A proactive approach to Cell Line Development: Three challenges driving the push for proactivity

01st January 1970

Global demand for therapeutics remains high. Keeping up with this need calls for innovation, and many companies are turning to biologics for the answer, with 55 biologics approved in 2021 alone.¹

In this second part of the proactive approach to Cell Line Development (CLD) series, we explore three key challenges facing biologics developers and manufacturers driving the growing need.


1. The increasing complexity of biologics

 In the past five years, rising numbers of increasingly complex biologics – including fusion proteins, bioconjugates (such as antibody-drug conjugates), and bispecific antibodies – have entered the drug development pipeline. Their intricate and often unfamiliar composition when compared with traditional therapeutics like monoclonal antibodies (mAbs) can cause difficulties throughout the development and manufacturing process. Without the ability to quickly identify potential risks and challenges as well as action solutions, developers and manufacturers can expect extended delays or even the need for lead candidate reselection when working with these new, complex biologics. Access to expert skills and experience is also invaluable; it can significantly ease complex biologic production.


In addition to innovation, a proactive approach is required to efficiently identify and overcome the risks and potential challenges. Identifying challenges, such as poor product yield, cell line instability, and problems with scalability early within CLD allows effective process design to deliver these therapeutics to patients in need.


2. Demand for speed to IND

 Pressure for faster timelines to critical milestones in drug development arises from many parties. This includes patients in need of critical medicines, investors wanting to reach milestones before providing further funds, and drug developers seeking a return on investment.

Failure to provide all the necessary information when applying for FDA approval could lead to significant delays or application rejection. IND filings require a large amount of information regarding the manufacturing and development process and in-depth analysis of the chosen lead biologic, which can take up to 18 months to prepare and submit.² CLD optimization, upstream development, and downstream development using a proactive approach to overcome potential challenges early on can help generate the necessary information faster.


3. Regulatory requirements for biologics

Due to the routine use of mAbs as treatments, their production within the biopharma industry is well defined. The FDA has applied well-known guidelines as a standard practice for producing all biologics.

However, the varied nature of biologics means method design must be developed and optimized specifically for the compound of interest and may need to deviate from those set out for mAbs. As a result, the FDA has highlighted attributes that must be carefully quantified due to their influence on molecule pharmacology:

  • Antigen specificity
  • Affinity and on- and off-rates
  • Avidity (for bispecific antibodies that target two molecules on the same cell)
  • Potency
  • Product-related impurities (such as aggregates, fragments, homodimers, and other mispaired species)
  • Stability
  • Half-life

Establishing a clear link between Critical Quality Attributes (CQAs) in manufacturing and clinical performance is imperative when justifying bioanalysis results to the FDA to demonstrate that the biotherapeutic is compliant. A proactive approach is essential when characterizing these listed attributes as this process relies strongly on communication between all involved in discovery, development, and manufacturing. Effective communication between stakeholders  becomes even more critical during Phase II, as efficacy gains prominence, whereas for an IND the focus primarily lies on safety and manufacturing control.


Overcoming the challenges ahead

 A clear understanding of regulatory requirements is vital for progressing a biologic through to the clinical trial stage. Using an experienced partner with proven credibility in progressing a biologic to IND filing can help mitigate risks, bring an understanding of molecule complexity, offer regulatory insight, and work to maintain strict timelines. A fring communicative partnership provides key information and helps save time.

Gaining key regulatory insights at the earliest development stage, such as during CLD, can also help to streamline production, as key regulations could be implemented in advance, saving time further down the production line. As discussed in this series’ first blog, proactivity helps reach demands and brings biotherapeutics to patients at accelerated speeds with optimized processes and early identification of potential risks.

As experts in the expression of biologics, including antibodies, antibody fragments, fusion proteins, and vaccines, Abzena could help to accelerate your next project. Abzena is a life science CDMO with over a decade of CLD experience. Partner with Abzena today. Find more information by downloading our whitepaper: “Cell Line Development: The Linchpin in Successful

Biotherapeutic Development.”

  1. https://www.fiercepharma.com/special-report/2021-s-new-drug-approvals
  2. https://www.criver.com/products-services/safety-assessment/ind-enabling-studies?region=3696