Behind the Headlines Episode 27

Ask the Expert

Small Molecules, APIs, and Excipients—Trends, Challenges, and Opportunities

Drug Digest September 2025

Artificial intelligence, machine learning, and novel instruments are helping drug developers.

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

J.P. Morgan Report Lists Biologics, Obesity, China

Top Trends Reshaping Pharma R&D

Rentschler Biopharma DCAT video

Benedikt von Braunmühl (CEO) and Federico Pollano (vice president of business development) at Rentschler Biopharma explain what sets their CDMO apart. Viewers will learn about:

What exceptional CDMO expertise means: 25% of all FDA approved biopharmaceuticals in 2023 were supported by the company

Rentschler Biopharma’s US offerings, as well as commercial and development expertise

How the company is leveraging its expertise in the field of gene therapy

Videos

Explore how Rentschler Biopharma duels biopharmaceutical innovation, spanning from pioneering biological products to cutting-edge cell and gene therapies

Rentschler Biopharma: A 50-year Legacy of Exceptional CDMO Expertise

Beyond Expectations as a CDMO

to highlight the importance of working with Alcami. Learn more about: 

How Alcami stays ahead of the curve and makes the smart investments in capacity and technology to meet market demand and address sector challenges.

Understand Alcami's position to support the future of pharma and biotech, ready with innovative solutions and strategic partnerships that streamline and optimize the path to patients for clients’ therapeutics. 

Whether clients tap Alcami for one service or seek the benefit of a seamless end-to-end solution, the company’s Lab Services, Drug Product Manufacturing, and Pharma Storage and Services are fully integrated and optimized.

Bill Humphries (CEO, Alcami) dives into an overview of Alcami's capabilities and how they value their client's innovations. 

Alcami: Beyond Expectations

Feliza Mirasol is the science editor for 

SK pharmteco, a contract development manufacturing organization (CDMO), has entered into a manufacturing and supply pact with Ferring Pharmaceuticals under which the CDMO will scale up manufacturing capacity for the drug substance of Adstiladrin (nadofaragene firadenovec-vncg), Ferring’s gene therapy for treating a form of bladder cancer. The companies will scale up capacity to commercial levels to ensure long-term future supply, according to company press release. 

Once technology transfer in complete, SK pharmteco, will be qualified as another source for the manufacture, testing, and release of the therapy, dependent on regulatory approval by FDA. FDA approved Adstiladrin in December 2022 (1) for treating adult patients with high-risk bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma 

 (CIS). The therapy is applicable for patients with or without papillary tumors.

“Ferring takes its responsibilities to patients with high-risk BCG-unresponsive NMIBC very seriously—especially when pioneering in the emerging field of gene therapy commercial manufacturing,” said Bipin Dalmia, global head, Uro-Oncology Franchise, Ferring Pharmaceuticals, in the April 18, 2024 press release. “Following our January announcement (2) of full availability of Adstiladrin across the US [United States] and expansion of our clinical trials program, this agreement with SK pharmteco comes alongside major investments in our own manufacturing capabilities to assure the breadth of our long-term supply base. Stable and sustainable supply is a vital part of our mission to fill this unmet clinical need for the patients we serve.”

In addition to this contract manufacturing agreement, Ferring Pharmaceuticals indicated in the press release that it is well underway with expanding dedicated capacity for the therapy at its facilities in Finland and in the US, where the company has a campus in Parsippany, NJ. The company expects to have updates on these capacity expansion projects later in 2024.

The increased prevalence of bladder cancer across geographies drives the need to scale up supply of strategically important bladder cancer treatments. The companies stated in the press release that, “The World Bladder Cancer Patient Coalition has reported that bladder cancer became the ninth most common cancer in the world (a rise from tenth) according to new data published in February 2024 (IARC GLOBOCAN 2022) [3].”

“SK pharmteco is proud to partner with Ferring Pharmaceuticals as a manufacturer of the breakthrough gene therapy Adstiladrin,” said Joerg Ahlgrimm, chief executive officer, SK pharmteco, in the release. “Our integrated approach, incorporating customizable clinical and commercial GMP [good manufacturing practice] manufacturing solutions with comprehensive in-process testing, quality control, and lot release programs, provides unparalleled support to our partners throughout their product lifecycle and is in perfect alignment with our mission of expediting the delivery of potentially life-saving therapies to patients across the globe.”

1. FDA. FDA Approves First Gene Therapy for the Treatment of High-Risk, Non-Muscle-Invasive Bladder Cancer. Press Release, Dec. 16, 2022.
2. Ferring Pharmaceuticals. Ferring announces full availability of ADSTILADRIN (nadofaragene firadenovec-vncg) in the US. Press Release, Jan. 16, 2023.
3. World Bladder Cancer Patient Coalition GLOBOCAN. GLOBOCAN 2022: Bladder Cancer 9th Most Common Worldwide. Press Release, Feb. 14, 2024.

Articles

SK pharmteco, a CDMO, will manufacture, test, and release Adstiladrin (nadofaragene firadenovec-vncg), a gene therapy from Ferring Pharmaceuticals for treating bladder cancer.

SK pharmteco to Ensure Supply of Ferring Pharmaceuticals Gene Therapy

Hand shaking which print screen on wooden cube block in front of human icon for business deal and agreement concept | Image Credit: © Dilok – © Dilok - stock.adobe.com

N4 Pharma, a pre-clinical stage specialist pharmaceutical company, has formed a research collaboration agreement with SRI, a global R&D company, to increase intracellular delivery to specific target cells. The collaboration will combine N4’s Nuvec, a silica nanoparticle delivery system created to carry nucleotides to be developed as cancer therapies and vaccines, with SRI’s FOX Three Molecular Guidance System (MGS). The companies intend to co-market the combined technology and work to develop and follow new business opportunities collaboratively.

SRI’s MGS is a system that uses propriety technology to enable the delivery of macromolecular payloads first to target cells, and then to subcellular locations within those cells. It was designed to overcome cellular barriers that were stopping intracellular delivery of large-molecule biotherapeutics. SRI has successfully tested the MGS technology on more than a dozen macromolecular payloads, including functional enzymes, nucleic acids (such as small interfering RNA [siRNA], antisense oligonucleotides, and DNA), antibodies, nanoparticles, and liposomes. It has delivered these payloads to targeted, intracellular molecular-target locations that were previously considered unreachable.

Nuvec’s irregular surface structure allows the nanoparticle to trap and protect siRNA, RNA, and DNA in their delivery to the cell membrane. When it is inside the cell, it releases the genetic material into the cellular machinery, allowing for the chosen pathway response (protein transcription, protein silencing, or other immune response). When combined with MGS, there is potential to facilitate targeted and effective treatments in precision healthcare.

In an N4 press release, Kathlynn Brown, president of SRI’s Biosciences division, said, “We’re excited to work with N4 Pharma to advance nucleic acid therapies and expand the number of applications of their Nuvec nanoparticle technology using the FOX Three Platform. The key properties of Nuvec, including preventing enzymatic breakdown of nucleotides and large surface area allowing multiple copy number of cargo, together with the targeting provided by MGS, may significantly enhance the use of nucleotide therapies. This strategic partnership marks an exciting journey towards expanding treatment possibilities and transforming the landscape of biomedicine” (1).

We are delighted to be working with SRI and to have entered into this collaboration agreement. Combining our technologies successfully will lead to working with major pharma companies in the fields of oncology and vaccines with the exciting potential to develop novel products,” said Nigel Theobald, chief executive office of N4 Pharma. “SRI collaborates with a broad range of strategic partners from small and virtual biotechnology companies to top 10 pharmaceutical companies and other leading industry partners, which will give us unparalleled access to potential commercial partners on the back of any successful combined technology resulting from our research. This marks an exciting new chapter for N4 Pharma, and I look forward to providing further updates as the research work progresses, as well as on our other work streams such as oral applications of Nuvec and the development of ECP105 for an orphan indication with Nanogenics” (1).

N4 Pharma. N4 Pharma Announces Collaboration with SRI to Target and Treat Cells in the Human Body that Have Been Previously Unreachable. Press Release. Apr. 25, 2024.

The collaboration will combine N4’s nanoparticle delivery system with SRI’s molecular guidance system.

N4 Pharma and SRI to Collaborate on Intracellular Delivery to Specific Target Cells

Scott Billman is vice president Global Engineering, Real Estate, and Facilities, at Solventum.

Medical Ampoule Production Line at Modern Modern Pharmaceutical Factory. Glass Ampoules are being Filled. Medication Manufacturing Process. | Image Credit: ©IM Imagery - stock.adobe.com

Through the systematic incorporation of innovative equipment, the pharmaceutical industry can push the limits of efficiency, agility, and quality, giving patients faster and more cost-effective access to groundbreaking therapies. Several key, cutting-edge features and technologies are leading the way for the next evolution of pharmaceutical manufacturing, facilitating benefits like increased flexibility, more efficient quality assessment, and more seamless management of therapies across the production line.

Flexibility and smaller batch sizes through single-use technology

Traditionally, the equipment and facilities used in pharmaceutical manufacturing have been purpose-built, meaning they were engineered for specific products or modalities. While this allowed facilities to consistently produce a specific therapy or dosage form, purpose-built equipment lacks flexibility and cannot adapt quickly to new production needs. In contrast, today's pharma industry must navigate supply chain fluctuations while generating therapies that are increasingly complex and personalized. To adapt to these market trends, manufacturers are increasingly moving toward flexible, cost-effective single-use systems (SUS) that can enable the production of multiple therapies within one facility, maximize production efficiency for smaller batches, and maintain high product quality and safety standards.

As opposed to reusable stainless-steel or partially disposable systems that must be manually cleaned and sterilized between batches, the equipment in SUS is meant to be utilized once before disposal (1). At a high level, SUS improve throughput by increasing the speed at which a line can be switched over to accommodate the production of a different batch or product. As far as environmental impact, SUS can reduce the need for chemicals, water, and energy needed to sanitize equipment regularly (2). Moreover, work continues to improve sustainable behaviors across the manufacturing lifecycle, such as recycling single-use waste (3).

Facilities that use single-use technology, such as the 2023 International Society of Pharmaceutical Engineering (ISPE) overall Facility of the Year Awards (FOYA) winner, have streamlined production thanks to the reduced risk of contamination (4). Manufacturers that utilize single-use equipment are positioned to expand the number of modalities and therapies that can be produced in a singular facility in response to market demands and therapy approval.

Increased product integrity and flexibility with closed systems

Closed-system designs are another advancement that facilitates flexibility while potentially improving product integrity. 

 are built and operated to keep a product from being exposed to the room environment during manufacture (5). This technology is exciting because of its ability to help ensure product integrity, reduce contamination risk, and improve facility agility. As additional benefits, closed systems tend to have fewer steps and operational interference, streamlining processes and reducing process time. They can also improve worker safety through the reduced need for human intervention in processes. The future of pharmaceutical manufacturing will likely continue to build on the benefits seen by closed systems.

Faster access through continuous manufacturing

Traditional pharmaceutical manufacturing is often bogged down by operational challenges that limit the capabilities of facilities and slow production speed, preventing patients from accessing the therapies they need. Continuous manufacturing can help overcome this problem.

 takes processes that have been previously developed or licensed as step-by-step batch operations and adapts them into a continuous flow (6). In a continuous manufacturing flow, steps where the manufacturing process must be held for sampling and testing can be removed. Furthermore, because operations can be sustained for extended periods, continuous manufacturing can decrease cycle times, increasing the amount of product manufactured using the same equipment. This could drive down operating costs while sustaining product quality, ultimately speeding up access to therapies.

While continuous manufacturing has begun to be implemented more extensively, adoption varies across modalities (7). Implementation of continuous manufacturing for small molecules, for example, has the potential to move faster because of the well-characterized and defined nature of the processes. In comparison, large molecules pose a challenge because of their more complex manufacturing processes.

To facilitate widespread adoption, there are some factors that must be overcome across modalities (8). When changing a step-by-step process into a continuous flow, manufacturers must find ways to control and/or verify critical process parameters are being met while the new process runs. To implement continuous manufacturing on existing, licensed products, extensive comparability testing must be performed, in addition to completing necessary filing and approvals. The time and cost associated with this can be a daunting hurdle. This is especially true for new therapies, where the necessary equipment, technologies, and process understanding required for creating a continuous flow must be built from scratch. As a result, the implementation of continuous manufacturing is still in development for many commercial processes and facilities.

Quality with less waste through process analytical technology

Assessing the quality and safety of a therapy throughout its production is another area ripe for technological advancement, particularly process analytical technology (PAT). PAT includes at-line or in-line technologies that sample, test, and analyze products to ensure quality benchmarks are being met. PAT can provide timely measurements of quality and performance to ensure final quality while eliminating the need to pause the process, sample the product, and send the samples for analysis. Not only does PAT potentially save manufacturers time, but it can also reduce waste, a valuable development for personalized therapies that must be produced in small batch sizes. After encouragement 

 in the early 2000s (9), PAT is now widely viewed as an important and necessary shift for pharmaceutical manufacturing that goes hand-in-hand with other innovations, such as continuous manufacturing.

The implementation of PAT provides vast amounts of real-time data on the manufacturing process, enabling optimization and defect detection. When real-time data are available, manufacturers readily see if a process is deviating from expected performance parameters and take corrective action if needed. In the long term, PAT provides data that can help build operational knowledge that allows for continuous improvement in the manufacturing process.

Much like continuous flow processing, PAT is widely known but its degree of implementation differs between modalities. While some core technologies exist, PAT is generally more widespread in small-molecule oral solid dose manufacturing. In comparison, the implementation of PAT in manufacturing large molecules or more complex therapies—such as biologics and cell and gene therapies (10)—is in an earlier stage. There are several reasons for disparities in implementation, but the complexity of different manufacturing processes adds a distinct layer of difficulty. Additionally, it is challenging for many manufacturers to find or develop PAT sensors or devices that are robust enough to operate commercially. This challenge is particularly acute when considering that lab-based processes and equipment must be adapted outside lab-based settings for manufacturing use. Despite these challenges, ongoing innovation has made it possible for some facilities, including several ISPE FOYA category finalists and winners in recent years, to implement PAT, indicating that the momentum for this technology is growing (11,12).

Innovation across the industry through digitization and digital twinning

Implementation of the technologies discussed thus far has been facilitated by the increasingly common use of fully digital validation, paperless manufacturing operations, and automation. Across the industry, the digitization of information, records, and processes continues to serve as the foundation for innovation.

Looking into the future, technological innovations like the implementation of 

 will be valuable in providing predictive insights into the manufacturing process for more complex or unique therapies (13). A digital twin is a digital, virtual simulation or model of an actual facility, combining data, machine learning, and AI. Importantly, digital twins are often connected to real-world sensors and thus built and trained on real-world data. Manufacturers can use a digital twin to model or simulate manufacturing processes to predict outcomes. A digital twin can also provide predictive analytics to find areas of the manufacturing process that could be high-risk, pose a problem, or are critical to success. Digital twins are already used to plan and evaluate facility designs, simulate risky scenarios, and train staff. Despite the challenge of building a robust and accurate digital twin, their value and ability to empower manufacturers to make data-driven decisions and avoid future problems makes them an exciting innovation in digitization.

Into the next evolution of pharmaceutical manufacturing

Continued progress across many therapeutic areas is thrilling in a field that often moves slowly and cautiously. However, the technology and processes used to shepherd advanced therapeutics through development to commercialization must also evolve. Luckily, innovators have risen to the challenge, bringing hope for accessible, quality therapies of the future.

Samaras, J.J.; Micheletti, M.; and Ding, W. Transformation of Biopharmaceutical Manufacturing Through Single-Use Technologies: Current State, Remaining Challenges, and Future Development. 

Pietrzykowski, M.; Flanagan, W.; Pizzi, V.; Brown, A.; Sinclair, A.; and Monge, M. An Environmental Life Cycle Assessment Comparison of Single-Use and Conventional Process Technology for the Production of Monoclonal Antibodies. 

Ottinger, M.; Wenk, I.; Pereira, J.C.; John, G.; and Junne, S. Single-Use Technology in the Biopharmaceutical Industry and Sustainability: A Contradiction? 

2022 October. DOI: 10.1002/cite.202200105

ISPE. 2023 Category Winner for Pharma 4.0. 

Estape, D.; Walker, A.; Orichowskyj, S.T.; Vega, H.; and Pratt, D.J. Proof of Closure: Life Cycle of Closed Systems. 

Lee, S. L.; O’Connor, T.F.; Yang, X.; Cruz, C.N.; Chatterjee, S.; Madurawe, R.D.; Moore, C.M.V.; Yu, L.X; Woodcock, J. Modernizing Pharmaceutical Manufacturing: From Batch to Continuous Production. 

Burcham, C.L.; Florence, A.J.; Johnson, M.D. Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing. 

National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Board on Chemical Sciences and Technology. Continuous Manufacturing for the Modernization of Pharmaceutical Production: Proceedings of a Workshop. Washington (DC): National Academies Press (US). Continuous Manufacturing for the Modernization of Pharmaceutical Production: Proceedings of a Workshop. 2019 Jan. 30. Available from: 

https://www.ncbi.nlm.nih.gov/books/NBK540224/

Guidance for Industry, PAT–A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance

Wang, B.; Bowles-Welch, A.C.; Yeago, C.; Roy, K. Process Analytical Technologies in Cell Therapy Manufacturing: State-of-the-Art and Future Directions. 

Kim, E.J.; Kim, J.H.; Kim, M.; Jeong, S.H; and Choi, D.H. Process Analytical Tools for Monitoring Pharmaceutical Unit Operations: A Control Strategy for Continous Process Verification. 

ISPE. 2024 ISPE Facility of the Year Submission Finalists. 

https://ispe.org/facility-year-awards/submission-finalists

Chen, Y.; Yang, O.; Sampat, C.; Bhalode, P.; Ramachandran, R.; Ierapetritou, M. Digital Twins in Pharmaceutical and Biopharmaceutical Manufacturing: A Literature Review. 

As breakthrough therapeutics in the pharma pipeline approach commercialization, pharmaceutical manufacturing facilities must evolve to meet demand.

Facilities of the Future: Meeting the Demands of Breakthrough Therapeutics

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

Vial and injection syringe with DNA chromosome. Health care research, gene editing, molecular biology science, cell genetic analysis, medical DNA genetic engineering technology science background. 3D | Image Credit: ©Corona Borealis - stock.adobe.com

Sudden demand for large-scale manufacturing of messenger RNA (mRNA) drug substances during the COVID-19 pandemic has few parallels in the history of pharmaceuticals. Some might posit penicillin production during World War II as an analog, or perhaps early insulin availability. Pandemics and epidemics such as smallpox, typhus, cholera, influenza, HIV/AIDS, or the bubonic plague, all relied more on infection control for resolution than on manufacturing capacity. New therapeutic uses for mRNA are now ramping up good manufacturing practice (GMP) demand, especially for clinical trial supply. Moderna collaborated with CARsgen Therapeutics to combine an mRNA therapeutic cancer vaccine with a solid tumor chimeric antigen receptor (CAR)-T cell therapy, aiming to treat multiple cancers (1). Pfizer partnered with Beam therapeutics to co-develop mRNA and base editing approaches (2), while BioNTech and DualityBio have a partnership to develop differentiated antibody-drug conjugates, for solid tumors (3). In terms of upstream manufacturing for novel mRNA drug products, this technical complexity forms a tidal wave of question marks.

A prominent paper (4) examined reducing complexity by evaluating what common process could be standardized through extrapolations of clinical trial complexity, based on four published papers Phase I-II dose ranging studies. While not the amounts of product required during the COVID-19 pandemic, clinical trial doses quickly mounted up in terms of both volume and also manufacturing challenges related to techniques pursued, but also formulation delivery requirements. The authors state, “from the four studies, the average mRNA usage was 5500 μg and for the 75 trials in 2021, 412 500 μg of RNA would need to be formulated, purified, sterile filtered, and fill-finished. At concentrations of 100 to 200 μg of mRNA per mL, this would amount to 2063 to 4125 mL of drug product” (4). As an interesting foray into possible future manufacturing, the authors went on to contrast traditional mRNA with a self-amplifying method. Often, this is cited as potentially a 100 to 1 decrease in required finished product due to higher potency performances, but this study chose a picturesque perspective, saying, “assuming the entire population consists of 7.7 billion people, and each person receives two doses, a total of 15.4 billion doses or 4.5 million L of the vaccine is required. In perspective, 4.5 million L would fill two Olympic-sized swimming pools (2500 m3), whereas saRNA [self-amplifying RNA] vaccines, which we assume are 100-fold more potent, would only require 0.02 Olympic-sized swimming pools. Assuming that production costs, which account for materials, RNA, and LNP [lipid nanoparticles] production, scale linearly, vaccinating the entire population with Pfizer/BioNTech’s mRNA vaccine would cost approximately 150 billion USD. In contrast, with saRNA, it would only cost approximately 1.5 billion USD” (4).

Commercial-scale mRNA is produced through chemical, recombinant, or enzyme-based methods. For chains under 100 nucleotides, the standard chemical technique “utilizes phosphoramidite chemistry and solid-phase support promoting chain elongation from the 3′ end to the 5′ end” (2). It is amenable to automation, as is recombinant production through host cells such as 

), which has some cost advantages as it can utilize legacy protein manufacturing lines, already in GMP compliance. Enzymatic processes are newer to arrive and have tradeoffs still being worked through. A study conducted by the Duke Human Vaccine Institute explored creating standardized robust manufacturing processing steps, saying they confronted the lack of established quality standards by, in part, surveying vendor operations “through questionnaire and/or audit relating to the vendors’ quality systems and operations as they pertained to manufacturing and/or testing of the materials” (5). The study adopted the Weismann–Karikó method of production, the upstream process requiring three enzymatic steps of plasmid linearization, mRNA transcription, and DNA template digestion. In the starting out phase, fundamentals the authors emphasized were that “for optimal 

 transcription yields, it is critical to start with high quality template DNA. Some key quality attributes that are required before use include the presence of only a single band of linearized DNA, a supercoiled ratio of at least 70%, and a sequencing-verified correct poly(A) tail length” (5). They also noted that “endotoxin control was the primary raw material risk due to its variability in raw material lots and the difficulty of its removal in subsequent downstream purification steps … reaction agitation, temperature, incubation time, and reactant concentrations were also carefully examined for each reaction step in order to yield a robust upstream platform process across multiple mRNA constructs” (5).

Chris Spivey is director, Industry Relations and Strategic Partnerships

A tidal wave of questions floats the need for more upstream automation.

The Making of mRNA

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Report on the Performance of Drugs and Biologics Firms in Conducting Postmarketing Requirements (PMRs) and Postmarketing Commitments (PMCs) for Fiscal Year (FY) 2022.

 The agency reported that applicants successfully completed or released most of the PMRs/PMCs for the year reported on. Few PMRs/PMCs are delayed, with the majority moving along according to schedule.

As stated by the FDA, a PMR is “a study or clinical trial that an applicant is required by state or regulation to conduct postapproval” (1). A PMC is “a study or clinical trial that an applicant agrees in writing to conduct postapproval, but that is not required by statue or regulation.” PMRs and PMCs can be instituted as a condition of an approval or post approval of a drug. There are various reasons that the agencycan require application holders to conduct postmarketing studies and clinical trials, such as: to assess a known serious risk, assess signals of that risk, or identify a serious risk related to the use of a drug product; to study new drugs for pediatric patients, if these drugs are not properly labeled for children; to verify and describe the effect or clinical benefit of drugs that have been approved with accelerated approval provisions; or for a drug which human efficacy trials are not ethical or feasible, and therefore was approved on animal efficacy data.

The FDA requires applicants of approved drugs and licensed biological products to submit annual reports on the status of each clinical safety, clinical pharmacology, clinical efficacy, nonclinical toxicology study, or clinical trial that the applicants have committed to conducting or were required by the agency to conduct. They are required to report to the FDA on the requirements and commitments made for new drug applications (NDAs) and abbreviated new drug applications (aNDAs).

This report combines data from both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) and provides information on PMRs/PMCs as of September 30, 2022. As of the date of reporting, there were 386 unique applicants with open PMRs/PMCs under 798 unique NDAs and biologics license applicants (BLAs). There were 277 unique NDA applicants (and 591 associated applications) and 109 unique BLA applicants (and 207 associated applications) with open PMRs/PMCs. Applicants must submit an annual status report (ASR) on the progress of each open PMR/PMC within 60 days of the US approval of the original application or an alternate reporting date that was granted by FDA. There were 746 NDAs and BLAs with an ASR due in 2022 (547 NDAs and 199 BLAs). Of the 547 NDA ASRs due, 83% were received on time, 10% were received late, and 7% were expected but not received. Of the 199 BLA ASRs due, 82% were received on time, 14% were received late, and 4% were expected but not received.

Report on the Performance of Drugs and Biologics Firms in Conducting Postmarketing Requirements and Commitments Fiscal Year 2022

https://www.federalregister.gov/documents/2024/04/23/2024-08649/report-on-the-performance-of-drug-and-biologics-firms-in-conducting-postmarketing-requirements-and

The majority of PMCs/PMRs are proceeding according to schedule.

FDA Reports on Status of Postmarketing Requirements and Postmarketing Commitments

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

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - stock.adobe.com

Novartis announced, in an April 23, 2024 press release, that its radioligand therapy, Lutathera, has gained FDA approval as a treatment for pediatric patients aged 12 years and older with somatostatin receptor-positive (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs), inclusive of foregut, midgut, and hindgut GEP-NETs.

“Lutathera is now the very first therapy approved specifically for children with GEP-NETs, offering new hope to young patients living with this rare cancer,” said Tina Deignan, Therapeutic Area head, Oncology US, Novartis, in the press release (1). “Radioligand therapies have extraordinary potential to shape the future of cancer care. With this approval, we have taken another vital step toward fulfilling that vision, strengthening our commitment to researching and developing the RLT [radioligand therapy] platform across multiple cancer types and treatment settings.”

FDA’s approval was based on the ongoing open-label, multicenter, single-arm, Phase II NETTER-P trial, which has been designed to evaluate the safety and dosimetry of Lutathera in patients between the ages of 12 and 18 years old who have SSTR+ GEP-NETs (2). The results of the Phase II NETTER-P trial were consistent with those found in adult patients via the NETTER-1 trial.

“While GEP-NETs in children and adolescents are rare, the impact can be devastating. [This] approval addresses a critical need for new treatment options for these vulnerable patients,” said Dr. Theodore Laetsch, trial investigator and director, Developmental Therapeutics Program, Children’s Hospital of Philadelphia (CHOP), a NETTER-P clinical trial site, in the press release (1). “The introduction of radioligand therapy significantly advanced how we treat GEP-NETs, and I’m encouraged that younger patients now have the potential to benefit from this innovation.”

Additionally, in January 2024, Novartis announced the results of the Phase III NETTER-2 trial, demonstrating that Lutathera plus long-acting release (LAR)octreotide reduced the risk of disease progression or death by 72% when used as a first-line therapy in adult patients with SSTR+ well-differentiated grade 2/3 advanced GEP-NETs (3).

“This is the first positive Phase III trial of a radioligand therapy in the first-line setting, and the overall efficacy and safety results are amongst the most clinically relevant observed to date in this kind of advanced cancer, addressing a significant unmet need for patients with newly diagnosed advanced GEP-NETs,” said Jeff Legos, global head of Oncology Development at Novartis, in a press release (3). “The positive results are a significant advancement and further reaffirm our strategy to research and develop radioligand therapies in earlier lines of treatment or stages of disease to improve outcomes for patients.”

1. Novartis. Novartis Radioligand Therapy Lutathera FDA Approved as First Medicine Specifically for Pediatric Patients with Gastroenteropancreatic Neurodocrine Tumors. Press Release, April 23, 2024.
2. NIH. Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients with GEP-NETs and PPGLs. 

 (accessed April 24, 2024).
3. Novartis. Novartis Lutathera Significantly Reduced Risk of Disease Progression or Death by 72% as First-Line Treatment for Patients with Advanced Gastroenteropancreatic Neuroendocrine Tumors. Press Release, Jan. 19, 2024.

FDA has granted approval for the use of Novartis’ radioligand therapy, Lutathera, to treat pediatric patients with gastroenteropancreatic neuroendocrine tumors.

Novartis’ Radioligand Therapy Gains FDA Nod for Pediatric Patients 

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

glass frozen ampoule with a virus vaccine on the texture of cold ice top view, background with backlight on the theme of pharmaceutical drugs from viral diseases.| ©Александр Беспалый - stock.adobe.com

Messenger RNA (mRNA) molecules are inherently unstable and readily degrade when exposed to ubiquitous enzymes such as RNase and undergo pH-dependent hydrolysis of phosphorus-oxygen bonds when exposed to water. That instability creates challenges for manufacture, formulation, storage, and transport of mRNA-based vaccines and therapeutics. While encapsulation of mRNA drug substances in lipid nanoparticles (LNPs) enhances their stability (and facilitates their delivery into cells), mRNA-LNP products still typically require low-temperature storage and present distribution challenges in areas where cold-chain management is limited.

Increasing mRNA Product Stability with Lyophilization

One solution for overcoming mRNA instability is lyophilization, or freeze-drying, which is used in the manufacture of many biologic and small-molecule drugs that exhibit instability in aqueous solutions. Lyophilization involves the removal of frozen water (ice crystals) via sublimation under vacuum at low temperature to ideally produce a solid cake that typically can be stored at room temperature for extended periods. The challenge with mRNA-LNP products is to find the right lyophilization conditions that do not harm the product particles (change their size and polydispersity, among other attributes) and produce a solid with desirable properties.

While there was insufficient time during development of the mRNA-LNP COVID-19 vaccines to identify an effective lyophilization process, several companies have since then developed effective lyophilization solutions. Pfizer/BioNTech and Moderna are two well-known firms with candidates in the clinic. But it was the small biopharma company Arcturus Therapeutics, in collaboration with CSL, that received the first marketing approval of a lyophilized mRNA-LNP product. Its self-amplifying mRNA COVID-19 vaccine ARCT-154 was approved by Japan’s Ministry of Health, Labor, and Welfare (MHLW) in November 2023 (1).

The main challenge: maintaining integrity

While lyophilization is an important means of addressing stability issues associated with mRNA therapeutics, allowing the transport and storage of these products without the need for ultracold chain infrastructure, there have been challenges to effectively harnessing the benefits of lyophilization for these products, according to Vincenza Pironti, strategic marketing director at Recipharm.

The sensitivity of large, highly charged mRNA molecules, even when encapsulated in LNPs, to oxygen, light, heat, and temperature must be taken into consideration, contends Joseph E. Payne, president and CEO of Arcturus Therapeutics. The temperature transfer during lyophilization and the use of a vacuum places a strain on the LNPs. “It is necessary to develop a subtle and sophisticated method that does not perturb or discombobulate the nanoparticles during both freeze-drying and reconstitution,” he says.

Doing so, Payne adds, requires a considerable amount of resources and years of innovation, and typically involves the use of the right combination of buffers and excipients to stabilize the mRNA-LNPs during dehydration and rehydration.

These challenges, Pironti says, include ensuring the lyophilization process is effective at optimizing product stability and protecting the integrity of the LNPs. “In practice this means there needs to be a good final cake within the vial that can be readily reconstituted when it is time to administer without detrimental effects to the formulation,” she explains.

That can be particularly difficult to achieve for low-dosage formulations such as mRNA-based therapies due to the ratio of ingredients to dose volume, observes Pironti. “What is needed in these cases is the use of appropriate cryoprotectants or bulking agents within the formulation, which must be compatible with the formulation and the vial and ensure the stability of final drug product,” she observes. She also notes that comprehensive analytical testing of both the formulation and the LNPs well ahead of commercialization can help identify the right lyophilization methods to support product stability and shelf-life once the therapy is in commercial use.

Equally important, according to Christian Dohmen, executive director, technology development & CMC with Ethris, is to ensure that the LNPs are fully intact after reconstitution. There are many factors that contribute to product deterioration of lyophilized mRNA/LNPs, including particle size, mRNA integrity, and encapsulation efficiency. “If left unaddressed, the combined effect of these factors leads to deterioration of the product and decreased biological activity as well as undesired immune recognition (e.g., due to formation of aggregates), ultimately leading to reduced therapeutic potency,” he explains. In addition, he comments that aggregation of LNPs during the reconstitution process after lyophilization is another challenge for lyophilized mRNA products.

Pironti recommends using long freeze-drying cycles to prevent any damage to the LNPs within the formulation that could undermine performance and stability. Ethris has, Dohmen says, optimized its product design and lyophilization process to account for these factors and improve the potency of the resulting product as well as a reconstitution process that prevents aggregation from occurring.

Cynthia A. Challener, PhD, is a contributing editor to 

Developing freeze-drying processes requires patience and deep product and process understanding.

Bristol Myers Squibb and Cellares, a US-based integrated development and manufacturing organization (IDMO) specializing in cell therapy manufacturing, announced on April 22, 2024 that they have established a new agreement to reserve global capacity and supply for manufacturing chimeric antigen receptor T cell (CAR-T cell) therapies. The deal is valued at up to $380 million in upfront and milestone payments. 

Cellares Cell Shuttle is More Valuable Than the Sum of the Value of the Individual Parts

 with Fabian Gerlinghaus, CEO and co-founder, Cellares, on 

Under the agreement, Cellares will optimize, automate, and tech-transfer select CAR-T cell therapies from Bristol Myers Squibb onto Cell Shuttle, Cellares’ automated and high-throughput cell therapy manufacturing platform. Cellares will dedicate multiple Cell Shuttle and Cell Q systems, including fully automated, high-throughput quality control, to Bristol Myers Squibb for exclusive use. These Cell Shuttles and Cell Q systems will be deployed in Cellares’ smart factories located in the United States, European Union, and Japan.

In a company press release, Bristol Myers Squibb stated that, “Manufacturing cell therapies is both operationally and technically complex. Because cell therapies are rapidly transforming the way many different diseases are treated, the demand for these treatments is increasing significantly.” The collaboration with Cellares enables Bristol Myers Squibb to expand manufacturing capacity to meet the demand required from its diverse range of cell therapies. Cellares provides a platform technology that is scalable and carries the potential to improve turnaround times, according to Bristol Myers Squibb in its press release.

“The agreement with Cellares is our latest step forward in support of our comprehensive strategy to unlock the full potential of CAR-T therapy to deliver transformative treatments to as many patients as possible, as quickly as possible,” said Lynelle B. Hoch, president, Cell Therapy Organization, Bristol Myers Squibb, in the press release. “Our collaboration with Cellares strengthens our existing internal manufacturing capabilities for CAR-T cell therapies by giving us access to the first end-to-end fully automated cell therapy manufacturing platform, to help ensure we meet the high demand for these differentiated treatments, now and in the future.”

This agreement builds on existing collaborations between Bristol Myers Squibb and Cellares. Bristol Myers Squibb participated in Series C financing in August 2023 to fund the launch of Cellares’ commercial-scale 

 in Bridgewater, NJ, for cell therapy manufacturing, which, according to Cellares, is the first of its kind. The 118,000-ft

 smart factory is expected to be good manufacturing practice-ready in the second half of 2024. The facility is designed to integrate advanced robotics, purpose-built technology, and interconnected software and will be capable of producing 40,000 cell therapy batches per year (1). Also in August 2023, Bristol Myers Squibb joined Cellares’ Technology Adoption Partnership (TAP) Program to evaluate the Cell Shuttle’s automated manufacturing capabilities.

“This agreement with Bristol Myers Squibb is aligned with our strategy of establishing a global network of high-throughput, automated Smart Factories to meet the growing and worldwide demand for cell therapies,” said Fabian Gerlinghaus, CEO and co-founder of Cellares, in the company press release. “We look forward to demonstrating how our innovative technology’s emphasis on standardization will accelerate commercial-scale manufacturing and worldwide deployment. Our collaboration with Bristol Myers Squibb and our collective expertise furthers our mission to accelerate access to life-saving cell therapies for patients globally."

Gerlinghaus went into further detail about the development and analytical planning behind the company’s cell therapy manufacturing platform and the importance of automation to the manufacture of cell therapies in 

Bristol Myers Squibb Joins Cellares Program Focused on Automated Cell Therapy Manufacturing as Cellares is Launched as First IDMO

In a new agreement, Cellares will utilize its Cell Shuttle fully automated cell therapy manufacturing platform to manufacture select CAR-T cell therapies under development by Bristol Myers Squibb. 

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