In a statement today, MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany, confirmed a US $65 million (€ 59 million) investment in the expansion of its high-potent active pharmaceutical ingredient (HPAPI) and ADC manufacturing capabilities and capacity at its facility near Madison, Wisconsin.

With this investment, MilliporeSigma creates one of the largest single-digit nanogram containment manufacturing facilities for the large-scale manufacturing of increasingly potent compounds that have the potential to treat cancer.

Completion of the facility in Wisconsin is expected by mid-2022 and should add approximately 50 full-time jobs starting in 2021.

“ADCs have posted incredible growth over the last decade and regulatory agencies’ approval in recent years demonstrate their promise as targeted therapy,” said Andrew Bulpin, Head of Process Solutions at MilliporeSigma.

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“With more than 35 years of experience in this space, we have been a frontrunner in the development and manufacturing of biologics, conjugation processes, and small molecules. This investment underscores our commitment to working with innovators to bring new treatments to patients quickly and more efficiently,” Bulpin added.

Manufacturing facility
MilliporeSigma’s new 70,000-square-foot commercial building in Madison, Wisconsin, will be one of the largest dedicated HPAPI manufacturing facilities specifically designed to handle single-digit nanogram occupational exposure limit materials. The facility will incorporate containment areas to produce next-generation linker and payload materials for ADCs.

The Wisconsin facility will be developed in addition to the company’s campus in St. Louis, Missouri, which was the first commercial ADC facility in North America, and which specializes in ADC bio-conjugation, active pharmaceutical ingredients, excipient, and adjuvants manufacturing.

A growing number of approved ADCs
With 9 Food and Drug Administration (FDA-) approved ADCs commercially available in the United States,  antibody-drug conjugates have sown to be a powerful class of therapeutic agents in the treatment of cancer and hematological malignancies, who are now also emerging as potential treatment beyond cancer.

The ADC industry is delivering strong growth and is expected to reach US $15 billion by 2030 [1].

Manufacturing Challenges
While ADCs can provide many benefits compared with other therapeutic options, they also present a unique set of challenges. ADC manufacturing processes consist of multiple distinct stages, including the functionalization of the antibody, the conjugation reaction, and the downstream purification and formulation steps, requiring expertise in biologic production, small molecule synthesis, and conjugation technology.  And while cell line engineering and antibody production may be relatively straightforward, payload preparation, in turn, may involve 12–25 complex synthetic organic reactions, adding to the overall complexity of manufacturing.

In addition, the complexity, coupled with the fact that manufacturing involves the handling of extremely toxic and potent substances, as well as the potential of significant risk related to occupational exposure of manufacturing staff, necessitate a stringent containment infrastructure, requiring major investments.

Furthermore, the structural exceptionality of ADCs not only requires expertise in a number of different technologies for small and large molecules but also access to robust analytical methodology, including in vitro cytotoxicity, characterization, serum stability, mechanistic and functional assays.

Manufacturing challenges may be specially noted during the scale-up of ADC manufacturing, adding engineering challenges to the biopharmaceutical manufacturing process. One way to address these challenges includes scaling ADC manufacturing by continuous processing. MilliporeSigma’s new Wisconsin-facility will be designed to include novel manufacturing technologies such as continuous flow manufacturing for ADCs, a developing technology using principles adapted from the field of flow chemistry, using continuous conjugation reaction chemistry technologies to enable continuous purification of ADCs following conjugation.

While some biopharmaceutical companies carry out in-house development and manufacturing of their ADC products, the majority of companies, estimated at more than 70%, are outsourcing the development and manufacturing to specialized contract development and manufacturing organizations (CDMO), including companies like MilliporeSigma, which offers extensive experience in both the clinical and commercial manufacturing of these targeted therapeutics. This trend is primarily driven by a growing number of small companies and start-ups that are presently involved in the development of ADCs.[2]

MilliporeSigma’s comprehensive service portfolio combines the steps of drug development and production — from pre-clinical to commercial — from a single source. This consolidation helps reduce risk and streamlines the process of getting therapies to patients faster.

[1] Antibody Drug Conjugates Market to Be Worth $15bn by 2030. European Pharmaceutical Review, 30 Aug. 2019, Online. Last accessed on September 9, 2020.
[2] ADC Contract Manufacturing Market, 2015-2025. Roots Analysis Private. August 2015. Online. Last accessed on September 9, 2020.

Featured Image: Manufacturing facility at MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany. Photo courtesy: MilliporeSigma. Used with permission.

This article was updated on September 11, 2020 to include a correction related to the new facility in Wisconsin.

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