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At the European Bioanalysis Forum (EBF) conference in November 2021, Quotient Sciences [1] and Orphalan [2] presented a poster describing a comparative analysis of a novel method for calculating serum non-ceruloplasmin-bound copper (NCC) levels in patients with Wilson disease (WD).

WD is a genetic disorder of copper transport, which can be diagnosed and monitored using serum NCC levels. During a Phase I clinical trial of a potential new treatment for WD, the US Food and Drug Administration (FDA) highlighted that the current standard method of determining NCC levels, NCC-EDTA, may underestimate NCC levels. As a result, Orphalan developed a novel assay to determine NCC levels using copper protein speciation (NCC-CuSp) and liquid chromatography with inductively coupled plasma mass spectrometry (LC-ICP-MS). The aim of the project was to compare NCC values obtained from the novel NCC-CuSp assay and the standard NCC-EDTA assay in WD patients.

During the clinical trial, the WD patients had blood samples taken at regular intervals, and serum NCC levels were evaluated by both the NCC-CuSp and NCC-EDTA methods. Paired data was compared using a Bland–Altman plot (difference plot), which is a statistical method used to analyze the agreement between two different assays.

The overall level of agreement between the NCC-EDTA and NCC-CuSp methods from all paired samples and across the complete range of values obtained from the WD patients was moderate. On average, the NCC-EDTA values were found to be lower than the NCC-CuSp values. This project highlighted how imprecise measurements of NCC levels may lead to inappropriate medication titration in WD patients.

Poster authors

1. Quotient Sciences: S. McDougall

2. Orphalan: T. Morley, O. Kamlin

3. National Measurement Laboratory at LGC: H. Goenaga-Infante, E. Del Castillo

4. International Drug Development Institute: K. D’Hollander

Find out more about Quotient Sciences’ bioanalytical services.

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At the European Pediatric Formulation Initiative (EuPFI) conference in September 2021, Quotient Sciences [1] and Kadmon (a Sanofi company) [2] presented a poster describing a taste assessment study of belumosudil, a ROCK2 selective inhibitor developed by Kadmon (a Sanofi company) for the treatment of immune disorders, that was carried out by Quotient Sciences. An oral suspension was being investigated as a possible pediatric formulation for patients aged between 3 months and 12 years, and the aim of this study was to identify an optimal flavor and/or sweetener combination to improve palatability.

Twelve healthy, adult volunteers took part in a ‘sip-and-spit’ taste assessment of six different formulations, including one unflavored/unsweetened reference and five different flavor/sweetener combinations. The participants filled in a questionnaire to rate the overall acceptability and seven key taste characteristics of each formulation on a nine-point Likert scale.

The study identified multiple successful flavor and sweetener combinations that were able to improve palatability. It was determined that a formulation with either sweetener alone or in combination with a flavor would be suitable to enhance palatability and to take forward into a relative bioavailability assessment versus the reference adult tablet formulation.

Poster authors

1. Quotient Sciences: Ashley Willson, Mark Beville, Nand Singh, Nazim Kanji

2. Kadmon (a Sanofi company): Olivier Schueller, Galit Regev

To find out more about how Quotient Sciences can support your pediatric development program, click here.

Quotient Sciences [1] and Kadmon (a Sanofi company) [2] presented a poster at the European Pediatric Formulation Initiative (EuPFI) conference in September 2021, describing a program that was carried out by Quotient Sciences to develop a pediatric formulation for belumosudil, a ROCK2 selective inhibitor developed by Kadmon (a Sanofi company) for the treatment of immune disorders. The aim was to develop a new oral suspension formulation using age-appropriate excipients suitable for patients aged between 3 months and 12 years, which could be taken forward into a relative bioavailability assessment versus the reference adult tablet formulation.

Formulation design and excipient selection was based on literature reviews and regulatory guidance. Formulations with different combinations of suspending/thickening agents, preservative, sweetener, and flavors were assessed to identify the most promising systems. Lead flavor and sweetener combinations that improved palatability were identified in a taste assessment study, and the thickener/suspension system was developed and optimized. Belumosudil grades that had been jet-milled and pin-milled were assessed as part of the development studies, which confirmed that jet-milled belumosudil was preferred in achieving dose homogeneity. A lead formulation was selected following short-term stability testing. Process development studies enabled scale-up of the formulation for clinical trial manufacturing.

As a result, a belumosudil oral suspension that met the quality target product profile (QTPP) and was suitable for patients aged between 3 months and 12 years was successfully identified, enabling CTM manufacturing for a relative bioavailability assessment versus the reference adult tablet formulation.

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Poster authors

1. Quotient Sciences: Mark Beville, Ashley Willson, Josephine Gray, Nazim Kanji

2. Kadmon (a Sanofi company): Olivier Schueller, Galit Regev

In early development, the main goal for a new chemical entity is to demonstrate proof of concept (POC) in patients in the most time- and cost-effective way possible. 

Typically, simple, fit-for-purpose formulations are used in first-in-human studies to minimize upfront development time and CMC costs prior to generating clinical safety and pharmacokinetic data. However, given the increasing number of poorly soluble active pharmaceutical ingredients in the industry development pipeline, this approach has limitations, especially where enabling formulation technologies may be required to ensure adequate bioavailability. 

With over 30 years of experience, Quotient Sciences' suite of technologies and formulation strategies to address solubility challenges range from particle size reduction and spray-dried dispersions, to hot melt extrusion and lipid-based formulations. Additionally, using our Translational Pharmaceutics^® platform, we are able to streamline the development of poorly soluble molecules through the use of flexible study protocols and rapid cycles to make and test drug products. This enables faster, more reliable optimization of formulations based on arising human clinical data to reduce development risk and maximize the probability of clinical success.

In this article, we review some scientific posters published by Quotient Sciences that highlight innovative strategies to overcome challenges with poorly soluble molecules in early development.

"Flexible formulation assessments in FIH studies for poorly soluble drugs accelerates dosage form development, manufacturing and supply for patient POC trials"

Presented by Quotient Sciences at AAPS PharmSci 360, October 2020

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The purpose of this study was to investigate how the integration of formulation development and drug product manufacturing activities can affect FIH-to-POC programs for poorly soluble drugs. Integrated early development programs were designed for two molecules, based on their physicochemical and biopharmaceutic properties. In both programs, drug products were prepared either by pharmacy compounding of the NCE, compounding of a GMP (Good Manufacturing Practice) intermediate, or GMP manufacture of the finished drug products. All formulations were prepared in real time during the FIH clinical study, using arising safety and PK data to inform the drug product selection for the next study period as part of an adaptive clinical protocol. In both studies, an optimized solubility-enhanced formulation was efficiently identified to take forward into patient POC trials – a lipidic capsule formulation in the first study, and a micronized API capsule formulation in the second study.

This poster highlights how the integration of flexible compounding and GMP manufacturing within FIH-to-POC programs can streamline development, maximize the potential for clinical success, and save time and costs for poorly soluble molecules. Drug development programs using this approach have been shown to save, on average, 18 months of time when compared to traditional manufacturing practices.

"A First-in-Human (FIH) Study to Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses, and Alternative Formulations of R941552 (R552): A Selective Receptor Interacting Protein 1 (RIP1) Kinase Inhibitor"

Presented by Quotient Sciences and Rigel Pharmaceuticals at the ASCPT conference, March 2022

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R552, a potent and selective RIPK1 inhibitor, is being developed by Rigel Pharmaceuticals for the treatment of autoimmune and inflammatory disorders, and pre-clinical data suggested that solubility may limit exposure. The purpose of this FIH study was to assess the safety, tolerability, and PK of R552 when administered in a lipid solution, as well as alternative SDD suspension and tablet formulations. It was found that R552 was generally safe and well tolerated at the dose levels tested, the PK of R552 was linear, and no clinically significant food effect was observed. A suitable SDD tablet formulation for R552 was identified for future patient studies.

This poster highlights how SDDs can offer an effective strategy to overcome challenges with solubility-limited exposure.

"Applications of Lipid-based Formulations and the Benefits of Integrating Manufacturing and Clinical Testing in Formulation Selection"

Presented by Quotient Sciences at the PBP conference, March 2022

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The purpose of this study was to analyze pharmaceutical and clinical data from multiple development programs conducted by Quotient Sciences over 16 years to understand the drivers for, and outcomes from, selecting and dosing different lipid formulations. Data from 34 lipid formulation programs were analyzed for the following features: formulation application, Biopharmaceutical Classification System (BCS), and in-vitro characterization methods. Various lipid-based dosage forms were developed, including solutions, suspensions, SDDs, and modified-release (MR) tablets.

This poster highlights how lipid formulations can successfully be used for solubilization, enhancing oral bioavailability, and reducing food effects for BCS Class II and IV drugs. Conventional in-vitro testing methods for different lipid formulations are poor predictors of in-vivo performance, whereas our integrated Translational Pharmaceutics platform enables the rapid identification of optimal lipid formulations based on clinical performance.

At the International Society for the Study of Xenobiotics (ISSX) conference in September 2021, Quotient Sciences [1] and ObsEva [2] presented a scientific poster describing a ¹⁴C open-label, two-part radiolabeled study in female subjects to assess the absorption and disposition of nolasiban after oral and intravenous (IV) administrations and to determine the mass balance, routes and rates of metabolism and excretion, and absolute bioavailability.

Nolasiban is an orally active oxytocin receptor antagonist being developed by ObsEva to enhance the receptivity of the endometrium to embryo implantation.

The radiolabeled drug product was manufactured in a GMP (Good Manufacturing Practice) suite co-located with the clinical pharmacology unit. Cohort 1 received a single oral dose of ¹⁴C-nolasiban. Total radioactivity analysis was performed on blood, plasma, urine, and feces samples. Plasma samples were analyzed for nolasiban. Cohort 2 received a single oral dose of nolasiban followed by an IV infusion of ¹⁴C-nolasiban. Plasma samples were analyzed for nolasiban and ¹⁴C-nolasiban.

Mass balance data showed that a mean of 94% of the administered radioactivity was recovered over the 240-hour sampling period. Renal elimination was found to be the main route of elimination. The absolute bioavailability of nolasiban was evaluated to be 77.4%. The proposed metabolic pathway for nolasiban was characterized by oxidation (hydroxylation) and conjugation with glucuronic acid.

Overall, the integration of the radiolabeled human IV microtracer, mass balance, and metabolism study was an efficient and effective method to understand the human drug disposition of nolasiban.

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Poster authors:

1. Quotient Sciences: I Shaw, S Sidhu

2. ObsEva: L Marchand, J-P Gotteland

3. Ex-ObsEva: O Pohl

4. Pharmaron-UK: R Cooke

Seamlessly integrated programs to bridge molecules from discovery into clinical development

There are many challenges that drug developers face when bridging from drug discovery into pre-clinical and clinical development. Traditionally, the pharmaceutical industry has been structured around different functional disciplines (“silos”), and a sponsor often has to split their drug development program across multiple service providers, including contract development and manufacturing organizations (CDMOs) and contract research organizations (CROs). This places the project management burden on the sponsor, creates white space in the development timeline, limits knowledge and material sharing, and is ultimately time-consuming and costly.

To address these challenges, Charles River and Quotient Sciences have formed a collaboration, which leverages the expertise of both companies to create a world-leading capability that supports customers from discovery through to clinical development. 

In this article, we explore the unique features and benefits of the collaboration.

Why have Charles River and Quotient Sciences decided to collaborate?

Charles River provides medicinal chemistry, in-vitro and in-vivo biology, drug metabolism and pharmacokinetics (DMPK), early pharmaceutics, and non-clinical safety services to support customers from early discovery, through to Investigational New Drug (IND)/Clinical Trial Authorization (CTA) submission, and on to delivery of a new medicine.

Quotient Sciences provides drug substance synthesis and manufacturing, drug product design and development, clinical trial manufacturing, and clinical testing services, supporting customers from lead candidate selection all the way through to commercialization.

Through our collaboration, customers can access unique integrated programs that bridge molecules from early discovery to proof of concept (POC) and beyond. This removes obstacles from the critical path, reduces development risks, and shortens the clinical development pathway. Charles River and Quotient Sciences’ capabilities provide deep scientific expertise, flexibility for customers, dedicated project teams, and a bespoke service that is tailored to each development program.

What expertise and experience does each company bring to the collaboration?

Each company brings unique expertise and experience to the collaboration.

Charles River has worked on over 80% of the drugs that have been approved by the US Food and Drug Administration (FDA) over the last 3 years. They have discovered 92 pre-clinical candidates, and their scientists are named as co-inventors on over 420 patents.

Quotient Sciences works on over 150 new molecules each year, has published over 200 peer-reviewed papers and posters with customers, and has been conducting first-in-human (FIH) trials in the US and UK for over 30 years. When it comes to integrated program delivery, Quotient Sciences has completed 500 integrated programs using their unique, flagship platform, Translational Pharmaceutics®, saving an average of 18 months of development time for customers. Translational Pharmaceutics integrates drug substance, drug product, and clinical testing services under a single organization to accelerate development timelines and reduce costs.

Together, we have a leading market position. With over 100 years of combined company experience supporting hundreds of biotechs and all top 20 multi-national pharmaceutical companies, we have successfully worked on thousands of molecules across all stages of development.

What services and solutions are available through the collaboration?

We offer integrated programs that span our two organizations to shorten development timelines, including:

• Discovery – lead optimization and early pharmaceutics, translational biology, gap analysis
• Candidate development – selecting the right molecules to move into development
• Safety assessment – late lead optimization to IND-enabling studies and beyond
• Early development – accelerating molecules through FIH to POC
• Late development – accelerating products through to market authorization
• Project management – planning and integration of critical path activities, risk management
   

How does the collaboration work in practice?

Our approach to integrated program delivery is designed to remove the white space in drug development. Scientific solutions and key development goals are at the heart of every program, and our agile and adaptive approach ensures that we meet project needs. Each integrated program has a dedicated project governance team that spans the entirety of the project to ensure on-time delivery. Our customers benefit from a culture of quality science, technical excellence, and direct peer-to-peer communication with subject matter experts to drive strong collaboration.

What are the benefits of the collaboration for customers?

Our customers benefit from holistic scientific advice and recommendations. We work in multi-disciplinary project teams, offering unique discovery, CMC (chemistry, manufacturing, and controls), clinical, and biopharmaceutics know-how all within one team. Projects are data-driven and led by the science.

Through tight integration of discovery and development activities, we cut through traditional industry silos and accelerate timelines. In our highly interactive project teams, cross-functional experts work closely using cutting-edge technologies. This provides earlier and more informed decision-making, efficient technology transfer, and joint problem-solving.

The collaboration also reduces supply chain challenges and simplifies the outsourcing process. We manage the critical path and scheduling of activities for our customers. There is a seamless transition across the partnering organizations, providing a global reach and flexible capacity.

Overall, there is a seamless transition into clinical research. We provide the full set of deliverables required to be “clinic ready”, minimize risks, and improve the chances of clinical success.

Can you give an example of how the collaboration made a difference to a customer’s program?

For a US biotech client focused in the oncology space, Charles River rapidly identified an alternative candidate molecule based on efficacy data to progress into late lead optimization. Quotient Sciences provided GMP manufacturing of the drug substance and associated analytical and ICH stability studies to support the clinical studies. Early engagement with Quotient Sciences led to rapid supply of increasing quantities of drug substance with parallel safety assessment and clinical formulation design.

Key project benefits included:

• efficient technical transfer within established project teams
• minimal transition time between discovery and development
• rapid process development of the chemistry, improving the overall yield from approximately 40% to 70%
• removing chromatography steps by selecting an appropriate salt form that was advantageous.

The outcome was that over 100 g of GMP drug substance was delivered to scheduled timelines and specifications, achieving significant savings for the client.

Summary

Through this collaboration, Charles River’s customers can benefit from Quotient Sciences’ expertise in drug substance, drug product, and clinical testing, while Quotient Sciences’ customers can benefit from Charles River’s expertise in drug discovery, medicinal chemistry, biology, DMPK, early-stage pharmaceutics, and formulation and safety assessment. Other key benefits include reduced management burden and risk, integrated project management, and increased efficiencies by removing duplication between discovery and development partners. Together, we offer integration and a seamless transition through the discovery-to-development process.

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Check out this video, to learn more.

The role of clinical operations is key in the delivery of successful clinical trials and plays an important part in the overall drug development process. 

Core responsibilities for clinical operations include ensuring volunteer safety, smooth delivery of clinical trials in accordance with the protocol, and adherence to Good Clinical Practice (GCP) guidelines at all times.

We have a proven track record in clinical pharmacology spanning over three decades and over 1,300 Phase I studies completed. With expertise in first-in-human studies, our industry-leading medical directors are able to rapidly recruit large groups of healthy volunteers.

In this article, Ian Nisbet shares more about our approach clinical operations.

Where do you conduct clinical studies at Quotient Sciences?

We are a world leader in the delivery of clinical pharmacology studies. Our Phase I studies are run at our clinical unit in Miami, FL (144 beds and integrated pharmacy compounding capabilities included), and from our clinical unit in Nottingham, UK, where we have 85 beds available.

We have highly experienced medical/clinical teams on both sides of the Atlantic that includes Principal Investigators and Sub-Investigators. Across our clinical teams, we have colleagues dedicated to volunteer safety and the successful delivery of clinical studies.

Each of our clinics can be fully integrated with our global formulation development and manufacturing capabilities, through our unique Translational Pharmaceutics® platform.

What types of clinical studies are conducted at Quotient Sciences, and what is the purpose of each study type?

We conduct a range of Phase 1 studies, including:

• Translation Pharmaceutics programs, which integrate drug substance, drug product manufacturing, and clinical testing activities to accelerate development timelines
   
• First-in-human studies (FIH studies), which evaluate the safety, tolerability, and pharmacokinetics (PK) of a new drug in healthy volunteers
   
• Drug-drug interaction studies (DDI studies), which assess if the safety and efficacy of a drug are altered when it is taken alongside other drugs
   
• Food effect studies, which investigate the effects of food on the rate and extent of absorption of a drug when it is taken shortly after a meal (fed conditions) compared to when it is taken under fasting conditions
   
• Thorough QT studies (TQT studies), which test the cardiac safety of a drug
   
• Bioavailability studies, which determine whether a drug can reach the systemic circulation and its intended site of action while minimizing undesired side effects
   
• Bioequivalence studies, which compare two drugs, or two sets of formulations of the same drug, to show that they have equal bioavailability, either for generic drugs or when a formulation of a drug is changed during development
   
• 14C human ADME mass balance studies, which obtain a comprehensive picture of the absorption, distribution, metabolism, and excretion of a drug in the body using radiolabeling
   
• Japanese bridging studies, which compare the safety and efficacy of a drug in different ethnic groups

When conducting FIH studies, what types of samples are usually collected and how is this done?

Typically, safety and tolerability are the primary objectives for FIH studies, where we capture safety data including vital signs, electrocardiograms (ECGs), blood parameters, and adverse events across a wide range of single and multiple doses. Often, we may also collect additional cardiac data via telemetry or Holter monitoring.

Our clinical units have all the necessary clinical equipment available to perform safety monitoring and data collection in accordance with the clinical protocol.

We also collect blood and/or urine and fecal samples for analysis, so that PK or pharmacodynamic (PD) profiles can be generated to provide an understanding of how the drug is processed by the body. On occasion, it may also be necessary to collect genotype samples to help assess whether the metabolizer status impacts on drug absorption.

How are samples processed in the clinic?

Samples are collected on the ward and transferred to our sample processing laboratories to be processed. We have a barcode tracking system in place to track the samples through the collection/processing pathways, which typically include centrifugation followed by plasma/serum isolation.

Our in-house laboratories have the capability to perform PD sample processing, including the collection and processing of peripheral blood mononuclear cell (PBMC) samples for isolation. There are several processing techniques available that may be utilized during sample processing, with Quotient Sciences typically using the Cell Preparation Tube (CPT) or LeucoSep methods. PBMC collection and processing require specific blood collection tubes, reagents, and equipment to be available and for each step in the method to be followed accurately to ensure isolation of the cells can occur.

Samples are processed in accordance with the Lab Manual for appropriate storage until they are shipped to the nominated bioanalytical laboratory for analysis. Once analyzed, the data is returned to the data sciences PK function for PK analysis to be performed.

How does Quotient Sciences ensure the safety of study volunteers?

All studies conducted at Quotient Sciences are risk-assessed to ensure we can determine the appropriate levels of oversight and monitoring needed to safely conduct the study. We meet regulatory GCP requirements by having best practice procedures that encompass the highest standards for protecting trial volunteers.

Our clinical teams are made up of experienced physicians, nurses, and clinical technicians. Clinical staff are trained in Basic and Immediate Life Support, with all of our physicians trained in Advanced Life Support. Our clinical units have all the necessary emergency equipment and medicines available to handle any medical emergency.

How do you ensure that Quotient Sciences volunteers have a positive experience while they take part in clinical studies?

Our volunteer-centric approach takes into account the key touchpoints at each stage of our volunteer’s journey and includes feedback questionnaires. 

Our Volunteer Centricity group is specifically focused on ensuring feedback is acted upon and priorities around volunteer wellbeing are considered. The group engages with a Volunteer Advocacy panel, made up of some of our long-standing volunteers, to ensure that feedback is sought on topics such as the wording of patient information summaries, admission times, transportation to the site, and study design.

Additionally. our clinical units have recreational and dining spaces for our volunteers to relax and unwind, and our Volunteer Liaison Officers are responsible for arranging activities and providing a comfortable environment for them. 

I am proud of our highly skilled teams and the steps that they take to ensure volunteers feel safe, valued, and looked after while participating in a trial with us.

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At the Respiratory Drug Delivery (RDD) conference in April 2020, Quotient Sciences [1] presented a poster describing the development of an X-ray diffraction (XRD) method for the quantification of active pharmaceutical ingredient (API) recrystallized from amorphous API in a low-dose dry powder inhaler (DPI) formulation.

Amorphous APIs are thermodynamically unstable and prone to recrystallization over time or upon exposure to humidity, which can significantly affect the efficacy of a product. For formulations containing amorphous APIs, ICH guidelines dictate that acceptance criteria must be determined for the polymorph content of the API. While it is relatively straightforward to identify the crystalline content of an API in isolation using XRD, it is challenging when the API is in a formulation with other excipients.

In this study, a model DPI formulation was developed containing a low dose of an amorphous API that is known to recrystallize under certain conditions. To quantify the degree of crystalline API, spiked samples containing mixtures of amorphous and crystalline API in different ratios were prepared. During the method development, different sample sizes and analysis times were evaluated. XRD analysis was performed using a Panalytical X’Pert Pro instrument, with a copper radiation source and X-Celerator detector. Data analysis was performed using the HighScore software.

The data generated in this study demonstrated that a relatively simple XRD method for the detection and quantification of very low levels of recrystallized API can be developed and validated. In the future, this will be a useful tool to support the development of low-dose DPI formulations and characterize the physical form of the API.

Poster authors

1. Martin Wing-King, Jason Gray, Yuncheng Yan, Jose Ruiz, and Bildad Nyambura
 

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Find out how Quotient Sciences can support the development of your inhaled drug product.
 

I chose to enter the pharmaceutical industry because I had a passion for science and a determination to have a positive impact on the world. It seemed that breakthroughs were being made almost every day that could lead to better treatments for diseases and conditions, and I wanted to be a part of that. Fast forward several decades, and I am privileged to work here at Quotient Sciences with some of the world’s best scientists innovating drug development to get new medicines to market faster. "Molecule to cure. Fast.^TM" has become our mantra, and the benefits of our unique, integrated Translational Pharmaceutics^® platform have been recognized across the industry and I know very much appreciated by our clients. Even so, it is very easy to lose sight of the tremendous impact we are having, particularly when we are busy, so as we approach the end of 2022, it is a great opportunity to look back at some of our key scientific achievements.

Together with our clients and collaborators, in 2022 Quotient Sciences’ scientists have published 10 papers in peer-reviewed journals, covering subjects as diverse as nanoparticle synthesis, clinical pharmacology, human ADME studies, and pediatric drug development. I think this is a tremendous reflection of the multidisciplinary environment we have here at Quotient Sciences, one that enables us to deliver truly integrated programs for our clients and accelerate their product development. Furthermore, with the world opening up after the pandemic, our scientists and thought leaders presented at numerous conferences around the globe, communicating to the wider scientific community some of the innovations and advancements we have been involved in. This resulted in 15 poster presentations, 15 seminars, and 13 podium presentations. Thank you to all of my colleagues and our collaborators for publishing their work and contributing to the global scientific community.

In addition, throughout the year we have continued to invest in our people and facilities so we can better serve the needs of our clients. In February, we announced the integration of drug substance into our Translational Pharmaceutics platform, uniting drug substance, drug product, and clinical testing activities all within one organization and led by a single program manager. In September, we completed major investments and expansions at our Nottingham, UK, and Reading, UK, facilities, with the new clinical pharmacology space and expanded development laboratories increasing our capacity to conduct integrated Translational Pharmaceutics programs for our clients. Furthermore, in October, we completed a major expansion of our drug substance manufacturing facility in Alnwick, UK, allowing us to support our clients into the later stages of development.

I am delighted that Quotient Sciences was recognized with multiple CRO Leadership Awards this year. The CRO Leadership Awards recognize top-performing outsourcing organizations in the drug development space. We received leadership awards in all five categories: Capabilities, Compatibility, Expertise, Reliability, and Quality. We were also honored with two champion awards in Expertise and Reliability. In addition, we were a finalist for Best CRO in the OBN Awards this year. The OBN Awards are designed to celebrate innovation and outstanding achievement across all corners of the life sciences industry.

These are of course only a small sample of our scientific achievements, and day in and day out one of my colleagues is making a breakthrough, sometimes small, sometimes larger, but each continues our relentless mission to get medicines to patients faster.

Details and links to the scientific papers and posters that we published in 2022 are provided below. Please contact us if you would like any further information on any of our publications or our drug development capabilities.

Kind regards,

Andy Lewis, Global Vice President of Integrated Pharmaceutical Sciences

Scientific papers

• "Effect of Miricorilant, a Selective Glucocorticoid Receptor Modulator, on Olanzapine-Associated Weight Gain in Healthy Subjects: A Proof-of-Concept Study", published in The Journal of Clinical Psychopharmacology
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• "Characterization of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of Velsecorat Using an Intravenous Microtracer Combined with an Inhaled Dose in Healthy Subjects", published in Drug Metabolism and Disposition
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• "Practical and operational considerations related to paediatric oral drug formulation: An industry survey ", published in The International Journal of Pharmaceutics
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• "Controlled synthesis of SPION@SiO₂ nanoparticles using design of experiments", published in Materials Advances
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• "Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial", published in EBioMedicine
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• "Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects", published in Clinical Pharmacology in Drug Development
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• "A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors", published in Clinical Pharmacology in Drug Development
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• "Absolute Bioavailability, Mass Balance, and Metabolic Profiling Assessment of [¹⁴C]-Belumosudil in Healthy Men: A Phase 1, Open-Label, 2-Part Study", published in Clinical Pharmacology in Drug Development
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• "CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production", published in Arthritis Research & Therapy 
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• "Absorption, metabolism and excretion of opicapone in human healthy volunteers", published in The British Journal of Clinical Pharmacology
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Scientific posters

• "Safety, tolerability, and pharmacokinetics of the oligomer modulator anle138b: a first-in-human randomised, double-blind, placebo-controlled phase 1 trial", presented at the Advances in Science & Therapy International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) 2022
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• "RANDOMISED OPEN-LABEL STUDY TO ASSESS RELATIVE BIOAVAILABILITY OF DIFFERENT ORAL FORMULATIONS, THE EFFECT OF FOOD ON ABSORPTION AND THE ABSOLUTE BIOAVAILABILITY OF AZD9833 (CAMIZESTRANT) IN POST-MENOPAUSAL HEALTHY FEMALE VOLUNTEERS", presented at the 123^rd Annual Meeting of the American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2022
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• "Applications of Lipid-based Formulations and the Benefits of Integrating Manufacturing and Clinical Testing in Formulation Selection", presented at the 13^th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical (PBP) Technology 2022
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• "The use of electrospraying as a means of drug loading into mesoporous silica particles for enhanced dissolution", presented at the 13^th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical (PBP) Technology 2022
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• "Why Archiving is a Crucial Part of Any Clinical Trial", presented at the 38^th Society of Quality Assurance (SQA) Annual Meeting 2022
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• "Preparation of Coamorphous Ciprofloxacin Formulations with Enhanced Deposition Parameters for Dry Powder Inhalation", presented at Respiratory Drug Delivery (RDD) 2022
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• "A Decade of Human ADME at Quotient Sciences: Reviewing Key Study Design Variables and Outcomes ", presented at the International Society for the Study of Xenobiotics (ISSX) 2022
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• "Understanding the Absorption, Metabolism and Excretion of Masitinib in Healthy Male Subjects ", presented at the International Society for the Study of Xenobiotics (ISSX) 2022
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• "A Phase 1, Randomized, Double-Blind, Placebo-Controlled, First-in-Human Study to Assess Safety, Tolerability & Pharmacokinetics (PK) of Amilo-5MER in Healthy Volunteers", presented at the British Pharmacological Society, Pharmacology 2022
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• "Development of a novel oral suspension formulation of a candidate API for administration to paediatric patients", presented at the 14^th Annual European Paediatric Formulation Initiative (EuPFI) Conference 2022
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• "Formulation and Taste Assessments in First in Human Studies – Evolving beyond Safety, Tolerability and Pharmacokinetics", presented at the American Association of Pharmaceutical Scientists (AAPS) PharmSci360 2022
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• "KILO SCALE SYNTHESIS IN DAISY CHAINED FLOW REACTORS", presented at the American Association of Pharmaceutical Scientists (AAPS) PharmSci360 2022
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• "Benznidazole pharmacokinetics in adults and children: Application of PBPK modeling to explore the impact of age on benznidazole pharmacokinetics", presented at the 13^th American Conference on Pharmacometrics (ACoP) 2022
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• "QUALIFICATION OF GASTROPLUS^® PBPK MODELLING SOFTWARE TO SUPPORT DECISION MAKING IN CLINICAL DEVELOPMENT", presented at Pharmacokinetics UK (PKUK) 2022
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• "A Phase I Study of the Cancer-specific Vaccine FMPV-1 in Healthy Male Subjects to Assess Safety and Immune Response", presented at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2022
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High-potency active pharmaceutical ingredients (HPAPIs) are becoming increasingly common in drug development pipelines. This is especially the case in the oncology sector as researchers look for therapies with greater selectivity and pharmacological activity. 

However, highly potent active pharmaceutical ingredients present additional chemistry, manufacturing, and controls (CMC) challenges due to the containment required to protect both operators and manufacturing facilities. Production processes may also require greater precision and control due to the very small quantities of drug present in the final dosage form.

For drug developers, working with a contract development and manufacturing organization (CDMO) that has a long track record of successfully handling HPAPIs is essential. With over 30 years of experience in CDMO small-molecule drug development, we have expertise to overcome the challenges that arise with HPAPIs. Our facilities are configured with the necessary engineering controls for handling and processing HPAPIs. 

In this article, learn about why it is important to classify HPAPIs, how HPAPIs are evaluated, how facilities are qualified to handle highly potent API, and strategies to ensure containment and safety when handling HPAPIs.

Why is it important to classify HPAPIs?

The concept of Acceptable Workplace Exposure Levels (AWELs) and Occupational Exposure Limits (OELs) is based on the premise that workers who are handling material may be exposed to a defined level of chemical substances without significantly increasing the risk of adverse health effects. The maximum concentration for this exposure is based on the known toxicological characteristics of the compound in question. When an exposure limit is established, workplace controls must be designed to achieve the appropriate level of containment in order to ensure adequate protection of employees.

In recent years, a number of systems have been proposed for categorizing drug substances according to their potency, based on the use of OELs or Occupational Exposure Banding (OEB) systems. The basis for the development of these systems in the pharmaceutical industry was for the prevention of adverse health effects when working with active pharmaceutical ingredients (APIs).

What is the PBLEC system?

The concept of the Performance-Based Level of Exposure Classification (PBLEC) system is based on establishing controls determined by the hazards and risks posed by handling specific compounds. These compounds do not usually have an AWEL or OEL established. 

The PBLEC concept of control strategies gives the necessary guidance to achieve the desired level of containment or control. Engineering controls are the primary method of control to ensure employee safety. Further administrative and personal protective equipment (PPE) controls are secondary and tertiary controls, respectively.

New drugs in the early stages of development often have very little safety data available, making Environmental, Health, and Safety (EHS) classification difficult. The PBLEC guideline allows EHS professionals to categorize compounds that have very little safety data in order to estimate their toxicity.

Each PBLEC band covers a range of airborne concentrations of substances in an 8-hour time-weighted average (TWA). These are classified from PBLEC1 compounds, having an OEL >1000 µg/m³, through to PBLEC5 compounds, with an OEL ≥0.1 μg/m³. PBLEC1 compounds have low pharmacological activity and are considered relatively safe to handle. PBLEC5 compounds are extremely toxic and/or have very high pharmacological activity. 

How are HPAPIs evaluated at Quotient Sciences?

At Quotient Sciences, the 5-band PBLEC system is used. We evaluate each program depending on the type of drug product and batch size required. The factors considered when classifying a compound include AWELs or OELs for structurally related compounds, pharmacological class/activity, mutagenicity, carcinogenicity, and reproductive toxicity. 

In our facilities, PBLEC4 compounds are considered highly potent and PBLEC5 compounds are considered extremely potent, with both requiring special handling and HPAPI controls. 

We apply the PBLEC system to analytical, formulation development, and manufacturing operations. The three areas have individualized strategies outlined for personnel working with the APIs. These include containment of the compounds, personal protection, training, disposal, signage, ventilation, and industrial/occupational hygiene monitoring. 

How are HPAPI facilities and engineering controls qualified?

Surrogate monitoring or control performance target (CPT) testing is used to assess the suitability of Quotient Sciences’ HPAPI manufacturing suites and engineering controls. This testing is conducted using a non-potent powder (e.g. sodium naproxen) with a high dustiness quotient and challenging electrostatic properties to mimic the API. The purpose of this testing is to simulate operating conditions and prove the effectiveness of the engineering controls/facility design.

How do you ensure containment and safety when handling HPAPIs?

To handle HPAPIs safely, manufacturing practices have moved away from reliance on PPE alone, with current practices focusing on “containment at source” to prevent operator exposure. This is achieved through the effective use of engineering controls (e.g. local exhaust ventilation (LEV) devices, full hard-shell or flexible containment, and closed transfer systems). The type of engineering control required is dependent on the PBLEC category of the API and the risk of operator exposure to inhalable powder particles from the manufacturing process. 

In addition to the primary engineering controls, to ensure containment at source, other facility designs (e.g. air change rates, high-efficiency particulate air (HEPA) filtration, airlocks) and administrative controls (e.g. safe methods of working, operator training) are employed. PPE that is appropriate to the task is also required.

Containment strategies may differ slightly in the laboratory compared to the manufacturing area due to the lower quantity of API being handled (i.e. milligram compared to kilogram scale), but the same principles of operator protection are employed.

Summary

Quotient Sciences has invested in our capabilities to provide the necessary containment, engineering controls, and personnel protection needed to safely handle HPAPIs and to prevent cross-contamination. 

Our global drug development facilities have undergone multiple EHS audits to ensure that they meet current Good Manufacturing Practice (cGMP) standards and have been inspected by several major global regulatory agencies. Our risk-management program includes ongoing EHS monitoring and surrogate testing to ensure consistent control over our processes, facilities, cleaning procedures, and standard operating procedures (SOPs).