Felicity Thomas is Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

According to research, post-pandemic R&D growth is healthy in the pharma industry with the number of drugs in the R&D pipeline now exceeding 20,000 in 2022—which represents an expansion rate of 8.22% from 2021 (1). This heightened spending into researching novel chemical modalities and substances can be absorbed by some pharma companies as an internal cost; however, development of a suitable and ultimately successful formulation strategy to advance a molecule to commercialization can benefit from external expertise. As such, it has also been projected that the expanding R&D pipeline will be a driver for the formulation development outsourcing market (2).

“An outsourcing partner should have a good understanding of CMC [chemistry, manufacturing, and controls] perspectives with the developer’s interests in mind, which enables the developer to have a sharp vision of potential scenarios to develop for first-in-human (FIH) trials, but also considers factors that will influence filings and the product’s commercial success,” says Thierry-Thien K Nguyen, director of Product Development, Catalent Biologics. “In addition, an outsourcing partner should collaborate with customers to develop PrOACT (identify problems, objectives, alternatives, consequences, and trade-offs) and enable customers to make the most informed decisions to reduce risk and increase the program’s chances of success.”

To support optimal formulation strategies, not only must outsourcing partners invest in building a resource pool with the right skill set, but they must also provide continuous training development programs and bring in the right infrastructure, adds Anil Kane, PhD, senior director, global technical scientific affairs, pharma services, Thermo Fisher Scientific. “Employing the right tools (modeling, simulation, predictive) at the right stage of pre-clinical, clinical or late-stage development is important and has a huge potential for application, interpretation, and science-based decision making in adopting smart formulation strategies,” he says.

A tool that is aiding in early development is computer-based predictive modeling, reveals Kane. “This predictive modeling avoids trial-and-error-based search of the right solution to solve the complex technology and excipient selection process, thus helping to reduce the time and investment in early clinical development,” he specifies. “An algorithm-based in-house developed software can predict technologies that will offer a higher probability of success among several options such as micronization, amorphous solid dispersions (spray drying or hot melt extrusion), lipid-based delivery, complexation, and others.”

“During formulation and process development, at an early preclinical/clinical stage, an in-depth understanding of material properties and their impact on formulation and process is critical,” Kane continues. It is possible to simulate the behavior of bulk materials in oral solid dosage forms using discrete element modeling (DEM)/compaction simulation tools, he explains. “The use of these tools mitigates formulation/process challenges early in development and helps speed up process development and troubleshooting,” Kane says.

Additionally, Kane emphasizes that modeling has found further use in aiding the design of formulation strategies for immediate-release and controlled/extended-release oral solid dosage forms through physiologically based pharmacokinetics modeling. “Predicting animal/FIH doses, 

 correlation (IVIVC), food effects, bioequivalence, pharmacokinetic/pharmacodynamic (PK/PD), and so on, using software has helped in the assessment of formulation impact on PK, compartmental PK analysis of animal data, evaluation of animal bioavailability, and defining an FIH clinical dosing strategy,” Kane states.

Focusing on large molecules, Nguyen points out that there have been several innovations that have significantly impacted formulation strategies during recent years. In addition to predictive models using artificial intelligence (AI) and machine learning (ML), Nguyen highlights high-purity, parenteral-grade excipients in cryopreservation media for autologous and allogeneic cell therapies; novel excipients for use in vaccines, viral therapies, and high-concentration biologics formulations; lipid nanoparticle components and associated manufacturing technology for encapsulation; and continuous sterile freeze-drying technology, as key innovations.

However, each of these innovations faces several challenges, such as toxicology/pharmacology and pharmacovigilance data requirements for novel excipients before they can be widely adopted, Nguyen stresses. “Some innovations are more acceptable, such as lipid nanoparticles (LNP) in messenger RNA/LNP formulations,” he says. “To overcome these challenges and enable technology adoption, those aspects identified using a quality-by-design (QbD) approach need to be addressed in order that patient-centric requirements are satisfied, and a clear understanding of product quality attributes and associated process parameters is demonstrated.”

There has been much advancement in the field of information technology recently, confirms Nguyen, such as the implementation of AI- and ML-based techniques in a variety of industries. “However, the pharmaceutical industry has been slower than others to adopt AI- and ML-based techniques, perhaps because of the lack of clear regulations, a paucity of funding for research into these fields, and a scarcity of reputable quality training programs,” he notes.

Yet, Nguyen continues, when digitalization is implemented both thoroughly and properly into formulation development strategies, it is possible to improve cost and time efficiencies in drug product formulation and process development. If applied correctly, it is possible to enable past information on formulations, APIs, and processing conditions to be amassed; allow the creation of a large common library to teach/train new ML algorithms; support the creation of algorithms that predict how similar molecules/entities would behave

in given formulation environments; and will provide the potential for quicker access to data and greater processing power, which would make the formulation candidate selection more efficient, he specifies.

“Finally, with a predictive AI model, minimal data sets could more accurately anticipate a molecule’s stability,” Nguyen adds. “For formulation in a traditional manufacturing site, digitalization benefits could be realized in the next few years, which have already been explored in both academia and industry. For personalized medicine, bedside and 

 formulation, and in combination with wearable devices, there is still some way to go, but the future is exciting.”

Advances in analytics and digitalization are being leveraged by many Big Pharma companies to improve drug development productivity, asserts Kane. Approaches to increase productivity or success rates in drug design that are adopted by researchers, medicinal chemists, and pharmaceutical experts include big data, AI, ML, neural networks, quantitative structure-activity relationship modeling, and others, he states.

“The traditional approach to drug formulation development relies on iterative trial and error, requiring a large number of resource-intensive and time-consuming 

 experiments,” Kane says. “ML-directed drug formulation development offers unparalleled opportunities to fast-track development efforts, uncover new materials and innovative formulations, and generate new knowledge in drug formulation science (3).”

At the dosage form level, advancements are allowing for more comprehensive data collection. For example, digital pills that feature ingestible sensors in an oral drug delivery dosage form will revolutionize diagnostics, clinical monitoring, data collection, and data analytics in the healthcare industry, Kane emphasizes. “Smart medicines involve a target applied directly to the medicine via a coating or ink, and a sensing device (a cell-phone application) is used to read the medicine and convert the signal into a digital format in a matter of seconds. With smart medicines, every dose becomes a basis for patient communication, engagement, and data generation,” he says. “The transition to smart medicines offers an enormous source of value creation to the pharmaceutical industry.”

It is important, however, to ensure the quality of the data being collected, warned Nguyen. When collecting data that will be used to build a library and then to train machines, for example, the data should conform to ALCOA+ [attributable, legible, contemporaneous, original, accurate, and additionally that it is complete, consistent, enduring, and available] guidance and should be unbiased, he explains.

“Good input and good process shall yield good output, otherwise, with less representative data the predictive model would misrepresent, and unintentionally skew toward an unwanted design space,” Nguyen says.

“Continuous manufacturing (CM) continues to be of interest for specific products by the emerging, mid-size and Big Pharma companies for one or more of the well-documented and proven reasons—reduced API usage from early to mid-stage development to commercialization, robust simplified formulation, scale-up efficiencies, speed to clinic and to market, supply chain flexibility, reduced cycle time, and potential reduced overall cost of supply while having a greater assurance of quality,” Kane asserts. “A CM process certainly changes the formulation strategies, as there will be far more controls and checks at critical processes as compared to a batch process that utilizes multi-unit operations. Selection of excipients and a process needs to be aligned with the continuous manufacturing equipment design and scale.”

Process analytical technology (PAT) tools, such as near infrared and Raman spectroscopy, are integral for continuous manufacturing programs, continues Kane. Additionally, to be able to expand the continuous solid dose program and bring customer programs to commercialization, it has been beneficial at Thermo Fisher Scientific to use real-time release—for finished product release testing—as well as predictive models and in-suite tools to support the required testing, he adds.

“Advanced continuous manufacturing approaches are often considered for mAbs [monoclonal antibodies], therapeutic proteins, or other biologics that are compatible with such a process,” states Nguyen. “[Advanced CM] is more challenging to adapt for cell therapies and less-standard modalities made through complex, smaller-scale processes.”

Across the board, however, demonstrating homogeneity in bulk drug substance and assurance of dose uniformity are key aspects of formulation and fill/finish, Nguyen points out. “From this perspective, CM and process intensification, while making much advancement in terms of drug substance upstream (cell culture) and downstream processing (purification), still faces such challenges that it is often decoupled from fill/finish operations. As a result, at the end of the process, bulk drug substance containers need to be stored and handled within the correct conditions and shipped to fill/finish sites to process as batches upon demand,” he says.

“For a product that requires only a single formulation and single strength, formulation considerations could be built in during the ultrafiltration/diafiltration (UF/DF) step and the finishing step to create formulated bulk material,” Nguyen continues. “Upon receiving at the fill/finish site, it would require pooling, blending, filtration, aseptic filling, and packing.”

When considering the quality requirements, as is the same with batch processing, the framework of CM should start with a patient-centric design, the target product profile, followed by CMC target profile, Nguyen states. “At each unit operation, risk needs to be evaluated, and the learnings carried over to the next steps to understand what can be further removed, polished, controlled, mitigated, or monitored,” he says. “Understanding the endpoint and requirements would help developers anticipate what shall be considered upfront to avoid costly correction or redevelopment later in a product’s lifecycle. Moving from early phase to late phase, as product and process knowledge are accumulated, the presumptive attributes and process parameters would be further refined as critical versus non-critical, or key versus non-key for a product and its process.”

“Digitization of operations, use of augmented and virtual reality, AI and ML, increased use of robotics, and using connected data systems to drive better quality and business decisions need to be actively pursued in many parts of the business,” asserts Kane.

Through digitization, it is possible to reduce the number of conditions that need to be performed in the design of experiment within formulation, Nguyen adds. “If a reliable predictive model can be built using a high-quality, diverse, and unbiased database, then that will drastically help improve formulation strategies in terms of time, cost, and likelihood of success, and would contribute to bringing drugs to patients more quickly.”

“Therefore, expertise and experience in utilization of the modeling tools is critical to bring speed and efficiency to clinical programs,” Kane summarizes. “In late-stage clinical studies, it is critical to adopt sound, science-based risk-assessment and risk-mitigation strategies to optimize formulations and process of manufacture.”

1. I. Lloyd, “Pharma R&D Annual Review 2022: Navigating the Landscape,” White Paper, Citeline Informa Pharma Intelligence (March 2022).
2. Research and Markets, 

Global Formulation Development Outsourcing Market Size, Share and Trends Analysis Report by Service (Preformulation, Formulation Development), by Formulation (Oral, Injectable), by Therapeutic Area, by Region, and Segment Forecasts, 2022–2030

, Market Report (June 2022).
3. P. Bannigan et al., 

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.


Vol. 46, No. 10
October 2022
Pages: 16–19

When referring to this article, please cite it as F. Thomas, “Adopting Smart Development Strategies,” 

Articles

External expertise is beneficial in helping companies select the right tools at the right stages of development to ensure success.

Adopting Smart Development Strategies

Traditional drug development is costly and time-consuming, with many hours, days, and years spent researching and developing novel chemical entities that, for the most part, will likely fail to get to the commercial finishing line. Repurposing a drug can offer companies an approach to drug development that is much more time- and cost-efficient and offers a higher chance of success. According to research, 30% of repurposed drugs gain approval, which is three times higher than the rate for new drugs (1).

There are three main strategies to repurposing a drug product: determining a novel therapeutic indication for an already known drug (repositioning); developing a new formulation of a drug product (reformulation); and combining two or more drugs that were already being used as single drug products (combination) (2). Despite the various benefits of repurposing existing drug products can offer, each strategy also has certain challenges to overcome that can act as a deterrent to developers.

“Reformulation can be used very effectively to develop improved medicines and treatment options for patients,” confirms Jan Jezek, chief scientific officer of Arecor. “For example, creative formulation can be used to improve the pharmacodynamics and pharmacokinetics of a drug.” Highlighting a specific case of creative formulation, Jezek points to the development of a novel formulation of insulin that has is being developed by Arecor, which accelerates the drug’s absorption post-injection, leading to improved glycemic control.

“Another example benefit of reformulation is to convert a lyophilized powder medicine to stable liquid ready-to-use (RTU) product formats, which are becoming increasingly important to enable fast, safe, and effective treatment of patients,” Jezek continues. “Innovative formulation approaches can also lead to improvement in stability of small- and large-molecule products and enable their use outside the cold chain, which can significantly improve convenience of use.”

Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm, emphasizes that reformulation can be performed for several key reasons. “[Reformulation] can allow developers to improve the performance and patient centricity of an existing drug. For example, it may be done to create a version of an existing drug that is more convenient and easier to use for the patient, increasing quality of life or boosting adherence and, in turn, therapy success,” he says.

Additionally, Jagdish remarks that reformulation can be used to enhance solubility, to improve absorption, or to boost the stability of a drug product formulation. “In all cases, reformulation can save a considerable amount of time and financial resource compared with the discovery and development of an entirely new chemical entity,” he states.

Moreover, it is possible to use reformulation as a way of extending the line of an older drug product, Jagdish points out. “[Reformulation] offers an opportunity to change an excipient or evolve the manufacturing process to deliver marginal gains in performance or ensure compliance with new regulatory requirements,” he says. “Regardless of the reasons for the reformulation, assessment of the regulatory implications of reformulation is essential.”

First and foremost, Jagdish stresses that it is critical for companies to be aware of the regulatory requirements of the target geography of the reformulated drug product. “There is considerable variation in the regimes in each country, so pharmaceutical companies should evaluate their compliance needs on a case-by-case basis,” he says. “For example, the US Food and Drug Administration (FDA) has published its guidance for industry on Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route, which can help companies understand the regulatory requirements in the [United States]” (3).

For Jezek, considering the formulation excipients and whether those being used in the reformulated product are indeed approved for the intended use—administration route and desired dosage regimen—is critical. “[Whether or not the excipients are considered novel] impacts the complexity of development as it is necessary to justify the use of the excipients and to demonstrate the safety of the excipients required. Novel excipients will carry a higher regulatory and development burden,” he specifies.

When approaching a reformulation strategy for a drug product, developers should define the target product profile at the outset, Jezek continues. “In other words, the formulation scientist needs to understand the desired stability and other requirements that the products must meet, such as specific impurity levels, to be approved by the regulatory authorities,” he says.

Reformulating an existing drug product can be a time- and cost-effective way of rejuvenating a product line while also making a therapeutic more patient-friendly. To find out more about how external expertise can help sponsor companies achieve success in reformulation strategies, 

 spoke with Jan Jezek, chief scientific officer of Arecor, and Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm.

 How might companies benefit from using a partner for reformulation tasks?

 An innovative formulation technology company, such as Arecor, can use its expertise, know-how, and technology to develop novel formulations of therapeutic medicines with enhanced properties, enabled by the formulation, which would otherwise not be possible. These enhancements can improve treatment options and outcomes for patients. The technology can be applied to a variety of new products in development to maximize their benefit for patients. However, the reformulation technology can also be applied to existing marketed products as part of life cycle management.

 Reformulations are often considered by big-brand pharmaceutical companies as a strategy for enhancing the lifecycle management of their patented product and to delay generic entry as far as possible. These companies often have many lead molecules to work upon, meaning it can be hard to find the capacity required for reformulation in-house. Working with a contract development and manufacturing organization (CDMO) partner can help them find that additional resource, enabling them to manage multiple reformulations simultaneously while freeing in-house capacity to focus on innovation.

For generic companies, reformulation gives them an advantage in terms of 505 b(2) filing. [FDA] 505 b2 approvals give additional exclusivity to a product. When applied to a reformulated drug, it can help to prevent generic entry until the expiry of the filing. As such, they keep development in-house, provided they have the internal capacity and infrastructure. However, if the generic company is reformulating to change excipient or manufacturing process, they may well prefer to outsource to a CDMO to provide the necessary expertise and infrastructure so they can concentrate on other projects.

After defining the target product profile, the developer needs to understand the degradation pathways that can potentially impact the stability of the drug product during storage, Jezek adds. Appropriate methods must be established so that any degradation pathways can be measured and understood. “Such methods are often referred to as stability‑indicating methods,” he notes.

“The last challenge, which is most critical for successful reformulation, is to be able to select the right combination of inactive ingredients that will collectively interact with the small- or large-molecule drug in a way that reduces the degradation rate and thus enables the desired product profile,” Jezek confirms.

According to Jagdish, the challenges that pharmaceutical companies need to overcome when approaching a reformulation project depend upon the type of reformulation they are undertaking. “For example, when developing a new formulation of a drug for the same indication, achieving bioequivalence for the new formulation with the existing one poses a significant challenge, because it is no longer a like-for-like comparison,” he asserts.

“Reformulation can also be considered to reduce the size of the dose of a medication, to improve safety profile and patient compliance,” Jagdish continues. “Again, in this case, there is a need to demonstrate that the efficacy of the lower dose is equivalent to that of the already clinically proven and approved higher dose.”

Providing another example, Jagdish points out that when developing a fixed-dose combination therapy from two independently approved drugs, demonstration of the bioequivalence can also be tricky. “Here, in addition to maintaining bioequivalence with the two existing single-dose products, companies have to ensure the compatibility of the two drugs when in the same formulation,” he says.

When reformulating large molecules, Jagdish emphasizes that additional challenges—when compared with those facing small-molecule formulators—need to be addressed. Challenges such as solubility, absorption, and stability, he specifies.

Because large molecules are commonly administered via intravenous injection, it can be desirable and more patient-friendly to reformulate a drug product to be administered in an alternative way. “Often the focus of a change in the route of administration for a biological medicine is to enable a change from a time-intensive intravenous administration to a single subcutaneous injection,” Jezek confirms. “This [change] requires developing a highly concentrated formulation of the product that can be delivered via a small volume in a single injection.”

However, by reducing the volume of injectable product, the viscosity can become problematic. “Challenges that need to be overcome in developing these high concentration formulations is high viscosity (which can make the product too difficult to inject) as well as the propensity of proteins to aggregate (resulting in the formation of particles, which are unacceptable in pharmaceutical compositions),” Jezek explains. “In addition, proteins are subject to chemical degradation such as hydrolytic cleavage or oxidation. Innovative approaches to formulation design are often required to overcome these challenges.”

Yet, there are relatively easier reformulation routes, such as updating the excipients or the manufacturing process to extend the product’s line, Jagdish states. “Reformulation in these cases often simply involve step changes in the production process or the preparation of ingredients to enhance product quality or to improve manufacturing efficiency,” he specifies. “New ingredients are not generally involved, reducing the number of challenges that need to be overcome.”

1. N. Sommerford, “Drug Repurposing Basics,” Blog, IQVIA, May 12, 2022.
2. S. Murteira, et al., 

Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route


Vol. 46, No. 10
October 2022
Pages: 30–31

There are many benefits of employing a reformulation strategy, but companies must also overcome a variety of challenges too.

Reformulating Success

On 8 Sep. 2022, an announcement was made that Her Majesty Queen Elizabeth II had passed away at Balmoral peacefully at the age of 96 years (1). The Queen had reigned as monarch of the United Kingdom for 70 years, making her the longest-serving monarch for the country throughout its history.

Although not necessarily commonly associated with the pharmaceutical industry or life sciences, the Queen had played her part well in helping the nation get to grips with scientific innovation. A prime example of her Majesty’s role in promoting innovation came through her prestigious Awards for Enterprise. With these awards, the Queen provided a royal seal of approval for numerous life science businesses—most recent awardees include SGS’s Quay Pharma, CatSci, Momentum Pharma, and OncImmune—raising each company’s profile on a global scale, boosting staff morale, and increasing commercial value (2).

Additionally, her Majesty was a patron of the Royal Pharmaceutical Society, a role she accepted following the death of her father, King George VI (3). And, in fact, it was the Queen who had granted the society with the title of ‘Royal’ in 1988.

As pointed out by Steve Bates OBE, CEO of the BioIndustry Association, in a blog post, the Queen’s 70-year reign had encompassed swathes of change and innovation within the biotechnology field (4), such as the advancements that have occurred over the years in genomics. When Elizabeth II began her reign in the 1950s, Francis Crick and James Watson had just realised their ground-breaking conclusion that the DNA molecule exists in a double helix three-dimensional structure (5). Six decades later, in 2016, her Majesty officially opened the Francis Crick Institute, which is the largest biomedical research institute under one roof in Europe and is where researchers investigate the fundamental biology of human health and disease (6).

Richard Torbett, chief executive of the Association of the British Pharmaceutical Industry, neatly summed up the sentiment of the country’s pharma sector in a press release (7). “The Queen led a life of duty and service to the people of the UK and Commonwealth and was an inspirational figurehead for the UK around the world,” he said. “She leaves behind an unmatched legacy of dignified leadership and our industry joins with the rest of the nation in mourning at this sad time.”

1. BBC, “Queen Elizabeth II has Died,” News Release, 8 Sep. 2022.
2. UK Gov., 

 [Accessed 23 Sep. 2022].
3. Royal Pharmaceutical Society, “The Death of Queen Elizabeth II,” News Release, 8 Sep. 2022.
4. S. Bates, “Queen Elizabeth II A Life Sciences Perspective,” BIA Blog, 9 Sep. 2022.
5. L.A. Pray, 

, 1 (1) 100 (2008).
6. The Francis Crick Institute, “The Queen Opens New Francis Crick Institute Building,” News Release, 9 Nov. 2016.
7. ABPI, “ABPI Statement on the Death of Her Majesty Queen Elizabeth II,” Press Release, 8 Sep. 2022.

When referring to this article, please cite it as F. Thomas, “A Royal Tribute,” 

Pharmaceutical Technology Europe pays tribute to the role Her Majesty Queen Elizabeth II had in promoting innovation within life sciences.

A Royal Tribute

An increasingly ageing population, rise in chronic conditions, and intensified focus on paediatrics are trends perpetuating the need for the development of appropriate therapeutic regimens to which patients will comply correctly. To learn more about the role of alternative drug delivery formulation in expanding the potential indications of a drug product or improving compliance, 

 spoke with Kimberly Shepard, associate director R&D, principal engineer, and Jonathan Cape, head of Multiparticulate Technology, both at Lonza Small Molecules; Brian Wilson, new business development, Celanese; and Wen Chin Foo, senior pharmaceutical scientist, Roquette Pharma Solutions.

 What factors are currently driving growth in the alternative drug delivery formulation market? Are there any growth trends that will be important in the future?

 For lung indications such as asthma and COPD [chronic obstructive pulmonary disease], local delivery by inhaler has been the standard of care for decades. Biotherapeutic treatments such as monoclonal antibodies (mAbs) have been approved more recently for lung indications, but via intravenous or subcutaneous administration. In cases where systemic administration is not needed for treatment, direct delivery to the lung would be hugely beneficial for the patients. There have been efforts in recent years to create dry powder inhaled formulation of these kinds of drugs, using spray drying as a single-step process to stabilize the fragile biomolecules, and engineer respirable particles for inhalation. The advantages for patients with lung conditions are, potentially, so significant that a continued focus on these formulations will be inevitable.

 There has been a real drive, over recent years, to develop dosage forms aimed at paediatric populations. These dosage forms are often distinct from adult products, with challenges ranging from taste masking, controlled release, and even bioavailability enhancement. CDMOs [contract development and manufacturing organizations] with the necessary experience and technologies have been taking a leading role in helping innovator companies develop commercializable products for the paediatric market. Both FDA’s [US Food and Drug Administration’s] Best Pharmaceuticals for Children Act (BPCA) and the European Medicines Agency’s (EMA’s) Paediatric Regulation incentivize companies to develop and commercialize products suitable for infants and children. The six months of market exclusivity they provide are a real incentive—two years in Europe for orphan indications—and it’s working, with maybe 15 paediatric approvals every year now in the United States. These incentives are proving a significant growth driver for paediatric products, including multiparticulate formulations, as they can be particularly useful when formulating medicines for these young patients.

 Alternative drug delivery formulations can help overcome limitations of traditional dosage forms. These solutions are designed to provide improved bioavailability, reduced off-target effects, expanded compatibility across a variety of molecular classes, and lower treatment burden for patients. Market focus has been on identifying alternative dosage forms that offer sustained delivery of complex molecule types, with the goal to improve efficacy and provide better outcomes.

The industry is focused on innovating novel, sustained-release solutions to deliver biologics and RNA therapeutics. Sustained-release dosage forms allow precise delivery using improved targeting, localized delivery and solutions that help deliver drugs across physiological barriers, a recognized impediment to drug efficacy in the past. Success in sustained, controlled-release drug delivery represents an opportunity to reduce treatment burden and ensure patient adherence. Another interesting trend is the effort to improve patient outcomes through controlled release of multiple drugs concurrently. Fixed-dose combinations and multi-preventative technologies are potential applications of this approach.

Advancements to develop fixed-dose combinations and multi-preventative technologies for multiple pathways or multiple indications will continue. Oncology is an exciting therapeutic area where this trend has renewed focus and the concurrent delivery of multiple therapeutics may prove efficacious in treating heterogeneous tumours or the tumour microenvironment.

 The rising demand for innovative small-molecule drug delivery forms is being fuelled by the need to get more patients to adhere to their prescriptions. With the number of people aged over 60 years set to double by 2050 and global instances of chronic disease on the rise, the need for effective drug delivery formats has never been greater (1,2). Despite this, as many as 50% of patients do not take their medication as instructed (3). Pill fatigue, triggered by patients feeling overwhelmed by the amount of drugs they must take, is one of the many causes of medical noncompliance (4). Groups with specialized dosage requirements—like children, older adults, and people with disabilities—are especially susceptible to pill fatigue and other forms of nonadherence, because most conventional medications aren’t suited to their needs.

Alternative drug delivery forms such as orally disintegrating tablets (ODTs) and orally disintegrating films (ODFs) give pharmaceutical brands an invaluable opportunity to adapt. With a broader range of treatment options, drug makers can address a wider spectrum of clinical needs, improve bioavailability, reduce toxicity, and improve patient compliance.

In terms of large-molecule biologic drugs, there is a slow transition away from the traditional parenteral route (intravenous [IV], intramuscular, or subcutaneous injections) towards new and exciting delivery strategies. Intensive research is currently underway to overcome the unique challenges posed by biologic APIs and make them suitable for more patient-friendly delivery forms. Intranasal and pulmonary delivery strategies, for example, are actively being explored for protein and peptide therapeutics, in addition to buccal and transdermal administration for vaccines. Most of these alternative drug delivery formulations are still in the preclinical or clinical stages of development, but there have been a few examples of licensed products entering the market in recent years.

 How might alternative drug delivery formulation approaches help companies avoid potential attrition during development?

 While drug attrition has generally decreased over the past 10 years, the rate of failure still remains high—almost 90% by some estimates (5).Alternative small-molecule delivery routes offer manufacturers many advantages for increasing drug viability—from the potential to avoid first-pass metabolism to lower doses and fewer side effects—but they also present their own inherent formulation challenges. As with conventional drug formulations, these issues can be overcome through the judicious selection of functional excipients and a drug design tailored for commercial success. Cyclodextrins and their derivatives, for instance, are commonly used in nasal, ophthalmic, pulmonary, and transdermal delivery systems to improve drug solubility, permeation, and bioavailability, as well as the stability of pharmaceutical actives (6).

In biologic vaccine development, low toxicity and high immunogenicity are the key measures for success. Buccal administration of particulate vaccines using ODFs appears to be a promising strategy for eliciting an enhanced immune response, activating both mucosal and systemic immunity (7). In comparison to parenteral administration, this noninvasive vaccination route also delivers a higher rate of medical compliance and is better suited to the needs of vulnerable groups like paediatric patients.

 For lung cancer in particular, dose-limiting toxicity has caused the failure in clinical trials of many promising candidates that are delivered systemically. To combat this, local treatment of lung cancer by the inhalation route is an area of great interest. Biotherapeutics delivered locally to the lung will have little to no systemic exposure, helping to reduce the risk of adverse effects in patients. It will also enable higher doses to be delivered directly to affected tissues. This same approach can also, of course, apply to lung indications outside cancer, from common diseases such as asthma to orphan conditions like idiopathic pulmonary fibrosis.

 Multiparticulate formulations consist of a large number of small particles, with each particle delivering the same unit dose. Typically, they will be 100–350 µm, might be CR/MR [controlled-release/modified-release] matrices or IR [immediate-release] matrices, and could also have CR/MR coatings. These particulates are then used to make the final dosage form: this could be an encapsulated product, a sachet, or a tablet. They can address numerous patient-centric and pharmacokinetic problems, and help de-risk clinical programmes, in addition to optimizing the product’s attributes.

For example, CR/MR multiparticulates, whether lipid-based or spray-layered cores, can address Cmax spikes during initial absorption that may lead to side-effects. Whichever way they are made, they can be coated to mask taste, or to give targeted release in the GI [gastrointestinal] tract. Furthermore, the multiparticulate intermediate flows through the GI tract with the fluid phase of GI compartments, reducing the propensity for gastro-retention that can occur with larger enteric coated tablets and capsules. All of these attributes can improve both performance and patient compliance and allow a more tailored approach to be taken for the medicine’s target product profile.

 Therapeutics in development typically fail due to one or more of the following: formulation issues, poor ADME [absorption, distribution, metabolism, and excretion] properties, toxicity effects, or lack of efficacy. Alternative drug delivery dosage forms provide a path to overcome these common barriers associated with attrition in drug development.

Sustained-release implants and injectables are great examples of how ADME-related issues and toxicity effects can be overcome by a sustained, localized delivery approach. These sustained dosage forms are a unique way to mitigate problems associated with delivery across difficult physiological barriers. Localized delivery from an implant or injection can increase the therapeutic effect at the targeted compartment or tissue.

Oncology and CNS [central nervous system] are areas with high attrition rates that may benefit from the use of novel, sustained-release drug delivery formulations. These formulations can offer new routes for NCEs [new chemical entities] experiencing an impact from first pass metabolism, shorter plasma half-life, or toxicities at high concentrations.

 Can alternative drug delivery formulations aid with increasing patient compliance?

 If we look at the ophthalmology market as a case study, low patient compliance can lead to vision loss or even blindness. The majority of the market is focused on developing approaches to reduce treatment burden and slow progression of diseases like glaucoma and age-related macular degeneration. Sustained-release dosage forms have found a home in this market where a six-month release implant can significantly improve patient compliance for a range of chronic eye diseases.

 Alternative drug formats give manufacturers greater scope to tailor medications to patient needs, and in turn, improve compliance. Take ODTs [orally disintegrating tablets], for example—these dosage forms disperse on contact with saliva in the mouth, rather than needing to be swallowed and dissolved in the stomach. This aspect not only makes them easier to take for people with low ability to swallow, but also means they deliver a faster onset of action—further contributing to better adherence. For patients with acute dysphagia, intranasal administration routes are ideal for delivering small doses with minimal discomfort.

Extended-release dosage forms are another great example of how brands can combat pill fatigue with alternative formulation approaches. With this type of delivery method, patients can take just one dose, which is slowly released throughout the day, rather than having to take multiple pills at set intervals. Streamlining the dosing experience like this can have a profound impact on patients’ ability and willingness to complete their full course of medications. The benefits of gradual release formats are not confined to oral dosage forms either. Multiple day transdermal and subcutaneous depot formulations are prime examples of extended-release delivery routes that offer an effective alternative to traditional multi‑dose oral regimens. Transdermal microneedle patches for instance, provide a painless way to overcome the skin barrier in the delivery of large molecule biologics, and are therefore gaining popularity as an alternative delivery route for vaccines.

 In many cases, biotherapeutics for lung indications must be delivered invasively, whether by IV infusion or subcutaneous injection. In the case of IV infusions, multiple visits to a medical provider will also be required. Formulating a biotherapeutic in a dry powder inhaler eliminates these invasive injections and offers the potential for convenient at-home administration.

 Multiparticulate formulations can address two significant problems patients can face, whether as clinical trial participants or once a drug is commercialized: problems with swallowing tablets or capsules (dysphagia), and the taste-masking of granule suspensions. Dysphagia is particularly common in paediatric and geriatric patients, and all too often is overcome via crushing a tablet or emptying a capsule, and then mixing with a suitable vehicle. But either way, mouthfeel is often poor, with the rough surface feeling like sand in the mouth, and heterogeneous particle sizes leading to them getting caught in the teeth. Multiparticulates are much more uniform in particle size distribution and are more likely to be easy to swallow with a better mouthfeel. If there is an enteric coating, this will remain in place rather than being destroyed or removed. Improving taste is important for paediatric patients, particularly for those who are unable to swallow a standard tablet or capsule. Coated multiparticulates can hide the taste in a suspension formulation, making it far more palatable. They are similarly useful for sachet or reconstituted powder formulations for adult populations. Either way, patient compliance is likely to be better.

1. WHO, “Ageing and Health,” Fact Sheet, 

, 4 Oct. 2021.
2. PricewaterhouseCoopers, “Chronic Diseases and Conditions Are on the Rise,” Healthcare Insights, 8 May 2015.
3. J. Kim, et al., 

., 43 (1) 30–34 (2018).
4. E. Roy, “Pill Fatigue,” 

, 18, 162 (2020).
6. S. Jacob and A.B. Nair, 

, 79 (5) 201–217 (2018).
7. R.P. Gala, et al., 


Vol. 34, No. 9
September 2022
Pages: 13–15

When referring to this article, please cite it as F. Thomas, “Delivering a Difference in Formulation” 

It is possible to overcome some of the limitations of traditional dosage forms by employing alternative drug delivery formulation strategies.

Delivering a Difference in Formulation

In the words of House Stark of Winterfell, “Winter is Coming,” and with the lengthening nights and colder climate comes the potential for greater COVID-19 infection rates and new viral strains. Unsurprising, there have been announcements on vaccine agreements, and further research has been highlighted in the news.

An announcement was released, in early August 2022, by Moderna that its agreement with the European Commission (EC) for COVID-19 vaccine doses had been amended (1). According to the release, the company will now provide the EC with its Omicron-containing bivalent vaccines (pending regulatory approval) versus the originally agreed upon Spikevax doses of messenger RNA (mRNA) vaccines.

There are, in fact, two next-generation bivalent candidates that Moderna is advancing through development—mRNA-1273.214, based on the BA.1 subvariant of Omicron, and mRNA 1273.222, based on the BA.4/5 strain. A conditional authorization for the use of mRNA-1273.214 has already been granted by the United Kingdom’s Medicines and Healthcare products Regulatory Agency, and Moderna is working with other regulatory bodies for authorization of both booster vaccines (2).

Across the Atlantic, Pfizer and BioNTech have also submitted an application for emergency use authorization of an Omicron BA.4/BA.5-adapted bivalent COVID-19 vaccine with the US Food and Drug Administration, and the companies have shared study data on their Omicron BA.1 bivalent vaccine candidate with the regulators (3).

Moving to a bit earlier in the R&D pipeline, there is a potential oral tablet vaccine under development by clinical-stage biotechnology company, Vaxart. Recently, Vaxart reported additional Phase I clinical data on its Spike/Nucleocapsid (S+N) oral tablet COVID-19 vaccine, which indicated that it induced long-lasting mucosal IgA antibodies against coronaviruses (4).

“These findings support our view that the cross-reactivity of our vaccine candidates’ mucosal immune responses could have a significant impact in the fight against evolving SARS-CoV-2 variants,” said James Cummings, Vaxart’s SVP and chief medical officer, in a press release (4).

1. Moderna, “Moderna and the European Commission (EC) Amend COVID-19 Vaccine Agreement to Supply Omicron-Containing Bivalent Candidates; EC Purchases Additional 15 Million Doses,” Press Release, 9 Aug. 2022.
2. Moderna, “Medicines and Healthcare Products Regulatory Agency (MHRA) Authorizes Moderna’s Omicron-Containing Bivalent Booster in the UK,” Press Release, 15 Aug. 2022.
3. Pfizer, “Pfizer and BioNTech Submit Application to US FDA for Emergency Use Authorization of Omicron BA.4/BA.5-Adapted Bivalent COVID-19 Vaccine,” Press Release, 22 Aug. 2022.
4. Vaxart, “Vaxart Publishes Clinical Data Suggesting its Oral COVID-19 Pill Vaccine Candidate Induces Long-Lasting Mucosal Immune Responses that are Highly Cross-Reactive,” Press Release, 20 July 2022.

When referring to this article, please cite it as F. Thomas, “Winter is Coming!” 

As winter approaches, the next generation of COVID-19 vaccines are being prepared and scheduled, ready for distribution across Europe and the world.

Winter is Coming!

In this exclusive Drug Digest video interview, Meg Rivers and Felicity Thomas, 

editors, interview experts in sterilization and aseptic processing. Alex Van Hagen of Watson-Marlow Fluid Technology Solutions discusses how to approach selecting sterilization methods, installation of aseptic machinery, how single-use technology factors into aseptic processing, and areas for improved automation. In a quick-fire interview, Hamish Hogg of Cherwell Laboratories talks about the eagerly anticipated publication of the revised EU GMP Annex 1 guidance, potentially problematic aspects of the revised guidance, and tips and tricks for companies to ensure compliance.

 is a molecular biologist by training and the current North UK life sciences sector specialist for Watson-Marlow Fluid Technology Solutions. In this position, Alex provides experience-based consultation to the life sciences sector, taking each project from cradle to gate. Previously, Alex worked in academic research centered on producing sustainable microbial cell factories for the production of fossil-fuel-based chemicals using renewable carbon sources, and his work has been presented internationally. In addition, Alex has been a guest lecturer at bioscience continued professional development courses within the UK and sits on an industry expert liaison panel at the University of Lincoln.

 has been the microbiology product specialist at Cherwell Laboratories since January 2019. He has a background as a biomedical scientist for the NHS in microbiology. Later, he expanded his career into medical devices companies, delivering technical support to end users and training to the internal and external corporate teams and customers.

This episode of Drug Digest is sponsored by:

Drug Digest is a tech talk video series with the 

 editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

Automating pharma and biopharma processes

Videos

Pharmaceutical Technology editors interview aseptic and sterilization experts from Watson-Marlow Fluid Technology Solutions and Cherwell—diving into sterilization, aseptic processing, and the revised EU GMP Annex 1 guidance.