Risk mitigation in drug discovery & development: Get data!
Introduction
Success in the pharmaceutical industry can be elusive – and it does not come cheap. Recent estimates suggest that the likelihood of approval from Phase I clinical trials is approximately 10% and that the cost per approval is $1-2 billion. This risky proposition is tolerated because drug approval can bestow riches in the form of positive publicity, increased revenues and an elevated share price, all of which are boosted further if the molecule is a first-to-market treatment creating a world-wide monopoly.
This raises two key questions:
- How do you bring the cost of drug development down, allowing small pharma, biotech, spin-outs and academia to enter the market?
- How do you speed up the drug development process?
The single answer to both questions is: analytics.
We can all agree that analytical characterization and subsequent data analysis is critical to the success of drug discovery & development campaigns – from start to finish. What is less appreciated is the timing of analysis, to help facilitate early decision-making, avoid unnecessary risks, and enter the clinic with a drug candidate that gives you the best chance of success.
Here are three examples of how you can creatively use our analytical instrumentation and services portfolio to help make early decisions and build confidence, whilst reducing cost and increasing efficiency.
Fail fast on lead compounds
Giving up on compounds that will not reach the clinic is the pharma industry’s ‘conventional wisdom’. The key, then, is quickly getting enough data to support such a decision and avoiding the dreaded ‘sunk-cost fallacy’. It is well known that one of the key determinants of a compound successfully reaching the clinic is its physicochemical properties profile. What is less appreciated and often overlooked is the role of solid form, which can influence the physicochemical properties of the compound and can make the difference between reaching the clinic and falling into obscurity.
Our advice: to investigate solid form on several front runners while you have time – do not wait until you reach your next milestone and nominate your clinical candidate. A polymorph screen and polymorph interconversion study may uncover a more stable polymorph of your clinical candidate that is less soluble and less bioavailable. This type of result has led to the withdrawal of products from the market and could mean your program going into reverse. Early-stage solid form exploration is effective risk management.
On a more positive note, you may be pleasantly surprised to obtain a salt form or co-crystal that has superior properties, resulting in a longer-lasting and more efficacious drug – and this might not have been your original favorite to progress!
Understand the physical characteristics of your candidate
Knowledge of how a drug candidate’s solid form relates to its solubility, bioavailability and efficacy is an important first step, but the physical characteristics also have a role in determining the manufacturability of the drug candidate. Key properties include crystallinity and melting point which can, for instance, influence how easy large-scale purification is to achieve.
Understanding the physical characteristics of the drug candidate and the intermediates encountered during the synthetic route can result in simplified manufacturing protocols. Batches of final compound can therefore be delivered earlier, enabling advanced milestones to be brought forward. Furthermore, the same insights can reduce and indeed eliminate batch-to-batch variability, resulting in fewer manufacturing campaigns that fail to come in at specification. This will allow you to be more confident and aggressive in your timelines, and you will also give your manufacturing team fewer sleepless nights!
Start thinking about the desired physical properties of your drug candidate when you are in the process research & development stage of your workflow. Knock your synthetic route into shape, but at the same time think to the future and your manufacturing campaign – which, based on current demand, you have probably already booked! Identify your critical quality attributes and invest in optimizing your material properties – allowing you to quickly spot issues such as contamination and enhanced amorphous content that could result in deviations and delays to your process. Losing your space at the manufacturing facility is one possible outcome of this scenario, but which can be mitigated by taking the above-mentioned steps.
Find a reliable and comprehensive service provider
Outsourcing your full workflow to one reliable and experienced service provider could do wonders for your budget and timelines.
In the hit-to-lead phase, a team of chemists will be churning out analogs for potency assessment, and a battery of ADMET assays to evaluate those suitable for future development. These chemists will be in constant dialog with the development teams, planning for success and paving the way for the future by identifying bottlenecks and shortcomings. Take it from us – the chemist who best understands the synthesis from experience will be the best source of inspiration for future improvements.
We’ve already discussed how drug discovery & development hinges on analytical characterization, but the requirements change as you advance through the process. At the hit-to-lead stage, purity profile and compound identification can be accomplished with routine NMR and UPLC-MS experiments. As you advance towards and into GMP manufacturing, you will need bespoke and compliant analytical methods. Set these up as early as possible – you might be surprised what you can use them for!
With your process research & development work package complete and your accompanying analytical suite ready to go, you are primed to enter the manufacturing facility … or not. Changing your supplier at this late stage could throw your plans into disarray. You will unintentionally miss out on full knowledge transfer between the teams of chemists. Moreover, transferring analytical methods and onboarding with a different supplier with different instrumentation may mean the methods do not perform as they were intended and so will be ineffective for benchmarking or assessing critical quality attributes. You will have to take a step back to move forward – and may have to pay twice. Look to mitigate the risks which are within your control, and find yourself a reliable and experienced service provider – it will free up your bandwidth for everything else you need to do!
Want to know more? Speak to an expert
Analytics is the foundation on which drug discovery & development pipelines are built. Use the available analytical tools to prioritize compound selection and fail fast. Potency is not everything in drug candidate selection – look to understand the optimal solid form, and investigate potential polymorphism and other physical characteristics such as particle size, which may serve as an early warning siren for problems ahead. Consider a provider that has a track record in taking projects from the bench into the clinic.
Contact us today to see how our experts can support your journey.