Drug substance plays a key part in ensuring a drug program achieves its major milestones, keeps to budget and delivers on its corporate goals. As every molecule and development program is unique, there is no single drug substance synthesis and manufacturing solution, so understanding what processes and technologies are available, what strategy is best, and who to partner with is key.
To increase the likelihood of clinical success, drug developers must identify challenges and potential red flags early on in the candidate selection stage. This minimizes downstream risks, helps to determine a suitable synthetic route for scale-up, and facilitates an easier transition into the formulation development phase. As a result, pharmaceutical companies increasingly prefer to partner with contract development and manufacturing organizations (CDMOs) that have end-to-end capabilities, where knowledge sharing between process research and development (PR&D), analytical, and formulation teams leads to rapid parallel development and optimization of both drug substance and drug product. Placing traditionally siloed drug substance and drug product development activities within a single organization that also has commercial manufacturing capabilities accelerates clinical development and builds in quality and robustness of supply.
Timing is everything, and successful drug substance development and manufacturing depends on having the expertise, agility, and flexibility to solve any problem that may arise in a timely fashion. Quotient Sciences, a drug development and manufacturing accelerator, brings together depth of knowledge, breadth of experience, and cutting-edge technologies to solve complex drug substance and drug product problems related to scalability, efficiency, and economy. They provide fully integrated drug substance, drug product, and clinical services spanning from candidate selection through commercial manufacturing under a single organization. This integration of services enables them to quickly identify challenges and develop solutions based on real-time data before they become bottlenecked, which in turn lowers the risk of timeline delays for their customers.
Important considerations for drug substance development
Polymorphic form issues
Understanding the polymorphism of a drug compound plays a key role in both drug substance and drug product development, because it can negatively impact the downstream stability, solubility, and bioavailability of a drug. Polymorphic form changes are a frequent issue in drug development, so the key is ensuring only the desired polymorph is produced, otherwise the consistent efficacy of the final drug can be affected by changes to its solid-state structure. A full analysis of the drugs’ solid state will indicate its propensity to form various polymorphs.
These polymorphs all have the same chemical composition and synthetic route, but they have varied crystalline structures with different physical properties such as melting points. It is important that they are screened to select the best solid-state for formulation development and manufacturing. Recrystallizing the drug compound under different conditions will help determine the likelihood of occurrence of varied thermodynamic and kinetic solid products.
Quotient Sciences uses computational modeling and simulation to narrow the field of polymorph possibilities, which acts as a predictive tool for choosing the right solid-state formulations to move forward into the clinic.
Applying real-time data
According to Richard Castledine, Head of PR&D, Drug Substance, at Quotient Sciences, “We are fortunate to have a wide array of state-of-the-art process analytical technologies (PAT) at our Alnwick, UK, facility, which we use to generate real-time data for processes that are under development. We are keen to increase the digitalization of our PR&D space, enabling us to make greater use of modeling predictive tools to make faster, better-informed decisions.”
“These tools help us understand more precisely the mechanisms by which impurity generation and reaction progression are occurring. When we couple that with other techniques, such as the design of experiments (DoE), we can develop a robust appreciation of the process design space and understand the parts of the chemical space that give consistent purity profiles and consistent yields, which in turn delivers consistent throughput,” says Castledine.
“PAT enables us to make use of software and artificial intelligence (AI) as a predictive control tool. This means that when we go into the laboratory, we are confirming those results rather than exploring the whole space. The benefits to the customer are that it significantly shortens development time and makes the whole process more cost-effective.”
Analytical method development
When developing a drug substance manufacturing process, considering the impurities that are produced is as important as the drug substance itself. “By carrying out analytical method development in parallel to the development of the active pharmaceutical ingredient (API) synthesis, we can readily identify and quantify new impurities, which informs the direction of work undertaken by our development chemists,” shared Castledine.
“This provides understanding from a very early stage of development about the fate of impurities and control points within the synthesis. It also means that timelines can be reduced, so that non-Good Manufacturing Practice (non-GMP) demonstration batches can be started as soon as the synthetic methodology is available and stability studies of the API can be initiated as soon as enough material has been prepared.”
Determining the best manufacturing process – traditional batch vs continuous flow
When evaluating a new synthetic route for a target molecule, one of the first decisions to be made is whether to employ a traditional batch-based synthesis or to make use of continuous processing methodology. Both approaches offer advantages and disadvantages, and the optimum solution will vary on a case-by-case basis. Parameters to be considered are the rate of reaction, the volumetric efficiency of the process, and the presence of any heterogeneous, reactive, or high-energy materials in the reaction mixture.
Quotient Sciences has access to large-scale batch and continuous processing assets and are able to design the optimum equipment set-up to match the chemistry of the transformation required rather than compromise the chemical process to fit the ubiquitous batch reactor. Where continuous processing options are the best match, they often offer increased process reliability, improved impurity control, greater compatibility with PAT, and a faster path to scale-up.
Streamlined processes to reduce time to market for drugs
Integrated drug substance and drug product services
When asked about some key processes that Quotient Sciences provides to clients that help streamline drug substance development and reduce time to market, Castledine states that the key improvement is the drug substance to drug product integration.
“Within Quotient Sciences, we have fully integrated drug substance, drug product, and clinical testing services, which gives us the ability to break down traditional industry silos, allowing us to streamline the outsourcing process for our customers.”
“Integrating all activities under a single organization encourages better workflows and processes and builds close relationships between multidisciplinary experts. We pride ourselves on cross-functional communication and knowledge sharing, and our drug substance team members work very closely with our colleagues in formulation development and drug product manufacturing to ensure the best outcome for our customers’ programs,” he says.
“As soon as we start to develop an API, we begin having conversations about the quantities that are available versus what is needed for the clinical program. We also discuss formulation strategies, timelines/decision points, and the customer’s desired target product profile (TPP).”
“Drug substance team members also provide the characterization and screening data that is generated as part of API crystallization, to inform the formulation development team about how the API is likely to behave under certain conditions,” says Castledine.
“For drug substance chemists,” he says, “the most useful and valuable information is understanding what kind of polymorphs form under different conditions. This data is also critical for drug product formulation development because it can give an early indication of whether a molecule may or may not have stability or solubility issues.”
“Understanding a molecule’s behavior is key when trying to design a formulation for the clinic. Technology selection is based on the solubility and permeability of a compound utilizing the Developability Classification System (DCS), so the sooner that this data is available to a formulation team the shorter the lead time to a developed formulation,” he says.
“Typically, in the CDMO space, polymorph screening, drug substance, and drug product services are all conducted at separate organizations,” says Castledine, “in a siloed manner and at different times in the development lifecycle. However, at Quotient Sciences, we can screen polymorphs in-house and provide that data in real-time to both drug substance and drug product development teams to aid in the development of our clients’ programs. Having these capabilities within a single organization also allows us to make informed decisions based on emerging data and rapidly accelerate our customers’ development timelines.”
Quotient Sciences’ drug substance services
Quotient Sciences’ capabilities in drug substance services include:
- Analytical method development and validation
- Salt selection and polymorph screening
- Non-GMP, GMP, and commercial drug substance manufacturing
- Pre-formulation development
- Thermal hazard and reactivity assessment
- Stability testing
- Proven acceptable range (PAR) and critical process parameter (CPP) determination
- Impurity identification and synthesis
- Genotoxic impurity (GTI) assessment
- Process validation
- Investigational Medicinal Product Dossier (IMPD)/Investigational New Drug Application (IND) preparation
- Technical investigations
- Freedom-to-operate (FTO) assessments
Developing workable API solutions
When asked about some issues Quotient Sciences has faced and solved as an end-to-end CDMO for clients, Castledine shared, “We worked on a project where the API was showing good data in terms of its efficacy, but the client was having significant difficulties developing a sufficiently soluble formulation.”
“We were tasked to develop a second-generation compound that would benefit from improved solubility. Alongside the development of the second-generation compound, we also undertook further formulation development work on the original molecule and were able to develop a workable formulation for the customer’s first molecule,” he says.
“The advantage to the customer was that they no longer had to switch to their backup candidate and were able to continue with their first-generation compound, which was more advanced in the development lifecycle. We have subsequently become the primary drug substance supplier to that client and are progressing the project through to commercial validation and supply under a single organization.”
When asked to describe a service that Quotient Sciences provides that is unique in the drug substance design and production field, he explains, “Our approach to integrating drug substance synthesis and drug product manufacturing reduces risks and overall client timelines.”
“Delivery of the first GMP batches of an API in development is typically on the critical path,” shared Castledine. “To address this, we streamline and integrate the activities leading up to this point to remove barriers and reduce timelines. We provide pre-approved analytical methods and manufacturing instructions to our GMP facility to initiate manufacturing. It is also helpful to have some stability data at this stage, either real-time or accelerated, to assign a retest period to the first batch of API at release.”
“Furthermore, our commitment to embracing new and emerging technologies means that we are at the forefront of innovation regarding drug substance synthesis, which allows us to access reaction conditions that are out of reach of many of our competitors. From a customer perspective, this means that we are able to pursue more innovative solutions, reducing overall costs and getting new medicines to market faster.”
In summary, there are many challenges and considerations that drug developers must be aware of before kicking off their drug substance program. Having a clear understanding of your molecule and its behavior, along with selecting the best manufacturing process, will help guide decision-making, aid downstream development, and move your drug substance off the critical path. In addition, leveraging a partner with in-house drug substances, drug product, and clinical capabilities can provide significant efficiencies and increase the potential for both clinical and commercial success.
For more information on Quotient Sciences’ drug substance synthesis and manufacturing services, please visit: https://www.quotientsciences.com/drug-substance/