At the heart of any successful medicine launch is a robust manufacturing process that will reliably make the product in a reproducible fashion and at a commercial scale. Stacey Treichler, Group Product Manager at Catalent Biologics, reports
Reaching manufacturing milestones for a small molecule drug is a significant operation; however, achieving success with a biologic drug is substantially more challenging. Much of this complexity arises from the fact that biologic medicines are made by living cells.
These are far more difficult to standardise than the chemical reagents that are typically used to make small molecule drugs. Although the biggest pharmaceutical companies may well have significant in-house expertise, the same is not true for smaller biotech businesses; so, partnering with an experienced contract development and manufacturing organisation (CDMO) can be invaluable in assisting the innovator company to develop a robust process.
CDMOs can also assist larger companies during the development process by providing specific skills, technologies or expertise that can speed up the product’s route to market.
Genetically modified cells are the “machinery” used to manufacture protein-based medicines such as monoclonal antibodies. The initial step in the development process is, therefore, inserting the relevant DNA sequences that code for the target protein into a cell line that is suitable for commercial production.
This cell needs to be clonal, with every cell being genetically identical. It should also be able to generate a high yield of protein that has the correct properties, including conformation and any of the post-translational modifications that are required to achieve optimal pharmacokinetics and pharmacodynamics.
At the start of the proof-of-concept stage, it is often convenient to use transient expression. This enables very many variants to be screened with only small amounts of material being made. However, it is unlikely that this will match up to the yield achieved with the final clonal cell with permanently expressed DNA; the post-translational modifications, such as glycosylation patterns, are likely to vary too.
Whereas one pharma company or CDMO may be able to do all the steps of the development process themselves, right the way from cell line development to final process characterisation, it is probable that more than one team will be involved.
However, transient expression is a useful tool to quickly establish that the correct protein is being expressed … and it can prevent some of the early development work having to be repeated with the final cell line.
Ultimately, the final cell line must be monoclonal with guaranteed stability. Ideally, it will make the target protein in a titre of at least 4 g/L. To meet regulatory requirements, it must be fully traceable; and, for commercial viability, secure intellectual property is essential.
All companies undertaking biologic drug development, whether a pharma company or a CDMO, will have its own approach to the development of a cell line and, therefore, the titre and stability that will be achieved. Whatever technology is selected, the cell line must be able to ensure that the genes are all expressed in the correct ratio so that the right protein is manufactured.
The issues are exacerbated for bi- and multispecific antibodies that are more complicated to construct as lower levels of expression are common.
The choice of cell line is critical and Chinese hamster ovary (CHO) cells are by far the most frequently used. There are a number of techniques and technologies that can be used to optimise cell lines so that they perform consistently in production while minimising development time, and these include automated methods to screen for the clonal selection of cell lines.
Access to rapid manufacturing capabilities such as mini bioreactors also allows a scalable design of experiment (DoE) approach to process development and characterisation.
The choice of growth media, in particular, is critical
Both the protein’s quality and cell productivity are driven by the combination of host cell and cell culture conditions, in combination with the technology used to develop the cell line. The choice of growth media, in particular, is critical: obviously, these must be compatible with the cells and they should also not cause the protein to aggregate.
The cell line development platform provides the basis for the chemistry, manufacturing and controls (CMC) package and gives the starting point for all manufacturing steps, regardless of whether early clinical batches or full commercial quantities are being manufactured.
With a suitable cell line in hand, the next step is to create a cell bank. Ideally, a CDMO will be well-versed in making cGMP-compliant cell banks, as well as the analytical methods required to evaluate both the cells and the proteins. This is important to establish and prove that the protein’s structure remains the same from the early clinical batches through to final production.
Another aspect wherein experience is important is in determining the stability of the biologic throughout the manufacturing process and during storage — right up to the point when it’s dosed to the patient. Information on this, again, is an important part of the packages put together for regulatory filings.
It is important to carefully assess in advance the way in which the technology will be transferred from one team to the next if delays or problems are to be avoided. It is advisable that the analytical work should be done at the same place where the process work is located, as this is the area where the tech transfer complexity is greatest.
Perhaps the most important consideration when selecting a CDMO for commercial-scale manufacture is whether it has sufficient cGMP capacity to make the product in adequate quantities. Although bioreactors that meet the volume demands for Phase I and even Phase II trial supplies are common, the same is not true for Phase III and commercial scale.
Yet, the entire scale-up process from first-in-human to commercial batches will likely go most smoothly if a single supplier has the flexibility to scale-up in house.
It is also important not to overlook the productivity of the cell line. This has a substantial effect on the overall cost of goods as a more productive cell line reduces the volume requirements of the bioreactor (fewer batches will need to be made). This will be increasingly important for products that are high volume or when the dose administered to patients is large.
Although developing a highly efficient manufacturing process increases the project costs at the outset, the savings once the product reaches the market can be substantial if fewer, smaller batches are required. It does, of course, take longer, and the trade-off between an earlier launch and long-term savings needs to be evaluated carefully.
A Big Pharma company may be more able to withstand the cost of the upfront investment with the promise of savings down the line than a biotech reliant on hitting research milestones as early as possible to secure continued funding for development.
In a perfect world, the development and scale-up process for an antibody will be problem-free: the cell will be easy to engineer, a high titre will be achieved rapidly and the process will be well behaved.
In practice, however, advertising aggressive timelines in advance may prove overly optimistic, as only those simple antibodies that are amenable to platform processes stand much chance of proceeding this quickly; even then, this makes many assumptions.
In reality, it is often the case that a protein may prove more difficult to express than had been anticipated or there may be problems generating a stable cell line. Non-traditional antibodies such as bispecific or fusion proteins are more likely to prove problematic and are almost guaranteed to take much longer to develop than a simple monoclonal antibody.
Even for complex antibodies, there are steps that can be taken that will accelerate the process
However, even for complex antibodies, there are steps that can be taken that will accelerate the process. For example, a high-performance cell line technology is likely to minimise the time taken by upstream process development … and further time savings might be made by using automated clonal selection technology and process development techniques.
Downstream processing development can be initiated using stable pool material, and material for toxicology studies can be made with the research cell bank ahead of the completion of the GMP master cell bank. Final batches can even be shipped as soon as they are filled, ready to release once the concurrent analytical testing is complete.
Regardless of the nature of the final product, taking an integrated approach is almost guaranteed to be the fastest and most efficient option during development. Minimising the number of service providers assists in speed, as handovers between companies will always slow the process down.
By selecting an outsourcing partner that is able to do most, if not all, of the process development steps in house, an investigational biological drug will reach the clinic more quickly — to the benefit of both patients and the biotech company’s bottom line.