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 

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.”

Articles

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.

Chris Spivey is the editorial director of 

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.

Lithuania Set to Become Home to Largest Biotech City

Specialist integrated contract development and manufacturing organization (CDMO), Hovione, has acquired ExtremoChem, which is a start-up company with a portfolio of rare sugars, expanding its technology platforms.

According to a Nov. 16, 2023 press release, the acquisition gives Hovione access to ExtremoChem’s portfolio of rare sugars. These high-performance functional materials are synthetic analogues of the natural molecules found in extremophiles–organisms that can survive in uninhabitable environments—and have shown the potential to stabilize biopharmaceuticals during production, purification, formulation, and transportation.

“Proteins and other biopharmaceuticals account for a significant share of our customers’ pipelines,” said Dr. Jean-Luc Herbeaux, CEO, Hovione, in the press release. “The acquisition of ExtremoChem’s synthetic sugars combined with Hovione's particle engineering capabilities provides our customers with a unique set of tools to optimize formulations that address stability issues encountered during the life cycle of biopharmaceuticals.”

“I am delighted that ExtremoChem has been acquired by Hovione,” added Filipe Aguiar, managing director, ExtremoChem, in the press release. “Hovione has a long history of developing and industrializing innovative technologies for the pharma industry. This acquisition will help ensure that the science we developed at ExtremoChem will have a wider and faster market adoption.”

This latest news from Hovione further bolsters the company’s position in seeking to expand its technology platforms, which it reports is needed to meet customer demand for integrated and differentiated development and manufacturing services. The acquisition of ExtremoChem adds to new partnerships forged by Hovione, such as that with 

 for the advancement of a dry powder inhaler platform and with 

 to expand the use of the Epidel platform beyond ophthalmic applications.

Hovione has acquired start-up company, ExtremoChem, expanding its technology platforms.

Hovione Expands Technology Platforms with ExtremoChem Acquisition

PharmTech Europe spoke with Concetto Andrea Rizza, Marketing and Communications manager, ICE Pharma at CPhI Barcelona 2023.

Centering Sustainability and Environmental Impact in the Supply Chain

spoke with Concetto Andrea Rizza, Marketing and Communications manager, ICE Pharma, on the show floor at CPhI Barcelona 2023. Founded more than 70 years ago, ICE Pharma has a network of manufacturing facilities and subsidiaries in North and South America, Europe, Asia, and Oceania. They are a key supplier to the pharmaceutical industry for active pharmaceutical ingredients (APIs) including Ursodeoxycholic acid (UDCA) and Inosine Pranobex. They also supply excipients, cell culture media for diagnostics, GMP intermediates and research chemicals. One of their key differentiators is their commitment to sustainable and environmentally friendly practices, extending beyond into workforce recruitment and partner development activities. They recently published a 

, and their booth at CPhI attracted a lot of attention for embodying their green approach, which is evidenced in this video discussion.

For several years, Ice Pharma have tracked their greenhouse emissions and have taken steps to reduce their impact, including the installation of highly efficient modern technologies, continuous improvement initiatives, and material investments. While they aim to drive product innovation, to develop new drugs, and to address unmet medical needs in biliary acid research and innovation, they simultaneously seek to become less reliant on animal by-products, and to reduce chemicals and energy resources in production.

ICE Pharma has made a commitment of at least 50% of their R&D investments to initiatives that drive product continuity and sustainability each year, including alternative ingredients and processes with a lower environmental impact. To do this, they must engage a minimum of two customers per research initiative by addressing product sustainability, and introduce one new molecule as a lead candidate for pre-clinical studies every two years. Further, they seek to ensure that suppliers constituting 80% of their spend on bile and other materials are covered by a Responsible Supply Chain Management program, by 2027. The CPhI booth is a living embodiment of these goals as it is constructed from post-consumer recycled materials and will be stored and re-deployed at future conferences, saving these materials from the typical landfill fate.

Chris Spivey, editorial director for Pharmaceutical Technology and Biopharm International, spoke with Concetto Andrea Rizza, Marketing and Communications manager, ICE Pharma, on sustainability and ICE’s green approach at CPhI Barcelona 2023.

The United Kingdom’s industry body, the Association of the British Pharmaceutical Industry (ABPI), has reacted positively to the Autumn Statement from the government’s Chancellor, Jeremy Hunt.

In his Autumn Statement, Hunt outlined the government’s plans to foster growth within the UK, including “dynamic and innovative” investment into the life sciences. The plans encompass, among other things, investments of more than £750 million ($936 million) to go towards UK R&D, £20 million ($25 million) for a new cross-disciplinary proof-of-concept research funding scheme, and £520 million ($649 million) to strengthen manufacturing resilience for potential future health emergencies.

Responding to the Autumn Statement, Richard Torbett, the chief executive of the ABPI, said in a Nov. 22, 2023 press release, “The Chancellor has recognized the high potential of UK life sciences to deliver the jobs and growth the country needs. This package of support will help boost our sector's investment in UK-based research and manufacturing.

“The £520million funding boost for manufacturing is a major step forward in delivering on our shared ambitions for long-term growth. Also welcome is the plan for a new merged R&D tax credit scheme and the move to make permanent the full expensing capital allowances model. Together, these steps will help give confidence to companies looking to make larger, long-term investments into the UK.

“Set alongside commitments in the new Voluntary Scheme agreement to improve the ecosystem for innovative medicines, as well as progress to address challenges in industry clinical trials, the UK is getting back on track to realise the Prime Minister's vision of being a life sciences superpower.”

UK industry body, ABPI, has responded positively to the recent Autumn Statement.

Industry Responds to the UK’s Autumn Statement

The Shape of Things to Come: Advances and Improvements in Excipients

In this exclusive Drug Digest video interview, Felicity Thomas, Europe/senior editor, 

Group, interviews experts innovations in oral and topical drug delivery. During the video, Ashley Rezak and Nick DiFranco from Lubrizol Life Science Health look at the overarching oral and topical drug delivery trends and how these are impacting excipient innovation in particular. Mucoadhesion and solubility/bioavailability enhancement are particularly focused upon during the chat, with Ashley and Nick wrapping up the conversation about hindrances to the excipient sector and ways that recent developments, such as CDER’s pilot review program, are helping industry to overcome these difficulties.

Nick DiFranco, MEM, Global Market Segment Manager for Oral Drug Delivery at Lubrizol Life Science Health

Nick DiFranco, MEM, is the Global Market Segment Manager for Oral Drug Delivery at Lubrizol Life Science Health. In his role, Nick coordinates a multi-disciplinary team offering excipients and services for controlled release and solubility enhancement in oral solids and liquids, including Carbopol and Apinovex polymers. Prior to this role, Nick held positions as an Applications Scientist and Market Manager at Lubrizol supporting long-acting drug delivery and CDMO services. Nick holds a BS in Biomedical Engineering (Biomaterials focus) and a Master of Engineering and Management degree from Case Western Reserve University.

Ashley Rezak, Global Market Manager—Topical Drug Delivery for the Pharmaceutical Excipients division at Lubrizol Life Science Health

Ashley Rezak currently serves as the Global Market Manager—Topical Drug Delivery for the Pharmaceutical Excipients division of Lubrizol Life Science Health. She obtained her BSE in Biomedical Engineering, with a minor in Polymer Engineering, from Case Western Reserve University. Ashley joined Lubrizol in 2018 and has held several roles with the company since then. She is currently responsible for marketing, business development, and strategy efforts pertaining to topical pharmaceutical ingredients.

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.

Solid Dosage Drug Development and Manufacturing

 APIs, Excipients, and Formulation Advances

In this episode of Drug Digest, Pharmaceutical Technology’s European/Senior Editor, Felicity Thomas, chats about the biggest trends impacting oral and topical drug delivery and how these trends are impacting the excipient sector with Nick DiFranco and Ashley Rezak from Lubrizol Life Science Health.

Drug Digest: The Shape of Things to Come: Advances and Improvements in Excipients

PharmTech Europe discusses technology that enables the “democratization” of mRNA manufacturing with Scott Ripley, Cytiva.

Democratizing GMP Manufacturing for the New Therapeutic Pipeline

At the 11th International mRNA Health Conference in Berlin, Germany, held Oct. 29– Nov. 2, 2023, conversations on the show floor Illustrated the exuberance that a Nobel Prize confers on messenger RNA (mRNA) technology, while highlighting the molecular diversity challenges and opportunities new therapies create when entering the manufacturing process.

Many mRNA therapies and other types of genetic medicines in clinical development are designed to be delivered with the help of lipid nanoparticles. One such platform is Cytiva’s Precision Nanosystems NanoAssemblr microfluidic-based nanoparticle manufacturing platform, which enables the development of genetic medicines with potentially increased stability, efficacy, yield, and quality of non-viral genetic medicines, according to Scott Ripley, general manager, Nucleic Acid Therapeutics and Precision Nanosystems, Cytiva, in a discussion with 

® at the conference. Ripley was enthusiastic about this platform’s ability to “democratize” the good manufacturing practice (GMP) manufacturing aspects for advanced therapies, while managing to cope with the increased molecular diversity of the molecules being handled.

“For example,” Ripley says, “the mRNA platform is unique in that, on one end of the spectrum, it is vaccinating the planet, on the other end, it’s personalized cancer vaccines.”

All these must fit into the new GMP manufacturing ecosystem. The fact that the poster sessions in Berlin were plentiful and quite well attended gave attendees a window into what new approaches and angles are being tried and offered a glimpse as to what is in store for the future of medicines.

PharmTech Europe discusses technology that enables the “democratization” of mRNA manufacturing with Scott Ripley, general manager, Nucleic Acid Therapeutics and Precision Nanosystems, Cytiva, at the 11th International mRNA Health Conference in Berlin, Germany.

In part two of an interview with Thomas Langenickel, he Langenickel highlights the challenges in developing mRNA th

mRNA Advances Allow Drug Development Focus on Rare Diseases (Part Two)

 at the leading scientific conference for the field, the 11th International mRNA Health Conference in Berlin, Germany, held Oct. 29– Nov. 2, 2023, with Thomas Langenickel, MD, chief medical officer at Ethris, a Germany-based biotechnology company specializing in next-generation RNA therapeutics and vaccines. In the second part of this interview Langenickel describes challenges with current pulmonary mRNA approaches.

The scientific and technical challenges lay in effectively managing stability through ambient temperature ranges, end-use stability and equal access throughout the supply chain, and the biological deployment conditions affecting ultimate biodistribution. Ethris has interim results on a technique to store lyophilized lipid nanoparticles (LNPs) at ambient temperatures successfully for up to six months. Mechanical stress (sheer forces) during manufacturing as well as shipping to and handling within the clinic (such as drawing drug product into the syringe) can create aggregation of LNPs or leakage of mRNA from the LNP. This can lead to increased immunogenicity, difficulties in nebulizing from clogging, and even batch failures during manufacturing itself.

Currently available vaccines injected into musculature show up in the brain, liver, spleen, and all major perfused organs, instead of more narrowly targeting, for example, lung tissue types. The Ethris manufacturing platform does not require high pressure liquid chromatography, which reduces costs but also some of the sheer forces mentioned earlier.

Langenickle has more than 15 years of experience in clinical development and translational medicine in cardiovascular and respiratory disease areas. He previously held the position of executive director and head of Respiratory Profiling at Novartis and served as medical director at Bristol-Myers Squibb.

In part two of an interview with Thomas Langenickel, MD, chief medical officer at Ethris, Langenickel highlights the challenges in developing mRNA therapeutics for pulmonary diseases.