Participant recruitment is one of the biggest bottlenecks in clinical research today. 

In early drug development, effective volunteer recruitment is critical for building a robust package of clinic trial data, ensuring scientific validity, containing study costs, and maintaining timelines. In studies that require specific types of volunteer populations, it’s important to develop a focused plan for recruitment.           

Different populations may demonstrate widely varying responses to drug therapies due to physiological, lifestyle, or other disparities. To safeguard those for whom standard requirements may not offer sufficient protection, special populations provide an evaluation of factors such as dosage or dose interval modifications to address these differences.

For example, individuals over the age of 65 are more likely than younger individuals to take multiple drugs concurrently, making drug interactions of particular concern. Because older populations respond differently than younger patients to drug therapy, obtaining clinical efficacy and safety data for these populations is critical in early drug development.

Furthermore, growth in global pharmaceutical markets is driving drug development in Europe and Asia. Multi-ethnic approaches to clinical trial programs, such as ethnobridging for native Asian populations living in other countries, must account for cultural differences to satisfy international regulatory authorities.

If you’re a sponsor, it will be of utmost importance to work with a trusted contract research organization (CRO) that is transparent about timelines and can guide your expectations. 

An experienced partner can effectively target hard-to-recruit populations such as the elderly, post-menopausal, hypertensive, and healthy smokers, to name a few.

An organization that has completed multiple studies with similar types of populations will have a baseline understanding of recruitment challenges and can provide an honest assessment of the time expected to recruit the full cohort. When studies have stricter criteria or more screening procedures for qualification, recruitment will require more time. It’s important to find a partner that provides a realistic, trust-based approach to recruitment rather than one that promises to quickly recruit every participant.

In addition to identifying appropriate study participants, the right partner can help minimize screen failures due to multiple exclusion/inclusion criteria. 

Such a partner will demonstrate a successful track record with metrics including:

• Number of studies completed
• Database size and number of active healthy volunteers
• Recruitment timelines and strategies for special subject populations
• Communicate effectively

Sponsors may consider the following five tips when it comes to interviewing and partnering with a CRO for their early drug development needs.

Inquire about the volunteer database

When rapid study startup is critical, a robust database provides an immediate starting point for recruitment. A large database demonstrates that the CRO has access to an adequate population of volunteers who understand clinical research and are amenable to participating. Consistent recruitment activities and a database of multiple trials also can help keep volunteers active.

Consider your CRO's location

Whether your trial must be conducted at a single site or multiple sites, you may want to consider the location of the sites available and their advantages and disadvantages. Facilities in larger cities tend to recruit from more ethnically diverse populations or those with better access to public transportation options. The longer the facility has been in existence, the more established relationships it will have with the local community and population.

Know what questions to ask your CRO's

To determine how the CRO will prioritize your study, ask whether it is recruiting for multiple studies of the same kind concurrently. If so, your study would compete with others for the same volunteers and consequently have access to a smaller pool of potential participants, which could delay your recruitment completion. Ask about recruitment and screening timelines, because extended timelines could indicate difficulty recruiting that population. Determine if full trial cohorts can be enrolled at one time or if there is a need to divide them into sub-cohorts for admission, which could be another indicator that the site has difficulty enrolling a specific population.

Employ best practices regarding patient safety

If you have concerns about volunteers participating in overlapping studies, work with a partner who uses a registry that tracks volunteers and their participation in trials, including the date of the last dose of a study drug. This information will help establish a sufficient wash-out period, during which the participant receives no active medication. Such registries are confidential and established through fingerprinting, and they enhance patient safety as well as facilitate data integrity.

Find a CRO that can integrate services

Look beyond the CRO’s ability to recruit large cohorts of volunteers and examine its track record of complete study delivery, including the expertise of its team of medical directors and project managers, as well as other capabilities. The right partner can also guide protocol development and study design to maximize your clinical data output, and rapidly deliver data and insights quickly to move you to the next milestone.

When you are looking for a partner who is dedicated to Phase I trials and early development, choose Quotient Sciences. 

To find out more about our clinical pharmacology capabilities, get in touch with us today.

Nutan Gangrade, former Managing Site Head of Quotient Sciences' Chelsea Parkway and Garnet Valley facilities, has overseen over 200 clinical manufacturing programs and the manufacture of 5 commercial products in the 17 years that he has been with the organization. In this article, we speak with him about his experience in the industry and about the capabilities offered at our Philadelphia sites.

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

After getting my graduate degree in Pharmaceutics from the University of Georgia, I started as a formulation scientist at Chase Pharmaceutical Company in Newark, NJ. At Chase, I was mainly involved in developing generic formulations and I learned about many of the manufacturing techniques and the basics of GMP. Then, I moved to American Cyanamid Company, where I got extensive training and learned about the whole process of drug development from discovery to launch. I had the opportunity to lead the product development group and be part of several teams including discovery chemistry/pharmacology, toxicology, IND CMC development, scale-up, and technology transfer to commercial manufacturing sites. 

I later worked at Wyeth Ayerst, Dupont Merck, and Bristol Myers Squibb in the CMC product development before joining QS Pharma in 2002, which was acquired by Quotient Sciences in 2017.

You mentioned that you started your career as a formulator, how was the transition from sponsor to CDMO?

My formulator experience formed the foundation of my career. I learned a lot about the development, quality, and regulatory aspects of the industry. I decided to leave BMS and work for a start-up CDMO primarily to be able to help virtual and small companies that could not undertake development in-house. The goal was to provide the best chance of success for their molecules in clinical studies.

It has been a rewarding experience, working on the CDMO side. My experience in big pharma plays a key role in my thinking when we interact with our customers. I want our team to be an extension of our customers’ team. Our teams have worked on several products, many of which are in the market now.

Before the Quotient Sciences acquisition in 2017, you were with QS Pharma for almost 12 years at the Chelsea Parkway facility. Tell us about the facility and programs that Chelsea Parkway support?

The work in our early days of existence grounded us as a reliable and flexible service provider who could develop products and meet customers’ expectations of quality and speed. Our Chelsea Parkway facility started in 2002 as a CDMO to provide early-stage development services to customers. As the pharmaceutical industry changed its focus, we had to change our growth strategy. 

We decided to diversify our portfolio to include late-stage development and manufacturing. The Chelsea Parkway site became more involved in process development and larger-scale manufacture of clinical supplies. By 2008, we had leased the entire building and expanded our analytical labs, GMP area and warehouse. In 2012, we decided that we would manufacture products for the market. We expanded again and built a commercial manufacturing wing, more warehouse/dispensing areas, and a large clean equipment GMP area. 

We built a team to support commercial manufacturing and in 2015, we had our first successful pre-approval inspection by the FDA. We launched our first commercial product in 2017 followed by four more. Today, we have a very strong pipeline of early-phase programs and many of these clients will stay with us through launch if their molecules are successful in clinical trials. 

For all of us, the day is always extremely busy but I look forward to coming to work every day. There are many sides of my work that are gratifying in many ways. First, we work for a noble cause: we develop and manufacture drugs that help treat serious diseases. We are helping patients by bringing the drugs to them as quickly as possible. 

Second, it is absolutely the most wonderful group of people that I have ever worked with. As a team, we have achieved many successes and grown the company significantly. It is a great joy to see Quotient Sciences grow, with more colleagues joining us. We have hired and trained many colleagues who are now in leadership positions. I see myself helping to take Quotient Sciences to the next level as we undergo our next cycle of growth.

In addition to Chelsea Parkway, Quotient Sciences recently commissioned a brand-new facility just 2 miles down the road in Garnet Valley, PA. What was the need and overall goal of building this facility?

Over the past 2 years, we have more than doubled our headcount and are continuing to hire people in almost every functional area. We are looking for dynamic people who are customer and team-oriented. I am proud to say that the Quotient brand has helped the site attract high-caliber staff. Our goal is to make the company the best place to work at in our industry.

As our late-stage portfolio is growing, we needed to expand to ensure we could support our customers’ early-phase projects. Building the Garnet Valley drug product manufacturing facility provided additional capacity and enabled us to separate early-stage and late-stage work. The two require a different kind of facility and expertise. We decided to build the new facility from the ground up, which meant we were able to customize the specifications to our exact requirements. 

The new facility will house all early-phase development, Phase I-II CTM, and support Translational Pharmaceutics programs in the US; where we can formulate and manufacture drug products and then integrate with clinical testing at our Miami clinical pharmacology facility. The Chelsea Parkway facility will now be dedicated to commercial manufacturing and some large-scale clinical/late-stage programs.

What do you think is one of the biggest successes at the Philadelphia locations?

The acquisition of the Philadelphia site was an extremely significant strategic step in the growth plan for Quotient Sciences as it provided the capabilities and experience to continue to work with clients beyond Phase I/II and develop or transfer client products for further scale-up. 

The Philadelphia facilities also provided a footprint in the US where the highest number of pharma and biotech customers reside. Over the last couple of years, we have successfully used our global footprint to help customers advance their programs into later development. An example is with the company DRGT, described in our case study. DRGT worked with all six of our sites over the past few years on a program that started out in Phase I and is now nearing commercial launch.

Local pharmaceutical companies still represent a good portion of the clients that come through the Philadelphia facilities. How do local biotech/pharmaceutical companies benefit from the collaboration with a development and manufacturing company on their doorstep?

While the Philadelphia sites support clients from all over the world, proximity plays a significant role in our business. Many of our customers are located on the East Coast and most of the time, our customers want to be at our site to observe manufacturing or development activities or for face-to-face meetings. It is very convenient for customers close by to make a short trip to oversee their project without losing too much time from their busy schedules.

Now that Quotient Sciences has a Phase I clinic in Miami and the Philadelphia facilities can conduct Translational Pharmaceutics programs in the US, do you believe that this will change the types of programs that Philadelphia supports?

The Translational Pharmaceutics platform has been a main differentiator for our UK sites for years and our goal is to have that be the case for the US sites, as well. 

We are already bringing in Translational Pharmaceutics programs into our Garnet Valley facility and continuously working with potential customers that will utilize our innovative platform. Not only does this save customers significant time and money, but our customers can also quickly transition to later-stage clinical supplies without losing time. This huge differentiator sets us apart from other small molecule CDMOs in the local area and the world. 

There is no other company like ours in the world that can provide such scientifically sound, efficient, and quality drug development that saves money and time. I hope that more customers will take advantage of our expertise and services.

As a company that prides itself on science and innovation, Quotient Sciences has continued to work collaboratively with our customers over the last 12 months to publish research findings from programs of work that we perform. 

In 2019, Quotient presented 11 podium talks and 13 scientific posters at international conferences, and was involved in four peer-reviewed articles published in scientific journals.

We are grateful to our customers who have been willing to have their work published and to all of the scientists involved in the design and delivery of these projects. Sharing the information with the wider pharmaceutical development community will help with our collective goal of accelerating the delivery of new medicines to patients around the world.

Details and links to some of the top papers and posters are below. If there is something of particular interest and you would like further information then please get in touch.

White Papers, Scientific Papers & Articles
 

WHITE PAPER: Assessing the Financial Impact of Translational Pharmaceutics®
“Tufts Center for the Study of Drug Development (CSDD) white paper sharing study results that indicate Quotient Sciences’ Translational Pharmaceutics® platform reduces development times by >12 months and lowers R&D costs by >$100 million per approved new drug, compared to traditional multi-vendor development paradigms.” 
Access here
 

Peer-Reviewed Publications
 

Genentech - Absence of  Pharmacokinetic interactions between Bruton's Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate
Access here

Mitsubishi - Absorption, disposition, and metabolic pathway of amiselimod (MT-1303) in healthy volunteers in a mass balance study
Access here 

DRGT - Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers
Access here
 
A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability, and pharmacokinetics
Access here
 

Scientific Posters

 
European Paediatric Formulation Initiative (EuPFI)  

"Development of Oral Liquid Products for Neonatal Patients"
Access here

"Development of a Paediatric Oral Suspension of a Novel Drug for the Treatment of Kidney Disease"
Access here


AAPS Pharm Sci 360

"Applications and Benefits of Healthy Volunteer Trials to Accelerate Oncology Drug Development"
Access here

"Comparison of Two In-Silico Modeling Programs, ADMET Predictor®, and Percepta® to Predict Intrinsic Solubility and pKa of Poorly Soluble Drugs"
Access here

"A Phase I Study Allowing Clinical Screening of Multiple Solubility-Enhancement Formulation Technologies, and an Assessment of Food, PPI and Dose Linearity Assessment with the Selected Formulation of BOS172767, in Healthy Volunteers"
Access here

"Development of a Solubilised Capsule Formulation Using Co-Micronisation and Precipitation Inhibition"
Access here

"Rapid Transition of a Novel Celecoxib Formulation from a Fit-for-Phase Presentation to a Commercializable Product Using an Innovative Integrated Drug Development and Clinical Testing Platform"
Access here


American Heart Association (AHA)

Huya Biosciences International - "HBI-3000: A Novel Drug for Conversion of Atrial Fibrillation - Phase 1 Study Results"
Access here

 

Case Studies

Druggability Technologies (DRGT)

"DRGT is developing DRGT-46 as a novel therapy for pain. Gabor Heltovics, CEO of DRGT, explains how Quotient Sciences enabled the rapid development, clinical assessment, and commercial readiness of its DRGT-46 product using integrated services across Quotient’s network of harmonized development and manufacturing sites in the UK and the US."
Access here
 

If you have any questions about our services, get in touch.

What are some of the key considerations in the selection of a candidate compound?

Before setting out on a journey traveling to a destination, it is normal to do some research. You may rely on previous knowledge, look at a map, consider the type of transport, and find out what the likely disruptions or hazards are on your route to ensure they can be avoided.

Developing a drug is also a journey. You will need to develop an understanding of your candidate compound and have an idea of your destination; what is the target disease, the patient group, the likely route of administration, the target product profile, and importantly, what are the potential pitfalls along the way?

From the outset, if for example, your compound is inherently unstable, has very poor solubility, or is hygroscopic, you know your product development journey is going to be more challenging. Therefore, finding people with the right knowledge, skills, and technologies will be important to identify and overcome potential obstacles. The earlier in your journey that these problems are identified the better. The simplest and most effective pathways can be established, reducing both the time and cost of your development, or when appropriate the development of a compound can be stopped and efforts focused on other molecules which show more promise.

After a series of lead compounds are identified, a selection process takes place to prioritize which compound(s) to take forward. Pharmaceutical and biotechnology companies take different approaches to their early development work, and the approach chosen may be based on their internal experience, resources, culture, budget, timeline, availability of API, and their attitude to risk.

In our 30 years of drug development experience, we observed that delaying the basic characterization of a compound may lead to significant issues later in development.

Our approach to drug product development

Quotient Sciences adopts a holistic approach with multidisciplinary development teams of experts in biopharmaceutics, DMPK, materials science, and formulation development, brought together to help guide the process. In early-stage screening, our flexible approaches are always tailored to the molecule and the delivery route, data-driven and technology-agnostic. We are mindful that strategies need to be fit-for-phase, cost-effective, and rapid.

For solid oral delivery systems, it is important to first characterize the solid-state properties of the input API using a range of analytical techniques. We recognize that at the very early stages of development, API can be in short supply, and the synthesis of multiple batches may yield slightly different properties, including the degree of crystallinity, polymorphism, purity, particle size, morphology, and wettability. These variations may affect your initial toxicity studies and therefore understanding your early batches will assist with troubleshooting and specification setting once a validated synthetic route is established.

Often at this stage, the API is amorphous or only partially crystalline. Therefore, one of the main early drivers of a project is to obtain a crystalline form to allow purification of the API as part of the API manufacturing process and so we are often tasked with performing an initial crystallization screen as a first step. These quick screens are used to obtain an early indication of the polymorphic tendency of the molecule.

Next, a solubility screen would likely be initiated looking at solubility in differing pH, biorelevant media, and common process solvents. If solubility is low and likely to affect bioavailability, it would be prudent to examine the possibility of solubility enhancement via modification of the solid-state properties or salt form of the API, before adopting additional formulation enhancement solutions to improve solubility (for example amorphous solid dispersions).

If the API has ionizable groups, a salt screen may also be considered. Modifying a free form or changing salt form can impart many advantageous properties of API, not least solubility, crystallinity, and stability. We design our salt screens with your molecule at the core, the counter ions to be studied are chosen based on several factors, not just the pKa of your molecule. We also consider molecular weight, likely dose strength, and the possible formulation process, to ensure optimal outcome from a wide variety of conditions using only minimal API quantities.

This screening approach is favored at Quotient Sciences because of its rapid turnaround time and typically it only uses milligram API quantities per experiment, whilst still enabling a meaningful characterization to be performed. Based on the results obtained, potential hits are then prioritized for scale-up to allow more detailed solid-state characterization, selection, and comparison to the initial input API.

At some stage in the development process, an understanding of any potential polymorphism of your API is likely to be required, as this can affect many important downstream considerations including the quality, manufacturability, bioavailability, safety, and performance of your product. The timing of polymorphism characterization may depend on API supply, timelines, and budget, however, in our experience, this should be performed as early as possible.  Unexpected changes in the API during formulation development or manufacture can result in costly and time-consuming delays to development plans.

Like solid-state characterization, our polymorphism screens are designed with the API in mind. While initially there may appear to be a limitless possibility of solvents to use, our experience has demonstrated that by using routine process solvents/solvent mixture systems and concentrating on multiple kinetic and thermodynamic crystallization processes, the most relevant forms will be identified. The other advantage to this approach, compared to other high throughput solvent-mediated screens, is that it allows for the identification of formulation processing issues so that these may be mitigated against before the costly formulation development takes place.

Once a candidate has been selected, additional testing can also be employed. For example, accelerated forced degradation studies can be performed to ensure the integrity of the chosen form, and initial excipient compatibility screens can be performed to identify possible adverse interactions during formulation development. Our Modelling and Simulation team can also perform physiologically based pharmacokinetic (PBPK) studies to provide a mechanistic understanding of the likely performance and disposition of your drug product in vivo and inform risk-based decisions on both the formulation and clinical design, ultimately reducing the cost of development.

What are the typical solid-state characterization approaches used in the screens?

• Polarized light microscopy - allows us to rapidly determine and easily see if a crystalline material is present. Additional information about the crystal's habit and size also gives vital information to help inform decisions and planning.
• X-ray powder diffraction - is used to determine the crystal form and the signature patterns can be used to track the solid form through different formulation processes and throughout stability.
• Dynamic vapor sorption - gives vital information on the hygroscopicity of the compound and hydrate formation. We also routinely use dynamic vapor sorption to understand the wettability of the API and batch-to-batch variability due to subtle changes in crystal habit. These properties are key in dictating future storage and processing conditions.
• Thermogravimetric analysis - is used to measure weight changes over a temperature range. This is useful for determining the presence of hydrates or solvates and to determine degradation temperatures when using heat-induced processing conditions.
• Differential Scanning Calorimetry - is used to determine the melting point and purity of our material. It can also be used for our initial excipient compatibility screening studies and glass transition determination for amorphous solid dispersions screens/characterization.
• Confocal Raman Spectroscopy and mapping - are used to identify the solid form within formulations, and investigate changes during stability and are generally an excellent tool to aid investigations into formulation, stability, or processing problems.
• Solution and perfusion Calorimetry - are the techniques to measure low-level discriminatory surface disorder and amorphous content, again particularly needed for inhalation compounds to ensure amorphous content post micronization is controlled and understood.
   

Why is this relevant for the future development of the compound?

Understanding and controlling the solid-state properties of your API is a key part of the candidate selection and development journey. 

Early in development, modest investment in these initial studies and guidance from experienced scientists will help you on your drug development journey. You will be able to build up knowledge of your API, identify potential pitfalls, and ultimately de-risk your development program, getting you to the final product destination as quickly and efficiently as possible. 

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.

The ability to move quickly and cost-effectively from candidate selection to first-in-human clinical trials is a theme that comes up often from clients. One way which we strive to do this is through services offered from our compounding pharmacy in Miami, FL.  

The compounding pharmacy is part of our clinical pharmacology services in Miami, FL, where we conduct Phase I trials with healthy volunteers.  

In this article, learn about the capabilities of our Miami, FL on-site compounding pharmacy, and ideal uses for pharmacy compounding to accelerate FIH to POC trials.

What are the advantages of choosing pharmacy compounding for FIH trials?

Quotient Sciences simplifies the drug development supply chain, acting as a single partner with integrated project team and services. We can help through all stages of development.  

At our Miami site, fit-for-purpose pharmacy preparation can be used to quickly start FIH trials. In this approach, a FIH trial using a simple and cost-effective dosage form, such as powder- in-capsule or bottle (also called PIC or PIB, or drug in capsule/bottle), solution or suspension, 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.  

Emerging clinical data within the FIH study itself can be used to inform formulation technologies (such as solubility enhancement) enabling selection of a technology and/or drug product to move forward with. This means that simultaneously, we can develop and manufacture solid oral drug product, like a tablet, for Phase 2 patient trials within the same program. This allows for POC patient trials to begin with immediate GMP clinical trial material supply.  

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 that we can carefully manage CMC investments and minimize API usage.  

Are there certain programs that benefit from choosing pharmacy compounding?

We have used compounding for a range of drug candidates including small molecules, peptides, fusion proteins, and monoclonal antibodies. These have been across oral and intravenous dosage forms, and for a range of therapeutic areas.  

As discussed, compounding delivers significant benefits for accelerating to FIH programs and when transitioning from FIH to POC. A simple drug in capsule or drug in bottle for reconstitution at bedside is the quickest route to clinic with compounding and dosing occurring within 24 hours.  

Compounding is beneficial on any early clinical program where there is a desire to get data rapidly and keep dose flexibility throughout the trial. In addition to FIH single and multiple ascending dose (SAD/MAD) studies, pharmacy compounding has used in other study types, including:

• Absolute Bioavailability and Relative Bioavailability studies
• Drug Drug Interaction (DDI) studies
• TQT studies
• Food Effect and PK studies
• Studies in special populations (e.g. Elderly)
• Device trials
• Formulation screening studies

Sterile compounding with sterilization by aseptic filtration is another quick route to clinic as proof of concept especially for chronic indications such as HIV infections, CNS indications, oncology, viral infections, certain rare diseases, and metabolic conditions.  

Another advantage of pharmacy compounding is its adaptability in dose-finding studies for combination therapies, where precise modulation of each active pharmaceutical ingredient (API) is essential. This approach is well suited to drug delivery systems requiring an initial burst release followed by sustained drug exposure. By systematically varying the proportions of immediate-release and modified-release components, the optimal formulation for therapeutic efficacy can be efficiently identified.  

In molecules with limited stability, compounding allows for early assessment of their potential for further development.

For small 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, the best formulation, with accompanying formulation technology, can be selected and a new solid oral dosage form manufactured, ready for packaging and shipment for patient trials.

When was the compounding pharmacy at Quotient Sciences – Miami last renovated?  

In 2020, we upgraded the Miami compounding pharmacy to add more IP storage space, including refrigerated storage space at 2 to 8°C and freezer storage at -20°C.  

Clean rooms in the facility were 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 and Hazardous investigational products  

The laboratory space also expanded to support our new pharmacy and provide efficient processing of higher volumes of biological samples.  

What dosage forms can be handled at Quotient Sciences – Miami?

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.  

More about Quotient Sciences – Miami pharmacy compounding and clinical pharmacology  

Learn more about our pharmacy compounding capabilities in our info sheet and see a preview of the Miami pharmacy in this video. 

In this interview, we speak with Clare Preskey about her day-to-day in the Nottingham clinic. 

Clare Preskey is Executive Director of Clinical Operations, responsible for the oversight of day-to-day activities that take place in our Nottingham Phase I clinic. 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. 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.

Later, I moved into Project Management, where I gained valuable experience in customer management and developed a broader understanding of our business. I held several roles within Project Management, last as a Team Lead prior to moving into a clinical operations role. I have always held a passion for clinical sciences and operational excellence, so my current role is a great fit. 

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

When I first joined the company, we were a much smaller business: one building containing a 30-bed clinical unit, a GMP suite, and approximately 100 employees. The people at Quotient Sciences are at the heart of the business; we have a great culture and tight-knit teams. Close teamwork is imperative when managing complex and integrated projects in short timeframes for our customers. 

Quotient Sciences has always had a focus on continuous improvement and high-quality standards. The biggest change has been the expansion in facilities and capacity, including the evolution of our Translational Pharmaceutics platform, over the last 10 years. Despite our growth, the ethos of who we are and what we do has not changed. We’ve been able to retain our core values, agility, and integrated processes.

We never stand still; we are always pushing boundaries, trying to do things better and more efficiently! I am privileged to work with such committed, talented teams. 

How do the different functions work together to deliver Translational Pharmaceutics programs?

Teamwork is key to any Translational Pharmaceutics program and establishing cohesive communication channels across departments. Our processes have been built over many years, with SOPs and protocols geared to be adaptive. Planning is also an essential practice that is embedded in our operational processes (e.g. kick-off meetings) to ensure the highest quality project delivery that is the right first time.

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 Sciences is dynamic and fast-paced. Every day brings different challenges and opportunities! 

We work with so many different customers, molecules, and study designs. My colleagues 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.

I love what we do and I always feel energized to come to work, ready to learn and take on the next challenge.