Susan Haigney

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FDA’s Patrizia Cavazzoni, director, Center for Drug Evaluation and Research (CDER), and Peter Marks, director, Center for Biologics Evaluation and Research (CBER), provided an update on the agency’s 

 (the Hub) in a Nov. 1, 2024 FDA Voices blog post (1). The Hub was created in July 2024 (2) as a cross-center program that operates as a single point of engagement with stakeholders in the development of treatments for rare diseases. The Hub is the agency’s way of creating a community that can share new approaches for drug development for rare diseases.

In establishing the Hub, FDA gathered feedback from stakeholders through a public meeting, held on Oct. 16, 2024 in collaboration with the Reagan-Udall Foundation. The meeting included advocates from rare disease patient groups, academics, regulators, and other stakeholders who discussed how the Hub can work with the community to prioritize work.

A Hub director was also appointed. Amy Comstock Rick will be the Director of Strategic Coalitions for the Hub and be accountable to both Cavazzoni and Marks. Previously, Ms. Rick worked as a consultant at Leavitt Partners and was president and CEO of the Food & Drug Law Institute.

“Ms. Rick brings to this new role more than 20 years of experience as a leader and trusted ally in advocating for policies throughout healthcare, biomedical research, and nonprofit communities, which includes extensive engagement with patient communities and government agencies on issues related to rare diseases. We are excited to have her join and begin creating the important partnerships needed to strengthen the Hub’s engagement throughout the rare disease community,” stated Cavazzoni and Marks in the blog post.

As part of their work with the Hub, Marks and Cavazzoni plan on collaborating with other FDA centers that work with rare diseases, such as the Center for Devices and Radiological Health, the Oncology Center of Excellence, and the Office of Orphan Products Development. In addition, a Rare Disease Innovation Hub Steering Committee has been established to bring the groups together, and a new CBER-CDER Rare Disease Policy and Portfolio Council has been created. The council will bring experts from the different FDA centers together to discuss scientific, regulatory, and policy issues.

“The collaborative model of the Hub will build upon the knowledge and skills of staff within their respective centers, promote adoption of best practices, and avoid confusion over decision-making authorities within those organizations. Meetings between the FDA and sponsors relating to specific drug or biological products will remain the same, as will the way decisions are made about specific programs and how advisory committee meetings are structured and run,” Cavazzoni and Marks stated. “By working together, we believe that we can further facilitate the development, evaluation, and availability of safe and effective therapies. We are committed to ongoing and open communication and look forward to continuing this dialogue with the rare disease community.”

Cavazzoni, P. and Marks, P.FDA Takes Exciting Steps Toward Establishing the Rare Disease Innovation Hub. 

https://www.fda.gov/news-events/fda-voices/fda-takes-exciting-steps-toward-establishing-rare-disease-innovation-hub

FDA. FDA Rare Disease Innovation Hub to Enhance and Advance Outcomes for Patients.

Articles

CDER Director Patrizia Cavazzoni and CBER Director Peter Marks provided an update on the rare disease innovation hub in a new FDA Voices blog post.

FDA Rare Disease Innovation Moves Forward

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Abzena, an end-to-end contract development and manufacturing organization, is expanding its quality control testing capabilities at its San Diego, Calif., biologics development and current good manufacturing practice site, the company announced on Oct. 30, 2024. The expansion is part of the company’s strategy to meet market demand for quality testing. According to Abzena, the additional laboratory space will enhance its existing analytical toolkit for antibodies with microbiology release testing. The expansion will also improve scalability with advanced materials separation.

The standalone microbiology lab offers separate product testing from other areas of the facility, in alignment with industry and regulatory standards. Product microbiological testing is segregated from utility and environmental microbiological testing in order to minimize cross-contamination. Production capacity is optimized by the separation of high volumes of clinical materials, which results in yields up to 99%, according to the company. “This design methodology offers superior operational efficiency and improved scalability while minimizing overall ecological impact,” the company stated in a press release (1).

“This announcement comes at a very timely moment with World Quality Month quickly approaching. As an organization focused on quality excellence, increasing our QC [quality control] footprint is a testament to our commitment to continuous improvement and innovation,” said Troy Wright, senior vice-president and global head of Quality at Abzena, in the release. “This expansion provides even greater sample integrity in the management of our microbiological testing capabilities. We are now positioned to deliver faster results and better support for our customer network, ultimately providing quality and compliant products to patients around the world.”

In other Abzena news, the company announced on Sept. 26, 2024 that its mammalian cell line development platform, AbZelectPRO, reduces timelines by more than 30% and improves overall protein production levels. The platform can bridge from DNA to research cell bank in 10 weeks and produces up to 8 g/L of high-performing titres before process development, according to the company (2).

Abzena recently attended CPHI Milan in October 2024, and 

caught up with Nicolas Camper, senior director—Bioconjugation Chemistry at Abzena, to talk about advancements in conjugation and linker technologies in antibody-drug conjugate (ADC) development and manufacturing (3).

“There have been a lot of new developments in terms of conjugation and linker technologies. There is a definitive move towards site-specific conjugation technologies and away from stochastic conjugation approaches that allows [us] to prepare better-defined antibiotic-[drug] conjugates,” Camper said in the interview.

Another new development that has been observed over the past few years is that linkers are becoming more sophisticated. “Quite often, when you conjugate cytotoxic drugs, they are quite hydrophobic, and that can impact the performance of your ADC. So, there has been a lot of effort put into developing more hydrophilic linkers,” Camper noted.

Abzena. Abzena Announces Major Expansion in Microbiology Laboratory Space in Suppor of Biologic Manufacturing. Press Release. Oct. 30, 2024.

Abzena. AbZelectPRO Enables Biopharma Customers to Reach their Research Cell Bank in 10 weeks with 8g/L. Press Release. Sept. 26, 2024.

Mirasol, F. CPHI Milan 2024: New Developments in ADC Technologies. 

The company will be expanding its quality control testing capabilities at its San Diego, Calif. biologics development and manufacturing site.

Abzena Expands Microbiology Laboratory Space

The World Health Organization (WHO) announced on Oct. 29, 2024 that it has activated the Global Health Emergency Corp (GHEC) in collaboration with Member States and other partners in response to mpox outbreaks (1). This is the first time GHEC, which was established by WHO in 2023 as a response to COVID-19, has been activated to support countries dealing with mpox. Leaders from affected and other countries met on October 22 as part of the GHEC activation to discuss effect control measures, best practices, and the coordination of efforts.

Mpox was declared as a public health emergency by WHO in August of 2024 (2). “The emergence of a new clade of mpox, its rapid spread in eastern DRC [Democratic Republic of the Congo], and the reporting of cases in several neighboring countries are very worrying. On top of outbreaks of other mpox clades in DRC and other countries in Africa, it’s clear that a coordinated international response is needed to stop these outbreaks and save lives,” WHO Director-General Tedros Adhanom Ghebreyesus, PhD, said at the time of the announcement (2).

“WHO and partners are supporting the government of the Democratic Republic of the Congo and other countries to implement an integrated approach to case detection, contact tracing, targeted vaccination, clinical and home care, infection prevention and control, community engagement and mobilization, and specialized logistical support,” said Mike Ryan, MD, executive director of WHO’s Health Emergencies Programme, in the October 29 press release (1). “The GHEC enhances the ability of the many effective responders at national and regional levels to collaborate and ensure the success on the ground in interrupting transmission and reducing suffering.”

GHEC’s objective is to strengthen the response to health emergencies and provide a platform in which countries and health networks can collaborate the response, including deployment of experts and leaders. GHEC is assessing workforce capacities in eight countries including DRC and Burundi, which have been the most impacted by the mpox outbreak. There have been 22 areas identified by GHEC that are in need of epidemiology, surveillance, laboratory capacity, infection prevention, risk communication, and community engagement. WHO has deployed 55 experts to the impacted countries, as of October 17, that include WHO staff through the Global Outbreak Alert and Response Network (GOARN) and the African Volunteers Health Corps. GOARN is also mapping partner support on a bilateral basis to impacted countries and the coordination structure in the region, including providing experts, supplies, financial support, and strengthening capacity.

“By mobilizing trained professionals from within the continent, we ensure that responses are not only timely but also contextually relevant,” said Abdou Salam Gueye, MD, PhD, regional emergency director for the WHO Regional Office for Africa, in the press release (1). “The dedication and expertise of these responders are essential in saving lives and building resilient health systems capable of withstanding future threats.”

In other mpox news, a report based on outcomes of a workshop held on Oct. 2, 2024 by the International Coalition of Medicines Regulatory Authorities was announced by the European Medicines Agency on Oct. 25, 2024. The current epidemiological status and the availability of mpox vaccines in African countries was discussed during the workshop. Discussion at the workshop was focused on the prioritization of treatments for children because children are the most vulnerable group in the DRC and have the highest fatality ratio (3).

WHO. WHO and Partners Activate Global Health Emergency Corps for the First Time in Response to Mpox Outbreak. Press Release. Oct. 29, 2024.

WHO. WHO Director-General Declares Mpox Outbreak a Public Health Emergency of International Concern. Press Release. Aug. 14, 2024.

EMA. Fostering Regulatory Collaboration to Improve Access to Mpox Medicines. Press Release. Oct. 25, 2024.

WHO and its partners are providing support to countries dealing with mpox outbreaks.

WHO Activates Global Health Emergency Corp in Response to Mpox

Arrow speed abstract blue background, communication data transfer technology concept. | Image Credit: ©Suppachok N

Emerging therapies and new modalities, such as cell and gene therapies (CGTs), have developed fast in the past decade. This ever-evolving development of not only new formulations but also new delivery methods has created an ever-complicated industry. Technology transfer is a critical step in drug manufacturing, specifically when contract manufacturers are involved.

 an efficient technology process ensures transferrable processes. “A well-defined and robust technology transfer process involves a systematic approach to transferring manufacturing processes, protocols, and knowledge from the research and development phase to the clinical and potentially commercial manufacturing setting” (1). “This process ensures the developed cell and/or gene therapy can be produced consistently, efficiently, and in compliance with regulatory requirements. The same requirements exist for transferring analytical methods to contract development and manufacturing organizations (CDMOs) or equivalent” (1).

“Tech transfer becomes more complex with emerging therapies and new modalities, particularly in method transfer, as these therapies are often derived from living cells, making consistency challenging to maintain,” says Satish Shetty, senior director, Product Development & Project Management, Halo Pharma (part of the Noramco Group). “Additionally, the manufacturing processes are highly intricate and rely on specific environmental and process conditions, which further complicates the transfer.”

Ahmed Youssef, senior manager USP, Process Development at Ascend, points to timing as being key for technology transfer with emerging therapies. “It takes an innovator around 12 to 24 months to make a product ready, tech transfer it, [and] complete the safety studies for it,” says Youssef. “But there could be other solutions that could be offered in the background that could make this more efficient, faster, and more attractive to product developers.”

Planning for technology transfer is essential, according to Hewitt 

 A smooth transfer requires careful evaluation, strategic decision making, and planning (1). Risk assessments are also crucial at this stage. “By proactively addressing these risks and implementing mitigation strategies during the initial assessment and planning stage, organizations can enhance the efficiency, reliability, and safety of the transfers” (1).

“A continuous feedback loop also encourages ongoing learning, incorporating insights from manufacturing teams into refining protocols. Regulatory alignment ensures compliance and adherence to guidelines. In essence, successful knowledge transfer ensures that the innovation harnessed in research is translated effectively, leading to consistent, high-quality outcomes in CGT manufacturing and accelerating the availability of transformative treatments to patients in need” (1).

Patient-centric therapies that might require small-batch manufacturing require flexible approaches to technology transfer, according to Andréa Simard, manager, Technical Services, Halo Pharma (part of the Noramco Group). This is particularly true for CDMOs that usually perform large-scale manufacturing. “Equipment train must be adjustable, and in-process control strategies should ensure process capability while meeting clinical or commercial needs,” Simard says. “Quality must be designed into the product through good knowledge of input materials and a robust manufacturing process, so that endpoint confirmation does not require extensive sampling and testing, which can greatly reduce the units available for the patients.”

However, Youssef remarks that tech transfer is a similar process no matter what batch size is involved. “Normally, when you tech transfer, you need to take risk-based approaches [and] appropriate measures to be able to tech transfer [a] process successfully and properly,” he says.

Brianna Kempfer, project manager at Sterling Pharma Solutions agrees. “The process of tech transfer is much the same, no matter the scale; a CDMO must evaluate the information provided: assessing any potential hazards, the scientific feasibility, and qualify the necessary synthetic and analytical methods. Through laboratory scale work, chemistry can be optimised and demonstrated to understand which parameters of the process are the most critical when scaling up and manufacturing.”

The smaller scale of patient-centric medicine production offers options for process development such as reagent and solvent choice, according to Kempfer. “Because of the smaller volumes of manufacturing, the costs of goods are usually higher, and so development of an efficient process that minimiszs potential losses in purification and isolation steps is crucial.”

One must understand technologies involved in formulation, as well, stresses Simard. “For example, formulation must consider patient-specific factors such as taste masking for bitter drugs or ease of administration for pediatric and geriatric populations,” she says. “Additionally, specialty packaging plays a crucial role in simplifying complex dosing regimens, making it easier for patients to adhere to treatment plans.”

Many bio/pharma outsourcing organizations have been moving to become full-service, end-to-end CDMOs. But does working with a contractor who offers services from every step of a drug’s lifecycle improve technology transfer. It depends, asserts Youssef. “If you mean by end to end, the whole process, from the start of plasmid manufacturing till commercial manufacturing of the batches and then the fill and finish and release, understand that the advantage would be that you're running all of that under one MSA [master supply agreement], one big MSA. But know that, not all CDMOs are expert and skilled in each unit operation when they offer the end-to-end process,” says Youssef.

Shetty points out that there are several reasons why tech transfer may be less complicated with an end-to-end service provider. “[A] unified sending unit (SU) and receiving unit (RU) enable seamless knowledge transfer. Tech transfers are often complicated by development knowledge getting lost through site transfers, and delays from having to set up project logistics at a new CDMO, so having both teams in the same organization is a solid advantage.”

End-to-end service providers often provide consistency in the equipment used between the different phases of development and manufacture, notes Shetty. There is also often the same project manager and core team involved, as well as the same excipient grades and reduced supply lead times. End-to-end providers also feature “fewer knowledge gaps and better identification of potential scale-up issues,” according to Shetty. “Consolidating R&D and supply chain expertise minimizes logistical delays and fosters smoother transitions, troubleshooting, and overall customer experience,” Shetty concludes.

“When scaling up between clinical phases and commercial launch, it is common for a process to move between sites, and potentially between countries, within an end-to-end provider, so this results in the need for a tech transfer. Whether this is an internal or external transfer, there is little difference in the process that needs to be undertaken,” says Kempfer.

When it comes to sponsors and contract organizations working together to ensure a secure tech transfer, Youssef specifies that the CDMO should shoulder the responsibility. “A good CDMO [should] have structured communication, because communication is key … when you're talking to your business partner. We always build that in a more collaborative environment,” says Youssef. “[A CDMO needs] to protect the IP [intellectual property] rights of their clients, their partners, as well as good documentation practices, in addition to a solid IT department. All of that gives the assurance to the security of the data and the security of the transfer information between the CDMO and their partner.”

Simard stresses that communication is key for secure tech transfer. “The first step is to define success criteria and core values, ensuring both parties have a mutual understanding of each other's capabilities, limitations, and the project's critical milestones. When issues arise, they should be treated with speed and transparency in an atmosphere fostering collaboration rather than finger-pointing, so that solutions and a path forward may be found as a team,” Simard says.

Expectations, milestones, goals, and needed processes should be communicated and understood, says Kempfer. “The more information that can be shared at the start will reduce the potential of unexpected problems; however, having a transparent relationship between parties, where communication is open will allow progress to be monitored, and any issues that do arise to be shared and understood as quickly as possible. Having a key point of contact within the CDMO who can liaise with all of the key members of the project team across multiple disciplines, allows a customer to gain direct access to progress and ensure that communication is as efficient as possible,” Kempfer states.

Trust and transparency should be established, confirms Shetty. Differences in facilities and excipients should be understood, and process documentation should be simplified. “[One should] ensure regular communication between subject matter experts, rather than relying solely on project managers,” Shetty summarizes. “[Sponsors and contractors should] proactively work as a team to identify and resolve potential issues [and] focus on a common goal that benefits both parties.”



1. Hewitt, M.; Bellot, L.; Anderson, C. Best Practice Tech Transfer Methods for CGTs. 

Emerging therapies, patient-centric medicines, and the ever-changing world of bio/pharmaceuticals complicate technology transfer.

Tech Transfer in the New World of New Modalities

The European Medicines Agency (EMA) announced on Oct. 25, 2024 that international regulators have published a report based on outcomes of a workshop held on Oct. 2, 2024 by the International Coalition of Medicines Regulatory Authorities (ICMRA) (1). The workshop, which was held virtually, included representatives from international medicine regulatory authorities, such as FDA, EMA, and the Japan Pharmaceuticals and Medical Devices Agency, and the World Health Organization (WHO) to discuss access to mpox medicines during an outbreak. WHO declared mpox a public health emergency of international concern in August 2024.

The current epidemiological status and the availability of mpox vaccines in African countries was discussed during the workshop. The use of mpox vaccines in pregnant people and in children was also discussed, specifically efforts to fill the gap of evidence for these patient groups. Attendees also discussed effectiveness surveillance systems and regulatory pathways for mpox vaccine and drug approvals. The need for large clinical trials was emphasized by participants so that the appropriate evidence may be generated to quickly develop and approve these medicines.

“One of the major challenges during these outbreaks has been the unequal availability of medical interventions, such as antivirals and vaccines, with low-income countries in Africa facing the greatest difficulties. While high-income countries were able to access vaccines more readily, African countries, where mpox is endemic, have struggled with delayed regulatory approvals and inaccessible prices,” the report states (2).

According to the report, children are the most vulnerable group in the Democratic Republic of Congo and have the highest fatality ratio. Because of this, the workshop discussion prioritized pediatric treatments. FDA granted emergency use authorization for the MVA-BN vaccine for children; this vaccine has been used in the United States safely. Canada has authorized the vaccine for people 18 or older but has made a discretionary recommendation for use in children. EMA expanded the indication for the vaccine to be used in children 12 to 17 years old.

“There is limited evidence for the use of MVA-BN vaccine in pediatric populations under 12 years of age; the safety profile is however not expected to be different in this population. The WHO Strategic Advisory Group of Experts on Immunization has also recommended that the MVA-BN vaccine can be used in children if the benefits outweigh the risks,” the report states (2). “For these reasons, regulators within ICMRA stand ready to support decisions in countries most affected, including for use in children less than 12 years of age. However, misinformation is of concern and robust communication strategies need to be implemented.”

During the workshop it was recommended that a dose-sparing strategy using the intradermal route of administration be considered due to the gaps in the vaccine supply and the number of doses that are needed for high impacted countries. It was also recommended that a different vaccine, LC16m8, be considered, as it is currently approved for use in all age groups in Japan.

New vaccine development discussion brought to attention the different regulatory pathways for approval and that alternatives to placebo-controlled studies should be considered, as well as alternative methods of administration.

“ICMRA unanimously agreed that fragmentation in clinical research, as has happened so far with mpox, must be avoided, as studies need to be conducted rapidly and efficiently in the best interest of patients. More collaboration towards merging efforts from investigators into larger unified clinical trials is advocated,” the report states.

ICMRA. Summary Report of the International Coalition of Medicines Regulatory Authorities (ICMRA) Workshop on Mpox, October 2, 2024. 

https://www.icmra.info/drupal/news/mpox_news_announcement_25oct2024/mpox_ws_report_2oct2024

The report highlights international regulators’ plans for the development and availability of vaccines to prevent and drugs to treat mpox.

Regulatory Collaboration on Mpox Treatments Summarized in Report

Science laboratory test tubes, laboratory equipment | Image Credit: © BillionPhotos.com - © BillionPhotos.com - stock.adobe.com

Modifi Biosciences, a company formed in 2021 as a spinout of technology developed at Yale University, announced on Oct. 23, 2024 that it is being acquired by Merck, known as MSD outside of the United States and Canada (1). Modifi Biosciences develops direct DNA modification enabled cancer treatments. The novel class of small molecules target a DNA repair protein called O6-methylguanine methyl transferase (MGMT). The company’s research was published in 

in 2022 (2) and has had pre-clinical data amassed through a number of tumor models, including patient-derived xenograft models of gliomas.

“In founding Modifi Biosciences, we sought to radically change the oncology treatment paradigm for cancer patients with glioblastoma and other tumors,” said Ranjit S. Bindra, MD, PhD, Modifi Biosciences co-founder, Harvey and Kate Cushing, professor of Therapeutic Radiology at Yale School of Medicine, and scientific director of the Yale Brain Tumor Center at Smilow Cancer Hospital, in a press release. “We are honored to have Merck recognize the potential of our science, and as an oncology company, they are perfectly positioned to advance our innovations through clinical trials and commercialization.”

“DNA repair defects are a frequent hallmark of tumor cells and a major cause of resistance to cancer therapy,” said David Weinstock, MD, vice-president, discovery oncology, Merck Research Laboratories, in the release. “The talented Modifi Biosciences team has developed an innovative approach that we believe has potential for treating some of the most refractory cancer types.”

“We designed our small molecules to have the ability to uniquely overcome clinical resistance mechanisms that have been known for decades but until now have been non-actionable. Additionally, we created the molecules in a manner which allows them to be rapidly progressed from bench-to-bedside,” said Seth Herzon, PhD, Modifi Biosciences co-founder and the Milton Harris ’29 PhD Professor of Chemistry in Yale’s Faculty of Arts and Sciences and professor of Pharmacology and Therapeutic Radiology at the Yale School of Medicine, in the release.

The acquisition agreement has Merck, through a subsidiary, taking possession of all outstanding shares of the company for $30 million with potential milestone payments up to $1.3 billion.

In other news by Merck, the company entered into a license and collaboration agreement in October with Mestag Therapetuics, a Cambridge, UK-based biotech company to identify novel targets for inflammatory disease treatments, using Mestag’s reversing activated fibroblast technology platform. The proprietary platform models the pathogenic role of fibroblasts in human disease.

“Mestag was founded on … insights into fibroblast–immune biology, and as an early innovator in this area of research, we have built a robust pipeline of antibody programs and created a unique and productive target discovery platform,” said Susan Hill, PhD, chief executive officer of Mestag, in a company press release (3). “We are acutely aware of the significant unmet needs faced on a daily basis by patients suffering from inflammatory diseases. We are thrilled to collaborate with [Merck], together driving continued innovation for the benefit of patients.”

Modifi Biosciences. Modifi Biosciences Acquired by Merck. Press Release. Oct. 23, 2024.

Lin, K.; Gueble, S.E.; Sundaram, R.K.; Huseman, E.D.; Bindra, R.S.; Herzon, S.B. Mechanism-based Design of Agents that Selectively Target Drug-resistant Glioma. 

Mestag Therapeutics. Mestag Therapeutics Announces License and Research Collaboration with MSD to Identify Novel Targets for Inflammatory Diseases. Press Release. Oct. 8, 2024.

Merck is acquiring the Yale-spinout, which develops direct DNA modification-enabled cancer treatments. 