Transitioning from traditional pharmaceuticals to biopharma
17 October 2013
Author: John Milne PhD, training manager, National Institute for Bioprocessing Research and Training
Biopharmaceuticals are medical drugs produced using biotechnology – that is, therapeutic products created through the genetic manipulation of living cells or organisms. They are products that possess complex structures including proteins, peptides, nucleic acids and other large molecules that are produced using methodologies other than chemical synthesis or extraction from natural sources.
The market for small molecules is suffering in the main due to reduced pipelines and the competition from generic competition. Biopharmaceuticals represent the fastest-growing sector of the pharmaceutical industry, with all current indications suggesting double-digit growth annually over the next decade. The growth is mainly as a result of the greater efficacy and reduced side effects of biopharmaceuticals when used in a clinical setting.
The majority of biopharmaceuticals are proteins which are expressed in recombinant host organisms, typically microbial systems for simpler proteins (e.g. insulin). However, many biopharmaceutical products are too large and complex to be made in bacterial systems and, in these cases, mammalian cells are the host system of choice in industry.
Mammalian cells such as the Chinese hamster ovary (CHO) cell possess the necessary cellular machinery to produce a biopharmaceutical product more compatible with human therapeutic use. In particular, the proteins produced from mammalian cells will possess posttranslational modifications which result in products which are more ‘human-like’ with higher quality and efficacy when administered to human patients.
COMPLEX AND COSTLY MANUFACTURING
When compared to traditional pharmaceuticals produced using chemical synthesis, the manufacturing process for protein-based therapeutics is more complex and costly. The first stage of process to manufacture begins with the cell culture (upstream) phase of manufacture. In this stage, a vial of cells (stored typically in liquid nitrogen) is thawed and a process is commenced to expand the vial of cells in a stepwise manner, progressively increasing the volume until a suitable production volume has been reached.
In the production reactor, the cells grow in a controlled environment and express the desired target product, which will be secreted from the cell into the surrounding cell culture medium. When the culture has reached a suitable end-point, the crude product will be separated from the host cells in a series of operations such as centrifugation, microfiltration and depth filtration. The product at this stage will be contained in a clear sterile media solution, but is not compatible with human use and hence requires a systematic purification process to produce a product fit for its intended use.
Downstream processing essentially involves a series of unit operations chosen on the basis of their ability to selectively purify the molecule of interest and to do this safely, economically and – crucially for industry – in a robust and reproducible manner from batch to batch. The purified product at the end of these operations is referred to as the drug substance.
The final part of the manufacturing process is to take the drug substance, add the appropriate excipients and stabilising agents for the particular product and fill the product into a series of vials or pre-filled syringes compatible with the method of injection. Alternatively, some drug products will be stored as a lyophilised powder prior to solubilisation at the time of use and administration to patients.
Given the importance of the formulation and filling aspect of manufacturing in terms of subsequent patient safety, such operations will necessarily take place in highly controlled cleanroom areas of a manufacturing facility and typically use isolator technologies to ensure ultimate safety of the product for treated patients.
ENGINEERING’S KEY ROLE IN BIOPHARMACEUTICALS
It is obvious from the above discussion that engineering as a discipline plays a key role within modern biopharmaceutical facilities, particularly in those facilities that possess large-scale manufacturing capabilities utilising large bioreactors and associated purification operations. While there are obviously some similarities in the roles that engineers play in traditional pharmaceutical plants and biopharmaceutical facilities, there are obviously some key differences.
Engineers working in clean utilities areas in both industries will be familiar with the demands of producing high-purity water, water for injection, Clean in Place (CIP) solutions, clean steam and compressed air. But, obviously, given the nature of the unit operations within biopharmaceutical manufacture, there will be obvious learning needs for engineers looking to upskill or transition across into the biopharmaceutical industry.
It is also worth noting that companies who in the past relied solely on traditional chemical entities to fill their pipeline will most probably now be considering the intake of more complex biopharmaceutical molecules to fill shrinking pipelines. This, in turn, will put pressure on current facilities within their corporate structure and ,in particular, the engineers within those facilities to demonstrate a thorough knowledge of bioprocessing activities if they want to compete and ultimately secure some of these new opportunities.
The National Institute for Bioprocessing Research and Training (NIBRT) is a world-class institute that provides both training and research solutions for the bioprocessing industry. The mission of NIBRT is to support industry by providing a unique learning experience for trainees in an state-of-the-art environment that replicates the most modern industrial bioprocessing facility. NIBRT can work with engineers directly to increase their knowledge and skillset within biopharmaceutical manufacturing through its customised training programmes.
In this regard, NIBRT is working closely with Engineers Ireland to jointly promote two training courses for engineers which involve both classroom learning and hands-on laboratory practicals. It is envisaged that working together with Engineers Ireland, further training courses will be established that will benefit the continuous professional development of its members. The two current training courses currently in place are also run in conjunction with Endress + Hauser who following a strategic alliance have provided a training rig to NIBRT, which addresses all elements of instrumentation and associated process control.
This unique, customised training rig is used to deliver an understanding of the theory of process measurement, control and digital communications and its application in an industrial process control environment. The rig can simulate a biopharmaceutical upstream cell culturing process and a CIP process. The processes are monitored by a wide range of instrumentation, including pressure, temperature, flow, level, near-infrared spectroscopy and foam monitoring.
DIFFERENCES BETWEEN TRADITIONAL PHARMA AND BIOPHARMA
In its ‘Introduction to Biopharma for Engineers’ course, NIBRT provides engineers with an introduction to the biopharmaceutical industry and highlights the similarities and obvious differences between traditional pharmaceutical products and the newer biopharmaceutical products currently receiving widespread attention.
The one-day course focuses on the utilities and equipment used in the manufacture of protein-based biopharmaceuticals and all attendees can experience such equipment at close hand in a high-level interactive tour of the facility, which encompasses a walk-through of the utilities and pilot manufacturing facilities, respectively. The course focuses on the role that engineering can play in the crucial discipline of contamination control and processing within cleanrooms, which is a key area that distinguishes traditional pharmaceuticals from biomanufacturing.
In its ‘Instrumentation and Control’ course, NIBRT addresses all elements of instrumentation including measurement, digital communication, process control and life-cycle management. This two-day course is practice based, so trainees get hands on experience with all the various tools involved in instrumentation.
The course is ideal for instrumentation engineers and plant technicians who require greater awareness and understanding of the theory and current industrial best practice of equipment operation. It is also suitable for engineers and technicians who require to gain knowledge and practical experience of instrumentation and control systems to assist them in their work, e.g. process engineers or validation scientists.
John Milne has a BSc in biochemisty and a PhD in molecular enzymology from University College, Dublin. He has over 13 years’ direct industry experience in all aspects of the manufacture of biological products including process development, optimisation, scale-up, clinical production and ensuring GMP compliance in regulated facilities. Milne joined NIBRT in January 2013, in the role of training manager. For information on either of the above courses and course schedules can be found from NIBRT and Engineers Ireland or by emailing: email@example.com://www.engineersjournal.ie/2013/10/17/transitioning-from-traditional-pharmaceuticals-to-biopharma/https://www.engineersjournal.ie/wp-content/uploads/2013/10/Pharma-engineer1-1024x683.jpghttps://www.engineersjournal.ie/wp-content/uploads/2013/10/Pharma-engineer1-300x300.jpgBioEngineers Ireland,pharma