Integrating Strategies for Formulation Success

A swelling population that is aging and increasingly suffering from chronic conditions is leading to a greater demand for bio/pharmaceutical products. However, developing a bio/pharmaceutical therapy is a long and expensive journey that does not always end in commercial success or even, for many drugs in the pipeline, commercial viability at all. In fact, according to research, attrition rates for drug candidates remains stubbornly high, sitting at around 90% for those drugs that have reached the Phase I trial stage (1).

Transformative technologies

Some key trends impacting many industries worldwide, including the bio/pharmaceutical industry, are digitalization and robotics. These trends are also expected to positively impact drug formulation by improving efficiencies and, hence, lowering the potential risk of failure.

“Digital enablement, in general, is gaining momentum, with around 75% of business-to-business customers preferring engagement with digital platforms over in-person interactions,” remarks Shahrzad Missaghi, senior manager, Product Development at Colorcon. “Intuitive digital platforms empower companies to make the right decisions at the start of the process and reduce formulation iterations.”

According to Sibaji Biswas, executive director and chief financial officer at Syngene International, machine learning (ML) and artificial intelligence (AI) have the potential to provide the bio/pharmaceutical industry with significant opportunities to enhance the formulation process and avoid potential failures. “For example, AI and ML technologies are already being increasingly used to predict drug–excipient interactions, which allows for the rapid selection of optimal formulation compositions,” he says. “These predictive models are also employed in the pharmaceutical space to forecast the properties of drug products, such as tablets, based on data sets generated during development.”

In concurrence, Himanshu Gadgil, CEO, Enzene, notes that ML and AI are proving to be transformative for many industries and offer significant formulation advantages by way of improved efficiency and effectiveness. “ML leverages vast amounts of historical data to predict outcomes and identify trends,” he says. “By analyzing [these] data, AI can anticipate the properties of new formulations and validate them before they undergo costly laboratory testing. This capability not only streamlines the development process but also reduces costs by identifying potential issues early on, thus minimizing the risk of failures.”

Some customized generative pre-trained transformer or open-access platforms, such as FormulationAI, are being developed specifically around formulation development, asserts Vincent Levet, director, Formulation Development and Production, Ardena. “[These platforms are] offering solutions that can enhance the creativity of scientists, for instance by helping to review literature very quickly, evaluate compounds through predictive models, or support the actual formulation process by generating design of experiments (DoEs) studies and help to analyze the data,” he says. “However, as it is still in its early stages, it’s important to mention that the adoption of AI also brings concerns regarding IP [intellectual property] protection and potential data breaches, which is particularly crucial as companies must protect their pipeline to survive.”

Lacking sizeable data sets

“AI is [only] as good as the data used to train it,” warns Hanns-Christian Mahler, CEO and board member of ten23 health. While AI is a tool that has the potential to provide value in formulation development, it is important to start off with expert knowledge and an understanding of specific liabilities and challenges of molecules or therapeutic modalities—the critical quality attributes (CQAs), he adds.

“Adequately large data sets of molecules that are characterized in depth and where differences and similarities are well understood, in combination with expert knowledge, can effectively guide and train AI,” Mahler says. “Sadly, most companies do not have such large data sets by themselves, so some cross-company initiative may be needed to support such developments.”

The large datasets, such as those seen in other AI applications used in other industries, are simply not available yet within the bio/pharmaceutical field, agrees Bernard Sagaert, CEO, etherna. “However, making sure that your data [are] structured in a way that makes [them] accessible to perform the first steps in AI and ML has helped [the industry] already in limiting screening efforts and predicting certain pathways to follow,” he says.

Near future focus

For Vinay Patil, product development manager at Sharp Services, the focus for AI and ML tools will be placed upon gaining efficiency in target identification. “[Because] formulation development can only begin once a target compound has been identified and characterized, I expect that more AI/ML efforts will be made in the drug formulation process as the technology matures, and once the industry gains additional experience and, more importantly, success in the use of AI for drug discovery,” he affirms.

At Abzena, an integrated biologics contract development and manufacturing organization (CDMO) and contract research organization (CRO), AI and ML are being leveraged to create a model that is capable of predicting formulation stability over long-term storage using early-stage data, adds Gary Watts, senior manager in Analytics, Abzena. “This model has been validated with multiple formulations of various therapeutic molecules and is particularly beneficial in projects with tight timelines driven by client needs,” he says.

“With the use and evolution of ML and AI, companies have a greater ability to prototype quickly and in a more cost-effective way,” continues David Ferrizzi, director of New Product Development, Colorcon. This ability affords companies opportunities to tackle challenges that may have been insurmountable previously. “For example, certain diseases that were not a focus before are now coming into focus,” he says. “Personalized medicine and a focus on speed and lower total cost are also enhanced as a result of ML and AI.”

Personalized approaches

“Patient-centricity plays a crucial role in formulation design and the final product’s market success,” says Biswas. “An integrated strategy is often more effective to create an optimized product for the patient, keeping in mind the clinical conditions and individual therapy requirements.”

While patient-centric approaches were traditionally centered on transitioning from immediate-release to modified-release products and creating therapies suitable for patients with a given clinical condition, the landscape is now changing to more personalized approaches, Biswas explains. “One emerging trend is patient-customized medications, where formulations are tailored to meet individual needs, reflecting a shift towards individualized therapies,” he specifies. “New chemical entities are also being formulated with advanced technologies including devices to minimize side effects and reduce dosing frequency, further enhancing patient convenience and compliance.”

Sagaert points out that there are numerous factors to consider to obtain a patient-centric formulation. “Companies need to constantly have all aspects of the platform and the product in mind,” he states. “For RNA-LNP [RNA-lipid nanoparticle]-based products, this is clearly making sure the RNA is non-immunogenic and highly expressed in the target cells, and not expressed in other cells to reduce dose and side effects. The LNPs need to target the right cells and organs to avoid off-target expression as much as possible, and the route of administration needs to be as convenient as possible for the patient in his disease setting.”

The primary consideration, however, is the patient population, adds Mahler. “Studying patient preferences and patient needs for a given indication and use case is key,” he says. “For the various modern therapeutics, such as biologics, ADCs [antibody-drug conjugates], CGTs [cell and gene therapies], oligos, all of these require sterile injection of infusions. For some indications and modalities the answer is probably to aim for subcutaneous (SC) administration using syringe or cartridge solutions with adequate (possibly high concentration) formulations, in combination with a device such as [an] autoinjector, pen, or on-body injector (OBI). Even in the case of cancer therapies, developing products for SC use offers significant benefits for patients.”

“‘Personalized’ medications are a hot topic in current times, and there have been greater efforts to understand the differences in sub-groups of patients such as different ethnicities and those prone to certain conditions,” continues Watts. “Until the science is clearer, formulation strategies must continue to focus upon the target patient population for each drug individually and ensure that this aligns with the design of the final drug format.”

Focusing on pediatric patients, Asma Patel, vice president, Integrated Development Services, Quotient Sciences, remarks that patient centricity is a growing need as these patients require age-appropriate and palatable dosage forms. “In pediatrics, liquid and solid dose formulations that are easier for infants and children to swallow are preferred, including solutions, suspensions, powder for reconstitution, and minitablets, and the taste and palatability challenges of these forms need to be overcome and confirmed by taste assessment studies,” she says. “There are also applications for these dosage forms for other patient populations, such as the elderly and those with disabilities, where easier-to-administer or easier-to-swallow dosage forms can ensure ease of administration, patient compliance, and efficacy.”

“Patient compliance and convenience are key elements in the design and development of formulations,” says Missaghi. “Gaining a deep understanding of patient preferences is the first step in informing the design of the dosage form.” For solid oral dosage products, formulators must consider factors, such as taste, size, shape, color, dosing frequency, and swallowability, which can all help with patient satisfaction and lead to compliance, she confirms.

“Companies can ensure that they’re developing formulations with the patient in mind by soliciting patient input throughout the development process,” adds Patil. “When possible, the proposed drug should be developed as a flexible dosage form. And on the clinical side, drug sponsors should ensure that the protocols are written in such a way that minimizes the burden on participants to the most reasonable degree possible, such as reducing the number of visits, offering home-based assessments, and using virtual consults when possible.”

According to Levet, by employing quality-by-design principles, formulators can define target product profiles matching the needs of the patients, and they can also identify CQAs that focus on patient safety and clinical efficacy from the outset of development. “Choosing excipients that are safe and can enhance drug stability and patient tolerance also plays a big part in being ‘patient-centric’,” he says. “Finally, fast-tracked and phase-appropriate development approaches, designed to get the right level of information to be able to reach the next clinical trial phase and evaluate (but also reject) new therapies as fast as possible allow, in the end, a better focus of the resources available, and ultimately quicker patient access to the most efficient treatments.”

A partner’s role

“Selecting the right development partner with a proven track record can be a deciding factor in clinical and eventually commercial success,” asserts Patel. “When selecting a CRO/CDMO partner, the availability of integrated CMC [chemistry, manufacturing, and controls] and clinical research services from one company can be invaluable to streamline drug development processes, along with having a strong foundation of formulation development expertise.”

Partners play a crucial role in drug formulation, particularly during early development, confirms Missaghi. “Some key areas a partner can enhance the process include: offering technical capabilities and competence, including development and troubleshooting experience; knowledge of regulatory and quality standards, aiding in compliance; and a full understanding of the formulation landscape including patient adherence, common pain points, and industry challenges,” she says.

Levet points out that the broad skillset and experience offered by outsourcing partners is invaluable for drug formulation. “[Outsourcing partners] guide customers towards efficient and cost-effective formulations without overextending resources on a compound’s development before its potential is fully realized over the clinical phases,” he says. “With a ‘phase-appropriate’ development, they can help expedite the development process, which is essential, particularly for small and virtual companies to secure funding for subsequent phases.”

“Phase appropriateness is [essential] because it is a very important lever in expediting the screening and evaluation of drug candidates,” concurs Biswas. “This approach helps expedite drug candidate evaluation, allowing rapid assessment in Phase I but without compromising necessary quality. Smaller biotech’s operating on milestone-driven development, require CDMOs’ expertise for quick, risk-based decisions. Outsourcing partners with their extensive and diverse experience can provide a solid and effective platform for quicker delivery of these milestones through deployment of phase appropriate systems and processes.”

Sponsor’s look for a range of integrated development services when selecting an outsourcing partner, therefore, a capable partner should offer comprehensive solutions that include the breadth of the drug development process, asserts Gadgil. “Moreover, in today’s digital era, it is increasingly important for outsourcing partners to embrace innovations like AI and real-time data integration,” he concludes. “An effective outsourcing partner will not only showcase expertise across these domains but also leverage modern technologies to offer integrated, forward-thinking solutions for drug development.”

Reference

1. Sun, D.; Gao, W.; Hu, H.; Zhou, S. Why 90% of Clinical Drug Development Fails and How to Improve It? Acta Pharm. Sin. B. 2022 12 (7) 3049–3062.

About the author

Felicity Thomas is associate editorial director for Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 48, No. 8
August 2024
Pages: 10–13

Citation

When referring to this article, please cite it as Thomas, F. Integrating Strategies for Formulation Success. Pharmaceutical Technology 2024 48 (7).