I have been following the single use (SU) technology space for the manufacturing of biopharmaceuticals for over a decade. Sometimes, I have been on the sidelines and other times actively involved in projects which extensively incorporated SU systems. All the way back in 2011, I was part of a team that delivered the first large scale 5 sqm SU TFF skid for cGMP manufacturing. So I have a little knowledge on the subject.
One thing that has struck me since the earliest days of SU systems development, is the fact that the process manifolds are typically built the same way. I used to build transfer sets for 2L autoclavable fermentors in the 1990s during my ‘lab rat’ days. These manifolds include significant numbers of hose barbs, tie wraps and silicone tubing. These types of transfer assemblies were notorious for leaks, dead legs, low-pressure rating, collapsing in the presence of slight negative gauge pressure and other disadvantages which have been carried over to more recent SU manifold designs.
This lack of evolution has almost certainly limited the adoption of SU technology. It has also undoubtedly frustrated end users of SU systems to no end! The core technology of hose barbs and tie wraps on silicone is many decades old and more suited for a process development lab, not cGMP manufacturing. However, in the last few years, great strides have been made in the design of SU systems and their associated components. This innovation provides an opportunity to dispel some common myths around the limitations of SU systems.
Myth 1: Single Use flow paths or tubing sets can’t take elevated pressures approaching 4 bar greater, or mild vacuum without the use of reinforced hoses.
The use of purpose-built exoskeletons, XO’s, allows the use of simple silicone liners without the need for expensive higher pressure rated reinforced hoses both on the suction and feed side of the pumps.
Myth 2: It is not possible to have ‘zero dead leg’ pinch valve’ blocks.
Let’s first eliminate the notion of ‘zero dead leg’. In the common stainless-steel block diaphragm valves, there is in most cases a “dead leg” of some sort inside the block between the various weirs. These “dead legs”, however, do meet the ‘2D rule’ prescribed by the current standards, like ASME BPE. With the aid of XO’s, it is possible to have SU block valves that meet or beat these same requirements but in a completely disposable format that eliminates the need for extensive cleaning regimes.
Myth 3: It is not possible to build 1-1/2” ID flow path skids with SU technology.
Once you realize the freedom that designs which incorporate exoskeletons and block valves provide, it is possible to raise the bar in terms of flow path IDs. Then the question becomes whether you would really need such a system? Can a system incorporating all of these new design elements make that size an afterthought? All the latest industry trends point to investments being made in facilities of the future, which are designed for ease of scaling out (and not scaling up) - from clinical stage to commercial manufacturing. So while the increased capability is nice to have, will smaller systems, prevail over the previous paradigm of larger and larger scales.
Myth 4: SU Systems have generally higher hold-up volumes than stainless steel skids.
When the use of hose barb fittings is limited or eliminated entirely, the system footprints can be greatly minimized. Multiple hose barb connections can be eliminated by the use of silicone manifolds that utilize over-molded connectors and hygienic clamp connections as well as integral sensors. These incremental changes, as well as the use of XO based block pinch valves and very compact clamp-on ultrasonic flow meters, can have a significant effect. If implemented correctly they can provide a 1:200 turndown with 2% accuracy and a 10x reduction in holdup volume all in a robust package. Non-product contact pressure transducers and SU flow cells that incorporate multiple sensors into one component along with other similar concepts can drastically reduce the SU system working volumes. Note - further development is acknowledged to be required to bring down the turndown and minimal working volume of the recirculation bags in SU TFF skids to better suit the needs of high concentration low volume products.
Myth 5: Extractables and leachables (E/L) studies that are extensive and time-consuming always have to be repeated, if we move from small scale to large scale and the manifolds and skid are sourced from two different suppliers at two different scales.
While in some cases this could be true, if the scaled application has a low potential for process or product impact, because the manifolds are made principally from the same material (eg. platinum cured silicone) and the bulk of the product contacting surface is this material, it is possible to use a risk-based approach to leverage the E/L study carried out at the small scale and combining it with a comparison of the E/L data from the larger system to avoid performing a full-fledged product/process specific E/L study at the large scale. You can refer to PDA TR66 “Applications of Single-Use Systems in Pharmaceutical Manufacturing” for a very thorough analysis of this subject.
Over the years, biopharmaceuticals have garnered a reputation for being life-changing drugs that come with a huge price tag due to a combination of upfront drug development and continuing manufacturing costs. The manufacturing costs are linked to huge capital investment in large facilities based on multi-use technologies that need extensive validation and utilities along with significant cleaning and sterilization requirements. With the convergence of so many technological and commercial changes like... personalized medicine, rapid screening in product development, better assays and analytical tools, QbD, risk-based approaches in quality assurance, pricing pressures from biosimilars, continuous (semi-continuous) manufacturing, process intensification (eg. higher titre processes, in line buffer conditioning, etc.) and last, but not least, cutting edge developments in single-use technology (eg. better sensors, XO’s, etc.), the future for biopharmaceuticals is trending towards the opportunity for significant reduction inpatient treatment costs. This should be good news for the millions of patients in developing countries who are yet to have access to this class of drugs.By Anand Saravane, Process/Project Consultant at Artesyn Biosolutions