A Changing Outsourcing Environment
The pharmaceutical research and development (R&D) industry has changed significantly over the last decade. In particular, big pharma is transitioning to a leaner business model that relies heavily on external partners. Since 2007, the explosion of biotech has resulted in a sharp increase in the number of companies actively engaged in research, more than doubling the number of drug candidates under development (Figure 1).1
As a result of this growth, outsourcing large components of the development process has become necessary to both manage capacity and access scientific and process innovations required to develop drug molecules as efficiently and cost-effectively as possible.
This article addresses the challenges drug developers face while managing disparate resources through separate contract development and manufacturing organizations (CDMOs) and contract research organizations (CROs). It covers the benefits and key applications of an integrated CDMO/CRO outsourcing model, and discusses its success in Europe and current operationalization in the United States.
Functional Outsourcing Creates Silos
Across the industry - from virtual biotech to large pharma – drug developers are managing R&D costs, addressing capacity constraints, and accessing innovation by outsourcing activities that were historically handled in-house. To keep pace with changing R&D needs, CDMOs and CROs are now handling contracted work in various modalities, offering everything from full-time employee labor agreements to full development programs.
The rise in outsourcing initiatives over the last 10 years has driven fundamental change in how the industry is structured. The service sector, which has grown in size and scale to accommodate the industry’s needs, now mirrors departments seen within large pharma. With a variety of separate vendors each handling specific activities - including discovery chemistry, preclinical toxicology, clinical research, formulation development, and manufacturing – the lack of horizontal integration has not only replicated inefficiencies in workflows and processes but has generated a siloed mindset across the drug development process. As a result, knowledge about the drug itself is easily lost in translation from vendor to vendor, ultimately hindering a drug molecule’s acceleration to proof-of-concept (POC) and beyond.
Questions Facing Drug Developers
- How can I quickly start a First-In-Human (FIH) clinical trial with a fit-for-phase drug product?
- How can I progress into the clinic with limited quantities of drug substance?
- How can I rapidly optimize my formulation before starting a pivotal patient trial?
- How can I overcome formulation challenges such as low solubility?
- How do I bridge from a simple Phase I dosage form to a robust drug product without losing time?
- How can I manufacture drug product on demand to meet the precise needs of the clinical trial and patient recruitment?
Breaking Silos Requires Integration
As the industry changes, drug development companies need new strategies to help them overcome a multitude of research challenges and achieve milestones as quickly as possible. Specifically, we are seeing innovation in the service sector where a focus on smarter R&D has aligned multiple CDMO and CRO activities into a highly integrated model that takes place with a single vendor, under a compressed timeline (Figure 2).
This model has broken down barriers, created an opportunity to improve efficiencies, and fostered a consistent exchange of information that allows the outsourcing partner to coordinate and adapt the drug product manufacturing requirements (“make”) with the specific needs of the clinical development plan (“test”).
Implementing an Integrated Approach in Different Geographies
This type of integrated CDMO/CRO outsourcing model has been used successfully in Europe for more than a decade. The Medicines and Healthcare products Regulatory Agency (MHRA) recognized the advantages of flexibility in early development, which led Quotient Sciences to integrate formulation development, real-time adaptive manufacturing, and clinical research in studies across the United Kingdom.
The Benefits of Integrating Real-Time Adaptive Manufacturing and Clinical Research
Applying an integrated platform to the early stages of drug development is ideal. The horizontal integration of CDMO and CRO capabilities enables a shortened make-test cycle where a trial sponsor can integrate drug product manufacturing within the clinical program.
Shortened Cycle Times
Using a fit-for-phase manufacturing strategy, make-test cycles can be shortened to a matter of days rather than weeks or months. In a two-week cycle, for example, products are manufactured in real-time at the precise dose or composition required, immediately before administering to subjects in a clinical trial. The development team is then able to review the emerging clinical safety, pharmacokinetic (PK), and pharmacodynamic (PD) data, creating a feedback loop to fine-tune the drug product within the study, prior to the next dosing period. This process reduces cost investments in drug substance and drug products, enables precise dose manufacturing, and allows human data to drive key decisions (Figure 3).
Formulation Design Space Flexibility
When developing a new drug product, it is difficult to predict how the formulation composition will affect the drug’s behavior in a clinical study. Traditionally, development teams rely on surrogate animal or in vitro tools to make predictions of clinical performance, but that introduces a notable level of risk into any drug development program.
The inclusion of a formulation design space, however, enables real-time flexibility to adjust the quantitative composition of the formulation based on arising clinical data (Figure 4). Coupled with real-time manufacturing, it is possible to assess multiple formulation technologies and drug products in a clinical trial without having to secure regulatory or institutional review board (IRB) approval every time the dose or formulation is adjusted. This gives drug companies the flexibility to adapt quickly to any emerging clinical or biopharmaceutics data that arises, to optimize drug products as needed and move through early clinical studies efficiently.
Key Applications of an Integrated CDMO/CRO Model
Accelerating molecules from first-in-human to proof-of-concept
A simple fit-for-phase drug product strategy is typically used in the FIH study to provide dose flexibility with minimal upfront investments.
However, this may not be sufficient for molecules with challenging drug chemistry and does not address how to bridge to a solid oral dosage form for subsequent POC trials. However, real-time adaptive manufacturing makes it possible to adjust dose levels, formulations, and drug product types within the FIH trial and then maintain a continuous supply of the lead drug product as the drug candidate progresses into patient trials.
Real-time adaptive manufacturing for patient trials
In early patient trials, real-time adaptive manufacturing offers a creative but simple solution by manufacturing only the precise drug product required to meet the needs of the patient and the clinical trial. Biotech and pharma companies can balance the requirements of the clinical protocol (e.g., subject numbers, patient recruitment) with any chemistry, manufacturing, and control challenges that present themselves (e.g., shelf life and drug product availability).
This approach conserves valuable drug substance and reduces drug product manufacturing costs until scale-up for late-phase trials and commercialization. This is especially beneficial with orphan drugs, rare diseases, and pediatric indications where patients are often enrolled one at a time and where the product may need to be “tuned” to specific subject needs.
Developing optimized and scalable drug products
Most new drugs emerging from the industry pipeline have suboptimal properties including poor solubility and may require formulation technologies to achieve their full potential. By using real-time adaptive manufacturing within a clinical bioavailability study, it is possible to rapidly screen, optimize, and select new formulations based on emerging clinical data. Using this approach, multiple formulation technologies can be evaluated head-to-head based on their clinical performance.
Conclusion: The Benefits of an Integrated Approach
Horizontal integration across a combined CDMO/CRO organization provides significant benefits and efficiencies in early drug development. By adapting and fine-tuning the formulation composition and manufacturing process to the specific needs of the clinical trial, drug developers can accelerate product development and shorten timelines to POC. With compounded timeline savings of more than six months, investment savings of more than $500,000, and drug substance conservation of up to 85 percent, an integrated early development program not only improves trial efficiency, it significantly improves productivity and eases the drug company’s management burden. For a drug product forecasted to generate $500 million to $1 billion in annual revenue, such savings can conserve millions of dollars per day.
After nearly two decades of success in the United Kingdom, the advantages of integrated make-test programs are now being realized in the United States. With the operational footprint to run integrated studies under an investigational new drug (IND) application now in place, drug companies in the world’s largest R&D market—where the greatest number of molecules are in development—can now benefit. Not only will the integration of “make-test” cycles improve development precision and maximize a drug candidate’s potential for success within a single study, they will help drug development companies deliver new medicines to the people who need them faster.
References
- Lloyd, I. Pharma R&D Annual Review 2018. Pharma Intelligence. Informa UK Ltd., London.
Author Biography
Kieran Crowley has nearly 20 years’ experience leading formulation and product development teams in the pharmaceutical industry, including selecting and optimizing drug delivery systems based on the physicochemical and biopharmaceutics properties of drug candidates. With expertise in oral delivery of poorly soluble compounds, Dr. Crowley has successfully advanced products using a variety of methods including hot melt extrusion, nanomilling, and lyophilization. At Quotient Sciences, Dr. Crowley oversees the design and implementation of adaptive clinical programs and integrated product manufacturing, driving real-time decision making in early development. Dr. Crowley received his Ph.D. in pharmaceutics from the University of Bradford, U.K., and was a post-doctoral researcher at the University of Wisconsin-Madison.