Companies that prioritize optimal synthetic routes, stable API forms, and verified analytical tools pave the way for phase I clinical manufacturing success.
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Developing small molecule drugs is exceptionally challenging. Pharmaceutical companies face high costs, high attrition rates, and significant risks. A particular challenge is getting a small molecule to the clinic.
This article summarizes what is required to advance a small molecule candidate from R&D to GMP-compliant phase I clinical manufacturing, focusing on critical considerations across chemical synthesis, analytics, and materials science.
The R&D-GMP gap
A considerable gap often exists between the synthetic routes developed for R&D and those suitable for a GMP campaign. Whereas the latter must adhere to stringent GMP regulations while also being suitably scalable and cost-effective, R&D methods frequently include slow, low-yielding, non-scalable, and capricious steps.
Some synthetic approaches in the development phase may struggle to produce more than 100 mg of active pharmaceutical ingredient (API), let alone the quantities required for clinical development.
In addition, R&D chemistry is generally performed in a laboratory setting by PhD-trained chemists, whereas GMP manufacture must be carried out by skilled operators in a dedicated manufacturing facility, typically with quite different equipment - a robust process is crucial for success.
While bridging this gap often demands extensive synthetic route optimization, companies are not required to develop a flawless route for early clinical phases.
Given the high failure rate at each stage of clinical development, companies may choose not to pursue further development beyond critical milestones, especially in situations where financial and resource constraints are important.
Such situations include small pharma and biotech firms, startups, spin-outs, or when companies try to sell their assets to larger pharmaceutical organizations for clinical trial progression.
Companies must determine whether their synthetic approach is adequate for GMP manufacturing, and how they can strategically optimize their routes to be appropriate for phase I clinical trials while avoiding wasting time, money, and resources.
SELECTing phase-appropriate route development
The SELECT framework is a rational approach that helps companies address these concerns. Broadly, SELECT helps pharmaceutical companies assess and develop their synthetic routes by considering six critical aspects of route optimization: Safety, Environment, Legal, Economics, Control, and Throughput.
Looking at SELECT with phase I in mind
While environmental, regulatory, and throughput considerations are important in phase I, they should not be the focus of route optimization and selection: these considerations are much more significant at later clinical development stages.
In phase I, it is sufficient that a route does not infringe on another company's intellectual property and produces enough API. In the best-case scenario, the route would have a low environmental footprint and be amenable to further phase-appropriate optimization.
For phase I readiness, route optimization and evaluation should prioritize safety, economy, and control.
- Safety: Safe working procedures are essential in all sectors, including the pharmaceutical industry. Therefore, a synthetic route with an acceptable safety profile is a necessity for phase I, regardless of how high-yielding or simple a route is to execute.
Optimizing a synthetic route for safety may require a variety of steps. These could include ensuring sufficient headspace and venting of the reaction vessel to prevent pressure buildup, and using the appropriate equipment and engineering controls to regulate exotherms and prevent runaway reactions with crash-cooling capability.
- Economics: Small companies in phase I clinical trials often rely on seed money or venture capital investment, as they lack access to the expansive budgets that larger pharmaceutical companies frequently enjoy.
Phase I requires a cost-effective synthetic approach. Ideally, a phase I optimized approach should include low-cost starting ingredients and reagents that are commercially available in the long run and supported by solid and trustworthy supply networks.
The employed method should also reduce the number of reaction steps, use fewer metal catalysts, and take less time by avoiding complex and laborious purifications (such as column chromatography). The latter is particularly essential because it means that companies could limit the time spent in production facilities, which is costly.
- Control: In GMP manufacturing, a method that is merely safe and efficient is not sufficient: manufacturers must also ensure that the reaction profile and reaction product are consistent every time.
This requires the careful regulation of critical process parameters (CPPs) to consistently deliver a stable product that meets critical quality attributes (CQAs). Manufacturers must, for example, guarantee that the purity, color, water content, residual metal levels, solid form, and a variety of other characteristics are as intended and within permissible limits.
Products that do not meet specifications can have severe repercussions. For example, the discovery of a novel contaminant can halt manufacturing and result in missing clinical trials, incurring substantial costs and timeline delays.
Smaller companies simply cannot afford to fail at manufacturing, given the direct costs involved, the risk to future funding, and the considerable delay in the race to market.
To effectively control a reaction, companies must have a deep understanding of it, including what reaction conditions can be tolerated, the reaction's impurity profile, and how to effectively clean up any impurities.
The key to control
Obtaining sufficient analytical data is an important step toward understanding and controlling a reaction. Regulations require that companies must develop and validate a set of suitable analytical methods in accordance with pharmacopeial expectations and ICH guidelines.
These analytical methods allow producers to accurately assess the purity and other properties of raw materials, process solvents, and APIs for release. They are also crucial for verifying that materials meet regulations and preventing low-quality, unstable APIs from entering the clinic, which could cause harm to patients.
N-Nitrosamine contamination
Potentially hazardous, carcinogenic, and mutagenic substances may make their way into the API manufacturing process, which is governed by ICH M7 rules. One of the most pertinent contaminant classes is N-nitrosamines, which are a possible human carcinogen.
In 2018, the European Medicines Agency (EMA) became aware of nitrosamines in various human medicines. As a result, a three-step approach is now being followed, including:
- The assessment of drug products for the potential presence of N-nitrosamines
- Analytical testing where potential risks were identified
- Remediation where an N-nitrosamine was determined to be present in a product above an acceptable level
As a result, the existence of minor N-nitrosamines and bigger, more complex N-nitrosamine drug substance-related impurities (NDSRIs) must be fully studied and their hazards assessed.
Drug makers must establish that there are no detectable quantities of nitrosamine impurities in their API, raw materials, intermediates, or process impurities. This requires extensive analytical testing and emphasizes the critical need for proper analytical methodologies to support clinical manufacturing.
On solid form
One of the many potential CQAs that manufacturers must assess and regulate is the solid form of an API, which is often overlooked during the early development stages.
This is remarkable given the potential hazards. Indeed, receiving the incorrect solid form at the conclusion of manufacturing might leave businesses with few or no remedial choices.
APIs can exist in a variety of solid forms, each with unique physical, chemical, and mechanical properties that can influence bioavailability, manufacturability, and stability. Identifying a salt of the API with the best physiochemical properties is a great place to start.
Polymorphism - or a solid's ability to exist in two or more crystalline forms - should be examined. Ideally, producers should find, and then consistently make, a polymorph that will remain stable beyond the API or API complex's desired shelf life, even if this necessitates an additional post-manufacturing procedure.
Stability is critical here because, regardless of how well an API performs in other areas, an unstable polymorph might degrade with time, resulting in a less effective and perhaps deadly drug. To determine the best solid form for clinical manufacture, organizations should incorporate screening into their pre-GMP workflow.
There are several tools and solutions available to assist businesses in determining a solid shape that is both effective and stable. Again, a set of reliable and reproducible structural characterization techniques, such as X-ray powder diffraction (XRPD), is essential for gaining insight into an API's solid form before a GMP campaign.
A confident path to the clinic
Getting a small molecule into phase I clinical trials is a monumental task, and the stakes are high. But success is by no means not out of reach.
Companies that phase-appropriately optimize their synthetic route, prioritize a stable API solid form, and use a range of verified analytical tools will be well on their path to phase I clinical manufacturing success.
With decades of experience in process research and development and GMP manufacture, MHRA-accredited facilities and a dedicated team of expert chemists, Concept Life Sciences meticulously balances cost, quality and time to support you in developing a purpose-fit chemical route and seamless delivery of your API.
Acknowledgments
Produced using materials originally authored by Dr David Fengas and Dr Jamie Stokes from Concept Life Sciences.
About Concept Life Sciences
Concept Life Sciences is a leading contract research organisation (CRO) serving the global life sciences industry. For over 25 years, the company, and its heritage companies, have provided consultative and collaborative drug discovery and development services. Our approach, supported by passionate scientists and world-leading capabilities, enables clients to overcome complex scientific challenges across a broad range of therapeutic areas, improving program success rates. The company has successfully helped 29 candidates advance to the clinic.
The company offers sophisticated translational biology services coupled with exceptional end-to-end chemistry capabilities across all modalities, including small molecules, biologics, peptides and cell & gene therapies, with the ability to seamlessly integrate capabilities and provide bespoke solutions to address client needs.
Collectively, the company’s high-quality services and commitment to customer service across the drug development pathway enhance efficiency in drug discovery, helping clients advance their drugs to clinic in as little as 32 months, well ahead of the industry average of 60 months.
Driven by a passion for science, Concept Life Sciences has around 230 employees, with around 70 % holding PhDs. The company operates from state-of-the-art UK facilities, headquartered near Manchester, with additional operations in Edinburgh, Dundee, and Sandwich. The headquarters is one of the UK’s largest medicinal chemistry CRO sites with key discovery services all under one roof.
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