Bioanalytical services to accelerate drug development
Delivering rapid bioanalytical data is critical to drug development. From drug discovery, through to preclinical and clinical studies, understanding drug exposure and behavior are imperative to dose selection, and accelerating drugs to clinic and commercialization.
Through the use of robust bioanalytical techniques, biological samples can be processed and analyzed to identify and quantify compounds of interest, such as small molecules and their metabolites, as well as peptides, proteins, nucleic acids and other analytes.
by Quotient Sciences
Quotient Sciences provides a fully integrated and streamlined service that starts with candidate selection through to commercial manufacturing. It has in-house capabilities that can prepare a full Investigational New Drug Application (IND)-enabling package, submit the New Drug Application (NDA) and take the drug to market.
Successful drug substance development depends on having the agility to solve any problems that arise in a timely fashion. As a result, pharmaceutical companies are increasingly preferring to partner with contract development and manufacturing organisations (CDMOs) with a reputation for having end-to-end streamlined drug synthesising abilities to turn drug substance molecules into new drugs and get them to market as fast as possible.
Quotient Sciences brings to bear a depth of knowledge, breadth of experience and cutting-edge technology to solve complex problems related to scalability, efficiency, and economy. Identifying challenges and quickly developing solutions before they become bottlenecked lowers the risks of delays, so having well-defined and controlled processes is important.
Polymorphic form issues
A frequent issue faced is polymorphic form changes to the drug compound, 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 drug’s solid state will indicate its stability against forming various polymorphs.
Their (polymorphs) chemical composition might be the same to start with but they also all have varied crystalline structures. Thus, they are screened to obtain the best solid-state for formulation and manufacture. Recrystallising the drug compound under different conditions will help determine the occurrence of varied thermodynamic and kinetic solid products.
Quotient Sciences use computational modelling to narrow the field of polymorph possibilities, which acts as a predictive tool for choosing the right solid-state formulations.
Applying real-time data
According to Richard Castledine, Head of Process Research and Development, Drug Substance, at Quotient Sciences, “We are fortunate to have a wide array of process analytical technologies (PAT) at our Alnwick facility, that we use to generate real-time data for processes that are under development. We’re keen to increase the digitalisation of our PR&D space. What that means in practice is making greater use of modelling predictive tools, so that we are utilising what we refer to as smart PR&D to make faster, better-informed decisions,” he says.
“We can then begin to 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 (DOEs), in which we can develop a robust appreciation of the process design space and understand the parts of the chemical space that give consistent purity profiles, consistent yields, delivering consistent throughput,” says Castledine.
“PAT enables us to potentially make use of software and artificial intelligence as a predictive 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.”
Streamline processes to reduce time-to-market for drugs
When asked about some key processes that Quotient Sciences provides to clients that help streamline drug substance processes and reduce their time to market, he states that the key improvement is the drug substance to drug product integration.
“Arcinova [now part of Quotient] already had elements of an integrated drug substance and drug product offering, but within Quotient, we now have more capabilities, which includes clinical testing, which gives us the ability to break down traditional industry silos, allowing us to streamline the outsourcing process for our customers.
“We pride ourselves on cross-functional communication. Our drug substance team members work very closely with our colleagues in formulation development and drug product manufacturing,” he says.
“As soon as we start a project to develop an API, we start having conversations about the quantities of API that are available versus what’s needed for the clinical programme, we also discuss formulation strategies, timelines/decision points and the customer’s desired target product profile.
“Drug substance team members also provide the characterisation and screening data that they’ve generated as part of API crystallisation, 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. “These data are also critical for drug product formulation development because they can give an early indication as to whether a molecule may or may not have stability or solubility issues,” says Castledine.
“Understanding a molecule’s behaviour is key when trying to design a formulation for the clinic. Technology selection is based on the solubility and permeability of a compound utilising the Developability Classification System (DCS), so the earlier these data are 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 organisations, says Castledine, in a siloed manner at different times in the development lifecycle. However, at Quotient, 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 client’s programmes. Having these capabilities within a single organisation also allows us to make informed decisions based on emerging data and rapidly accelerate our customer’s development timelines.”
Quotient Sciences drug substance services
In terms of drug substance services within Quotient Sciences, its main capabilities are:
- Process research and development
- Analytical method development and validation
- Salt selection and polymorph screening
- Non-GMP, GMP, and commercial drug substance manufacturing
- Pre-formulation development
- Design of experiments
- 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)/IND preparation
- Technical investigations
- Freedom-to-operate (FTO) assessments
Developing workable API solutions
When asked about some issues Quotient Sciences faced and solved as an end-to-end CDMO for clients, Castledine says, “We worked on one project where the API was showing good data back in terms of its efficacy, but the client was having really significant difficulties in terms of developing a sufficiently soluble formulation.
“We were tasked to develop a second-generation compound that it was believed would benefit from improved solubility. Alongside the development of the second-generation compound, we also undertook further formulation development work, and that team was able to develop a workable formulation of the [original] molecule, ” he says.
“The advantage to the client 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 we are progressing the project through to commercial validation and supply.
The ongoing work towards commercial validation for this project, which began under Arcinova, is progressing with Quotient, says Castledine. “We have additional capabilities now, so for instance as part of Quotient we could potentially supply the commercial drug product, which was previously beyond our capabilities as Arcinova.”
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 overall client timelines.
“Furthermore, our commitment to embracing new and emerging technologies means that we are at the forefront of innovation regarding drug substance synthesis, this allows us to access reaction conditions that are out of reach of many of our competitors. From a client perspective, this means that we are able to pursue more innovative solutions, reducing costs and timelines.”
For more information, please visit Quotient Sciences’ drug substance synthesis and manufacturing