The question – “How much does it cost for the analytical phase of drug substance development” – is a really difficult one to pin down. Not only are there so many unknown areas that are beyond the control of the best scientists before they get into it, but the culture of different sponsoring companies and where they wish to put the majority of their cash resources also affects the final costs.
One of the biggest mysteries is knowing what the analyticals are going to uncover. Until this stage, it’s impossible to know how many impurities may be in the final molecule or to what levels they may be. This article will break down the potential costs.
Since analytical development is always specific to a particular molecule and its route of synthesis, the key to ensuring that costs are controlled and to provide the best possible outcome for the sponsor, as well as its partners, is to have a strong regulatory strategy, which will drive how the work needs to be done.
A well thought-out regulatory strategy that aligns the regulatory activities with the business strategy for that product will provide direction to the project team by identifying the important regulatory elements that need to be addressed. In addition to a regulatory strategy, companies must also have a regulatory plan – a document that describes specific steps and actions required to successfully meet the regulatory strategies objectives, including regulatory submissions.
Some key components might include:
The regulatory plan will establish specific project deliverables, deadlines, responsibilities and resources needed, as well as specific testing requirements and their relationship to the established standards and guidance.
While the regulatory strategy and plan may be in place, there are still many unknowns that occur during analytical development. Molecules are very complex and impurities are tough to pinpoint since they can come from a variety of places, such as the raw materials. Currently, ICH guidelines require extremely minuscule levels of impurities — 0.5 percent at most.
In later stages of development there is the need to identify all impurities and see if they are genotoxic, containing a destructive effect on a cell’s genetic material and affecting its integrity.
This is increasingly becoming a huge area of concern, since genotoxicity becomes a key issue as the drug dosage increases, and consuming large amounts of potentially genotoxic compounds in large dosages can create health issues.
Companies in Phase One can choose to conduct more rigorous development to determine genotoxicity or conduct it at later stages when it becomes a necessity.
While early-stage programs can get away with doing less work when there’s less scrutiny, the impurities and chemical structure of these impurities need to be detected before going into more advanced stages of development.
Once a process is established, a company can decide if more horsepower is needed for further Method Development.
Most companies charge approximately $100,000-150,000 for support during Method Development.
Later stages of method validation can be more intensive and cost closer to $200,000-300,000, so it can be in some cases more cost-effective to do more robust method development at earlier stages to insure a successful validation program.
A key goal of Method Development is to develop Stability Indicating Methods (SIM). According to FDA guidelines, a SIM is defined as a validated analytical procedure that accurately and precisely measures active ingredients (drug substance or drug product) free from process impurities. During later stage development, a force degradation study is often conducted to ensure that the analytical procedure is suitable for its intended use through-out the shelf life of a drug product. If the substance decomposes during this study, more development work will be needed, yet some companies choose to do it, while others decide to forgo it until later.
Ensuring due diligence in each of these early-stage trials may cost more in the short-term, but they can help prevent future problems that can cause a product to fail while in clinical trials, when at least three out of five projects do in fact fail.
Given the odds for successfully bringing a drug to commercialization, companies need to weigh their decisions carefully – do you invest more in the analytical development before the product is scaled up and do the bare minimum to pass FDA muster, or do you take your chances? Given the uncertainties of drug development it might make sense to do everything possible that can be controlled right from the start to ensure the best possible outcome.
At PCI Synthesis, we have two decades’ worth of experience, working on dozens of projects each year. We understand how to work with small molecules, especially as our sponsors ask us to push the frontiers of science to develop new Active Pharmaceutical Ingredients (APIs) to cure illnesses, manage chronic diseases and conditions, treat pain and help patients live healthier lives.
To help current and prospective sponsors, we’re continuing to develop and expand our library of blog posts that examine each stage of the drug discovery process. To keep abreast of our latest updates and insights, please consider subscribing to our quarterly newsletter: PCI Synthesis Quarterly Newsletter.