Manufacturers face the challenge of meeting growing demand for personalized biopharmaceuticals.

Automation Aids Cell and Gene Therapy Production

Despite many development challenges, stable producer cell lines show real promise.

State of Producer Cell Development for Lentiviral Vector Manufacturing

CPC presents a green alternative to chromatography that supports sustainable operations.

Exploring How CPC Progresses Green Chemistry Practices

Experts outline the benefits of single-use consumables relative to traditional approaches.

Weighing the Benefits of Single-Use Consumables

Considering the differences between small- and large-molecule drug products can help determine analytical testing methods for E&L.

Considerations for Analytical Testing for E&L

Rentschler Biopharma, a global contract development and manufacturing organization (CDMO) for biopharmaceuticals, announced on Sept. 13, 2023 that it has received the cGMP Manufacturing Compliance Certificate following a successful inspection by the UK Medicines & Healthcare Products Regulatory Agency (MHRA) at the UK site. According to the press release, the ATMP business was announced in early 2021 and the facility is in the Cell and Gene Therapy Catapult’s Manufacturing Innovation Centre in Stevenage, UK.

“MHRA’s approval marks a major milestone for Rentschler Biopharma, and we are excited to offer our services from process and analytical development through cGMP manufacturing. Our team is highly knowledgeable, bringing years of experience in the field of AAV,” said Dr. Robert Panting, general manager of Rentschler’s ATMP business, in a press release. “We provide a tailored program for each client, in line with their needs and stage of development, while working closely with them to move projects forward as rapidly as possible. We are thus continuing the Rentschler tradition of offering a truly client-centric approach with the ultimate goal of helping patients. With our first clients already on board, we look forward to adding other exciting programs soon.”

According to the press release, following the MHRA inspection, Rentschler Biopharma’s ATMP business can now offer its full range of services for the clinical supply of AAV, including bioprocess and analytical development through to cGMP manufacturing at the Stevenage facility in the UK.

“Our contribution to improving the health and quality of life of seriously ill patients, is made possible by continuously expanding our expertise in the production of essential biopharmaceuticals. By launching Rentschler’s ATMP business, we aim to address an important gap in expertise and support for innovative, early-stage cell and gene therapy programs,” said Dr. Christian Schetter, chief scientific officer of Rentschler Biopharma, in a press release. “It is gratifying to achieve this important milestone of MHRA approval, bringing us closer to reaching our objective of supporting clients already from the earliest stages of CMC development. We are continually looking to understand not only current client needs but future ones as well, which is how our ATMP offering came to fruition. We will continue to listen to our clients to anticipate how we can improve our offering and collaborate in advancing medicine to save lives, together.”

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Rentschler Biopharma’s ATMP business can now offer its full range of services for the clinical supply of AAV, including bioprocess and analytical development through to cGMP manufacturing at the Stevenage facility in the UK.

Rentschler Biopharma ATMP Facility Receives MHRA Approval

Drug development is inherently costly and time-intensive, with potential attrition a persistent burden on companies’ finances (1). As companies gain a deeper understanding of cell and molecular biology and seek to develop more complex therapeutics for patient populations, they will also need to be more innovative to ensure commercially viable success is achieved (2).

An area that has witnessed significant breakthroughs over recent years has been that of cell and gene therapies. The market for these emerging therapies is projected to grow at a compound annual rate of 22.41% between 2022 and 2030 (3), driven by an expanding pipeline and increasing regulatory approvals.

Despite the successes that have already been achieved with emerging therapy development and manufacturing, companies are still facing numerous challenges. Aspects such as demand for accelerated development timelines, advancing technologies, and the growing issue surrounding sustainability are monopolizing the priorities of bio/pharma companies. However, through new opportunities, like allogeneic cell therapy, it is hoped that greater benefits to patients, particularly those in undertreated populations, will be achieved (4).

In speaking with Anis H. Khimani, PhD, senior strategy leader, Life Sciences Strategy Group at Revvity, 

 discussed with how new therapies are moving from their academic origins into industry.

Continued investment in cell and gene therapies

PharmTech: Is there anything specific you are seeing in terms of new emerging therapy development or manufacturing in the industry as of now?

Khimani (Revvity): Cell and gene therapies are delivering on the promise of curing diseases.Initially starting with CAR-T [chimeric antigen receptor T cells] treatments for hematological malignancies, therapies are now in the clinic for rare inherited genetic disease, infectious diseases, and solid tumors. Each of these therapeutic areas brings with it new technical and clinical challenges. From accurately targeting the diseased tissue, to ensuring that the corrected gene is expressing proteins at sufficient level to resolve the clinical symptoms, to ensuring that the products are robust, affordable, scalable, and accessible.

The more recent introduction of base editing offers the promise of more complex multiplexed editing with reduced off target editing and significantly lower indels and translocations. This approach is expected to reduce the time required to create therapies because editing can be performed concurrently instead of needing to be performed sequentially. Multiplex base editing has also been shown to have no impact on cell viability, so the yields will be unaffected. One example of base editing, the Pin-point™ system, has been demonstrated as able to knock-out immunogenic proteins and knock-in a targeted CAR within the same editing reaction, creating an effective functional CAR-T cell line with tumor-killing activity.

Addressing new short- and long-term challenges

PharmTech: Are there any new challenges or hurdles in the cell therapy space that should be addressed for the short- and long-term?

Khimani (Revvity): The production of cell therapies rely on accurate and safe editing without compromising the health of the cells being edited. To achieve this, there needs to be tight controls over cell isolation, editing, expansion, analysis, and delivery to the patient. The increasing number of processes being developed to address the cell therapy market will need to be consolidated at some point to create a standardized, scalable therapeutic approach. This will help to reduce manufacturing times and costs of treatment, and also create a framework for clinical trials and subsequent regulatory approvals, getting treatments to patients faster.

The benefits of utilizing allogeneic cell therapies

PharmTech: Why are companies starting to look at allogeneic cell therapies more closely?

Khimani (Revvity): Allogeneic therapies follow the traditional drug manufacturing process more closely than autologous cell therapies. The therapy can be scaled up so that the same product can be used to treat multiple patients, standardizing the product and reducing the cost per patient treated. As the tools used for gene editing to create allogeneic cell therapies continue to evolve and become more robust, it is imaginable that there will be an increasing interest and eventual preference for allogeneic cell therapies over autologous cell therapies.

Industry players and allogeneic therapies

PharmTech: Are allogeneic cell therapies a bigger opportunity for industry players, such as contract development and manufacturing organizations (CDMOs) and contract research organizations (CROs), and why?

Khimani (Revvity): Decentralizing manufacturing processes provides an opportunity for CDMOs and CROs to integrate into product pipelines. These industry players are already contributing their own expertise to accelerate allogeneic cell therapies, such as developing new analytical methods. As the cell therapy market continues to mature and CDMOs and CROs manage an increasing number of projects related to the development of this new generation of therapies, they will also mature their expertise, systems, and processes and grow their presence with the cell therapeutics industry. Cell therapies are rapidly evolving and are being developed to treat a broad array of disorders, so it is foreseeable that companies within the market will differentiate into having deeper expertise in a smaller number of specific therapies and/or areas of expertise over time.

PharmTech: What do you hope to see for the future of allogeneic cell therapies/any other emerging therapy development or manufacturing?

Khimani (Revvity): We hope that the combined learnings of this emerging and rapidly expanding class of therapies will see the acceleration of treatments and possibly cures for many devastating diseases. The first autologous cell therapy was approved in 2016, the first autologous CAR-T therapy was approved in 2017 and the first allogeneic stem cell therapy was approved in 2011, so we’re still at the starting line. Most promising, the development to approval timelines for cell therapies are trending faster than conventional therapeutics and the FDA has established a new, specialized office to process the increasing number of regulatory submission for cell and gene therapies.The current clinical trials address a broad range of conditions, including hematological malignancies, solid tumors, ocular conditions, infectious disease, autoimmune conditions, long COVID, inherited genetic diseases such as spinal muscular atrophy (SMA), severe combined immunodeficiency (SCID), neurological diseases including Parkinson Disease, depression, and diabetes. The breadth of indications continues to expand as we learn more about how to produce and administer cell and gene therapies, so it is an exciting era of medicine to be a part of.

Agrawal, G.; Keane H.; Prabhakaran, M.; Steinmann, M. The Pursuit of Excellence in New-Drug Development. McKinsey & Company, Nov. 1, 2019. https://www.mckinsey.com/industries/life-sciences/our-insights/the-pursuit-of-excellence-in-new-drug-development

McKinsey & Company. How AI Can Accelerate R&D for Cell and Gene Therapies. 

, Nov. 16, 2022. https://www.mckinsey.com/industries/life-sciences/our-insights/how-ai-can-accelerate-r-and-d-for-cell-and-gene-therapies

Cell and Gene Therapy Market (by Therapy Type: Cell Therapy and Gene Therapy; by Indication: Cardiovascular Disease, Cancer, Genetic Disorders, Infectious Diseases, Neurological Disorders; by Delivery Method: In-Vivo and Ex-vivo; by End-Users: Hospitals, Cancer Care Centers, Wound Care Centers, Others)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2022–2030

Fontanillo, M.; Paulick, K.; Poda, P.; Silberzahn, T. Out of the Shadows: A Brighter Future for Pharma Technical Development. McKinsey & Company, Sept. 16, 

. https://www.mckinsey.com/industries/life-sciences/our-insights/out-of-the-shadows-a-brighter-future-for-pharma-technical-development.

Despite the successes that have already been achieved with emerging therapy development and manufacturing, companies are still facing numerous challenges. 

Handling New Therapies Moving Through Drug Development at a Rapid Pace

Nurix Therapeutics announced on Sept. 7, 2023 that it has entered a multi-year, multi-target strategic collaboration agreement with Seagen, to further advance a new class of medicines, called degrader-antibody conjugates (DAC), for use in cancer treatment. According to the press release, the collaboration between the two companies will focus on an innovative approach to combine two powerful technologies to target cancer, antibody-drug conjugation (ADC) and targeted protein degradation (TPD), with the intention of creating drugs with new mechanisms of action, improved specificity, and anti-cancer activity.

“By combining the tissue and tumor specificity of antibodies with highly potent and catalytic targeted degradation of cancer driver proteins, we believe that DACs may represent a next generation of cancer medicine for a wide range of solid tumors and hematologic malignancies,” said Arthur T. Sands, MD, PhD, president and chief executive officer of Nurix, in a press release. “With Seagen, our strategic goal is to advance ADC technology to the next level to provide patients with new DAC drugs that deliver greater anti-tumor efficacy and safety compared to currently available agents.”

According to the agreement terms, Nurix will receive an upfront payment of $60 million and the potential to receive up to approximately $3.4 billion in research, development, regulatory, and commercial milestone payments across multiple programs. Further, as a part of the multi-year collaboration, Nurix will use its proprietary DELigase platform to develop a suite of targeted protein degraders against multiple targets nominated by Seagen that are fitting for antibody conjugation. According to the press release, Seagen will be responsible for conjugating these degraders to antibodies to make DACs and advancing these DAC drug candidates through preclinical and clinical development and commercialization.

“The targeted protein degrader modality provides unique advantages over payloads currently employed across the ADC field,” said Gwenn M. Hansen, PhD, chief scientific officer of Nurix, in a press release. “This collaboration is a new application of our DELigase technology, and we are delighted to work with Seagen, a pioneer in the development and commercialization of ADC therapeutics, to create a new generation of drugs to fight cancer.”

Seagen will be responsible for conjugating these degraders to antibodies to make DACs and advancing these DAC drug candidates through preclinical and clinical development and commercialization.

Nurix Announces Strategic Collaboration with Seagen

On Sept. 6, 2023, Charles River Laboratories International and PathoQuest announced the publication of the results of a seminal study in 

, which demonstrated the proprietary, good manufacturing practice (GMP) grade, next-generation sequencing (NGS)-based assay from PathoQuest had a greater capability of detecting viral contaminants when compared to 

The objective of the study was to compare classical 

 testing methods used to screen cell lines for adventitious viruses with a GMP-compliant viral transcriptome NGS assay. Further, the study was conducted as a head-to-head comparison of standard 

testing and NGS-based testing of cell substrates.

According to the press release, the team of Charles River experts prepared test materials and ran the 

 assays, while PathoQuest’s team tested the material with their proprietary NGS-based assay. There were cells infected with a wide variety of viruses reflective of the diversity and various patterns of virus-cell interactions in a real-world setting for biologics to determine the range of detection. Additionally, the infected cells were increasingly mixed with uninfected cells to further assess the analytical sensitivity and analyzed across several conventional 

 tests and with the NGS-based transcriptomic assay.

The results showed that PathoQuest’s proprietary NGS approach is an effective, more robust replacement to 

 adventitious virus testing of cell substrates used in the production of biologics, like monoclonal antibodies, vaccines, cell, and gene therapies.

“Our study demonstrates that PathoQuest’s unique NGS assay significantly increases the capability of detecting viral contaminations in cell substrates like cell banks, the starting material for biologics production, and in bioreactors during biologics production. The test has been validated to GMP standards and provides the pharmaceutical industry a faster, more efficient, and reliable testing option compared to animal-based testing,” said Professor Marc Eloit, DVM, PhD, head of the Pathogen Discovery Laboratory at the Institute Pasteur and Founder of PathoQuest, in a press release.

The results showed that PathoQuest’s proprietary NGS approach is an effective, more robust replacement to in vivo adventitious virus testing of cell substrates used in the production of biologics, like monoclonal antibodies, vaccines, cell, and gene therapies.

Charles River and PathoQuest Publish Study Validating Proprietary Next-Generation Sequencing Viral Safety Assay 

Orano Med and Orbit Discovery announced on Sept. 11, 2023 that they have entered a collaboration to discover specific peptide receptor radionuclide therapies against cancer cells and advance the development of novel radiopharmaceuticals. According to the press release, the agreement states that Orbit will implement its bead-based peptide display engine to discover peptide leads specific to targets related to specific tumors.

“We’re delighted to continue expanding our existing portfolio of partners by collaborating with Orano Med who have a strong track record of discovering novel radiopharmaceuticals,” Neil Butt, chief executive officer, Orbit Discovery, said in a press release. “We’re very proud of our proprietary screening platform at Orbit and acknowledge its role in empowering the next wave of peptide therapeutics.”

Radioligand therapies rely on the concept of combining the ability of biological molecules, like peptides, to target cancer cells with the short-range cell-killing capabilities of radioisotopes. According to the release, the approach results in an increased cytotoxic potential toward cancer cells while still limiting toxicity to nearby healthy cells.

This collaboration will strengthen the capabilities of Orbit’s peptide display engine to identify peptide candidates specific to tumor-associated targets, and the technology enables the screening of large peptide collections through the combination of DNA encoded libraries and bead-based presentation, according to the press release.

“Since the inception of Orano Med, we have recognized the value of collaboration,” said Julien Dodet, chief executive officer, Orano Med, in a press release. “In our strategy to develop and deliver 212Pb Targeted Alpha Therapy for cancer patients, we’re delighted to work with Orbit Discovery and leverage its technology and expertise in peptide ligand discovery to build our pipeline of radiotherapies.”

The agreement states that Orbit will implement its bead-based peptide display engine to discover peptide leads specific to targets related to specific tumors.

Orano Med and Orbit Discovery Enter Collaboration for New Novel Targeted Radioligand Therapies 

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

FDA announced on Aug 30, 2023, that it is creating two compliance policy guidances initiating a year-long stabilization period for those in the pharmaceutical supply chain that need time to adhere to Drug Supply Chain Security Act (DSCSA) requirements for electronic drug tracing at the package level. The policy effects trading partners, mainly manufacturers, wholesale distributors, dispensers, and repackagers. The requirements are scheduled to change on November 27, 2023, and the stabilization period lasts until November 27, 2024.

The DSCSA went into effect in 2013, and outlines the requirements for the electronic tracing and identification of prescription drug distribution in the U.S. It requires trading partners to supply, accept, and maintain documentation on prescription drugs and their chain of ownership in the U.S. supply chain, from manufacturer to dispenser. The current DSCSA requirements as of September 1, 2023, will be changed on November 27, 2023. The new requirements will include mandating that trading partners manage documentation of product and ownership electronically (previously, partners were permitted to do so in paper format).

Enhanced Drug Distribution Security Requirements Under Section 582(g)(1) of the Federal Food, Drug, and Cosmetic Act – Compliance Policies

Wholesale Distributor Verification Requirement for Saleable Returned Drug Product and Dispenser Verification Requirements When Investigating a Suspect or Illegitimate Product —Compliance Policies

 Revision 1 (WDVRS). WDVRS Revision 1 adds a year extension (from November 27, 2023, to November 27, 2024) to a guidance released on October of 2020 that directs distributors to verify product identifiers before distribution. EDDSR covers FDA’s new compliance policies for product tracing at the interoperable, electronic, package level; these policies will go into effect on November 27, 2023.

FDA intends for trading partners to use the stabilization period to “build and validate interoperable systems and processes, manage products and data, and ensure continuity of the supply chain and product availability to patients.” It is not intended as a justification for delaying compliance efforts with the DSCSA.

The new policy will require trading partners to supply, accept, and manage all documentation of product and ownership of prescription drugs electronically.

FDA Establishes Stabilization Period for Updated DSCSA Compliance Policies

Feliza Mirasol is the science editor for 

The opening of a new solutions center in Bengaluru, India, by Illumina, a US-based company specializing in DNA sequencing and array-based technologies, in August 2023 not only expands Illumina’s capabilities in genomics, but also expands access to genomics in that country.

The new center houses a fully equipped laboratory with the latest next-generation sequencing and array technologies. It is also fully resourced with field applications and service engineers that can offer broad genomics capabilities. The center will also provide training and education to increase technical expertise and access to genomics locally.

The new center is a permanent facility on the ground in Bengaluru for Illumina, which has spent the past 16 years working in partnership with Premas Life Sciences, an India-based contract research organization and provider of niche technologies in genomics, cell biology, and biopharma. With the help of the new solutions center, Illumina will continue collaborative work with Premas to grow the genomics market in India, according to an Aug. 17, 2023 company press release.

"Expanding Illumina's presence in India allows the company to collaborate and be part of a vibrant biotech ecosystem with skilled labor, strong research and development resources, and supportive government policies," said Gretchen Weightman, senior vice-president, Asia Pacific, Middle East & Africa, Illumina, in the company press release. "In our 25th anniversary year, it's a very exciting time to be growing our physical presence in India to drive access and the further adoption of genomics to transform human health, particularly in oncology and infectious disease."

Illumina’s business in India is led by Abhishek Gupta, country manager, and, according to Weightman in the press release, "Abhishek brings vast knowledge and experience to Illumina India, and we look forward to supporting him and the team as they collaborate with and support our customers." said Weightman.

The new solutions center also presents the opportunity to pursue equitable access and more diverse data in India. "Democratizing genomics and making it available to the many and not just the few will take a collaborative approach. We must better reflect diversity in genomic data and drive awareness for, access to, and adoption of genomic technologies, through partnership," Weightman said in the release.

Illumina’s new solutions center in Bengaluru, India, will expand access to genomics in the country.

Illumina Establishes New Center in India to Expand Genomics Capabilities

Optibrium announced on Aug. 31, 2023 the acquisition of BioPharmics to further expand the 3D drug design and modelling offering and to focus on research and development and application science, according to the press release.

BioPharmics developed a series of industry-leading algorithms and software for 3D ligand-based and structure based computational drug design, including software for 2D to 3D ligand conversion and conformer generation, molecular docking, molecular similarity, and binding affinity prediction. Additionally, these highly performant products have all been analyzed and their results demonstrated in numerous peer-reviewed papers, specifically published jointly with key pharmaceutical industry partners, according to the release.

“After years of close collaboration, we are delighted that Optibrium was chosen to support BioPharmics’ continued scientific innovation and expanding customer base,” said Dr Matthew Segall, CEO, Optibrium in a press release. “We are delighted to welcome Ajay and Ann to the team. Their extensive experience in computational chemistry and biology, alongside BioPharmics’ world-leading software for 3D ligand- and structure-based design, will bring Optibrium to the forefront of these essential technologies for small molecule discovery and design.”

Dr Ajay Jain, founder and CEO of BioPharmics, added that their team believes that there is no better team to continue the powerful software developments that BioPharmics has introduced over the years. “I look forward to working as part of the Optibrium team to expand their internal expertise in 3D drug design, as well as on future drug discovery innovations,” he said in a press release.

Optibrium announced on Aug. 31, 2023 the acquisition of BioPharmics to further expand the 3D drug design and modelling offering and to focus on research and development and application science.

Optibrium Acquires BioPharmics

ten23 health, a contract development and manufacturing organization (CDMO), announced a capacity expansion for the manufacture of sterile drug product at its Visp facility, according to a press release.

Due to customer demand for sterile fill and finish services, the expansion will head to VIVA 1, Visp Valais, Switzerland, at a sterile manufacturing facility. Following successful completion of the GMP inspection by Swissmedic and an obtained GMP license, the new storage areas are set to become operational in September 2023. Additionally, the output of ten23’s existing sterile manufacturing facility in Visp will be gradually increased by a further 50% capacity by hiring more staff to operate an additional shift.

According to the press release, further expansions of the pharmaceutical development and manufacturing services of ten23 are happening at the BASE and VIVA facilities to continue to support complex sterile product development, testing, and manufacturing. Two additional filling lines for sterile commercial supplies of ready-to-use syringes, cartridges, and vials and liquid or freeze-dried clinical and commercial vial supplies will all be a part of VIVA 2. This project is signed for manufacturing in 2024 and 2025.

“We are thrilled to offer our customers additional sterile manufacturing capacity for

sophisticated and highly precise Drug Product-presentations such as syringes and cartridges,

increased capacity until the two new production lines becoming fully operational.” said Professor Hanns-Christian Mahler, PhD, CEO of ten23 health, in a press release. “With recent demand increases for clinical as well as commercial drug launches, our customers are keen to take advantage of increased capacity from the existing VIVA 1® facility, before the new plant VIVA 2® will be utilized for larger scales.”

Further expansions of the pharmaceutical development and manufacturing services of ten23 are happening at the BASE and VIVA facilities to continue to support complex sterile product development, testing, and manufacturing.

ten23 Expands Sterile Manufacturing Capacity at VIVA 1 Facility 

On Aug. 28, 2023, Embark Laboratories announced it has been acquired by Novo Nordisk, including its lead metabolic program, in addition to entering a three-year research and development collaboration to discover and develop novel pharmaceuticals to treat obesity and related comorbidities, according to the press release.

Under the acquisition agreement for Embark Biotech, Novo Nordisk receives the full rights to develop and commercialize the lead program. Additionally, the research and development collaboration with Embark Laboratories provides Novo Nordisk with the option to acquire selected assets based on the Embark Biotech findings across several indications, including obesity and type 2 diabetes, according to the release.

“Novo Nordisk has been engaged in obesity research for 25 years, and we continuously search for new ways to address this serious chronic disease. We are excited about the opportunity to advance Embark Biotech’s lead program and look forward to co-creating novel treatments for cardiometabolic diseases with Embark Laboratories to complement our in-house R&D,” said Brian Finan, vice president of Obesity Research at Novo Nordisk, in a press release.

“There is a clear strategic fit between the novel biology we have discovered and Novo Nordisk’s expertise and focus on developing new drugs in the cardiometabolic space. We are thrilled to pass on the baton for our lead metabolic program to Novo Nordisk. This deal and Embark’s success are direct outcomes of the unique and innovative ecosystem in Denmark that has been cultivated by the BioInnovation Institute and the University of Copenhagen and through initiatives from the Novo Nordisk Foundation and the Innovation Fund Denmark,” said Zach Gerhart-Hines, chief technology officer at Embark Laboratories in the release.

Novo Nordisk receives the full rights to develop and commercialize the lead program.

Novo Nordisk Acquires Embark Biotech

Zevra Therapeutics and Acer Therapeutics announced on Aug. 31, 2023 that they have entered a definitive agreement where Zevra would acquire Acer in a merger transaction having a total potential value for Acer stockholders of up to $91 million, according to a press release.

Additionally, additional cash payments are possible in relation to the Contingent Value Rights with respect to milestones involving Acer’s early-stage program ACER-2820 (emetine). Zevra also purchased Acer’s secured debt at a discount from Nantahala Capital through a series of transactions in capital efficient structure, according to the release. Both companies have a focus to developing and commercializing treatments for rare diseases with a strong focus on patients and supporting communities with little to no existing therapeutic options.

“We believe that Acer’s portfolio of rare disease programs, including the recent US commercial approval of OLPRUVA for urea cycle disorders UCDs, is a perfect strategic fit for Zevra and creates significant opportunity for us to positively impact patient lives while creating shareholder value,” said Joshua Schafer, chief commercialization officer and executive vice president of Business Development of Zevra Therapeutics, in a press release. “We are excited about Acer’s clinical programs and are confident in the potential of OLPRUVA to bring UCD patients a more convenient and cost-effective treatment option over current therapies. Acer would bring unique rare disease operations and capabilities that would serve as a foundation to support the commercialization of Zevra’s pipeline as it advances.”

“This merger would support Zevra's vision of becoming a leading rare disease company bringing life-changing therapies to patients with a significant unmet need,” said Christal Mickle, Zevra’s interim chief executive officer and chief development officer in the press release. “The commercial launch of OLPRUVA in the US requires a small, highly-focused commercial team, which is complementary to what we intend to build for arimoclomol, our product candidate for the treatment of Niemann-Pick disease Type C (NPC). We believe there is potential to realize significant synergies across our commercial organizations as both UCDs and NPC are metabolic related conditions and there is overlap among those physicians that treat both disorders.”

Both companies have a focus to developing and commercializing treatments for rare diseases with a strong focus on patients and supporting communities with little to no existing therapeutic options.

Zevra Therapeutics to Acquire Acer Therapeutics 

In biotherapeutic production, delivery of the therapeutic agent is a significant factor for achieving successful therapeutic effect. With this consideration in mind, the delivery mechanism requires forethought. Among the more innovative drug delivery systems being developed today are those employing nanoparticle technologies.

The development of nanoparticles in recent years has expanded into a range of clinical applications. Nanoparticles were developed to address the limitations posed by free therapeutics as well as to overcome biologics barriers, including systemic, environmental, and cellular barriers. Work in nanoparticle development has focused on ways to optimize drug delivery systems so that these systems can be applied across patient populations and across different diseases (1).

“Safe and effective delivery of therapeutic cargo to its target tissue at a clinically relevant dose is crucial for developing successful drugs regardless of the route of administration,” says John Lewis, PhD, CEO of Entos Pharmaceuticals. “Nanoparticle engineering must be purpose-driven and designed around the physical and biochemical properties of the therapeutic cargo and the disease it is designed to treat. The cargo size, charge, and ability to tolerate chemical modification greatly impact the type of nanoparticle used in a drug development program.”

“Additionally,” Lewis states, “the complexity and cost of manufacturing must also be considered when developing novel therapies. All of these factors need to be considered at the start of the drug development process to maximize both clinical and commercial success.”

The biggest benefits and challenges of using nanoparticles come with designing a nanoparticle delivery system that can deliver a molecule to the right target tissue safely and efficiently, Lewis explains. What’s more, it is challenging to design nanoparticles that do not require complex or costly manufacturing.

“For example, viral vectors transduce target cells with high efficiency but can only be used to deliver DNA, have cargo capacity limits, can be costly to manufacture, and cannot be used for repeat dosing due to their immunogenicity,” Lewis points out.

Currently marketed lipid nanoparticles (LNPs) also have limitations, Lewis adds, such as poor biodistribution that preferentially targets the liver, poor tolerability, especially at high doses, and lack of utility for delivering DNA. To address such limitations, Entos developed a technology platform (Fusogenix PLV) that combines tiny fusion proteins with well-tolerated lipids. The company’s approach combines the best features of viral vectors and LNPs to deliver RNA, DNA, or novel gene-editing technologies safely, effectively, and repeatedly by direct fusion with target cells, Lewis states.

“The nature of your engineered nanoparticle will determine if its benefits outweigh its challenges,” says Lewis.

With much discussion in the biopharma industry surrounding nanoparticle technology, specifically for its use in bio-drug delivery, LNPs are at the forefront. “Among the myriad of nanoparticles, LNPs are the leading candidates for delivery of many different biological drugs, which includes nucleic acids such as mRNA [messenger RNA], siRNA [small interfering RNA], pDNA [plasmid DNA], gene editing tools such as CRISPR [clustered regularly interspaced palindromic repeats]/cas9 and oligonucleotides,” says Rajiv Kumar, PhD, principal scientist, Applied Research and Clinical Team, West Pharmaceutical Services (2,3).

Kumar notes that some current key focus areas in the LNP space revolves around designing new novel lipids, such as ionizable lipids to improve the efficiency of delivery and the release of encapsulated payloads from nanoparticles; targetability of LNPs; and improving the toxicity profile of LNPs (4,5). Despite LNPs accounting for the majority of nanoparticles for biologics drug delivery in clinical trials today, preliminary reports have begun to shine light on a new generation of hybrid nanoparticles, such as the combination of lipids and polymers, says Kumar. These reports have been showing high potential in these hybrid nanoparticles of successful biologic drug delivery (6), he adds.

“Polymer nanoparticles and microparticles have shown some early promise in delivery of proteins (peptides and antibodies), however, more work is required to fully utilize the potential of polymer nanoparticles for biologics delivery,” (7) Kumar states.

As LNPs are currently the most well-known and used nanoparticle technology today for biologic-based drug delivery, a closer look at their technical advantages can suggest further applications in the future.

According to Kumar, the types of advantages (3) that LNP systems convey over conventional drug delivery systems include:

Encapsulation: in the case of nucleic acid-based therapies, the encapsulation of nucleic acids in the core of nanoparticles protect them from degradation by nucleases, thus providing higher stability and protection.

Immunogenicity: LNPs minimize adverse immunogenic responses.

Size advantage: the size and compositions of LNPs enable the therapeutic payload, such as nucleic acids, to efficiently cross negatively charged cell membranes and be released into the cell’s cytoplasm.

Target-specific: targeting of specific disease sites or organs can be achieved by conjugating targeting molecules on the surface of LNPs.

Safety: the biodegradable nature of lipids used in LNPs provides a safe and non-toxic platform for delivering biological drugs.

However, despite the advantages that a nanoparticle technology-based drug delivery system may have, what are the risks inherent in their manufacture?

Kumar elaborates that LNPs are the most complex of manufactured nanoparticles in terms of composition and activity. For instance, each individual lipid component (ionizable lipid, helper lipid, cholesterol, and polyethylene glycol [PEG]-lipid) has a specific role—from encapsulation to formation of nanoparticles and from stabilization to successful delivery and therapeutic efficacy. “Although standard lipid components are in place, a precise tuning and optimization is required for designing a LNPs system for a specific biologic drug payload delivery,” (2) he explains.

In addition, LNP production requires an extremely precise process of mixing different components into specific ratios, says Kumar. The reason for this strict precision is to obtain monodisperse nanoparticles that have high encapsulation efficiency. Following initial production, the nanoparticles must then be purified by ultrafiltration/diafiltration processes to conduct buffer exchange and remove any impurities or solvents from nanoparticle suspension. Finally, the purified nanoparticles are sterile filtered before fill/finish (8).

Some of the key challenges in the manufacturing of LNPs are the quality of nanoparticles, which must be monodisperse and with a high payload content; they require highly precise and uniform mixing; and complex downstream processing, especially purification using ultrafiltration, Kumar highlights. Moreover, containment is a challenge. “One of the main risks is the selection of the right type of containment system (e.g., types of vials and stoppers), which still needs to be evaluated as some of the coatings can have an adverse impact on the quality/stability of nanoparticles during storage and transportation,” he explains.

Should the challenges and risks in nanoparticle production be mitigated, then the biopharm industry would have a powerful drug delivery system that, in the end, may alleviate patient concern over safety. Some of the key benefits for the biopharma industry include the availability of a flexible platform for encapsulating a variety of drugs, including hydrophobic drugs (i.e., most small-molecule drugs), hydrophilic drugs (i.e., biologics, protein therapeutics, antisense oligonucleotides), and highly negatively charged drugs (i.e., nucleic acids), emphasizes Kumar.

Furthermore, new disease targets would be accessible through the expedient of designing targeted nanoparticles systems, and combination therapies could be more feasible by means of designing nanoparticles systems that can encapsulate two drugs together for synergistic/combination effects, Kumar adds.

Meanwhile, the benefits to patients include better therapeutic outcomes since nanoparticle-based delivery of drugs results in higher therapeutic benefits compared to conventional drugs. In addition, because nanoparticles-based systems are designed to accumulate in a specific organ or disease site, the undesired side off-target effects typically seen with conventional drug delivery are minimized in patients. This benefit is especially attractive for some of the highly toxic oncology drugs, Kumar says.

A new area being explored in the field of drug delivery is the use of exosomes as delivery vehicles. Exosomes are naturally occurring nanovesicles derived from cells that play an integral role in intercellular transport of materials. It has been shown that exosomes can incorporatetherapeutics, such as small molecules or nucleic acid drugs, and deliver them to specific types of cells or tissues; that is to say, exosomes can achieve targeted drug delivery (9).

As above, the benefit of targeted drug delivery is that it increases local concentration of a therapeutic and can thus minimizes side effects. Exosome engineering, however, is still in its infancy. However, early research has shown that exosome-mediated drug delivery demonstrates low toxicity, low immunogenicity, and high engineerability (9).

Kumar notes that exosomes have been studied in biomarker applications and therapeutic agents in several degenerative diseases and oncology applications (10), but that they have already been deployed in several clinical trials and have shown satisfactory results in not only biomarker applications, but also as drug delivery systems, in vaccine applications, and as therapeutic agents themselves (11). However, although exosomes hold potential, their heterogenous nature pose manufacturing challenges, especially related to their isolation and purification. Manufacturing of exosomes requires further exploration and improved standardization, Kumar states.

The use of nanoparticle engineering may be agood solution for current challenges in the delivery of therapeutics, but overcoming manufacturing issues will be required to standardize production and ensure safety, efficacy, and efficiency.

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Volume 36, No. 9
September 2023
Pages: 8–10

When referring to this article, please cite it as Mirasol, F. Nanoparticle Engineering in Drug Delivery Under the Microscope. 

Nanoparticles offer the potential for a safer, more effective method of drug delivery to the patient.

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