Quotient Sciences (“Quotient”), a leading drug development services and manufacturing organization, is pleased to announce that its Vice President of Pharmaceutical Sciences, Andy Lewis, has been appointed as Secretary of the Controlled Release Society (CRS).

CRS is the world’s leading scientific society, established to promote delivery science and technology, and is dedicated to the science of controlled release. The CRS serves members from more than 50 countries, with two-thirds of CRS membership representing industry and one-third representing academia and government.

Dr. Lewis has over 20 years of experience in the pharmaceutical and drug delivery industry. He currently leads a team of 120 scientists working on formulation development, clinical manufacturing, and pharmaceutical analysis projects. Dr Lewis is dedicated to overcoming drug delivery challenges, including solubility enhancement, controlled release, and transmucosal delivery of proteins and peptides. He is a member of the Academy of Pharmaceutical Scientists of Great Britain where he served on the Membership Committee and Board of Scientific Advisors, and for four years was Director-at-Large of the CRS.

Dr. Lewis will commence his service to the Controlled Release Society following the conclusion of the 2019 CRS Annual Meeting & Exposition held in Valencia, Spain, July 21-24, 2019.

Pharmaceutical R&D continues to grow significantly year-on-year with increasing numbers of pharma companies and therapeutic molecules in development. 

According to the Pharmaprojects Pharma R&D Annual Review 2018, this expansion has been concentrated in Phases I and II more so than in late-phase development with over 2,000 new therapeutic molecules entering clinical research in 2018. 

To address this growing need, Translational Pharmaceutics®, an integrated formulation development, real-time adaptive manufacturing, and clinical testing platform, has been proven to accelerate timelines and reduce costs in early drug development. 

This innovative approach helps drug developers reach proof-of-concept (PoC) milestones as quickly and efficiently as possible and accelerates the development of optimized and scalable drug products.

Limitations of traditional outsourcing

Despite increases in spending, the industry struggles with poor R&D productivity. Outsourcing has become more siloed, with separate vendors focusing solely on discovery chemistry, discovery biology, preclinical toxicology and safety, clinical testing, or formulation development and manufacturing.

In the conventional outsourcing approach, the developer engages with multiple vendors, creating both a management burden and gaps in the development timeline. The contract development & manufacturing organization (CDMO) and the contract research organization (CRO) operate in separate worlds, with limited shared knowledge and no operational synergy between vendors, making it difficult for the pharma company to build efficiencies into the drug development process.

An innovative approach

The early stages of drug development have been proven to be amenable to an integrated platform that ties together formulation development, real-time adaptive manufacturing, and clinical testing.

Integration of the “make” and “test” supply chains allows drug products to be manufactured to GMP within days of dosing, rather than weeks or months when using conventional processes. By using 14-day “make-test” cycles, a drug product is manufactured and dosed, clinical data are generated (for example safety, pharmacokinetic, pharmacodynamic, or biomarker), and then a decision is made on how to modify the drug product, formulation composition or dosage strength for the next study period.

Our CDMO and CRO integration helps drug developers:

• reach proof-of-concept (PoC) milestones as quickly and efficiently as possible
• accelerate the development of optimized and scalable drug products
   

Benefits of an integrated platform

Implementing a Translational Pharmaceutics® approach can trim six months or more from a typical drug development timeline. As well as immediate cost savings in early development, for a drug product forecasted to generate $500 million to $1 billion in annual revenue, such efficiencies can increase future revenue potential by millions of dollars per day.

In addition, given that Translational Pharmaceutics® enables development decisions to be made based on clinical data rather than surrogate in vitro or preclinical data, the program maximizes the potential for success, avoiding the time and cost of potentially repeating multiple rounds of development cycles.

Our customers reap direct cost savings from a significant reduction in the amount of drug product that must be manufactured and the amount of drug substance (API) used in a trial.

Large CDMOs typically insist on larger than required minimum batch sizes for drug product manufacturing; however, a highly flexible and adaptive manufacturing approach tailored to the clinical trial can reduce API consumption by >85%. That is a significant advantage in early development where API is produced at a small scale and must be carefully rationed to cover a plethora of activities.

When a sponsor outsources all these functions to a single partner that offers these capabilities under a single project manager, an integrated early development program can significantly ease the sponsor’s management burden, as well as the contracting responsibilities. 

This can have tremendous benefits to small biotech companies with limited resources, but also to large pharma companies that can divert their resources to other molecules in their pipeline.

How pharma and biotech companies are applying Translational Pharmaceutics®

You can read some case studies providing examples of how our integrated programs have overcome early drug development challenges, such as the optimization of new formulations and the development of scalable drug products, and have helped pharma companies efficiently reach PoC milestones.  

In the meantime, learn more about Translational Pharmaceutics® here, or feel free to ask our experts directly.

As a company that prides itself on science and innovation, Quotient Sciences works collaboratively with our customers to publish research findings from programs of work that we perform.

In 2018, we were involved in 14 scientific posters, 10 podium presentations, and 5 peer-reviewed publications.

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 our collective goal of accelerating the delivery of new medicines to patients around the world.

Details and links to this quarter’s papers and posters are provided below. If there is something of particular interest and you would like further information then please get in touch.

Scientific papers

• Developed in partnership with Genentech, “Application of a Novel ‘Make and Test in Parallel’ Strategy to Investigate the Effect of Formulation on the Pharmacokinetics of GDC-0810 in Healthy Subjects” highlights RapidFACT®, our streamlined, data-driven approach to drug product optimization platform to help bridge from Phase I/II to Phase III formulations. 

• Developed in partnership with MEI Pharma, “Safety, Pharmacokinetics, and Pharmacodynamics of ME-401, an Oral, Potent, and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, Following Single Ascending Dose Administration to Healthy Volunteers” highlights a first-in-human study in healthy volunteers to rapidly identify the appropriate dose and schedule for an oncology drug candidate

   

Scientific posters

Presented at the AAPS Annual Conference 2018

• *Awarded Best Abstract* "Rapid Development and Clinical Assessment of New Rectal and Oral Formulations for Ulcerative Colitis Using Real-Time Adaptive GMP Manufacturing and Supply"
• "Identification and Optimization of Critical Process Parameters of Roller Compacted Capsules: From Development to Registration Batches"
• "Development and Approval of a Palatable Glycopyrronium Bromide Liquid Formulation for Pediatrics"
• *Awarded Best Abstract* "Development of a Modified Release Tablet Containing an API Prone to Form Changing and Gelling in Aqueous Media"
• "Evaluation of Process Transferability of Poorly Flowing Blend Between the Blenders Manufactured by Different Vendors"

Presented at the European Paediatric Formulation Initiative (EuPFI)

• "Creating Acceptable Tablets (CAT) - A feasibility study to assess the swallowability and acceptability of different sized placebo tablets in children and young people: an interim analysis"

Presented at the North American Cystic Fibrosis Conference (NACFC)

• "A Pharmacokinetics and Lung Deposition Study in Healthy Volunteers Comparing the Delivery of Colistimethate Sodium (CMS) When Administered as an Investigational New Combination Product (Colistairtm), by eFLOW® Rapid Nebulizer or as Colobreathetm"

Presented at the American College of Allergy, Asthma & Immunology Conference (ACAAI)

• "A Phase 1/1b Study of an Inhaled Formulation of Itraconazole in Healthy Volunteers and Asthmatics"

The search for new therapeutic treatments has unveiled a class of compounds known as High-Potency Active Pharmaceutical Ingredients (HPAPIs), whose current market size (as of 2019) was approximately $17 billion and is expected to increase to $25-30 billion over the next 5-7 years¹. 

HPAPIs produce a response, or pharmacological effect, at a very low dose and offer benefits in numerous areas such as oncology drug development.

It is essential to understand the hazards posed by any new drug compound before its handling or manufacturing, but it becomes more important for HPAPIs due to the risks associated with potential exposure. There is often an incomplete toxicology package available for new compounds at the early stages of drug development to make proper safety assessments. In such cases, the compound is evaluated for factors including but not limited to carcinogenicity and cytotoxicity, source of origin (synthetic/semi-synthetic/biologic), targeted disease and mode of action, preferred dosage form and estimated dose if known, and physicochemical properties.

To ensure safe handling, pharmaceutical scientists and manufacturing technicians who work with HPAPIs must be suitably protected, and there must be rigorous controls and procedures in place at the facility where HPAPIs are handled. It's critical to have procedures in place to minimize cross-contamination among products made in the manufacturing facility. In some cases, personnel may also be placed under medical monitoring to ensure their long-term safety from any future, untoward effect. 

We use a five-band system called the “Performance-Based Level of Exposure Classification," or PBLEC, to categorize a compound in one of five bands.

PBLEC 1 is the least potent compound, offering no pharmacological activity, to PBLEC 5, which is highly potent, toxic, or with high pharmacological activity. To meet safety and regulatory expectations, we routinely check our containment procedures and processes to mitigate cross-contamination risk and adopt best practices in the handling of HPAPIs.

We ensure that there is no cross-contamination through the implementation of various procedures based on source (by elimination and protection), risk (by reduction), and vulnerability (by engineering and administrative controls), such as:

• Special GMP manufacturing suites with restricted access are used to manufacture HPAPIs, which have air-handling units with single-pass air and HEPA filtration. The suites are negatively pressured to ensure that the surrounding atmosphere is not impacted and have an airlock for entry and an air and mist shower for the exit.
• Facilities are evaluated using surrogate testing. Manufacturing equipment is evaluated and designed to minimize exposure and mitigate the risk of cross-contamination. Dedicated equipment parts and additional containment are also used when necessary. Verification of cleanliness of both equipment and facility after use by analyzing cleaning swabs using HPLC/UPLC.
• Our personnel undergo rigorous training in the handling of HPAPIs and wear appropriate Personal Protective Equipment (PPE), including a Powered Air-Purifying Respirator (PAPR)
   

Choosing a CDMO with expertise in handling HPAPIs

Working with a CDMO who has a long track record of successfully handling HPAPIs is essential. 

Contact us today to learn how we can help your next program.

References:

1.    N. Walker, HPAPI Market Trends, 2018, https://www.contractpharma.com/issues/2018-09-01/view_features/hpapi-market-trends/

2.    Bornett D., Pharm. Technol., 2008 (4) Supplement (2008). http:// www.pharmtech.com/high-potency-apis-containment-and-handling-issues

As a new molecule progresses through drug development, the way it is formulated as the drug product or dosage form will change for it to successfully achieve key clinical milestones. 

In early development, the first-in-human (FIH) clinical trial is often a single-center study and typically involves dosing a small number of healthy subjects over a short duration of days or weeks. In this study, the drug is administered in increasing doses and as such, a “fit-for-phase” drug product with high dose flexibility is often used, such as a simple solution, suspension, or powder-in-capsule. 

This type of drug product can usually be prepared on-site, at a small scale, and with limited stability studies and analytical release testing. Simple pharmacy preparations may be sufficient for FIH clinical studies, but when moving beyond Phase I into later stages of clinical development, these products are unsuitable for both patient convenience and scalability to meet larger batch size requirements for Phase II trials.

Scaling batch sizes for Phase II and Phase III trials

Subsequent Phase II and Phase III patient trials involve a larger number of patients and often take place at multiple clinical sites, across states and countries, and over a longer period. To support these trials, the development team will need to bridge to an optimized drug product, such as a solid oral dosage form like a tablet, to ensure patient compliance and suitability for shipping globally. Product batch sizes manufactured to support Phase II and Phase III trials will need to increase to support the increased number of patients. If the molecule is successful in clinical studies, batch sizes will be scaled up to meet the demand for a commercially approved product.

Requirements for different product formats at each stage of development can result in delays and budget overruns when it comes to product optimization and scaling up. Sometimes, CMC delays can be prevented by careful planning, and integrating development activities and technology considerations in the formulation design process. 

Bringing new molecules to market as quickly as possible

To improve R&D productivity and bring new molecules to market as quickly as possible, drug companies are actively seeking new ways of streamlining drug development using alternative outsourcing models. At Quotient Sciences, we coordinate drug product manufacturing requirements with a clinical development plan, to make and test formulations in a streamlined fashion. This leads to significant time efficiencies and cost savings. 

Druggability Technologies (DRGT; now Tavanta Therapeutics) was a specialty pharmaceutical company dedicated to the development and commercialization of high-value proprietary drugs to deliver measurable improvement in clinical utility. They used the Quotient Sciences Translational Pharmaceutics® platform to advance the development of DRGT-46, a fast-acting formulation of celecoxib. 

Clinical data was able to help DRGT drive formulation selection in real-time, allowing the company to efficiently bridge from a Phase I drug product to a dosage form suitable for patients in late-stage clinical trials. Continue reading the DRGT-46 case study to learn more about how Translational Pharmaceutics® was applied. 

When you are looking for a partner who can help develop your drug product from first-in-human through to proof-of-concept and beyond, rely on Quotient Sciences. Contact us today to get started with your program.

Modified release dosage forms are increasingly used to enhance oral drug product performance. 

For decades, modified-release drug products formed part of a line-extension category and were launched in a strategic way to offer a better product relative to commercial immediate-release (IR) products, thereby extending the life of the brand. Today, pharma and biotech companies are increasingly considering MR technologies earlier in the development process of a new chemical entity (NCE) to obtain greater differentiation against other products in development or on the market.  All stakeholders including investors, patients, doctors, and payors welcome this trend, especially where clearer therapeutic benefits are shown.

Many drug product improvements can be achieved using modified-release technology, including:

• Improved patient compliance - modified-release technology can allow for simpler, once- or twice-daily dosing
• Enhanced pharmacokinetic (PK) profile – modified-release dosage forms can be suited to the therapeutic window or to the patient’s needs, such as adjusting drug blood levels between daytime and nighttime
• Reduced side effects - a modified PK profile can lower the Cmax of the drug or its metabolites while still maintaining therapeutic plasma levels

The benefits of modified-release products are significant but can come with technical challenges that prevent or complicate their development. Modified-release formulation approaches range in complexity, and the formulation selection needs to be based on the properties of the drug substance and the target drug release profile. R&D programs can encounter large delays and cost overruns when the wrong modified-release technology is selected.

Our experience in the development of modified-release products spans controlled release, gastro-retentive, delayed release, pulsatile, and biphasic release technologies.

When evaluating a modified-release product opportunity, we often start with two fundamental questions: 

• What is the appropriate MR technology to achieve the therapeutic goal of the drug?
• What is the right development plan to efficiently demonstrate proof-of-concept for the MR product?

A variety of modified-release formulation technologies are available to be manufactured using common tableting, encapsulation, and coating processes (either pan or fluid bed coating). The specific modified-release behavior is also determined by the functional excipients used. 

A common approach is to use hydrophilic polymers in a tablet that form a gel matrix in in-vivo that controls drug release out of the matrix. Polymer coatings are also applied either on tablets or multi-particulates, for example using beads, with functionality that may be pH-dependent. An erodible coat, or a coat that controls drug diffusion through a semi-permeable coat or orifice, may also be used. Both the excipients and the final products used are generally non-proprietary. 

Among the more complex modified-release technologies are osmotic tablets, using the approaches described and sometimes also including a small orifice that contributed to release-rate control, and gastro-retentive formulations that apply a range of swelling, floating, or adhesion methods to delay gastric-emptying of the dosage form.

A traditional approach to screen and selecting formulation prototypes begins with in vitro testing and animal models, and then a lead prototype or prototypes are selected for clinical testing. This approach and overconfidence in non-clinical to clinical predictions can be flawed when developing oral modified-release formulations because the behavior of the modified-release formulation is highly dependent on human physiology and this dependence occurs over a longer duration of drug release. 

Across modified-release drug programs, we often see that clinical performance of modified-release products differ considerably from in vitro or animal test predictions. This often provides a surprise for the drug development team but confirms why non-clinical tests should not be the backbone of a modified-release product development program. Using Translational Pharmaceutics, we can make formulation adjustments in response to human PK data during the clinical study to accelerate development timelines, using a science-driven approach proven to accelerate and derisk drug development. 

For more insight about this topic, watch our recent webinar, Non-Clinical vs Clinical: Risks & Considerations When Developing Modified Release Dosage Forms, or to discuss your next modified-release drug program, contact us today. 

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. During my short tenure there, 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. Later I 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 very 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 at Quotient, 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 new Garnet Valley (GV) facility provided us with additional capacity but also enabled us to separate early-stage work from late-stage. 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 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 Quotient with a footprint in the US where the highest number of pharma and biotech customers reside. Subsequently, with the Reading UK site also being added, Quotient now has a good mix of early and late development capabilities on both sides of the pond. Over the last couple of years, we have successfully used our global footprint to help customers advance their programs into later stages of development. A recent example is with the company DRGT and this is described in our case study. DRGT has worked with all six of the Quotient sites over the past few years, on a program, which 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.