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

Drug Digest

Emergence of advanced manufacturing technology to ensure quality of biopharmaceutical drugs combined with efforts to identify a regulatory pathway indicate that a distributed manufacturing model is within reach.

Considering the Promises of Point-of-Care Manufacturing

One of the main purposes of stability testing is to establish shelf life for these drug products. The goal of this paper is to create an Excel spreadsheet, which can be used for statistical testing of more than three stability batches for poolability.

Pooling of Batches for Stability Data Analysis

Predictive modeling facilitates the identification of coformers, cocrystal components, and complexing agents.

Predictive Modeling for Formulation Development: Coformers, Cocrystals, Complexes

Monoclonal antibody and viral vector manufacture share similarities, but vector scale up faces unique challenges.

Gleaning Scale-Up Lessons from mAbs for Viral Vectors

Using image analysis to characterize complex finished products is crucial in particle analysis.

Differentiating Particle Size and Shape Information in Drug Products with Multiple Components

Digital Transformation in the Biopharma Industry

Drug Solutions Podcast

Feliza Mirasol is the science editor for 

Novo Nordisk announced on Nov. 23, 2023 that it will invest more than DKK 16 billion (US$2.3 billion), starting in 2023, to expand its existing production site in Chartres, France. The company plans to significantly increase the capacity of the manufacturing site by adding aseptic production and finished production processes, as well as an extension of the site’s current laboratory for quality control.

With the expanded facilities, the site’s footprint will be more than doubled. The investment includes capacity for glucagon-like peptide-1 products, according to a company press release. Construction projects for the expansion have been initiated and will gradually be finalized between 2026 and 2028. More than 500 new jobs are expected to be created, and production activities are expected to run 24/7 upon completion of construction.

“This significant investment announced today confirms the importance of our French manufacturing site, one of our strategic production sites, as a cornerstone of the growth we are experiencing as a company. By maximizing the skills and infrastructure we already have on the site, we are expanding our capacity in an efficient way,” said Lone Charlotte Larsen, corporate vice-president of Novo Nordisk Production Chartres, in the press release.

“Our continued investments in our manufacturing sites across the globe demonstrate the belief we have in our current and future product portfolio and its relevance for people living with serious chronic diseases,” said Henrik Wulff, executive vice-president, Product Supply, Quality & IT, Novo Nordisk, in the release.

Articles

Novo Nordisk will invest more than DKK 16 billion (US$2.3 billion) to expand its production facilities in Chartres, France.

Novo Nordisk to Make Multi-Billion Dollar Investment in Expansion of Production Facilities in France

Chris Spivey is the editorial director of 

In sickle cell anemia mishappen and sticky hemoglobin cells cannot carry oxygen properly and frequently clump, clogging blood vessels and sometimes causing searing pain termed a vaso-occlusive crisis. It is debilitating. β-thalassemia isn’t etiologically closely related, however, similar to sickle cell disease (SCD), genetic defects are passed on from both parents, which leads to low hemoglobin production. This creates fatigue, jaundice, shortness of breath and irregular heartbeats. A fresh (Nobel prize winning) tool to redress both mutational situations was recently given Medicines and Healthcare products Regulatory Agency (MHRA) approval, in a world-first approval for complicated next-generation therapeutics (

). Clustered regularly interspaced short palindromic repeats (CRISPR) was successfully applied to both disease states, in a therapeutic called Casgevy (exagamglogene autotemcel, or exa-cel).

CRISPR is so new that this MHRA approval caused quite a stir in both the medical and pharmaceutical worlds. Even at the end of November 2023 the American society of Hematology didn’t appear to convey much about this news, nor the attendant questions and issues that must still be addressed. These include potential immunogenicity because of biology outside of the CRISPR itself, and also access alongside cost and reimbursement.

Casgevy galvanizesproduction of a form of hemoglobin normally made only in developing fetuses. “Production of this fetal hemoglobin is typically shut off soon after birth by a gene called 

, allowing fetal-hemoglobin production to resume. This provides some hemoglobin that is not misshapen and dampens the effects of the abnormal form. Vertex and CRISPR Therapeutics reported that, at nine months after treatment, 31 of 32 participants in their clinical trial had not had a single vaso occlusive crisis. Before treatment, they’d had an average of about four each year” (2).

CRISPR remains somewhat controversial for potential off-target effects. On top of this, after it makes its cut in the DNA of the 

 gene, CRISPR relies on the cell’s natural DNA repair machinery to stitch the strands back together. The step can introduce new errors. All of this is well known and becoming better understood; however, in its advisory committee briefing, Vertex stated: “There is no known or hypothesized mechanism whereby a DNA edit would revert to reduce the reactivation offetal hemoglobin (HbF) after exa-cel treatment. The long-term engraftment of edited cells also demonstrates the successful editing of long-term hematopoietic stem cell (HSCs) that are known to persist for a person’s lifetime” (3).

What is potentially equally worrisome for Casgevy are new findings from Wellcome Sanger Institute, University of York, and Boston Children’s Hospitalscientists outlining an observation that “cell competition” following gene therapy, may increase leukemia incidence. “The cause is likely not the gene therapy treatment itself, say researchers, but the therapy process, which involves gene editing outside the body and re-transplantation of stem cells back into the patient.” The authors go on to say “Instead, the process of genetically modifying these stem cells outside the body and re-transplanting them back into the patient makes blood stem cells that already have these mutations more prominent, thereby increasing their influence on the blood and immune systems.” The authors hypothesize younger patients might be an easier cohort to manage these therapies through, as their stem cells inherent have fewer mutations to “select” as triggering undesirable outcomes, and that “Continuously tracking these mutations and gaining a deeper understanding of these processes will profoundly impact the future well-being of sickle cell patients around the world.” (4)

While they are approximately 100,000 SCD patients in the United States, the disease seems related to malaria, and hence the vast majority of sufferers live in resource-poor nations. Vertex Pharmaceuticals said it had not yet established a price for the treatment in Britain and was working with health authorities “to secure reimbursement and access for eligible patients as quickly as possible. In the US, Vertex has not released a potential price for the therapy, but a report by the nonprofit Institute for Clinical and Economic Review said prices up to around $2 million would be cost-effective. By comparison, research earlier this year, showed medical expenses for current sickle cell treatments, from birth to age 65, add up to about $1.6 million for women and $1.7 million for men.” (5)

Not only cost but access to the “manufacture” of this treatment is also a barrier to widespread implementation. “In the US, there are approximately 200 specialized centers for bone marrow transplants. There are only three such centers for all of sub-Saharan Africa—in Nigeria, Tanzania, and South Africa. Making these types of CRISPR-based therapies available throughout the continent will require massive investment in clinical infrastructure. The road from now, having gene editing that is possible and implemented where most people live, it’s not that close,” said Ambroise Wonkam, a geneticist at Johns Hopkins School of Medicine and the University of Cape Town who also serves as president of the African Society of Human Genetics. “We have to put that into perspective” (6).

Casgevy was used here as synecdochic for the surging tidal wave of new modalities. The choice might well have fallen to ARCT-154, a self-amplifying messenger RNA (sa-mRNA) COVID-19 vaccine for initial vaccination and booster for adults 18 years and older, which was even more recently given approval by Japan's Ministry of Health, Labor and Welfare (MHLW). While ARCT-154 was tested on 16,000 patients compared to Casgevy in 40 patients only, and. while the cost and access is no barrier compared with Casgevy, both therapeutics herald new ways of thinking, new types of testing and validation, and new types of manufacture and end-point monitoring. Following on from the revolutionary COVID-19 vaccines, what comes next is more complicated, more difficult to price for reimbursement, and more effective in terms of cure rates. The toothpaste is out of the tube, and the industry must learn to adapt to take best advantage of what is becoming available, no matter how messy the process.

1. MHRA. MHRA Authorizes World-First Gene Therapy that Aims to Cure Sickle-Cell Disease and Transfusion-Dependent β-thalassemia. Press Release, Nov. 16, 2023
2. Ledford, H. Is CRISPR Safe? Genome Editing Gets Its First FDA Scrutiny. 

 (7986), 234–235. DOI: 10.1038/d41586-023-03317-7
3. FDA. 

Cellular, Tissue, and Gene Therapies Advisory Committee October 31, 2023 Meeting Announcement

, Oct. 31, 2023.
4. Wellcome Sanger Institute. New Research Sheds Light on Cancer Risk in Gene Therapies. 

, Nov. 16, 2023.
5. Cheng, M. The World’s First Gene Therapy for Sickle Cell Disease Has Been Approved in Britain. 

, Nov. 16, 2023.
6. Molteni, M. With CRISPR Cures on Horizon, Sickle Cell Patients Ask Hard Questions about Who Can Access Them

Chris Spivey is the editorial director for 

Exagamglogene autotemcel seen as synechdoche.

New Medicines, Markets, and Manufacture: CRISPR for Sickle Cell Disease and β-thalassemia

TAU Systems, a US-based producer of compact laser-driven plasma accelerators and light sources, announced on Nov. 21, 2023 that it has signed a lease for a state-of-the-art building in Carlsbad, Calif., in which it will establish TAU Labs. The facility will be the first of the company’s light source applications and R&D centers, which will give users easier access to the latest particle and imaging systems. The first phase of construction is expected to be complete in 2024, according to a company press release.

The company is developing compact particle accelerators and specialized X-ray sources that combine the capabilities of large accelerators with a small footprint. This design is meant to provide easy and affordable beam-time access for any company or research institute, and, by doing so, the facility democratizes accelerator access, allowing for the progress of semiconductors, space-bound electronics, battery technology, biotechnology, and nuclear energy, among other industries, according to the press release.

TAU Systems' particle and light sources comprise the electromagnetic spectrum—from ultraviolet (UV) to gamma wavelengths—and will be installed in a 22,300-ft

 building located at the Carlsbad Research Center. The lab space will house several laser-driven particle and light sources as well as broad technical expertise. Industrial users will have wide access to extreme UV and X-ray light sources as well as million electron volt electrons and other particle beams.

"Laser-driven particle accelerators are incredibly powerful tools that enable unprecedented advances in a wide range of fields, from next-generation semiconductors and batteries, and custom-designed medicines to the advancement of fundamental physics. However, getting beam time on the very few facilities available globally is stifling progress,” said Bjorn Manuel Hegelich, CEO, TAU Systems, in the press release. “TAU's application centers will democratize access to these exciting machines and expedite crucial technological breakthroughs."

"Our high-repetition-rate laser driver also makes TAU Labs an ideal location to test the resistance to space radiation of satellite electronics. It will help make space systems more robust and prolong the life of satellites," said Jerome Paye, chief operating officer, TAU Systems, in the press release.

TAU Systems plans to establish TAU Labs, a new next-generation, laser-driven plasma accelerator laboratory, in Carlsbad, Calif.

TAU Systems to Establish TAU Labs, a New Laser Plasma Accelerator Application Center

On Nov. 21, 2023, Genentech, a member of the Roche Group, announced that it has entered into a multi-year strategic research collaboration with NVIDIA, a US-based computing company. The companies plan to combine Genentech’s artificial intelligence (AI) capabilities, extensive biological and molecular datasets, and research expertise with NVIDIA’s accelerated computing capabilities and AI to speed up drug discovery and development.

The collaboration is meant to significantly enhance Genentech’s advanced AI research programs by turning the company’s generative AI models and algorithms into a next-generation AI platform, which would be designed to expedite the discovery and delivery of novel therapies. Under the agreement, the companies aim to accelerate and optimize Genentech’s proprietary machine learning algorithms and models on the NVIDIA DGX Cloud. The cloud provides a training-as-a-service platform that has been built on dedicated NVIDIA AI supercomputing and software, including NVIDIA BioNemo for generative AI applications in drug discovery.

Also under the agreement, NVIDIA will share its computing expertise with Genentech’s teams of computational scientists, under which Genentech’s models will be optimized and scaled. This process may also improve or enhance NVIDIA’s platforms.

The collaboration will also help accelerate Genentech’s “lab in a loop”, in which extensive experimental data will feed computational models to uncover patterns and make new, experimentally testable predictions. Scientists can then quickly assess these predictions in the lab, and the results are fed back into the models to improve the underlying computational model. This loop is expected to allow for the iterative development of better therapies, according to a company press release.

“By harnessing the power of AI models and algorithms with our unique data and experiments, we're unlocking scientific discoveries with incredible speed and generating insights at an unprecedented scale,” said Aviv Regev, executive vice-president and head of Genentech Research and Early Development (gRED), in the press release. “Bringing science and technology together has always been a foundation of biomedical breakthroughs at Genentech. We are thrilled to join forces with NVIDIA to further optimize our drug discovery and development to deliver treatments that transform people’s lives.”

“The greatest impact of generative AI is to revolutionize the life science and healthcare industry,” said Jensen Huang, founder and CEO of NVIDIA, in the release. “Our collaboration to create Genentech’s next-generation AI platform will dramatically accelerate the pace of drug discovery and development.”

Under this multi-year collaboration, Genentech and NVIDIA will use AI to optimize and accelerate each company’s platforms to discover and develop innovative therapeutics.

Genentech and NVIDIA Form AI Research Collaboration for Drug Discovery and Development

 Excipient World is a US event focused exclusively on excipients. Participants will join professionals from pharmaceutical, biologics, veterinary medicine, combination device, and consumer healthcare product companies for three days of learning and collaboration. The educational program will feature over thirty subject matter experts discussing issues related to the pharmaceutical manufacturing process.

Events

Excipient World is a US event focused exclusively on excipients.

Excipient World Conference & Expo: May 13-15, 2024

PTE discusses mRNA advances with Guillaume Roelandts, Head of Products and Marketing, Quantoom Biosciences, at the 11th International mRNA Health Conference.

Tackling Production Challenges through Greater Access to mRNA Technologies

, discusses messenger RNA (mRNA) advances with Guillaume Roelandts, Head of Products and Marketing, Quantoom Biosciences, at the 11th International mRNA Health Conference in Berlin, Germany. Quantoom Biosciences is a team of scientists, engineers, and clinicians committed to solving some of the biggest DNA and RNA production challenges facing vaccines and therapeutics by delivering greater access and autonomy to mRNA technology. This discussion introduces the company’s background and explores its future direction. It also covers Quantoom’s expertise in process development for mRNA synthesis and purification, and the process of validating a GMP cleanroom machine with regulators.

Quantoom Biosciences is part of Univercells, a global life sciences group with the mission of making biologics accessible to all. Launched early in the pandemic in June 2021, Quantoom entered into a strategic collaboration with eTheRNA to build an advanced, small footprint technology platform for the production of affordable RNA-based therapies. The platform can be used within existing facilities or rapidly deployed to areas of urgent need.

Milestones in Quantoom’s development include a grant from the Bill and Melinda Gates foundation and the acquisition of SynHelix, which developed a technology that, with the use of bacteria, is an alternative to DNA amplification. SynHelix, later renamed Quantoom Research France, is focusing on integrating a “new generation DNA bioreactor” that could provide great benefits in productivity and cost reduction, both for R&D and production needs. The World Health Organization (WHO) interest in Quantoom, through their tech transfer program, has led to mRNA production facilities and BioPharm technologies being placed in several emerging countries.

Chris Spivey, editorial director for Pharmaceutical Technology, discusses messenger RNA (mRNA) advances with Guillaume Roelandts, Head of Products and Marketing, Quantoom Biosciences, at the 11th International mRNA Health Conference in Berlin, Germany.

MilliporeSigma, the US and Canada Life Science business of Merck KGaA, Darmstadt, Germany, announced on Nov. 21, 2023 that it has opened the second phase of its new €29 million (US$43 million) Biologics Testing Center in Shanghai, China, which opened in 2022. The expansion includes an added 1500 m2 of lab space, which are the first biosafety laboratories for the company in the Chinese market. This expansion enables the company to serve local clients, according to a company press release.

The new lab space offers testing services for cell line characterization and lot release from pre-clinical development to commercialization. MilliporeSigma can now offer biosafety testing services for monoclonal antibodies, other recombinant proteins, and cell and gene therapies to the local market.

The first phase of the new testing center allowed the company to provide testing services for viral clearance studies, while the second phase adds capabilities for cell line characterization to help ensure the safety, purity, and identity of cell banks. The testing center also offers current good manufacturing practice-compliant lot release testing for unprocessed and purified bulk harvest for meeting the requirements for biologics that are entering preclinical and clinical studies and for licensed biologics.

“The opening of the facility deepens our partnership with our Chinese clients who are at the forefront of shaping modern medicine,” said Dirk Lange, head of Life Science Services, Life Science business sector of Merck KGaA, Darmstadt, Germany, in the press release. “The Biologics Testing Center in Shanghai now provides critical local services backed by our more than 75 years of global experience in the testing market.”

MilliporeSigma has expanded its biosafety testing laboratories in Shanghai, China, with the completion of new lab space at its new €29 million (US$43 million) Biologics Testing Center.

MilliporeSigma Expands Biologics Testing Center in China

 spoke with LIGHTHOUSE Instruments regarding the company's new products for robust headspace data generation. Learn more about:

How LIGHTHOUSE Instruments supports customers to generate science-based product and process data.

In which application areas laser-based headspace analysis is the preferred method over traditional methods used in the pharmaceutical industry.

An introduction to new headspace platforms for efficient robust data generation.

Video interview with LIGHTHOUSE Instruments

LIGHTHOUSE Instruments Launches New Products for Robust Headspace Data Generation at the CPHI in Barcelona

Videos

LIGHTHOUSE Instruments introduces new technology for robust headspace data generation and areas of application.

Earlier this fall the Centers for Disease Control and Prevention (CDC) gave an alert to likely shortages of drugs to treat infants with lower respiratory tract disease associated with respiratory syncytial virus (RSV). RSV itself is becoming more of a scary household name, sometimes being linked to COVID-19 and seasonal influenza in what has sometimes been dubbed a “tripledemic”.

“A big part of the flu increase in November,” said Scott Roberts MD, a Yale medicine infectious diseases specialist, in a news release on the tripledemic, “was our lack of immunity from having not been exposed to the virus for several seasons due to masking and other precautions, many of which have fallen to the wayside” (1).

COVID-19 primarily spreads through air transmission, whereas RSV spreads via contaminated surfaces. “Flu, on other hand, is somewhere in the middle, and can spread from respiratory droplets, aerosols, and through contaminated surfaces,” added Roberts in the news release (1).

It’s important, therefore, to practice what the CDC calls “respiratory etiquette,” specified Thomas Murray, MD, PhD, a Yale Medicine pediatric infectious diseases physician, in the news release (1). “That means coughing into a tissue and disposing of it immediately in the garbage.”

However, on July 17, 2023 FDA approved a new drug, Beyfortus (nirsevimab), to prevent RSV in babies and toddlers. John Farley, MD, MPH, director of the Office of Infectious Diseases in FDA’s Center for Drug Evaluation and Research, said in an FDA press release about the approval, “[This] approval addresses the great need for products to help reduce the impact of RSV disease on children, families and the health care system” (2).

Beyfortus has been approved for use in all infants up to the age of eight months old, which is different to the previous treatment, palivizumab, that was only approved for those infants considered to be at the highest risk of contracting RSV. Furthermore, Beyfortus is only required to be administered once, whereas palivizumab needs to be given once a month during RSV season (3).

This new therapy, along with other approvals and breakthrough therapy designations for alternate drugs, such as Arexvy from GSK (4),or RSVpreF from Pfizer (5), have given the public health system the feeling it was superlatively winterized. Unfortunately, supply has significantly lagged demand for Beyfortus, to the point that senate democrats are demanding answers about this shortage—lawmakers, led by Sen. Tammy Duckworth, have requested more detailed information from AstraZeneca and Sanofi about the supply issues and why there was unpreparedness for demand (3).

It’s easy to blame pharmaceutical companies, but the situation is much more nuanced than simply stating manufactured supply was too low. While that’s true, and while that’s partly because COVID-19 created an expectation for more vaccine hesitancy among parents than actually occurred, costs and payments played into readily available supplies, meaning payment and incentive systems also needs extra scrutiny in this case.

About half of pediatric vaccines in the US are paid for by the federal government through the vaccines for children program. Its main goal is to remove cost as a barrier so that eligibility is narrowed down to “Medicaid-eligible, under or uninsured, or American Indian or Alaska Native” children (6).

The remainder of vaccines are paid by private insurance; however, payment by insurance companies is made after the pediatrician has administered the dose. As a result of this method of payment, there is uncertainty as to whether the insurance company will cover the full cost of the vaccine, which is risky for the pediatrician (6).

Because most pediatric vaccines are inexpensive, the payment approach by insurers isn’t typically a dominant factor in terms of overall supply and access. However, Beyfortus is much more expensive, costing nearly $500 a dose, which is not likely to be manageable for a medium-sized practice to be able to vaccinate their patient population (6).

While it is debatable if RSV is part of a tripledemic, it is part of a perfect storm when it comes to supply and access of treatment. With demand for treatment difficult to estimate and a novel vaccine with a price tag misaligned with the vast majority of pediatric vaccine precedents; under-ordering from pediatric practices was inevitable andfurther fed into the lower demand models being used by manufacturers for production. Lastly, a lack of natural immunity from being “closeted” due to the pandemic has had a knock-on effect, inflating more cases than would otherwise have naturally occurred. The supply issues with RSV drugs have demonstrated a good case example for industry to learn from going forward.

1. MacMillan, C. ‘Tripledemic:’ What Happens When Flu, RSV, and COVID-19 Cases Collide? 

Yale Medicine Nov. 22, 2022 (Updated: Jan. 12, 2023

).
2. FDA. FDA Approves New Drug to Prevent RSV in Babies and Toddlers. 

, Press Release, July 17, 2023.
3. Weixel, N. Senate Democrats demand answers from manufacturers over RSV drug shortage. 

, Nov 17, 2023.
4. Playter, G. FDA Approves First RSV Vaccine. 

May 10, 2023.
5. Pharmaceutical Technology Editors. Pfizer Receives FDA Breakthrough Therapy Designation for Respiratory Syncytial Virus Vaccine Candidate. 

, March 2, 2022.
6. Landman, K. The RSV Shot Shortage isn’t Just a Supply Problem. 

Looking at the role that RSV and pediatric medical practices play in drug shortages.

Why We Were Not Properly Winterized for RSV Season

Editor of Pharmaceutical Technology Europe

Northway Group—a group of 17 enterprises within the fields of medicine, healthcare, biotechnical formation, and investment operations—has announced its latest project, in a Nov. 16, 2023 press release, that will see a vast biotech city be built in Vilnius, Lithuania.

The biotechnology hub, BIO CITY, will be the largest in Europe and home to an impressive six large biotechnological complexes—four of which will be state-of-the-art good manufacturing practice (GMP) plants and two of which will be scientific research centers. The whole site will be in an area equivalent to the size of 10 football fields and is expected to cost a total of €7 billion ($7.6 billion) over the course of a decade.

“We envision BIO CITY as a frontrunner in the European biotechnology, by uniquely integrating various biotech segments into a single, synergistic ecosystem,” said Prof. Vladas Algirdas Bumelis, founder and CEO of Northway Biotech and Celltechna, in the press release. “This multifunctional complex will catalyse interdisciplinary collaborations, the quick realisation of ideas and technological advancements. Our unique model, which brings together diverse biotechnology fields in one location, is set to revolutionise the European biotech landscape.”

A gene therapy center will be the first facility to open in the BIO CITY in 2024. Currently under construction by Northway Group’s subsidiary, Celltechna, the center will specialize in gene therapy research and GMP manufacturing and will span 8000 m2. Additionally, the center is expected to create more than 100 high-value jobs for the region.

“Our state-of-the-art [gene therapy] facility will be instrumental in both research and production, offering new treatments for previously incurable diseases. This will not only augment our CDMO [Contract Development and Manufacturing Organisation] capabilities, but also position us for global competition and collaborations,” added Bumelis.

“A science-based economy, supported by bright minds and intelligent entrepreneurs, is the foundation for Lithuania’s long-term economic prosperity. In the past, our growth was constrained by a lack of fossil resources, but today, we are boldly moving forward, relying on modern technologies,” said the president of the Republic of Lithuania, Gitanas Nausėda, in the press release. “The new biotechnology hub embodies the direction of Lithuania’s innovative economy. It also promises new inventions that will enable people with serious illnesses to become full members of society, thereby reducing exclusion.”

The largest biotech hub is set to be built in Lithuania by Northway Group.