key process impurities at an early stage, the chemistry team can make rapid modifications to the process to either prevent their formation altogether or develop purification processes to remove them. We also carefully analyze trace metal impurities, where relevant, as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines have strict limits for the number of residual metals that can be tolerated in a drug substance. Homogenous transition metal catalysts based on palladium, rhodium, and iridium are commonly used to carry out useful synthetic reactions, so it is important to ensure that adequate purification steps are included in the drug substance synthesis to limit the quantity that remains in the drug substance.

Throughout this stage of development, our process chemists benefit from access to a range of parallel reaction equipment which, combined with in-situ reaction monitoring, allows us to quickly collect large amounts of data-rich experimental information, and make evidence-based decisions to develop the best possible process.

Once the process parameters have been determined, we perform the chemistry at an intermediate scale (typically 5 L) as a demonstration of the process. This confirms whether the developed process will perform as expected when carried out at a larger scale, using glass reaction vessels that mimic the layout of those found in our manufacturing suite. The drug substance that is generated in this demonstration batch is representative of the material that will be produced in the subsequent GMP campaign and can therefore be used to support stability studies of the drug substance as well as toxicology and formulation studies. Having successfully demonstrated the process at this intermediate scale, we will then carry out a GMP manufacture in our dedicated facility to produce the drug substance in the quantities required by our customer.

We have a dedicated team of flow chemists and chemical engineers who are continually assessing synthetic routes for opportunities to leverage our expertise in continuous technology.

The team develops chemical processes in flow which can offer numerous advantages over traditional batch chemistry and in some cases can even allow us to develop reactions that would not be possible to scale up in batch. 

Our recent case study on the optimization of a flow process for a thermal rearrangement underscores the project timeline benefits that can be achieved when judicially incorporating flow processes at an early stage in drug development.

This is part two of our three-part series focused on scaling drug substance.

Continue reading part 1: How do you design a safe and scalable synthetic route for your drug substance?

Continue reading part 3: How do you successfully bridge into drug product development?

Learn more about our drug substance capabilities

In the previous blog post in this three-part series, we discussed how to streamline the manufacturing of your drug substance. Read part 2 in the series: How do you streamline manufacturing of your drug substance? 

After streamlining drug substance manufacturing, the next challenge is formulating your drug substance (active pharmaceutical ingredient [API]) with other inactive ingredients (excipients) into a finished dosage form (drug product) for clinical trials.

The interface between drug substance and drug product is a key part of the drug development pathway. Drug substance and drug product development are often carried out by different organizations, which can be inefficient and costly, leading to poor knowledge and material transfer, and delivery delays. The complexity of today’s drug molecules and target product profiles (TPPs), and the timeline pressures that drug developers are faced with, exacerbate these challenges.

At Quotient Sciences, we address these challenges by providing fully integrated drug substance, drug product, and clinical testing services, all within one organization.

This means that we can manage drug substance and drug product development in parallel and develop manufacturing processes that are controllable, robust, and scalable with minimal risk. This ensures that when we develop a drug product and supply it to our customers, there is no need to re-run studies as they move downstream through successive clinical stages. This saves drug developers time and money and ensures significant value to the end product.

For integrated drug substance and drug product projects, our cross-functional project team members bridge the gap between drug substance and drug product, shortening program timelines by sharing knowledge and materials from project initiation and continuing to work side by side for the duration of the project, ensuring that nothing gets missed along the way.

Our highly skilled scientists have decades of experience working in manufacturing at larger scales and know what a process should look like for downstream success. With closely aligned workstreams, our process chemists work alongside analytical and solid-state chemists to ensure rapid development and optimization of the drug substance. Our formulation scientists and solid-state chemists together provide clear and unambiguous data for optimizing the drug substance form, leading to rapid dosage form design and drug product manufacturing.

Each cross-functional project team is overseen by a single project manager, who seamlessly manages the end-to-end process, provides regular status updates, and ensures timely project delivery for our customers. 

We work with clients of all sizes, from small biotech companies to large pharmaceutical companies, tailoring our services to meet their specific project goals.

For small biotech companies, we provide high-quality data packages that have been designed by people who know exactly what large pharmaceutical companies value and expect, leading to a smoother transition and a higher value for the transaction. For large pharmaceutical companies, the ease of material transfer reduces overall risk and shortens the time for the clinic to know whether their formulation is successful to move forward with.

The integration of drug substance and drug product services within one organization has multiple benefits, including ease of material transfer, seamless coordination, and knowledge sharing between drug substance and drug product groups, which enhance the likelihood of clinical success and reduce the overall risk. However, the ultimate benefit is a significant reduction of drug development timelines from candidate selection to clinical development. 

On average, drug development timelines are reduced by 3–6 months by utilizing an integrated approach, which translates into significant R&D cost savings and gets new medicines to patients faster.

This is part three of our three-part series focused on scaling drug substance.

Continue reading part 1: How do you design a safe and scalable synthetic route for your drug substance?

Continue reading part 2: How do you streamline manufacturing of your drug substance?

Learn more about our drug substance capabilities

Drug development has its challenges, but when it comes to programs that require specialized formulation expertise, such as applying solubility enhancement techniques to improve a poorly soluble API, the challenges in achieving clinical and commercial success are even greater. 

All drug development programs are challenging, given the numerous stages an active lead molecule or new chemical entity (NCE) must transition through to gain regulatory approval and demonstrate its benefits in patients. The challenges in achieving clinical and commercial success are even greater for complex programs requiring specialized formulation expertise, such as solubility enhancement or modified release, and in developing suitable formulations for pediatric patients.

At Quotient Sciences, our scientific teams leverage our integrated capabilities as a contract research, development, and manufacturing organization (CRDMO), along with decades of expertise in drug development, to support our customers through even the most challenging drug programs. 

Using our flagship platform for drug development, Translational Pharmaceutics^®, we integrate real-time cGMP manufacturing with clinical testing—all done within a single organization and under the guidance of a single program manager—to remove conventional siloes in drug development. This approach can aid formulation design with the ability to screen a range of technologies and dosage forms using biorelevant in-vitro screening tools and physiologically based in-silico models to flag developability problems, before quickly transitioning drug candidates into human pharmacokinetic (PK) studies to understand a molecule's full potential for success. 

Below, continue reading case studies that explore how Quotient Sciences' integrated CRDMO services and Translational Pharmaceutics® have been applied to overcome formulation challenges in complex drug programs. You can also learn more about how Translational Pharmaceutics^® works in this video.

Formulation development and screening of solubility-enhancing formulations

Poor aqueous solubility, leading to solubility-limited exposure, has been recognized as a major challenge in the development and evaluation of NCEs during early discovery, pre-clinical, and clinical development stages. There are various formulation strategies to improve solubility, with the primary goal of improving oral bioavailability. 

Our approach to solubility enhancement is based on an understanding of molecular properties, using the Developability Classification System (DCS) to choose the most appropriate formulation approach for a molecule. Understanding the drivers of poor exposure to a drug allows formulation efforts to be focused on appropriate techniques that provide meaningful improvements for in-vivo performance. We have the capability to evaluate chemical modifications, such as salt and polymorph screening, and physical modifications, such as particle size reduction, complexation, solubilization using a lipid-based approach, and stabilization using amorphous forms. Solubility enhancement can be addressed at different stages. 

In one client program, a poorly soluble NCE was facing challenges of low oral exposure, non-linear PK, high variability, and a large positive food effect in the first-in-human (FIH) study. These issues were preventing the client from advancing the compound into patient studies. To overcome these challenges, drug products based on three solubility-enhancing formulation platforms were developed: a micronized formulation using particle size reduction of the active pharmaceutical ingredient (API), a self-emulsifying drug delivery system using a lipid-based formulation, and an amorphous formulation using a spray-dried dispersion. These drug products were produced on a small scale for quick clinical assessment in human subjects without the need to conduct larger-scale, cost-prohibitive process development and lengthy stability programs for multiple technologies. 

A two-part study was designed for the drug program:

• In part 1, Translational Pharmaceutics^® enabled the integration of clinical manufacturing and dosing in healthy volunteers using a six-period cross-over design to obtain comparative human PK data from the three enabling formulations. 
• In part 2, higher doses were administered to establish safety margins for patient studies, and dose linearity was determined based on the area under the curve (AUC). 

Integrating solubility-enhancing formulation development, clinical manufacturing, and FIH testing using Translational Pharmaceutics^®, a new lead formulation was identified in about 6 months. The formulation overcame the solubility barriers and allowed the compound to progress to patient studies.

Formulation development and optimization of a modified-release (MR) dosage form to meet the target product profile (TPP)

Numerous formulation strategies are available for designing MR dosage forms. One of the key challenges when developing an MR formulation is to identify the in-vivo release rate and dose required to achieve the TPP. 

While in-vitro dissolution data are generated to describe formulation release, the assumption that this will represent in-vivo performance is unproven until clinical data are available. Often, with MR formulations, a reduction in overall exposure (AUC) is observed when delivering to lower regions in the gastrointestinal (GI) tract, where absorption can be reduced. Contributing factors include reduced fluid volumes (for dissolution and solubilization), and surface area, and differing permeability. Similarly, there are recognized challenges and risks of using pre-clinical models to design MR formulations due to significant inter-species anatomical and physiological differences. 

In these cases, Translational Pharmaceutics^® is extremely valuable in identifying the optimal platform, dose, and release rate to meet the TPP of specific molecules of interest. 

In this client program, an NCE in development for the treatment of inflammatory diseases was being dosed twice a day (BID) or three times a day (TID) during early trials due to a short half-life and a slower terminal phase. The client wanted to develop a once-a-day (QD) product to increase patient compliance and therapeutic outcomes. The TPP had a lower peak-to-trough ratio compared to the immediate-release (IR) product and coverage of the lowest efficacious concentration over the desired duration. Matrix-based MR dosage forms were proposed to reduce the dosing frequency.

Two studies were designed to achieve these objectives:

• In the first study, matrix minitablets in capsule or monolithic matrix tablets were developed and evaluated using in-vitro dissolution rates of 80% release over 8 and 12 hours. While a QD PK profile was achieved in the fasted state with the slower in-vitro dissolution rate with both types of matrix-based drug products, the formulation was susceptible to a food effect when administered with a high-fat meal. This resulted in most of the exposure occurring within the first 12 hours of dosing, which is not optimal for QD dosing.
• In the second study, building on the first, a proprietary technology platform (DiffCORE™) was evaluated from the client with the goal of overcoming the food effect. 

Translational Pharmaceutics^® enabled the evaluation of multiple variables in this two-part adaptive clinical study, including formulation modifications, food effect, and dose levels/tablet strengths. Flexibility was maximized by the inclusion of a two-dimensional formulation design space in the regulatory submission, which allowed quantitative changes in release rate and dosing during the clinical study to achieve the desired PK profile. Multiple formulation iterations were tested in the same individuals in both the fed and fasted state within a short timeframe, rapidly identifying the most optimal formulation that enabled QD dosing (2).

Summary

Translational Pharmaceutics^® supports drug programs across the full development pathway, with capabilities to:

• Fast-track molecules to FIH, or from FIH to POC
• Optimize clinical formulations through solubility enhancement techniques
• Evaluate novel drug delivery technologies for all routes of administration

We are currently the only outsourcing partner able to offer the ability to develop, manufacture, release, and dose drug products within one organization. This maximizes the probability of success and significantly reduces development time and costs for our customers, getting new medicines to patients faster (3).

The Tufts Center for the Study of Drug Development (CSDD) quantified the platform's major benefits, showing significant savings in reaching key milestones as quickly and efficiently as possible. To read their findings, download a copy of the Tufts report assessing Translational Pharmaceutics.

References

1. Zann V, McKenzie L, Crowley K, Sweet-Smith S, Shabir-Ahmed A, Andreas K, Mountfield R, Milton A. A Phase I Study Allowing Clinical Screening of Multiple Solubility-Enhancement Formulation Technologies, and an Assessment of Food, PPI and Dose Linearity Assessment with the Selected Formulation of BOS172767, in Healthy Volunteers. Poster presented at AAPS meeting, November 2019.

2. Tompson D, Whitaker M, Pan R, Johnson G, Fuller T, Zann V, McKenzie L, Abbott-Banner K, Hawkins S, Powell M. Development of a Once‑Daily Modified‑Release Formulation for the Short Half‑Life RIPK1 Inhibitor GSK2982772 using DiffCORE™ Technology. Pharm. Res. 2022;39(4).doi.org/10.1007/s11095-021-03124-7.

3. DiMasi J and Wilkinson M. The Financial Benefits of Faster Development Times: Integrated Formulation Development, Real-Time Manufacturing, and Clinical Testing. TIRS, June 2020.

Selecting the right outsourcing partner for your drug development program is an extremely complex process. Within the pharmaceutical industry today, drug developers are increasingly outsourcing pre-clinical development, clinical research, and drug product manufacturing to external contract service providers (CDMOs and CROs). While this can provide benefits, such as the ability to leverage external expertise and technologies, it can be challenging for the drug developer to manage multiple vendors, projects can be slow to start, disconnects can lead to delayed timelines, and it can be extremely costly. This points to a need for a simplified outsourcing model.

How does an integrated services model accelerate drug development?

Traditionally, the pharmaceutical industry has been structured around functional silos. In a conventional outsourcing approach, a sponsor has to split their drug development program between one or more CDMOs and a separate CRO. This places the project management burden on the sponsor, creates gaps in the development timeline, and limits knowledge and material sharing. Ultimately, this restricts productivity, slows down the drug development process, and is costly for the sponsor.

At Quotient Sciences, we have the unique ability to integrate drug substance, drug product, and clinical testing activities all under one organization and a single program manager. This unique platform is called Translational Pharmaceutics^®, and it breaks down traditional industry silos to accelerate molecules through development. This streamlined approach seamlessly supports our customers’ programs across the entire drug development pathway, from candidate selection through to commercialization.

How does Quotient Sciences’ unique Translational Pharmaceutics platform work?

Translational Pharmaceutics employs rapid ‘make-test’ cycles, where drug products are manufactured, released, and dosed in a clinical study in days rather than months, shortening the time to decision-making human data. Emerging clinical results inform formulation composition selections in real-time, maximizing the potential for success by avoiding the risk of relying on up-front, non-predictive surrogate tools.

We have also integrated drug substance activities into our platform, further streamlining early development activities. Precious active pharmaceutical ingredient (API) material can be conserved and critical path activities can be minimized when supplying materials for Good Laboratory Practice (GLP) toxicology and first-in-human (FIH) clinical studies.

Our expertise in understanding the scientific dependencies between drug substance properties, formulation design, and clinical outcomes therefore enables us to enhance development efficiency. By closely aligning drug substance, drug product manufacturing, and clinical testing workflows, this encourages close relationships between multidisciplinary experts and creates a more agile approach to pharmaceutical development. The addition of drug substance into our integrated platform enables us to shorten the time from candidate development to FIH, accelerate molecules from FIH to proof of concept (POC), select and optimize clinical formulations, and accelerate products to commercial manufacturing.

What sets Quotient Sciences apart from other contract service providers?

Many contract service providers claim that they provide fully integrated solutions, but in reality, that is not the case. Quotient Sciences is currently the only outsourcing partner able to offer sponsors the ability to manufacture, release, and dose under one organization.

Translational Pharmaceutics has a long-standing history and proven track record of delivering integrated programs in the US and the UK. The unique platform is approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the US Food and Drug Administration (FDA), and it has been used by pharmaceutical and biotechnology companies on over 500 drug programs. We also have over 200 scientific publications on the topic in the public domain.

Why does proven, in-house expertise really matter? 

As an organization, Quotient Sciences has over 30 years of experience in drug substance, drug product development, and clinical testing. This year, we celebrate 15 years of Translational Pharmaceutics and the design and delivery of integrated programs based on the unique needs of our customers’ molecules. Our highly skilled scientists and cross-functional teams work closely together and share knowledge and materials for the duration of a project.

Each cross-functional project team is overseen by a single program manager, who seamlessly manages the end-to-end process, provides regular status updates, and ensures timely project delivery for our customers. We work with clients of all sizes, from small biotechnology companies to large pharmaceutical companies, tailoring our services to meet their specific project goals.

What are the different applications of Translational Pharmaceutics?

Translational Pharmaceutics has been used by customers across the whole of the development life cycle, to develop new chemical entities and manage the life cycle of existing commercial products.

Translational Pharmaceutics can assist at each development phase, including:

• closely aligning workflows around drug substance synthesis, formulation development, drug product manufacturing, and clinical testing to shorten the time from candidate development to FIH
• accelerating molecules from FIH to POC in patients
• selecting and optimizing clinical formulations based on human data
• accelerating products to commercial manufacturing and launch.

While the majority of studies have been performed for oral molecules, the platform has been used for all routes of delivery, including:

• parenteral (intravenous, subcutaneous, and intramuscular)
• inhaled (pulmonary and nasal)
• topical
• ocular.

For complex molecules, key technologies for oral delivery that can been applied include:

• solubility and bioavailability enhancement (for example, via particle size reduction, amorphous dispersions, and lipidic systems)
• modified-release formulations (for example, matrix tablets, coated tablets/multiparticulates for sustained/delayed release, and gastroretentive technologies)
• taste-masking strategies for pediatric dosage forms.

What are the overall time and cost-saving benefits of Translational Pharmaceutics?

In 2020, Quotient Sciences commissioned the Tufts Center for the Study of Drug Development (CSDD) to conduct a study comparing completed Translational Pharmaceutics programs to benchmarked industry drug development timelines. The study concluded that for programs utilizing Translational Pharmaceutics, on average, development timelines were reduced by over 12 months, delivering financial gains of more than $200 million per approved new drug through a combination of reduced R&D costs and earlier access to commercial sales.

All drug developers wish they had a crystal ball that could predict the future outcome of their molecules. Having the ability to know whether you have clinical or commercial success before investing the time and money required would be a game changer. 

Unfortunately, magic and mystics do not have the proven and peer-reviewed data needed to make clinical decisions. Fortunately, Modeling and Simulation (M&S) provides another way to predict the clinical performance of a molecule, based on a much more robust and holistic approach.

M&S is a proven scientific approach used to inform key drug development decisions, and it can be employed throughout the development lifecycle of a drug. Specifically, physiologically based pharmacokinetic (PBPK) modeling integrates knowledge of a drug’s characteristics (measured or in-silico properties) with physiological information, allowing for maximum leverage from data already obtained. Drug developers can use this approach early in the candidate development stage to help guide their formulation strategy and ensure that their program is well prepared for entering the clinical phase.

We employ M&S during candidate development, where measured data on lead candidates can be sparse. 

Our M&S team can use this limited dataset to enable an initial understanding of a client’s molecule and how it may behave in humans. In the first instance, this may be simply a prediction of the fraction absorbed or a Developability Classification System (DCS) assessment, which can be made solely from physicochemical properties, such as solubility, logP, pK_a, and permeability. If measured data for any of these parameters is not available, we can easily predict these properties from the chemical structure using the GastroPlus^® software “ADMET Predictor”, which contains quantitative structure–activity relationship (QSPR) models for many properties, such as human effective permeability (P_eff) and logP among others. By obtaining this key information early, we ensure our customers are prepared and can identify a formulation strategy well before moving into the clinical phase.

What is a DCS assessment? 

We typically conduct a DCS assessment following (or just prior to) candidate selection, which helps to inform molecule developability and the formulation strategy. We utilize biorelevant solubility data (in fasted-state simulated intestinal fluid) and permeability information (predicted from either in-vitro or in-silico data using GastroPlus ADMET Predictor) along with the expected therapeutic dose to classify our client’s molecule. This classification informs early in the development process whether simple techniques, like micronization, are likely to be appropriate for our client’s molecule or whether more sophisticated technologies will be required.

How is fraction absorbed predicted?

At Quotient Sciences, we use the PBPK modeling software GastroPlus to predict the dissolution and absorption of a compound in the gastrointestinal (GI) tract. This software mechanistically predicts the behavior of a drug, considering the physicochemical properties of the molecule (e.g. ionization status, solubility, and lipophilicity) and the changing environment of the GI tract (e.g. pH, volume, surface area, and bile salt concentrations). Fraction absorbed can be predicted across a dose range and for different scenarios, such as with and without food or in the presence of acid-reducing agents like proton pump inhibitors. Knowing how much (and where) a drug is likely to be absorbed in different scenarios can help to inform the formulation strategy for the clinical phase.

Can PBPK modeling also be used to predict first-in-human (FIH) performance?

Yes, PBPK modeling can be used to predict the performance of drugs in humans prior to obtaining any in-vivo clinical data. Prediction of pharmacokinetic (PK) parameters is more complex than purely prediction of fraction absorbed or DCS assessment. It usually involves us building pre-clinical PBPK models first to demonstrate a robust understanding of the mechanistic behavior (dissolution, absorption, distribution, clearance, and excretion) of the candidate drug in vivo. We then build a human PBPK model utilizing the learnings from the pre-clinical models and incorporating human-specific data, such as human clearance prediction. We use this model to predict human PK performance across a dose range and to conduct risk assessments. We usually perform risk assessments around parameters such as particle size, dose or gastric pH, precipitation risk, and food effect. We can use the information from risk assessments to guide further experiments or the formulation strategy as Phase I clinical trials approach. Although other methods for the prediction of performance in humans can be conducted, PBPK modeling, with verification of predictive performance first performed in pre-clinical species, is superior to empirical methods (e.g. allometry) for predicting PK in humans.

What are the key benefits to our customers when we utilize PBPK modeling during the candidate development phase?

The key benefits of utilizing PBPK modeling early are maximum utilization of early-stage pre-clinical information to inform downstream formulation decision-making. This includes informing the formulation strategy, identifying key experiments to be conducted prior to entering the clinic (e.g. assessing precipitation risk), or performing uncertainty analysis on key parameters, such as clearance, to understand how sensitive this parameter is on predicted PK parameters.

Ultimately, by facilitating a much more robust understanding of a molecule’s behavior earlier, M&S allows for more informed decisions to be made, leading to potentially significant time and cost savings along the drug development path.

To find out more about Quotient Sciences’ candidate development services, click here.

Small molecules continue to dominate new pharmaceutical product launches, comprising 33 of the 50 approvals by the US Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research (CDER) in 2021. 

The continued high level of interest in small molecules presents multiple opportunities to select a candidate that is developable, with subsequent progression toward first-in-human (FIH) clinical testing. 

However, there is a high level of attrition during the pharmaceutical research and development process, which is an indicator of the vast number of potential drug substances considered for progression. Therefore, it is vital to choose molecules for pharmaceutical candidate development very carefully.

Given the plethora of new chemical entity (NCE) candidates, pharmaceutical research groups frequently face challenges when selecting the most promising candidate for development purposes.

With all this in mind, how do drug developers know which strategy and approach is right for their molecule at this early stage?

Key considerations in the candidate selection stage

The first step in a drug development program is choosing the optimum molecule from a range of potential leads that have been optimized within drug discovery. At this stage, lead compounds will be ranked based on their activity in primary and secondary assays, demonstrating acceptable specificity and selectivity for the biological target that is proposed to be key for the desired therapeutic area. Best practice is to also consider the ‘developability’ of the lead compounds in conjunction with any evidence of potential in-vivo activity, by taking a holistic approach. It is important to assess each compound’s pharmacokinetic (PK) profile and to evaluate the potential toxicity using simple screens such as the Ames test and cytotoxicity assays.

Our drug development consultants use our 30+ years of experience in clinical research outcomes to profile each new molecule that we look at.

We start by using in-silico modeling of any pre-existing data associated with the lead compounds. This initial assessment helps to highlight any critical data gaps, which we can then fill with small-scale experimental work. Drug substance quantities are often limited at this stage, so we select material-sparing experiments to generate fundamental molecular-level characteristics, which helps to ensure that we choose the correct molecule.

For example, to successfully develop an oral solid dosage form like a tablet, the solubility and permeability of the lead compound will have a significant impact on the speed and extent of its drug development program to become ‘clinic ready’. By associating molecular properties with in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) models, we can significantly increase the robustness of candidate selection, which subsequently reduces the failure rate during clinical trials.

By classifying the ‘developability’ of the compounds in advance, we can help avoid formulation pitfalls by designing a molecule-specific pharmaceutical development plan.

Candidate selection case study: Progression of small molecule developability

Background: A US biotech company had identified nine structurally related compounds as potential candidates in an oncology discovery program. Quotient Sciences was asked to select the best candidate based on material science and oral bioavailability considerations. The quantity of each compound was limited to less than 500 mg for the assessment.

Program: Initially, the crystallinity, physical state, morphology, and salt formation for each compound were assessed. Subsequently, the inherent equilibrium solubility and pH-solubility relationships, with the inclusion of biorelevant media, were investigated. The best candidate was selected for a salt screen and physical form assessment. As part of this study, high-performance liquid chromatography (HPLC) assay and related substances method development was initiated. Non-clinical formulation development was then performed across three alternative technologies guided by the Developability Classification (DCS III), including the use of permeability enhancers that were suitable for oral liquid administration. These were evaluated by the client to establish their in-vivo PK profiles.

Outcome: Quotient Sciences was able to select one suitable compound for optimization based on material science and solubility determinations. A hydrochloride salt form was selected based on the fundamental physical properties of the molecule. Non-clinical studies confirmed the most effective formulation, with subsequent progression of one molecule through Good Laboratory Practice (GLP) toxicology to a successful Phase I clinical study.

Candidate development: Bridging from candidate selection to the clinic

Having selected a lead candidate drug molecule, the next goal is to complete all of the necessary and sufficient activities that will gain regulatory approval to begin a Phase I clinical trial in humans. 

As well as presenting an acceptable PK profile and demonstrating in-vivo efficacy, it becomes important to show that the candidate drug has a good safety pharmacology margin with an acceptable drug-drug interaction (DDI) profile. Access to increasing quantities of drug substance becomes more critical at this stage, and it is important to consider the feasibility of Good Manufacturing Practice (GMP) suitable for early development.

We select the appropriate salt or physical form to optimize a molecule for both manufacturability and downstream product performance. In addition, we can incorporate excipients or different counter-ions as co-components to further improve product performance while facilitating formulation development. We use state-of-the-art instrumentation to probe solid-state characteristics and purity profiles of different active pharmaceutical ingredient (API) forms under specific stress conditions, which can be used predictively to further accelerate the progression of the drug substance to a clinically optimal product. 

Our detailed understanding of the molecular properties and their relationship with bulk properties offers speed, novelty, and robustness with no compromise on quality. For example, as we scale up the production of the drug substance, we will look to characterize the isolated material for both amorphous and crystalline content. By recognizing a thermodynamically metastable state, we can provide enhanced product performance and mitigate the risk of conversion to an undesired, thermodynamically more stable state by establishing tight processing controls for GMP drug product manufacture.

With the emphasis on pre-clinical studies to demonstrate an acceptable safety margin by administering relatively high doses to look for in-vivo acute or chronic toxicity, it can be significantly difficult to predict human PK at the much lower, therapeutic dose. The molecular structure, physical form, salt selection, and choice of excipients in the clinical formulation are intertwined and interdependent factors that contribute to the observed human PK performance.

Science-led candidate selection and candidate development

The decision to select the right molecule at the end of the discovery phase is a critical milestone in advancing any new medicine. Candidate development involves the coordination of a number of different activities across a number of different disciplines. The speed and complexity of the subsequent candidate development journey to a First-in-Human (FIH) clinical trial is intrinsically linked to the molecular structure and the selection of the right salt, the right polymorph, the right formulation, and ultimately the design of the right product and the right clinical trial. Engaging early in the candidate selection stage with a drug development scientist with clinical experience can help provide a broader, more holistic assessment of the optimized lead molecules.

Our unique integrated approach gives customers access to expertise and capabilities that aid in selecting the optimal candidate for moving forward into development.

We also have the knowledge of how to holistically translate molecular-level characteristics throughout the entire development process. This approach to candidate development demonstrably reduces the overall time and cost of getting new medicines to patients in need.

In its broadest sense, the need to reformulate can occur at any stage in the product development lifecycle. This could range from small changes to the formulation, to improve processability for example, to more significant changes, such as changes to the dosage strength. Furthermore, the need for an entirely different formulation may be identified. Examples could include switching to a different drug product to ensure suitability for the development phase of a new drug, generation of age-appropriate formulations for patients, or as part of the lifecycle management strategy for a product, such as the development of a modified-release (MR) formulation to reduce dosing frequency.

However, the success of a reformulation is dependent on scientific expertise, the right technology, availability of appropriate models for formulation testing, and a lot of strategic planning.  

The general industry trend towards outsourcing to specialist contract organizations has further complicated this challenge. These specialist organizations are invariably reflective of the functional silos that exist in traditional pharma, offering the strong capability, experience, and infrastructure required in their field. However, their specialism also means that multiple providers are required to deliver each drug development activity, each of whom must play their part in total alignment with all other contributors. Naturally, issues occur along the way and development timelines are impacted. This all points to a need for an integrated service provider with all these capabilities in-house who can streamline the outsourcing model and improve the likelihood of success for a reformulated product.

What sort of reformulation might be required and when?

Early development

In early development, relatively simple, fit-for-purpose formulations are frequently employed to expedite entry into clinical development, and the efficacious dose may not be known until after dosing to healthy volunteers and the pharmacokinetics (PK) in humans is known. Such early formulations may therefore be designed to provide some dose flexibility and may also require dosing of multiple dosage units in the first-in-human (FIH) studies to define the target dose for later-stage studies. Once all of this is known, the product may need to be reformulated in order to deliver the required dose in as few dosage units as possible for proof-of-concept (POC) studies.

Furthermore, at this stage of development, relatively little will be known about the relationship between the formulation and the critical quality attributes (CQAs) of the drug product. As more is learned as the product advances through development, optimization of the formulation may be required. For example, incompatibilities with or degradation of the active pharmaceutical ingredient (API) during long-term storage might be identified, requiring modification of the levels of particular excipients or their substitution. This might also be required for product launches in different territories due to differing regulatory requirements or stability challenges in different climatic zones. Whatever the reason, an in-depth understanding of the issue at hand is required to justify the need to reformulate and the appropriate strategy to employ. Depending on the extent of the changes to the formulation, bridging clinical studies may be required to understand the impact, if any, on the bioavailability and PK of the API. 

At Quotient Sciences, we take an integrated approach to reformulation projects in the early development stage. Our unique platform, Translational Pharmaceutics^®, enables us to fully integrate drug substance, drug product, and clinical testing, all under one organization and a single program manager, breaking down traditional industry silos to accelerate molecules through development. Real human data is used to drive formulation decision-making and technology selection, which greatly increases the likelihood of downstream clinical success. This seamless integration of activities allows for closely aligned workflows that efficiently conserve API consumption, reduce overall development risk and costs, and fast-track molecules from candidate development to FIH and onward to Good Manufacturing Practice (GMP) drug products for POC studies.  

Late development

In late-stage development, a complete reformulation of an API is usually only justified if there are significant issues with the formulation’s performance in manufacturing (e.g. on scale-up), prior to use (e.g. stability), or in use (e.g. performance). An exception to this, however, might be where there have been significant changes to the target product profile (TPP). This could occur, for example, following end-user feedback on the current drug product, the targeting of a new indication with a different patient demographic (e.g. pediatric population or 505(b)(2)), or as part of the product lifecycle management strategy. In this situation, there could be a switch to a totally different product format or route of delivery and/or require the use of an alternative formulation technology. While the changes made to the formulation could be significant, learnings from the previous formulation development program are invaluable in informing development and key performance targets (e.g. PK parameter targets) to give a head start to the development program.

Depending on the formulation technology employed, “critical-to-performance” formulation variables may be identified, such as the levels of a functional excipient. As the precise level of such a formulation variable required to achieve the desired performance may not be known, to maximize the chances of success of the program, formulators can employ a “formulation design space”. This involves bracketing formulations within the design space by generating supportive batch analysis and stability data at the extremes of the design space. Obtaining regulatory approval for the design space enables the development team to dose any formulation within the design space and make formulation modifications in response to the arising clinical data until the performance targets are met. This approach requires tight integration of the chemistry, manufacturing, and controls (CMC) teams with their counterparts in drug metabolism and pharmacokinetics (DMPK), regulatory, quality assurance (QA), and clinical to align around the formulation to be dosed once in the clinic, but it can save significant time by maximizing the chances that the new formulation hits the required targets.

In the later stages of development, our Translational Pharmaceutics platform can be applied to integrate formulation development, real-time adaptive GMP manufacturing, and clinical testing activities. Flexible study protocols and rapid “make-test” cycles enable the development and optimization of formulations in real time based on clinical data. This approach can be used to evaluate and select solubilization technologies, optimize MR systems, develop pediatric dosage forms, and change routes of delivery. As part of regulatory submissions, we obtain approval to make formulation adjustments within a mapped design space. This means that any formulation within certain defined parameters can be rapidly made and tested to determine the impact on the drug release rate and PK profile, enabling us to efficiently identify the optimal formulation without the need for regulatory amendments. This greatly reduces development risks, maximizes the probability of commercial success, and saves time and costs.

Case study 1: Enhancing drug solubility before Phase II

BOS172767, a Biopharmaceutics Classification System (BCS) class II molecule, was being developed by Boston Pharmaceuticals for the treatment of autoimmune diseases. The FIH study showed poor oral bioavailability and a significant food effect, which prevented the project from advancing into patient studies. An enhanced formulation was required to help overcome these challenges and to identify a formulation suitable for long-term clinical development.

At Quotient Sciences, using Translational Pharmaceutics, three solubility-enhancement platforms were developed and rapidly screened in the clinic, including a micronized form of the API, a self-emulsified lipid delivery system, and a spray-dried dispersion. The drug products were produced at a small scale for quick POC assessment without the need to conduct larger-scale, cost-prohibitive process development and lengthy stability programs for multiple technologies. The human PK study used a five-period cross-over design in 16 healthy volunteers.

The micronized formulation delivered the best human PK outcome, which enabled the sponsor to advance with a simpler and cheaper technology into larger-scale clinical development. The overall timeline from initiating formulation laboratory work to receiving clinical PK data was 6 months.

Case study 2: Development of an optimized MR tablet formulation for initial POC trials

SLx-2101, a novel phosphodiesterase-5 (PDE-5) inhibitor, was being developed by Surface Logix as an antihypertensive agent. Data from early development studies with an immediate-release tablet formulation determined that an MR formulation was needed to reduce C_max-related adverse events and ensure the 24-hour PK profile remained within the therapeutic window to achieve a once-daily treatment regime.

At Quotient Sciences, using Translational Pharmaceutics, hydroxypropyl methylcellulose (HPMC)-based matrix MR tablets were developed for assessment in an adaptive relative bioavailability Phase I study to optimize the MR tablet formulation based on human clinical data. A two-dimensional formulation design space was established, covering dose strengths between 10 and 20 mg and sustained drug release durations between approximately 12 and 20 hours. Representative formulations at the extremes and mid-points of the design space were manufactured and characterized to demonstrate that the performance of the formulation can be controlled by varying the drug loading and HPMC content in the formulation. The formulation design space was submitted as part of a Clinical Trial Application (CTA) and approved for clinical investigation.

The clinical study was a five-period sequential design with interim data reviews between each dosing period to allow iterative investigation of the design space and identification of the optimal drug product composition. The formulation design space allowed a wide range of formulation compositions to be evaluated in response to emerging clinical data, with the optimal MR formulation identified in 7 months.

Summary

In summary, reformulation may be required at any stage in the drug development lifecycle. Successful reformulation is dependent on many factors and can be difficult to achieve within traditional industry silos. At Quotient Sciences, through our Translational Pharmaceutics platform, we possess the expertise and capabilities needed to reformulate products for clinical and commercial success. By taking a unique, integrated approach that is tailored to each program, we provide optimal results for our customers in the most efficient and cost-effective manner, getting new medicines to patients faster.

Get more information about our fully integrated Translational Pharmaceutics platform.

We work in a dynamic and innovative industry, which is constantly seeking new ways to do things better in order to accelerate the availability of new medicines for patients. However, the approach towards Good Manufacturing Practice (GMP) manufacturing of pharmaceutical dosage forms for clinical and commercial use has largely remained unchanged over several decades, with a focus on batch processing at large scale, often requiring complex equipment trains. For oral dosage forms, this has proved highly successful in the development and delivery of dozens of blockbuster drugs to address huge clinical and patient needs.

However, in recent years, we have started to see a shift in the types of new therapeutics reaching the marketplace. More than half of new US Food and Drug Administration (FDA) drug approvals since 2018 have been for rare diseases, which are defined as affecting less than 200,000 people in the US or no more than one in 2,000 of the general EU population. This development has challenged our industry’s historical manufacturing paradigm. Batch sizes of hundreds of kilograms or millions of dosage units will no longer be required or needed. Instead, there will need to be a greater emphasis on small-scale, flexible manufacturing to address this demand, where product supply is fully tuned to the size and shape of these emerging patient populations.

Separately, we are also seeing drivers for personalization of new medicines. Bespoke, patient-centric dosage forms will become increasingly important to ensure optimal therapeutic outcomes, whether for tailored milligram/kilogram dosing, customization based on diagnostic or pharmacogenomic screening into stratified populations, or tuning of product composition or format to ensure acceptability in pediatric and geriatric age groups.

At Quotient Sciences, we have successfully pioneered the use of real-time, adaptive GMP manufacturing within a clinical study through our integrated Translational Pharmaceutics^® platform. This unique approach enables us to respond quickly and flexibly to manufacture and supply bespoke products for healthy volunteers and patients based on study needs. What will be the next evolution…or revolution?

Additive manufacturing (also known as 3D printing) is now commonplace in many industries. However, for pharmaceuticals, it is still nascent and arguably balancing on the cusp of translation from academic research into industry practice. We do have regulatory validation with SPRITAM®, the FDA-approved commercial product launched by Aprecia in 2015, but what will the future impact of 3D printing be, given the changing dynamics in clinical research discussed above?

Undoubtedly, opportunities will exist within first-in-human (FIH) studies, when the use of an immediate-release (IR) oral solid dosage form is desired or required. Having the ability to select a unit dose strength with unique precision and manufacture a handful of tablets would drive significant efficiencies in time, cost, and active pharmaceutical ingredient (API) consumption during the single- and multiple-dose escalation study.

We see another key opportunity in the development of modified-release (MR) tablets. The ability for rapid prototyping and clinical assessments of fast- and slow-releasing formulations would allow expedited assessments of regional bioavailability in humans. This would make it possible to determine MR potential without necessarily investing in the development of conventional dosage forms, technologies, and processes. Simplicity is further enhanced by the unique ability for geometrically controlled drug release from a single formulation composition. For a new molecule with half-life risks flagged from in-vitro drug metabolism and pharmacokinetics (DMPK) studies, this assessment could be readily factored into the FIH study as an optional part if initial human data dictates.

A major impact will also be realized in patient trials for special populations, such as pediatrics, where bespoke dosage strengths may be required based on a child’s body weight or surface area, or where a personalized medicine may be required for palatability and acceptability to ensure patient compliance and desired therapeutic outcomes. Tailoring the product to the patient may also be needed in rare and ultra-rare disease populations, where recruitment for patient trials will be slow, unpredictable, and extended over many sites and geographies. 3D printing could ensure a sponsor gets the right product to the right place at the right time, either through a centralized manufacturing hub or remote printing operations.

Of course, challenges will exist, which will need to be circumvented. Key will be ensuring vertical integration of 3D printing operations, so prototypes used in early trials can be taken seamlessly into later-stage and commercial manufacturing. As another benefit, 3D printing should facilitate this in terms of scalability of the equipment, avoiding the need to manage product and process changes.

Through academic collaborations and projects with industry partners, Quotient Sciences is actively developing capabilities for the 3D printing of oral solid dosage forms and exploring their potential to further enhance agility for our customers within healthy volunteer and patient trials. As an organization with a culture focused on science and innovation, we are very excited to see how developments will progress in this space.

Read findings from three recent Quotient Sciences scientific posters that highlight strategies we've used to streamline the development of modified-release formulations.

Modified-release (MR) formulations play a vital role in improving patient compliance and therapeutic outcomes for oral drug products. However, identifying the optimal formulation technology and delivery rate to achieve the desired in-vivo release profile can be challenging.                                     

Traditional modified-release development programs follow a rigid, linear process that relies on pre-clinical models to predict performance in humans. This can be risky, given the poor correlation of bioavailability between pre-clinical species and humans. As a result, repeated cycles of pre-clinical and clinical testing are required to arrive at a sufficient formulation, which can be costly and time-consuming. This points to a need for a streamlined approach.

We have over 30 years of expertise in developing and manufacturing modified-release drug products. 

Using our Translational Pharmaceutics^® platform, we are able to integrate drug substance, drug product development, real-time adaptive Good Manufacturing Practice (GMP) manufacturing, and clinical testing activities to streamline the development of these programs. Flexible study protocols and rapid "make-test" cycles enable the optimization of modified-release formulations in real time based on rising clinical data.

As part of regulatory submissions, we obtain approval to investigate a range of formulation compositions bound within a formulation design space. This means that any formulation within the design space can be rapidly made and tested to determine the in-vivo performance of that product via its pharmacokinetic (PK) profile. Clinical data from one dosing period determines the formulation composition that is made and tested next, enabling efficient identification of the optimal formulation in an accelerated timeframe. This reduces development risks, maximizes the probability of clinical success, and saves time and costs.
 

Pharmaceutical and clinical performance comparisons of modified-release multiparticulates and matrix tablet formulations.

Presented at the American Association of Pharmaceutical Scientists (AAPS) PharmSci 360 conference in October 2021. Quotient Sciences' Authors: Asma Patel, Wu Lin, Aruna Railkar, Peter Scholes.

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The purpose of this study was to review practical experiences of head-to-head pharmaceutical and clinical comparisons of two commonly used MR technologies for sustained drug release, multiparticulates, and matrix tablets, to identify an optimal MR formulation.

In most of the eight integrated clinical programs that were analyzed, the in-vivo performance of both technologies was similar, but a higher food effect was observed for matrix tablets in some cases. In all eight of the programs, matrix tablets were selected over multiparticulates, which suggested that the overall benefits of matrix tablets, including development and commercialization being simpler and cheaper, outweighed any slightly greater clinical benefits of multiparticulates.

This poster highlights how the use of formulation design spaces, integrated manufacturing and clinical testing, and flexible study protocols can enable parallel assessment of multiple MR platforms, in order to reduce development risks, efficiently identify the best technology to achieve the desired target product profile (TPP), and ultimately maximize the probability of success.
 

"Development of modified-release matrix tablet formulation using solid lipid Compritol^® 888 for a poorly water-soluble drug"

Presented at the AAPS PharmSci 360 conference in October 2021. Quotient Sciences' Authors: Dolly Jacob, Wu Lin, Kieran Crowley, Alaa Hosny, Charlotte Clay, Katie Clarke, Peter Scholes.

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This poster highlights how solid lipid excipients offer a promising strategy in the development of MR formulations for poorly water-soluble drugs.

In this study, an MR tablet was required to reduce C_max-related side effects observed with the immediate-release formulation of a poorly water-soluble drug. The purpose of the study was to evaluate the use of Compritol 888, a synthetic solid lipid excipient that can be used as an insoluble matrix for sustained drug release, to achieve the required MR profile.

The impact on the drug release rate of adjusting the following variables in the matrix MR tablet was assessed: the level of Compritol 888, the drug loading, the use of lactose as a soluble filler, and the use of the surfactant sodium dodecyl sulphate (SLS) as a wetting agent. It was found that by adjusting the level of Compritol 888, a wide range of drug release rates could be achieved. The drug release rate was also affected by the drug loading, with a faster drug release rate observed with lower drug loading. The soluble filler promoted tablet erosion and smoothed out the overall drug release profile, whereas the surfactant did not affect the drug release rate.
 

"Using formulation design spaces and clinical data to optimize the development of modified-release (MR) dosage forms"

Presented at the Controlled Release Society (CRS) conference in July 2021. Quotient Sciences' Authors: Aruna Railkar, Asma Patel, Peter Scholes

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This poster highlights how the use of formulation design spaces, integrated manufacturing, and clinical testing, and flexible study protocols enables efficient evaluation of critical-to-performance variables in MR formulations, which reduces development risks and maximizes the probability of success.

The purpose of this study was to conduct a review and meta-analysis of 50 integrated MR formulation development programs, including assessing the following features: active pharmaceutical ingredient (API) properties, formulation technologies, critical-to-performance parameters, formulation design space variables, in-vitro characterization methods, and clinical design flexibility.

It was found that at least 10 different MR technologies were used across the 50 programs, with diversity in physicochemical, biopharmaceutic, and drug metabolism and pharmacokinetic (DMPK) API properties influencing which technology was most suitable for achieving the target PK/product profile. For 12 of the programs, more than one technology platform was evaluated in a single clinical protocol to identify an optimal formulation. In total, more than eight different formulation attributes had clinical flexibility maximized by incorporation into a design space, with individual programs concurrently evaluating up to three different design space variables.

Summary

With a strong emphasis on science and innovation, Quotient Sciences continues to research new and improved ways to streamline the development of MR programs.

Contact us today to find out how Quotient Sciences can support your next modified-release program.