Health Solutions: Gearing up pharmaceutical manufacturing

By Diego Tonelli and Valeria Iansante

When Alexander Fleming¹ arrived at his laboratory on the morning of 3 September, 1928, little did he know he was about to change the course of human history. A petri dish he had accidentally left out became contaminated with mould that killed the bacteria he was observing. The discovery led to the development of one of the world’s first mass-produced antibiotics, penicillin, which has saved more than 200 million lives² since it was first used.

The story of pharmaceuticals is the story of discovery and ground-breaking research. But as the pharmaceutical industry has grown into one of the world’s largest industries, so has the cost of innovation. A 2020 study estimated that companies spend approximately $1 billion on research and development to bring a new medicine to the market.

The development of new medicines and therapies, however, needs to be followed by significant advances in pharmaceutical manufacturing. But pharma companies have tended to lag behind firms in other industries in adopting new technologies. Here we explain why they have been struggling – and how to deal with the problem.

Regulation and innovation

The pharmaceutical industry is heavily regulated³. Understandably so. Patient safety comes first, which is why any significant change to the manufacturing process needs to be approved by regulatory agencies. This means that pharma companies must consider how the drug will be manufactured while it’s being developed. They need to ensure quality at every step – from formulation to production and packaging. There is no room for mistakes. Every package of medicine must be precisely the same.

Once determined, following a development path characterised by trials and errors, the process needs to be exactly replicated for each batch of the product. This approach:

• ensures that drugs are always of the same quality (technically speaking, “within specifications”)
• reduces waste of active pharmaceutical ingredients (substances necessary to manufacture pharmaceutical products) and money, minimising the risk of batches that don’t comply with the high standards required
• makes the manufacturing process less prone to change.

Another important factor is the type of drugs the pharma industry predominantly produces. So called small-molecule drugs⁴ make up 90% of the global pharmaceutical market by volume⁵. Small-molecule drugs include aspirin, antihistamines and most of the other drugs in your medicine cabinet. Thanks to their simple chemical structure, small molecules are relatively easy and cheap to manufacture. To reduce their cost even further, companies often outsource (at least part of) their small-molecules production to markets characterised by very low per-unit cost of production. For example, China and India produce 60% of the world’s paracetamol, 90% of its penicillin and 50% of its ibuprofen⁶.

Heavy regulation and outsourcing, combined with the high cost of bringing new drugs to market, have made pharmaceutical manufacturing particularly unreceptive to quick changes and the adoption of incremental innovation. This has in turn led to a decline in the value of manufacturing activities, as well as diminished investments by industry leaders. No investment means no innovation.

But new treatments are pushing the pharmaceutical industry to rethink its approach to manufacturing.

From small to large molecules

Scientific discoveries over the last half century have led to the development of a different type of drugs based on larger molecules – biologics⁷. The first biologic drug was approved in 1982⁸ to treat diabetes. While insulin of animal origin had been around as a medicine for decades before, this was the first genetically engineered, biosynthetic “human” insulin. And this is what makes biologics different from small molecules. Unlike small molecules, which are chemically derived, biologics, or biopharmaceuticals, are extracted from, semi-synthesized by, or manufactured in living organisms⁹.

Biologics include vaccines, hormones as well as many other treatments that offer millions of people a chance for a healthier and longer life. What makes biologics so relevant is the way they interact with the biological mechanisms occurring within the human body, for example with a patient’s immune system, enabling a more targeted treatment. This is why they have played a crucial role in the development of treatments for patients with cancers, autoimmune and rare diseases.

Their complexity, however, makes it more difficult to produce and distribute them. Cell therapies¹⁰, an advanced type of biologics, are particularly challenging to manufacture. As they consist of whole living cells, these products need to be prepared using highly sophisticated and controlled processes, to ensure that their biological functions are not altered. In addition, the traditional approaches used to ensure sterility, such as heat or filtration, cannot be used as they would damage the cells. Therefore, alternative approaches need to be put in place. The complexity of biologics also makes them expensive. In 2017, biologic drugs represented 2% of all US prescription drugs, but 37% of net drug spending¹¹.

Advances in manufacturing technology are therefore needed to bring the costs down and scale up the production of biologics, particularly to increase their access globally.

The European Investment Bank has recognized this issue. In 2019, the bank supported Mabion¹², a Polish developer and manufacturer of biosimilars¹³, and Univercells¹⁴, a Belgian biotech company focused on developing four essential and undersupplied global health vaccines, to be produced at affordable prices, high quality and large volumes. The European Investment Bank financed Univercells again in 2021 to support the company’s efforts in the manufacture of COVID-19 vaccines¹⁵.

One size doesn’t fit all

The advancement of scientific research and the understanding that different individuals may respond differently to the same drug led to a paradigm shift in medicine. To use the drugs more effectively, we need to tailor them to each patient’s needs. Knowing how a patient might react to a certain therapy is a complex issue, but significant progress has been made in this field over recent decades.

Personalised medicine¹⁷ is an innovative concept that turns the traditional “one-size-fits-all” approach of small molecules and biologics on its head. It’s an approach in which the treatment is tailored to the patient’s own genes, disease subtype, risk, prognosis and predicted individual response to prevent, diagnose or treat a certain condition.

Gene therapies¹⁸ play an important role in personalised medicine, and that role is only expected to grow in the future. It is a technique that modifies a person’s genes to treat or cure a disease¹⁹. Gene therapies either replace a disease-causing gene with a healthy one, deactivate it or altogether introduce a new or modified gene into the body to help treat the disease.

Increased selection of patients who may better respond to a certain treatment based on their own biologically unique features (the so-called “patient stratification”) could lead to more personalised treatments and increased chances of prevention. The European Commission has recognized personalised medicine as the answer to rising healthcare costs associated with chronic diseases and an ageing population. This is because no money is wasted on trial and error treatments – the patient gets the right treatment at the right time.

Such customisation, however, requires a total rethink of classical pharmaceutical production. In some instances, one batch of a medicinal product may treat only one individual patient, with obvious challenges related to the implementation of cost-effective manufacturing processes allowing for such small-scale productions.

Manufacturing solutions

From mass production of small molecules to hyper personalization, it’s quite a leap. Current technology and the regulatory environment are still not entirely suited to personalised treatment solutions.

After years of offloading small-molecule manufacturing, pharmaceutical companies are bringing their manufacture back into the fold. The development of new biologics and personalised medicine are pushing companies to re-establish the link between research and development and manufacturing activities, and to develop innovative production processes that can easily adjust to the scale needed.

This goes without saying for gene therapies and personalised medicine, where manufacturing is an integral (sometimes unique) component of the development of the treatment itself, constituting an invaluable source of know-how, which is often translated into critical intellectual property.

The necessary technology to scale up production of innovative biologics is already being developed. The COVID-19 pandemic has accelerated these developments and put a spotlight on certain technologies, such as mRNA, which can accelerate the development and manufacturing processes and significantly reduce their costs. The EIB has also responded quickly to this shift, by supporting German companies BioNTech^20 21 and Curevac²².

 

Besides the adoption of new technologies, there is also a push towards higher digitalization, continuous production and more flexible manufacturing approaches for more advanced medicinal products.

The decentralisation of manufacturing is the next step. To prevent shortages in supply, as occurred during the COVID-19 pandemic, companies may consider  hub-and-spoke models. Manufacturing spokes should be set up in different geographical regions to prevent overreliance on a single production facility. But this is not an easy task. To achieve this, companies require a supportive ecosystem and a highly skilled workforce.

Last but not least, the production of pharmaceuticals is a relatively energy- and resource-heavy process. Its climate impact²³ must also be considered when designing the production processes of the future.

The pharmaceutical industry needs to pick up speed. The COVID-19 pandemic has given the industry another push to invest more and better in manufacturing. And innovation in pharmaceutical manufacturing is the only way to make the new generation of medicine and therapies available to everybody.

American author Katharine Dunne famously wrote that “prior to penicillin, death was an everyday occurrence”. Innovation in medicine and the development of advanced personalised therapies may improve health care even more than penicillin did, treating diseases once considered “incurable”. However, manufacturing strategies need to be developed at the same pace, to ensure that innovative treatments can be available for the patients who need them.

Diego Tonelli is an economist in the Life Sciences division at the European Investment Bank. Valeria Iansante is a specialist in the Life Sciences division at the European Investment Bank.

1. Sir Alexander Fleming - Biographical (nobelprize.org)
2. Alexander Fleming - New World Encyclopedia
3. Quality: manufacturing | European Medicines Agency (europa.eu)
4. Small molecules - Latest research and news | Nature
5. Small vs Big: Understanding the Differences between Small Molecule Drugs and Biologic Drugs | IMMpress Magazine
6. European Parliament
7. Biologics - Latest research and news | Nature
8. Insulin (Human) - an overview | ScienceDirect Topics
9. (PDF) Biologics versus small molecules: Drug costs and patient access (researchgate.net)
10. Cell therapies - Latest research and news | Nature
11. Biologics vs. small molecules: Drug costs and patient access - ScienceDirect
12. Juncker Plan: EIB loan for Mabion highlights support for Poland’s young biotech sector
13. Bring on the biosimilars (nature.com)
14. Univercells boosted by EUR 20m European financing to accelerate the delivery of its vaccine portfolio (eib.org)
15. Belgium: EIB boosts innovative biotech company Univercells with €30 million of European financing to support COVID-19-related projects
16. Univercells | Biologics For All
17. Personalized medicine - Latest research and news | Nature
18. Gene therapy - Latest research and news | Nature
19. What is Gene Therapy? | FDA – U.S. Food and Drug Administration
20. EIB provides funding of EUR 50 million to BioNTech as part of the Investment Plan for Europe
21. Investment Plan for Europe: European Investment Bank to provide BioNTech with up to €100 million in debt financing for COVID-19 vaccine development and manufacturing (eib.org)
22. Germany: EIB and European Commission provide CureVac with a €75 million financing for vaccine development and expansion of manufacturing
23. Carbon footprint of the global pharmaceutical industry and relative impact of its major players - ScienceDirect