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

Felicity Thomas

Antimicrobial resistance (AMR) has long been on the radar of global organizations as a serious threat to human health. However, there are few potential antimicrobials in the clinical development pipeline, and a collaborative effort to tackle the issue is becoming ever more imperative.

Going back more than two decades, in 2001, the World Health Organization (WHO) laid out a framework of interventions, with the aim of slowing the emergence and reducing the spread of antimicrobial-resistant microorganisms (1). Over a decade later, in 2014, WHO published its first global report on data surveillance for AMR, including any available data from national and international surveillance networks (2). Shortly thereafter, in 2015 during the World Health Assembly, countries from all over the world committed to the framework set out in the Global Action Plan on AMR (3).

Moving forward five years to 2020, more than 20 leading biopharmaceutical companies came together with WHO, the European Investment Bank, and the Wellcome Trust to form the AMR Action Fund—a partnership aimed at bringing two to four new antibiotics to patients by the year 2030 (4). Most recently, in April 2022, the AMR Action Fund announced its investment in two companies.

“Adaptive Phage Therapeutics and Venatorx Pharmaceuticals are poised to change the treatment landscape for drug-resistant infections and deliver significant benefit to patients,” said AMR Action Fund CEO, Henry Skinner, in a press release (4). “We plan to commit over $100 million in capital this year in companies developing clinically differentiated antimicrobials with the potential to treat the most urgent unmet clinical needs.”

This action could not come soon enough, as recent analysis demonstrated the urgency of the AMR matter. According to a paper, published in 

 at the beginning of 2022, reported as being the most comprehensive analysis of the burden of AMR to date, bacterial AMR is a health problem on a magnitude similar to that of HIV and malaria, with the potential to be even worse (5).

“Our investments are substantial, but we alone are not enough to take on the global challenge of AMR,” added Skinner (4). “It is now imperative that policymakers around the world enact market reforms to support investment in these urgently needed medications.”

WHO Global Strategy for Containment of Antimicrobial Resistance

Antimicrobial Resistance Global Report on Surveillance

Global Action Plan on Antimicrobial Resistance

, 26 May 2015.
4. AMR Action Fund, “AMR Action Fund Announces First Investments in Adaptive Phage Therapeutics and Venatorx Pharmaceuticals,” Press Release, 4 April 2022.
5. Antimicrobial Resistance Collaborators, 

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

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

Articles

The AMR Action Fund has made its first investments, marking an important step forward for the partnership to achieve its goal of bringing new treatments to the market for priority pathogens.

A Future Investment

In this episode of the Drug Solutions podcast, Felicity Thomas, European Editor, talks to a panel of experts on drug dosage forms trends that have been impactful in recent years and those that may have an impact in the future. Some talking points include recent overarching dosage form developments, the value and importance of patient-centricity, and the potential effect of novel excipients. The panel of experts involved in this discussion were Anita Solanki and Dr. Jnanadeva Bhat, both from ACG Group; Cornell Stamoran, from the Catalent Applied Drug Delivery Institute; Dr. Ali Rajabi-Siahboomi from Colorcon; Brad Gold, from Metrics Contract Services; Hanns-Christian Mahler, from ten23 health and swissfillon; and Anil Kane, from Thermo Fisher Scientific.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

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In this episode of the Drug Solutions podcast, Felicity Thomas, European Editor, talks to a panel of experts on drug dosage forms trends that have been impactful in recent years and those that may have an impact in the future. 

Drug Solutions Podcast: Drug Dosage Form Trends

It is well-known that oral solid dosage (OSD) forms remain the market leader, with recent research estimating the market size to be worth nearly $8.5 billion by 2027 (1). “OSD forms such as tablets and capsules continue to be popular dosage forms in the healthcare sector being the preferred delivery system due to them being patient friendly,” confirms Anil Kane, PhD, MBA, senior director, global technical scientific affairs, pharma services, Thermo Fisher Scientific. “However, the number of biologics and large molecules [is] growing, and this is also seen in the increase in the demand for sterile injectable dosage forms.”

For Cornell Stamoran, PhD, vice-president of Strategy and co-chair of the Catalent Applied Drug Delivery Institute, a key trend impacting drug dosage forms has been the increasing complexity of drug formulations. “[This increasing complexity has been] driven by strong pipeline growth of newer modalities and mechanisms, the need for targeted delivery, and bioavailability-challenged compounds, along with more frequent use of formulations and dose forms to enable patient self-administration, or reduce the complexity of treatment regimens,” he says. “We have also seen important progress in gene therapies using adeno-associated viral (AAV) vectors and lipid nanoparticles to deliver messenger RNA (mRNA).”

“A key consideration in my view is that, with the ever-increasing diversity and complexity of novel therapeutic modalities and APIs that must be injected to achieve efficacy, the need for sterile medicines will see a corresponding rise,” states Hanns-Christian Mahler, CEO of ten23 health. It is likely, he continues, that as a result of this trend there will be a drive towards easier-to-administer (or self-administered) medicines via devices, for example, which should improve compliance and overall therapeutic success.

“Ever-changing industry dynamics in recent years have had a considerable impact on the development and use of dosage forms for drug delivery,” specifies Jnanadeva Bhat, head—Formulation R&D (Pharma & Nutra), ACG Group. “One such change has been the improvement of existing products which can offer significant advantages, such as better therapeutic efficacy, whilst at the same time minimizing development expenses and timelines.”

As a result, Bhat continues, there has been an increase in the drug dosage form portfolio in general for the industry. Additionally, more research is being performed on larger and more complex entities and biologics so that challenges, such as solubility and bioavailability issues can be overcome, he states. “Low solubility molecules have been a major dosage form development challenge,” Bhat says.

However, Bhat points out that OSD forms have remained a stable trend with continuing popularity over the years. “There is continuous competition and research in this area of pharmaceutical dosage forms to be ahead of the race, and also to reach a greater segment of the population,” he states. “In particular, capsules have a multitude of benefits in terms of easier development and administration. The significant demand we are seeing right now creates room for more innovations across product lines.”

“There is a strong desire to move from injectables to simpler oral administration; this would provide opportunities for life-cycle management as well as patient-centricity, especially in enabling technologies to allow oral delivery of biologics,” emphasizes Ali Rajabi-Siahboomi, vice-president—chief innovation officer, Colorcon. “The oral route remains the gold standard. It considers patient convenience and self-administration, in addition to dose accuracy and speed of manufacturing of tablets for oral route.”

“In 2020, oral solid products accounted for nearly 40% of the 53 novel drug products approved by the Center for Drug Evaluation and Research (CDER) (2). And of the 21 newly approved OSD products, 14 were tablets and seven were capsules,” remarks Kane. “In 2021, the total number of approved drugs was 50, of which 52% (26 products) were injectable dosage forms and 46% (23 products) were OSDs (15 tablets and eight capsules),” (3).

Stamoran concurs that OSD forms are preferential, certainly for innovator small-molecule drugs, but for biologics there is strong growth in infusion delivery. “Across both small- and large-molecule injectable launches, the use of prefilled syringes and autoinjectors is increasing,” he adds. “Also notable is a growing focus on dose forms that are most appropriate for pediatric and geriatric patients, driven in part by the increased expectations of regulators.”

A trend that has been exceptionally prevalent in 2021 is the fast launch of vaccines to combat COVID-19, which have progressed from bench to use in billions of patients at incredible speeds, Kane stresses. “A direct impact of the pandemic is the increase in demand for sterile injectable dosage forms for vaccines in vials. There are many other vaccines and injectables in development, as well as clinical trials that have resulted in increased demand on capacity for sterile injectable formats,” he says.

Another major trend has been the increasing complexity and risk of the drug product supply chain, asserts Thomas B. “Brad” Gold, PhD, vice-president, Pharmaceutical Development, Metrics Contract Services. “Fall-out from the pandemic, as well as other geopolitical dynamics will continue to impact the reliable supply of the many elements critical to finishing and dispensing drugs to patients,” he adds. “Managing the longer lead times necessary for obtaining critical excipients and primary packaging for example will continue to challenge contract manufacturers and have the potential to impact market timelines.”

“Many new chemical compounds have high potency and are sensitive to environmental conditions like moisture, oxygen, and heat, as well as potential interactions with other formulation components or gastro-intestinal environments, causing them to undergo oxidation, hydrolysis, or another degradation path,” emphasizes Rajabi-Siahboomi. However, advances in computing power and new capabilities in artificial intelligence (AI) are providing opportunities for accelerated innovation in drug dosage design, he specifies.

“Technological advancement is supporting ongoing drug development and the manufacturing innovation needed to sustain it,” continues Gold. “For example, we are seeing continuous improvement to critical processing approaches and techniques, especially handling complex and increasingly potent compounds. Equipment manufacturers are responding with system designs that integrate containment technologies to control operator exposure and prevent other issues like cross contamination.”

Moreover, as manufacturing technologies evolve, manufacturers are afforded the opportunity to introduce new and improved processes and production efficiencies, which are supported through the technology’s ability to gather process data, Gold adds. “The more data these systems provide the more useful the feedback is at improving robustness and determining if the process capable of being validated in the first place. Best practice is calling for the increased application of process analytical technologies (PAT) for example, to support continuous improvement,” he says.

“Digitization and automation can provide accurate and efficient support,” agrees Rajabi-Siahboomi, who explains that it is possible to use technological advances, such as AI, to be able to screen and identify molecules that can be progressed further through development. “AI screening has a high potential for undruggable sites—the term ‘undruggable’ is used to describe a protein that is not pharmacologically capable of being targeted; recently, however, substantial efforts have been made to turn these proteins into ‘druggable’ targets. The resulting new compounds have high potency and may potentially be unstable,” he says. “AI will enable better insight into identifying target proteins.”

Additionally, Rajabi-Siahboomi notes that three-dimensional (3D) printing technology is gaining momentum within industry, for the purposes of solid dosage manufacture. “3D printing allows the production of tablets with more than one active substance characterized by different properties and with different dissolution profiles. It has good potential, depending on the production method, as it can provide unique patient-centric dosages and improve stability by producing individual dosage forms that can be presented to patients in a short time,” he states. “This technology is still in development with some success in the nutraceuticals market and limited approvals in pharma.”

For Bhat, there are two ways in which technology has helped to shape dosage form evolution. “One aspect is related to operations and manufacturing, and the other is related to the research and development of novel dosage forms,” he says. When considering the former—operations and manufacturing—Bhat reveals that through the various innovations in equipment and techniques it has been possible to accelerate processes. “Automation improvements have also been aimed at continuous manufacturing, maximum production yield, and minimum losses,” he adds.

In terms of dosage form innovations, there are numerous novel ways to deliver, manufacture, and formulate therapeutics, Bhat continues. “For example, prefilled syringes and automated injectors for injectable dosage forms are accurate, reliable, and convenient. They reduce the need for medical supervision and facilitate easier self-administration,” he specifies. “In the case of oral delivery, nanotechnology in formulation development has emerged with many advantages in terms of increased efficacy and bioavailability of drug molecules. Thus, continuous innovation and evolution can reduce or bridge the gap between demand and developmental challenges in dosage forms.”

There have been significant advances in drug delivery thanks to innovation in materials science and manufacturing processes, explains Stamoran. “For example, development of new softgel capsules now allow these dose forms to offer inherent enteric protection and extended-release formulation,” he says. “We have also seen innovations in functional coating technology, non-glass alternatives for injectables, and new excipients, which can enhance a drug’s performance or even shift treatment regimens to less invasive routes of administration.”

Furthermore, process innovations are enabling development progression, such as the improved scale of production for therapeutic proteins thanks to breakthrough cell-line development, Stamoran points out. “Additionally, equipment and process innovations have enabled critical scale-up increases for AAVs in the field of gene therapy, while the potential implementation of continuous manufacturing in both API and dose form manufacturing also continues to progress,” he adds.

According to Mahler, it can appear that there is limited innovation in the area of sterile products, as a result of the reliance of pharmaceutical products on prior use to ensure safety and regulatory compliance. “Lyophilization remains the drying method of choice for products that require drying; primary containers are typically made of glass; there aren’t really any novel formulation excipients,” he notes.

“At the same time, technology has advanced very significantly,” Mahler asserts. “And whilst innovation may not be apparent at first sight, it surely is on the second: the understanding of stabilization mechanisms has significantly grown, we now understand the role of some excipients like polysorbates in the formulation, we understand the various interactions between the process and the formulation and the packaging components. Hence, development of sterile medicines has become much more informed, enabled by analytical technologies.”

Kane believes that there will be a notable change in the dosage forms under development thanks to technological advances and improved understanding of processes. Areas of particular interest for Kane are biologics in OSD forms and the oral delivery of human microbiome and probiotics.

“Increased knowledge of technology and processes such as lyophilization, cryo-protection, targeted drug delivery, [and] in-vitro simulation models coupled with unprecedented recent developments in materials such as surfactants, permeation enhancers, polymers, muco-adhesive materials, and so on, are propelling advances in these areas and are likely to make oral delivery of biologics, microbiome, and probiotics a clinical reality,” Kane says. “Advances in specialized processes such as spray drying and lyophilization will help formulating peptides, oligonucleotides, enzymes, and proteins into stable solid or liquid states that can be formulated into capsules or tablets.”

Prominent technological advances, such as AI, additive manufacturing, blockchain, and other Industry 4.0 technologies, are impacting various aspects of drug development confirms Rajabi-Siahboomi. For example, AI is providing industry with more efficient ways of isolating potential clinical candidates and continuous manufacturing is offering cost and time-efficient production of therapies, he states.

Extrusion technology is an invaluable resource to help developers enhance material properties so that innovative manufacturing techniques, such as 3D printing, may be employed, Rajabi-Siahboomi continues. “Hot melt extrusion (HME), which enhances material properties, is emerging as a key technology for the continuous manufacture of drugs within the pharmaceutical industry. One notable advantage is the ability to produce a variety of formulations, such as solid dose forms, which improve drug bioavailability,” he says.

“Also, inline PAT tools can be integrated with the HME process to support a quality-by-design (QbD) approach to continuous manufacturing,” Rajabi-Siahboomi explains. “HME extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier, increasing dissolution rates and bioavailability. The most common difficulty encountered in producing such dispersions is the stabilization of amorphous drugs, which prevents them from recrystallization during storage. Advances in both materials and equipment have increased the development of equipment and chemicals for specific use with HME.”

Digitized solutions that can provide useful information, such as digital pills, smart pill, smart medicine, and on-dose authentication, are considered to be of importance by Kane. Digital pills—where an ingestible sensor is embedded in a pill—can be used for the provision of data on the administration of the therapy as well as the physiological condition of the patient, he explains. “Ingestible sensors in smart oral drug delivery dosage forms such as tablets and capsules will revolutionize diagnostics, clinical monitoring, data collection, and data analytics in the health care industry,” Kane adds.

“Smart medicines are a digitized form of traditional medicines. There are typically two components required to digitize a medicine—a target and a sensor,” Kane continues. “With smart medicines, the target is applied directly to the medicine via a coating or ink, and the 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.”

On-dose authentication technologies can help to monitor patients and their administration of a therapeutic regimen, as well as ensure the medicine is authentic. The technology incorporates identification, such as bar codes and spectral images, on the dosage form, Kane specifies.

“A variety of formulation and manufacturing strategies are supporting more accurate, controlled OSD delivery to improve efficacy and patient outcomes,” emphasizes Gold. By way of example, he highlights how mini-tablets are emerging as a format that can provide an increased patient-centered dosing experience. “Configurable in single- or multiple-unit oral forms, mini-tablets have enormous potential to promote dosing flexibility and target dose forms to meet the unmet needs of different patient populations, like children or patients who have trouble swallowing,” Gold says. “Because of their size, usually less than 3 mm or less, these forms can be used to accomplish a number of oral drug delivery strategies.”

The most impactful dosage form technology for Anita Solanki, lead—White Papers, Formulation R&D (Pharma and Nutra), ACG Group, has been fixed-dose combinations (FDCs). “Combining two or more drug molecules can offer improved efficacy, as opposed to increasing the dose of a single drug—this is known as the synergistic effect,” she specifies. “To sum up, minimized drug resistance, maximized patient centricity, and the synergistic effect are the advantages for FDC in drug delivery.”

“For small molecules, the most significant changes in the time I have been involved in drug delivery are the advances in characterizing and addressing bioavailability challenges for oral delivery, which have become increasingly prevalent in the industry’s pipeline compounds,” states Stamoran. “Starting with better assessment tools to predict bioavailability characteristics, to a more comprehensive technology toolkit to solve the issues noted, the path to addressing these challenges today is far easier than in the past.”

In the case of large molecules, Stamoran highlights three developments as being most impactful: “the advances made in design, manufacture, and use of AAVs for gene therapy, including increasing understanding of patient safety-related factors of high-dose therapies; the large-scale clinical validation of lipid nanoparticle-based delivery of mRNA (COVID-19 vaccines); and the emerging opportunity for linkers and a site specific bioconjugation technology, with a wider therapeutic window and improved manufacturability of antibody-drug conjugates,” he says.

“There is a conspicuous move in the direction of personalization and customization of treatment for the coming decade. 3D printing techniques are important in the field of pharmaceutical applications because of the possibility of faster formulation of tailor-made medicines which can be employed in personalized treatment,” notes Solanki. “Patient-centered dosage forms could be developed via 3D printing. Not only personalized dosage forms, but also different drug combinations, shapes, and release patterns can be achieved with 3D printing technologies.”

Inhalation as a drug delivery route is undergoing extensive research and will remain a hot topic for the future as it is no longer restricted to respiratory disorders alone, remarks Solanki. “Capsules based dry powder inhalation formulations are one of the preferred choices, because of their affordability in comparison to other inhalation dosage forms. Inhalation device and product combination will make sure that an unskilled patient receives the intended effect, whilst also being easy to handle and carry,” she says.

Gold expects there to be two trends in particular that will be influential on dosage forms and formulation over the course of the next decade. He believes that medicinal chemists will be increasingly able to understand the genetic resistance (or lack thereof) to certain compounds and that it will be possible to rebuild lost tissue, treat joint and bone pain, and many other diseases and conditions, thanks to advances in autologous and allogenic regenerative stem cell therapies.

“The continuing evolution of emerging modalities will continue to push delivery technology innovation needs, to deliver to specific targets, enhance safety profiles, and ensure manufacturability and patient usability,” stresses Stamoran. “Sustainability continues to grow in importance, both in terms of raw material production/green chemistry, and the operation of development and manufacturing activities. Finally, there are active legislative proposals in the [United States] that may establish an FDA pathway for new platform technology review, providing a smoother route for rapid adoption of innovation.”

Smart medicines and, more specifically, on-dose authentication, will be trending in the future, according to Rajabi-Siahboomi. Through these novel technologies, not only is it possible to deter counterfeiters, but it is also possible to help patients engage better with their medicines, he specifies. “In other words, ‘smart’ medicines not only bring authentication closer to the patient but also help them feel more comfortable with how they take the medicine,” Rajabi-Siahboomi states. “Non-adherence is a huge challenge for healthcare systems and patients may have many reasons for not taking their medicine. All patients can benefit from greater information and support that ultimately improves safety and adherence.”

For Mahler sustainability should be a primary consideration. “My perception is that many companies have excused a lack of product sustainability focus with the need to treat the patient(s). In my view, both aspects should not be mutually exclusive,” he summarizes. “Cradle-to-grave considerations for modern dosage forms are required to be embedded early in development. And this should and has to go way, way beyond CO

Oral Solid Dosage Pharmaceutical Formulation Market: Industry Analysis and Forecast (2021–2027) by Dosage Form, Drug Release Mechanism, Distribution Channel, and Region

Advancing Health Through Innovation: New Drug Approvals 2020

Advancing Health Through Innovation: New Drug Approvals 2021


Vol. 46, No. 3
March 2022
Pages: 16–20

When referring to this article, please cite it as F. Thomas, “The Shape of Dosage Forms,” 

Technological advances are helping shape the dosage forms of the future.

The Shape of Dosage Forms

Accelerated formulation strategies can aid with cost and time-efficiencies in drug development. However, there are key challenges of which developers must be aware to ensure success. To discuss the primary hurdles to accelerated formulation strategies and best practices for developers, 

 spoke with a panel of experts. The panel included Paul Kippax, Pharmaceutical Sector director at Malvern Panalytical; Chris Roe, senior research fellow, and Vanessa Zann, senior drug development consultant, both at Quotient Sciences; Cornelius Pompe, vice-president R&D at Leukocare; and Alexander Faude, director Process Science, downstream processing, and Marvin Kadisch, director Process Science, upstream processing, both at Rentschler Biopharma.

 Could you run through the primary challenges facing developers when employing accelerated formulation strategies in drug development?

 The main challenge with accelerating formulation strategies is knowing which dosage form technology is the most appropriate to give optimum exposure in patients. There is widespread acknowledgement of the lack of predictability of preclinical data for formulation assessments. Improvements in 

 tools are emerging; however, there are still significant risks for innovator companies, particularly given continued drug delivery challenges presented by molecule chemistry. This uncertainty is magnified when batch sizes and stability packages are needed for new formulations, for testing in the clinic to even be considered.

 Truly understanding the drivers of poor product performance is a key challenge to overcome. Using the correct techniques can provide meaningful improvements in 

 performance that can aid in rapidly progressing formulation efforts. At the same time, developers need to avoid the risk of trying to progress overly complex formulations, which may add unnecessary time or cost to the drug development process. While speed is critical, it shouldn’t come at the expense of sufficient product quality.

 No matter what type of drug product you are developing, the principal challenge—or opportunity—is to identify and deploy the techniques that are relevant to assessing your sample’s critical material attributes (CMAs). If you are not applying the right methods, you may not achieve the design space understanding that will ensure you’re tracking quality throughout development and into manufacturing—this could lead to expensive late-stage failures.

So, it’s vital to take a sample-centric approach to understand which CMAs define the performance of your formulation. For example, is it relevant to measure particle size for your API? If you’re working with a highly-soluble biopharmaceutical classification system (BCS) Class I product, then particle size may not be an important indicator, but for BCS Class II products, particle size is key.

It is also important to consider how changing conditions impact your drug substance. For example, are crystal polymorphs an issue when formulation conditions change? If so, how must the formulation adapt to maintain product stability and quality? Being able to answer such questions by accessing the right analytics at the right time is the fastest way to optimize the formulation design space for your product.

 Accelerated strategies are of paramount importance to reduce the time-to-market and to make innovative therapies accessible to patients in a timely manner. However, these strategies imply a certain risk profile, which has to be assessed on a case-by-case basis. Experienced service providers can be instrumental in tailoring such strategies to the specific project requirements and define measures for risk mitigation to accommodate the intended acceleration.

 The greatest challenge that developers face is the availability of early and representative material supply. This [challenge] can be a defining factor in the success of the project. Risks in such projects can be mitigated by employing an integrated approach, such as the one followed by the Rentschler Biopharma and Leukocare alliance.

 It is the experience and expertise that service providers (such as the strategic alliance of Rentschler Biopharma and Leukocare) bring to the table. The goal is to ultimately find a best-fit solution for accelerated strategies, while maintaining high quality.

 Are the challenges more significant for large-molecule products versus small-molecule ones, in your opinion?

 The challenges associated with accelerated formulation strategies for small versus large-molecule products certainly differ, but developers may face a comparable degree of complexity for both product classes. Differences mainly arise from critical quality attributes (CQAs) specific to these products. In addition, the degradation pathways and kinetics may largely deviate from each other. The regulatory requirements that apply to these products are also specific in several aspects.

 The challenges for large molecules are still present but different. Large molecules will typically be administered parenterally via intravenous (IV) or subcutaneous (SC) routes, hence formulation options will be more limited compared to the likes of solubility enhancement or modified release development solutions for oral small molecules. There will be less dependency of the formulation composition on its clinical performance. The challenges still remain with regard to predictability from preclinical species and also manufacturing and stability for drug products.

 Arguably the most significant challenges for large molecules would be to achieve adequate exposure from the oral route to exert a systemic therapeutic effect, given this is often seen as the gold standard for convenience and compliance. Issues for large molecule oral formulation strategies include poor permeability and potential instability in the gastrointestinal tract, both of which need to be addressed via compound selection and/or formulation technologies. Success is possible, as evident from the recent [US Food and Drug Administration] FDA approval of Rybelsus (Novo Nordisk), an oral glucagon-like peptide (GLP)-1 agonist (1).

 Every product brings its own unique challenges, and there are certainly established hurdles to clear with both small- and large-molecule drug candidates. For example, if we consider drug substance stability, the complexity of establishing, maintaining, and indeed measuring this attribute for large molecules can be extremely challenging as the analytical landscape is quickly evolving, whereas the key analytical tools for small-molecule APIs are well-established and understood.

However, small molecules have their own challenges in terms of solubility issues and also their wide variety of administration routes and dosage forms. The analytical toolsets that are applied to ensure efficacy, quality, and safety must reflect these diverse requirements. For all dosage forms, the questions are the same, but the analytical approach applied will differ.

Again, taking a sample-centric approach to the application of analytics in your formulation design space will ensure these challenges are addressed in a way that accelerates your development programme.

 What sort of activities can developers pursue to ensure their accelerated formulation strategies are successful?

 It’s vital to keep your end-goal in sight. Ask yourself upfront, ‘what are the critical quality attributes and which analytics should be applied throughout the workflow to ensure they’re achieved?’ With the focus firmly on your sample, you can quickly home-in on the best formulation for your product.

It may be useful to consider contracting-in consultancy, services, and/or instrumentation that meets your specific requirements. Partnering with a contract services provider allows you to access new analytics and expertise and develop relevant and accelerated approaches.

Whether the analytical workflow takes place in your own laboratory or in that of a contract research organization, applying an orthogonal approach provides the most thorough and detailed picture of your formulation and ensures nothing is missed that might cause issues later in development. A critical design workflow that uses robust datasets to inform decision‑making, together with an orthogonal approach to validate your findings, will ensure you find the ‘sweet spot’ formulation for your product, faster.

 In the very initial phase, developers are advised to define a holistic target product profile covering chemistry, manufacturing, and controls aspects beside non-clinical, clinical, and commercial features. Depending on the available prior knowledge about the specific molecule or other molecules of the same modality, a basic characterization should be performed. Thereby, predominant degradation pathways can be elucidated by applying stress modes, which reflect conditions encountered during manufacturing, storage, supply, and administration of the drug product. These activities inform the design of iterative formulation screening and optimization studies. The application of tailored designs of experiments generates insights into how formulation parameters impact CQAs and supports the generation of design spaces. Formulations with optimized stabilizing properties can then be identified by confirmatory stability studies under target and accelerated storage conditions.

 To elaborate on iterative formulation screening: This starts with explorative produced product, and the subsequent optimization studies lead to an incrementally maturated process for the generation of drug substance. Also, an appropriate panel of quality control methods is an absolute must to ensure the success of the accelerated formulation strategy.

 For oral small molecules, having a data driven formulation strategy based on the compounds’ biopharmaceutic properties is likely to result in a greater chance of success. Employing the developability classification system (DCS) to molecules will allow a targeted formulation strategy for poorly soluble compounds that is based on whether the absorption is either limited by dissolution rate (Class IIa) or solubility (Class IIb). Where there is uncertainty (border-line case) in the classification, Quotient Sciences would recommend assessing both a particle-size reduced formulation (a DSC IIa strategy) and a solubility-enhanced formulation (DCS Iib strategy) to cover both situations to maximize the potential for success.

The focus around solubility can begin in the candidate development stage. If good solubility properties can be built into the drug molecule at the compound selection stage, this can help avoid downstream formulation optimization requirements. At Quotient Sciences, fully integrated drug substance and drug product activities are offered in-house, allowing both preclinical and clinical development activities to be run in parallel on a single programme. This approach simplifies the supply chain, shortens time from discovery to clinic, and allows developers to assess a number of formulation strategies within first-in-human (FIH) studies or enter their FIH studies with an optimized dosage form. By the end of FIH studies in both situations, the sponsor has generated data not only on safety, tolerability, and pharmacokinetics (PK), but also has a formulation suitable for future patient studies. Additionally, druggability assessments can be performed alongside salt and polymorph screening to ensure that the best compound is selected for development. Lead compounds can be manufactured in sufficient quantities to support toxicology and preclinical studies. Formulation and solid-state investigations should provide clear and unambiguous data for optimizing drug substance form, leading to rapid drug substance, dosage form design, and drug product manufacturing.

 For large molecules where oral delivery is required, one optimizing strategy is to formulate with penetration enhancers to increase oral absorption either through modification of the tight junctions or membrane perturbation. There are 

o permeability assays that can be used to assess large-molecule permeability in the presence of various formulation components that are available to increase permeability, both early and relatively rapidly within the development programme. However, these models have limitations in terms of being able to test formulated drug products that do not damage the 

More complicated preclinical animal models are often required to assess the oral formulation performance of large molecules, for example whether oral dosing or a more complicated study with intraduodenal dosing is required, necessitating specialized surgery. Oral absorption may only need to be increased by a small amount to result in a viable oral product compared to an IV formulation, and hence this avenue is often pursued; however, assessing the levels of formulation enhancement required in an oral formulation can be challenging to optimize.

1. FDA, “FDA Approves First Oral GLP-1 Treatment for Type 2 Diabetes,” 


Vol. 34, No. 3
March 2022
Pages: 17–19

When referring to this article, please cite it as F. Thomas, “Successfully Accelerating Formulation Strategies,” 

Developers need to consider key challenges when approaching accelerated formulation strategies to ensure success.

Successfully Accelerating Formulation Strategies

Protein therapeutics are an important class of medicines that are used to treat a variety of diseases. According to market research, the protein therapeutics market is estimated to grow at a compound annual growth rate of 6.86% between 2020 and 2027 (1). This growth is expected to be driven by the rapid rise in chronic disorders, advancements in technologies, broadening awareness of protein therapeutics, increasing adoption of plasma-derived therapies to manage chronic disorders, and mounting government initiatives to develop healthcare sectors (1).

However, therapeutic proteins are notoriously less stable than conventional pharmaceuticals; and due to their complex molecular structures, they can be challenging to develop successfully (2). “Compared to small molecules and peptides, proteins are much more complex,” explains Khanh Courtney, PhD, senior director, Biologics, Element. “Therefore, the understanding of the biophysical and biochemical characteristics of a protein biomolecule is critical in the identification of critical quality attributes (CQAs) to ensure consistent safety and efficacy.”

As proteins are formed by long chains of amino acids that interact with each other, secondary and tertiary molecular structures are formed, notes Courtney. Beyond the tertiary structure, the protein can bind to itself, which results in even higher order structures, such as dimer, trimer, and oligomer, she states.

“Certain amino acids could be post-translationally modified with phosphate groups, methyl groups, simple sugars or complex sugars, and so on, leading to a highly complex protein therapeutic molecule,” Courtney says. “The folding of the protein, the higher order structure, [and] the composition of its post-translational modifications, particularly of the glycans, are all examples of protein characterizations that could impact the potency and function of the molecule.”

“Protein characterization is of [the] highest importance throughout all stages of the value chain from discovery to development, through to quality control,” emphasizes Martin Vollmer, strategic program office lead for Biopharma, Agilent Technologies. “Characterization of a protein provides information about its structure and composition, which is directly linked with its function, leading to a greater understanding of differences and ensuring that quality criteria of developed biopharmaceutical products are met according to regulatory guidelines, ensuring drug efficacy and drug safety.”

For Scott J. Berger, PhD, senior manager, Biopharmaceutical Markets, Waters Corporation, whether making a protein drug via a recombinant or synthetic process, development should start with protein characterization and having as much knowledge as possible about the product. “These processes are imperfect, so they are going to make products with low-level variations that are subject to degradation pathways that further raise product variability,” he specifies. “It’s this complexity that creates reliance on sophisticated analytical tools.”

Tools, such as liquid chromatography (LC) and mass spectrometry (MS), have provided process scientists with the ability to monitor important attributes of a molecule in response to changes in the process, Berger adds. “This [capability] gives scientists the flexibility to incrementally refine their process to improve drug quality and yield by establishing analytical comparability,” he says. “Characterization assays often translate to targeted methods for process monitoring and product release where you are verifying that you have control of your process and product quality.”

A key challenge related to protein characterization is that methods usually require a lot of test material, Courtney stresses. “Ideally, protein characterization is done in the early stages of chemistry, manufacturing, and controls (CMC) program development so that critical attributes are identified early on. Unfortunately, the early stage of CMC, for instance during process development, consists of small-scale productions done at the lab bench and have low yield,” she states. “This challenge can be, and is being, dealt with by the advancement of analytical methodologies that can assess more than one characteristic at a time in a single sample preparation or method.”

An example of how this challenge is being overcome can be found in the use of high resolution, high sensitivity MS. “This approach can be used to decipher the peptide map of the protein, post-translational modifications, deamidation, disulfide bonds, aggregation, molecular mass verification, glycan structure elucidation, and even tertiary structure determination, all in one approach,” Courtney explains. “By packaging multiple attributes into one method, a small yield of protein produced at the lab bench could produce a wealth of data to assess protein characteristics to better inform manufacturing and quality decisions.”

There are several immediate challenges to protein characterization in Berger’s opinion. “First, is the increasing complexity of the molecules,” he says. “We’re seeing the appearance of bi- and tri-specific molecules, antibody-drug conjugates [ADCs], and complex fusion proteins, all of which have more attribute variation than your typical monoclonal antibody, requiring enhanced analytics to define and monitor them.”

Additionally, in light of the increasing number of accelerated reviews by regulatory agencies, a challenge has arisen in the form of being able to fully characterize molecules in a compressed timescale and at the same time as stability studies and formulation development are taking place, Berger points out. “So, there is an increasing need for efficient analytical platform methods that can utilize prior knowledge to accelerate these studies,” he states.

“Another challenge many organizations face is the lack of actionable knowledge during the clone selection stage of product discovery/development,” Berger continues. “Use of LC–MS at this stage can ensure that a biosimilar, for example, matches up to the target analytical profile of the innovator molecule when it comes to a set of key and critical quality attributes.” When used as a part of a quality-by-design (QbD) approach, LC–MS can help to ensure that the desired product attributes are built into the molecule, he notes. If there is insufficient knowledge about a molecule at this stage of development, it is possible that impurities or instabilities won’t be discovered until after the product is placed into clinical production, Berger warns.

For bench scientists, experimental bias can be a significant challenge, Berger highlights. “A top reason why assay-to-assay test results vary from one scientist to another has to do with complicated and multi-step sample preparation methods,” he says. “For multi-attribute monitoring of biomolecules by LC–MS, it’s important that you have a very high-quality and reproducible sample for meaningful results. To address this need automated sample prep technologies are being investigated by many groups as a tool to improve sample quality and reproducibility by eliminating the human factor from potentially biasing assay results.”

Undesirable secondary interactions can adversely impact analytical data when analyzing organic acids, organophosphates, oligonucleotides, phosphopeptides, acidic glycans, and phospholipids, Berger notes. “One example of a secondary interaction is the non-specific adsorption by certain biomolecules to the metal surfaces—or even to bio-compatible materials like titanium—of liquid chromatographs and chromatographic columns,” he states. “Another type of secondary interaction is caused by the highly active surfaces of proteins which have a propensity to interact with the hydrophobic and electrostatically-active sites on the silica and hybrid silica chromatographic particles in the UHPLC [ultra-high performance LC] or UPLC [Ultra-Performance LC] column.”

These secondary interactions cause difficulties when characterizing and monitoring drug products by size exclusion chromatography (SEC), which is used to determine protein sample size variants claims Bill Warren, Principal Bioseparation product manager, Waters Corporation. If these attributes are not carefully controlled then the safety and efficacy of the product can be adversely affected, Warren specifies. “It’s for this reason that regulatory agencies require drug firms to accurately quantify the protein size variants like mAb aggregates, monomers and fragments in protein drug products,” he says.

Vollmer emphasizes that protein characterization is highly complex and is only becoming more complex over time. “In the past, it was mainly monoclonal antibodies (mAbs), hormones, vaccines, modified human proteins, and similar therapeutic proteins. Now with the discovery of antibody [drug conjugates (ADCs) fusion-proteins, bi-specific Abs, and other modalities, the task of protein characterization now requires a much more flexible approach,” he asserts.

This increasing complexity is then also tied to the skill of the analytical scientist that needs to perform the characterization, Vollmer stresses. “There are a multitude of assays that need to be performed and the instrumentation required is more sophisticated, but costly,” he explains. “Big hurdles are, therefore, the cost of implementation, operation, and skilled personnel.”

“Another important challenge is the large amount of data that needs to be analyzed for meaningful information and further action,” Vollmer continues. “More broadly, regulatory hurdles and inertia in the industry are often roadblocks for fast innovation.”

“LC and MS have been the empowering technologies for the well-characterized biotherapeutic,” Warren says. “LC is essential for fully analyzing an intact protein or its sub-units for glycan profiling or peptide mapping or for looking at protein charge or size variants.”

A technique that is useful for characterizing protein size variants is SEC, Warren adds. There have been several new SEC columns that have been brought to the market recently, he states, that address “the problem of secondary interactions (both ionic and hydrophobic) when separating protein aggregates, monomers, and fragments over a molecular weight range of 10,000 to 6,500,000 Daltons.”

Berger also notes that through combining LC and MS, it is possible to establish the primary structure (product sequence), which is a regulatory filing requirement. “With LC–MS, you get to explore the product variation, its stability, and degradation pathways, which ‘hot spots’ to monitor to ensure that the product qualities and your processes are under your control,” he says. “LC–MS is also ideal for looking at a molecule’s higher order structure, which relates to the folding and stability of these biotherapeutics, and how they interact with their protein targets, or themselves when it comes to things like molecular aggregation.”

The structural information obtained by LC–MS can drive product development and can also form the basis of intellectual property, Berger points out. “Understanding higher order structure and stability dynamics may require the use of techniques like hydrogen deuterium exchange or ion mobility mass spectrometry (IMS-MS) and more recent techniques, such as collision-induced unfolding (CIU). CIU is an approach where the mass spectrometer is almost like a calorimeter, adding energy to the protein molecule and seeing how it unfolds within the IMS-MS,” he says. “These techniques allow you to ask questions that go beyond primary structure to understanding the dynamics of its folded structure and interactions with its protein target.”

Courtney highlights three techniques that are important for protein characterization: “High resolution, high sensitivity, orbitrap MS for protein and glycan identification, and structural elucidations; capillary electrophoresis to determine charge heterogeneity; and circular dichroism for secondary structures.”

Although there is no single standard technique to characterize proteins, Vollmer concurs that LC and high-resolution MS are regarded as the gold-standard thanks to the “rich” information such techniques offer on physiochemical properties of the protein. “Other alternative techniques are capillary electrophoresis (CE) and CE–MS because they can provide excellent resolution,” he adds.

“Spectroscopy, such as ultraviolet, Raman, near infrared, or fluorescence, are also widely applied to determine more specific requirements, such as concentration or purity. These techniques are fast and can even be applied inline,” Vollmer concludes. “Cell analysis technologies, such as metabolic analyzers, real-time cell analyzers, cell-imagers, and cell counters are applied to characterize suitable clones and host cells for protein manufacturing.”

Protein Therapeutics Market Research Report: by Type, Application, Protein Function, End User—Forecast to 2027

, Market Report (February 2021).
2. A. Bolje and S. Gobec, 

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


Vol. 46, No. 3
March 2022
Pages: 36–39

When referring to this article, please cite it as F. Thomas, “Empowering Protein Characterization,” 

Scientists can work to overcome the challenges associated with protein characterization through empowering technologies.

Empowering Protein Characterization

The COVID-19 pandemic highlighted how vital cold chain is for the pharmaceutical industry, particularly as some vaccines needed to be produced, transported, and stored at –70 °C. Market projections for cold chain logistics of pharmaceuticals are projected to grow at a compound annual growth rate of 9.03% by 2025, which is reported to be driven by greater global demand for pharmaceuticals, increasing initiatives to promote cold chain, and more demand for reefer containers from the pharma industry (1).

To meet the increase in demand for temperature-controlled solutions, logistics providers are being required to adapt their approaches and employ more advanced technological solutions, while still adhering to strict regulatory requirements. 

 spoke with Nick Gilmore, Global Head of Sales and Marketing, Tower Cold Chain, to learn more about how cold chain solutions have changed, what the regulatory landscape is looking like for logistics providers, and potential future trends for the sector.

 How have cold chain solutions had to adapt to meet the growing demands for cold chain logistics?

 Putting the European success of the COVID-19 vaccine rollout to one side, the demand for effective temperature-controlled packaging solutions in the pharmaceutical supply chain has increased significantly in recent years. Indeed, with a growing prominence for personalized medicines, we are now beginning to see the advancements of precision therapies in the pharmaceutical cold chain industry. There is no longer a ‘one-size-fits-all’ approach to medical intervention. Instead, we’re seeing a move towards bio-specific treatments, tailored to a particular individual’s needs based on their genome. And, with manufacturing adjusting to smaller batch, precision medicines, the vendors, and outsourcing partners must adapt too as the need for transparent, closely controlled global supply chains rise.

It is critical for pharmaceutical manufacturers to partner with a cold chain expert that is committed to continually expanding and evolving, to keep pace with the growth and complexities of transporting temperature-sensitive pharmaceuticals. Cold chain shipping providers should have the technology, resources, and network in place for handling lower volumes of products with tight manufacturing-to-patient timeframes. Delivering a consistent customer outcome, is a need not a want. Put simply, manufacturers will choose partners who offer both proximity and availability assuring products will arrive on time, undamaged, and with no temperature excursions.

Where historically pharmaceutical products were manufactured in one central factory, today they are more often produced, mixed, filled, and packaged in separate locations, thus demanding greater distribution and movement. It is no longer just about the final leg of the journey to patients. Logistic organizations who can offer customers a network of fully stocked hubs and service centres, located across multiple countries, can maximize their proximity and availability, and offer localized sourcing, will be in a strong position to become a partner of choice.

Factoring in the high value of pharmaceutical goods, their perishable nature, and susceptibility to temperature changes, manufacturers require not just optimized networking, but assurance of product integrity for patients and businesses alike. It is here that the choice of the most appropriate cold chain solution makes all the difference.

 As cold chain technologies advance to accommodate industry demands, are European regulations changing appropriately to address the novel technologies being used?

 The pressure is on for logistics players, manufacturers, governments, and non-governmental organizations to improve their capabilities in supporting the life sciences industry, whilst adhering to standards enforced by regulatory bodies to ensure product quality and safety. One solution to meet this industry need is through digitalization.

The volatility of the pharmaceutical market combined with today’s increasingly connected, fast-paced, customer-focused world means data is no longer a bonus feature, but a vital part of cold chain operations. Smart packaging which delivers end-to-end traceability and precise shipment tracking is now a cornerstone of supply chain fulfilment.

Dataloggers, designed to monitor external and internal temperatures throughout the containers journey, can be built into containers, which is an aspect included in those provided by Tower. Using Bluetooth Low Energy Technology, each logger communicates wirelessly, sending real time, accurate data to the cloud. This data communication allows for in-transit compliance checks and on-delivery sign-off, establishing a complete electronic and hard-copy audit trail across the entire logistics process providing complete visibility and transparency to customers.

Assurance of product integrity is paramount in cold chain which is why reliability is a key foundation for logistics providers, such as Tower. Data downloaded from over 15,000 shipments demonstrates fewer than 0.1% of temperature excursions on average, a vital indicator in the maintenance of the cold chain.

 The European Commission is driving more ‘sustainability’ issues within its pharmaceutical strategy, how might/is this aspect impacting cold chain for pharmaceuticals in Europe? Are there similar demands for more sustainable solutions being demanded from countries outside the European Union too, such as the United Kingdom?

 The EU’s pharmaceutical strategy (2) holds significant potential to drive sustainability in the pharmaceutical sector—and is an opportunity not to be missed. The strategy’s key goal is to reduce the impact of pharmaceutical substances on the environment and pave a way for the pharmaceutical industry to contribute to climate neutrality in the EU, with a focus on reducing greenhouse emissions along the value chain.

With such demand for greener supply chain management not just in the UK and EU but globally, many pharmaceutical organizations are reassessing their processes, seeking out external partners with sustainability-first mindsets. In line with government and consumer efforts to address single-use plastics, manufacturers have been compelled to look for sustainable packaging alternatives to ship products. As such, reusable cold storage containers are growing in reputation as a sustainable method for medical logistics. All players in the cold chain have a role to play in sustainability.

 After Brexit, are there any specific considerations that you must take into account for cold chain logistics across the continent now?

 With post-Brexit consequences still impacting supply chain shortages and labour capacity, pharmaceutical logistics providers are focusing on developing strategic solutions to mitigate the effect of ongoing difficulties. For example, Tower is seeking to mitigate the potential impact of Brexit by expanding its international hub network, with service centres opening not just in Europe, but also throughout other global regions. By optimizing the global network for localized delivery, it is possible for logistics providers to react even more quickly to customer requests.

Reports of bounced loads by carriers are causing major disruptions in the logistics industry, with Brexit as its catalyst (3). Local customs procedures require the broker to move between local and national government customers offices and then to the Ministry of Health for approval before pharmaceutical products can be released for import. Add Brexit regulations into the mix, and the risk of delay has increased massively.

To alleviate the threat of temperature excursion, pharmaceutical organizations require temperature-controlled containers, robust enough to protect products, and reliable enough to reduce the risk of wastage. Passive containers are a beneficial solution to this demand as they can provide temperature consistency and external security for the product without the need of an external source of electricity or manual checks—passive systems operate using phase change materials, utilizing water, ice, or dry ice to maintain thermal accuracy.

 Could you provide your expert opinion on possible future trends that will be influential to cold chain logistics in Europe?

 With its capital-intensive equipment, strict temperature requirements, and energy dependence, the cold chain has always been a demanding logistics segment. Today, the cold chain is grappling with additional challenges: serving a global market, driving out costs and waste, addressing capacity and resource constraints, and dealing with continually mounting regulations—all whilst handling valuable pharmaceutical cargo. It is vital that cold chain logistics service providers adapt and thrive, to futureproof themselves in an ever-complex industry.

An international market. With the amount of sensitive biopharmaceutical and biologic products expanding, coupled with the demand for advanced pharmaceuticals in middle to low-income countries, cold chains will continue to be pushed to globalize in the coming years. Pharmaceutical organizations are increasingly relying on their external suppliers to operate lean supply chains, with extended distances to ship products quickly and efficiently. Logistic providers must ensure these needs are met, offering a global network for localized deliveries—all whilst complying with each country’s regulations to maintain the strictest requirements.

Technological investment remains critical. Like all supply chains, cold chain operators must continually upgrade technology to ensure efficiency, integrity, and safety. Demand for increased visibility will drive cold chain third-party logistics to innovate and add value to services. Cold chain logistics providers must invest in the latest on-board equipment built into containers to track temperature and location, and to make data available to partners and customers in real time, to prevent or mitigate loss.

Digitalization and the Internet of Things, which are being assessed by Tower, can provide operators with the ability to work faster and better, through both automating and optimizing processes to provide the highest quality and consistency to customers. Systems are integral to the way cold chain operators work and these technologies will help to deliver new ‘SMART’ solutions to the market.

Competition continues to intensify. While the demand for cold chain logistics services is increasing, competition has also intensified. Providers are introducing new, innovative services or are upgrading existing solutions for cold chain logistics. As a result, there are more choices as well as more competition in the market.

Pharmaceutical organizations are also facing competition from generics and biosimilars (less expensive versions of biologics with expired patents). Whilst reliability is still the number one priority in cold chain services, there is an increased focus on cost-efficiency.

The total cost focus in the pharmaceutical industry, coupled with the increased competition and digital self-service means that customers have more choices when selecting solutions to meet their needs. Suppliers to the pharmaceutical sector must be proactive and continuously look to update their services to stay ahead.

The example of the last few years underlines how turbulent and fast changing the pharmaceutical supply chain can be. With demand set to increase further, this complexity isn’t going to go away. That’s why it’s vital to anchor cold chain decisions in the essential elements that won’t change.

Cold Chain Logistics Market for Pharmaceuticals Industry by Service and Geography—Forecast and Analysis 2021–2025

, Market Report (July 2021).
2. European Commission, “

 [Accessed 1 March 2022].
3. S. Clarke, “Road Freight Between Britain and EU is Down by a Third, Data Shows,” 


Vol. 34, No. 3
March 2022
Pages: 25–27

When referring to this article, please cite it as F. Thomas, “Cold Comfort for Bio/Pharma,” 

Continuous improvements in technologies and services will help cold chain operators meet future industry demand.