Watch: Chief Manufacturing and Development Officer Tertia Dex explains the KappaMab manufacturing process

The monoclonal antibody manufacturing process is complex, involving many stages and processes. KappaMab is our lead clinical therapy and a potential treatment for Kappa-type Multiple Myeloma.

In this video, HaemaLogiX Chief Manufacturing & Development Officer Tertia Dex explains the KappaMab manufacturing process, including why manufacturing is an important factor in commercialisation and how we manage the risks associated with it.

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What's involved in the manufacturing process for an antibody like KappaMab?

Monoclonal antibodies like KappaMab are quite complex to manufacture. It starts with a recombinant DNA product _(see note 1 below)_ or a vector which is transfected _(see 2.)_ into a cell line, and once you develop a cell line that's stable and able to express your protein of interest, it's at that stage that you can grow up those cells in a piece of equipment called a bioreactor. In that bioreactor, we hold those cells with all the nutritional contents that it needs. We remove all the metabolites and toxic products to that cell line and then that cell line also expresses that one protein of interest through that recombinant DNA technology.

We at that stage need to purify that one protein of interest from all of the other proteins that the cells require to grow and maintain their healthiness. So, the purification process may take several weeks after which we formulate the product into a stable formulation and then we fill it into sterile vials which are packaged and labelled ready for the clinic.

Does your product meet global cGMP standards?

Yes, it's a good question. So even though we're out here in Australia, we have one of the best regulatory authorities in the world. They're a highly technical regulatory authority and they follow global cGMP guidelines including a guideline called PIC/S which is globally harmonized so we must meet those standards in order to conduct clinical trials here in Australia, but our product also is going to undergo clinical trials in other jurisdictions such as the us and Europe maybe the UK and various other jurisdictions, so whenever we manufacture KappaMab or any of our products, we ensure that we meet all those global regulatory standards through the contractors we're working with and that includes standards for the US, Europe, UK, Australia and of course the licensee.

Wherever we're making the product, we want to ensure that they have their own global standards that they're meeting, and their local cGMP licence is applicable to their local authority.

What's the history of the process development and how does this translate to commercial potential?

So, the history of the process development work for this for KappaMab is that the product's been manufactured at seven different, several different scales. What we do is we've contracted with a reputable supplier who has had this platform development process they have developed over 30 years, especially their cell lines, so they earn a lot of knowledge around performance and stability of the cell line so once we're able to use this platform process, we can scale that up successfully from bench all the way through to thousands of litres which means over time we've manufactured the product at several different scales that then demonstrates the robustness of that process to deliver consistent quality attributes at each scale, and by contracting with these large reputable companies with those platform processes, it gives some other pharmaceutical companies or anyone interested in investing a lot of confidence, that we're using a standard process that has existed for decades and that we can produce product of consistent product quality. The other thing to think about when you're manufacturing products with the commercial aspects in mind, is that you need to yield a high level of production during your expression of your protein and across your purification process so that your cost of goods is commercially viable. I'm very pleased to say that the process for KappaMab is extremely economical. It's one of the largest expressing batches I’ve seen in my time in the industry and we're able to then keep the scale of the batch quite small when we go to commercial supply which means that the cost of those batches remains economical for a commercially viable product

In a complex program, how do you reduce the risk to market?

So, reducing the risk to market takes a number of steps. One of the most important steps is very early on your program defining those critical quality attributes of your product. What is it that you need your product to look like? Develop an analytical package around that product to ensure that you can deliver the product quality that's required both from a safety perspective, an efficacy perspective and also a purity perspective and you also need to understand the secondary and tertiary structures of your molecules to ensure that effective function is working as expected. So doing that work up front and developing a very strong understanding of the nature of your product through strong analytical package is really important. Secondarily, you want to ensure that your process development work is thorough, and for KappaMab for example, we've used a platform process that has been around for 30 years. The company who owns that Intellectual Property has offered that to the industry and it means that you get that consistent robust a scalable process in order to manufacture product of that product quality that you've defined up front and then the other thing of course is to have the right team around you and a very strong regulatory and business strategy. When you have the right strategy and the right team, you reduce a lot of risk around developing your product through to the commercial stage.

How much more complex is it creating antibody drugs versus small molecules?

Large molecules are a lot more complex to manufacture than small molecules. It's because of the use of recombinant DNA technology transfecting a mammalian cell line in order to express this one protein of interest. Mammalian cell lines need the same amount of nutrients and metabolites, metabolite stability that we need to survive. So, we're mammalian cells in a very large growth vessel and our cells need oxygen. They need nutrients, they need toxic waste products to be removed and that's the same for a cell line for large molecule expression. So, once you're able to create that highly controlled and stable environment for those cells to grow, it's at that point you need to remove the cells they express the protein of interest. Unfortunately, that's expressed with a number of other host cell proteins in order for those cells to grow and that could be in the thousands. Then we need to purify that one protein of interest from those thousands of host cell proteins at the same time, controlling the level of aggregation fragmentation of the product, ensure that we don't put the molecule under other stresses such as oxidative stress and deamidation and different things and so the process then itself you may have over a thousand manipulations in order to grow those cell lines, purify the one protein of interest and then finally sterol fill it into the final container closure system ready for use in the clinic. So that process can take up to about six months when you start from one vial, go all the way through to your intermediate drug substance expression, sterile fill your drug product ready for packaging and then of course analyze and test the product to ensure it meets the quality specifications.

How hard is it to crack the manufacturing process for a drug like KappaMab?

To crack the manufacturing process - it is not easy. It takes a lot of industry experience. So one of the best things you can do in order to develop a process suitable for your product, is to utilize the industry knowledge that already exists; so utilizing things like platform processes cell lines that have been in the industry for many decades that have a proven regulatory track record and also using contractors who usually have the most amount of knowledge in the industry, given they see a different molecule every other week or every other month and their exposure across the years means that they accumulate a level of experience that translates into value for your product. So, using those platform products processes gives us an ability to have confidence in its robustness and scalability. Every product is different, so you do need to develop a different process for every product, but it gives you at least those decades-long industry experience in order to apply a platform approach especially for products such as KappaMab which is a monoclonal antibody that we can robustly manufacture this product all the way through to commercial scale.

Now that you've completed this process for KappaMab, what benefits can you take forward into setting up the same process of LambdaMab?

So, I’d suggest for LambdaMab we'd use a very similar approach. So, we would select a cell line that has lower regulatory risk, so a cell line that's been around that's been approved by regulators that is shown to be stable and that can consistently scale up into the larger scales in order for it to be ready for commercial scale but leveraging those platform processes and platform cell lines that exist and getting that confidence through our first program with KappaMab. We know that we can apply very similar approaches for LambdaMab being also a monoclonal antibody, but in saying that for every product there is a set level of development that you will need to do in order to ensure that you've got the right conditions for manufacturing that product. So there's some translationary learnings there for LambdaMab, but most importantly working with a platform process and an experienced CMO will benefit us.

Notes

1: Recombinant DNA products are simply products that have been made by isolating a segment of DNA that is of interest, and cloning it. The copies are referred to as ‘recombinant DNA’.

2. Transfection is the process of introducing a foreign substance into a cell