Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Chris Spivey

Sexy Science in Pharmaceuticals: Hot-Melt Extrusion

Traditionally, hot-melt extrusion (HME) is co-located with downstream processing and solid-dosage form manufacturing. Regulatory bodies continue to encourage quality-by-design (QbD) approaches, quality management maturity (QMM), and process analytical technology (PAT) improvements. These are all essential tools in a well-organized HME platform and work together to enhance product outcomes, but also to improve process understanding. HME, as an approach, is aptly suited to this framework.

As molecular diversity ramps up, the total number of difficult-to-formulate drugs poses severe manufacturing challenges.Creativity, innovation, and bringing in material science practices from other fields seems a fruitful approach.

“Approximately 30–40% of all marketed drugs have low solubility (BCS Class II and IV). Overall, it is estimated that up to 90% of small-molecule APIs in development face solubility challenges; as such, solubility enhancement approaches are critical for the successful advancement of therapeutics that have yet to reach the market” (1).

This episode of Sexy Science in Pharmaceuticals brings together two world-class scientists to discuss one of the top solutions for low solubility. For bioprocessing and manufacturing larger molecules, low solubility and protein aggregation also needs addressing, as does dedicated storage and handling throughout. We discuss these challenges and cite several paths around or through these issues.

As an opening introduction to this discussion, we examine the general aspects of HME supporting bioavailability enhancements for poorly soluble BCS class 2 and class 4 compounds. Examples discussed include Noxafil, an oral suspension used in adults and children to help prevent or treat fungal infections from widespread dissemination throughout the body (also used to treat a fungal infection called “thrush” caused by 

in the mouth or throat area), and Belsomra for insomnia.Both products are part of the Merck portfolio.

In this part of the discussion, a robust processing space to obliterate crystalline structures to create a single-phase homogenous solid amorphous dispersion is defined. Also, we draw up a more green sustainable future without high solvent use and disposal—HME not requiring large volumes of acetone, in contrast to spray drying dispersion processing. In HME, as the temperature rises beyond the glass transition temperature for that material the polymer becomes a liquid. The drug solubilizes into that molten phase. So, we have now a liquid phase that has dispersed drug crystals, which over time break down in the extruder, dissolve, and diffuse into that molten matrix to create a single molecularly dispersed phase. We then use X ray diffraction to look for (hopefully) the absence of crystalline peaks associated with the API. 

In another quality check to see if we’ve been successful, we use differential scanning calorimetry where we want to see a single glass temperature observed in the material, thus showing we’ve also eliminated drug rich domains.

In this part, we discuss HME biological macromolecules for slow release subcutaneously implantable vaccine delivery and injection molded microneedle patches. Aggregation in proteins and frailties of virus like particles leading to inhomogeneity needs to be addressed.

The commercial philosophy of spray dying in early R&D stages, then switching to HME for commercialization is outlined in this discussion. In general, looking at mixing and quenching.Dealing with whole bacterial spore cells extruded into polymer matrices to degrade polyurethanes (in environmentally friendly and sustainable ways), in collaboration with BASF, is also described.

1. Merck. Enhancing API Solubility During API Processing and Formulation Development. eBook, PharmTech.com Oct. 26, 2023.

Professor Jonathan Pokorski, Department of Chemical and Nano Engineering, UC San Diego Jacobs School of Engineering

Professor Pokorski’s laboratory works to bridge chemical synthesis, molecular biology, and materials science to make new materials for biomedical applications. The Pokorski lab is particularly interested in marrying protein and polymer science to generate new materials for drug delivery, imaging, and vaccination. Pokorski received his doctoral degree in organic chemistry from Northwestern University in 2007, where he designed, synthesized, and tested diverse peptidomimetic systems for use in medical diagnostics and therapeutics. Following his PhD studies, Pokorski moved to The Scripps Research Institute, where he used both chemical and genetic engineering of viral nanoparticles to synthesize novel drug delivery systems. During his postdoctoral training, Pokorski first earned an NIH Ruth Kirschstein fellowship and later secured an NIH Pathway to Independence Award.

Prior to his appointment at UC San Diego in 2018, Pokorski began his independent career as an Assistant Professor at Case Western Reserve University in the department of Macromolecular Science and Engineering. Pokorski was a finalist for the prestigious John Diekhoff graduate mentoring award at CWRU from 2013 to 2017, was named an ACS PRF new investigator, and is a Kavli fellow. Research in the Pokorski lab is funded through grants from the National Institutes of Health, National Science Foundation, and the American Chemical Society.

Dr. James DiNunzio, Senior Principal Scientist, Merck

Dr. James DiNunzio is currently a Senior Principal Scientist at Merck & Co., Inc. in Rahway, NJ where he heads the Hot-Melt Extrusion Subject Matter Expert Network Team and co-leads the Continuous Processing Technology Development Team.Since joining Merck in 2013, he has contributed to multiple programs in the disease areas of oncology, virology, and CNS (central nervous system) disorders.Prior to Merck, he served as a Senior Scientist in the Pharmaceutical & Analytical R&D group at Roche where he was responsible for the formulation design of poorly soluble compounds using enabled technologies.He has also held positions of increasing responsibility at PharmaForm and Forest Laboratories.

Dr. DiNunzio received his PhD in Pharmacy (Pharmaceutics) from The University of Texas in 2009 specializing in thermal manufacturing of amorphous dispersions.He also holds M.S. and B.S. degrees in Chemical Engineering from Columbia University and The State University of New York at Buffalo.He currently serves on the Editorial Advisory Boards of AAPS 

.He has authored over 25 research papers and book chapters in the field of hot-melt extrusion and formulation design for bioavailability enhancement.His current research interests include formulation design for bioavailability enhancement, melt extrusion process design for challenging systems, and the development of continuous manufacturing technologies.

Videos

This premiere episode of Sexy Science in Pharmaceuticals features Professor Jonathan Pokorski, UC San Diego Jacobs School of Engineering, and Dr. James DiNunzio, Senior Principal Scientist at Merck & Co., Inc. in Rahway, NJ, discussing the benefits of hot-melt extrusion.

Behind the Headlines: Winter Vaccine Recommendations; Nobel Prize Predictions; Biosecure Act; and more.

This Behind the Headlines news roundup panel discussion discusses news items such as research results from the June Lab at the University of Pennsylvania presented at the Hanson Wade 9th CAR-TCR Summit; winter vaccine recommendations, particularly for respiratory syncytial virus (RSV) and Beyfortus access and deployment; upcoming early October Nobel prize announcement predictions; digital biology analytics, quantitation, alongside point of care (POC) and distributed manufacturing. The panel also talks about the Biosecure Act and manufacturing reshoring; Federal reserve interest rate cuts of a full half a percent (1); and the general investment and financial outlook.

RSV has become a near household phrase since, and partly because of, the COVID-19 pandemic. This is because anyone wearing a face mask wasn’t exposed to the typical bioburden in their immediate environment, and hence natural immunity wasn’t built up the way it normally would be. Upwards of 90% of all children will have contracted it by age 2 (2), and during our lifetime it is expected a typical person will have suffered varying degrees of symptoms multiple times. Characteristically, these symptoms are mild and commonly include a sore throat a persistent cough, with perhaps sneezing and a runny or blocked nose. While RSV often gets better by itself, it is a serious threat to young babies, sometimes producing bronchiolitis, making it a challenge for newborns to breathe. Regarding geriatrics, those with weakened immune systems and especially anybody with heart and lung conditions, RSV can produce pneumonia, leading to hospitalization and potentially early death. This is particularly true during winter months, where virulence factors seems to peak, though like COVID-19 itself, we have seen smaller peaks during the height of summer also.

The Centers for Disease Control (CDC) recommends all babies be protected from severe RSV by one of two immunization options: A maternal RSV vaccine given to the mother during pregnancy, or an RSV antibody given to your baby. Most babies do not need both. The CDC now recommends an RSV vaccine for pregnant people to protect their babies from severe RSV disease. “Pregnant people should get a single dose of the maternal RSV vaccine (Pfizer’s Abrysvo) during weeks 32 through 36 of pregnancy. These vaccines are administered September through January in most of the United States. Protection provided by a maternal vaccine, passed from the mother to the baby, wanes over time. Because these vaccines are administered September through January, the protection passed to the baby will last for their first RSV season” (3).

On our shortlist for the 2024 Nobel Prize in Physiology or Medicine, to be announced on Monday, October 7, 2024 at the earliest, were Pieter Culllis, Tom Madden for lipid nanoparticles; Carl June, Bruce Levine, and Michel Sadeliene for CAR-T; Hans Clever and Donal Inger for Organoids; Sean Hart for laser force Cytology; and Steven Rosenberg for the development of tumor infiltrating lymphocytes.

Cox, J. Fed Slashes Interest Rates by a Half Point, An Aggressive start to its First Easing Campaign in Four Years. 

Russell, S. New Respiratory Syncytial Virus Caccine to Protect Millions Most at Risk this Winter. Aug. 22, 2024, Blog Post. National Health Service, England.

CDC. Respiratory Syncytial Virus Infection (RSV), Immunizations to Protect Infants. 

Chris Spivey, Director of Industry Relations and Strategic Partnership, MJH Life Sciences

This Behind the Headlines news roundup panel discussion discusses news items such as research results from the June Lab at the University of Pennsylvania presented at the Hanson Wade 9th CAR-TCR Summit; winter vaccine recommendations, particularly for respiratory syncytial virus (RSV) and Beyfortus access and deployment; upcoming early October Nobel prize announcement predictions; digital biology analytics, quantitation, alongside point of care (POC) and distributed manufacturing. The panel also talks about the Biosecure Act and manufacturing reshoring; Federal reserve interest rate cuts of a full half a percent (1); and the general investment and financial outlook. 

Bolstered by a pilot program launched by the Biden administration, ReciBioPharm’s chief scientific officer, Aaron Cowley, discusses ongoing progress in developing continuous manufacturing for mRNA.

Forging Ahead with Continuous Manufacturing for mRNA (BIO 2024)

The summer of 2023 was a busy time for government investment in messenger RNA (mRNA) manufacturing advances. As part of the Biden administration moonshot initiative, the Advanced Research Projects Agency for Health (ARPA-H) announced the launch of “Curing the Uncurable via RNA-Encoded Immunogene Tuning” (CUREIT) project. This effort, led by a team at Emory University in Atlanta, Ga., with up to $24 million in new funding, has the goal of developing “… generalizable mRNA platforms that can be harnessed to train the immune system to more effectively fight cancer, … other applications could extend to autoimmune disorders, transplants, and infectious diseases” (1). A month prior to the Biden administration’s announcement, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER) at FDA, allocated an award of $82 million to Massachusetts Institute of Technology (MIT) researchers to create a center for continuous mRNA manufacture (2). The main manufacturing subcontractor for this three-year pilot program is ReciBioPharm. The over-arching goal is to establish the first biologic drug using a fully continuous manufacturing integrated process, from 

Aaron Cowley, PhD, Chief Scientific Officer, ReciBioPharm. Image courtesy of ReciBioPharm.

At the BIO 2024 conference held in San Diego, Calif., on June 3–6, Pharmaceutical Technology Group’s Chris Spivey spoke with Aaron Cowley, PhD, chief scientific officer at ReciBioPharm to check in on the pilot program’s progress. Cowely stated that “being able to have eyes on the process, and the product, as it goes along the full train of manufacturing, and being able to release that data in real-time, that is the overall goal.” When addressing potential scale-up bottlenecks or other obstacles, particularly on the analytical side, Cowely went on to say, “the beauty of this grant is that we are able to take the best technologies, regardless of company source, and incorporate them, to see what’s working and what’s not work[ing] [for continuos manufacture]. After a year and a half, we already have a process development system that’s capable of going from [IVT] through [to] fill/finish, fully operational, so we’re collecting data. We have the process analytical technology (PAT) that’s actually driving the process already. We can see the kinetics of the process. We can see the impurity profile. We can take the material and send it to waste, if it's not meeting criteria, or move it ahead to the next unit operation … we’ve been using off-the-shelf PAT equipment, but not in the way it’s been traditionally deployed.”

The pilot project has placed a heavy emphasis on process modeling with the help of machine learning to repeatedly evolve the system performance and product outcomes. Cowley said they’ve hit paydirt by now being able to remove system variability and are now “able to control what others currently cannot control. It’s like manufacturing in a vacuum. So, it’s much easier to track your product, and the quality of your product.”

1. The White House. As Part of President Biden’s Unity Agenda, Biden Cancer Moonshot Announces Launch of ARPA-H’s CUREIT Project Led by Emory University to Develop New Tools to Strengthen the Immune System and Save Lives. Press Release. Aug. 23, 2023.
2, Winn, Z. MIT Researchers to Lead a New Center for Continuous mRNA Manufacturing. 

Hayley Crowe, executive vice-president and general manager Global Life Sciences at Ecolab discussed at BIO 2024 how technology innovations have enhanced downstream bioprocessing.

Discussing Downstream Bioprocessing Innovations that are Enhancing Manufacturing Efficiencies (BIO 2024)

Ecolab’s acquisition of Purolite in 2021 deepened Ecolab’s support for the bio/pharmaceutical manufacturing process. Post acquisition, Ecolab has focused on developing innovations to support large-scale biomanufacturing, a large, growing market with an estimated $5 billion global fluid separation and purification market size (1), growing at double-digits in biopharma applications, due, in large part, to burgeoning opportunities in the messenger RNA (mRNA), vaccine, and antibody therapeutic sectors. For Ecolab, this growth represents recurring revenue of nearly $0.4 billion in high-end ion exchange resins with “approximately 95% consumable revenue products for purification solutions critical to customer operations. Highly recurring business model as it is usually part of FDA drug filings in life sciences” (1). Puralite adds to this with its unique jetted agarose resin beads with tight size specifications, affinity Protein A resins generally, and its new DurA Cycle product, in partnership with Repligen. The announcement of DurA Cycle follows news of the launch of a previous resin for the purification of complex bispecific proteins and the investment in a new bioprocessing production facility based in Landenberg, Pa., which complements its UK-based facility, providing dual-continent manufacturing capabilities to address growing customer demand.

At BIO 2024 in San Diego, Calif., which was held on June 3–6, 

® Group’s Chris Spivey spoke with Hayley Crowe, executive vice-president and general manager Global Life Sciences, Ecolab. Crowe has a wealth of experience in bioprocessing, mass spectroscopy, and in life science R&D generally.

She pointed out that “the jetting technology has really changed the way we manufacture our Protein A resins. Historically, an emulsification process was used, which produces a wide range of bead sizes as a Gaussian distribution. If you say something is 50 microns, it might be 25 to 105 microns, which means a lot of post processing is needed to sieve out the fine [particles] and scale it down to the bead size you want.”

“In jetting,” Crowe explained, “you can actually dial it in…. we use acoustics [funneled through] a coke can, pushing the resins out, and are able to dial in the sizes. When we say 50 microns, its [variability] is 45 to 55 microns.”

Operational efficiencies from these resins include improved mass transfer kinetics and faster flow rates, but Crowe also pointed out that Ecolab is finding that “ [if] there are a lot of sustainability gains due to higher yields, [then] [w]e run fewer cycles, which reduces the total amount of water used in the process, along with reduced buffer usage. It is pretty incredible.” 

The way the beads are formed with jetting technology lends themselves to having a higher ligand density, which allows for higher dynamic binding capacity (DCB). “Our newest product, launched this week at BIO, is proving to deliver these higher DCBs—we’ll say up to 80—but it is very molecule- and process-dependent, and we have customers gaining greater than that, in their early testing phases.”

Rounding out the conversation Crowe talked about security of supply. “We have dual-source supply with full lines of capacity in different regions, so you can obtain product should something go wrong. During COVID, we all experienced shortage of supply … the pain of living through that made us ask, what if that happened again, and are we prepared? If another pandemic or similar occurred, we’ve made sure we’d be ready to go,” she asserted.

Meanwhile, on current customer trends Crowe averred that, “We’ve transitioned into this plethora of different molecules, which makes a big difference in terms of purification resins. It’s not a one-size-fits-all anymore. And having a tool box where you are able to test different Protein A resins to give you the best yield, or to decrease aggregation, or to offer the best operational efficiency [means] it’s really important to test the different Protein A resins at this stage, and not just stick with the same thing that always worked for the [p]ast 30 or 40 years because, guess what, molecules are different now, and they behave differently.”

Behind the Headlines: Weight Loss Drugs; Price Controls; and Free COVID Therapies

This Behind the Headlines news roundup panel discussion covers news items such as the weight loss drugs battle between Novo Nordisk and Eli Lilly, entering new territory through Lilly’s partnership with HAYA Therapeutics and long non-coding sequence mining. It was questioned whether HAYA would have turned its platform toward obesity without that market commanding so much commercial attention at present.

“The partners will identify multiple regulatory genome derived RNA-based drug targets to address these chronic conditions. Under the terms of the collaboration, HAYA will receive an upfront payment, including an equity investment, and is eligible to receive up to an aggregate $1 billion in pre-clinical, clinical and commercial milestone payments, as well as royalties on product sales. HAYA’s proprietary regulatory genome discovery platform enables the identification of tissue-, disease- and cell-specific long non-coding RNA (lncRNA) targets and the development of RNA-targeting therapies, with potentially better efficacy and less toxicity than current treatments, to reprogram disease-driving cell states … This partnership with Lilly demonstrates the significant advances we have made with our revolutionary regulatory genome RNA-guided platform and validates the potential of targeting lncRNA for chronic conditions," said Samir Ounzain, CEO, HAYA Therapeutics, in a press release (1). "We look forward to working closely with Lilly, an established leader in developing treatments for metabolic diseases, to help bring patients novel disease-modifying therapeutics that could offer greater efficacy, safety and accessibility than currently available treatments” (1). 

The panel also discussed The Centers for Disease Control’s Director Many Cohen’s decision to make free vaccines available for those who otherwise couldn’t afford them ($62 M). Starting in late September 2024 from the 

 website, each household can order up to four free at-home tests, which will be delivered through the mail. This is a popular program that has sent out more than 900 million tests since 2021, according to Dawn O’Connell, Health and Human Services’ assistant secretary for planning and response. O’Connell said the government’s Paxcess program, which is run by drugmaker Pfizer, will continue to distribute free Paxlovid through the end of the year to people who test positive for COVID-19 and who are uninsured or who are on Medicare or Medicaid (2).

An advance in mitochondrial basic biological understanding with ramifications for potential disease etiology and diagnostics, alongside drug targeting was also discussed. A recycling system in self-repairing mitochondria has been reported by imaging scientists at the hospital for sick children (SickKids). A report by 

 stated, “their research demonstrates mitochondria can recycle a localized injury, removing damaged folds called cristae that contain proteins and molecules needed for energy production. The researchers believe this mechanism could present a future target for the diagnosis and treatment of conditions characterized by mitochondrial dysfunction, including infections, fatty liver disease, aging, neurodegenerative conditions, and cancer” (3).

The panel also discussed the Biosecure Act passage and re-shoring pharma manufacturing to North America. In a survey of small, emerging biotech firms in the United States, the Biotechnology Innovation Organization (BIO) found that 65% work with China-based contract development and manufacturing organizations in some capacity. Switching to new manufacturers, or manufacturing in the US, would temporarily halt production and potentially cost more in labor (4).

HAYA Therapeutics. HAYA Therapeutics Announces Collaboration with Lilly to Discover Novel Regulatory Genome Targets for Obesity and Related Metabolic Conditions Using Proprietary RNA Platform. Press Release. Sept. 4, 2024. 

https://www.hayatx.com/news-and-publications/haya-therapeutics-announces-collaboration-with-lilly

Goodman, B. Free Covid Tests, Treatments Will Return to Help the Country Cope Over Fall and Winter, US Officials Announce. 

https://www.cnn.com/2024/08/23/health/free-covid-tests-treatments-2024/index.html

Genetic Engineering & Biotechnology News. Recycling System in Self-Repairing Mitochondria Discovered. 

https://www.genengnews.com/topics/translational-medicine/recycling-system-in-self-repairing-mitochondria-discovered/

Vedantam, K. US Manufacturing Unprepared for BIOSECURE Act’s Repercussions. 

https://www.biospace.com/policy/us-manufacturing-unprepared-for-biosecure-acts-repercussions

Alex Philippidis, Senior Business Editor, Genetic Engineering & Biotechnology News

Benjamin McLeod, Director, Cell & Gene Therapy Segment, NanoMosaic Inc.

This Behind the Headlines news roundup panel discussion covers news items such as the weight loss drugs battle between Novo Nordisk and Eli Lilly, entering new territory through Lilly’s partnership with HAYA Therapeutics and long non-coding sequence mining. There was much discussion on how the inflation reduction act and Medicare price controls may or may not pertain—given the uncertainty around the presidential election results, and subsequent policy directions. The Centers for Disease Control making cost free COVID-19 diagnostics and therapies available was also evaluated. 

Vernal Biosciences’ CEO and founder, Christian Cobaugh, discusses the outsourcing landscape for mRNA production.

A Discussion on the Outsourcing of mRNA Production (BIO  2024)

 Group’s Chris Spivey spoke with Christian Cobaugh, PhD, Vernal Biosciences’ CEO and founder, about the outsourcing landscape for messenger RNA (mRNA) production. Vernal’s simplified business model for manufacturing all stages of mRNA R&D galvanized the company into contributing comments to FDA’s 

Guidance on Platform Technology Designation Program for Drug Development

 (1), in which—once consistent with the statutory conditions required to be compliant with chemistry, manufacturing, and controls (CMC) processes—applicants can re-use certain foundational modules without having to go backwards and prove that module repeatedly. Cobaugh, along with Vernal’s senior director of commercial and technical operations, Grant Henderson, PhD, and guest contributor, Khaled Yamout, analytical sciences, quality, and manufacturing consultant at Y-Chem Consulting, shared their thoughts in an Aug. 1, 2024 blog article (2). 

Christian Cobaugh, PhD, CEO & Founder, Vernal Biosciences. Image courtesy of Vernal Biosciences.

Looking at the field of mRNA service providers Cobaugh divides the landscape into two categories. “There [are] those that just generally do GMP [good manufacturing practice] for multi different types of drug products. and then there [are] more specialty companies that were set up to make nucleic acids. In our position [in] mRNA, we have several years of trial runs on the manufacturing technology platform, performing research-grade processing before we flipped over into GMP,” he said in the BIO interview with Spivey.

While innovation on specific steps were needed, one of the areas requiring the most improvements were the analytics, Cobaugh said, noting that “there's a lot of complexity there. Part of manufacturing is controlling what you're manufacturing, and, in order to do that, you've got to have unimpeachable analytical and QC [quality control] capabilities. And so that was something that kept me up at night, [but] no longer does. The number of platforms that we've got to use for release testing is quite daunting. and we've mastered pretty much all of them.”

Among the most promising of the new higher performing analytical approaches is next-generation sequencing (NGS). Cobaugh pointed out that “NGS offers … an opportunity to go deeper and pick off multiple critical quality attributes from the same test, which, along with consolidating platforms more broadly, presents significant cost of goods savings in the long run.”

Located in Vermont, Vernal has been manufacturing mRNA and lipid nanoparticle (LNP) products for clients since 2021. The company offers custom mRNA, mRNA sequence design, GMP mRNA and LNP–mRNA manufacturing, and LNP-formulated mRNA products. Vernal takes a stage-gated approach to offer GMP mRNA and LNP production services and recently upgraded its manufacturing space, QC lab, warehouse, and additional lab and office space in a total building area of 23,000 square feet. The company is also planning a new 20,000 square-foot GMP mRNA manufacturing plant, which it expects to bring on line in the near future.

Draft Guidance for Industry, Platform Technology Designation Program for Drug Development

 (CDER, CBER, May 2024).
2. Cobaugh, C.; Hendersonm G.; Yamout, K. FDA Guidance on Platform Technology Designation Program for Drug Development. 

vernal.bio/news-insights/blog-fda-guidance-on-platform-technologies

Chris Spivey

Articles