Feliza Mirasol is the science editor for 

Feliza Mirasol

Speaking at the “Advancements and Challenges in Antibody-drug Conjugate Manufacturing” presentation at INTERPHEX this week, Ashley Harp, a process engineer with CRB Group, stated that antibody drug conjugate (ADC) manufacturing nowadays demands much higher containment requirements than in the past.

In particular, Harp discussed current requirements for facility design for ADCs, which have gotten more complex and sophisticated since the first ADC was approved decades ago. “We're now 24 years since the first ADC was approved, and we have 12 marketed FDA-approved ADCs in the [United States],” she remarked. Yet, although there are higher containment requirements today, ADC manufacturing facilities are still relatively typical high-potency API (HPAPI) facilities—with added personnel protection and product containment, she clarifies.

The linker technologies for ADC manufacturing can have many variations, Harp pointed out, such as having a linker that’s conjugated to the drug (payload) or a linker that’s conjugated to the antibody before the drug is added. However, the majority of the ADC products on the market follow a similar process, she said. These ADC facilities must serve the ultimate goal of providing an environment that processes the product correctly and delivers a safe and effective product to the patient. The added containment requirements, however, are to protect the facility personnel, Harp emphasizes.

Another challenging aspect in ADC manufacture is the constant need to develop analytical capabilities for product detection, Harp also said. “Making sure that you are getting the molecule that you expect and also having the capabilities to detect the molecule on surfaces or in the air (to run industrial hygiene testing, for example) [is important],” she said. Today, Harp pointed out, “we are able to detect levels lower than a single nanogram in much of the analytics [that are run], that it is amazing to me.”

Harp also stated that, while biotech companies require knowledge in their design considerations for ADC facilities, there are many “good regulations and guidance available … [that] bring in … local regulations and requirements for personal protection and product protection.”

“Because we are in a GMP [good manufacturing practice] space, once you hit [the] clinical [stage] … [particularly] Phase II and Phase III … and then first [commercial] manufacturing, we can't just make [the products] in a chemical manufacturing facility. These are going to eventually be injected into someone, so we have to always keep that in mind,” Harp stated.

ADC’s have been the subject of focus recently for bio/pharm companies. Bristol-Myers Squibb, Johnson & Johnson, and Genmab entered multi-billion deals all involving pipelines of ADC therapies (1-3).

INTERPHEX is being held in New York City on April 16–18.

Bristol Myers Squibb and SystImmune Enter Global ADC Collaboration Worth Potentially up to $8.4 Billion

J&J Completes $2 Billion Ambrx Acquisition, Boosts Pipeline for Next-Gen ADCs

Genmab Expands ADC Pipeline with $1.8 Billion Acquisition of ProfoundBio

Articles

The improvement of ADC manufacturing now demands increased containment requirements and continually advancing analytical detection of molecules in manufacturing spaces.

Improving ADC Manufacture Means Stricter Containment Requirements and Continuous Advancement of Analytics (INTERPHEX 2024)

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Among a list of top 10 commonly seen observations during FDA inspections is the question of process validation, said Daniel Roberts, senior director of Regulatory Compliance at Sidley Austin, a global law firm, and a former FDA drug investigator. Roberts spoke in a keynote session, “FDA Regulatory Updates—Trends & Insight,” at INTERPHEX in New York City, which is being held on April 16–18, 2024.

“There [are] always [many] things to consider regarding process validation, such as making sure that your process validation is adequate and current,” Roberts said. He explained that sometimes companies with older pharmaceutical manufacturing practices get complacent with their processes, some of which were validated decades ago for a drug product that has long been on the market. However, he noted that it is important for companies to keep updated with current good manufacturing practice (CGMP) requirements.

“That is why we say the ‘C’,” Roberts emphasized, urging that companies need to take into account that their manufacturing processes must be compliant with “current” GMPs, rather than just the GMPs under which an older manufacturing process would have been validated.

“Oftentimes there will be changes in plans, and [a company’s] process validation that was done decades ago may not be reflective of [its] current processes,” Roberts said. Thus, it is important to have a process in place where it is periodically evaluated to see if it is still adequate or if it should be revised. “That is a good practice to have and, again, expectations of process validation were different in [for example] 1986 versus 2024, so just making sure that you’re current with regulatory expectations is important [for regulatory inspections].”

Another important point that Roberts made in the keynote was to emphasize the increased focus FDA has on data integrity, particularly the movement toward electronic data. “Maintaining electronic data accuracy is FDA's focus,” he said. Over time, companies are moving away from paper and more towards electronic data, and because of that, Roberts stressed that companies must have controls in place for these electronic data. However, he pointed out that data integrity still involves historical data that are on paper records.

Some of the principles of data integrity include making sure that the data are traceable back to the raw data, legible, and contemporaneously recorded. For example, Roberts said, an operator should not be weighing an item and then later recording that information based just on memory. “Making sure that things are getting recorded in a timely manner and that things are original and active kind are a big portion of this [data integrity],” he noted.

“When you submit an application to the agency, and especially when you're talking about pre approval inspections, when FDA's on site doing inspections, [the agency] wants to make sure that the data you submitted is true and accurate and right,” Roberts explained.

Former FDA drug investigator, Daniel Roberts, discusses the importance of updating process validation and maintaining proper data integrity at a keynote session during INTERPHEX.

Keynote Session Highlights Importance of Process Validation and Data Integrity (INTERPHEX 2024)

Watson-Marlow Fluid Technology Solutions (WMFTS), a manufacturer of peristaltic pumps and associated fluid path technologies, has launched WMArchitect, a range of flexible, single-use solutions for biopharmaceutical fluid management. This platform is built on the company's predecessor product lines, such as puresu and asepticsu. The new offering aims to streamline biopharma processing, safeguard product, and reduce regulatory burden, according to an April 15, 2024 company press release.

WMFTS now offers customized designs from its component library as well as a selection of standard, ready-to-use single-use assemblies. The WMArchitect offering represents an end-to-end, single-use fluid path management solution consisting of:

Customized designs: single-use assembliescan be custom-designed to meet specific requirements with an open architecture model that allows for flexibility and compatibility with existing fluid-contact materials already used in a company’s bioprocess.

Single-use fluid transfer assemblies: these fluid-transfer assembliesare ready-to-use, are pre-designed, and offer lot traceable tubing and components for optimizing fluid transfer between equipment and process steps. The latter can be selected from a menu of validated components.

Fill/finish single-use assemblies: these fill/finish assemblies are designed tosafeguard therapeutic products during the filling process using a range of sterility-assured assembly configurations. Representative assemblies are routinely tested to determine bioburden and presence of particulates and endotoxin.

Validation testing: WMFTS specialists offer support to WMArchitectusers using bioprocessing expertise and customized validation packages. The aim is to help reduce a company’s regulatory burden.

“By listening to the evolving needs of our biopharmaceutical customers, we have created WMArchitect to provide an expert solution that supports them in mitigating their regulatory and supply chain risks,” said Nicole Hunter, head of Global WMArchitect, in a company press release. “WMFTS understands that, often, off-the-shelf products are merely a starting point. We customize our standard products to provide a complete and tested solution from a single supplier that is tailored to meet a company’s specific requirements.”

WMArchitect is suitable for high-purity biopharmaceutical process development, clinical trials, and small-to-large-scale production batches. The most critical component for maximizing performance is at the point where the tubing meets the pump, the company acknowledged in its press release. In recent years, single-use components such as tubing, connectors, and valves have allowed for more 

. For instance, single-use tubing, connectors, and valve components can eliminate cleaning-in-place (CIP) and sterilizing-in-place (SIP) procedures. Removing these steps, which are often costly, time-consuming, and contribute to downtime, can increase manufacturing throughput and productivity of a facility. Furthermore, the time and personnel once used for CIP/SIP (e.g., of stainless-steel process lines) can then be reallocated to other areas of production, thus increasing overall efficiency of the manufacturing process (1).

WMFTS’ assembly solutions are designed synergistically with the company’s peristaltic pump technologies and filling solutions to ensure reliable, repeatable performance for even sensitive processes. In addition, a dedicated WMArchitect business unit offers benefits such as reduction of validation burden, support of internal validation protocols, an open architecture approach that allows flexible integration, synergistic use with the company’s peristaltic pumps of filling systems, and supply security based on the company’s global manufacturing and supply network.

The company will be showcasing its WMArchitect single-use solutions line at INTERPHEX, held in New York City on April 16–18, 2024.

Fluid Handling Systems are Seeing Benefit from Single-Use Technologies

WMFTS has launched WMArchitect, a single-use product line that offers ready-to-use single-use assemblies and custom-designed workflows for biopharma fluid management. 

WMFTS Showcases New Single-Use Solutions Designed to Optimize Fluid Management 

Much of the current development of messenger RNA (mRNA) in the biopharma industry is focused on using mRNA-based therapeutics in the targeted treatment of cancers. Obstacles still persist, however, in the delivery method of the therapeutic. One solution lies in the formulation stage, where, for instance, lipid nanoparticle (LNP) technology has become a common mode of delivery, owing to its success in the mRNA-based COVID-19 vaccines. In an interview with Stefaan De Koker, vice-president, Technology and Innovation, etherna, 

® explores the criteria that make mRNA a good choice as a therapeutic and looks at how LNP technology is becoming a well-established vehicle for delivering mRNA. 

Evaluating the Partnership between mRNA and LNPs

Pharmaceutical Technology’s Innovations in mRNA eBook

According to De Koker, mRNA combines three significant advantages compared to other drug modalities. First, mRNA is an extremely flexible platform. For instance, mRNA sequences can be easily modulated, and, hence, they can encode virtually any therapeutic protein, “whether it’s in the cytosol of the cell, on the membrane, or even a secreted protein,” said De Koker. The ability to easily modulate mRNA sequences was on reason why mRNA was well suited to a pandemic case, such as COVID-19. It also makes mRNA well suited for developing personalized immunity, such as, a cancer vaccine. In this instance, the vaccine can be adapted to the antigen profile of a tumor.

A second major advantage of mRNA is the ease of manufacturing, says De Koker. It can be produced quickly, which, again, was exemplified by the COVID crisis, where, within a few months, mRNA vaccines were in clinical studies, he emphasizes. “They were also clearly much faster to reach approval compared to more conventional therapeutic modalities, [such as] protein-based vaccines or viral vector-based vaccines,” De Koker adds.

The reason behind mRNA’s quick synthesis is that production can be done entirely 

, and thus there is no need for cells to produce it, De Koker emphasizes. mRNA manufacture is based on an 

 transcription reaction, which uses a viral polymerase to amplify the mRNA. Moreover, De Koker explains, mRNA contains only four building blocks, which means it has constant physical and chemical properties. “Thus, regardless of the protein [one] wants to encode, [they] would have the same physical/chemical properties. This, [therefore], allows [one] to develop generic manufacturing processes,” De Koker says.

A third beneficial aspect of mRNA is the fact that the immunogenicity of the platform can be modulated. “This means that the mRNA and the formulation can either be made less (for therapeutics) or more immunogenic (for vaccines) based on the application. It really makes the immune system believe that the viral infection is ongoing, and it needs to respond to that infection by mounting a strong immune response,” De Koker explains.

“These three things together—the flexibility, the speed of manufacturing, and ability to modulate the immunogenicity of the platform—makes mRNA a versatile platform for vaccines and other uses,” De Koker states.

When referring to this article, please cite it as Mirasol, F. Evaluating the Partnership between mRNA and LNPs. 

Pharmaceutical Technology Innovations in mRNA 

The LNP success in mRNA vaccines leads to their establishment as a standard in mRNA delivery.

In back-to-back agreements, Charles River Laboratories International will provide plasmid DNA (pDNA) manufacturing services to Axovia Therapeutics and Ship of Theseus. Announced on April 9, 2024, the Axovia agreement involves the manufacture high quality (HQ) gene-of-interest plasmid, which will support Axovia’s development of gene therapies for ciliopathies, including Bardet-Biedl Syndrome (BBS). Under the Ship of Theseus agreement, announced on April 4, 2024, Charles River will offer its expertise to manufacture pDNA to serve as the active drug substance for that company's lead candidate. 

Axovia is working on a lead program, AXV101, an adeno-associated virus serotype 9 (AAV9)-based gene therapy. The therapy targets retinal dystrophy associated with BBS. In preclinical studies, the gene therapy was shown to modify the underlying disease and halt retinal degeneration, stopping BBS-induced weight gain and the development of obesity. FDA granted orphan drug and rare pediatric disease designations to Axovia for AXV101. In the deal, Axovia will utilize Charles River’s plasmid platform, eXpDNA, and pDNA manufacturing expertise.

“We are committed to supporting Axovia in the pursuit of creating treatment options for patients living with ciliopathies. The Charles River team brings decades of expertise in HQ plasmid development, and we look forward to using these capabilities to make a difference for patients,” said Kerstin Dolph, corporate senior vice-president, Global Manufacturing, Charles River, in a company press release.

Ciliopathies are caused by cilia dysfunction resulting from genetic mutations that cause defective or dysfunctional cilia in many organs. Dysfunctional cilia can lead to blindness, deafness, chronic respiratory infections, kidney disease, heart disease, infertility, obesity, and diabetes. According to the press release, more than 20 ciliopathies have been identified. Collectively, they affect an estimated 1 in 1000 people.

“This collaboration brings us closer to accomplishing our goal to develop potentially transformative therapies for ciliopathies. We are excited to leverage Charles River’s expertise in plasmid DNA production to help drive our work forward,” said Victor Hernandez, co-founder and chief scientific officer, Axovia, in the release.

Meanwhile, Ship of Theseus, a therapeutics company specializing in degradation-resistant homeobox (HOX) family biologics, is developing a proprietary suite of biologics based on HOX family transcription factors. These transcription factors are responsible for directing the differentiation of tissue stem cells towards their respective lineages for the repair and maintenance of correct tissue and organ function. According to a company press release, “proprietary modifications may enable these regulators to be used as therapeutics.”

Under the collaboration, Charles River and Ship of Theseus will develop therapeutics for a broad variety of target indications such as diabetic and chronic wounds, neutropenia, psoriasis, androgenetic alopecia, women’s health and infertility, and epithelial cancers. This collaboration will be led by Charles River’s good manufacturing practice (GMP) pDNA contract development and manufacturing organization center of excellence in Keele, United Kingdom. The Keele site will provide pDNA backbone generation, plasmid synthesis, GMP master cell bank generation, pre-production evaluation, and GMP pDNA manufacture, including in-house release testing.

“Ship of Theseus is proud to collaborate with Charles River as our manufacturing partner of choice. We trust the team’s decades of success developing, producing, and reliably delivering plasmid DNA and look forward to bringing our therapies to patients,” said Jeremy Elser, founding CEO, Ship of Theseus, in the press release.

Source: Charles River Laboratories International for 

Charles River has entered into separate agreements with Axovia Therapeutics and Ship of Theseus to offer plasmid DNA manufacturing services for a gene therapy and a lead candidate program, respectively.

Charles River to Provide pDNA Manufacturing Services in Two Deals

Memel Biotech, a Lithuania-based contract development and manufacturing organization, announced on April 4, 2024 that it has launched a fully integrated advanced therapy development and manufacturing service at its facility in Klaipeda, Lithuania, which will serve markets in the European Union (EU). With this new service, the company aims to target partnerships with emerging and established biotech companies seeking to enter the advanced therapy medicinal product (ATMP) space. The company will operate a new good manufacturing practice (GMP) facility, where it will offer discovery-to-delivery service for all three classes of ATMPs: cell therapy, gene therapy, and tissue-engineered therapy.

Memel has built its technical expertise in product formulation, process and analytical development, process scale-up and automation, GMP manufacturing, validation, and logistics. The company has also maintained up-to-date knowledge of regulatory approval demands and processes in key markets, according to a company press release. The company’s manufacturing range encompasses mesenchymal stem cells, induced pluripotent stem cells, extracellular vesicles, immune cells (including natural killer cells and dendritic cells), and gene modified cells, including chimeric antigen receptor T cells.

“Advanced therapies have enormous potential to make life changing impacts on patients, but there is no escaping the fact that they are complex and challenging to manufacture and deliver,” said Agnė Vaitkevičienė, CEO, Memel, in the press release. “Based on our previous experience in the sector, we believe Memel has the portfolio of services and skills to meet the challenges companies that are aiming to make a difference face—from initial formulation to scale-up—whilst conforming to the still emerging regulatory framework. In addition to European clients, our location also offers an ideal EU entry point to [the] US [United States] and ROW [rest of world] companies.”

 under a project to be launched by the Northway Group, a collection of 17 enterprises within the fields of medicine, healthcare, biotechnical formation, and investment operations. In November 2023, the group announced its plans to build BIO CITY, expected to be the largest biotechnology hub in Europe and home to six large biotechnological complexes. Four of the complexes will be state-of-the-art GMP plants, and two will be scientific research centers. With a total area equivalent to the size of 10 football fields, BIO CITY is expected to cost €7 billion (US$7.6 billion) over the next decade (1).

According to Olga Potapova, president of the Cureline Group, a US-based company that provides management of scientific and pre-clinical research, development of diagnostic products, and organization of biological and tissue testing, “Memel is a natural extension of the [Cureline] Group’s portfolio. We have closely followed the development of the advanced therapies sector over the last decade in particular. Rather than try to repurpose any existing CDMO we believe the time is right to create a truly specialized partner who can take an active role in helping customers achieve their missions to bring these exciting new treatments to patients. Lithuania, with its highly skilled workforce, supportive environment, stability, and EU membership, is also an ideal location.”

1. Northway Biotech. The Largest Biotech City in Europe Will Soon Be Built by Northway Healthcare Group, with an Investment Amounting to 7 Billion Euros. Press Release, Nov. 16, 2023.

With the launch of a new manufacturing service, Memel Biotech will offer services for discovery through to formulation for advance therapy medicinal products.