- Speaker #0
Welcome to EDQM On Air, a podcast on public health brought to you by the European Directorate for the Quality of Medicines and Healthcare of the Council of Europe. We hope you enjoy this episode and we invite you to stay tuned to learn how the EDQM and its stakeholders work together for better health for all. Today's episode is all about biological medicinal products, often referred to as biologics, which are a class of pharmaceutical products derived from living organisms or their components. Unlike traditional chemical medicinal products, which are synthesized through chemical processes, biologics are produced from biological sources, such as microorganisms, animal tissue, or even human cells. These substances are extremely powerful and versatile, helping us manage or even cure conditions that were once thought incurable. like smallpox, diabetes, or haemophilia. Additionally, biologicals are currently on the cutting edge of pharmaceutical science, with incredible innovations such as CRISPR and CAR T-cells yielding extremely promising results, making us stronger in our fight against disease. But how did we get to this point? What were the first biologics, and how did they evolve over time to get to where they are now?
- Speaker #1
Well, the history of biologicals in modern medicine definitely started with vaccine. In 1886, Louis Pasteur developed the first rabies vaccine, and this was followed in the years after with cholera, typhoid, pertussis, and smallpox vaccine, thanks to which smallpox could be eradicated from the planet.
- Speaker #0
This is Emmanuelle Charton from the European Pharmacopoeia Department of the EDQM. She's kindly agreed to come on the podcast as a guest. to walk us through the history of biologics, from the first vaccines to today's Nobel-winning innovations.
- Speaker #1
So, vaccines were the predominant biologicals in the first half of the 20th century. In the second half of the century, another class of biological products were put on the market, and these are products derived from blood, human blood, human plasma, or from animal tissues. The problem is with these products, there were some significant public health issues. And this is why in the 90s, biotech products were very much welcome. At the end of the century, it was really a turning point in the field of biologicals. One started to create new molecules, for example, genetically modified insulin to make it more rapid or less rapid. Monoclonal antibodies, very specific molecules that can specifically attack some cells to treat cancer. And now after one and a half centuries, we reached a point where we can literally cut our own genome with molecular scissors.
- Speaker #2
Thank you so much, Emmanuel, for that intro. And thank you for being on the podcast with me. Now, to get to the point straight away. When did biologicals start evolving within the framework of the European Pharmacopeia?
- Speaker #1
I can say it started immediately after the birth of the European Pharmacopeia in 1964, with vaccines once again the oldest class of biologicals. In the first edition of the European Pharmacopeia in 1971, there were already one general monograph on vaccines for human use, and 30. individual monographs on vaccines for human use. And these were followed a few years after by a general monograph on vaccines for veterinary use and seven individual monographs for veterinary use. And it is very interesting to read in the reports of the discussion at the time that the problematics met by the experts who elaborated these monographs were very similar to the problematics we meet nowadays. For example, they had to address the complexity of these medicinal products and they had to draw attention to specific parts of the manufacturing process. And they could not find a place where it would fit in the monograph. The identification section or the test section or the assay would not be the right place. So to address complexity of these, they decided to create the so-called production section. And in 1991, the first text including such a production section was a monograph on vaccine, vaccine for veterinary use, this general monograph I was just referring to. So it's very interesting to note that it is a vaccine monograph which paved the way to the production section, which is now very commonly used in many monographs. But so much for vaccines, let's move on to the next category of biological products I would like to talk to you about. And these are products extracted from human blood or human plasma or from animal tissues. In the second edition of the European Pharmacopeia appeared monographs on heparins, insulins, enzymes, hormones, immunoglobulins, coagulation factors. I would like to give the example of HGH, the human growth hormone substance. This substance is extracted from the pituitary gland of human cadavers, and it was used to treat nanism. The monograph for HGH was published in 1987, but deleted 10 years after because the product had been removed from the market, and the reason being patients treated. with this substance had developed Creutzfeldt-Jakob disease. There were other public health issues related to this category of product. Everybody has heard about the contamination of blood products in the end of the 70s, 80s. So until 1985, these products were subject to contamination. And at the time, 1985 was the date when measures were put in place to avoid contamination with HIV and other viruses, and systematic control screening for these viruses were put in place. And this is exactly when work started at the European Pharmacopoeia to work on one of the most important monographs in the field, and this is human plasma for fractionation. The work on this monograph was very long, it took many years, discussions around it. Within groups of experts were very intense. But you have to imagine that at the time, the EU blood directives were not there. So the experts had to address tricky problems such as the qualification of donors. But what you can read also in these reports is that there was a real need for a tool that would allow the free circulation of human plasma. for fractionation in Europe within all the member states of the European Pharmacopeia. And the experts worked very hard on this task to finally publish a monograph. And this was in 1993. And since then, the monograph is regularly revised to continue to guarantee safe use for patients across Europe.
- Speaker #2
Okay, thank you. I have a question based on what you've said so far. It seems that... Biologicals as a category of substance have caused numerous public health crises. It seems that a lot of complications have happened in relation to biologicals, as you said with the human growth hormone and everything, for example. So are they somehow more dangerous than other types of substances?
- Speaker #1
Absolutely not. Don't get me wrong. I could not have made the history of biological products without mentioning these crises. They happened, they were addressed, but after that, the products were safe. And all the products I mentioned a few minutes ago, they are still in the pharmacopoeia. It was only HTH which was removed. But they cover the quality of products which are absolutely safe. So I did not want to make it sound that these products are unsafe. I just wanted to mention about these events. And maybe I would like to emphasize two main drawbacks for these substances. First of all, that they depend on the availability of blood. So they depend on the will of some people to donate blood or plasma. Let me take an interesting example, and this is related to heparins. I just mentioned it a few minutes ago. So the heparin substance is extracted from the intestine of pigs. And if there were no pigs available, there would be no heparin. And you have to imagine that almost every single patient lying in a bed in a hospital is being administered intravenously heparin. And the manufacturers of heparin very much rely on the availability of this. And a few years ago, there was an outbreak of, it was African swine fever, which killed a number of pigs, which generated a shortage of heparin. So availability is a big issue for all these substances. So first drawback, availability. And the second is that these products are prone to contamination. But if contamination is well under control and avoided, then there is no safety issue. This is why these products are safe, to answer your question. Now this gives me an opportunity to move on to the next class of biologicals, which do not have these drawbacks, and these are biotherapeutics. also called biotech products. And in the European Pharmacopeia, they are called products of recombinant DNA technology. These appeared in the 90s, in the third edition of the European Pharmacopeia, first with a general monograph on these, and then with individual monographs for human insulin, interferons, hepatitis B vaccine, erythropoietin. Somatropin, the biotech equivalent to HGH, very interesting molecule. So the biotech products continued to flourish into the 21st century, for example, with coagulation factors, polytropin and insulin analogs. And the last class of biotech product which appeared in the European pharmacopoeia are monoclonal antibodies. These present an enormous potential. So there is one general monograph for monoclonal antibodies for human use, and one single individual MAB monograph in Fliximab. So these biotech products, what characterizes them is that they cover a huge range of size. And these are proteins which can go from 5 kilodalton for insulin until 150 kilodalton. for a monoclonal antibody. And this is very big. These are very big and complex molecules. And while establishing monographs for these biotech products, it became evident that flexibility in the text was necessary to address the complexity of the molecules. This is because these proteins First of all, they could result from different manufacturing process, but inherently they present a big heterogeneity. So biotech products have been a trigger for the experts to reflect on how to write meaningful standards while allowing for flexibility. And it would be too long to explain there all the examples of what was the purpose of the biotech. taken for these monographs. But what I can say is that now these monographs are robust quality standards while allowing for alternative approaches. So if there is one category of product which boomed significantly into the 21st century, these are definitely ATMPs, the so-called advanced therapy medicinal products or cell and gene therapy. And If you allow me to explain in a very simplistic way what they are in comparison to the biotech products, I would say that, first of all, many of these are proteins. And in the case of biotech products, the gene coding for the proteins would be inserted into the genome of a bacteria or a cell. And then these bacteria or cells would... produce the expressed protein into a medium, culture medium, and then you would purify the substance from this culture medium. In the case of gene therapy, you inject the genome of the protein directly into the human body via a vector, this vector being most of the time virus, which is harmless, or even for... what are called genetically modified cells. You would collect the cells from a patient, send them to a manufacturing facility where its genome would be modified, and then the cell re-administered to the patient. And the cell would then produce either a substance that would kill a cancer cell or produce a deficient. protein, a protein which is deficient from the patient body. But there are lots of different ways gene therapy products can be made. And this is all very complicated. And the challenge has been how to write a European pharmacopoeia text which could cover all of these. And as early as the year 2000, the experts of the European Pharmacopeia tried to reflect on how to write such a text. And in the year 2005, the Chapter 514 Gene Transfer Medicinal Products for Human Use was published in the European Pharmacopeia. And this was 13 years before the first gene therapy product was approved in the EU. It served all these years as guidance. to develop gene therapy products, and it is still serving nowadays. And we have very good feedback from stakeholders that it is a robust quality standard. Here as well, the European Pharmacopeia has shown that it can adapt itself to every specific situation. And in this field, it's a big challenge because things are moving fast.
- Speaker #2
All right, thank you, Manuel, for taking us through this very... comprehensive journey through the evolution of biologicals. My question for you now is, how does this field look like today? And what do you think its future holds, especially in the context of the European Pharmacopeia?
- Speaker #1
Very good question. What I can do is share with you what I'm seeing nowadays. For example, in the field of monoclonal antibodies, there are hundreds of them either approved or used in clinical trials. And the challenge is to cope with this multitude of products. One cannot write a single monograph for the hundreds of monoclonal antibodies that are or are going to be on the market. So a solution might be to instead develop platform chapters, which then would apply to many monoclonal antibodies and such texts would then have much more impact. than a product-specific monoclonal antibody monograph. And this is currently being investigated by the expert of the pharmacopoeia. In the field of cell and gene therapies, we are working in the integration of knowledge that results from the recent approvals of CAR T cells with always one thing in mind, flexibility. And as far as advanced technologies are concerned, There's going to be soon for publication the release of a general chapter called HTS, High Throughput Sequencing, also known as Next Generation Sequencing or Massive Sequencing. It is a very powerful tool which allows the detection of viral contaminants, especially in biologicals, in vaccines. And it uses databases or... digital libraries for the search of these contaminants. So it raises new challenges, such as how to describe computer validation, the so-called big data, but these are exciting developments. And remember, I started with vaccines, and I would like to also finish this story with vaccines. Currently, there are texts under development to cover this. mRNA vaccines, and this work started immediately going out of the pandemic. Messenger RNA vaccines are biologicals, but in fact, if you think of it, these are synthetic strands of messenger RNA wrapped into synthetic nanoparticles with some structural excipients, but these have nothing to do anymore with living organisms. So, this does not completely fit the definition you gave at the start on what a biological is. Still, in any case, the pharmacopoeia has been present from the start and is still there 50 years after the first vaccine monographs were published.
- Speaker #0
Today, with the help of my guest Emmanuel Charton, We took a deep dive into the evolution of biologics through time, and we discovered how they're revolutionizing medicine to this day. We also touched on the role of the EDQM in the development, regulation, and standardization of biologics, and saw how the EDQM has helped tackle several major public health crises related to biological drugs. If you enjoyed this episode, please subscribe to our show on your podcast platform of choice to make sure you don't miss out on new releases. Thanks again for tuning in, and we'll see you in the next one.
