In my two previous essays in this series on Single Use technologies published over the past ten months in American Pharmaceutical Review, I described the following regarding the use of single use systems in bio-pharmaceutical drug production: In the first essay, I showed the unexpected yet significant environmental footprint advantage of these single use systems compared with traditional stainless steel systems (1). In the second essay, I showed the unfortunately high level of overcapacity in the industry (2). This overcapacity will be around for a long time to come and will likely result in a low uptake of single use systems for commercial bio-pharmaceutical drug manufacture. In the second essay, I pointed out that the one area of particularly high value for single use systems will be for the production of active drug material used in performing clinical trials. The flexibility improvements offered through the deployment of single use recovery systems are significant. The virtual elimination of cleaning steps in the purification of monoclonal antibodies, proteins, or conjugated monoclonal antibodies provides the bio-pharmaceutical drug manufacturer with significant schedule and quality advantages when such batches of clinical trial material are needed.
This third essay in the series investigates these schedule and quality advantages over traditional fixed stainless steel systems. In my previous essays, I provided a cost analysis of alternate technologies, and in this essay, I will only make minor further reference to costs. Much of this essay is based upon my review of presentations prepared by Tim Mathews of Genentech. I also had several telephone conversations with him. Mathews is a Senior Engineer and Group Leader in Genentech’s Process Development Engineering Department. I could not have completed this essay without his help. He provided me with a wealth of information in my preparation of this essay. Readers of American Pharmaceutical Review should contact Tim Mathews if they have detailed questions on the engineering specifics of the technologies covered in this essay.
In the clinical development of a biological drug such as a monoclonal antibody or an antibody that is also conjugated with another smaller drug, one is never certain of the outcome of the clinical trials that will be undertaken. This uncertainty is both for the efficacy as well as the safety of the new molecular entity. Many drugs start out with high hopes and big expectations only to end without any commercial introduction or marketing success. To deal with the uncertainty of outcome, the industry uses a method termed as the probability of technical success (PTS). The PTS method is used to adjust expected cash outlays and cash inflows to determine the anticipated or expected net present value (NPV) of a drug starting with early research, clinical development and subsequent market introduction. In the earliest stages or phases of clinical development, the overall PTS to completion of a drug is lower than after Phase 2 trials are successfully completed. The reason for the lower earlier PTS is that the overall PTS is the product of the PTSs for each phase of development. Drug development is a high stakes business and any technology that can lower initial investment or speed up the schedule for drug development is highly sought after by all drug companies. Based on the need for higher flexibility, lower cost, and rapid deployment many vendors are now offering single use technologies that do afford some or all of these improvements. Many of these single use systems were introduced in only the past five years, and several more will be introduced in the next couple of years.
The single use or disposable systems can be deployed in new facilities or the systems can be retrofitted into areas of older facilities where the systems purpose is to streamline and debottleneck the older existing facility. A significant advantage of the single use system is that the risk of loss of capital associated with supporting the manufacture of the clinical drug can be minimized by avoiding capital spend until it is “just in time” as well as minimizing the amount of capital spend. For early stage clinical drug production, single use systems also afford the advantage of accommodating short runs and higher change over rates between the various drug products that will be manufactured in a single combined use facility. If the clinical trails for a particular drug are successful and the authorities approve the drug for sale in the market, then the single use process can be portable and the process can be relocated to another manufacturing facility. The ultimate site of manufacture could be in house or at a contract manufacturing organization (CMO) external to the drug company. Other areas that provide greater flexibility of operation via the deployment of single use systems are the lowering of the complexities and scale of supporting mechanical systems and plant utilities. I have written at length about the lowered environmental foot print and the significantly greener manufacturing operation associated with single use systems. Smaller facility footprints, fewer operating personnel as well as reduced allowance for depreciation will also significantly lower the cost of goods sold.
Recently, vendors have made available complete “off-the shelf” unit operations used for the recovery of biological drugs. These include complete chromatography and tangential flow filtration (TFF) systems with all the associated sensors and controls. Another operation that makes abundant use of single use systems is “Inline Dilution”. This is a method to prepare and store buffers that start with concentrated buffers solutions in much smaller bags, water is then blended in line with the concentrated buffers allowing the buffer with the desired concentration to be used directly in the purification unit operation. Tim Mathews has presented case studies on the use of such in line systems (3). The use of in line dilution significantly reduces the buffer preparation and hold tank requirements of a biopharm manufacturing facility. Mathew’s data show that in present practice most the aqueous solutions used in recovery processes are very dilute. These aqueous solutions include salt and buffer solutions. Three quarters of these aqueous solutions used in the recovery process can be concentrated ten fold. A ten fold increase in concentration implies a ten fold decrease in stored volume. Approximately four in ten of the aqueous solutions can have their concentration increased fifty fold. Mathews also analyzed the possibility of concentrating buffers for the following purification unit operations: Affinity Chromatography; Cation Exchange Chromatography, Anion Exchange Chromatography; and Ultra Filtration Diafiltration (UF DF). His analysis has shown that in total for all of these systems the full set of required buffers can be concentrated forty fold versus standard design conditions. This application is where single use systems will have the most significant economic and operational impact in the production of bio-pharmaceutical drugs. The previously extremely large buffer volumes are now reduced to fit in conveniently sized bags. As an example the regeneration buffer used in an affinity chromatography process was reduced from nearly twelve thousand liters to a mere forty liters.
By referencing the above examples, the operational and financial value of single use buffer bags has been clearly demonstrated. I will now focus on some example of the use of single use Tangential Flow Filtration (TFF) systems and chromatography columns rather than the buffer bags associated with these unit operations. Many drug companies who are developing targeted therapies with specific monoclonal antibodies. In particular targeted therapies in oncology are now being produced by conjugating a small molecule that is typically a toxin onto the monoclonal antibody. A linker is used to conjoin the small toxic molecule to the monoclonal antibody. This category of drug is referred to as an Antibody Drug Conjugate (ADC). Several of these molecules have progressed through Tox studies and some are even in their Phase 3 trials. One can imagine that the complexity of manufacturing a monoclonal antibody, the linker and the toxin and then correctly and uniformly combining the three components is much greater than the manufacture of any of the components. These drugs are also extremely expensive to manufacture. Another demanding requirement in their manufacture is that they simply cannot tolerate any cross contamination with any other drugs nor can their cross contamination with other drugs be tolerated due to the highly toxic nature of the small molecule drug that is being conjugated onto the monoclonal antibody. The manufacture and purification of these antibody drug conjugates are cases where single use tangential flow filtration and single use chromatography columns make a lot of sense. Multi use traditional systems theoretically could be “cleaned” to the point where no remaining chemicals from the previous campaign remain, however it is far simpler and far less costly to use single use systems for this type of drugs. Also it is less time and resource consuming to use single use systems for the purification of these antibody drug conjugates.
I am certain that several of the manufacturers of single use bioreactors who read my previous essay on the glut of commercial production capacity were a little dismayed with my conclusion that no vast market opportunity would develop for their bioreactor systems. These vendors should now take heart that if they do develop high quality and highly flexible single use purification unit operations, a nice market will possible develop for them. For the vendors of single use systems, it is much easier to show value to clients in situations where the single use system provides greater operational flexibility and or the single use system will improve the speed to market. It is pointless to compete in an already oversupplied market.
Biotech manufacturing facilities are typically designed with several fermentation units. Some factories have as many as 12 fermentation units. Most factories have been designed with a single purification train although in some case a second purification train was added. If indeed the manufacturers of purification equipment can provide high quality and competitively priced single use purification systems bio-pharmaceutical drug manufacturers may be willing to add additional purification lines and thereby debottleneck their facilities. To summarize purification is an area where single use systems can play a major role in improving the productivity of the industry. The adaptation of concentrated aqueous buffer and salt solutions with in line dilution is another processing area where single use bags can make a big difference.
References
- Single Use Technology and the Carbon and Water Footprints of Biopharm Manufacturing, Lindsay Leveen, American Pharmaceutical Review. Volume 12, Issue 6. September/October 2009.
- Single Use Technology Part 2: Bioreactors- To Be or Not To Be: That is the Question, Lindsay Leveen, American Pharmaceutical Review. Volume 13, Issue 1. January/February 2010
- Inline dilution and buffer bags, an integrated approach, Mathews Tim, IBC San Francisco Conference, December 7th, 2006.
Lindsay Leveen, “The Green Machine”, has worked with and consulted to major corporations in areas of energy deregulation, fuel cells, biotech, telecommunication, alternate fuels, power generation, transmission and distribution, as well as a variety of other process based technologies. Lindsay now works at Genentech as the Product Management Team leader for Lytics (Activase, TNKase and Cathflo) and was the Associate Director of Strategic Planning for this leading Biotech Company. Lindsay has lectured on sustainable development at leading universities and numerous industry conferences. He has written a book that is now used as a university text in Japan for energy policy and sustainable development. Lindsay has a knack to simplify and explain thermodynamics in everyday terms. He studied thermodynamics for his graduate thesis in Chemical Engineering at Iowa State University. The Green Machine blogs each week atwww.greenexplored.com