The drug development process, from drug discovery to clinical proof of concept (PoC), is expensive and high risk. Estimates of the research and development (R&D) cost per new medicine, accounting for the price of failures, range from $944 million to $2.826 billion.
Discovery and preclinical development account for 42–50% of the total estimated R&D cost.1 Furthermore, 40% of the drug development programmes that reached the PoC decision point were terminated, 10% were put on hold and only 50% proceeded to full development.2
However, the high rewards of a successful development, both from a patient point of view and a commercial perspective, excite scientists, researchers and investors alike.
Drug discovery, which is the initial phase of new drug development projects, is mainly driven by preclinical pharmacology and toxicity. The main objective and milestone in drug discovery culminates by achieving clinical PoC, a pivotal step marked by the approval of the first clinical trial application.
Once a pharmacological target is identified and lead chemical compounds emerge from the drug discovery process, several activities are initiated in parallel to accelerate drug development. These include the following:
- development of a GMP chemical synthesis route for the active pharmaceutical ingredient (API) to derisk scale-up, purification and crystallisation
- characterisation of the API regarding solubility, solid state, purity, stability and potential degradation pathways
- in vitro and in vivo (animal models) evaluation of drug metabolism and pharmacokinetics to gain knowledge of the drug’s permeability, potential induction or inhibition of liver enzymes, metabolite formation and excretion routes
- safety and toxicological screening
- initial drug product development of a fit-for-purpose formulation for preclinical studies and to evaluate the processability of the API.
Drug development is a multidisciplinary process during which data are generated in various scientific fields. The collection of this data represents the critical learning curve for a drug and is essential for entry into clinical trials, risk mitigation and, ultimately, formulation into a marketable product.
Although run in parallel, the results generated from these tests often rely on each other.
The systematic processing and documentation of these chemistry, manufacturing and control (CMC) data pose a major challenge, especially in expedited drug development and approval procedures that result in a limited timeframe to collect this data.
This is particularly true for smaller companies that might not have the necessary expertise or capacity to generate these datasets.3
CMC challenges and regulations in early drug development
Health Authorities provide CMC guidelines to clarify that a minimum level of information and data is expected to ensure patient safety in clinical trials. They also offer advanced consultations to bring innovative drugs to patients quickly.
The European Medicines Agency (EMA) CMC guidelines provide general guidance regarding the expected information to be presented in the Investigational Medicinal Product Dossier (IMPD).
For investigational medicinal products (IMPs), the information required in the quality dossier should be phase-appropriate and focus on the risks, thereby considering the nature of the product, the patients and the underlying disease of the population being studied.4
Similar guidelines have been put forward for Investigational New Drug (IND) filings by the United States Food and Drug Administration (FDA) and the Pharmaceutical and Medical Device Agency (PMDA) in Japan.5,6
The FDA conducted a comprehensive survey to assess the success rate of IND submissions for oncology drugs. Unsuccessful IND filings primarily affected first-in-human (FIH) studies, putting the corresponding clinical trial on hold.
More than 40% of these unsuccessful IND filings were related to CMC problems and were submitted predominantly by sponsors with limited regulatory experience.
Advanced consultations with regulators, such as pre-IND meetings with the FDA, are often underutilised in these cases or incomplete IND files, missing vital CMC data, are submitted.
Resolving the quality issues took 114 days on average but, in some cases, more than 2 years. The review also demonstrated that sponsors with regulatory experience benefited most from FDA consultation in pre-IND meetings.7
CMC is therefore a critical building block for product quality throughout the process, from drug development to marketing.8,9
Effective CMC navigation
In the early development phase, non-clinical studies such as pharmacodynamics, drug metabolism, pharmacokinetics and toxicology are run in parallel with the CMC-related activities such as manufacturing and characterisation of the API and drug product formulation development.
Often non-clinical studies and CMC studies run interdependently of each other. However, it is paramount to build a comprehensive and co-ordinated project plan that combines critical data from both to obtain valid evidence on the efficacy, safety and druggability of the compound.
From a CMC perspective, the API should at least be characterised in terms of solid-state properties, impurities, stability and solubility using appropriately validated analytical methods.
This characterisation should not only be done to meet regulatory requirements but also to map potential risks in terms of future large-scale manufacturability, drug product development and impact on bioavailability and safety.
Impurities, for example, have always been an area of major concern, even more so since the revelation of high nitrosamine concentrations in blood pressure medicines known as “sartans.”
The formation of nitrosamines occurred during synthesis optimisation, leading to GMP non-compliance and resulting in stricter regulatory guidelines owing to patient safety concerns.10
Nitrosamine risk assessments are now common practice and impurities in general should be tightly controlled via a relevant strategy.
Other aspects, such as solid-state attributes of the API — that is, potential polymorphism, particle morphology and particle size distribution — are critical properties that should be considered early on during lead compound selection to
- secure relevant non-clinical data
- determine the critical quality attributes (CQA) of the API
- evaluate their impact on drug product development.11,12
For example, the selection of an unstable polymorph can result in polymorphic transition during drug product manufacturing and storage.
A multidisciplinary team can avoid future issues by building on the quality by design (QbD) principles for both API and drug product manufacturing, as well as the early establishment of quality systems.10,12–16
This will ensure the generation of a stage-appropriate product, process understanding and adequate CMC documentation.
Leveraging external expertise for risk mitigation during drug discovery
Efficient risk management is essential in the complex landscape of drug discovery and early drug development. External expertise and collaboration offer valuable resources and insight to address challenges and optimise processes.
By integrating multidisciplinary approaches and leveraging specialised knowledge, drug development teams can navigate hurdles effectively, ultimately enhancing the likelihood of success.
External collaborations encompass a diverse array of disciplines, ranging from chemical synthesis and physicochemical analysis to formulation development and regulatory affairs. Each facet contributes unique insights and expertise, fostering a holistic approach to problem solving.
For instance, solubility challenges represent a common obstacle in drug development, impacting bioavailability and therapeutic efficacy. Collaborating with experts versed in nanotechnology enables the exploration of innovative solutions such as nanoparticle-based formulations.
These approaches can significantly enhance drug solubility and bioavailability to improve therapeutic outcomes.
However, changing to a nanoparticle-based formulation might also introduce additional risks from a toxicological perspective or necessitate additional method development regarding the characterisation of particle size distribution.
External partnerships offer the possibility to involve experts with different areas of expertise to facilitate seamless progression from concept to clinical PoC. By aligning objectives and harnessing collective expertise, teams can expedite development timelines and optimise resource allocation.
Embracing collaborative strategies for CMC success
Propelled by scientists throughout various organisations, from virtual companies to large pharmaceutical entities, drug discovery serves as the cornerstone of pharmaceutical innovation.
This journey towards clinical realisation necessitates not only comprehensive non-clinical studies encompassing pharmacology, toxicology and kinetics, but also meticulous attention to CMC work and documentation.
The significance of CMC in this process is often underestimated, yet it plays a critical role in ensuring the safety, efficacy and quality of IMPs.
As highlighted in the FDA review of IND filings, the success of clinical trial applications heavily depends on sponsor experience and pre-IND meeting advice.
Timely consideration of CMC, coupled with appropriate expertise and collaboration, can be instrumental when making milestone decisions that contribute to the overall success of drug development projects.
By combining expertise from diverse domains including chemical synthesis, characterisation, analytical method development, formulation, clinical supply and regulatory affairs, drug developers can effectively navigate complexities and accelerate progress toward successful market entry.
This collaborative ethos underscores a shared commitment to advancing pharmaceutical innovation and improving patient outcomes.
References
- S. Simoens, et al., “R&D Costs of New Medicines: A Landscape Analysis,” Front. Med. (Lausanne) 8, 760762 (2021).
- M.E. Cartwright, et al., “Proof of Concept: A PhRMA Position Paper with Recommendations for Best Practice,” Clin. Pharmacol. Ther. 87(3), 278–285 (2010).
- E. Dye, et al., “Examining Manufacturing Readiness for Breakthrough Drug Development,” AAPS PharmSciTech 17(3), 529–538 (2016).
- www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemicalpharmaceutical- quality-documentation-concerning-investigational_en.pdf.
- www.fda.gov/drugs/investigational-new-drug-ind-application/ind-applicationsclinical-investigations-chemistry-manufacturing-and-control-cmc-information.
- S. Singh, et al., “Insight on PMDA Regulatory Procedures, Key Stages, Timing, and CMC Requirements for Bio-Therapeutic Products in Japan,” J. Pharma. Res. Rep. 2(1), 8–13 (2021).
- M.L. Manning, et al., “An FDA Analysis of Clinical Hold Deficiencies Affecting Investigational New Drug Applications for Oncology Products,” Regul. Toxicol. Pharmacol. 110, 104511 (2020).
- N.S. Cauchon, et al., “Innovation in Chemistry, Manufacturing and Controls — A Regulatory Perspective from Industry,” J. Pharm. Sci. 108, 2207–2237 (2019).
- M. Algorri, et al., “Transitioning Chemistry, Manufacturing and Controls Content with a Structured Data Management Solution: Streamlining Regulatory Submissions,” J. Pharm. Sci. 109, 1427–1438 (2020).
- www.ema.europa.eu/en/documents/report/lessons-learnt-presence-n-nitrosamine-impurities-sartan-medicines_en.pdf.
- N.C.F. Stofella, et al., “Solid State Characterization of Different Crystalline Forms of Sitagliptin,” Material 12, 2351 (2019).
- E. Van Gyseghem, et al., “Solid State Characterization of the Anti-HIV Drug TMC114: Interconversion of Amorphous TMC114, TMC114 Ethanolate and Hydrate,” Eur. J. Pharm. Sci. 38, 489–497 (2009).
- https://database.ich.org/sites/default/files/Q11%20Guideline.pdf.
- https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf.
- https://database.ich.org/sites/default/files/Q9%20Guideline.pdf.
- https://database.ich.org/sites/default/files/Q10%20Guideline.pdf.