The scale-up process for moving products from preclinical to commercial scale manufacture presents several challenges and complexities. As the goals of medicinal and process chemists largely differ, it is essential for the process to be effectively managed in order to prevent minor errors impacting a successful outcome.
In moving a drug substance to commercial scale manufacture, chemists face many scalability and processing challenges. With the potential for minor errors to lead to huge failures, the process must be meticulously managed to ensure a positive outcome. As marked differences will unavoidably exist between the goals of the medicinal and process chemists involved, these should be understood at the initial stages of any project. Medicinal chemistry places emphasis on the diversity and flexibility of the synthetic route, while in process chemistry, a practical, safe and cost-effective process must be identified to synthesise a compound on a larger scale.
Anders Högdin, PhD, Senior Sales Director at Recipharm, discusses how projects can be streamlined as they move from medicinal chemistry into a development chemistry environment and looks at the key considerations during both the medicinal and process chemistry stages.
There is no substitution for experience when it comes to taking substances from pre-clinical to clinical and then to commercial scale. Processes applied by medicinal chemists can often lack effectiveness when they are performed on a bigger scale. Consequently, a synthesis proven in a lab can all too easily fail when it is transferred to a large-scale production environment.
These factors should be considered at the early stages of any scale-up project, with clear development steps laid out and responsibilities defined for all individuals involved. By doing this, the opportunity is afforded to troubleshoot potential problems before they occur which can greatly increase the chances of a project achieving its delivery date.
Although Research and Development (R&D) are synonymous with each other, within an organisation they are often two very different departments that may not even be located within the same building, city or even country. Emerging pharma companies may only possess the research element, while larger pharma and Contract Development and Manufacturing Organisations (CDMOs) may offer both.
During the research stage, medicinal chemists are focused on whether a certain idea is feasible. They operate outside the regulated environment with emphasis placed on securing intellectual property (IP) rights and overcoming any challenges surrounding patent strategy.
Later stage development chemists are more concerned with the scale-up of procedures, and how drug substances can be effectively moved forward. Good Manufacturing Practice (GMP) is key and the strict regulatory environment dictates greater focus on quality and traceability. This is demonstrated through extensive documentation, Quality by Design (QbD) quality control and assurance (QC/QA) activities.
While the aim for medicinal chemists is quickly producing many different test substances, process chemists are producing larger amounts of one substance in a robust and repeatable way. Overall yield is, therefore, typically of greater importance to a process chemist. In addition, medicinal chemists have free reign for selecting from any available raw materials. Comparatively, cost and material availability are more important factors to consider for process chemists. In addition, there is a stronger focus on the impurity profile. Medicinal chemists can usually wait to remove impurities until the last purification step. For quality purposes, process chemists need full control of impurities throughout the entire process.
These differences demonstrate the complexity of the scale-up process and the potential challenges that need to be overcome.
Candidate drug substances have often been produced in just a few grams, or sometimes less, prior to late preclinical and early clinical phases. This means that process chemists need to produce more material to perform the necessary in-vivo toxicology studies. Additionally, preparations need to be made for clinical stage GMP-material. Toxicology material will have a tested impurity profile and, further down the line, it will be beneficial to have the same profile for the material going into first-in-human studies.
Although there isn’t a need for a commercial process during the production of the first kg, having the end target in mind may make things easier later in the scale-up process. However, as there is always the balance between time and cost the first scale up protocols may very well include compromises that will not find their way into later phases and the final process.
Route scouting plays a fundamental role in identifying a safe, practical and cost-efficient process for the synthesis of a compound at large-scale. The existing chemistry route is first fully evaluated to identify if it offers the necessary scalability. Here, a number of questions should be asked. For example: is the process safe to scale up? Are the raw materials available on a larger scale? Are they affordable? Are there any patents on any reagents or procedures that would hinder commercialisation of the process? Are there any solid and stable intermediates? How are they isolated and purified? Are there any environmental aspects to consider?
To understand if there are any recognised alternative routes that can be targeted, a literature review will usually take place to generate a number of theoretically viable routes. The route finally chosen after careful testing in the lab is determined by a combination of factors such as number of process steps, raw material availability, safety, impurity control, stability of intermediates etc. Although there is often a focus on shortening the length of the synthesis, in many cases the decision is determined by other factors with the overriding goal of saving time and costs.
That said, regulatory expectations may also dictate that a synthetic step should be added to have an appropriate number of GMP-steps in the process. Chemists may also be required to develop a stable intermediate during the synthesis and may add a salt forming step allowing for purification of the intermediate by crystallisation.
Throughout the development process, several parameters and activities are to be considered. Many of these are already taken into account during the route scouting. In continued work, QbD and Design of Experiments (DoE) will play an integral part. Also, since control of impurities is of such a central importance another critical prerequisite for successful up scaling is to make sure that the analytical methods are properly developed at a very early stage.
Control of potentially mutagenic impurities plays an increasingly important role when moving from early development into commercial stages and the awareness of these already at an early stage of development may turn out to be beneficial in the end.
Regardless of final dosage form chosen, API production for the clinical development (and commercial) stage also necessitates solid state development for isolation of both solid/stable intermediates and API, but also for control of polymorphic forms, solvates, etc., which can have a critical role for the downstream formulation development of solid dosage forms.
Understanding quality requirements, drug safety and GMP is crucial. Globally, regulators such as the FDA and EMA provide guidelines on how these should be addressed during the production of clinical scale drug substances. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss and agree on the scientific and technical aspects of drug registration. Their regularly updated guidance documents provide the framework for all activities during the course of a substance development programme, describing everything from control of manufacturing, to how to set specifications, acceptable levels of impurities, Quality by design etc. Although these guidance documents provide a very comprehensive framework and support, the need for extensive experience and expertise on interpreting and executing these guidelines is vital.
It is incredibly rare that the medicinal chemistry route for a drug substance goes on to become the final production route. There is simply much more to the process of scaling a drug substance from mg to kg. than greater quantities of materials and larger reaction vessels. Development of an efficient process early on in a project, the avoidance of shortcuts, the outlining of clear responsibilities for all involved, as well as a collaborative mindset between all disciplines is essential. Long term, route scouting will save projects both time and money, while focusing attention on the right analytical methods will control impurities and serve to improve the safety of a substance.