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India’s growing biopharma market: monoclonal antibodies R&D and production Designing sterile connection systems

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Monoclonal antibodies (MAbs) have been extraordinary tools in the field of bioscience due to their high level of specificity and selective binding ability.

Besides its applications in diagnostics, such as the identification of cell surface markers and analysis of cell function, the various therapeutic applications of MAbs in the treatment of cancer, autoimmune disease, cardiovascular disease and infectious diseases are also rapidly gaining traction.

Globally, the MAbs therapeutics market is projected to be worth more than US$245.8 billion by 2024, a huge jump from US$86.7 billion in 20151.  The industry has also seen a growing number of approved products in the market – in 2017, the United States Food and Drug Administration and the European Medicines Agency approved 10 monoclonal antibody drugs globally, achieving a record high2.

In India, the Ministry of Science and Technology launched a USD$250 million program to promote the production of biopharmaceuticals in 2017, assisted by the World Bank for its “Innovate in India” program, hoping to grow India’s share in the global biopharma industry from 3% in 2017 to 5% by 20203 .

The biopharma industry is thriving from this strong government support to tackle the rising disease burden and to establish India’s biopharma industry on the world stage. Some progresses have already been made – Delhi’s National Institute of Immunology (NII), has reported generation of MAbs to detect typhoid fever and hepatitis B virus, and are in the process of developing monoclonals against rotavirus and virulent stains of E. Coli. Also, in collaboration with NII, the Ranbaxy laboratories have developed a pregnancy test kit that detects human chorionic gonadotropin in the urine of pregnant women, which are already available in the market4 .

Production and Challenges
The production of a batch of MAbs begins when antibody-producing B-lymphocytes are isolated from immunized mammals and fused with immortal myeloma cells to form hybridomas. The hybridomas are cloned, screened and selected on the basis of antigen specificity and immunoglobin class. After each potentially high-producing colony is confirmed, validated and characterized, cloned are scaled up to produce the desired antibody5 .

In this process, researchers are constantly looking for robust systems that are high-functioning, easy to use and maintain, and are cost-and-time-efficient even when ramping up production for high-volume output. One key consideration is to reduce the likelihood of contamination as much as possible is to utilize single-use systems in the process, so as to prevent the wastage of resources and improve yield. Cell cultures will have to be discarded once contaminated with competitive organisms such as bacteria, fungi and yeasts; while residual proteins might inhibit proper cell growth or pass through purification with the target protein, yielding inconsistent results.

It is hence crucial for biopharma companies and laboratories to adopt the right connection technology for their single-use systems, which is an important but often overlooked component of designing the optimal fluid pathway. In a clinical or academic laboratory, product development looks very different than in a biopharmaceutical manufacturing company. Not only are the technologies different, but the longer-term objectives are different as well. Biopharma companies typically undertake development with the ultimate objective of commercializing the therapy, requiring aseptic connections to be established in any environment, especially in ones with a high bioburden. Selection of the wrong connection technology can have serious implications on the scalability, reproducibility, and security of the process.

Choosing between Tube Welders and Aseptic Connectors
Traditionally, closed systems using tube welders or open systems using quick connects are used. However, they do not necessarily have the flexibility required of today’s research or manufacturing environments to allow on-the-fly changes during cell culture, where it is desired to have a system that allows any type of tubing to be connected to any other, such as genderless connectors with multiple terminations.

Tube welders may work well for some small-scale applications. Typically, these are situations where a small number of connections per day are required, with only one size and one type of tubing is used, or where a small number of production batches are required. However, the equipment is expensive to purchase and maintain, and typically takes a long time to install as the process may depend on the availability of a trained operator, a functioning backup welder and electricity availability. It takes about 3-7 minutes to complete a single weld, not including the time in between welds when multiple welds are needed. It is also highly likely that particulates are generated in the flow path during welding, which could potentially enter the system. Additionally, tube welders do not work with silicone tubing, and may experience difficulties operating in tight or hard to reach spaces.

Breakthrough in sterile connections have made single-use connectors designed for small-scale and large-scale connections a great alternative to tube welders, especially with the incorporation of genderless designs (no male and female halves). They offer a robust construction, ensuring an easy to use and reliable performance with no additional hardware required. Design features in the genderless AseptiQuik® S (⅛” to ¼” ID) and AseptiQuik G (¼” to ¾” ID) offers a lightweight, cost-effective option for sterile connections, which can withstand pressures in high vibration applications, giving an edge over tube welders that can rupture under the same conditions.

Male-to-female connections like luer fittings, quick connects and gendered aseptic connectors require more part numbers both at the component level and the finished good, assembly level. On the other hand, genderless connections simplify the supply chain ordering process and ensure that a connection can always be made at the user site. Issues of receiving single-use systems with incompatible types of connections (i.e. both have a male connector) can be eliminated with the use of a genderless connector. Moreover, aseptic connectors with multiple terminations offerings (such as , 1/4”,3/8” and ½” hose barbs and 3/4” sanitary) are useful for adapting various tubing sizes at the point of connection. Aseptic connections can be added to a bioreactor at any time through the addition of a manifold with several genderless connectors for medium feed sampling or harvests. Furthermore, aseptic connectors allow connection to be done even in hard to reach areas, a flexibility that tube welders do not offer.


Choosing between Open Connectors and Aseptic Connectors
Open connector refers to any connector technology that requires a sterile or aseptic environment in which to make a sterile connection, such as luer fittings and MPC-type quick connectors. They are typically favored for their intuitive use, inexpensive cost, wide variety of sizes and a broad number of sourcing options.

To prevent contamination from happening, open connectors will need to be used under a laminar flow hood. These connectors are installed on a single-use system and plugged or capped to seal the connector and maintain sterility until use, followed by bagging the complete assembly and gamma irradiating it for sterilization. If open connectors are used to connect a system in an uncontrolled environment (e.g., an open laboratory bench), once the caps or plugs are removed from the connector, the connector fluid path is no longer sterile as it is exposed to the environment. The connectors are reasonably secure once the connection is made, and the operator has to physically depress a latch or turn the connector to disconnect them. However, this does not totally prevent accidental disconnection.

Aseptic connectors, on the other hand, allow the end user to make a sterile or aseptic connection in an uncontrolled environment (no flow hood), presenting a significant advantage to open connectors. Currently, most aseptic connectors work by utilizing a sterile protective barrier (i.e. membrane film) on each connector half to prevent bacteria and other contaminants from entering the fluid path prior to use. After initial connection, the barriers are simultaneously removed from the connector assembly to open a sterile fluid pathway.

The mechanisms by which the different aseptic connectors are assembled, connected, and operated vary widely. Some are very simple to use with three steps, and others are more complex, with up to ten steps to complete before an aseptic connection is made. This wide variability in operational capability must be taken into account when developing a process for the MAbs market. Generally, a connector that is simple to use, has few operational steps, and works with a wide range of different tubing types and sizes offers greater operational flexibility to the user and will have less potential for operator error.

Conclusion
As the industry for monoclonal antibodies continues to grow and mature, opportunities are vast but competition will also stiffen. Biopharmaceutical companies will need to continually innovate and explore new options to gain a sustainable edge over others. Establishing single-use aseptic connections is a small yet immensely significant component in the elaborate research process of biological therapy for cancer, directly influencing the success or failure of the monoclonal culture. The implementation of the right connectors can help establish critical links for achieving desired results accurately, timely, and cost-efficiently, all while continuing to exceed growing industry demands.

[1] http://www.transparencymarketresearch.com/monoclonal-antibody-therapeutics-market.html
[2] https://www.creative-biolabs.com/blog/index.php/new-monoclonal-antibody-drug-approvals-in-2017/
[3] http://www.dbtindia.nic.in/wp-content/uploads/Writeup_biopharmaMissioned29062017.pdf
[4] https://tifac.org.in/index.php/8-publication/103-monoclonal-antibodies?showall=1&limitstart=
[5] https://www.moleculardevices.com/monoclonal-antibody-production


About CPC
CPC (Colder Products Company) is the leading provider of quick disconnect couplings, fittings and connectors for life sciences, industrial and chemical handling markets.

For a free catalog or more information, contact: Web: cpcworldwide.com



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