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Developments in manufacturing processes for advanced therapies
Advanced therapy medicinal products (ATMPs) comprise a new category of medicines for humans and are based on biological materials such as genes, cells, or tissues.1 It is essential to minimize losses of these products at all costs. This is due to their high value and, in some cases, their unique and personalized nature, for example an individual’s cells. Reliable automated end-to-end processes are therefore crucial for the processing, transport, storage, and cold-chain management of ATMPs.
Modern therapies call for modern production technologies. Since the first industrial revolution, the evolution of production technologies has moved through various stages of innovation, from mechanization, followed by mass production, to automation through the use of computers; we are now entering the fourth stage, which for the biopharma industry has become known as “Pharma 4.0”. Pharma 4.0 involves digitalization and automation coming together to assist with highly complex product portfolios and lifecycles.2
ATMPs thus represent a huge opportunity to create biopharmaceutical manufacturing facilities with fully integrated digitalized and automated processes. This will result in increased flexibility, compatibility (vendor agnostic products and systems), speed, and efficiency, combining to confer companies with much greater agility if they take full advantage of these opportunities. Within this new field of ATMPs, new approaches to manufacturing will also be required to cope with volatility and scalability.
The three main types of ATMPs are gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered medicines. Gene therapies modify or substitute DNA in a cell, for therapeutic purposes, or replace damaged or harmful sections of DNA. Viral vectors play an essential role in these therapies, inserting DNA into the nucleus of a cell. Somatic-cell therapies involve the injection of viable cells into a patient to treat their condition. Somatic-cell therapy can be further categorized into autologous or allogeneic cell therapy.In the former, cells used for therapy are harvested from the patient themself, whereas in the latter cells are harvested from a donor. Tissue-engineered medicines refer to cells or tissues modified to repair, regenerate, or replace damaged or diseased human tissue.
The internet of things will advance biomanufacturing
Traditionally, pharma has been a late adopter when it comes to innovations. More than half of contract manufacturing organizations (CMOs) and biopharma manufacturers still manually dispense drug substances into primary packaging rather than using automated filling technologies. Furthermore, many manufacturers still use fixed, stainless-steel installations to produce pharmaceuticals, with slow uptake of single-use systems despite their proven advantages for bioprocessing. However, this may change with the rapid developments in the internet of things (IoT), which applies machine learning to production and transportation processes, manufacturing execution systems (MES), control strategies and decision-making by transferring data over a network without involving human-to-human or human-to-computer interaction. It is anticipated that the ongoing development of the IoT will bring concomitant advances in the biomanufacturing industry.
Being bold pays off
Biopharma companies that are bold and take advantage of these exciting new opportunities will reap great rewards. Innovative solutions such as automated filling of smaller single-use bags can reduce product losses, leading to cost savings by avoiding wastage and cross-contamination. Streamlining the entire manufacturing process can reduce process-dependent operational costs, with end-to-end solutions playing a key role in this optimization. Through the use of IoT technology, the entire process can be digitalized and overseen by artificial intelligence (AI) software, which will in turn enable ongoing and continuous optimization of the process. This process can subsequently also be readily adapted to meet the requirements of any updates to Current Good Manufacturing Practice (cGMP).
Single-use technologies and Pharma 4.0
Single-use technologies represent an important component of Pharma 4.0 as they contribute greatly to the scalability, productivity, and efficiency of biopharma cold chain processes. For example, robust protective shells can be employed to protect small single-use bags. Once closed the shell is robust, safe, and sterile. Made of high-quality stainless steel, there is no risk of malfunction due to weak materials, and it keeps the contents safe to temperatures as low as -200°C. This is ideal for ATMPs, such as cell and gene therapies, where drug substances of volumes between 1 and 250 mL are involved. Such protective shells can help reduce product losses toward 0%.
It is the additional features and unique functionality of these protective shells, however, that position them ideally for Pharma 4.0. First, the shells can be used to track and trace whatever materials are being transported inside them. This is achieved through the addition of radio-frequency identification (RFID) tags that enable automatic identification and tracking of the objects they are attached to. While the tag may be embedded in a single-use component, such as a sample tube, it can also be attached to the protective shell itself to facilitate direct communication with other single-use platforms, such as fill–drain platforms, freeze–thaw platforms, and cold-chain shipping containers, to provide real-time data about the contents. These data include, but are not limited to, filtration data, filling volume, speed of throughput, set-point temperature, and volume per bag. Furthermore, the data are stored and can be analyzed to further optimize cold-chain logistics. Any potential issues can be highlighted, such as the freezing process being too slow or any unexpected fluctuations in temperature. Through the evaluation of the automatically collected and stored data, any issues can be rapidly addressed and remedied, helping to minimize losses of high-value products such as ATMPS.
For long-distance transport, “smart shipping” solutions are available, for example cold-chain shipping containers for the international shipment of frozen 2D bioprocess containers. Together with electronic monitoring devices, placed both outside and inside the shipping container, this represents a solution for the ultra-smart tracking and surveillance of drug substances. Some systems feature automated alarms, reports, and archiving, with all tracked data stored in the cloud. Furthermore, some shipping containers are 21 CFR Part 11 certified, meeting internationally accepted criteria established for the electronic tracking of drug substances.
The way forward
Pharma 4.0, and innovations in general, should not be a cause of concern for the biopharmaceuticals industry. A simple way to begin moving toward achieving Pharma 4.0 readiness is by automating production processes, for example through the use of automated filling technologies. Where production processes require flexibility and/or speed, such as those required for ATMPs, single-use technology offers great advantages.
Single Use Support are leading experts in the field of single-use products that have been designed specifically for full, end-to-end automated processing with Pharma 4.0 compatibility in mind. Their range includes products for protection (RoSS and RoSS.KSET), automated aseptic filling (RoSS.FILL), automated plate-based freezing (RoSS.pFTU), ultra-low temperature storage (RoSS.FRDG), and smart shipping (RoSS.SHIP with tracking). Together, these products represent a Pharma 4.0 solution for the entire end-to-end process required for high-value biopharmaceuticals, including liquid transfer, fluid handling, and cold-chain logistics. Single Use Support products are best-practice examples of what single-use technology can achieve and can assist other biopharmaceuticals manufacturers to upgrade their processes and become part of the Pharma 4.0 revolution.
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