Author: Nick Hutchinson, Fujifilm Diosynth Biotechnologies

The demand for antibody and antibody-related therapeutics continues to increase. [1] The United States Food and Drug Administration has approved ~ 100 antibody therapeutics for a wide range of treatments. Nearly 600 antibody drugs are in clinical trials, [1] with ~75 of these in pivotal Phase 2 or Phase 3 studies.

Small or even virtual companies are developing many of these molecules. Technical teams working within these organizations must understand the activities needed to successfully commercialize the drugs. One critical activity is establishment of production strategies capable of supplying the material requirements of pre-clinical development, toxicology studies, clinical trials and then, if successful, market demand.

Patients cannot benefit from life-saving medicines if the drug’s launch is delayed due to lack of the material required for each phase of development. Furthermore, companies that miss clinical milestones suffer from delayed investments, thus reducing the opportunity to reach the clinic in a timely manner and capture market share, which lowers future revenues.

Many start-up biotech firms have a laser-like focus on the pre-clinical development of their antibody candidates, but sooner or later they must consider a manufacturing strategy that enables pre-clinical or clinical programs to stay on track.

Is manufacturability an obstacle to development?

One question drug developers should consider is the extent to which the manufacturability of the candidate is likely to be problematic and jeopardise material supply. Many of the standard, full-length antibodies have well-understood properties and are relatively easy to manufacture, allowing timely delivery to the clinic. However, there is an increasing number of modalities within this product class, [2] e.g., bispecifics, Fc-fusions and antigen-binding fragments, which may present additional production challenges. These can include challenges such as low expression from cell lines suitable for use in manufacturing, poor stability during purification processes or the need for non-standard analytical methods.

One company I spoke to, for example, knew that they needed to increase the productivity of their cell cultures from below 0.5 g/L to greater than 3 g/L in order for the product to be commercially viable. Another company developing a monoclonal antibody explained that they needed a titer of ~ 10 g/L to ensure production efficiency was sufficiently high to allow them to be price competitive. A third company found that the isoelectric point of their Fc-fusion molecule was relatively low and they needed a tailored purification process for their product.

Companies developing standard IgG1, IgG2 or IgG4 products can leverage manufacturing platforms. [3] These allow production of different monoclonal antibodies with the required quality specifications and at high productivity with little process development. They offer a significant time- and cost-saving over the alternative, i.e, developing new processes for each new candidate. Companies with a pipeline of products may choose to invest in their own manufacturing platform, but, for many early-stage biotech companies it makes little sense to spend investors’ cash on production assets when there is considerable uncertainty around the likely success of a program. For this reason, many will outsource process development and manufacturing to a contract development and manufacturing organization (CDMO), many of whom will have their own established platform processes.

Early material supplies of antibody candidates

Cell line development scientists can generate stable, clonal cell banks derived from a production-ready host cell line in as little as 10 weeks following transfection. Cell cultures with transfectant pools can produce tens to hundreds of grams of material in as little as eight weeks following transfection. Scientists developing antibody therapeutics can use this antibody for their pre-clinical activities and initial formulation development experiments. In our experience, even at the pre-clinical stage, the drug development process can consume substantial amounts of material. Accurately determining material requirements at this stage will help ensure sufficient antibody is available.

Preclinical material supply might be met with bench-scale bioreactors, but we have worked on programs where the material requirements were sufficiently large that a 200-L mammalian cell culture run was needed, even though the cell line gave a high titer. This clearly demonstrated the utility of having a platform process because no additional process development on either the bioreactor conditions or the purification steps was needed. Expert developers of cell lines know that their host cell line will grow to high cell density under their platform conditions, and will select clones that combine high productivity with the desired product quality profile using high-throughput screening technologies.

Process development scientists operating platform processes typically allocate time, which would previously have been dedicated to manufacturing development, to the refinement of operating parameters and studies of manufacturing robustness that increase the likelihood of that full-scale production lots will be successfully released.

Supplying Toxicology and Early Clinical Material

Pilot-scale batches allow companies to predict large-scale manufacturing performance and refine scale-dependant process parameters. Companies often use material from the pilot-scale batch for toxicology work, stability studies and for generating reference standard, against which the first batch for clinical use can be released. It generally takes 6 – 8 months to reach this stage from the start of cell line development, yielding hundreds of grams of antibody, if not more.

For many companies, the demand for clinical-grade drug, manufactured to current Good Manufacturing Practices (GMP), can be met using bioreactors no larger in volume than 2000-L. The initial batch can be released within 12-14 months from the start of cell line development. Each batch can supply between 1 to 10 kilograms of antibody.

Modern, high-throughput manufacturing facilities provide enormous amounts of capacity such that with a robust, high-titer cell line no further scale-up may be required and firms can commercialize their product within the same facility they used for clinical lots. Others elect to scale-up still further to large-scale stainless steel manufacturing facilities, especially if the market demand is high and the overall process productivity is modest. More recently, firms are considering going to market with manufacturing processes that utilize smaller bioreactors operated in a continuous, perfusion mode. We believe such processes can yield over 15 kg of antibody from a 500-L bioreactor over a 4-week period. Deciding which approach to adopt is never easy because of uncertainties around factors such as dose requirements, overall market demand and competitive pressures. Experienced CDMOs will support customers through this decision-making process and will be able to provide invaluable advice.

In conclusion, many small biotech companies with new antibody drug assets can mitigate risks to drug development and commercialization timelines by thoroughly understanding the material supply requirements for preclinical, toxicology and clinical studies. Once they know this, they can determine how the need can be met by manufacturing organizations during process development and GMP production operations as part as an over-arching strategy for product commercialization.