Production Facility for Therapeutic Protein Manufacture
|✅ Paper Type: Free Essay||✅ Subject: Sciences|
|✅ Wordcount: 3668 words||✅ Published: 8th Feb 2020|
The thirst for more is the basic instinct that pushed the man through his civilizations. Every advancement in science and technology is driven by this quest for furtherance. The domain of pharmaceutical development and fermentation technology has subjected to many dynamic improvements since its beginning from Pasteur’s lactic acid fermentation to the introduction of microbial cell culture systems to mammalian cell modification strategies. Bioreactors are such an innovation that revolutionized the pharmaceutical panorama. This article covers some quick insights on the state-of-the-art Single-use systems in drug development systems and a comparison with the traditional stainless steel reactor models, with emphasis on major design considerations to process economics to biomass yield.
The scenario we consider for this study is the establishment of a 1000 Kg capacity production facility for therapeutic protein manufacture using CHO cell system. We are limiting this study to reactor design and upstream for the course of time.
Every process aims at an effective reduction of product development timeline with minimal resources. The major challenge faced by the drugs that are in product development pipeline is also the targeting on this aspect of timeline reduction so that the drug can be available in the market without a delay. This is not only a matter of time but also a massive investment apprehension. The significant considerations during a bioreactor design include:
• Achieving process control over a rational range of process variables
• Reliable operation
• Time management
• Operational costs
• Avoiding process and product contaminations (Sterilisation attributes)
• Productivity, titer, and yield
• Energy and water requirements
• Product purification
• Waste treatment
We shall do a comparative analysis of this attributes for both Single use and Stainless steel reactors.
Design approach, Process control, and performance attributes
A very critical factor in a bioreactor modelling is achieving all the process parameters with the components installed in the system. With respect to stainless steel reactors, we have all the components used again and again over a period of time without compromising on any process parameters. This is achieved by regular checks, maintenance, validations and calibrations on a scheduled basis. In case of single-use bioreactors, each and every component are connected on a ready to use basis for one time. This means that we are going for a system that will by-pass all the validation constraints during every batch manufacture. 
A comprehensive research conducted by Pall Corporation, for their Allegro STR 1000 bioreactor suggests the following.
• It is suggested to use a cubical design model made out of synthetic material for the single-use system instead of the traditional cylindrical geometry. This ensures a good mixing performance, which is in line with the stainless steel model. This interpretation is based on the Computational fluid dynamic (CFD) studies conducted within the systems. Going for the cubical model doesn’t mean that we are going for a less researched model. Moreover, cubical models are very well validated models used for mixing, transfer, and storage in pharmaceutical production.
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• Next, we have considerations for ergonomics, which means ease of installation, flexibility in inflation, folding after the process and convenient shipping. The single-use cubical system facilitates all these features. The best thing about this design is the compatibility with the hardware or support frame on which the reactor bag is fixed. Compared to cylindrical models, this strategy enables an easy installation because of its distinct geometry and also reduce operational mistakes.
• A rigid base and protective covering provided on this system prevent the reactor from damage during transportation and shipping. This is also provided with color coding for easy installation which means even with two operators, the task of setting up can be achieved.
Another model that is specifically tested with CHO cells is Biostat CultiBag STR 1000L by Sartorius Stedim Biotech. They have conducted specialized performance studies on media storage and accelerated aging. This study also provides a major evidence on the Biocompatibility and tensile strength about the material they have used. These films were developed after a signature worst-case application trials and water-burst tests and are found robust. 
A control tower is installed for controlling gas flow and other critical quality attributes. This tower is enabled with a graphical user touch interface (GUI) for navigation and control. Amplifiers are integrated on this board for DO, pH, temperature and pressure sensors which are all disposable. A multistage cascade control is also aided with a trend analyzer.
With regards to the components, we have the following setup:
• The system is configured with a 4-gas mixing scheme that offers advanced sparger and overlay aeration and these are completely automated. On this, the air supply is through overlay and air, nitrogen, oxygen and carbon dioxide is delivered through the sparger. Rotameters, mass flow controllers and solenoid valves are also installed for the flow rate control.
• The pumps are peristaltic in nature and are digitally controlled and additional feed pumps are also provided.
• Temperature control is achieved through heating blankets provided around the reactor holder with safety cut-off and shutdown mechanism. The filter at exhaust is also enabled with heating to avoid contamination.
• Agitation is provided by a Noiseless radial magnetic coupling drive with a pre-installed stirrer with a choice of selecting 3-blade-segment impeller (axial flow pattern) or a 6-blade-disk impeller (radial flow pattern).
• The bag is fixed to the control tower on a separate stainless steel skid that allows easy assembly and dismantling is facilitated by viewing windows and ports for assembly.
• The whole unit is connected to SCADA software that provides a complete plug and play configuration with advanced provision for plotting, export, and accurate data acquisition.
Computational models deliver clear equivalent insights on the specific power input, mixing times, shear stress distribution and energy dissipation rates. This matches with the extrapolated statistical figures. These CFD results were generated using turbulent k-epsilon models.
The above-mentioned features enable the process to be designed in a completely disposable pattern with absolutely comparable characteristics with that of a stainless steel model in terms of design Process control and performance attributes.
Drug development framework is a lot related to time. Every process demands a considerable amount of time that contributes to the total process these numbers are usually in terms of years and decades. In a stainless steel model scenario, a lot of time is put into setting up the bioreactor ready for operation. This includes equipment and process validation time, sensor calibration time and sterilization time including Cleaning in place (CIP) and Sterilisation in Place (SIP). This also includes time taken for all these activity documentation. Even though this seems a small-time individually, considering the process as a whole, the time is considerably high. But when we opt for the modern single-use technology we can circumvent this time constraints as every component works on a plug and play algorithm.
Patient safety is of prime importance when it comes to pharmaceutical development. All the regulatory authorities around the globe have stringent guidelines for preventing product and process contamination. Contamination includes the intervention of organisms like bacteria, virus and other agents either into the medium or reactor. Here comes the role of cleaning and sterilization. In the traditional stainless steel systems, the equipment is usually fixed are generally cleaned using steam. Mostly, the vessels are automatically cleaned using spray ball through effective dispersion and this process is generally termed as Cleaning in Place (CIP). When it comes to sterilization, the process involves pre-rinse, hot alkali rinse, hot water rinse, hot acid rinse, and WFI rinse. This whole process is very extensive and includes jacket evacuation, streaming through air lines, vents and auxiliary lines, spray ball, pressurization, cooling by temperature loop. This can be done either using superheated water, chemicals or steam. This operation is termed as Sterilisation in Place (SIP), are done without disconnecting the components.
The whole process of sterilization, cleaning, its validation, and documentation takes a lot of time and highly labor intensive. By the introduction of single-use systems, all these rigorous requirements are avoided. Rather than time and cost, since the equipment as such is pre-validated and pre-sterilised, bioburden can be reduced. 
Pharmaceutical development is a billion dollar investment and shows a very low-profit return throughout the discovery phase. For a typical upstream process, the breakdown for economics or Cost of Goods (COGs) includes:
• Capital costs: Utilities, Process equipment, and Buildings.
• Materials/Consumable costs: Raw materials, Buffer, Water, SIP/CIP media, Resins, Filters, Connectors, tubing, manifold and bags
• Labor costs: Process, Quality department costs (Quality Assurance, Quality control, Regulatory authority)
• Other costs: Waste management, Maintenance
Practical studies say that the implementation of single-use systems reduces initial investment or capital costs. It is observed that almost 30% reduction of capital cost is observed by this. When it comes to building and floor design, a typical cleanroom cost ranges from $3000 to $5000 per square meter, thereby reducing floor maintenance charges. Sterilization and cleaning expenditure is also waved off by the new strategy. This has got an effect on validation and qualification also.
But in many of the cases, it is observed that operational costs for disposable system pass the costs of that of stainless steel reactor. On this aspect, the advantage goes to the traditional system. However, it is comparable in nature. 
Product yield or titer
The major objective of any bioprocess is to achieve a good productivity with minimal resources. Traditional bioreactor delivers a good productivity during the production phase. A reactor selection should be based on a detailed assessment of the cell line, its morphology, growth kinetics, and production behaviour. In our case, in order to yield while using single-use bioreactor, many practical trials were implemented and process specialists were able to achieve a comparable titer value.
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For this, we will consider an example of CHO cell used in Sartorius FlexBag STR design. In their study, a high-cell-density fed-batch of CHO cells were cultured for the production of Mab in a 1000L reactor for 17 days. The results observed were compared with that of the traditional models and was found highly comparable. All the parameter like cell growth, titer, and product healthiness were found to be inline. This was also verified and validated.
The test was also subjected to scale-up studies, which suggested that irrespective of the scale, productivity was achieved. The batch started with an initial cell density of 0.3 × 106 cells/mL, over 9 days yielded approximately 28 × 106 cells/ mL cell density with more than 97% cell viability. Using, SDS-PAGE technique, product-specific bands were also obtained. Also, no cell-inhibiting factors were observed throughout the process. In order to ensure the shelf life accelerated aging studies were conducted for 12-36 months, ensuring that aspect also. In addition, glucose and lactate concentrations were monitored during the run as well. The osmolality was also studied. All these were found to be under inhibitory levels. 
In small research centres and institutional labs, the scale doesn’t matter much. Their requirements are often limited to 3l to 5L to the 10L maximum. But when it comes to a process industry, Process scale-up is an important element to think about. In a pharmaceutical facility, the requirement is mostly in terms of hundreds to thousands of liters. This is one place where we need to think about the type of reactor used. Traditional stainless steel reactors do well under this requirement. Whereas, Single use technology advancement is still limited to a maximum of 2kL scale. For a requisite of say 20kL production capacity, it is practically not feasible to install ten 2kL or twenty 1kL single-use reactors. So when it comes to scale-up, credit goes to the traditional system. Another concern is about bag leaks, but the occurrence is extremely rare.
But up to 2kL, we don’t have any operational or installation constraints for the single-use systems. They do equally or rather perform better than the stainless steel model. In this current study, our requirement is 1000L, which means our choice is wise.
Environmental impacts include a comprehensive assessment of environmental change, emissions, and energy provisions. There are strict regulatory mandates when it comes to waste management and related attributes. When we compare the stainless steel technologies with the disposable ones, we could see that single-use reactors generate a considerable amount of waste. This mainly includes reactor bag, valves, joints and also the fermentation wastes. This can be often challenging at times and it is highly important to design a sustainable strategy for the same. The process engineers joined with the Environment, Safety, and Health (EHS) specialists should evaluate these parameters based on the guidelines. This concept shouldn’t be limited to disposable technologies, but also to traditional methodologies. It is always important to prepare a master plan for the environment. The first move should be segregation of waste to solid, liquid, chemical, toxic and other categories. Carbon footprint also needs to be considered and emphasis should be given for reducing and recycling of waste for other utility purposes. This can save a lot of money in addition to waste treatment.
Other than waste disposal, there should be a watch on the energy expenditure. This is equally important as the design and production. It is pointless to create a system in which energy overpass production. There arises the concept of sustainable production strategy of balancing all the points and joining the dots. Energy should be clearly estimated through effective energy auditing. It is vital to understand and document the energy consumption of every single component in the facility. This helps to find when and where the energy loss and gain are observed.
Now coming to a comparison between both of our systems, after a cumulative assessment of three factors, i.e. sterilization, cleaning, and supplies, it was very well clear that single-use practice gave total energy consumption values that were about half those of the traditional scheme. 
The transformation challenges
One of the major question, every company who is experienced in Stainless steel based bioreactor design, come up with is “Why should I take the risk?” Reusable technologies have got a long history and have got a sound expertise network available around the globe. This means that the process is highly validated, approved and acknowledged by the industries and regulatory agencies. Any problem with respect to that technology is easily available and troubleshooting is well easy and advanced. On the other hand, single-use technology is comparatively new and people refuse to accept this challenge. Their worries regarding in and out of disposable systems need to be sorted out. This is where the important transformation challenge persists. The first step to sorting out this issue is establishing a sound database of information. The scientific community that consists of industry experts, regulatory specialists, Quality analysts, and business administrators has already joined their hand to work on this. They have strong supporting statistics, graphical interpretations and analytic studies on how to get more from this innovation and make people aware of why this is a technology for the future. As a result, the pharmaceutical industry reaches a phase were misconception clouds will fade and acceptance windows open for innovation.
The biopharma industry is a highly conservative industry. Not every process person or a panel will agree to the suggestions and improvements in the systems. This is because of the fact that the sector as a whole is very sensitive and are under strict regulatory boundaries. But sticking on to regulatory requirements doesn’t means, not doing any innovation or moving forward to newer technologies. The best thing to do is to create a viable business model that promotes continual improvement with regards to design, productivity, and operations. A sustainable model balances compliance. This approach helps the business to be competitive.
Today, a variety of single-use models are available in the markets. These are well-validated models that ensure the desired product delivery with fewer resources and effort. In our scenario of 1000 Kg capacity production facility for therapeutic protein manufacture using CHO cell system, after a detailed consideration, we can arrive at a conclusion that Single use reactors are comparable to Stainless steel models in all the aspects and I opt for this technology of future.
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