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Manufacturing: Biomanufacturing Operations Leveraging CLD Technology to Overcome Associated ChallengesHigh-titre CLD platform is an effective tool to overcome a number of challenges when developing a cell line. What are the challenges associated with developing a high-titre CLD platform and how can utilising novel technologies help overcome them?
By Jin Yingji at Samsung Biologics
Constructing a High-Titre CLD Platform High-titre biologic production, with maximised productivity and quality, is crucial for the efficient biomanufacturing of a desired product. A cell line development (CLD) platform with high-titre capabilities can help streamline biologic manufacturing, getting essential treatments to patients faster.However, forming a robust, high-titre CLD strategy can be a resource- and labour-intensive process associated with significant costs. CLD typically follows an iterative process of screening, clone picking, testing and optimisation. As a result, the process is heavily reliant on manual input. CLD also requires extensive optimisation for the desired target, where modification of the chosen cell line aims to instil valuable characteristics.The long-term benefits of a high-titre platform include accelerated manufacturing time frames and maximised productivity, both of which lead to cost savings and a streamlined investigational new drug (IND) filing timeline. However, problems can arise throughout CLD, hindering production.
The Benefits of a High-Titre CLD Strategy
It is important to incorporate high-titre CLD as quickly as possible in order to maximise the advantages. The long-term benefits of helping to streamline the drug product manufacturing process include:
Increased productivity – High titres lead to higher product yield, forming more product per batch
Reduced costs – The production of higher quantities of product per batch can lead to significant cost savings, as it reduces the amount of resources needed, such as raw materials, labour and facility usage, to manufacture the same quantity of product
Enhanced scalability – Production of high-quality biologics in a larger bioreactor leads to higher quantities and facilitates commercialisation
Improved product quality – Increased expression of the target protein reduces the possibility of degradation, aggregation and other quality issues. Fewer downstream processing steps decreases the risk of introducing impurities or contaminants during manufacturing
Faster time-to-market – Increased yields over fewer batches result in forming more product faster. In addition, the number of downstream processing steps decreases, reducing biologic purification and formulation.
Overcoming High-Titre CLD Challenges
Despite the advantages offered by high-titre cell lines, it is important to remember that CLD is complex. There are various challenges that must be overcome to produce a robust and efficient cell line for the desired target. The problems that arise throughout CLD include:
Maintaining cell line stability – Genetic modification of a cell line, including knockouts and over-expression, can put cells under stress, leading to an unstable cell line
Ensuring process reproducibility – Cell lines can suffer from batch variation often caused by genetic drift (a change in the frequency of a gene due to chance disappearance), leading to the gene at the start being different from the final replicated gene and hindering consistency
Incorporating scalability – Scaled bioreactor conditions can significantly impact productivity, with parameters such as agitation rate, oxygen uptake and substrate supply changing with increasing volume
Limiting downstream processing – An extensive number of downstream processing steps to purify protein can lead to extended production timelines
Meeting regulatory requirements – All processes, equipment, materials and product characteristics must meet regulations. For example, native cell lines that are not optimised for the target protein can produce biologics of low quality that would not meet the purity, potency and safety requirements for patient use.
Careful evaluation of the equipment, materials and process design is vital to prevent delays, overcome hurdles and mitigate potential risks. However, unforeseen circumstances can hinder high-titre CLD and cause delays. Integrating technological innovation into operating systems can optimise CLD, resulting in high-quality, viable products that meet regulations.
New Technologies Drive Change
A method to optimise high-titre CLD is the use of methionine sulphoximine (MSX). As an analogue of glutamate and an inhibitor of glutamine synthetase (GS), MSX introduces selection stringency when generating cell lines. When subjected to media with optimal MSX level, selection pressures increase the productivity of the GS knockout cells, which transfect with the GS gene as well as the gene of interest.¹A recent study has shown that increasing MSX levels at the seed train stage improved cell line productivity when scaling a culture from a small to a larger volume. Adding MSX to seed cultures increased titre by 10-19% while also addressing stability issues. Cell lines with higher MSX concentrations exhibited improved stability with increased culture age across various culture scales, also proving consistency and scalability.¹Adding MSX to the culture media enhances biologic productivity, consistency and scalability, demonstrating that even small alterations to CLD can lead to significant improvements. Incorporating such systems into high-titre CLD can help to overcome development challenges. But with continuous innovation and technological improvements, identifying the appropriate solutions for your drug product can be difficult, and testing several techniques can be costly and labour-intensive. Meeting the legal prerequisites is vital and that includes adherence to intellectual property and licensing requirements – failing to comply with the law could result in extensive delays when bringing your drug product to market.
Meeting Intellectual Property and Licensing Agreements
With any new technology, process or material, there are licensing and intellectual property considerations that need to be evaluated. When choosing an appropriate CLD platform, it is important to ensure legal compliance from the onset.It’s possible that a chosen cell line may have associated intellectual property. Researching patent databases in advance prevents any infringement. A chosen cell line may be licensed by another company or third party, so it is essential to check that the correct licensing documentation is in place before use. The licensing agreement can also include fees linked to the use of the high-titre CLD platform. It is vital to consider potential costs in advance and integrate them into the biomanufacturing budget, in addition to reflecting the cell line value. Meticulously reviewing any agreements ensures that there is no conflict of interest, or unreasonable restrictions or demands.When the appropriate documentation and contracts are in place, the high-titre CLD platform can be built into the biomanufacturing process.
A Specialist Partner Can Offer Insight
A robust CLD programme provides guidance on process development, increases project visibility and mitigates risks to accelerate timelines to IND filing. A supportive partner can help ease some of the challenges of the complex process, providing invaluable insight into CLD techniques and regulations.Employing a partner with experience in constructing a high-titre CLD strategy can assist with identifying and incorporating novel technologies and solutions to overcome challenges. In addition, previous exposure to industry challenges and comprehensive knowledge of novel techniques can help to determine the best solutions for your drug product.Help with navigating the licensing and intellectual property space can ensure vital legal regulations are adhered to, with the proper licensing agreements in place to guarantee the safety of your process from a legal standpoint.Working with a contract development and manufacturing organisation (CDMO) that specialises in implementing a high-titre CLD strategy can further accelerate production timelines, helping you get your product to market and delivered to patients at speed.
Tian, J et al (2020), ‘Increased MSX level improves biological productivity and production stability in multiple recombinant GS CHO cell lines,’ Eng Life Sci 20, 112– 125
Jin Yingji is a lead scientist in charge of developing cell lines at Samsung Biologics. Before joining Samsung Biologics in 2018, she spent seven years developing cancer vaccines and glycosylation-based diagnostic systems for screening cancers and assessing antibody titres in humans immunised with prophylactic HPV vaccines. Jin holds a PhD in Virology from Chung-Ang University, South Korea.