Q&A: Accelerating Processes

Seahee Kim: Increasingly, cell-line development (CLD) is being outsourced to external CDMO partners to help accelerate products to patients. Methods and technical offerings in the biopharmaceutical contract development and manufacturing space have led to dramatic time reductions in CLD and further efficiencies in upstream and downstream processes. These advancements have helped to speed drug products to market.

In addition, continuous process improvement and years of experience with applied molecular and genetic science in this area have had a significant impact. Biomanufacturers are now able to develop more therapeutically valuable drugs faster than ever before, and manufacture them more efficiently as well.

Leading contract manufacturers have identified that one of the best ways to accelerate CLD and optimise development and manufacture of biologics is to use a well-understood platform. This results in shortened timelines and more rapid entry into the clinical stage. What used to take between seven months and a year, can now be accomplished in just three months, with a much greater degree of accuracy.

Platform technology transfer can also be involved earlier in the development stage. This can help minimise the risk associated with scale-up and technology transfer later in development and commercialisation.

A deeper, mutual understanding of the formulation’s unique process platform lessens the ‘facility gap’ between contract development and commercial manufacturing teams, and between platform technologies, spanning development, clinical, and commercial launch.

As a result, biopharma CDMO leaders have gravitated to a platform that efficiently produces robust and stable cell lines. Commonly used cell lines include Chinese hamster ovary (CHO) mammalian cell expression systems, such as CHOK1.

Although well characterised, modifications to the CHOK1 have the potential to increase expression yields. Seminal research has shown that cell-line platforms can build on technologies utilising CHOK1 cell lines, in which endogenous glutamine synthetase (GS) has been removed, or ‘knocked-out’. GS knock-out is achieved using transcription activator-like effector nucleases technologies. This renders cells auxotrophic for the essential amino acid L-glutamine and, therefore, speeds up and simplifies the selection and scale-up of clones.

The modifications within the cell line allow for more accurate clone selection when isolating producing cell lines. The platform also includes an optimised set of cGMP-produced chemically defined growth and production media, plus feed, all developed to maximise the growth and production of R proteins from producing clones.

Media and feed have been optimised to support both the initial cell-line engineering process and stable cell-line selection through to large-scale growth and production. Furthermore, media and feed formulations are animalfree, chemically defined media, suitable for preclinical and clinical development stages, and have dependable sourcing and robust manufacturability.

Cell lines that are fully compliant with GMP standards make them a useful tool for accelerating advanced CLD programmes. Some platforms can generate a manufacturing-ready cell line with a comprehensive parental cell line history document. The cell-line data are completely validated, and are considered as gold standard by regulators. All of this serves development agendas because compliance is assured, and cGMP processes are streamlined, while being less complex to validate.

With demand for all biopharmaceuticals expanding exponentially, the need for cost-effective capacity, as well as efficient processes to manufacture biopharmaceuticals compliantly, will only increase. That’s why the industry continues to seek innovative ways to make CLD more accurate, efficient, and less costly when manufacturing monoclonal antibodies, bi-specific antibodies, crystallisable fragment fusion proteins, as well as complex molecules.

To better serve both drug development and patient agendas, transformative technologies are now moving online. This allows the biopharma industry to make real, substantive gains in cell selection control and achieve enhanced levels of expression.

Across pharma development, the CHO host cell line is now being relied upon for manufacturing biopharmaceuticals. Equipped with a low-risk profile, a CHO-based cell-line platform can support faster development by leveraging platform processes. By using a combination of advanced technologies, developers can accelerate CLD activities by increasing the probability of selecting high-producing clones.

Another advancement that is predicted to increase is continuous manufacturing, which was heavily relied upon during the COVID-19 pandemic. A notable trend recently has been the movement from preclinical to full-scale production of drug substance and drug product. Many companies are already optimising both upstream and downstream processes with continuous processing, and are reaping the cost-saving rewards.

Additionally, a trend that could further transform the CDMO industry is digitalisation. Digitalisation will improve communications, partnerships, and data analysis. Advancements in digitalisation will also help facilitate flexibility, without impacting on quality. Furthermore, it may help to stabilise trust and transparency between CDMOs and their partners due to increased communication.

For the most part, the recent challenges of the pandemic and increased demand for better performing and less costly biotherapeutics of all kinds, has put an even greater emphasis on accelerating CLD and later commercial development timelines. Outsourcing of development and manufacturing to CDMOs is expected to rise with increasing demand due to COVID-19 and the global vaccination programme.

The pandemic has also highlighted the requirement for CDMOs to be flexible due to growing demand for COVID- 19-related products from clients. Moreover, demand from companies of varying size, from global pharma companies to new start-ups, has also drawn attention to the need for an even more customised and personalised experience.

If anything, the pandemic revealed just how responsive pharma can be. Expansion of facilities, partnering with other CDMOs, and building a localised skill set has risen since the onset of COVID-19 to meet capacity demands. As well as this, production times have decreased, with accelerated tech transfer and approval. From a CLD perspective: antibody-related therapeutic drug development normally takes about three months to select highly productive clones with stable product quality. By using a combination of high-performance cell lines, and high-throughput screening platforms, CLD timelines can be accelerated with faster and easier selection of highproducing clones. Consequently, this process is cut down to two months for CLD, resulting in a faster investigational new drug application approval.

Lastly, much of the ongoing development in mammalian CLD efficiency is patient-centric, ultimately intended to assure access to needed medications – something that will always be a global healthcare priority. Regardless, in the past two years, biopharma manufacturers have made great strides in using existing science, building on it, and creating better solutions that generate faster results and help speed drug products to patients.