Tech Trendz

SS vs. disposables: weighing the odds

Single use technologies have been the buzzword in modern global biopharma manufacturing, and Indian players too are taking to the technology, albeit in a phased manner. But benefits need to be balanced with the economical and environmental impact, finds Viveka Roychowdhury

"Disposable technologies are very useful in research laboratories as they afford a lot of flexibility when one is working on multiple protein products in parallel" - Dr Gopal Dasika Chief Scientific Officer Actis Biologics

The past three decades have seen a sea change in the face of global biopharmaceutical manufacturing facilities. Present day facilities have a more modular look than the spread out stainless steel (SS)-based biopharma facilities which grew out of the traditional blueprints of chemical facilities.

One of the reasons for the change is that "increased yields, in the case of most of the biopharmaceutical processes have led to possibilities of downsizing the process volumes," as Mahesh Kodilkar, Manager, Bioprocess Engineering, Intas Biopharmaceuticals Limited (IBPL) puts it. But as not all processes that are operated currently, have been able to transition to smaller scales owing to operational and regulatory reasons, and some continue being 'large-scale and stainless steel'.

The move towards smaller reactor sizes also coincided with the need for flexibility and thus single use technologies, like disposable capsules, filters to interface between the SS and single use components, membrane chromatography and virus removal filters, single-use bag programs which evolved to disposable mixing systems and bioreactors in various modes and capacities made their appearance to meet the changing needs of this ever evolving industry. These started replacing traditional SS fittings in certain areas, as they give the flexibility to switch from one product to another with minimum down time as well as save time spent on cleaning.

Some of the first single use technologies include Millipore's Millipak® disposable capsules launched in 1978 and the Millipak® range of filling machine filters which were designed for point-of-use filtration at the filling head. In 2009, Millipore's latest contribution to the single use biopharma manufacturing revolution was the Mobius® range of single-use 2-D and 3-D process containers and filter assemblies for Mobius® FlexReady Solutions, mixing and storage systems. With the latest equipment and integration of IT, these solutions have computer-controlled programs which have further reduced layout and cutting cycle and significantly improved lead times.

Similarly, Sartorius Stedim started out with filter capsules and today the newly introduced FlexAct portfolio focuses on the design and establishment of single-use unit operations. The FlexAct systems combine single-use components to an operation and are so flexible that these units can be used for a multitude of volumes, applications, and process steps.

G Somasundaram, Technology Group, DSP Unit, Millipore India mentions that, "Among the early adopters of Single Use process equipment are manufacturing environments that require bio-processing flexibility to accommodate new products and the new process modifications they entail."

Maik W Jornitz, Group Vice President, Marketing & Product Management, Filtration, Fermentation Technologies, Sartorius Stedim Biotech puts enhancements of production utilization at the top of the list for reasons to consider single use technologies. For example, he points out that single-use process steps could create the opportunity for multi-product process steps or streams. Additionally, the set-up time requirements of single-use systems are minutes instead of up to eight hours for a multi-use system. Also, cleaning and heat sterilization requirements are void, which means savings in water-for-injection, cleaning agents and energy consumption. In instances of high potency or cytotoxic drugs, single-use technologies protect the end-user, as these systems are closed components, he says.

"Economic downturns reduce the availability of capital investments, which resulted into a focus review of single-use technologies" - Maik W Jornitz Group Vice President Marketing & Product Management Filtration, Fermentation Technologies Sartorius Stedim Biotech

Backing this reasoning and speaking from experience, Kodilkar says, "Earlier, these systems were used only for hold applications. It used to be an arduous task, adapting single use systems for a unit step owing to non-availability of required sizes, suitable connectors and cradles. But now suppliers have filled up these gaps by bringing out smart options for applications right from seed development, fermentation, purification and right up to final filtration of a drug product." As far as capital equipment cost goes, Kodilkar says the reduction in the cost of bioprocess equipment with the choice of single use systems over fixed ones can range anywhere between 15 percent to 50 percent, based on process volumes, level and type of automation, etc.

Listing the savings on other parameters, Kodilkar reveals that cost of equipment cleaning, as against a SS facility, water requirement can be reduced up to 30 to 40 percent which in turn brings down the sizing and capital cost of pure water generation, distribution and waste water treatment systems in the plant.

An additional benefit for contract manufacturers of biopharma products, is that single use systems are preferred by clients, since they do not have to worry about carryover of someone else's product into their batch. Another obvious advantage for contract manufacturers, says Kodilkar, is product changeover duration where the facility remains mostly non-productive. In organizations working with traditional systems, product changeover procedures may take from three days to three weeks. With single use systems, this effort reduces to a plug & play operation that may not require more than a day.

The first steps

Kodilkar points out that for facilities looking to achieve greater operational flexibilities in terms of accommodating different processes of varying scales and volumes, a hybrid approach is a must.

Elaborating, Somasundaram says it would be possible to use SS tanks for some of the non-critical applications, while a complete disposable system is preferred in critical applications like formulation and filling. The hybrid systems would be used when you want to integrate the non-critical applications to the critical applications, for example, from the sterile holding tank through a capsule filter onto a sterile holding bag.

As Jornitz says, "Hybrid solutions are used right now everywhere, since the total disposable process has not materialized so far. Changes to established processing start introducing single-use technologies, mainly in form of filter/bag assemblies or as unit operations (FlexAct). Prime example for a hybrid need would be a typical monoclonal antibody process, which often uses a 20,000L stainless steel reactor followed by single-use harvest and UF/DF possibilities. The purification process uses Protein A affinity chromatography, which again is re-used, which can be followed by disposable intermediate filtration and membrane chromatography as polishing step. The decision of multi-use, hybrid or single-use truly depends on the process and volume needs."

While the manufacturing side may pose some speed breakers, researchers in R&D find the flexibility a real boon. Dr Gopal Dasika, Chief Scientific Officer, Actis Biologics says, "Disposable technologies are very useful in research laboratories as they afford a lot of flexibility when one is working on multiple protein products in parallel. If the cost of disposable technologies can be brought down, their use in research laboratories would certainly increase."

However Dasika cautions that it is important to remember that not all disposable technologies used in a biology research laboratory are easily scalable upwards. In research, disposables are often used for scaling down as well, as it provides meaningful data while conserving important reagents. Use of scalable single-use technologies is useful in shortening the timelines to produce materials for efficacy studies early in the development cycle.

Steady uptake …

"If the assembly part ( of single use technologies) is shifted to low manufacturing cost regions like Asia, the overall product cost will lower at least 10-15 percent.This will help tilting the balance in favor of single use systems" - Mahesh Kodilkar Manager, Bioprocess Engineering Intas Biopharmaceuticals Limited (IBPL)

Given these advantages, are Indian biopharma players keeping pace with the single use manufacturing revolution? Somasundaram of Millipore reveals that, "The acceptance has been gradual, but steady, as the advantages of disposable process equipment over traditional stainless steel process equipment in certain manufacturing settings become obvious." According to him, it is very simple and easy to train operators on these systems and experts in this field like Millipore, who are qualified can train the end users on these applications. For these reasons, he opines single use systems are getting more popular in the Indian market.

Jornitz too has a roster of Indian companies, which utilize Sartorius Stedium's single-use products, whether filter bag or single-use bioreactors. He says, "These companies were first of all interested in our offerings due to our experiences within this equipment field, but also due to the supporting services we offer. I would say Indian companies are early adopters and always look for the newest technology developments. This is what makes the Indian industry, market and personnel so attractive for outside investments and inside developments."

… but not fast enough

"Customers handling high value products have understood the benefits of disposable technologies" - G Somasundaram Technology Group DSP Unit Millipore India

But engineering consultants like Hyde Engineering + Consulting have a somewhat different tale to tell. John M Hyde, CEO and Founder, Hyde Engineering + Consulting, in an interview to Express Biotech in August 2008, had said, "the real opportunity that India has is that Indian biopharma manufacturers are not shackled with a lot of baggage that western companies are shackled with, in terms of traditional approaches to manufacturing, validation and compliance. So Indian companies can really kind of 'leapfrog' out of that tradition and position themselves to be on the cutting edge as time goes on."

Two years down the line, not many Indian biopharma players seem to be willing to take that leap. As with any new technology, there seems to be some resistance to change. According to Hyde, "The biggest change required is one of mindset. I have gotten the impression from some in the Indian biopharma industry is that the utilization of single-use technologies will result in higher costs of production, but this view is not supported by a complete cost analysis that includes differences in capital costs, time to market and ongoing maintenance and re-qualification expenses."

This seems to be one scenario where large companies could actually be at a disadvantage. "Smaller firms with less capital resources have more quickly adopted and implemented single use technologies," points out Dr Peter Watler, Chief Technology Officer, Hyde Engineering + Consulting. Many firms are saddled with business systems that require extensive cost and technology assessments to implement new technologies. As a result they have been slower to implement and reap the benefits of single use technologies in their GMP manufacturing facilities. He contends that a cost analysis can be manipulated to make either approach cost advantageous by simply changing a few input parameters such as the cost of steel, inflation and internal engineering costs.

Hyde says that though there are some Indian firms considering broader utilization of single-use components, the transition seems to be going slowly at this point. "We believe some Indian biopharma manufacturers maybe missing an opportunity to compete with and surpass other BRIC and western based firms," he says.

An important distinction made by Somasundaram becomes very relevant. He reveals that customers handling high value products have understood the benefits of disposable technologies, leaving us to conclude that the higher cost of single-use technologies could be justified only when manufacturing high value or highly potent products. As Hyde analyses, "Bulk of the Indian biopharma industry seems focused on contract manufacturing and biosimilars rather than new molecules and technologies. And as a result Indian companies seem to be reluctant to adopt single-use technologies to date most likely due to concerns about the acceptance by Western customers and regulators."

Dr Gopal Dasika, Chief Scientific Officer, Actis Biologics too feels that single-use technologies are far more prevalent in advanced economies than in India, but that is not to say that India is not keeping pace with the rest of the world. He points out that in the Indian context, due to significantly lower cost of trained manpower and availability of good quality SS, the benefits of switching over to single-use technologies may be minimal or non-existent. In India, where most manufacturers are producing biosimilars, using a judicious mix of single-use and conventional stainless steel technologies - a hybrid model - may make better sense economically, he reasons.

Figure 1: Single-use components for the manufacture of biologicals

Downturn could lead to upswing

"Smaller firms with less capital resources have more quickly adopted and implemented single use technologies" - Dr Peter Watler Chief Technology Officer Hyde Engineering + Consulting

Ironically, the economic downturn has increased the interest into single-use technologies due to the cost advantages, as well as increases in production capacities, says Jornitz. Moreover, economic downturns reduce the availability of capital investments, which resulted into a focus review of single-use technologies. Sartorius Stedim has seen a greatly increased interest in our single-use offerings worldwide, he avers.

Kodilkar too makes the point that out of the more than 1000 biotech based drug companies with leads in various stages of pre-clinical and clinical evaluation, a significant number of molecules are from small to mid size companies. "They would not be in a position to put in two-three years in constructing a facility, spending at least a couple of hundred million dollars for drug candidates which may or may not succeed. These companies or contract manufacturing units will turn towards single use systems. The time required to set up the production train as well as the operating cost will be significantly lower in this scenario and offer added advantage," he reasons.

Driving home this point, Hyde points out, "Just considering the time to market argument … what is the value of the 2.5 to four years of lost revenues due to the longer time taken to bring a traditional facility online? For high value biopharma products it will be many millions of dollars!"

Product economics vs process demands

"The biggest change required is one of mindset.…We believe some Indian biopharma manufacturers may be missing an opportunity to compete with and surpass other BRIC and western based firms" - John M Hyde CEO and Founder Hyde Engineering + Consulting

On the cost front, the decision to use single-use technologies or traditional SS systems is dictated by scale and product. As Kodilkar points out, "There is no one-size-fits-all situation here. For every product, based on production economics, there will be X number of batches per annum, below which, adopting single use will prove profitable. Beyond that threshold number of batches, traditional systems will have cost advantage."

Concurring, Somasundaram says, "It's a viable option if you are looking at a fermentation scale of 1000L, but anything above 1000L, single-use technologies become an unviable option."

Citing an example, Kodilkar says, "The cost of cleaning a 500 L stirred tank would be around $30 whereas the cost of a 500 L single use bag without any accessories is around $300. If this system is to be utilized for producing 50 batches per annum, the annual cleaning cost would be $1500. With single use systems, the annual consumables would cost in excess of $15000."

In fact, Jornitz makes the case that a green field biopharma process in a hard piped design would have a by far higher capital investment need and furthermore longer qualification requirements due to cleaning and set-up validation. Sinclair et. al. has shown in multiple publications that the investment requirements in a single-use process are far lower than multi-use process. Having said this, ROI calculation always depends on the particular application and process needs. One cannot define an ROI over an entire industry perspective, but has to analyze every enquiry as an individual case. For this reason, Sartorius Stedim Biotech works with calculation tools, which support the decision process of clients. The company will establish all the key parameters, install these into the calculation tools to come to an educated decision, whether the process should be multi-use, hybrid or single-use.

Watler makes the point that while recurring raw material/consumable costs (for single use technologies) are considerably higher, (in one case study they doubled from 15-30 percent of the costs of goods), this is offset with significantly lower initial equipment capital costs which can be 25-90 percent lower. While this is less of an issue for large firms with significant capital resources, this can be a deciding factor for smaller firms with limited capital resources.

Maintenance costs will also be significantly lower, he reasons, for example, with magnetic and levitating disposable mixers there are no seals or bearings to maintain and the motors receive far less stress than traditional mixers. As disposable pH, temperature and DO sensors are commercialized the maintenance on more complex systems such as bioreactors will dramatically fall.

"Undoubtedly the current cost of single use systems is high in the Indian context," says Kodilkar, "principally due to the fact that these systems are almost entirely manufactured in the high cost regions like Europe and US."

Manufacturing involves two key stages - base material production and assembly. The technological skills required for base material production are significantly higher. "If the assembly part is shifted to low manufacturing cost regions like Asia, the overall product cost will lower at least 10-15 percent. Necessary facilities and skills required to execute these functions are available here. This will help tilting the balance in favor of single use systems," he reasons.

As with any technology, wider usage will spawn more affordable options. On this front, Manocha feels the costs of single use technologies will eventually drop, with wider acceptance worldwide. Already single use technologies have reached 'prime time' for areas such as buffer storage, depth filtration, sterile sampling etc., where they are considered to be far more practical and economical.

Skill gap

"The costs of single use technologies will eventually drop, with wider acceptance worldwide" - Karan Manocha Regional Manager Asia-Pacific Hyde Engineering + Consulting

Manocha makes the point that single use products represent a small and a niche market in India and as a result there is a gap in the expertise available to implement this technology. "We work closely with clients in helping identify the right mix of single use and traditional solutions for their facilities and training their staff in implementing and the use of these technologies," he says.

That said, the total headcount required to run a biopharma manufacturing based upon the utilization of single-use components will require less training of staff as the support activities for the facility, such as equipment and software maintenance and re-qualification, will be reduced, points out Hyde. Operationally, too, says Watler, these systems offer significantly faster set-up, disassembly and cleaning, thus reducing manpower requirements.

Kodilkar points out that validation will remain a specialist function that requires a good understanding of the process, product and system. Analytical technology, equipment and skilled hands to execute this validation are no more a rarity in pharma companies in India, he opines. On the validation front, Somasundaram highlights that the major activity which the end user has to undertake is the extractable study, which the single use provider will have to perform. Extractables and leachables testing take the place of the usual cleaning and sterilization validation required in traditional systems.

Any validation exercise could potentially be spoiled by lack of training, stresses Jornitz. He explains that every piece of single-use equipment has different validation requirements. It is clear that the components need to be process validated according to current regulatory requirements.

This means for example that sterilizing grade filters, at least, have to undergo product bacteria challenge testing, as well as leachable testing. Single-use bags, bioreactors, membrane chromatography devices, virus removal filters etc. have all their very specific list of validation requirements. These validation activities are all supported by qualification documentation by the vendor and, in Sartorius Stedim Biotech's case, dedicated validation service organizations, which support the clients' specific needs.

The greener option?

Every solution however, seems to lead to another potential problem and with single use technologies, this could be the as yet unmeasured impact on the environment. As they will be disposed of as a solid waste, incineration costs could increase a facility's carbon footprint.

As Jornitz reasons, the environmental impact cannot be measured by waste alone, but requires a thorough analysis of the environmental impact balance. A multi-use tank requires copious amounts of purified and water for injection, both water qualities are prepared with a high level of energy. Furthermore, the energy intake to sterilize the tank requires consideration, the effluent treatment of the rinse water and cleaning agents. Set-up, cleaning requires a larger amount of manpower, which again require transportation to work, another energy factor. He hopes experts on this topic will work towards gathering more data along the lines of say, an expert balance sheet which compares the carbon footprint of a 100L tank versus 100L single-use bag. While not denying that the solid waste stream will increase, Watler reiterates that there are significant reductions in environmental impact as less energy (gas, electrical) is needed because of lower water, steam and labor requirements while using single use technologies. Efforts are already on to gather more data and he informs that they are participating on the ISPE Community of Practice to explore environmentally friendly methods of disposal and recycling.

Future trends

Jornitz reveals that in the design pipeline, are additional FlexAct systems, which will focus on specific process steps, for example media preparation, virus removal and inactivation and polishing steps.

In addition to Millipore's existing Flexready system for buffer and media preparation, clarification, tangential flow filtration and virus filtration, Somasundaram says the industry could also expect a range for the critical stage of final polishing. Millipore will also be looking at a concept of "MAb in a box".

On the industry front, Watler lists patient informatics, disease diagnostics and personalized medicine as the next trends to watch out for in biopharma manufacturing. Manocha mentions biobetters, which are essentially enhanced biosimilars modified using protein or glycoengineering and aim at having better efficacy, reduced risk of immunogenicity and lower dosing frequency than the first generation biopharmaceuticals. The Indian biopharma industry has the talent to tap all these opportunities, but managements will need to take that 'leap into unknown' and adopt cutting edge technologies faster or we will miss the biopharma bus.n

viveka.r@expressindia.com