Feliza Mirasol is the science editor for 

Feliza Mirasol

Evaluating Aseptic Processing and Manufacturing

Delving into Biopharmaceutical Development and Manufacturing

In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, and Feliza Mirasol, Science Editor, Pharmaceutical Technology Group, interview experts about aseptic processing and manufacturing. During the discussion, industry experts will evaluate the importance of aseptic processing and manufacturing, highlighting the challenges impacting industry, the intricacies of the regulatory landscape, the importance of understanding nuances between products and processes, the necessity of addressing QC/QA early on, best practices to ensure aseptic sterility, and potential future trends.

Maik W. Jornitz, Founder and Principal Consultant, BioProcess Resources

Maik W. Jornitz, founder and principal consultant of BioProcess Resources, is a 35-year veteran of the industry. He is highly experienced in single-use bioprocesses, aseptic processing, and a subject matter expert in sterilizing-grade filtration and filter integrity testing. He has published multiple books, book chapters and over 100 scientific papers on various bioprocessing and facility design topics. He is the former chair of the Parenteral Drug Association (PDA) board of directors and science advisory board, and member of multiple PDA Task Forces, including the European Union Annex I response team. He is board member and senior business and strategy advisor of DIANT Pharma. As a faculty member of various training activities, including PDA Training and Research Institute, he trains members of the industry and regulatory authorities frequently. In his previous roles, he was the CEO of G-CON for 10 years, he worked 26 years for Sartorius, with his last role being the senior vice-president for Global Product and Marketing Management Bioprocess. He received his Master of Engineering in Bioengineering at the University of Applied Sciences in Hamburg, Germany, and accomplished the Program for Executive Development at IMD Business School in Lausanne, Switzerland.

Dan Strange, PhD, Chief Technology Officer, Cellular Origins

Dan Strange has been working at the intersection of engineering and biology for almost 15 years, and he is an inventor on 20 patents. After completing a PhD in regenerative medicine at the University of Cambridge, he moved to TTP where he developed complex drug delivery devices. He was instrumental in the creation of multiple technology platforms successfully licensed to large pharma in deals worth over $100 million. For the past four years, Strange has focused on cell therapy manufacturing equipment. Strange is an active member of various automation working groups and was a reviewer on the Alliance for Regenerative Medicines A-Cell report on cell therapy manufacturing.

Drug Digest is a tech talk video series with the 

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In this episode of Drug Digest, discussion with industry experts will highlight the challenges impacting aseptic processing and manufacturing, the intricacies of the regulatory landscape, and the necessity of addressing QC/QA early on, among other critical aspects. 

Drug Digest: Evaluating Aseptic Processing and Manufacturing

Rentschler Biopharma, a biopharmaceutical contract development and manufacturing organization (CDMO), announced on Sept. 3, 2024, that it has launched an expanded service offering at Stevenage, UK, the company's advanced therapies site. With the expanded offering, Rentschler Biopharma now offers a new lentiviral vector (LVV) manufacturing toolbox for producing advanced therapy medicinal products (ATMPs), which complements the company’s existing adeno-associated virus (AAV) viral vector services.

The Stevenage site offers customized solutions for accelerating viral vector programs and includes novel, license-free toolboxes for AAVs and LVVs, according to a company press release. The company’s proprietary human embryo kidney 293 (HEK293) cell line offers additional time and cost savings for advanced therapy projects. The company’s services contributed to nearly 25% of FDA-approved biopharmaceuticals in 2023, Rentschler Biopharma stated in the press release.

“We made a strategic investment in the cell and gene therapy sector, starting with adeno-associated viral vector services, so we could offer our development and manufacturing expertise and sector experience to support innovators in this fast-developing space,” said Christiane Bardroff, chief operating officer, Rentschler Biopharma, in the press release. “We are now pleased to build on our success and augment this offering with lentiviral vectors. Our company remains dedicated to evolving our portfolio to enhance the health and quality of life for seriously ill patients around the world.”

Growing research and positive clinical results across a range of therapeutic applications has increasingly brought LVVs to the forefront in the advanced therapy space. Using LVVs for gene transfer has been applied to treat several genetic diseases, including beta-thalassemia. LVVs have also been used introduce genes to T-cells to modify them and generate immunity against cancer (1).

“The new lentiviral vector manufacturing toolbox highlights our commitment to providing cutting-edge solutions that enable our clients to advance their viral vector programs from pre-clinical and clinical development to market. By integrating lentiviral vector process development and manufacturing to our services, we are better serving the market by meeting the growing needs of the evolving and vibrant global advanced therapies sector,” said Robert Panting, general manager, ATMP, Rentschler Biopharma, in the press release.

Manufacturing LVVs has traditionally been difficult because 

, which are more delicate and sensitive than non-enveloped viruses. LVVs are therefore more sensitive to temperature, pH, shear, etc. (2).

Because of their sensitivity, purification approaches for LVVs are typically gentler, often applying one single-step chromatography and one concentration/buffer exchange step; however, final sterile filtration is still a challenge and may impact titer and yield. Designing a manufacturing process must therefore consider how to mitigate yield loss all along the way (2).

1. Ghosh, S.; Brown, A. M.; Jenkins, C.; Campbell, K. Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges. 

 (1), 7–18.
2. Mirasol, F. Comparing Viral Vectors for Gene Therapy Delivery. 

Articles

Rentschler Biopharma has expanded its service offerings at its Stevenage, UK, site with a new lentiviral vector manufacturing toolbox.

Rentschler Biopharma Offers New Toolbox for LV Manufacturing

AstraZeneca’s Imfinzi (durvalumab), a human monoclonal antibody (mAb), was approved by FDA earlier this month in combination with chemotherapy for treating adult patients with resectable early-stage (IIA-IIIB) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements. Following this regimen, patients are treated with Imfinzi in combination with neoadjuvant chemotherapy before surgery and as adjuvant monotherapy after surgery, according to an Aug. 16, 2024 company press release.

Also in August 2024, Imfiniza and Lynparza (olaparib) were approved throughout the 

 (EU) for treating certain patients with primary advanced or recurrent endometrial cancer (1). With this EU approval, Imfinzi plus chemotherapy can be used as first-line treatment, followed by treatment with Imfiniza and Lynparza (olaparib). In addition, Imfinzi, may be used to treat patients with mismatch repair proficient disease. A regimen using Imfinzi plus chemotherapy, followed by Imfinzi alone, can also be used for treating patients with mismatch repair deficient (dMMR) (1).

FDA’s latest approval was based on positive results from a pivotal Phase III trial (AEGEAN), which showed a statistically significant and clinically meaningful 32% reduction in the risk of recurrence, progression events, or death before and after surgery in patients treated with Imfinzi in combination with chemotherapy versus chemotherapy alone. These results were published in 

“This approval brings an important new treatment option that should become a backbone combination approach for patients with resectable non-small cell lung cancer, who have historically faced high rates of recurrence even after chemotherapy and surgery. When added both before and after surgery, durvalumab delivered a significant and meaningful improvement in outcomes in this curative-intent setting,” said John V. Heymach, MD, PhD, professor and chair Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, in the AstraZeneca press release.

Imfinzi was shown to be well tolerated, AstraZeneca stated in the press release. Furthermore, no new safety signals were observed in the neoadjuvant and adjuvant settings. Adding Imfinzi to neoadjuvant chemotherapy showed consistency with the known profile for this combination and did not compromise patients' ability to complete surgery, compared to chemotherapy alone.

“Today’s approval of Imfinzi in resectable early-stage lung cancer builds on its strong foundation of changing clinical practice in unresectable Stage III disease. We remain committed to bringing novel approaches [such as] AEGEAN to early lung cancer settings where cure is the goal of treatment,” said Dave Fredrickson, executive vice-president, Oncology Business Unit, AstraZeneca, in the press release.

In addition to the United States, Imfinzi is approved in the United Kingdom, Switzerland, and Taiwan (China) for this indication, also based on the Phase III (AEGEAN) results. Furthermore, the company has regulatory applications under review in the EU, China, and several other countries in this indication.

Further to its application in the treatment of lung cancers, Imfinzi is also approved in combination with chemotherapy (gemcitabine plus cisplatin) for treating locally advanced or metastatic biliary tract cancer and in combination with AstraZeneca’s Imjudo (tremelimumab), a mAb that blocks the activity of cytotoxic T-lymphocyte-associated protein 4 to aid in activating T-cells, for treating unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved in Japan and the EU as a monotherapy for unresectable HCC as well as in the US in combination with chemotherapy (carboplatin plus paclitaxel), followed by Imfinzi monotherapy, for treating primary advanced or recurrent endometrial cancer that is dMMR.

1. AstraZeneca. Lynparza and Imfinzi Combination Approved in the EU for Patients with Mismatch Repair Proficient Advanced or Recurrent Endometrial Cancer. Press Release. Aug. 14, 2024.
2. Heymach, J. V.; Harpole, D.; Mitsudomi, T.; et al. Perioperative Durvalumab for Resectable Non–Small-Cell Lung Cancer. 

 (18),1672–1684. DOI: 10.1056/NEJMoa2304875

Phase III trial results showed that Imfinzi (durvalumab in combination with chemotherapy reduced the risk of recurrence, progression, or death by 32% in patients with resectable non-small cell lung cancer before and after surgery.

AstraZeneca’s Imfinzi Gets Expanded Indication in Lung Cancer on FDA Approval

With the completion of its acquisition of Morphic Holding, a biopharmaceutical company developing oral integrin therapies for serious chronic diseases, earlier this month, Eli Lilly and Company (Lilly) boosts its immunology pipeline. Through the acquisition, Lilly gains MORF-057, Morphic’s selective oral small-molecule inhibitor of α4β7 integrin. The drug candidate is in development for treating inflammatory bowel disease (IBD), Lilly said in an Aug. 16, 2024 company press release.

The acquisition’s completion comes a month after Lilly first announced its intention in July 2024 to acquire Morphic in a strategic move to improve outcomes for patients with IBD (1). Under the agreement, Lilly began a tender offer to acquire all outstanding shares of Morphic for $57 per share in cash, or an aggregate amount of approximately $3.2 billion, payable at the close of the transaction. The transaction was approved by the boards of directors of both companies (1).

"We are committed to exploring innovative approaches for immunologic diseases and believe Morphic's pipeline holds promise in improving outcomes and expanding treatment options for people with devastating conditions [such as] IBD," said Daniel Skovronsky, MD, PhD, chief scientific officer of Lilly and president, Lilly Research Laboratories and Lilly Immunology, in the company press release.

MORF-057, Morphic's lead program, has the potential to improve outcomes and expand treatment options for IBD patients. MORF-057 is currently being evaluated in two Phase II studies in ulcerative colitis and another Phase II study in Crohn's disease. Morphic is additionally developing a preclinical pipeline of other molecules for treating autoimmune diseases, pulmonary hypertensive diseases, fibrotic diseases, and cancer (1).

"Acquiring Morphic reinforces our growing capabilities in gastroenterology, building on the strong foundation of Omvoh, our first-in-class molecule already approved and launched around the world for ulcerative colitis and under regulatory review for Crohn's disease. Further, the acquisition allows Lilly to research potential combination treatments that could better serve people beyond what is possible with currently available medicines," Skovronsky also said in the release. Lilly’s Omvoh (mirikizumab-mrkz) is indicated in the United States for treating moderately to severely active ulcerative colitis in adults.

In an earlier move this month, Lilly opened its Seaport Innovation Center (LSC) in Boston, Mass., which serves as a R&D facility in the Boston Seaport district for advancing the company’s efforts in RNA and DNA-based therapies. The center will also conduct R&D for discovering new drug targets for developing therapeutics across several disease areas, including diabetes, obesity, cardiovascular diseases, neurodegeneration, and chronic pain (2).

LSC is housed in a 12-story building and totals 346,000 square feet. The new site includes laboratories and office space. It will also house the first Lilly Gateway Labs location on the East Coast of the US. Lilly’s goal is to foster a culture of shared expertise and real-time learning in the hopes of accelerating the development of novel medicines. The center is expected to accommodate approximately 500 Lilly scientists and researchers as well as 200 people from companies within Lilly Gateway Labs.

1. Eli Lilly and Company. Lilly to Acquire Morphic to Improve Outcomes for Patients with Inflammatory Bowel Disease. Press Release. July 8, 2024.
2. Eli Lilly and Company. Lilly Opens State-of-the-Art Research and Development Center in the Boston Seaport. Press Release. Aug. 13, 2024.

The completed acquisition of Morphic expands Lilly's immunology pipeline with Morphic's oral integrin therapies for treating inflammatory bowel disease.

Completion of $3.2 Billion Morphic Acquisition Expands Lilly’s IBD Portfolio

Merck, known as MSD outside of the United States and Canada, entered into a definitive agreement earlier this month with Curon Biopharmaceutical (Curon), a privately held biotechnology companyunder. With the agreement, Merck, through one of its subsidiaries, will acquire full global rights to CN201, Curon's novel investigational clinical-stage bispecific antibody for treating B-cell associated diseases.

The deal is worth potentially up to $1.3 billion, comprising an upfront payment by Merck of $700 million in cash and up to $600 million in milestone payments for which Curon is eligible, contingent upon the development and regulatory approval of CN201, according to an Aug. 9, 2024 company press release. The transaction is expected to close in the third quarter of 2024, subject to customary closing conditions.

“We continue to identify opportunities to expand and diversify our pipeline,” said Dean Y. Li, MD, PhD, president, Merck Research Laboratories, in the press release. “Early clinical data have provided robust evidence for the potential of CN201 to target and deplete circulating and tissue B cells with the potential to treat a range of malignant and autoimmune diseases.”

CN201, a novel CD3xCD19-targeting T-cell-engager bispecific antibody, is designed to target B cells for elimination by T cells. It is currently being evaluated in a Phase I clinical trial for treating relapsed or refractory non-Hodgkin’s lymphoma and in a Phase Ib/II clinical trial for treating relapsed or refractory acute lymphocytic leukemia. According to preliminary data, CN201 demonstrated activity in patients with relapsed or refractory B-cell hematologic malignancies and has been shown to be well tolerated. It has demonstrated the potential to induce significant and sustained reductions in B-cell populations. Merck aims to evaluate CN201 as a treatment for B-cell malignancies and investigate its potential to provide treatment for autoimmune diseases.

“This agreement reflects the drive and dedication of the Curon team,” said Zhihong Chen, president and CEO, Curon, in the press release. “As a pioneer in immuno-oncology, Merck is well positioned to build upon the work done to-date and investigate the wide-ranging, first-in-class potential of CN201.”

Also in August, Merck expanded its existing co-development and co-commercialization agreement with Daiichi Sankyo for three investigational derivatives of exatecan (DXd) antibody-drug conjugates (ADCs). Under the expanded agreement, Merck’s investigational delta-like ligand 3 (DLL3) targeting T-cell engager, MK-6070, was added, and the companies will jointly develop and commercialized the drug candidate worldwide, except in Japan where Merck will retain exclusive rights, according to an Aug. 6, 2024 company press release. Merck will have sole responsibility for manufacturing and supply for MK-6070.

Under this expanded agreement, Merck gets an upfront payment of $170 million in cash; it has also satisfied a contingent quid obligation from the original collaboration agreement with Daiichi Sankyo. Meanwhile, both companies will share R&D and commercialization expenses and profits worldwide, excluding Japan. For Japan, while Merck retains exclusive rights, Daiichi Sankyo will receive sales-based royalties. Furthermore, R&D expenses related to MK-6070 in combination with ifinatamab deruxtecan will be shared between the companies according to their original agreement for ifinatamab deruxtecan.

MK-6070 is currently being evaluated in a Phase I/II clinical trial as a monotherapy in certain patients with advanced cancers associated with the expression of DLL3 and in combination therapy with atezolizumab for treating certain patients with small cell lung cancer (SCLC). In March 2022, FDA granted MK-6070 orphan drug designation for treating SCLC.

1. Merck. Daiichi Sankyo and Merck Enter into Global Development and Commercialization Agreement for MK-6070. Press Release, Aug. 6, 2024.

Merck, known as MSD outside of the United States and Canada

Merck, known as MSD outside of the United States and Canada, will gain CN201, a next-generation bispecific antibody, from Curon Biopharmaceutical in a  deal potentially worth up to $1.3 billion. 

Merck to Gain Investigational Bispecific Antibody in $1.3 Billion Curon Biopharmaceutical Deal

Andelyn Biosciences, a patient-focused cell and gene therapy contract development and manufacturing organization, announced on Aug. 6, 2024 that it has entered into a license agreement with the Broad Institute of MIT to include MyoAAV plasmids in its AAV Curator Platform, which expands the platform’s offerings.

Under the agreement, Andelyn will have use of the MyoAAV plasmids to perform research and development services for clients who are developing gene therapies. Andelyn will screen potential candidates and perform scale-up and pre-clinical development work to prepare for investigational new drug-enabling studies. The agreement also gives Andelyn permission to sublicense the MyoAAV plasmids to its clients for internal research purposes.

The MyoAAV plasmids were developed by researchers at the Broad Institute of MIT and Harvard. They are a new family of plasmids that produce adeno-associated viruses (AAVs) ten times more efficient in reaching muscle tissue and targeting the liver than wild-type vectors, according to a company press release. “With more precise targeting of muscle tissue, research shows MyoAAV-delivered therapies may require lower dosing,” Andelyn stated in the press release.

Andelyn will utilize its expertise in translational drug development to bring Broad's new class of engineered AAVs to biotech organizations as they target diseases in therapeutic areas with significant unmet need. The company expects that the new AAVs will ultimately reduce the effective dose demand while improving product safety.

“Our license from the Broad Institute furthers our goal of providing the industry access to critical tools and capabilities that facilitate the development of innovative therapies to bring more treatments to more patients. With access to the increased specificity of MyoAAVs, our clients now have the opportunity to maximize efficiency in their gene therapy processes and drive down the cost per patient,” said Matt Niloff, chief commercial officer of Andelyn, in the press release.

In May 2023, Andelyn was selected to manufacture AAV therapies using its Curator Platform under the California Institute for Regenerative Medicine (CIRM) Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC) (1).

CIRM established a partnership with Andelyn to advance BGTC’s goal of developing platforms and standards that will drive the development and delivery of customized or “bespoke” gene therapies for rare diseases. BGTC is focused on developing cures for eight such rare diseases. Andelyn’s role will be to optimize and scale the AAV gene therapy processes for treating congenital hereditary endothelial dystrophy–type 1.

“As a long-standing pioneer in AAV gene therapies and historical connection to the clinic, we have great synergies with the CIRM/BGTC. Andelyn is privileged to work with the CIRM/BGTC on its first AMP established specifically for rare disease and leverage our AAV Curator Platform to help overcome the major obstacles related to developing gene therapies,” Niloff stated in a company press release (1).

1. Andelyn Biosciences. Andelyn Biosciences Selected as Viral Vector Manufacturing Partner for the California Institute for Regenerative Medicine (CIRM) Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC). Press Release, May 23, 2024.

With the agreement, Andelyin Biosciences will add MyoAAV plasmids developed by Broad Institute of MIT and Harvard to its AAV Curator Platform.