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

Felicity Thomas

Swiss headquartered critical materials supplier, Biosynth, has announced its acquisition of a British manufacturer of synthetic peptides, Pepceuticals, in a Sep. 25, 2023 press release, bolstering its position within the peptide market.

Through this acquisition, Biosynth will gain Pepceuticals’ multi-kilogram good manufacturing practice (GMP) facilities and fill/finish capabilities. With these added offerings, Biosynth will be able to support all phases of the peptide product life cycle and hence assist their customers from clinical trials all the way through to commercialization.

“We are very excited for Pepceuticals to be joining Biosynth,” said Urs Spitz, CEO and president of Biosynth, in the press release. “The Pepceuticals team has great expertise in optimizing the production of peptides and working at GMP and larger scales, making it a natural fit for Biosynth as we round out our peptide offering.”

“The acquisition of Pepceuticals into the Biosynth family strengthens our position in the peptide field,” added Ehab Alramahy, senior vice-president, head of Peptide Division, in the press release. “As we've built the peptide division, our goal has always been to offer a seamless, comprehensive service to our customers. The acquisition represents an important step which allows us to extend our support to clinical trials and commercial supply.”

“Joining the Biosynth Group marks the start of an exciting chapter for our team,” stated Kamal Badiani, managing director of Pepceuticals, in the press release. “We look forward to working together, combining our expertise, and enhancing our offering to our customers. We are excited to join Biosynth and provide leading peptide manufacturing services.”

This latest addition to Biosynth’s peptide division reflects the company’s rapid reaction to an increasing market demand for peptide therapeutics across research, development, and commercial supply. In 2022, the company acquired vivitide and Pepscan, strengthening its peptide manufacturing services and catalog products, and then, in 2023, it added further peptide expertise through the acquisition of Cambridge Research Biochemicals.

Articles

Biosynth has further strengthened its peptide division with the acquisition of  Pepceuticals.

Biosynth Strengthens Position in Peptide Field through Pepceuticals Acquisition

Developing the ideal dosage form for pharmaceutical products has long been a priority for drug companies. A poor dosage form decision can lead to costly commercial errors and potentially low medication adherence by patients—an aspect that can be particularly important in the rising numbers of chronically ill patients. Not only should consideration be made to the therapeutic characteristics and potential manufacturability of the finished drug product; but also, whether the dosage form will ultimately be patient-centric and, hence, ensure optimum adherence of a treatment regimen.

“Drug dosage forms have evolved in recent years due to several factors, including the growing demand for custom drug delivery solutions, the increasing complexity of new therapeutic entities (NTEs) entering the development pipeline, and the aggressive competition in the pharmaceutical market,” reveals Ishani Maharaj, Application Development Specialist, Pharma Ingredients, Univar Solutions. “While oral solid dose (OSD) forms remain the preferred choice due to convenience and cost-effectiveness, applying innovative delivery approaches is essential to meet the unique needs of the target patient population.”

“The pharmaceutical sector is propelled by radical innovations, accelerating the pace of the therapeutic process achieving the transformative shift from life science to healthcare. From personalized medicine, advanced nanotechnology to sustainable formulations, 3D printing, combination therapy, and smart drug delivery, the landscape is undergoing a profound transformation,” asserts Jnanadeva Bhat, vice president, head—Formulation R&D at ACG-Worldwide. “The growing attention to rare diseases has catalyzed a revolution in the field of drug development, reflecting the industry’s responsiveness to unmet medical needs while setting the stage for pioneering advancements.”

In concurrence, Filipe Gaspar, vice president of Technology Intensification at Hovione highlights the growing proportion of orphan drugs—and the need for leaner and accelerated drug development paths along with it—as an important trend. “The change from large volume to small volume drugs, namely by the increased prevalence of rare/orphan drugs and precision medicine, is driving substantial changes in the pharma industry and driving innovation in many areas such as drug discovery, clinical design, supply chain management, development, and regulatory paths,” he says. “A very lean, API-sparing, and accelerated CMC [chemistry, manufacturing, and controls] development approach becomes critical to prevent being the bottleneck in drug approval.”

Therefore, Gaspar continues, continuous manufacturing is being more widely adopted as it provides a more streamlined approach, avoids the need for scale-up, and facilitates debottlenecking pharmaceutical development. However, he warns that despite the advantages brought about by transitioning from batch to continuous manufacturing, there are also challenges, such as a lack of access to continuous manufacturing technology for smaller pharma companies and biotech companies.

“Most small pharma and biotech [companies] do not have [continuous manufacturing technology] as a captive technology and the limited CDMO [contract manufacturing and development organization] network is still developing the expertise and expanding their capacity,” Gaspar adds. “By relying on batch processes, these innovators may incur on additional development costs and, most importantly, delay their drugs to market, sometimes many months, which can be critical to success of many drugs.”

Focusing on manufacturing, Lisa Caralli, senior director, Scientific Advisory, Catalent, raised the matter of spray drying for biologics as an efficient and scalable alternative to the traditional lyophilization technique. “The use of more modern techniques such as spray drying has been investigated as a way to formulate lipid nanoparticles with biologic payloads into a dry powder for oral delivery, as well as optimizing particle attributes for inhalation. While additional research is still needed to validate these approaches, they represent true innovation with a potential high impact for patients,” she says.

For Arnaud Verhaeghe, marketing director Pharma Oral Dosage at Roquette, the most influential trend over recent years has been the expanded focus on patient-centricity. “This [trend] has manifested itself in producers putting user needs first—devising innovative ways to help patients start and adhere to treatments,” he explains. “The popularization of dosage forms like functional gummies and jellies, orodispersible powders and tablets, orally administered vaccines, and more is the best example of this attitudinal shift in action.”

Additionally, Verhaeghe notes that due to the fact the success of such oral dosage forms, as mentioned earlier, hinges on a pleasant taste and texture, there have been good strides forward in the field of taste-masking as well.

“Continuous improvement in elevating traditional dosage forms to increase therapeutic efficacy, improve patient compliance, and enable more patient-centric options are becoming more practical with advanced technologies, innovative medical device designs, and new functional excipients,” Maharaj specifies. “From a formulator’s perspective, tablets and capsules are tunable and can achieve different release profiles, including immediate or modified release, fixed-dose combinations (FDCs), orally disintegrating tablets (ODTs), and other types of release profiles. This [flexibility] creates a lot of opportunity to develop oral dosage forms that are adapted for certain patient groups. ODTs have gained significant traction as they eliminate the need to swallow a pill and offer ease-of-use for the elderly and pediatric population.”

Commenting further on FDCs, Uwe Hanenberg, head of Product Development in Oral Solid Dose, Recipharm, iterates that this dosage form option has gained substantial popularity in recent times. “These formulations combine multiple APIs into a single dosage form, often utilizing advanced modified-release technologies,” he says. “By controlling the release of each API into the bloodstream, these combinations minimize side effects and extend the therapeutic effect in patients—reducing the number of daily doses required, which minimizes patient burden and enhances patient compliance with therapy.”

“The growing interest in oral medication has highlighted the importance of both personalized medication and FDC therapies as influential trends in the development of drug dosage forms,” confirms Manali Dalvi, lead white paper and articles at ACG-Worldwide. “[Additionally], FDC has provided the option to develop potential proprietary drugs, which offer greater savings compared to the NCE or their generic version. This strategic approach not only provides manufacturers with reinforced intellectual property support but also empowers them to prolong their market exclusivity.”

Repurposing existing active ingredients can also be leveraged to improve patient-centricity is enabled by FDA’s 505(b)(2) pathway, remarks Nick DiFranco, MEM, Global Market Manager, Oral Drug Delivery, Lubrizol. “The 505(b)(2) pathway accelerates drug product development by allowing companies to leverage the existing safety/toxicity data of a drug when developing improved formulations or changing dosage forms. This might include developing extended-release formulations that reduce the pill burden on a patient or creating smaller-sized tablets or granules that can be dosed directly for either a child or geriatric patient with difficulty swallowing,” he says. “Alternatively, it could be creating a long-acting injectable or utilizing altnernative excipients with reduced side effects. Particularly for poorly soluble APIs, the desire for patented formulations and advancements in delivery technologies, create opportunities for differentiated and optimized dosage forms.”

The movement of the industry toward a more patient-centric model has been key in driving innovation in dosage form design, stresses Caralli. “However, as a formulator, this puts a spotlight on bioavailability enhancing formulations, which often need to do more than improving aqueous solubility,” she states.

Overcoming solubility and bioavailability issues

“Approximately 60% of APIs under development, and more than 40% of those in reformulation, are poorly water soluble—meaning the pipeline is full of insoluble drug products,” emphasizes DiFranco. “If we want to continue bringing small molecules to market, we need new tools for formulation because traditional excipients aren’t always going to yield viable products. This is especially true in the oncology field, where the pipeline comprises many challenging classes of APIs, such as proteolysis-targeting chimeras (PROTACs).”

Ramesh Subramanian, chief commercial officer, Aragen Life Sciences, points to the investments being made into the development of novel drug delivery systems, such as liposomes, nanoparticles, and microspheres. “These systems help overcome the challenges of drug solubility, bioavailability, and targeted delivery, improving therapeutic outcomes,” he adds.

In Gaspar’s experience, amorphous solid dispersions (ASDs) are becoming the predominant platform to overcome poor bioavailability, leveraged by spray drying. “In turn, this has led to significant advances on the formulation of amorphous materials, namely in material and analytical sciences, the development of novel (sometimes enabling) excipients, and the need for appropriately formulated dosage forms,” he says.

“More lipid-based delivery solutions, solubility, and permeability increasing excipients are coming onto the market to enable formulators to improve the solubility profile of those lipophilic, hard-to-formulate APIs within an oral dosage form,” notes Maharaj. “This [market dynamic] alleviates numerous challenges with formulating Class II/IV drugs, resulting in increased therapeutic efficacy, but improved manufacturing efficiency, shortened development timelines, and reduced overall costs.”

Another option to help overcome bioavailability is nasal administration, Maharaj continues. “Nasal dosage forms such as nasal sprays, powders, suspensions, and gels have been on the market for years. However, this dosage form type can offer an ideal route and improved bioavailability for some drug types, particularly for central nervous system disorders. This offers immense potential for nasal dosage forms with innovation focused on delivery devices,” she states. “Excipient and process selection to produce the desired API particle size is critical for optimal deposition and absorption via the nasal cavity route.”

“The rise of biopharmaceuticals and biosimilars has led to innovations in formulation development,” specifies Subramanian. “These complex molecules require specialized formulations to maintain stability and ensure consistent therapeutic performance.”

Growth within the biologics sector is expected to continue at an impressive rate, which, according to Hanenberg has also spurred further advancements in OSD technology. “Although biologics have traditionally been administered parenterally due to the sensitive nature of their active ingredients, recent development work on some of these molecules, such as insulin, has allowed them to be formulated for oral delivery,” he says. “This shift enhances patient centricity by offering the convenience of OSD while introducing new formulation challenges for large-molecule drugs. As a result, we can expect more developers to turn their attention to such advancements in drug delivery.”

The notable shift in industry’s focus toward the development of protein and RNA therapies has been apparent over recent years, Caralli adds. “The investigation of nanoparticle delivery exploded after the COVID-19 pandemic: one such method involves using nanoparticles to deliver mRNA vaccines via the gastrointestinal tract, as researched by Robert Langer and his team at the Massachusetts Institute of Technology (1). These vaccines would not be constrained by the cold-chain restrictions of the injectable versions, allowing for the easier distribution of drugs to developing countries and rural areas,” she remarks.

Orally administered and other non-parenteral vaccines are great examples of ways in which patient compliance can be improved by pharma companies, stresses Verhaeghe. “Not only do these dosage forms remove the meticulous cold chain required for the use of liquid biologics—making them less susceptible to supply chain disruption—but they have been shown to be more attractive to patients, not least because of the elimination of off-putting needles.”

It is estimated that one in six people will be over the age of 60 years by 2030 (2), meaning that there will be a greater proportion of patients who may have difficulties with dexterity and swallowing, asserts Hanenberg. “OSD developers will have to reformulate their drugs to cater to these evolving patient needs, designing their tablets to be smaller and easier to swallow and packaging to be more accessible. They must also consider the needs of pediatric patients, catering their administration to counter bitter-tasting medicines with more palatable flavors and mouthfeel,” he says.

Assessment of whether or not a dosage form is appealing and satisfactory to the target patient population impacts drug adherence, which is just as important as ensuring the right excipients for the active are selected to facilitate optimal drug delivery and product stability, Maharaj confirms. “Patient-centricity is a trend that will continue to be a key driver in developing novel drug dosage forms in the future,” she emphasizes.

“The industry has witnessed a remarkable evolution in drug dosage forms, driven by a convergence of scientific breakthroughs, patient-centric approaches, and regulatory incentives,” concludes Bhat. “As we stand at the intersection of innovation and healthcare, it has become exciting to delve into the trends that are shaping the future of drug delivery.”

1. Kim, H.; Kirtane, A.R.; Kim, N.Y.; et al. Gastrointestinal Delivery of an mRNA Vaccine Using Immunostimulatory Polymeric Nanoparticles. 


Vol. 47, No. 10
October 2023
Pages: 12–16

When referring to this article, please cite it as Thomas, F. Driving Dosage Form Developments. 

Dosage forms are being shaped by numerous factors, with patient-centricity continuing to be an important driver of decisions in development.

Driving Dosage Form Developments

Demand and sales of Wegovy (semaglutide)—a weekly injectable weight loss therapy—have fuelled a surge in the market value of its Danish manufacturer, Novo Nordisk. The strength of this growth has seen the pharma giant become the most valuable company in Europe (1).

Soaring demand for the drug, celebrity endorsements, and a controlled launch onto the market in the United Kingdom have bumped up Novo Nordisk’s market share value. It has been reported that the company now has a market value worth £340 billion (€393 billion), which actually exceeds the worth of the entire Danish economy—£323 billion (€373 billion) (1).

And, the success is not limited to Europe, as the United States have also seen a 300% surge in drug prescriptions for obesity drugs, such as Wegovy and Ozempic, since early 2020 (2). However, global stocks of semaglutide (the active ingredient found within Wegovy) are running low, leading Novo Nordisk to restrict supplies of Wegovy while it tries to ramp up manufacturing efforts.

Added to the manufacturing challenges are some potentially disruptive regulatory concerns around the drug product. As reported by Bloomberg in late September 2023, the European Medicines Agency’s safety committee discussed potential safety issues linked to weight-loss and diabetes drugs, such as Wegovy, during anaesthesia (3). The probe from the European regulator’s safety committee follows guidance issued by the American Society of Anesthesiologists recommending that patients skip a dose of semaglutide containing drugs prior to surgery (4). Furthermore, Reuters has reported on an increasing scrutiny of regulators, both in Europe and the US, regarding the potential link between the obesity and diabetes drugs and suicidal thoughts in patients (5).

Despite these possible issues, which are being monitored by regulatory authorities and the drug manufacturers themselves, the market for weight-loss treatments, such as Wegovy, has the potential to reach a value of more than US$100 billion (€95 billion) by 2030 (6), which can only help further boost the pharma industry in the long run.

1. Kollewe, J. Wegovy Maker Novo Nordisk Becomes Europe’s Most Valuable Firm. 

, 5 Sep. 2023.
2. Constantino, A.K. Ozempic, Wegovy Drug Prescriptions Hit 9 Million, Surge 300% in Under Three Years. 

, 27 Sep. 2023.
3. Kreshe, N.; Muller, M. EU Probes Anesthesia Complication for New Weight-Loss Drugs. 

, 27 Sep. 2023.
4. American Society of Anesthesiologists. Patients Taking Popular Medications for Diabetes and Weight Loss Should Stop Before Elective Surgery, ASA Suggests. 

, News Release, 29 June 2023.
5. Respaut, R.; Terhune, C. Wegovy, Other Weight-Loss Drugs Scrutinized Over Reports of Suicidal Thoughts. 

Weigh to Go: Assessing the Wider Implications of a Slimmer Society

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

When referring to this article, please cite it as Thomas, F. Losing Weight, Gaining Value. 

Novo Nordisk’s obesity treatment has been so successful the company is now top of the ‘value pile’ in Europe.

Losing Weight, Gaining Value

In this exclusive Drug Digest video interview, Felicity Thomas, European/Senior Editor, 

Group, interviews experts about small-molecule APIs, excipients, and formulation advances. During the video session, a panel of experts—Bikash Chatterjee, Tara Dougal, Sean Daughtry, and Ramesh Subramanian—deliberate on the biggest trends impacting the industry, highlighting issues such as API supply and shortages, uptake in digital innovations, formulation advances to deal with potent compounds, and key sessions to visit while at CPHI. Additionally, David Tisi, director of Technical Operations, Senopsys, discusses novel approaches and solutions to pediatric formulations and taste-masking, while an expert Tara Fitzpatrick from C

 Pharma highlights the fundamental stages of gaining a certificate of suitability for APIs and the various trends shaping API and complex compound manufacturing.

 Director of Technical Operations, Senopsys

, President and Chief Science Officer at PharmaTech Associates

 Content Director—Pharma, Informa Markets

, Director of Technical Operations Analytical, CMSC Strategic Product Lead—AMKD, Vertex Pharmaceuticals


, Chief Commercial Officer, Aragen Life Sciences

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.

Small Molecule APIs, Excipients, and Formulation Advances: Pt 2

Solid Dosage Drug Development and Manufacturing

Videos

In this episode of Drug Digest, Pharmaceutical Technology’s European/Senior Editor, Felicity Thomas, discusses small-molecule APIs, excipients, and formulation advances, including a discussion about novel approaches and solutions to pediatric formulations and taste-masking, a rundown of the fundamental stages of gaining a certificate of suitability for APIs, and a deliberation on the biggest trends impacting the industry and key sessions to visit while at CPHI, with several key industry experts. 

Drug Digest: A Big Impact: Trends Shaping Small-Molecule APIs, Excipients, and Formulations

The European Commission (EC) has approved a novel oral fixed-dose combination treatment—INAQOVI (oral decitabine and cedazuridine)—for use in adult patients with newly diagnosed acute myeloid leukemia (AML) who cannot have standard induction chemotherapy.

According to a Sep. 19, 2023 press release, Otsuka Pharmaceutical Europe and Astex Pharmaceuticals’ INAQOVI’s commission approval was based on the results from a Phase III clinical trial (ASCERTAIN), which investigated the pharmacokinetic exposure equivalence of the therapy against intravenous (IV) decitabine in AML patients. The Phase III trial, which included 89 AML patients, successfully met its primary endpoint, demonstrating that the orally administered therapy achieved equivalent pharmacokinetic exposure to that achieved with IV decitabine and both with similar pharmacodynamic activity. The safety of the oral treatment option was considered to be consistent with that of the IV decitabine.

INAQOVI is an oral treatment combining decitabine (35 mg)—an approved hypomethylating agent (HMA)—with cedazuridine (100 mg)—an inhibitor of cytidine deaminase. The therapy works through inhibiting cytidine deaminase in the gut and liver, which allows for systemic exposure to decitabine through oral administration that is comparable to that achieved intravenously over a five-day period. With the EC’s approval, INAQOVI is the first oral therapy that incorporates a hypomethylating agent (decitabine) licensed within the European Economic Area for the treatment of AML patients.

Currently, AML patients are either administered IV chemotherapy infusions in a hospital setting, or administered hypomethylating agents parenterally when chemotherapy is not applicable. An oral option for the treatment of AML can help to improve quality of life for this patient population.

Furthermore, the European Medicines Agency agreed to a Paediatric Investigation Plan for the oral fixed-dose combination in June 2022, which has the potential to lead to clinical trials for the use of this therapy in children with AML.

Otsuka Pharmaceutical Europe and Astex Pharmaceuticals have announced the approval of INAQOVI by the European Commission.

EC Approves Fixed-Dose Oral Combination Treatment for AML 

Korean contract development and manufacturing organization (CDMO), Samsung Biologics, has announced, in a Sep. 18, 2023 press release, a new agreement for the large-scale manufacturing of an antibody cancer drug substance with global biopharma company Bristol Myers Squibb.

This new agreement between the two companies adds to their long-standing strategic relationship, originally formed in 

. According to the terms of this latest arrangement, Samsung Biologics will be responsible for the drug substance manufacturing of a Bristol Myers Squibb antibody cancer drug at its biomanufacturing facility, Plant 4, located in Songdo, South Korea.

“Our relationship with Bristol Myers Squibb spans over a decade, and we are proud and excited to help bring important medicines to patients around the world,” said John Rim, president and CEO of Samsung Biologics, in the press release. “This collaboration with Bristol Myers Squibb underscores our commitment to expediting the delivery and ensuring the continuous supply of client pipelines, enabled by our commitment to manufacturing quality, innovation, and capacity.”

, voluntarily disclosed by Samsung Biologics, this new deal is contracted run until the end of December 2030—subject to change depending on contract terms—and is worth a little under $242 million.

This expanded agreement with Bristol Myers Squibb is another boost to Samsung Biologics’ relationship with Big Pharma. In 

, the CDMO also announced a collaboration with Pfizer, focusing on long-term biosimilars manufacturing. Under the terms of this agreement, Samsung Biologics is using its Plant 4 facility to provide Pfizer with additional large-scale manufacturing capacity for a multi-product biosimilars portfolio covering oncology, inflammation, and immunology.

Furthermore, earlier in the year (March 2023), Samsung Biologics revealed that its plans to 

 at the Songdo site (Plant 5) in response to increased market demand. Operations at this plant are expected to start in 2025.

Samsung Biologics and Bristol Myers Squibb have further expanded their strategic manufacturing agreement to include the large-scale manufacture of an antibody cancer drug substance. 