SARS-CoV-2 brought home to us the fragility of global pharmaceutical production. To this day, supply bottlenecks are spreading. Whether it's the breast cancer drug Tamoxifen, fever juice for children, or now the stroke drug Actilyse - the shortage economy is new suffering for patients and pharmacists in the West. Supply chains, once just-in-time wheels of efficiency, now falter again and again. The cause is bottlenecks in the production chain. An active ingredient or a precursor sometimes comes from only one factory worldwide. If this factory cannot deliver, the global supply is in jeopardy.
If a bacterium were to trigger the next pandemic, the consequences would perhaps be even more devastating than during the current virus pandemic: those infected would need masses of antibiotics, worldwide. But 90 percent of antibiotics come from Asia. "We would have had an extremely difficult time covering our drug needs if it were possible that nothing could be exported from countries such as China and India when we had enormous domestic demand," says Matthias Braun, managing director of pharmaceutical production and manufacturing at Sanofi in Germany until May 2022. Global labor specialization and monopoly formation are one thing above all: profitable. Crisis-proof, on the other hand, they are definitely not. Against this backdrop, in the course of Germany's presidency of the EU Council in 2021, the then Federal Minister of Health, Jens Spahn, announced that the production of important pharmaceutical substances would be brought back to Europe.
Not much has happened since then. The production of pharmaceuticals has been shifting eastward for a long time and continues to do so inexorably. The number of producers in the EU has been shrinking for years. According to the German Institute for Economic Research, the number of pharmaceutical companies in China grew by 1.3 percent each year from 2010 to 2018. In Europe, including Switzerland, it shrank by 0.8 percent per year over the same period. Nearly all generic drugs, those medicines whose patents have expired and are sold cheaply, come from China and India. These drugs are basic medical care, such as preparations for fever, headaches and flu. Can such a trend, which is subject to the enormous driving forces of the market economy, be broken? Can pharmaceutical production be deglobalized?
The eastward drift of the pharmaceutical industry
The reasons for the migration of pharmaceutical production to Asia are trivial, as the example of the commonplace drug paracetamol shows: more than 15 years ago, Chinese manufacturers entered into nitrophenol production. Nitrophenol is toxic and suspected of being carcinogenic. As always, the environmental and occupational health and safety requirements for handling the chemical in China were unacceptably low compared with the EU, and so were wages. But nitrophenol is the basic substance from which paracetamol is made. European companies were quick to buy their nitrophenol cheaply and willingly in China, as this increased their own profit margins. Even today, the local pharmaceutical industry still says: "The profit is in the purchase. The only deciding factor is price; strategic and moral motives play practically no role. Since the production of paracetamol does not require any dedicated pharmaceutical expertise, but rather the molecule is manufactured on an industrial scale in two reaction steps, Chinese manufacturers soon began to produce the painkiller themselves.
"These people then systematically knocked European manufacturers out of the market with low prices and then raised prices," Sanofi manager Braun recounts. Of 120,000 metric tons of paracetamol required worldwide, two-thirds now comes from China and India. Turkey and the USA share the remaining capacity.
Dieser Text stammt aus: MIT Technology Review 7/2022
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A few euros is the price of a kilogram of paracetamol, the most important drug for fever and pain, which has been on the World Health Organization's list of essential medicines since 1977. "It's a race to the bottom," Braun acknowledges. "In China, you build factories like this ten times bigger than here, and you have 1.5 billion people who need the drug themselves." It sounds like an immutable fact: Paracetamol from Europe - it just doesn't work anymore.
The raw materials for drug production are weighed in fully automatically and conveyed into collection containers. In the Freiburg high containment factory, each production step has its own room.
(Bild:Â Pfizer)
The French government sees things differently and is currently attempting to revive paracetamol production with a governmental show of strength. In 2013, the last European plant there closed in Roussillon, south of Lyon. In the meantime, other companies have settled on the site. But the former factory owner, now Seqens, is still there.
New paracetamol factory to be built
And so Seqens is to build a new paracetamol factory with an additional 30 million euros from Paris. As early as 2023, 10,000 metric tons of the active ingredient are to be produced in Roussillon - in an environmentally friendly manner, using a new, CO2-reduced and now patented process. The production facility is expected to cover one-third of European demand. According to its own information, Seqens is making the largest investment in its history, at 100 million euros.
The project in Roussillon is just the icing on the cake of a gigantic state reindustrialization program by the French government. Seqens is to produce a total of twelve active ingredients, including the important anesthetic propofol, again on French soil. Whether the drugs "Made in France" will cost more once the government start-up funding is over is still an open question. At any rate, the paracetamol will be purchased by the French drug manufacturers Sanofi and UPSA; corresponding cooperation agreements have reportedly already been signed.
Once the active ingredient has been produced, a tablet press shapes the drug into the desired form. Since the press is not integrated into the production process of an active ingredient, but stands separately, it can be used for different drugs.
(Bild:Â Pfizer)
In neighboring countries, the French centralist revitalization campaign is viewed skeptically. Revitalizing a production that is dead requires an investment of years, not months. "It can be done. But it wouldn't happen without the state," says Axel Glatz, plant manager of a new Pfizer drug factory in Freiburg, Germany. It's a question of the strategic importance of primary care. The U.S. company is pursuing a different strategy to produce in Europe as well. "The keys are innovation, automation, digitization, very well-trained specialists and precisely production for the global market, because that brings the volumes at which we become economical," says Glatz.
Seven billion pills per year
This economical European production is to be ensured by what Pfizer calls "one of the most modern high-tech pharmaceutical factories in the world" in Freiburg since May of this year. The so-called high containment factory is hermetically sealed off from the environment because it processes active ingredients that are highly effective in particularly low doses. Seven billion tablets and capsules are produced here every year. Only a few people work on the two floors; robots and machines dominate. "Production is controlled by more than a hundred intelligently networked IT systems," Glatz describes. The products are shipped to 150 countries.
In one of the three neighboring factories at the Freiburg site, digitization goes so far that the work steps are combined on the computer: The weighing of the active ingredients, the mixing, the pressing - the various production processes have their own rooms. In total, there are 60 rooms. These, and thus the work steps, can be combined with each other as desired by computer. "This allows the plant to produce more flexibly, faster and with less strain on resources," explains Glatz.
Measure active ingredient levels
Freiburg is also home to the world's first plant for the fully automated production of tablets and capsules. A tablet is produced here in just a few seconds. The active ingredient content is measured during production with near-infrared spectroscopes. Raman spectroscopes check the identity and purity of the raw materials used through the container walls, reports Glatz. Computers independently evaluate the complicated spectra and control the system. "It takes only a few hours to manufacture a complete batch. In traditional manufacturing, it takes one to two weeks," he points out, arguing: With this high degree of automation and digitalization, and with the large production volumes, the high per capita labor costs no longer matter so much. This means that innovative medicines can still be produced competitively in Europe. Higher, faster and further should secure local production and thus local wages.
A EuroApi employee fills powder for the production of oligonucleotides and peptides at the Frankfurt site.
(Bild:Â Euroapi)
But hasn't this monopoly mantra, that one produces highly efficiently for all, proved particularly insecure since the start of the corona pandemic? Glatz replies that a lot can be done within the company to ensure security of supply. Pfizer does not manufacture a particular active ingredient at just one site, but always at several. In the case of critical raw materials, several suppliers are contracted. And if one blister machine for packing the tablets breaks down, 39 others are still running in Freiburg.
Against this background, contract manufacturing is also booming. It is Sanofi's response to the demand for more pharma in Europe. The Group founded the EuroApi platform in 2021. The concept behind this is that pharmaceutical companies do not necessarily have to manufacture their active ingredients themselves, but can just as easily buy them from a company specializing in contract manufacturing. These companies maintain facilities and specialized personnel, but do not develop and produce their own active ingredients. The EuroApi consortium is now to assert itself as a contract manufacturer for active ingredients "Made in Europe.
Mini factories for medicines
Less than an hour's drive from Pfizer's new high-tech plant, Markus Bergmann believes in a very different future for pharmaceutical production in Europe. It would not be the old generics and not the giant factories, but mini-factories at the bedside. At the push of a button, the individual medicine would come out of the machine like a drink.
The mini-factories will print drugs and vaccine from mRNA, the substance that makes up Biontech's and Moderna's corona vaccines. "We already have the machine, a little smaller than a car, here on the fourth floor in TĂĽbingen," says Markus Bergmann, managing director of the new subsidiary CureVac RNA Printer GmbH. The machine can produce one gram per week, or 80,000 doses of vaccine.
CureVac's mRNA printer is designed to decentralize the production of vaccines and, later on, cancer drugs.
(Bild:Â CureVac AG)
It is fed with DNA. At the push of a button, the DNA is broken down into its components with the help of enzymes. These serve as raw material for generating new mRNA. However, to obtain defined RNA, a second batch of DNA is required. This contains the blueprint for producing the desired mRNA. In the Covid vaccine, the injected mRNA contains the instructions for the body's cells to make the coronavirus spike protein. It is then produced on the surface by some of the body's cells, and the immune system learns to recognize it as foreign. It then also attacks the coronavirus in case of infection.
An era of mRNA drugs?
However, mRNA is very sensitive. In cells, it usually only survives a few minutes. CureVac's printer modifies it to make it more stable and packages it in lipid beads. Purifying the desired mRNA is also essential, says Bergmann, otherwise impurities could harm the patient.
CureVac expects to receive the license to print the first mRNA therapeutics before the end of this year. The company would like to use them to supply university hospitals and large research institutions worldwide for clinical trials. In principle, however, the drug factory could also be located directly at the patient's bedside or taken to countries that are currently struggling with a new variant of a virus, says Bergmann. The factory functions universally and can supply more than just one type of mRNA. The control system for this is currently being developed by Tesla Automation, originally the German mechanical engineering company Grohmann Engineering, headquartered in PrĂĽm. Elon Musk, or Tesla Motors, bought the specialist for microprocessors, memory chips, sensors and control units in 2017.
Trend toward individualization in medicine
Now just two vaccines against covid-19 are based on mRNA. Thousands of other drugs, on the other hand, are made from other substances. Nevertheless, Bergmann believes in an era of mRNA drugs and thus in his flexible mini-factory. The trend toward individualization in medicine gives him hope for change - especially in cancer medicine, where there is a sense of optimism. Patients are now treated differently after their cancer cells have been genetically and molecularly analyzed. CureVac wants to inject precisely that mRNA into the body that causes healthy body cells to form the cancer cell receptor and mobilize the body's defenses against it. Others have also been infected by the spirit of optimism: The U.S. start-up Nutcracker Therapeutics also wants to come up with an mRNA printer to advance into the field of cancer medicine.
"If mRNA therapeutics gain in importance, printing in small facilities is a highly interesting approach to making production more flexible," says Henrik Jeimke-Karge, press spokesman for the Association of Research-Based Pharmaceutical Companies. Others are more skeptical. Glatz adds: "When the genome was deciphered in the 1990s, it was said that we would soon have only gene therapeutics. But classical active ingredients will not lose their importance for many decades to come," he says.
In any case, the pharmaceutical industry would have to change fundamentally if it were to abandon hermetically sealed production halls in favor of bedside devices. Until now, every new active ingredient has required several clinical trials, and their design must meet strict criteria. From Asia to Europe, this regulatory practice has become established. However, Bergmann says, "In our case, only the device and the manufacturing process are then approved, not the drug itself."
Modular plants are in demand in Europe
Detached from the importance of mRNA therapeutics, the industry has caught a trend towards flexible and modular production. Modular plants in which different substances can be synthesized are now in demand in Europe, one hears from the plant manufacturers. On the one hand, they are a tribute to the increasing individualization in medicine - as taken to extremes with mRNA printers. On the other hand, they are a reflection of the increasing cost pressure in the pharmaceutical industry. Before an active ingredient becomes a drug, three extremely costly clinical phases have to be passed through, and the time in which the then approved drugs can be sold profitably under patent protection is short, at 20 years.
The pressure in the pharmaceutical industry to produce these drugs quickly in commercial sizes is great, because generic manufacturers are virtually in the starting blocks with the day of approval for active ingredients that promise broad use. However, planning and building a conventional greenfield plant can take up to three years - time that comes off the profitable 20 patent-protected years. Building modular plants can cut that time to less than two years, according to Exyte, an international plant engineering company based in Stuttgart, Germany. And even if the next pandemic comes, agility - the ability to react as quickly as possible with adapted formulations to new virus variants, for example - is more important than ever. In flexible production plants like the one in Freiburg, the modules for different products only need to be adapted and recombined.
Whether it's pills popping out of a machine next to a patient's bedside, factories running remotely without humans, or countries spending their money to rebuild basic health care, securing access to medicines may need one thing most of all: Diversity.
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