What is biopharmaceutics, and how does biopharmaceutics fit into the field of pharmaceutical drug development? Quotient Sciences Dr. Vanessa Zann, Senior Drug Development Consultant speaks with Pharmaceutical Technology about biopharmaceutics.

Quotient Sciences has over 30 years of helping pharma and biotech customers accelerate the development and optimization of drug products. Dr. Zann's article examines biopharmaceutics, an area which looks at the fundamental properties of the drug, dosage form, and the route of administration on the rate and extent of systemic drug absorption.

Read Dr. Zann's article in Pharmaceutical Technology

Our team of chemists and scientists review the properties of each drug candidate that we work with to develop formulations that improve the exposure profile of the compound. This is the key to understanding the biopharmaceutic properties of the compound. Contact us today to learn more about how we can apply our biopharmaceutics knowledge to your next program.

Solubility & Bioavailability: Difficult Beasts to Tame - Quotient Sciences Dr. Dolly Jacob, Director of Integrated Development Services speaks with Drug Development & Delivery.

Poor solubility is becoming increasingly prevalent in drug pipelines. Infact, across the pharmaceutical industry, about 70 percent of drugs that enter development possess insufficient aqueous solubility for adequate and consistent gastrointestinal absorption.

In a recent article with Drug Development & Delivery, Quotient Sciences, Dr. Jacob discussed how the industries solubility and bioavailability challenges increase for­mulation complexity, raise failure rates, and drive-up development costs. At Quotient Sciences we find solutions to unlocking the potential of each small molecule we work with.

"Drug developers utilizing the traditional formulation development model aren’t assessing a molecule’s devel­opability before pressing ahead into de­velopment or using key biopharmaceutics tools that can greatly aid in ensuring a molecule’s success, thus creating an indus­try need for a new and innovative way to develop drugs more efficiently."

Read article

Solubility Enhancement at Quotient Sciences

With nearly 30 years of experience, Quotient Sciences has established a broad suite of technologies and formulation approaches to address complex solubility and bioavailability challenges. Our expertise and approach allows us to accelerate the optimization of your drug products to improve oral bioavailability.

Discover more

NOTTINGHAM, UK; March 28, 2023 – Quotient Sciences, the drug development and manufacturing accelerator, today announced that it has grown the workforce at its Alnwick, UK, facility by 20% over the past 2 years. The Alnwick site’s growth has been fueled by its attractive location, variety of career opportunities, and strong people leadership.

Quotient Sciences Alnwick currently employs over 200 people across a range of scientific disciplines, including process chemistry, solid-state characterization, radiosynthesis, analytical science, bioanalysis, and formulation development. In October 2022, the company announced the completion of a major £6 million expansion of its drug substance manufacturing facility, which created an additional 80-100 new scientific and technical jobs at the facility.

Paul Ryan, SVP & Head of Candidate Development, said: “We are a growing site, creating opportunities for career growth both within the Alnwick team and as part of the wider Quotient Sciences organization. It is very inspiring to work on pharmaceutical projects that deliver on our manifesto, ‘Molecule to cure. Fast.™’, and hear first-hand from some of the patients who have benefited from the new medicines we have helped to deliver. In 2023, the pace of growth is set to continue with the expansion of our aseptic manufacturing capability at the Alnwick site, along with continued growth across all areas of the business. This will provide opportunities for technical and manufacturing roles in drug product manufacturing.”

For those interested in open positions, the Alnwick site is known for providing excellent career development opportunities for knowledgeable, ambitious, and hardworking candidates. This reputation was recognized in 2021, when the site was named “Most Inspirational North-East (UK) Science Employer” by STEM Learning as part of the STEM Ambassadors program. The state-of-the-art facility is in Northumberland, which is easily accessible from the A1. By joining Quotient Sciences, candidates gain the opportunity to work across a range of customer projects and scientific areas. The company offers a flexible working environment for many roles, which enables candidates to choose their work pattern.

During the interview process, candidates meet with multiple colleagues to find out more about Quotient Sciences, their interested role, and the facility. Candidates who were invited for interviews have previously commented that they like the flexible work arrangement, the technical and diverse range of work, and the welcoming colleagues onsite.

About Quotient Sciences

Quotient Sciences is a drug development and manufacturing accelerator providing integrated programs and tailored services across the entire development pathway. Cutting through silos across a range of drug development capabilities, we save precious time and money in getting drugs to patients. Everything we do for our customers is driven by an unswerving belief that ideas need to become solutions, and molecules need to become cures, fast. Because humanity needs solutions, fast. For more information, please visit quotientsciences.com.

Crinetics Pharmaceuticals announces CRN04894 pediatric program in partnership with Quotient Sciences.

NOTTINGHAM, UK; March 30, 2023 – Crinetics Pharmaceuticals, a pharmaceutical company that develops therapies for rare endocrine diseases, and Quotient Sciences, a drug development and manufacturing accelerator, have announced a partnership to support Crinetics’ CRN04894 pediatric program. The partnership will utilize Quotient Sciences’ unique Translational Pharmaceutics® platform to provide integrated formulation development, clinical manufacturing, and taste assessment studies to accelerate Crinetics’ development timeline.

Crinetics is currently developing CRN04894 as an investigational, oral, non-peptide product candidate designed to antagonize the adrenocorticotropic hormone (ACTH) receptor, intended for the treatment of diseases caused by excess ACTH, including Cushing’s disease and congenital adrenal hyperplasia (CAH). The pediatric formulation is an oral solution in development for children under two years of age that requires flavoring and sweetening to improve palatability.

Quotient Sciences has over 30 years of experience in pediatric formulation development and taste assessment studies. To support Crinetics’ CRN04894 pediatric program, Quotient Sciences will carry out an integrated, real-time adaptive GMP clinical manufacturing campaign alongside a Phase I clinical study in healthy volunteer subjects to assess the taste and palatability of several oral solution formulations. The development program will evaluate different flavoring agents and sweetener levels in order to identify the optimal formulation.

"There is an art to the development of taste-masked oral products for pediatric indications,” said R. Scott Struthers, PhD, Founder and CEO of Crinetics Pharmaceuticals. "Quotient Sciences’ expertise in improving the taste, smell, and texture of oral formulations makes them the ideal partner for Crinetics’ pediatric clinical programs."

Mark Egerton, PhD, CEO of Quotient Sciences, added: "We are delighted to partner with Crinetics to support the development and clinical testing for CRN04894. With the industry focused on developing acceptable and palatable pediatric formulations to address patient need and regulatory requirements, we are fortunate that our integrated Translational Pharmaceutics® platform offers customers the opportunity to accelerate their development timelines, so that patients can access much-needed medicines faster."

About Quotient Sciences

Quotient Sciences is a drug development and manufacturing accelerator providing integrated programs and tailored services across the entire development pathway. Cutting through silos across a range of drug development capabilities, we save precious time and money in getting drugs to patients. Everything we do for our customers is driven by an unswerving belief that ideas need to become solutions, and molecules need to become cures, fast. Because humanity needs solutions, fast.

About Crinetics Pharmaceuticals

Crinetics Pharmaceuticals is a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for endocrine diseases and endocrine-related tumors. Paltusotine, an investigational, oral somatostatin receptor type 2 (SST2) agonist, is in Phase 3 clinical development for acromegaly and Phase 2 clinical development for carcinoid syndrome associated with neuroendocrine tumors. Crinetics has demonstrated pharmacologic proof-of-concept in Phase 1 clinical studies for CRN04777, an investigational, oral somatostatin receptor type 5 (SST5) agonist in development for congenital hyperinsulinism, and for CRN04894, an investigational, oral ACTH antagonist in development for the treatment of Cushing’s disease, congenital adrenal hyperplasia, and other diseases of excess ACTH. All of the company’s drug candidates are orally delivered, small molecule new chemical entities resulting from in-house drug discovery efforts.

Crinetics Pharmaceuticals Company Contacts

Chas Schultz
Vice President of IR and Corporate Communications
(858) 450-6464
[email protected]

Quotient's Vice President of Pharmaceuticl Sciences, Dr Andy Lewis was featured in a recent article in Pharmaceuticla Technology Magazine.

"The Earlier the Better for Formulation Strategies"
November 2, 2021 | Pharmaceutical Technology, Pharmaceutical Technology, November 2021 Issue, Volume 45, Issue 11

Investing in formulation strategies earlier on in development will maximize the chance of success.

The bio/pharmaceutical industry is under more pressure than other industries to create innovative products because of the time limits placed on patents and exclusive licenses for drugs (1). However, pharmaceutical drug development also suffers from significantly high and variable rates of attrition, attributed to factors such as formulation issues, solubility and bioavailability challenges, alongside a lack of efficacy (2).

Expenditure on R&D is rising year-on-year, with estimates for this trend to continue into the future (1). Therefore, expectations to achieve greater success with each drug molecule in development are becoming more pressing. Complex and difficult to formulate molecules are ever more present in development pipelines, and an overarching industry trend toward niche therapeutic and specialized disease areas persists, so the importance of innovative formulation strategies implemented early in the development timeline is becoming alarmingly apparent.

Under pressure
“No matter the modality, there has been increasing pressure for a number of years to advance new medicines through development as quickly as possible,” says Andrew Lewis, vice-president of Pharmaceutical Sciences, Quotient Sciences. To achieve a rapid time-to-market, a successful formulation development strategy must be in place, and in order to do that, formulators must consider some key aspects, he adds.

Understanding ways to enable rapid first-in-human assessments while also meeting study objectives; transitioning to a drug product that is suitable for proof-of-concept studies in a time efficient manner; and working out time and cost-efficient strategies for scale-up as product development progresses are imperative, Lewis continues. “Some trade-offs may need to be made at different stages of development but viewing the program with the next stage in sight, enables integrated development strategies to be developed to mitigate risks and accelerate molecules through development,” he says.

Jessica Mueller-Albers, strategic marketing director Oral Drug Delivery Solutions, Evonik, agrees that pressure to speed up drug development has been increasing. “This [increased pressure] is because many new drugs target small therapeutic areas, where it is essential for pharma companies to be first in the market from an economic perspective,” she notes.

“In recent years we have seen that many of the drugs approved are high-priced specialty drugs for relatively small numbers of potential patients,” Mueller-Albers says. “This [trend] contrasts to the top-selling drugs of the 1990s, which were lower-cost and created for large patient populations. Regarding formulation, the trend towards more specialty drugs requires new formulation approaches that use enabling technologies.”

To illustrate how the industry trend is moving away from blockbuster-type drugs, Mueller-Albers highlights the messenger RNA (mRNA) technology platforms that came to prominence in 2020 through the launch and roll-out of certain COVID-19 vaccines. “This [technology] was a starting point for a new class of drugs, not only for prophylactic vaccines, but also therapeutic vaccines and other therapeutics for cancer and rare diseases,” she asserts. “Overall, mRNA has the potential to become a competitive modality across broad applications, especially as further advances in improving delivery and stability are made.”

Another example of a more specialized therapy is proteolysis-targeting chimeras (PROTACS), Mueller-Albers points out. “[PROTACS] are an emerging therapeutic modality with the potential to open a new target space via a degradation-based mechanism,” she says.

But in order to keep up with the time pressures, while developing specialty and niche therapies in particular, industry needs to improve R&D productivity, Mueller-Albers stresses. “The approach to improving productivity is reflected in the R&D budgets of different sized firms,” she explains. “Small companies generally devote a greater share of their research in developing and testing new drugs, which are ultimately sold to larger firms. Larger drug companies allocate a greater portion of their R&D spending to conducting clinical trials and developing improvements.”

Focusing on small companies, Stephen Tindal, director, Science & Technology, Europe, Catalent, emphasized the challenges they face regarding expertise. “One of the key challenges for any small pharma company is to hold sufficient expertise across the key disciplines of medicinal chemistry, material characterization, formulation and drug metabolism and pharmacokinetics (DMPK), in order to address all the possible combinations that could be required to progress a molecule from the modern discovery process,” he confirms.

If the trend of small companies developing APIs continues, then small teams will be required to navigate through the preclinical phase, which throws up resource and decision challenges, Tindal advises. “For example, in late-stage drug discovery, [the developer] may have a choice between four to six molecules, with each having its own unique potency, solubility, and API manufacturing challenges, and perhaps also the choice of whether to employ a salt form to improve poor solubility,” he says. “At this stage, the small team should choose to engage a formulator.”

Additionally, Sanjay Konagurthu, senior director, Science and Innovation, pharma services, Thermo Fisher Scientific, emphasizes the fact that between 70% and 90% of new chemical entities (NCEs) in development pipelines are poorly soluble. “NCEs often have bioavailability challenges when it comes to oral drug delivery, therefore, selection of the appropriate formulation technologies based on a deep understanding of the Developability Classification System (DCS) becomes important,” he notes. “A thorough understanding of the API physicochemical properties as it pertains to oral absorption is necessary to guide formulation strategies.”

The earlier the better
Generally, preclinical formulation development is focused on achieving a desired pharmacokinetic response in an animal model, while also keeping time and cost for formulation development at a minimum, Mueller-Albers confirms. “A structured approach starting at an early stage can help de-risk the drug development process and avoid costly late-stage failures,” she says.

“In order to properly triage a molecule in late-stage discovery, a formulator should be engaged to help provide a line of sight to the path for clinical evaluation and commercial development,” adds Tindal. “The assumption is that discovery molecules are precious, and formulation expertise will be able to progress any candidate, rather than discarding a molecule in favor of another with better properties at the end of a traditional API selection and development process.”

For Konagurthu, it is critical for formulation scientists to understand the benefits of investing in scale-up in the early phase of development. “At this stage, formulation scientists should obtain as much information as they can about what is happening at the mechanistic level of a formulation process because it is much less expensive to identify and address manufacturability problems earlier in the process than later,” he emphasizes. “In addition, evaluating formulation and process impact on product critical quality attributes help to mitigate scale-up problems.”

“Companies need ‘early formulation’ teams with expertise in physicochemical characterization and biopharmaceutics integrated with colleagues in drug discovery and medicinal chemistry to advise on candidate optimization and selection to maximize chances of success of a molecule” asserts Tindal. “But, it may not make sense to invest in a formulation technology until Phase I safety data is available, unless that study is performed in patients, where a finished dosage form may be desirable. As it can be challenging to fulfill both the clinical hypothesis and the long-term scale-up issues together, it is important to engage the formulator earlier to develop a long term strategy.”

Overcoming challenges

Very early on, when working with systemic oral small-molecule drugs, developers should consider delivering drug in solution to the gastrointestinal tract so that the drug can be absorbed, reminds Tindal. A positive to working in solution is that less API is required and is likely to provide more reliable data providing the API is at least reasonably stable. This could entail developing a solution, a powder, or a liquid that was in solution during processing and delivers a solution on dispersion, he adds.

“For these reasons, working with simple aqueous solutions, spray-dried amorphous dispersions, or lipid formulations, has turned the early development process on its head,” Tindal explains. “A formulator can accelerate API development, navigate through dose escalation studies, and use less API, all of which help to get more new chemical entities to Phase I proof of concept in healthy volunteers within an acceptable budget, with a focus on formulation development at a later stage.”

“The onus falls on formulation scientists to make sure they design a robust formulation that provides adequate bioavailability, stability, and manufacturability,” says Konagurthu. “This [responsibility] requires them to have proper knowledge about drug substance properties, how they interact, and any potential issues the scientist may face during formulation development.”

If the compound exhibits poor solubility or permeability for example, then the formulator should know to select a solubilization approach to improve oral absorption and bioavailability, Konagurthu continues. Some options available to formulators to overcome such issues include hot-melt extrusion, spray drying, coated beads, size reduction, lipid-based approaches, and so, on, he notes.

“By far the most common challenge when formulating small molecular weight drugs is improving poor solubility to maximize bioavailability,” Lewis confirms. “In developing the formulation strategy, it is essential to understand the basis for the poor solubility—whether it is dissolution rate limited or solubility limited—informed by the preformulation data package.”

Particle-size engineering technologies, such as micronization and nanomilling, can be used to improve the solubility of a dissolution rate limited API, whereas amorphous dispersions, using spray drying or hot melt extrusion, might be better for APIs that are solubility limited, Lewis states. “Also, in recent years we’ve seen lipid-based drug delivery systems and complexes become increasingly important tools in the quest to improve the oral bioavailability of poorly soluble drugs. It is not unusual for several technologies to be evaluated head-to-head in a clinical study in order to select one for further development based on their performance and implications for later development,” he adds.

Poor solubility or bioavailability of an API can be problematic in drug development and can lead to an incomplete or variable absorption of the drug, a higher impact of pH and food on drug absorption, and poorly controlled pharmacokinetics, Mueller-Albers asserts. “It is therefore extremely important to develop a formulation that maximizes the chance of good exposure, even if doing so requires additional time and cost. This is especially true as the solubility of new molecules becomes more demanding,” she says.

There are advanced solubilization technologies available that can help overcome the challenges of poor solubility, Mueller-Albers continues. Using the example of lipid-based technology, she states, “When drugs are orally administered, they can bypass first-pass metabolism through the lymphatic pathway. During intestinal lymphatic drug transport, long-chain and unsaturated lipids are assembled into chylomicrons (ultra-low-density lipoproteins) in enterocytes (intestinal absorptive cells). Chylomicrons are then exocytosed (excreted) from the cell and enter the lymphatic route. If lipophilic drugs are co-administered with these lipids, they are prone to incorporation into chylomicrons and can be delivered to the lymphatic system in the form of chylomicron–drug complexes. Thus, co-administration with lipids can enhance the lymphatic transport of lipophilic drugs.”

Novel approaches
To be able to select the most appropriate solubility enhancement technology and excipients for a molecule without requiring extensive and unnecessary testing it is possible to employ diagnostic tools, highlights Konagurthu. Using Thermo Fisher Scientific as an example, Konagurthu points to Quadrant 2, which uses proprietary computer algorithms to select the most effective solubility enhancement for a compound and which excipients should be used for formulation and process development.

“Furthermore, Thermo Fisher has developed an ‘Engineered Solutions’ approach to pharmaceutical product development by building predictive models that understand the interplay between materials, formulations, process, and biopharmaceutics,” says Konagurthu. “These predictive tools can de-risk formulation impact on scale-up and technology transfer to enable accelerated product development timelines.”

For Mueller-Albers, a significant new development in oral solid drug delivery technology is an empty ready-to-fill enteric capsule, designed to optimize gastric resistance and improve absorption for drug products targeted for release in the upper small intestine. “The high-quality hydroxypropyl methylcellulose capsules feature a precisely tailored functional coating that is well accepted by key regulatory bodies around the world,” she notes.

Additionally, a pilot program to review novel excipients has been launched by the Center for Drug Evaluation and Research that will provide new options for formulators to use in specialized drug products, Mueller-Albers discloses. “[The pilot program] is intended to allow excipient manufacturers to obtain FDA review of certain novel excipients prior to their use in drug formulations,” she says.

“Recent advances in small-scale ultraviolet probe dissolution apparatus have really helped to unlock the solubilization of API in bio-relevant media,” adds Tindal. “I would really like to see more advances in in-silico prediction, but remain skeptical that the models could be properly trained with a meaningful data set. Nonetheless, they can be very useful, if only for beginning a thought experiment, which can be a very useful part of the planning phase.”

“It is not uncommon for preclinical data to not reflect the human situation, which can lead to the wrong formulation strategy being selected, or sub-optimal formulation performance,” emphasizes Lewis. At Quotient Sciences, integrated adaptive clinical trials are used to guide formulation development and selection in human subjects, which, Lewis confirms, accelerates development. “These Phase I trials in healthy volunteers can be used to compare technological approaches head-to-head and select formulations for later dosing periods (e.g., multiple ascending dose) based on their performance,” he says. “We have also used these [trials] to bridge from a simple first-in-human formulation to a proof-of-concept ready formulation within study with a single regulatory approval.”

Furthermore, it is possible to obtain regulatory approval to dose any formulation within a design space that has been defined through the identification of a critical-to-performance formulation variable, Lewis continues. “The formulation to be manufactured and dosed can be modified, informed by the emerging clinical data (e.g., pharmacokinetic parameter) to ensure the target product profile is achieved,” he states. “This is all enabled by real-time adaptive manufacturing—products being manufactured immediately prior to dosing rather than months in advance of the clinical trial, accelerating development.”

Final thoughts
“Drug development is a balance between minimizing time to clinic and developing a promising formulation that meets pharmacokinetic targets,” reveals Mueller-Albers. “However, risk of failure of a molecule is not only related to its pharmacological and pharmacokinetic properties or its toxicity, but also to its manufacturability.”

A thorough understanding of the target product profile is necessary to be able to build a robust formulation strategy, emphasizes Lewis. Additionally, referring to the objectives and end-goals of a program is critical in order to ensure that the formulation developed meets the needs of each stage of development, he stresses.

“Formulators need to engage earlier, to overlap with the medicinal chemistry strategies, to partner with the medicinal chemists themselves in order to make decisions about API and drug product, and using formulation with API-sparing techniques that resolve any liabilities that the medicinal chemist cannot quickly fix without having to necessarily invest in a final formulation, but all the while, collecting data that move the project forward. Formulators also need to address all bioavailability factors and not just solubility,” concludes Tindal.

References
1. Statista, “Total Global Spending on Pharmaceutical Research and Development from 2012 to 2026,” statista.com, July 2021.
2. Therapeutics Research Institute, “Pharmaceutical Predictivity,” tri-institute.org, March 2021.

About the Author
Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Article Details
Pharmaceutical Technology
Vol. 45, No. 11
November 2021
Pages: 16–19, 29

Citation
When referring to this article, please cite it as F. Thomas, “The Earlier the Better for Formulation Strategies,” Pharmaceutical Technology 45 (11) 2021.

To access the article on Pharmaceutical Technology's site, visit: https://www.pharmtech.com/view/the-earlier-the-better-for-formulation-strategies

John McDermott, Quotient Sciences' Executive Drug Development Consultant, discusses Integrated Development Strategies Overcome Solubility Challenges, in Drug Development & Delivery's Special Feature in Drug Development & Delivery's Special Feature entitled: "Solubility & Bioavailability: Utilizing Enabling Technologies."

There is no one-size-fits-all solu­tion for improving bioavailability and solubility, and what is correct for one molecule could be over-engineering, or worse, limiting the potential of an­other drug. It is therefore crucial for development teams to understand the drivers of a given molecule’s solubility and its permeability properties to se­lect the correct technologies for as­sessment, and then back up that selection with data. “One of the biggest challenges we see is the expectation of an in vitro/in vivo cor­relation in developing these technolo­gies, which is not realized when clinical data is obtained,” says John McDermott, Executive Drug Develop­ment Consultant, Quotient Sciences. “Having access to human data to as­sess formulation technologies for poorly soluble drugs is therefore cru­cial in guiding formulation selection and optimization.”

Quotient Sciences has had the opportunity to work on several programs that have assessed the clinical performance of some of these novel and emerging technologies to enhance drug bioavailability. “We have seen some great successes for some drugs, and we have also had experiences where performance observed in preclinical and in vitro studies have not translated into humans,” he says.

Quotient Sciences delivers fully in­tegrated programs incorporating for­mulation development with clinical manufacturing, regulatory support, and clinical testing. This platform, termed Translational Pharmaceutics™, can be applied to accelerate the pro­gression of prototype formulations to clinical assessment and onward, to ef­ficiently and accurately assess candi­date formulations, and to improve the likelihood of clinical and commercial success, explains Mr. McDermott.

In one recent case study, a cus­tomer with a BCS II molecule had completed its first-in-human study, which demonstrated inadequate ex­posure and a significant food effect. These issues were stalling the project from advancing into proof-of-concept patient studies. To respond to this, the client needed to rapidly evaluate sol­ubility enhancement technologies and demonstrate its utility to enable effi­cacy assessments in order to proceed to the next project milestone.

In this program, Quotient Sci­ences developed three different solu­bility-enhancing formulations: a micronized form of API; a self-emulsi­fied lipid delivery system; and a spray-dried dispersion. A Translational Pharmaceutics study was performed to achieve a quick proof-of-concept as­sessment, removing the need to con­duct larger scale, cost-prohibitive process development and lengthy sta­bility programs for multiple technolo­gies. The human pharmacokinetic (PK) study used a 5 period cross-over de­sign in 16 healthy volunteers with the micronized formulation delivering the best outcome.

“By applying our Translational Pharmaceutics approach, the overall timeline – from initiating formulation lab work to having clinical PK data to select the optimal formulation – was just six months,” says Mr. McDermott. “While it’s exciting to be involved at the forefront of research in drug deliv­ery technologies, it’s important to re­main focused on the patient – and the best model for assessing humans is a human.”

Read the full article

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.

Pharmaceutical Technology Europe recently spoke with a panel of experts including Vanessa Zann, Senior Drug Development Consultant, and Chris Roe, Senior Research Fellow, with Quotient Sciences to discuss the primary hurdles to accelerated formulation strategies and best practices for developers.

Q: Could you run through the primary challenges facing developers when employing accelerated formulation strategies in drug development?

A - Zann: The main challenge with accelerated formulation strategies is knowing which dosage form technology is the most appropriate to give optimum exposure in man. There is widespread acknowledgement of the lack of predictability of pre-clinical 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.

A - Roe: 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.

Q: Are the challenges more significant for large-molecule products versus small-molecule ones, in your opinion?

A - Zann: 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.

A - Roe: 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).

Q: What sort of activities can developers pursue to ensure their accelerated formulation strategies are successful?

A - Zann: 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.

A - Roe: 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.

Continue Reading

Source: F. Thomas, “Successfully Accelerating Formulation Strategies,” Pharmaceutical Technology Europe 34 (3) 2022.

NEW ORLEANS, LA, March 23, 2022 – South Rampart Pharma (“South Rampart” or the “Company”), a clinical-stage life science company focused on advancing innovative medications for the treatment of pain and fever, announced today patient enrollment and dosing in its Phase 1 study evaluating SRP-3D (DA) for pain is underway.

“We are committed to improving the lives of people suffering from acute, chronic, or neuropathic pain by developing a new class of small molecule, non-opioid pain medicines. To date, SRP-3D (DA) has shown promising efficacy in reducing both pain and fever while lacking the liver and kidney toxicity associated with current prescription and over-the-counter analgesics,” said Hernan Bazan, M.D., Chief Executive Officer and Co-Founder of South Rampart Pharma and Professor of Surgery at the Ochsner Clinic. “We are pleased with SRP-3D (DA)’s development and clinical progress, and we know the market needs this. With patient enrollment and dosing now well underway, we continue to advance toward reporting topline results, expected in the third quarter of this year.”

The Company’s lead program, SRP-3D (DA), is a novel acetaminophen analog with a unique mechanism of action that lacks the liver toxicity present in acetaminophen. It is in development to treat various forms of pain.

The ongoing Phase 1 study is a randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and pharmacokinetics (PK) of single ascending oral doses of SRP-3D (DA). Further, it will characterize the pharmacodynamics and food effect on SRP-3D (DA) in healthy male and female subjects. South Rampart Pharma is enrolling 60 subjects in the Phase 1 study in Quotient Sciences, Miami, FL. The primary endpoint for the study is to provide SRP-3D (DA)’s safety and tolerability by assessing: adverse events (AEs), vital signs, electrocardiograms (ECGs), physical examinations, and multiple laboratory safety tests. Secondary endpoints include oral PK of single ascending dose (SAD) of SRP-3D (DA) administered as an oral suspension, followed by multiple ascending doses.

“Acute and chronic pain continues to affect a growing section of the global population. While opioids, acetaminophen, ibuprofen, and similar NSAIDs are widely available, there remains a significant need for effective pain medications with fewer adverse effects and without the abuse liability of opioid analgesics. I believe SRP-3D (DA) may represent a cutting-edge opportunity to treat pain effectively, and importantly, without the hepatic, gastrointestinal, cardiovascular, or kidney toxicity commonly associated with acetaminophen or NSAIDs,” added William K. Schmidt, Ph.D., Chairperson for the Annual Arrowhead Pain Summit and expert on analgesic drug development.

Pain is one of the most prevalent and costly public health issues worldwide1. In the U.S. alone, an estimated 20% (50 million) of adults experience chronic pain2, and more than 76 million have suffered from pain that lasts longer than 24 hours3. Currently available medications are either highly addictive or cause harm to the liver and kidney. For example, acetaminophen hepatotoxicity remains the most common cause of acute liver failure in the U.S., and opioids were associated with over 100,000 drug overdose deaths in 20214, a nearly 30% increase from the 78,056 deaths during the same period the year before.

South Rampart Pharma’s proprietary compounds have consistently reduced pain and fever in preclinical studies without liver and kidney toxicity associated with current common over-the-counter analgesics. In all of the Company’s FDA Investigational New Drug (IND)-enabling toxicology studies, SRP-3D (DA) was shown to have a favorable safety profile. Additionally, as a non-opioid SRP-3D (DA) lacks abuse potential.

About South Rampart Pharma
South Rampart Pharma is a clinical-stage life science company that aims to advance the safe treatment of pain by developing new small-molecule solutions that can overcome many risks associated with current pain medicines. The Company’s lead compounds have effectively reduced both pain and fever in preclinical studies without the liver and kidney toxicity of current non-opioid analgesics. As a new small molecule treatment option that is not a biologic therapy, South Rampart Pharma’s compounds have great potential as a value product that will be low cost and accessible to many patients. Please visit the Company’s website at southrampart.com and connect on Twitter, LinkedIn, and Facebook for more information.

About Quotient Sciences
Quotient Sciences is a drug development and manufacturing accelerator providing integrated programs and tailored services across the entire development pathway. Cutting through silosacross a range of drug development capabilities, we save precious time and money in getting drugs to patients. Everything we do for our customers is driven by an unswerving belief that ideas need to become solutions, and molecules need to become cures, fast. Because humanity needs solutions, fast. For more information visit quotientsciences.com

References:

Relieving Pain in America. (2011). National Academy of Sciences. doi: 10.17226/13172
Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults – United States, 2016. (2019, September 16). Retrieved from https://www.cdc.gov/mmwr/volumes/67/wr/mm6736a2.htm?s_cid=mm6736a2_w.
Partners for Understanding Pain. (n.d.). TOOL KIT – The ACPA Health Care Professionals September 2019. Retrieved from Tool-Kit-2019-Final-8-27-19.pdf.
https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2021/20211117.htm

Quotient Sciences contributes to Pharma Manufacturing "2022 Pharma Predictions" Article

Matthew Paterson, Vice President of Corporate Strategy, comments on growing demand for integrated drug substance and drug product services.

We're seeing a greater desire to move deeper in development toward proof-of-concept. Biotechs want to have confidence in drug substance and drug product suitability for development, mitigating risks for commercialization and in turn driving up their valuations. This means we’re observing strong demand for integrated drug substance and drug product services — to help biotech’s accelerate development programs, anticipate downstream challenges, and improve the likelihood of clinical success.

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NOTTINGHAM, U.K.; July 1, 2021 – Quotient Sciences, the drug development and manufacturing accelerator, announces that it has completed the rebrand of Arcinova, the Alnwick U.K.-based contract development and manufacturing organization (CDMO). Now called Quotient Sciences - Alnwick, the site has significant expertise in drug substance manufacture, isotope labelling, bioanalysis and drug product development, playing a key role in strengthening Quotient’s services portfolio from candidate selection to commercial manufacturing.

Quotient Sciences acquired Arcinova in February 2021 with the strategic goal of providing an "end-to-end" offering for customers and creating further differentiation for Quotient in the marketplace. The combined business uniquely supports customers with drug substance, drug product and clinical testing capabilities all under one organization. "By cutting through silos and integrating these capabilities, Quotient simplifies outsourcing for customers and creates substantial timeline acceleration," said Mark Egerton, CEO of Quotient Sciences. This differentiation extends the 12-month drug development time savings already delivered by Quotient’s flagship platform Translational Pharmaceutics^®.

Quotient strives to help customers save time and money in the pharmaceutical development process and the combined business has already identified several new integrated service packages that will be offered to customers in the coming months. These integrated programs include a holistic candidate selection offering and a streamlined program that fully integrates drug substance and drug product manufacturing.