Novartis talks Leqvio manufacturing approach at TIDES Europe

Leqvio (inclisiran) attained US Food and Drug Administration (FDA) approval in December 2021 for the reduction of LDL-C (bad cholesterol), having bagged European approval the year prior. Swiss pharma giant Novartis added inclisiran through the $9.7 billion acquisition of The Medicine Company the year prior and has since seen demand for the small interfering RNA (siRNA) therapy ramp up.

In 2023, Novartis clocked sales of $355 million, up 217% on 2022, when the drug was rolled out. For the first nine months 2024, sales already stand at $531 million, up 130% year-on-year. And according to GlobalData, Leqvio is projected to achieve annual sales of around $3.4 billion in 2030.

Inclisiran works by binding mRNA transcribed from target genes, forming double stranded molecules that cannot be translated into protein. The target mRNA encodes PCSK9, a protein that hampers the body’s ability to absorb low-density lipoprotein (LDL). By minimizing PCSK9 levels, inclisiran allows the body to process more cholesterol. The approach complements other LDL-tackling medications currently making their way to the clinic.

The manufacturing process is based on solid-phase synthesis followed by numerous downstream applications: cleavage and deprotection, ultrafiltration, ion exchange, high-performance liquid chromatography (HPLC), and ion-pair reversed-phase (IPRP) chromatography. These processes are done separately for the antisense and sense strands prior to annealing. During the cool down, the two chains bind, and the mixture is concentrated before the lyophilization and packaging steps.

When Novartis first acquired inclisiran, production was fully outsourced, with contract development and manufacturing organizations (CDMO) Agilent and CordenPharma supplying drug substance and drug product, respectively.

Letizia Volpe, head of Chemical Operations at Novartis, confirmed to delegates at the recent TIDES Europe conference in Hamburg, Germany, that Novartis still worked with the two CDMOs, but spoke candidly about the decision to invest in its own siRNA production capabilities through a CHF 70 million ($79 million) site in Schweizerhalle, Switzerland.

One line or two?

Novartis’s plant consists of four levels: the third floor hosts chromatography buffer preparation, the second is where the oligonucleotide synthesis takes place, and the first houses chromatography, ultrafiltration, and annealing process. Lyophilization takes place on the ground floor, while the basement houses water for injection (WFI).

The facility was conceived in 2020 and began making batches of inclisiran in August 2022. “In two very intensive years, we built up two lines with roughly 100 pieces of equipment and 12 kilometers of pipelines,” she said, before discussing the design considerations necessary for an oligonucleotide plant.

“One of the questions that we had to ask ourselves when we started to build was: do we go for a multi-purpose or dedicated plant? In our case, it was quite clear that we had to go for a dedicated plant at that stage,” she said.

“The next question was one single line, or more than one line? It was clear we would need –according to our forecasts – two lines. So we went for more than one line.” This led to the question of whether some of the equipment could be shared across the two manufacturing streams.

“The pros of having shared equipment is that you reduce the CapEx and you better optimize the space that you have available, but there are also consequences,” she said. As well as cleaning concerns between shared and non-shared equipment around production schedules, “the smooth alternation of production of different trains becomes difficult,” as does the ability to later “switch to a multi-purpose plant.”

Bioburden and solvent abuse

Another consideration during the planning stage of the plant was dealing with contamination issues surrounding the process and the need for a low bioburden control strategy. “The recommendation here is to start very early with consideration at this level during the design of the plant,” Volpe emphasized, including zoning concept and sterile filter usage. She also recommended carrying out tests of solutions from different steps of the process for their ability to promote or inhibit growth.

Furthermore, Novartis tried to tackle the issue surrounding the amount of solvent used in oligonucleotide batch production during the planning stage. Within the solid phase synthesis, several washings are performed after every coupling; the longer the strand, the larger the quantity required. Meanwhile, various buffers are required during the chromatography stages.

Among the solutions proposed by Volpe was the development of a solvent regeneration process. Downstream, oligonucleotide production can need over 2,000 kg of the solvent acetonitrile. A process has been developed at the Schweizerhalle site where 85% of the solvent can be regenerated and 78% of that can be recycled and reused in oligo production. This, she said, as well as reducing the cost of drug substance, has had a significant environmental impact – a 64% carbon dioxide reduction and an 84% reduction in organic waste.

Quotes have been edited for clarity.