D rug manufacturing has never been easy. But when Samuel Benoni Siegfried and his brother-in-law established the pharmaceutical factory Siegfried & Dürselen back in 1873, the range of drugs available in the clinic was still relatively narrow. For example, scientists at that time were still a year away from figuring out how to synthesize acetylsalicylic acid—commonly known as aspirin.

Over the past 150 years, the company—known today as Siegfried AG—has steadily grown into a multinational business, operating 11 facilities in seven countries. During this time, the number of pharmaceuticals on the market has soared, with over 20,000 drugs approved for sale in the US. But the complexity of modern drugs has also grown dramatically, with sophisticated therapies such as messenger RNA (mRNA) vaccines and personalized medicine. “The drugs are every day more focused and more individual to the patient,” says Carolina Bonifacio, Siegfried’s head of drug product development. “There are not too many acetaminophens any longer!”

These medical breakthroughs come along with manufacturing challenges. Many companies have moved to outsource key steps of their R&D and production processes to contract development and manufacturing organizations (CDMOs), which can assist with everything from early optimization of a promising lead to packaging it for distribution to pharmacies. Siegfried was a leader in this arena as well, transitioning from pharmaceutical manufacturing to a CDMO in 1983. This has proved a wise decision, according to Jürgen Roos, chief scientific officer at Siegfried, who notes that the CDMO sector is now a multibillion-dollar industry experiencing 6–8% growth each year.

Growth in the CDMO sector is driven by the diversification of drug technologies—for a pharmaceutical company, it doesn’t make a lot of sense to have a facility dedicated to one drug, Roos says. In addition to creating a financial burden, he says, this could leave drugmakers with a highly specialized facility that cannot be easily repurposed if the original drug fails in the market or once market demand declines. But that means that CDMOs also have to be adept at spotting trends, recognizing technological changes in the industry, and responding accordingly to ensure that drug companies have access to the facilities and expertise they need to stay ahead. “Many companies try to include one or two of these special technologies,” Roos says. “But we have a broad technology portfolio.”

Helping biologics across the finish line

Ten of the 20 top-selling drugs of 2021 were biologics, and one recent analysis predicts that sales of these drugs will outpace conventional small-molecule drugs by $120 billion in 2027. Biologics have gained momentum because they deliver therapeutic benefits that would be hard to achieve with other drugs—exploiting the remarkable affinity and specificity of antibodies to inhibit disease-associated proteins or delivering enzymes or nucleic acids to counter the effects of a detrimental mutation.

But biologics are also far more complicated to handle than small molecules. Since these agents originate from naturally occurring biologic building blocks—and in most cases are actually manufactured by living cells—the production process is costly and labor intensive. Subtle changes in temperature, pH, or other environmental conditions can undermine the production process, yielding a defective drug whose efficacy is reduced or even lost entirely.

One of the underappreciated challenges of the biologics manufacturing workflow is the fill-finish step. This describes the last mile of production, when the drug is dispensed into vials or syringes and packaged for distribution. Although it sounds simple, this stage entails a great deal of quality control—a Washington Post article in February 2021 noted that when the first COVID-19 vaccines were making their way to the clinic, federal officials described the fill-finish process as “the most important obstacle to increasing manufacturing.”

Marianne Späne, chief business officer at Siegfried, points out numerous difficulties involved with this process. For example, each drug preparation must be stored carefully and subjected to rigorous quality control to ensure that there is no degradation or loss of potency before packaging. And during packaging, each batch of vials or syringes must receive exactly the same dose at the same volume while maintaining fully aseptic conditions. Precision is essential, because each dose is precious. For a small-molecule drug, “if you spill a small amount, it is 1,000 euros,” Späne says, but spill the same amount of a biologics solution and “that’s a high 6-figure number of euros lost.”

Siegfried recently expanded its focus to provide fill-finish services to biologics manufacturers, and the pandemic has been a critical proving ground for establishing these capabilities. In 2020, the company partnered with BioNTech to package commercial quantities of the widely used Comirnaty mRNA vaccine, which BioNTech jointly developed with Pfizer. The following year, Siegfried entered a similar arrangement with Novavax. Collectively, these efforts have enabled production of hundreds of millions of ready-to-administer COVID-19 vaccine doses.

“We built up in record time a team that can handle this super-complex vaccine business,” says Späne, adding that this has set Siegfried up to partner with other biologics producers. And given the high cost of building out a production line—which are prohibitive for small start-ups and can even be an obstacle for big pharma companies—she expects demand for such services to only continue to grow.

Sustainable synthesis

Drug manufacturing may be an essential business, but it consumes considerable raw materials and energy while producing all manner of potentially harmful by-products along the way. Amid unprecedented global awareness of the precarious state of the environment, the pharmaceutical industry is under considerable pressure to make its operations as sustainable as possible.

This is not always an easy task. Many modern chemical manufacturing processes are the culmination of decades of evolution and refinement and therefore are challenging to change without affecting the impurity profile or creating regulatory hurdles. But there are still abundant opportunities to make drug production cleaner if one is willing to take a hard look. “We have come up with a metric to assess the greenness of our processes,” Roos says, “and based on this metric, we identify areas where we can improve these processes.”

This effort is already yielding dividends. Many synthetic chemistry workflows involve wasteful or undesirable steps—for example, requiring the use of high temperatures, toxic heavy metal catalysts, or organic solvents that are damaging to the environment. Through careful reassessment of these procedures, Siegfried is finding more sustainable ways to get to the same synthetic endpoints. In one case, the company was able to find shortcuts that allowed it to trim 4 steps from what had been a 10-step synthetic reaction. In addition to accelerating production, this streamlined workflow cut energy consumption, raw material requirements, and waste output for the manufacturing process by 50%.

Siegfried is also finding ways to recover and reuse solvents, thereby reducing the overall consumption of these critical reagents. The company is also exploring the use of pervaporation, which employs a semipermeable membrane to separate organic solvents from water or methanol. Although this process is still under development, Siegfried projects that it could further reduce solvent waste by up to 15-fold relative to current distillation-based processes.

Focused on the future

It is hard to forecast with any certainty what innovations the pharmaceutical industry will see in the years to come. One likely possibility is that therapeutics will continue to become more potent and personalized, as researchers uncover the hidden heterogeneity underlying many disorders. This means that drug companies—and the CDMOs they partner with—will need to gain the capabilities that would allow them to produce fairly small quantities of specialized therapeutics efficiently, safely, and sustainably. But Späne is confident that Siegfried is up to the challenge, with 150 years of industry experience under its belt and a proven track record of adapting to a changing world. “We are constantly investing in new technologies,” she says. And ultimately, the patient community will be the true beneficiaries of this investment—gaining broader access to precision medical treatments that far surpass the one-size-fits-all therapies of yesteryear.