Amidst escalating development costs, increased molecule attrition, and reduced R&D productivity the general philosophy in the last decade for first-in-human (FIH) studies has been to “go simple” and use rudimentary fit-for-purpose/phase formulations. 

A major benefit of this strategy is to minimize the upfront CMC investment, which (in theory) will reduce the time and cost of generating initial clinical data to characterize safety, tolerability, pharmacokinetics, and pharmacodynamics. As such, many FIH drug products are therefore simple formats, such as solutions, suspensions, powder-in-bottle, or powder-in-capsule, which require minimal development investments and can be prepared in a compounding pharmacy or basic manufacturing or dispensing processes. 

There are, however, some risks, which challenge the validity of a simple fit-for-purpose/phase philosophy in the context of today’s drug development priorities. First, most new chemical entities (NCEs) today present significant biopharmaceutics challenges, such as poor solubility, which greatly affect drug delivery success ¹.  Formulation technologies and GMP manufacturing operations are frequently needed to develop enhanced dosage forms for optimal delivery and bioavailability of the drug in the clinical study.  Secondly, the major value inflection point in early development is not the speed at which you achieve FIH, but rather the time it takes to get to proof-of-concept (POC) in a patient population. Simple FIH formulations will typically not “have the legs” to be utilized in early patient studies – where a suitable solid oral dosage form is required. This presents a number of hurdles for the development team to manage; extra time, increased cost, and the technical risks associated with product development.

In other words the current development model is self-contradicting – by “kicking the formulation can down the road” the time, cost, and flexibility benefits of the FIH trial are countered by the delays and risks in achieving an accelerated POC milestone.

A new approach is therefore needed – how can we achieve accelerated timelines while still managing CMC investments and mitigating development risk?  We believe the answer lies in retaining a relentless focus on good science and program integration, which includes:

• Understanding the biopharmaceutics properties and risks of NCEs
• Using the Developability Classification System (DCS) to inform formulation strategy and technology selection²
• Leveraging in silico and biorelevant in vitro characterization methodologies to simulate and predict the clinical performance of molecules and formulations
• Retaining simplicity for FIH drug products, using pharmacy compounding or basic manufacturing processes, but using enabled GMP intermediates if needed (e.g. spray-dried dispersions (SDDs), micronized drugs) to ensure adequate bioavailability
• Look to evaluate different formulation technologies and dosage forms within the FIH study or in parallel to select a lead system to move forward
• Exiting the FIH study having already developed a clinically proven solid oral drug product for patient trials
• Seamlessly start Phase II trials on time with an immediate supply of clinical trial material

This new model is not conceptual. Quotient Sciences has been designing and performing these programs for pharma and biotech customers for over a decade with integrated pharmacy compounding, GMP manufacturing, and clinical pharmacology operations.

A Tufts CSDD research paper has described how Quotient Sciences' Translational Pharmaceutics® platform has been used to significantly accelerate FIH-POC programs. This approach can save on average 15 months of development time for POC, equating to reduced R&D costs of $135m and an overall financial gain for molecules reaching the market of over $250m.

In today’s world, proven early drug development strategies are now available to reach both the FIH and POC milestones quickly and cost-effectively. It doesn’t have to be one or the other.

References:

1. Kalepu S, Nekkanti V “Insoluble drug delivery strategies: review of recent advances and business prospects”. Acta Pharm Sin B. 2015;5(5):442–453

2. Butler JM, Dressman JB “The developability classification system: application of biopharmaceutics concepts to formulation development.”  J Pharm Sci 2010 Dec;99(12):4940-54

As Sr. Director of Operations at Quotient Sciences, Miami, Harpreet is responsible for the day-to-day running of the clinical pharmacology unit. She oversees an experienced team of nurses, clinical, and laboratory staff to deliver healthy volunteer studies successfully, on time, and to the highest quality standards.

You mentioned that you started off in nursing, so why did you pursue a career progress into the pharmaceutical industry?

Early in my career as a dialysis nurse, I took care of patients with major health problems. I saw firsthand the benefits they received from newly marketed treatments and this made me determined to develop my career in clinical research. I earned a Master of Science degree in Nursing with a specialty in Clinical Research Management from Duke University and my role at Quotient allowed me to use my clinical background and education to set up and run early-phase studies.

I am passionate about using new technologies in drug development and have spearheaded our transition from paper to electronic source documentation and managed the start-up of an on-site laboratory within our Miami clinic.

Have you always worked in the Clinical Pharmacology space?

After working as an acute dialysis nurse, I moved into early-phase clinical research and have worked in the clinical pharmacology space for the last 21 years.  I love working in the early phase as it’s fast-paced, the projects move quickly, and customers are always keen to see the clinical data.   

As the Senior Director of Operations, what does your day-to-day look like?

No two days are the same and with a global client base, I have to work flexibly to provide support across different time zones.  A typical workday may include making rounds in the clinic, reviewing new protocols with our Sr. Medical Director, and discussing continuous improvement plans with operational colleagues. The one constant, however, is working side by side with my team, to overcome any challenges in the delivery of projects for our customers.

What do you enjoy most about your role and why?

Knowing that we are helping to develop new medicines and get them to patients faster is exciting and very rewarding. What better mission can one have?

How do you see your role evolving over time as the business grows?

In recent years I have been working with Quotient’s senior leadership to strengthen and expand the capabilities in Miami.  For example, we have just finished a huge project to build a new industry-leading compounding pharmacy, capable of preparing a broad range of dosage forms for first-in-human and early-phase clinical studies.  This project took nearly 9 months to complete and was a considerable investment for our organization.  We now have state-of-the-art cleanroom suites meeting USP 797 and USP 800 standards to prepare sterile and non-sterile dosage forms and handle both hazardous and non-hazardous compounds.

As the company grows, my role will continue to evolve as we broaden our service offerings to support our client’s needs in the drug development process.

Tell us about the Miami facility and what role it plays within Quotient’s early development network

The Miami site specializes in clinical pharmacology studies with a proven track record of almost a thousand studies over the past 25 years. With 144 beds and a large recruitment database of 20,000 healthy volunteers, we’re known for being able to rapidly start up new studies in record time and complete studies quickly with full cohorts of subjects.

We also work closely with our Quotient teams in Philadelphia (US), Nottingham, Reading, and Edinburgh (UK) to deliver highly bespoke programs of work that save clients considerable time and money. Translational Pharmaceutics® is our unique platform which integrates formulation development, manufacturing, and clinical testing to deliver exceptional benefits to clients. A recent white paper from Tufts CSDD concludes that Translational Pharmaceutics® reduces development times by 12 months on average and creates significant financial gains ($ multi-million) for biotech/pharma companies.

What benefits do clients receive by working with a development and manufacturing organization that also has clinical pharmacology expertise?

Quotient Sciences has development, manufacturing, and clinical pharmacology expertise across multiple sites in the US and UK.  Our clients are therefore able to place projects at any of our sites and Quotient can integrate different activities to accelerate their drug development plan. For example, our Philadelphia team can develop and manufacture new drug products (e.g. tablets or capsules) which can then be rapidly tested in clinical studies at our Miami clinic. This tight integration helps us get new medicines to patients faster.

Since Quotient Sciences acquired the Miami facility back in 2017, what additions and improvements have been made to better support our client’s needs?

Until the recent addition of our new pharmacy, a lot of our focus has been on strengthening our Project Management and Data Sciences functions and adopting a multidisciplinary team structure for project delivery.  We have also recruited and trained many new employees to increase our overall capability and capacity and laid the framework for continued growth and development. Feedback from client questionnaires indicates that these changes have made a really positive impact on their programs, especially with enhanced levels of project communications.

With all this expansion in facilities comes a need to continually increase headcount.  How much has changed in terms of the number of employees at the Miami location since you started up until now?

I have seen Quotient Sciences Miami grow significantly during my tenure. We have dedicated a lot of time towards becoming efficient and ensuring that our new employees become capable and experienced in supporting our existing team.  We also have great employee engagement and retention, and as such, I am surrounded by many dedicated and long-serving team members, many of whom have been with us for over 10 years. 

For any qualified candidates looking for a position at Quotient Sciences Miami, what can they look forward to?

Teamwork. Joining a great company like Quotient Sciences is a competitive effort on the part of new hires and we select only the top candidates to join our team.  Team members can expect a collaborative and hands-on approach to delivering projects and a leadership team that encourages working together, driving for results, and operational excellence.

Can you tell us about the new pharmacy capabilities? How does this help customers who want to start clinical studies quickly?

Quotient Sciences is the only drug development provider that can offer pharmacy compounding, GMP drug product manufacturing, and clinical testing all under the same organization.  Our experienced pharmacy team and new cleanrooms enable us to prepare low, medium, and high-risk compounded products for dosing in the Miami clinic. Using the formulation and manufacturing capabilities across the Quotient Sciences network, we can then help our clients seamlessly transition from simple first-in-human pharmacy formulations to a robust solid oral product for their downstream patient trials.  By simplifying the supply chain with an integrated project team and a single development partner this offering enables our clients to achieve proof-of-concept up to 15 months faster.

Tell us how the Miami facility can support our client’s clinical pharmacology needs and deliver studies with quality service and speed.

Our clinical pharmacology expertise encompasses first-in-human (SAD/MAD), DDI, food effect, TQT, and BA/BE studies. Our experienced and dedicated project managers work closely with the IRB and screening team to ensure timely enrollment. We are accustomed to helping clients with rapid study start-ups and with an on-site CLIA-certified laboratory for fast turnaround times, we work to get clinical data to our clients quickly – but not at the expense of quality. Our excellent regulatory inspection history speaks to the high-quality delivery by our project and clinical teams.

What else do you think differentiates Quotient from other drug development organizations?

Our clients rely on the expertise of Quotient Sciences to accelerate their drug development programs in a variety of ways. Uniquely, Quotient provides both clinical pharmacology/research (CRO services) and pharmaceutical development & manufacturing (CDMO services) to the pharmaceutical and biotech industry. These services can be provided individually, or as an integrated service which has been shown to dramatically shorten development times, reduce outsourcing costs, and significantly simplify supply chains for customers.

The number of licensed pediatric drug treatments on the market for children continues to remain substantially less than those for adults. Over the last 15-20 years, global regulatory bodies have placed a greater priority on the development of age-appropriate pediatric dosage forms to improve and protect children’s health^a,b,c. 

A combination of unmet patient needs, regulatory incentives, and potential penalties has now driven a significant upturn in industrial research to develop new pediatric medicines.

There are many important factors to keep in mind when developing a pediatric dosage form and the requirements can differ greatly from drug products designed for adult use^d,e. Development scientists must consider the route of administration, the safety profile, overall taste and palatability, the child’s age, weight, physiological condition, and the overall treatment plan. All of these key points must be balanced appropriately to successfully develop an acceptable pediatric product that achieves clinical, regulatory, and commercial success. Arguably, however, the greatest industry challenge remains a lack of clarity and guidance on how these development objectives can be successfully met.

In Part 1 of this two-part blog piece, Quotient’s Executive Director of Pediatric Services, Nazim Kanji, will cover key considerations in pediatric program design and formulation development strategies that sponsors should take into account if they want to successfully bridge from initial concept into later stages of development and through to commercialization.

Program design and target product profile (TPP)

The initial stage is to understand the TPP for the intended pediatric population(s) and the associated challenges and risks. The following factors should be considered:

• Drug-related factors such as dose, solubility, particle size, taste, and palatability
• Formulation-related factors including stability/shelf-life requirements, preservative systems, pH, and excipient selection for the target age group
• Patient-related factors such as age range, delivery route, administration methods, co-administration with foodstuffs, and container closure systems
• Clinical and regulatory factors including dose extrapolation from adult clinical data, posology, and target pharmacokinetic (PK) profile
   

Formulation development

The next stage is to conduct formulation studies to develop dosage forms in line with the TPP. Liquid dosage forms (solutions or suspensions) can offer flexibility in dosing across the target age groups from neonates through to adolescents by adjusting the volume delivered. A liquid dosage form can be manufactured as a ready-to-use, bulk formulation or as a powder for reconstitution with a shorter in-use shelf life.

Mini tablets also offer dose flexibility and are suitable across a wide age range. As interest in mini tablets has grown, their acceptability in younger patients, including neonates, has been demonstrated when co-administered with soft foods or a beverage^f.

Other common formats for pediatric patients include powder-based systems such as granules and multiparticulates, often co-administered with food, and portable dose formats such as chewable tablets and orodispersible tablets/mini tablets which can be administered without water.

Excipients used in pediatric formulations must be carefully selected and quantities justified as some excipients may cause adverse effects in children due to differing physiology to adults. For example, the preservative benzoic acid and its sodium salt may increase neonatal jaundice. The aim of the formulation scientist should be to minimize the quantity and levels of such components in a pediatric formulation.

To mask any adverse taste properties that could impact patient palatability and compliance, the formulator may have to consider alternative taste-masking strategies such as flavor or sweetener combinations, complexation or barrier coatings.

Understanding the risks and challenges that your molecule poses in the initial stage of program design plays a key role in developing a formulation that meets the needs of your pediatric patients and global regulatory agencies and that will ensure downstream success. 

In Part 2, Nazim Kanji will discuss the challenges and opportunities that sponsors face when dealing with clinical taste/acceptability assessments, clinical supply chains for patient trials, and commercial-scale manufacturing.

Click here to read Part 2: Taste/PK Assessments, Clinical Supplies and Commercial Manufacturing

For more information, take a look at our pediatrics capabilities or contact us.

References

a. Best Pharmaceuticals for Children Act; 2002

b. Pediatric Research Equity Act; 2003

c. Regulation (EC) No 1901/2006 on medicinal products for paediatric use (“Paediatric Regulation”); 2007

d. European Medicines Agency (EMA) CHMP. Reflection Paper: Formulations of choice for the paediatric population. EMEA/CHMP/PEG/194810/2005; 2006

e. European Medicines Agency (EMA) CHMP. Guideline on pharmaceutical development of medicines for paediatric use. EMA/CHMP/QWP/805880/2012 Rev. 2; 2014

f. Klingmann V, Acceptability of mini-tablets in young children: results from three prospective cross-over studies. AAPS PharmSciTech 2017; 18(2): 263-266

In Part 1 of our two-part blog piece on the 'The challenges and opportunities of Pediatric Dosage Form Development', Nazim Kanji, Executive Director of Pediatric Services at Quotient Sciences, covered key considerations in pediatric program design and formulation development strategies that sponsors should take into account if they want to successfully bridge from initial concept into later stages of development and through to commercialization.

Adult taste/PK study

After formulation development, the next stage is typically a clinical assessment of the proposed pediatric formulations in adult volunteer panels to evaluate and optimize the taste and/or PK attributes, before dosing the formulations in pivotal pediatric patient studies.

Over the last decade, Quotient Sciences has developed a novel platform called Translational Pharmaceutics® that integrates GMP manufacturing and clinical testing. Drug products are made and dosed quickly in a matter of days, with flexible CMC submissions and adaptive clinical protocols allowing formulation compositions to be optimized based on emerging clinical data. 

Translational Pharmaceutics is therefore an extremely efficient means of characterizing and optimizing the clinical performance of new prototype formulations.

This platform has been successfully applied to the assessment of pediatric formulations.

For example, in the selection of flavor/sweetener systems to overcome aversive drug properties, and to understand the PK performance of new age-appropriate medicines and thereby inform dose selection in the pediatric population.

Clinical supplies for pediatric patient trials

Once the pediatric formulation has been optimized, the drug product will then be taken into patient studies to assess efficacy in the target disease population. This can present the development team with new challenges, putting a strain on traditional product manufacturing and supply logistics, particularly if dealing with rare and orphan disease states. 

Typical challenges include:

• Sporadic, challenging, and slow patient recruitment
• Multiple sites and countries to recruit the required number of subjects
• Patient weight variability requiring dose flexibility (mg/kg or body surface area)
• Formulation stability may be limited
• Small batch size requirements

The historical practice of large product batch sizes with relatively long shelf lives and long cycle times to get products manufactured, released, labeled, packaged, and shipped is therefore unlikely to fit the supply requirements of typical pediatric clinical studies. Implicit in this is also a lack of ability to customize the drug product around unique, individual patient needs.

Challenges can be successfully addressed by using a real-time manufacturing and supply model that enables drug products to be tuned to individual patient needs and the design of the clinical trial.

Customized products can be manufactured, released, and shipped for global patient studies within 1-3 weeks of subject eligibility and formulation requirements being confirmed, to get the right product to the right patient at the right time.

Commercial manufacture of pediatric products

Finally, there will be a need to identify a long-term commercial partner with the capability to manufacture liquid or solid dosage forms and supply to global markets, for what may be relatively low-volume commercial products. 

Given that in-house Large Pharma and the CMO service sector have traditionally focused on high-volume and low-variation drug products, there is an emerging industry need for smaller-scale, batch manufacturing.

The development of pediatric medicines is an industry requirement to ensure safe and efficacious treatments are available for children of all age groups.

Many factors need to be considered for the successful development of pediatric products for which Quotient Sciences has unique expertise and provides an end-to-end integrated solution across the design, development, and supply continuum.

 For more information, visit pediatrics capabilities, or contact us.

As an integrated services provider, Quotient Sciences focuses on supporting our customers with the ability to move quickly and cost-effectively from candidate selection to commercial launch. 

Our compounding pharmacy in Miami, FL was built to meet USP 795, 797, and 800 compounding standards. The compounding pharmacy is part of our contract research organization (CRO) facility in Miami, FL where we conduct Phase I trials with healthy volunteers. 

In 2020, an upgrade was done to help our customers accelerate to first-in-human (FIH) testing and seamlessly supply drug products for downstream proof-of-concept (POC) patient trials. The laboratory space was expanded to support our new pharmacy and provide efficient processing of higher volumes of biological samples. It incorporates refrigerated centrifugation capability and storage at -20, -40, and -80C, and biological safety cabinets for microbiological work, allowing us to perform complex sample processing. Additionally, clean rooms in the facility are built to ISO Class 7 air quality standards with ISO Class 5 Primary Engineering Controls (PEC), which include laminar airflow workbenches (LAFWs) and biological safety cabinets (BSCs), allowing us to handle potent APIs. 

Within the pharmacy and clinic, we can handle a variety of dosage forms including active pharmaceutical ingredients (APIs) or processed intermediates in oral solutions, suspensions, powder-in-capsule (PIC) or powder-in-bottle (PIB), and sterile preparations for parenteral delivery. 

Flexible compounding and GMP manufacturing delivers significant benefits when transitioning from FIH to POC

By simplifying the supply chain with a single development partner and integrated project team, we are able to help customers through their stages of development, to:

• Quickly start a first-in-human (FIH) trial with healthy volunteers, using a fit-for-purpose pharmacy preparation
• Develop a solid oral drug product (such as a tablet) for patient trials within the same program
• Seamlessly start proof of concept (POC) patient trials with immediate clinical trial material supply

In this approach, a more cost-effective dosage form, such as PIC or PIB, can be used to start the FIH trial. This also has the benefit of improving timelines to the clinic, while still providing maximum dose flexibility to achieve Phase I objectives of obtaining PK and safety data. 

Later, emerging clinical data can be used to evaluate formulation technologies, such as solubility enhancement, within the FIH study to select a drug product to move forward with. The ability to manufacture and dose multiple formulation types in real-time, coupled with the ability to use smaller batch sizes and abbreviated data packages, ensures CMC time and cost investments can be carefully managed. 

For molecules that have solubility and bioavailability challenges, we help clients select the right formulation technology for their poorly soluble molecules. We apply a data-driven process based on the physicochemical and biopharmaceutic properties of the API with a full range of solubility enhancement technologies including lipidic systems, micronization, spray drying, and hot melt extrusion. Finally, once the optimal formulation and formulation technology is selected, the new solid oral dosage form can be manufactured, ready for packaging and shipment for patient trials.

Learn more about our pharmacy compounding capabilities, or contact us to get started talking about your next program.

We asked Clare Preskey, Senior Director of Clinical Operations, and Andy Lewis, Vice President of Pharmaceutical Sciences to share their thoughts on our Nottingham, UK clinical facility.

Andy Lewis, Vice President, Pharmaceutical Sciences at Quotient Sciences

As Vice President of Pharmaceutical Sciences at Quotient Sciences, Nottingham, Andy has over 15 years of experience in the pharmaceutical and biotech industry. He currently leads a team of scientists working in formulation development, clinical manufacturing, and pharmaceutical analysis that support client development projects.

What is your role at Quotient and what exactly does a VP of Pharmaceutical Sciences do?

I currently head up the pharmaceutical sciences (PharmSci) department in Nottingham which is focused on developing, manufacturing, and analyzing drug products that are dosed in our clinics to healthy volunteers and patients all over the world in later-stage clinical trials. It’s a huge team effort that also involves dedicated teams managing our supply chain, facilities, equipment, and logistics to meet stringent regulatory and quality standards and to ensure that our medicines are ready and in the right place at the right time. 

My responsibilities lie in making sure that our PharmSci team has everything they need to do their jobs to the best of their ability, both now and in the future. Developing the skillsets and careers of our workforce is important to me and a lot of my time is devoted to identifying opportunities for training and personal development.

Tell us about your background training, early career, and how it all has led you to your current role here at Quotient Sciences.

I originally trained as a pharmacist and quickly realized I wanted to work in the pharmaceutical industry during a summer placement in Zeneca (as it was then known) before completing my training at Pfizer. My first role as a scientist was at the University of Queensland in Brisbane, Australia where we were mathematically modeling drug uptake in the liver. We wrote several publications on this work before I returned to Nottingham to do a PhD. During my PhD, we developed in vitro models for drug metabolism and toxicity studies, and together with my supervisor we attempted to commercialize them as an alternative to preclinical animal studies through a University spin-out company.

Following that, I worked for another start-up biotech which was focused on advanced drug delivery. Gaining experience in a start-up environment was invaluable to me as it gave me exposure to many different aspects of the industry that I might not have had the opportunity to at other places. Startups are very fast-paced, entrepreneurial environments where it’s common to challenge the status quo and make risk-based decisions – always balancing time and cost.

In my next role, I moved to a mid-size biotech, Ipsen where I set up a new group to access externally developed innovations in drug delivery. Over 4 years, this group expanded to around 10 scientists, engineers, and technology scouts, with my team split across three sites in France. I had global responsibility for product development which included novel formulation technologies and drug delivery devices. By the time I left, we had projects at every stage of development – from preclinical through to lifecycle management. I was pleased to see one of the products we developed, which I’m a named inventor on, was launched a couple of years ago. Having worked with several different CDMOs on various projects I came to value Quotient’s integrated approach to drug development even more. When a job opening arose at just the right time, I joined Quotient and have now been here for about four years, which have flown, and I have loved every minute of it.

What was Quotient Sciences like when you started and how has it evolved over the years?

When I first started we only had the Nottingham and Edinburgh sites, and PharmSci in Nottingham was about two-thirds the size it is today. We were, and continue to be, very busy, delivering an increasing number of projects every year. We are lucky to have a talented pool of scientists in the East Midlands area of the UK and have managed to recruit and retain some brilliant people to support Quotient’s growth. By the end of my first year, Quotient had acquired facilities in Reading, Philadelphia, and Miami and all of a sudden, we were a global organization. This has given us tremendous development opportunities for our staff and I’m very excited to be part of the next phase of growth.

What do you enjoy most about your role and why? How do you see your role evolving as the business grows?

Undoubtedly, the thing I enjoy most about my role is the group of people I work with. Someone once said, “If you’re the smartest person in the room, you’re in the wrong room”, and I am lucky to be working with some brilliant people across the organization that I learn from.   But more than that is the spirit and camaraderie we have here at Quotient, it’s something quite special, and no matter what issue we’re dealing with you’re guaranteed people will be smiling. I’m not sure I’ve ever worked anywhere where so many people are friends just as much as colleagues.

What are the key formulation and manufacturing strengths at the Nottingham site and how do you support customer programs?

In Nottingham, we are experts in formulating small molecule APIs. We can develop, analyze, and manufacture almost all types of dosage forms – from simple drug in capsules to more complex ones such as DPIs and intravenous injections. Solid oral and inhaled dosage forms are our core strength, particularly modified release where we can employ numerous different technologies to obtain the desired performance. We also have specialized capabilities in the development of various radiolabelled drug products – for use in ADME studies, or gamma scintigraphy studies to visualize formulation performance in vivo. A key capability we have is real-time adaptive manufacturing – our cross-functional project teams work together to enable the manufacture and release of a drug product immediately before dosing. This is what we call Translational Pharmaceutics, our unique platform which is an industry disrupter –enabling us to respond to emerging clinical data and optimize drug products more efficiently than the traditional drug development processes.

Can you talk more about Translational Pharmaceutics® and how it is used today by customers?

Translational Pharmaceutics® is unique to Quotient Sciences and is a platform that accelerates drug development by integrating formulation development, real-time manufacturing, and clinical testing.

It was developed here in Nottingham and has been used over the last decade by global pharmaceutical and biotech companies across over 400 drug programs. Put simply it integrates a wide array of activities under a single service provider, reducing the “white space” in development and shortens times between clinical manufacturing and dosing, from months to days.

Translational Pharmaceutics is used to advance molecules across the full development cycle and key applications include:

• Transitioning molecules from first-in-human (FIH) to proof-of-concept (POC)
• Development and optimization of clinical formulations
   

Has there been any independent research looking at the time and cost benefits of Translational Pharmaceutics?

Yes, recently the prestigious Tufts Centre for the Study of Drug Development in Boston evaluated the time and subsequent financial benefits of Translational Pharmaceutics in a range of different program types. The recent paper by Joseph DiMasi in the Therapeutic Innovation & Regulatory Science (TIRS) Journal, quantified the financial benefits of Translational Pharmaceutics, demonstrating >12 months of acceleration of development and multi-million dollar reductions in R&D costs. This research makes me proud of what we’re doing in helping get new medicines to patients faster and having a positive impact on the health of many thousands of people around the world.
 

Clare Preskey, Senior Director, Clinical Operations at Quotient Sciences

As Senior Director of Clinical Operations, Clare is responsible for the oversight of day-to-day activities that take place in our Nottingham Phase I clinical unit.  This includes volunteer screening and management, oversight of our clinical laboratory and pharmacy teams to ensure on-time project delivery, and driving continuous improvement and innovation initiatives.

Looking back to when you were first starting your career, was your goal to be where you are now?

I have always held a passion for science and the study of physiology and pharmacology and I started my career at Quotient Sciences in 2010 fresh out of university as a Clinical Scientist. My key responsibilities were ensuring the well-being of our volunteers and the collection of clinical data.

I then moved into Project Management where I gained valuable experience in customer management and developed a broader understanding of our business. Over the past 9 years, I have held several roles within Project Management with my most recent role being a Team Lead.

I have always held a passion for clinical sciences and operational excellence and my current position of Senior Director, Clinical Operations is a natural fit for me.

What are some of the biggest changes and improvements that you have seen over the years at Quotient Sciences?

When I first joined Quotient, we were a much smaller business with one building containing our 30-bed clinical unit, a GMP suite, and approximately 100 employees. The biggest change is the vast expansion in facilities and capacity, and the evolution of our Translational Pharmaceutics platform. Quotient never stands still; we are always pushing boundaries in the industry, trying to do things better and more efficiently! Despite our growth, the ethos of who we are and what we do has not changed.

The people at Quotient are at the heart of the business; we have a ‘family-like’ culture with tight-knit teams. Close teamwork is imperative when managing complex and integrated projects in short timeframes for our customers. Quotient has always had a big focus on continuous improvement and high-quality standards - I am privileged to work with such committed and talented teams.

What do you enjoy most about your role and why?  How do you see your role evolving as the business grows?

The environment at Quotient is dynamic and fast-paced, and every day brings different challenges and opportunities! We work with so many different customers, molecules, and study designs. I love what we do, and I always feel energized to come to work every day, ready to learn and take on the next challenge. My colleagues at Quotient are incredibly passionate and dedicated to every one of our projects and customers. We learn and grow together, expanding our knowledge and gaining new skills. Getting things right the first time is very important to me.

What do you think is one of the biggest successes at the Nottingham site?

As a business, we have grown very quickly, but at the same time, we’ve been able to retain our core values, agility, and integrated processes. One of our biggest successes is that it still feels like a small company, even though we now have over 900 employees across 6 sites globally.

How do the functions of clinical operations and pharmaceutical sciences integrate seamlessly to deliver Translational Pharmaceutics to our customers?

Teamwork is key to any Translational Pharmaceutics program and establishing cohesive communication channels across multiple departments.  Our integrated processes have been built up over many years of experience, with SOPs and protocols geared to be highly flexible and adaptive, however, planning is also an essential ingredient embedded in all our operational processes (i.e. kick-off meetings, dummy runs) to ensure the highest quality project delivery that is the right first time.

At Quotient Sciences, our focus is on bringing lifesaving therapeutics to patients quickly. We work with more than 200 pharmaceutical and biotech companies across disease indications, and one area gaining increasing attention is the development of orphan drugs for rare diseases.

An orphan drug is a drug for a rare disease or condition, affecting a small percentage of the population (less than 200,000 people in the US, and not more than 1 in 5000 in the EU). Worldwide there are over 300 million people living with one or more identified rare diseases representing 3.5% - 5.9% of the global population. Some rare disease treatments have been “orphaned” or discontinued because there was not enough financial incentive to continue development or production. 

To encourage industry R&D the Orphan Drug Act by the FDA incentivizes drug development for rare diseases, which was reciprocated in Europe in 1999 via the Orphan Drug Regulation. These regulatory frameworks recognized the importance of developing new treatments to address these unmet clinical needs.

Can you provide a little bit of background on this important area of drug development?

Global regulatory agencies have sought to provide an impetus to pharma and biotech organizations for the development of new therapeutics for orphan diseases by offering enhanced regulatory support, expedited review times, reduced submission fees, and market exclusivity periods. We have seen the benefits of these incentives most prominently in the US, with over 50% of NDA approvals in the last two years being for rare diseases. In Europe of the 66 new medicines authorized by EMA in 2019, 7 of these (~10%) were orphan drugs.  From a global perspective, it is estimated that approximately 30% of new drugs in development today are focused on these therapeutic areas.  This is a great success story, but much more still needs to be done to address global patient needs.

What are some challenges that drug developers are still facing when developing these therapeutics?

There are four major CMC challenges that we have seen in the orphan drug space recently, which are arguably exacerbated by regulators providing pathways for expedited development. These include the effective development of patient-centric dosage forms based on molecule properties and patient needs, particularly given many rare diseases will be in pediatric populations. In addition, there are challenges to quickly identify optimized drug products, whose performance is preferably demonstrated in humans, prior to initiating protracted, difficult-to-recruit patient trials.  Linked to this are then the challenges of implementing a tailored manufacturing and supply plan for drug products into these patient trials, and then finally finding a long-term partner for the scale-up and commercial manufacturing of what will inevitably be low-volume products.

How can Quotient Sciences help address those challenges that you mentioned above?

In the orphan drug space, Quotient is keenly aware of the need to “start with the end in mind”. Our approach has been to prioritize the key API characterization data required, which allows our scientific experts to recommend a selection of the appropriate API form as well as inform a data-driven strategy for preclinical and clinical pharmaceutical development.

At Quotient Sciences, we have demonstrated the benefits of embedding formulation flexibility within FIH trials to enable a “patient-ready” formulation to be identified and be ready for POC studies in an average of 12 months, less than half the time of the industry standard. We accomplish this by integrating real-time manufacturing and clinical testing. Studies can start quickly with a simple FIH formulation, allowing parallel development of a solid oral format, which is introduced into a later part of the FIH protocol without the need for a separate clinical PK bridging study. At the end of dosing healthy volunteers in the FIH trial, the lead formulation is manufactured and supplied to the patient POC study. No further pharmaceutical development or clinical bridging work is required. This is ideally suited to rare disease therapeutics, as patient trials can be initiated with confidence in the clinical performance of the drug product.

We have also developed significant expertise in providing manufacturing and supply chain solutions for challenging patient trials for over a decade.  We are aware of the difficulties presented where recruitment rates are sporadic across multiple study sites in multiple countries.  There may also be a need to customize the drug product based on specific patient attributes. To that end, we are able to support complex clinical trials based on program needs, whether with “traditional” large batch manufacturing, all the way through to the personalized product manufacture. Our focus is on helping the customer get the right product to the right patient at the right time.

Looking ahead, modest market potential will mean an even greater focus on managing program time, cost, and risk. Lean and flexible programs will be imperative to progress molecules effectively and efficiently from candidate selection through to commercialization. By definition, access to patient populations during clinical research will be challenging and may require increasing personalization of the drug product based on individual patient needs. A flexible manufacturing and supply platform will be key. Finding the right commercial manufacturing partner will be challenging given the relatively low production volumes required and the high variability in product formats and configurations.

Q: So why is there so much buzz around oncology in the pharmaceutical industry?

A: Oncology drugs dominate today’s research focus with over >5500 molecules in development, representing over 35% of the total industry pipeline. In 2019, 10 new oncology drugs were approved by FDA, of which half had an orphan indication and all had been granted priority review.

Q: Can you explain some of the challenges drug developers face?

A: Given the number of molecules in development, there is so much pressure on development teams to identify successful drug candidates as quickly as possible, and accelerate patient access, particularly where no effective therapies are currently available. However, the oncology therapeutic area remains a challenging one to navigate and success rates are low. The likelihood that a molecule entering Phase I will reach market is around 10%, with the average duration of an oncology clinical trial taking 40% more time than other therapy areas due to the difficulty in patient recruitment.

Q: What trends are you seeing in the types of molecules in development?

A: Oncology drug development has seen a significant shift in focus over the past 20 years as molecule chemistries and drug technologies have improved. Historically most oncology drugs were cytotoxic compounds with poor safety profiles. However, in recent years a better understanding of cancer aetiology has improved drug target specificity of oncology compounds, leading to the advent of molecular target agents (MTA), with more favorable safety profiles. Targeted small molecules currently make up around 40% of the global oncology pipeline, whereas cytotoxins have fallen to just 7%. This movement has opened the opportunity to use more convenient dosage forms, with oral administration considered the gold standard for patient compliance. Understandably, compared to the intravenous dosage form, this move to oral administration brings a different set of biopharmaceutics challenges that need to be overcome.

Q: What experience does Quotient Sciences have in this space?

A: Over the past 5 years alone, Quotient has performed more than 300 projects on 91 different oncology drug candidates, for 66 biotech/pharma clients and spanning 34 different disease indications.

Q: What types of development and manufacturing services does Quotient provide to biotech/pharma companies developing oncology therapeutics?

A:  As a fully integrated drug development, clinical testing and manufacturing organization, Quotient Sciences is well positioned to address the challenges associated with developing small molecule oncology therapeutics.  We are dedicated to accelerating the development of new drugs for patients around the world providing individual services or fully integrated programs through our unique Translational Pharmaceutics platform.  We have supported over 50 oncology programs during the last 5 years and our extensive formulation know-how, coupled with our agile and flexible approach to clinical and commercial manufacturing, makes us a valued end-to-end solution provider for the development, testing and manufacture of oncology drug products.

Q: Are there any specialized areas or unique services that Quotient provides?

Global demand and growth for targeted oncology therapeutics has led to an increase in the manufacturing of high potent active pharmaceutical ingredients (HPAPIs). This has driven the need for high potency handling capabilities, particularly high-containment manufacturing facilities. Handling of these ingredients in the drug supply chain requires specialized equipment and enclosure systems in order to avoid cross contamination, product protection and to ensure operator and environmental safety. Quotient’s global state-of-the-art facilities possess the necessary handling and containment capabilities needed when development and manufacturing high potency APIs. Our highly potent handling GMP manufacturing suites are outfitted with the necessary engineering controls to handle PBLEC levels 1 through to 5 dependent upon the type of compound, dosage form, manufacturing process and batch size required.

In addition to handling high potency API’s, Quotient Sciences has demonstrated that formulation flexibility in Phase 1 healthy volunteer trials can be used to develop “patient ready” formulations for oncology molecules in less than half the time of the industry standard. This is accomplished by the close integration of real-time manufacturing and clinical testing, as part of our unique platform called Translational Pharmaceutics, which uses a 14-day “make-test” cycle, enabling formulation decisions to be made in real-time based on emerging human data.

Q: Where in the drug development process does Quotient support oncology companies?

Quotient Sciences supports small molecule oncology drug programs from candidate selection through to commercial manufacture  with  expertise in niche therapies including orphan and pediatric indications. We are dedicated to accelerating the development of these medicines for patients around the world, providing individual services or fully integrated programs..  

Our experience also includes late stage development and commercial product launch.  We understand the manufacturing challenges that may arise such as low volume demands, small batch sizes, limited API availability and high variability in patient recruitment times.  We specialize in developing customized programs, supporting batch sizes ranging from less than 1 kg and scaling up to over 500 kg for solid oral dosage forms and up to 350 L for liquid formats. 

Quotient’s facilities have been inspected and approved by all major regulators , with expertise and to manufacture  clinical and commercial product for the U.S., U.K., European and Japanese markets. From design of experiments (DoE), to registration batches and process validation, our team of formulation and manufacturing scientists have the experience needed in order to ensure a successful commercial launch.

The study of drug absorption, distribution, metabolism, and excretion, also known as ADME is used by researchers to analyze and investigate how the body processes a drug compound. 

In ADME studies, experts are seeking answers to some very important questions to help progress the drug candidate further into development toward regulatory submission:

• Where does the drug go in the human body?
• What happens to the drug inside the body?

Quotient Sciences has been delivering radiolabelled clinical studies for the pharmaceutical industry at our Nottingham, UK facility since 2006, with expertise conducting conventional human ADME studies, intravenous microtracer and microdose studies, and integrated study designs. We have been at the forefront of driving best practices to simplify study delivery while maximizing data output to ensure clients can learn as much as possible about their candidate drug from a study that should only need to be performed once in the development program for any new chemical entity.

ADME studies can be complex

For a relatively simple study design, such as a single radiolabelled dose and subsequent sample collection, the human ADME study can be a complex program of work to deliver. We have always focused on the need to simplify the process for our clients. Using a process-oriented approach, we've designed our Synthesis-to-Clinic® integrated ADME programs to bring together key building blocks for successful study delivery in a coherent fashion that is easy to work into an overall drug development timeline.

At the outset, the coordination of the synthesis of 14C drug substance and the justification of the proposed radiolabelled dose from animal dosimetry data are critical deliverables. Dosing on the human ADME study can’t be scheduled without an understanding of when the 14C drug substance will be delivered, and that can’t be determined until the radiolabelled dose is confirmed so the target amount of radioactivity in relation to the mass of drug can be fixed.

Gaining the necessary approvals for a radiolabelled study is similar to any other clinical pharmacology study. One difference is the addition of the submission to and approval from an Administration of Radioactive Substances Advisory Committee (ARSAC). As such, the experience of our regulatory department, which routinely progresses clinical trial applications through the MHRA and ethics committees, is pivotal in ensuring that we gain approval for these studies in an optimal timeframe.  

Ahead of submission, our team developed a bespoke drug product formulation for the study. For an ADME study, this is usually a simple solution, suspension, or drug in capsule for an oral drug product - something that is not very complex. However, there are limitations on the manipulation of the drug substance due to the radiolabelled content and restrictions on the use of excipients that may interfere with the subsequent sample analysis for metabolite characterization. It is extremely helpful to be able to rely on the experienced formulation capabilities built up over the years to ensure a fit-for-purpose drug product can be developed, along with the necessary data needed for the drug product section of the Investigational Medicinal Product Dossier (IMPD).

Conducting ADME studies in the clinic

Conducting an ADME study in the clinic is straightforward and involves the administration of the drug product followed by extensive sample collection from volunteers. There are strict limits to the number of radiolabelled studies that a volunteer can take part in and we adhere to those guidelines. 

Typically, a human ADME study will have a main residency period of a target duration written into the protocol. There will also be set discharge criteria and volunteers will complete the study when these are met. During the residency period, we will collect all excreta as well as an agreed schedule of blood samples for analysis. 

The discharge criteria are usually linked to the mass balance recovery and as such, the excreta samples collected from volunteers are analyzed daily so that we are able to construct a cumulative mass balance as the residency period continues. When the criteria are met, volunteers can be discharged. There are always contingencies for extra collections if the criteria are not quite achieved in the target time period.

Our metabolism laboratory conducts the analysis of excreta for mass balance and reports results daily, allowing us to generate the mass balance data that leads eventually to subject discharge. The radioactivity determined in the plasma and excreta samples then enables the pooling strategy for metabolite profiling which will identify any metabolites that might need to be fully characterized. The mass balance data will be reported routinely within the clinical study report while the metabolite characterization will be reported separately and appended to the clinical study report when it becomes available.

Providing the best ADME program outcomes for clients

We are often asked to incorporate an intravenous microtracer period into the study design of the human ADME study and these integrated IVMT/ADME studies now represent the majority of the radiolabelled studies we perform. At a basic level, these designs enable an assessment of absolute oral bioavailability of the clinical stage drug product together with the mass balance and metabolite characterization assessments. 

Extending the sample collections and the scope of sample analysis, and comparing data across the IVMT period and ADME period, lets us investigate the overall disposition of the drug product in greater detail. The extent of the additional scope of work will always be driven by the requirements of the client's development team and drug product.

The strength of our operational teams is a critical factor in the successful delivery of the studies we perform. The ability of our scientific and medical teams to perform detailed interpretations of the data generated from the studies performed helps in ensuring we can maximize our client's understanding of the routes and rates of elimination of their drug in the human system.

Contact us to learn more about our 14C human ADME capabilities and talk about your next program.

The global dry powder inhaler (DPI) market continues to rapidly grow. This is riding on the back of various factors such as the growing prevalence of respiratory diseases such as asthma, COPD, and others. Moreover, the rising demand for advanced healthcare devices for the treatment of chronic diseases is envisioned to increase the demand for DPIs.

DPIs are the preferred dosage form for respiratory diseases because the maximum drug load is delivered directly to the lungs, thus minimizing any unwanted systemic effects that can occur with oral or parenteral delivery. Despite the increasing need for respiratory drugs, there is still a high barrier to entry for new products due to the challenges with DPI development.

In this blog piece, Martin Wing-King, our Director of Project Management, will cover the development challenges and pitfalls involved in the development of DPI products. He will cover aspects from drug substance to formulation development, and device design.

What is a DPI?

A DPI consists of a powder (either engineered or API) on a carrier particle that is delivered using a device. The device is actuated and inhaled in order to produce a jet or burst of powder that is typically delivered to the lungs as the target delivery site.

There are many factors to consider when developing a DPI, including:

1. The shape of the drug particle affects the performance of the DPI, so It is imperative to have a clear understanding of the drug substance’s physiochemical characteristics, including:

• Crystallinity
• Particle size
• Morphology
• Hygroscopicity
• Chemical purity
• Residual solvents
   

2. Particle engineering plays a key role when developing a DPI. The shape, size, and the uniformity of the particles determine how they behave once aerosolized and dispersed within the lung.  Important considerations to take into account include:

• Can the drug substance be micronized to a suitable particle size for inhalation?
• Can an engineered particle be developed via spray drying to avoid the need for a carrier particle?
   

3. Selecting the right carrier particles for your API will determine the delivery performance of your DPI.  Carrier particles are used to improve the flowability of the API to the target delivery site, they increase dispersion of drug particles during emission and they also dilute the drug in order to improve accurate dose delivery. ⁽¹⁾

• The most common carrier used in DPI products is lactose, however, you must determine which particle size distribution (PSD) and morphology is best suited for the drug substance
• Do you need to use an additional excipient to improve stability and/or performance?
   

4. Selecting the delivery device type and container closure is the next step.  Unlike oral and parenteral dosage forms, DPIs involve a complex interaction between the delivery mechanism and the patient which can present many challenges, so you must consider the following:

• What kind of device is being used? Passive or active
• How patient-friendly?
• Reservoir, capsule, or blister strips
• Does the formulation or device need a specific container closure to protect it from moisture?
   

5. Container closure systems can also impact the successful delivery of your DPI.

A DPI container closure system consists of the device constituent part and any protective secondary packaging. Current designs of DPI products include pre-metered and device-metered DPIs, either of which can be driven by a patient’s inspiration alone (passive) or with power assistance of some type (active) for the production of drug particles intended for inhalation. ⁽²⁾   Important things to keep in mind when selecting your DPI’s container closure system include:

• Understanding the patient demographic for your DPI can greatly impact the selection of a containment closure system
• The type of manufactured drug product and product expiation can greatly influence the type of container closure system

6. Process development also needs to be well understood in order to develop a robust product. Considerations should be made on how easily the developed process can be scaled up.

• The first stage is typical of powder blend development. The typical variables here are the type of blender (low shear or high shear), sequence of addition, blend speed, time, and evaluation of environmental conditions such as temperature and humidity. 

Once a robust blend is developed, then the next stage would be the filling of the powder into the device or capsule/blister for actuation.  There is a range of different filling techniques (auger screw, dosator, tamping, vacuum drum, etc) available for filling of the powders, selecting the most appropriate mode of filling and associated equipment is also important to ensure that the powder performs as expected after actuation.

There are pros and cons with each of the available filling techniques, so these need to be carefully evaluated to get suitable product performance with also an eye on scale-up in the future.

Summary

Understanding the risks and challenges involved with developing a robust DPI product lays the foundation for the best chances of success.  

For more information on our inhaled drug development capabilities, click here.

References

1. Influence of physical properties of carrier on the performance of dry powder inhalers

Tingting Peng, Shiqi Lin, Boyi Niu, Xinyi Wang, Ying Huang, Xuejuan Zhang, Ge Li, Xin Pan, Chuanbin Wu

Acta Pharm Sin B. 2016 Jul; 6(4): 308–318. Published online 2016 May 4.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951591/

2. Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations Guidance for Industry
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) April 2018 Pharmaceutical Quality/CMC Revision 1

https://www.fda.gov/media/70851/download