Susan Haigney

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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. 

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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

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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.

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

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

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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. 

Merck Acquires Modifi Biosciences

Retrofitting Facilities for Cell and Gene Therapy Production

In his episode of Ask the Expert, Peter Walters, Fellow of Advanced Therapies at CRB Group, discusses the retrofitting of older and/or solid-dosage facilities into sustainable cell and gene therapy manufacturing facilities. According to Walters, cell and gene therapy facilities can be made very lean and sustainable, with some being 100% electric.“A lot of that has to do with the fact that there isn't a huge utility draw for that process,” says Walters. “A lot of those materials are going to be typically purchased and either made off site and brought in, or are made on site, but are low water usage, low utility usage.”

Walters says that, when retrofitting a facility, air handling, air locking, and personnel flows are factors to consider. “Cell therapy facilities tend to have at least a handful of spaces that want to be very high classified, and so you're [going to] need not only the air handling—ability to push a lot of air through those spaces in a very clean manner—but the air locking to get the material segregation movements [and] the personnel flows to get into those highly classified spaces. As we talk about gene therapy, sometimes viral vector spaces want to be BSL [biosafety level] spaces. They want to have certain levels of segregation. It's not uncommon to see vector facilities that have [a] two-corridor system; one dedicated to the supply of materials and one dedicated to outgoing waste and outgoing materials, and that helps drive segregation of flows and materials through your facility. It can be difficult to find a facility that's set up in such a way [as] to facilitate an easy retrofit.”

Click the video above to watch Walters answer the following question:

We wish to retrofit our solid-dosage facility into a sustainable facility for cell and gene therapy commercialization. What kind of cost should we expect?

Peter Walters is Fellow of Advanced Therapies at CRB Group.

Welcome to the Ask the Expert video series. This series is an extension of the PharmTech Group’s long-running print column in which industry experts answer common quality and regulatory questions from the industry. This new video series will expand on topic areas to include development and manufacturing concerns to help those working in the industry better understand bio/pharmaceutical requirements. Have a question you would like answered? Send it to 

, and it may appear in a future episode or print column.

Videos

In this episode of the Ask the Expert video series, Peter Walters, Fellow of Advanced Therapies at CRB Group, discusses how facilities used for solid dosage manufacturing may be retrofitted into sustainable cell and gene therapy production facilities.

FDA has approved a vaccine to prevent lower respiratory tract disease resulting from the respiratory syncytial virus (RSV) in adults 18 to 59 years of age who are at increased risk, Pfizer announced on Oct. 22, 2024. The bivalent RSV prefusion F vaccine, Abrysvo, has a broader indication to include those younger than 60 and is the only RSV vaccine approved in pregnant people who are at 32 through 36 weeks of gestation, and infants from birth to six months of age, according to the company (1).

“In the prefusion state, the RSV fusion protein (F) is a major target of neutralizing antibodies, serving as the basis of Pfizer’s RSV vaccine. Variations in the F protein sequence among RSV-A and RSV-B subgroups are clustered in a key antigenic site, a target for potent neutralizing antibodies,” stated the company (1).

According to Pfizer, FDA made its decision based on results from a Phase III clinical trial(NCT05842967), MONeT (RSV I M munizati ON Study for Adul T s at Higher Risk of Severe Illness), which looked at the safety and efficacy in adults with certain chronic medical conditions, such as asthma and diabetes.

“Immunocompromised adults, such as patients with cancer or autoimmune disorders, have a substantially increased risk of experiencing severe complications from RSV, yet there are currently no vaccines approved for those aged 18 to 59 in the [United States],” said Annaliesa Anderson, Pfizer senior vice president and chief scientific officer for vaccine research and development, in an August 2024 press release about the results (2). “We are encouraged by the positive top-line data from this study, which provide important evidence that Abrysvo has the potential to address a significant unmet need in this vulnerable population.”

“RSV represents a significant threat to younger adults with certain chronic conditions. After decades of vaccine research by the scientific community and Pfizer, we now have the opportunity to help alleviate the burden of RSV in this high-risk adult population,” said Aamir Malik, chief US commercial officer and executive vice president, Pfizer, in a press release (1). “With this approval, we are proud that Abrysvo is now the only RSV vaccine indicated for adults aged 18 to 49 at increased risk for the disease, expanding on its existing indications for older adults and pregnant women.”

Abrysvo was also granted marketing authorization in the European Union by the European Commission in August 2023 for older adults and maternal immunization (3).

“The approval of ABRYSVO in Europe marks significant progress in the scientific community's efforts to provide meaningful protection against RSV, a common respiratory virus that could potentially be severe and even life-threatening, especially for infants and older adults,” said Anderson, at the time (3). “Last year’s significant number of newborns, children, and adults being hospitalized across Europe demonstrated the immense need for protection against severe RSV cases. The approval of the vaccine for both older adults and infants through maternal immunization is a triumph for public health and we hope to see a tremendous impact for future seasons.”

Pfizer.U.S. FDA Approves Pfizer’s RSV Vaccine Abrysvo for Adults Aged 18 to 59 at Increased Risk for Disease. Press Release. Oct. 22, 2024.

Pfizer. Pfizer Announces Top-Line Results of Abrysvo for RSV in Immunocompromised Adults. Press Release. Aug. 12, 2024.

Pfizer. European Commission Approves Pfizer’s Abrysvo to Help Protect Infants through Maternal Immunization and Older Adults from RSV. Press Release. Aug. 24, 2023.

Pfizer’s bivalent RSV prefusion F vaccine has been approved to prevent lower respiratory tract disease resulting from the respiratory syncytial virus in adults 18 to 59 years of age who are at increased risk.


FDA Approves RSV Vaccine

On Oct. 18, 2024, REGiMMUNE and Kiji Therapeutics announced the two companies are intending to merge, creating a specialty company, REGiMMUNE/Kiji TX, for regulatory T cells (Tregs) targeting drugs for multiple modalities and indications. The two companies’ complementary portfolios will be used to create the new Treg biotech to address unmet needs by the modulation of the Treg function.

Treg function has been increased by both companies in different ways; REGiMMUNE has regulated the role of the Treg with a molecule enhancer to increase Treg function, and Kiji TX uses next-generation multigene engineered cell therapy IL10 enhancers to increase Treg anti-autoimmune functions. To reduce or eliminate Treg function, REGiMMUNE uses monoclonal antibodies. By combining these technologies, the companies hope to create an international Treg specialist that will focus on immune-oncology and autoimmunity.

REGiMMUNE/Kiji TX will target its pipeline on four therapies. “It will establish proof of concept with gene engineered mesenchymal stem cells (KJ01) in graft-versus-host disease (GvHD), and prepare for clinical entry in the second half of 2025, develop its iPSC platform (KJ02) for inflammatory bowel disease (IBD), psoriasis and CNS disorders, define clinical readiness with a Treg depleting/inhibiting monoclonal antibody (RGI6004) and advance clinical development with the launch of a Phase III clinical trial with a clinical stage small molecule Treg enhancer targeting GvHD (RG2001),” the companies stated in a press release (1).

“Tregs have proved themselves to be a leading promising modality in the cell and gene therapy field, both therapeutically and commercially. As a result of this potential, we have collectively created a global Treg specialist super-company to realize this potential,” said Miguel Forte, CEO, Kiji TX, in the release. “We will also be able to combine several fields, including small molecule, CGT and monoclonal antibodies to use Tregs to their full potential. These approaches are off-the-shelf and allogeneic, with a competitive advantage over autologous or patient matched Treg approaches currently in development in the sector. The new company now has a variety of options, including an IPO by mid-2025 in the Taiwan Stock Exchange. This will enable REGiMMUNE/Kiji TX to develop our multiple therapeutic pipeline in-house, as well as partnering for co-development or out-licensing.”

“Modulating Treg function in both directions has significant potential in a variety of conditions with major commercial benefits. Creating the new Treg specialist REGiMMUNE/Kiji TX will result in a company that will have the resources to achieve this potential. With a planned IPO in 2025, we will be able to combine leading modalities to develop therapies for conditions involving significant numbers of patients globally,” said Kenzo Kosuda, CEO, REGiMMUNE, in the release. “The global reach of the company and experience of the senior management also enables us to explore development across the globe to match the therapeutic potential and size of the market that is open to us.”

REGiMMUNE Limited, a clinical-stage biopharmaceutical company based in Taiwan, specializes in immunotherapies by harnessing Tregs for immune diseases and cancer. Kiji Therapeutics specializes in next-generation IPSC-MSC engineered cell therapy for inflammatory diseases. Kiji TX is developing superior potency multi-gene engineered stem cell therapies.

1. Kiji Therapeutics and REGiMMUNE. REGiMMUNE and Kiji Therapeutics Announce Intention to Merge. Press Release. Oct. 18, 2024.

The merger will create a specialty company, REGiMMUNE/Kiji TX, for regulatory T cells.