Targeted therapies such as antibody-drug conjugates (ADC) have opened new ways in targeting diseases like cancer and hematological malignancies. High-potent active pharmaceutical ingredients, also known as HPAPIs, are a critical element in these uniquely targeted therapies.

ADCs leverage the benefits of the high specificity offered by antibodies in combination with the high potency of small-molecule drugs to improve efficiency with reduced side effects. Unlike traditional chemotherapy, ADCs target tumors, and deliver a payload to destroy cancer cells while sparing the healthy, normal cells, thereby potentially reducing negative side effects for the patient.

From Left to right: Matthew J. Hanson, Head of Commercial ADCs, HPAPI & Complex Molecules, Dr. Matthias Bucerius, Senior Vice President, Synthesis & ADC CDMO, Joe Bergin, Head of Operations Madison & Verona, Synthesis & ADC CDMO.

Today, 11 ADCs have been approved by the U.S. Food and Drug Administration (FDA). In addition, one ‘generic’ (biosimilar) ADC has been approved in India, and one ADC has been conditionally approved in China. Also, to date, nearly 100 investigational ADC drugs are in the clinical stage, and more than 200 investigational ADCs are currently in early pre-clinical discovery and development.

Although ADCs have indeed achieved impressive clinical outcomes, experts say that there are still many challenges to overcome. First and foremost, there are adverse events caused by the cytotoxic payload, lack of biomarkers for screening patients, and development of drug resistance.

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The discovery of novel targets, new conjugation technologies, and cytotoxic payloads opens a new era of ADC therapeutics development. In addition, scientists are looking for the development of ADCs beyond oncology and hematology.

Critical for growth
In June 2022, MilliporeSigma, the U.S. and Canada Life Science business of Merck KGaA, Darmstadt, Germany, a leading science and technology company, celebrated the opening of its US $ 65 million facility expansion in Verona, Wisconsin. The company’s expansion includes a 70,000-square-foot facility especially designed to increase the company’s antibody-drug conjugate manufacturing capacity.

ADC Review spoke about MilliporeSigma’s expansion in Verona, the importance of HPAPIs in the development of ADCs, and the complexities involved in designing a new, state-of-the-art facility with Matthew J. Hanson, Head of Commercial ADCs, HPAPI & Complex Molecules, Dr. Matthias Bucerius, Senior Vice President, Synthesis & ADC CDMO, Joe Bergin, Head of Operations Madison & Verona, Synthesis & ADC CDMO and Jackie Ruff, Strategic Marketing Manager

ADC Review: Why was there a need for this expansion?

Matt Hanson: For starters, HPAPIs are a critical part of each ADC. With the growing number of approved ADCs and more in development, there is an increasing demand of these cytotoxic payloads. By leveraging our CDMO (Contract Development and Manufacturing Organization) expertise in producing HPAPIs and ADCs for our customers, we’re impacting the life and health of many patients with science. And, as we pioneer the path from treatments to cures, it’s our passion to help bring new treatments to market quickly that drives us to meet the unmet demand for novel cancer treatments. And to meet this demand, this new facility was needed.

ADC Review: Can you tell us a bit more about the importance of ADCs? How important are they for the treatment of patients diagnosed with cancer?

Matthias Bucerius: ADCs really stand for a novel class of targeted medicine with the ability to deliver a cytotoxic, cancer-killing agent directly to cancer cells, destroying these cancer cells, while, at the same time, sparing the healthy, normal cells.

In order to do this, an ADC consists of three elements: a monoclonal antibody as a targeting agent, a highly potent payload (this is the HPAPI), and the linker construct designed to tie both elements together. So, ADCs are a fairly complex construct, but they have proven very effective in targeting cancer.

Matt Hanson: What is important to understand is that with their success as a treatment option, ADCs have become a growth area with changing market dynamics.

Matthias Bucerius: The interesting part is that nine of the commercially available ADCs in the United States were approved by the US FDA after 2019. This is, no doubt, very interesting from a patient perspective, but also increased the need to expand facilities to produce these very complex medicines.

And don’t forget that there is a significant pipeline of new ADC constructs in early and pre-clinical development – from an increasing number of developers. So, it’s really a growing field.

ADC Review: You are referring to a completed product. Now, focusing on the HPAPI payload in ADCs, how does this fit in with what you are trying to do? And, here in Verona, you are not just focusing on the HPAPI for ADCs, right?

Matthias Bucerius: Correct, while HPAPIs are a critical element in each ADC, they can also be used for other indications, including stand-alone drugs.

In the development of these HPAPIs, there have been significant advances, including significantly increased potency levels. But this increase in potency also requires a more complex development and production process – and a very specialized infrastructure.

When you look at the supply chain, the development of ADCs is quite complex. ADCs require expertise in small and large molecule development, manufacturing, formulation and testing. To succeed, you need to understand the manufacturing of the monoclonal antibody, the HPAPI, and the linker and perfectly manage the conjugation process. And in each step, more analytical work conducted in the early phases of the development process helps these companies to better understand every aspect of their ADC. That’s quite a number of required unit operations. So, it is understandable that the manufacturing of about 70% of all approved ADCs as well as in ADCs in development, is outsourced to highly experienced CDMOs.

And that’s where we play a role. As a CDMO we are bringing our technology and our expertise when working with biotech and pharma companies. We specifically assist these companies with very early preclinical work, and work side-by-side with them through the different clinical phases, all the way to the commercialization. Our role is that of a very active partnership with these biotech and pharma companies.

Matt Hanson: I think one of the important things to recognize, too, specifically looking at the technology, is that the development of an ADC requires the ‘unification’ of a small molecule and a large molecule. This requires a very specific understanding of the manufacturability of an ADC as well as the underlying chemistry. And that specific expertise is something that not all CDMOs can offer.

ADC Review: Earlier on, you were talking about the complexity of the infrastructure required for the development of an ADC. So, can you share more details about what is required?

Joe Bergin: Well, one thing is clear: the advancement of the development of cancer therapies also requires new strategies in the development and manufacturing process – and this is reflected in the design of the facility. In addition, we’re operating in a highly regulated environment, which requires a lot of specialized knowledge.

Here in Verona we have been manufacturing products for more than 30 years. This helps us gain a lot of specialized understanding and expertise across different biotech and pharma client organizations. It helped us to develop a highly quality-driven manufacturing process and analytical design strategy for these clients.

We recently opened six new labs – and we’re very proud of that. But to appreciate what we’re doing here, it’s important to understand how complex the underlying processes are.

ADC Review: Can you tell us a bit about this process?

Jackie Ruff: For starters, it’s important to understand that medicines made using HPAPIs need to find that delicate balance of having a very powerful, active ingredient, while at the same time having reduced side effects to the patient. Designing these novel drugs requires real innovation. But at the same time, this also requires real innovation in the design of a facility that can produce these agents in the quantities needed to take these programs through clinical trials and into commercial production.

As far as the development of these HPAPIs, they require special attention because they are carcinogenic, mutagenic, or toxic to reproduction in humans at therapeutic doses [1]. But in general, we accept the hazardous properties of these agents because they are indispensable for the treatment of cancer and hematological malignancies.

So, it is important to understand that the occupational exposure of our employees to these HPAPIs has to be controlled in order to prevent work-related diseases. As part of the innovative design of our facilities, we need to guarantee the safety and security of our employees manufacturing these HPAPIs, not only protecting them with the right Personal Protective Equipment (PPE) but also creating a safe environment by considering occupational health and safety-oriented hazards, enable timely, consistent and well-informed hazard identification (i.e. occupational exposure limit) and limit personnel exposure to HPAPIs being manufactured. As part of this approach, our facility includes extensive containment equipment with interconnectivity of the containment equipment in our lab. But it also involves training our staff in setting and controlling company-based occupational exposure limits.

We’ve designed our facility here in Wisconsin with state-of-the-art containment in mind. So these new labs are an entirely closed system.  This means that from the start of production to fill & finish (packaging), all of the HPAPIs are contained in this closed manufacturing facility. And this is really challenging.

ADC Review: Describe the manufacturing steps involved.

Jackie Ruff: We produce highly complex and customized compounds for our customers, so, to get started with production, our operators will first bring in all of the raw materials they need so they can measure out what they need. This is entirely based on very detailed documentation. After completing this process, raw materials are directly transferred and loaded into a reactor needed to execute the complex chemistry that goes into making HPAPIs. Within the reactors in the contained areas, these materials can be mixed, stirred, heated, or cooled. And if necessary, we can bring in different size reactors depending on the needed volumes and material.

Once the synthesis has been completed and the final mixture of materials, often a complex mixture containing the raw materials, solvents, as well as the final product, we move forward with the next step. The next step involves purifying this mixture to achieve the desired final product, which is done through chromatography, the process of separating different chemical components in a mixture.

After we have purified and isolated the final product through chromatography, materials are, once again, transferred entirely through the closed system, to the next stage of processing. The final completed product can then be sampled, tested, and packaged in terms of final output quantities.

Our facility can produce batch sizes from grams up to a kilogram scale. All our final products go through rigorous quality control testing and all our documentation goes through meticulous quality assurance review to ensure that all the HPAPIs coming out of this facility are of extremely high quality for patients that depend on them.

ADC Review: It’s probably correct to assume such a process and the development of a manufacturing facility is not something that happened overnight, correct?

Matt Hanson:  That is very true, and as a company, we’ve looked at this facility, as well as what the market required and what was to become the desired facility, for a long time.

Matthias Bucerius: And it is important to understand that, as a company, we’re truly committed to impacting life and health with science. That’s what drives us, it’s a key driver for our investment strategy. In addition, we expect that the market will continue to grow significantly. And with our new facility here in Verona we are actually doubling our capacity to produce these really highly potent APIs that can be used in isolation or be part of an ADC (as a payload).

Matt Hanson:  And because we have built a new facility, we obviously had the opportunity to implement new technologies and create an infrastructure that matched the technical and regulatory requirements. This approach sets this facility apart from many other facilities around the world.

Joe Bergin: It’s not an easy task to create such a facility. It’s a highly complex process. And as a result of that, we have to involve highly trained professionals. But again, it has everything to do with our desire to impact life and health with science.

The expansion of our facility includes a 70,000 sq foot (more than 6,500 m2) single-digit nanogram containment facility. This requires very specialized equipment. However, it starts, first and foremost, with the actual design of a safe facility, creating a very low occupational exposure limit (OEL) to protect our employees from the hazard of the high potency APIs.

ADC Review: When you refer to a very low occupational exposure limit in single-digit nanogram levels, what does that mean?

Joe Bergin: I guess, indeed that is a lot of buzzwords. In short, it means less than 10 nanograms per m2. And a nanogram is one billionth of a gram, so, very, very tiny amounts. This measurement is based on the standards set by the government and is designed to provide adequate protection for our employees in manufacturing facilities like ours.

Interestingly, existing approaches to assess the health risk associated with occupational exposure towards HPAPIs are generally hazard-based. They aim to reduce employees’ exposure as low as is reasonably possible. But, as mentioned, guaranteeing containment and limiting exposure starts with the design of the facility.

ADC Review: So, where are you going from here?

Matthias Bucerius: When we look at key trends in the ADC space, we see a lot of innovation. And this innovation targets all three components of an ADC. So we see a broader spectrum of monoclonal antibodies, which will allow us to target a different set of tumors.

We also see a new generation of link structures – the linker chemistry – being developed. And then, regarding the payloads, we also see a lot of innovation.

So, to give you a few examples … We’ve recently launched, ChetoSensar™ technology. This technology addresses the hydrophobicity of ADCs. Many ADC candidates have poor aqueous solubility. We believe that this issue impacts clinical terminations in more than 20% of all ADCs in development. Our ChetoSensar™ technology improves ADC solubility, therefore giving hope to ADCs that were previously terminated.

Another example, as mentioned, HPAPI payloads commonly used for ADCs are highly-complex molecules that take many steps to synthesize. Based on our calculations, our DOLCORE™ platform significantly reduces the development and manufacturing time required. In the case of a Dolostatin-based ADC, we are able to increase speed-to-market by up to a year. In all cases, we’re innovating, and this benefits our clients, enabling them to bring their products to market faster.

So these are really neat add-ons for our CDMO services.

Joe Bergin: And that is the crux of what we’re doing – we’re advancing the science, we’re advancing manufacturing techniques, and all of this we adopt in our facility design. Now, in addition, regulations are also evolving. And this impacts our facility design. But thankfully we have a huge specialist team on site here in Verona and around the world in our global organization that we can draw upon to help us.

Matt Hanson:  In summing up, we’ve always been leading the way and that’s our motto, to really lead the way.

Note: Occupational Exposure Limits or OELs are calculated on the basis of Acceptable Daily Exposure / Permitted Daily Exposure or ADE/PDE. ADE is used specifically in the USA, while PDE is a European term from the EMA (European Medicines Agency) that has been mandatory in manufacturing pharmaceutical products.

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