CDMO SELECTION - Ready to Launch: Developing Your Biologic With an Eye Toward Commercial Supply

INTRODUCTION

The process of successfully launching a novel biologic drug onto the market is not as simple as succeeding in clinical trials and persuading the regulators that it is safe and effective; a manufacturing process that is capable of making the product reliably, reproducibly, and in commercial quantities will also need to be developed. In comparison to a small molecule drug, which may also be challenging, the development process for a biologic is even more complex, not least because the “machinery” that makes the drug molecules involves living cells. Many companies rely on a contract development and manufacturing organization (CDMO) to assist them in developing the cells and the process, and it is vital that the CDMO they select has the right capabilities and enough experience.

Catalent’s state-of-the-art facility in Madison, WI, leverages single-use technology for development and manufacturing.

The first step is to create a manufacturing cell line by inserting the DNA sequences that code for the protein into a cell line capable of being utilized for commercial production. This can be challenging, as there are multiple places where the sequences can be inserted. A clonal cell line is required – one in which every cell is genetically identical – and the clone that is selected should produce the maximum amount of protein, while still maintaining the conformation, post-translational modifications, and other properties necessary to achieve the desired pharmacokinetic and pharmacodynamic profile. In the early proof-of-concept stage of discovery, transient expression is a helpful tool, as it allows a large number of variants to be screened, and small amounts of material to be made. However, it may not be representative of the ultimate yield or manufacturability of a candidate protein in a clonal cell in which the new DNA is permanently expressed. Post-translational modifications, particularly glycosylation patterns, may also differ from those that will be produced in a more commercially viable manufacturing cell type. It is therefore important to confirm as quickly as possible that the correct protein is being expressed, and that it is of the required quality and functionality. Otherwise, there is a high likelihood that some of the early development work will have to be repeated once the final cell line has been created, potentially adding significant time and cost. The ideal cell line for scale-up has several essential features:

-it must be monoclonal and have proven stability,

-it will produce the protein in high titer (at least 4 g/L),

-traceability will be in place to ensure regulatory compliance, and

-intellectual property must be secure.

Catalent’s GPEx® cell line development technology generates high titer, highly stable production cell lines in a wide variety of mammalian cells, including CHO and HEK293.

OPTIMIZATION TECHNOLOGIES

Titer and stability will be driven by the cell line development technology, and different CDMOs each have their own approaches. For the sponsor company, it must make the decision as to which technology is most appropriate for the program. The chosen technology should be able to ensure each gene is expressed in the correct ratio to form the desired drug substance. This is particularly important for bi-specific and multi-specific antibodies, which require more complex assembly, and therefore, can result in lower expression levels of drug substance with the desired composition.

In addition to cell line development, there are several other tools that can be used by a CDMO to optimize the cell lines, ensure consistent performance at scale, and reduce time spent in development. Automated technologies, such as the Berkeley Lights Beacon^® platform, speed up clonal selection of cell lines that produce antibodies or Fc fusion proteins. Mini-bioreactor systems, such as the ambr^® systems, enable a scalable design of experiment (DoE) approach to assist with process development and process characterization.

The nature of the host cell line will greatly impact protein functionality and glycosylation patterns. Many different cell lines can be used, such as HEK293 and PER.C6, although Chinese hamster ovary (CHO) cells are by far the most common.

It is important to remember that the combination of cell line development technology and host cell, along with cell culture conditions, will drive not only cell productivity, but also protein quality. The media and supplements used in the cell culture must be compatible with the cells and the protein and not cause the protein to aggregate. A high-performance cell line development platform is critical, as it is the key component of the Chemistry, Manufacture and Control (CMC) package and underpins all future manufacturing steps, both at a clinical scale and once it reaches commercial quantities.

Once the cell line has been created, a cell bank must be created, and so when assessing potential CDMO partners, a sponsor needs to select one that is capable of creating a cGMP compliant cell bank. The CDMO must also have the capability to apply the necessary analytical methods to evaluate both the cells and the proteins they make. It is essential that the protein remains the same, regardless of the scale at which it is being manufactured.

The next step is to ensure, through robust formulation, the biologic’s stability during manufacturing, storage, and clinical administration. Ideally, the CDMO should have experience in this area too, as formulation development is typically on the critical path to successful investigational new drug (IND) filing and Biologics License Application (BLA).

It may be the case that the same CDMO is capable of handling the entire development process from cell line development through to process development, formulation development, and eventually process characterization. In this instance, it is likely that different groups will be working on different steps. A sponsor should assess the capabilities of the company in transferring a project between the various groups efficiently. This may or may not involve a transfer from one site to another, and any move offers its own challenges and risk of rework. The ability to carry out analytics on site is also recommended, as outsourcing this elsewhere – or to a third-party company – adds another layer of tech transfer complexity.

Scientists and engineers at the Madison, WI, and Bloomington, IN, sites have experience working with a wide variety of molecules, monoclonal antibodies, recombinant proteins, Fc-fusions, bi-/multispecifics, and other complex biologics.

COMMERCIAL CONSIDERATIONS

When choosing a CDMO for commercial-scale manufacture, it is important to establish that it is cGMP compliant and has the capacity to make the biologic drug substance at the necessary scale. A company may have bioreactors that are sufficiently large for Phase 1 and Phase 2 trial supplies, but these bioreactors may not be appropriate for the larger volumes required for Phase 3 and commercial launch. Ideally, a CDMO will have flexibility in manufacturing scale, with the capability to handle batches supporting Phase 1 through to commercial-scale.

The cell line’s productivity will have a significant impact on the cost of goods sold (COGS). If a cell line has higher productivity, it will require smaller batch sizes and/or fewer batches, which results in reduced cost. The larger the amount of protein required, the more important the COGS become. For sponsor companies that have a line of sight to commercial launch and supply, there is a benefit to investing resources upfront to develop a highly efficient manufacturing process.

However, when aiming to achieve high titers, there is a trade-off between potential COGS and development timelines, and sponsor companies ultimately must weigh the pros and cons of each approach. While a large pharma company may be willing to invest the time and money to improve manufacturing efficiency, a pre-clinical stage small or virtual biotech might need to reduce burn rate and reach the next milestone as quickly as possible so that they can secure more funding.

CASE STUDY IN IMPROVING MANUFACTURING EFFICIENCY TO REDUCE COGS

Catalent undertook a development project in which the Phase 1 need for a monoclonal antibody was about 3 kg. The strategy employed was to start Phase 1 work without process development to accelerate the timeline. Upstream process development, which used one round of DoE studies in the ambr mini-bioreactor system, was then carried out after Phase 1 to optimize the titer before Phase 2 trials commenced.

The difference in cost between the two batches was significant: the Phase 1 material was produced at a titer of 1.6 g/L, and three batches in a 1,000-L bioreactor were required to make sufficient biologic drug substance; whereas after process development, a titer of 4.2 g/L was achieved, and a single 1000-L batch was suitable to produce the same amount. Taking into account the cost of each batch, the Phase 2 material was less than half the cost of the Phase 1 material, and resulted in savings of over $3.5 million.

The savings can be better demonstrated at commercial-scale. For example, a drug that has an annual commercial requirement of 90 kg run in a 4,000-L bioreactor with a titer of 1.5 g/L would require 14 batches to produce enough material. By increasing the titer to 2.6 g/L, only nine batches are required, reducing the costs by nearly 40%. This shows that there is an immediate return on investment – and the potential to save tens of millions of dollars on manufacturing costs if a high-efficiency manufacturing process is developed.

TIMELINE ACCELERATION

Many CDMOs advertise extremely aggressive timelines, but a sponsor must ask whether these are truly realistic, what assumptions are being made, and what potential steps are being reduced or omitted to speed up the process? The timelines may be achievable with a “well-behaved” antibody that it is easy to produce in high titers, but this may not be the case for a difficult-to-express protein, or a non-traditional antibody.

Timelines for a simple monoclonal antibody (mAb) might be short if it is amenable to platform processes and minimal formulation development is required. Fc fusion proteins and recombinant proteins typically require longer timelines due to additional process development needs, and bi-/multi-specific antibody timelines can be longer still.

A high-performance cell line technology will reduce the amount of upstream process development that is required, and again, this can be combined with clonal selection using the Beacon platform and process development using the ambr system. A platform approach will speed up downstream process development if a mAb is purified using Protein A chromatography. Downstream processing can be initiated using stable pool material, and the toxicology batch can be manufactured using the research cell bank instead of the GMP master cell bank, which allows these tests to be carried out earlier. The drug substance batch can also be shipped under quarantine to a fill-finish provider, if it is being filled elsewhere, so the necessary tests can be carried out at the same time to reduce delays.

SUMMARY

An integrated approach is always going to make for faster timelines and more efficient development. Time is lost on the path to the clinic if multiple outsourcing providers are used, because handovers necessarily add delays. If the teams doing the cell line development, process development, drug product, and analytical work are all using the same systems and documentation, the whole process is almost certain to work more smoothly. Effective integration will increase the probability of the drug reaching patients more quickly, and for the sponsor company to achieve success, selection of the right CDMO is critical.

 ambr is a registered trademark of The Automation Partnership (Cambridge) Limited

 Beacon is a registered trademark of Berkeley Lights, Inc.

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Dr. Stacey Treichler joined Catalent Biologics in 2017 supporting the company’s biologics drug substance and drug product business areas. Prior to joining Catalent, she worked in senior product management roles in biologics drug substance, medical devices, and diagnostics industries, and was instrumental in launching products for bioprocessing, organ transplant, and food safety testing. Dr. Treichler earned her BS in Biology from Ursinus College, and her PhD in Molecular Biology from Rutgers University, New Jersey.