The Biomanufacturing Facility of the Future

Many new trends in pharmaceutical manufacturing have emerged in recent years as the industry adjusts to the demise of the blockbuster era. As many small-molecule blockbusters have come off-patent and innovation has slowed, the biopharmaceutical industry has flourished, spawning a growing number of drug approvals and new facilities. But despite successes, biopharmaceutical manufacturing has not been entirely untouched by the challenges facing the industry as a whole. As Gert Moelgaard stated, flexibility is likely to be a big driver of the future. Gert examined the broad trends affecting the industry and how we have to change as result. Here, I present an in depth look at the situation in the biomanufacturing space.

Whether manufacturing monoclonal antibodies, hormones or recombinant proteins, drug makers have to develop a ‘biological factory’ that can be incorporated in a manufacturing facility. The stars of today’s biomanufacturing facilities are the bioreactors that are used for cell growth, and the downstream equipment for harvesting, purifying, and concentrating drugs. Many of the current facilities sprang up quickly when the trend towards biopharmaceuticals became apparent, devoting manufacture to just one product to avoid cross-contamination. Today, these facilities are evolving to better match today’s new drugs and technological opportunities.

Biologics of the future

It is evident that the biomanufacturing facility of the future will depend on the biopharmaceutical drugs of the future. Currently, more than 3,000 biopharmaceutical drugs have been launched; over 6,000 are in preclinical/discovery stage; and 4,000 are in clinical development (1).

The biggest R&D pipeline – more than 4,000 products – exists in the cancer space. Of course, not all will be filed, but the number of products in oncology is set to increase dramatically. Increased understanding of the complex interplay between genetic, cellular and environmental factors suggests that there may be as many different cancers as there are patients. For example, trastuzumab is an effective drug for treating breast cancer, but only in the 25 percent of patients with tumors that overexpress HER2 (2). The cost to sequence a whole human genome is now less than $1,000 and takes only a few hours. In the future, I believe we’ll see sequencing of tumor genomes being used as point-of-care testing, allowing physicians to choose a drug on a molecular basis versus simply a histological analysis. For each new gene and molecular pathway implicated in cancer, there is the potential for a new biologic drug; therefore, not all of the new biopharmaceuticals launched can be blockbusters. Some will only be suitable for a subgroup of cancer patients, and facilities will be needed that can produce small quantities of many different biologics.

Another important trend is the rise of biosimilars. The first synthetic erythropoietin, granulocyte-colony stimulating factor, somatotropin and trastuzumab are all pioneering drugs that have now tumbled off the patent cliff; however, biosimilars are not nearly as straightforward as generic small-molecule drugs to manufacture. The molecular structure of biopharmaceutical drugs is related to the genetic background of the cell line used for biomanufacturing, with post-translational modifications, such as glycosylation, each having an impact. Each cell line is the exclusive property of the company that originated the product, so biosimilar companies have to generate a new cell line for each new biosimilar product they produce. Because the new cell line could be slightly different from the one used for the original product, biosimilar companies have to present results of toxicological studies and clinical double-blinded studies to prove that their biosimilar product is truly similar to the originator.

From a marketing standpoint, once a biosimilar drug receives market approval it must also differentiate itself from the competition. For generic or biosimilar drugs, price is the main differentiator. As a consequence, if the price of the originator biopharmaceutical decreases, then so too must the biosimilar, despite expenditures in clinical and toxicological studies. This is one reason why there is great pressure to reduce costs in the biomanufacturing area.

The sometimes-dramatic differences in the costs of biologics was highlighted recently by the case of anti-vascular endothelial growth factor (VEGF) to treat age-related macular degeneration (AMD). Ranibizumab is a monoclonal antibody targeting VEGF for the treatment of AMD. Its end-user price is $2,000 per month. Bevacizumab is a similar molecule, also targeting VEGF, but its indication is for the treatment of cancers. Its end-user price is less than $50. Such disparity has bewildered the public. From an industry perspective, the price of a drug must not only cover the cost of manufacture but also the risks and costs of innovative development. But the public is not ready to accept that there can be a 40-fold price difference in virtually identical products, both of which are profitable. Pressure from governmental authorities and patient associations is strong, and this is translating into increased pressure on costs. The biomanufacturing facilities that will survive in the future are those that that can help contain costs with increased flexibility and better yields.

Disposable flexibility

A key trend in bio/pharma manufacturing is the uptake of single-use systems. Single-use systems are generally comprised of hardware and disposable components – the hardware carries the tools related to the biomanufacturing step, such as motors of mixing systems; and the disposable component is single-use, for example, bags where buffers can be mixed

When using disposables, bioreactors are no longer rigid stainless steel tanks with welded pipes for adding cell culture media or buffers, with sensors that are difficult to calibrate and qualify. Processing after harvesting in stainless steel tubes that have to be washed, sterilized and qualified after each batch is also a procedure of the past. Disposable systems mean that we can produce a drug in plastic bags and pipes that don’t require washing, sterilization or validation. I believe it won’t be long before we can say, “goodbye” to glass and stainless steel for clinical – and even commercial-scale biomanufacturing.

From an ecological standpoint, the first impression may be that single-use systems are a backward step, since they are plastic and wasted after production. However, first impressions can be misleading – using disposables eliminates the use of thousands of liters of ultra-pure water usually required for cleaning. It also reduces the corresponding effluent discharge and subsequent pollution. As a result, the ecological equation is in fact thought to be in favor of disposable equipment (3).

The advantages of single-use equipment are attractive for one product, but for the production of multiple products become even more evident. In the past, each stainless steel biomanufacturing facility was used for one single product to avoid cross-contamination inside the tank. Single-use tanks can be discarded after production and replaced by another system, allowing several products to be produced in the same area, one after another. Another reason why facilities were devoted to one product in the past is that tanks and equipment had to be specific to the product. For example, consider the equipment required for downstream processing if the yield of the upstream step is 1 g per liter versus 6 g per liter. The size of the tanks, capacity of the chromatography columns and surface of the filters will be different. As you can imagine, it’s tricky to replace a 500 liter tank with a 2,000 liter tank quickly in a stainless steel facility where tanks are linked to others by welds. These bottlenecks are avoided with single-use systems.

Despite the advantages of disposable manufacturing, we currently don’t have the technology to use it in every process step for biomanufacturing. Purification steps, for example, cannot be handled with disposable equipment because chromatography resins are too expensive to use only once, especially the protein A resin that is required for purifying antibodies. Pre-packed disposable columns do exist at pilot scale, but even if they are developed for process scale, they will not be handled as single-use equipment. Unless we can find a new, cheaper purification membrane that can capture antibodies as efficiently as protein A – a tall order but a clear area crying out for innovation – this is likely to be the case for many years to come.

As a consequence, our biomanufacturing facility of the future will be able to produce several different products, but will use both stainless steel and single-use technology. I envisage it as a puzzle, where disposable pieces can be assembled to fit with the requirements of the production process of a given biopharmaceutical product. The puzzle can then be disassembled and reassembled when a new product requires a different configuration.

Quality control

Single-use systems represent a big change in the way manufacturers handle quality issues. The plastic bags have to be considered as expendables, while the hardware component of the disposable system is subject to Installation and Operation Qualifications (IQ/OQ). The providers of the plastic bags must be qualified by manufacturers from a logistical and quality standpoint, and traceability has to be in place. The plastic composition of the bags also has to be under control to avoid any issues, as the drug substance is in contact with it during processing.

Indeed, the question of extractables and leachables is something that is becoming a hot topic in biomanufacturing. Does the plastic release any particles when in contact with water? Does it release any particles when in contact with cell culture media, buffers and drug substances during manufacturing? Could any of the leachables be dangerous for patients when the drug is injected? Some consider these inquiries secondary questions, given that blood for transfusions has been stored in plastic bags for decades. However, the recent case of bisphenol A in baby bottles shows that extractables and leachables are certainly critical in healthcare. Plastics generate extractables and leachables, and it is the responsibility of the manufacturer to show that these particles are not dangerous for patients.

Today, the best technique to analyze extractables and leachables is mass spectroscopy, which can identify and quantify contaminant material. Analysis can be performed on plastics when water is processed in bags, when cell culture media and buffers are processed, with or without cell culture, with or without drug product, to ensure a good control of these particles during and after processing. Clearly, the biomanufacturing facility of the future would need to be equipped with state-of-the-art analytical quality control technology.

Fully closed and continuous processing

The way we use the above operational units will be another driver to increase yields and thus reduce cost of goods in the facility of the future. To that end, a big trend is emerging: fully closed processes and continuous processing.

The main reason for fully closed processes is to avoid contamination during processing. From thawing of the cell line devoted to the production of one given drug substance, to the fill and finish step of this product, contamination can be limited if the cells and the product are never in contact with the outside environment. Disposable bags and pipes can now be designed to allow closed processing, from the working cell bank to the final tube containing the product.

Continuous processing is another trend that is much more oriented to yield improvement and cost containment during the upstream steps. Instead of producing one batch with one cell culture that will be harvested once, the cell culture can be continuously supplied with cell culture media, and continuously harvested without stopping the culture, thanks to proper filtration and loops on the flow. This allows the production of more cells – and thus molecules – at the same time, as the culture continuously runs at high density and consequently at high yield (see, Towards Continuous Manufacture below).

Local knowledge

When imagining the biomanufacturing facility of the future, we shouldn’t forget sociological and economic trends. The environment and global warming, for example, are becoming more important issues for many. The public don’t understand why a drug has to be produced 20,000 km away, shipped to their country in a temperature-controlled box, with very high margins, when production could be handled locally instead, benefitting both the environment and providing local jobs. Of course, this is not limited to the pharmaceutical industry. President Obama wants American companies to bring jobs back to America. The same trend can be seen in Europe, especially in France.

As a consequence, even now there is a trend to build regional facilities. I fully expect that this will continue – and evolve. Instead of building large global manufacturing facilities for just one product, companies will build smaller facilities capable of manufacturing several products for regional sales. And in fact, regional manufacture is also beneficial from a regulatory standpoint, as expectations can vary from one country to another, despite harmonization efforts.

To conclude, economic and political trends will push companies to establish regional facilities where they manufacture several products for local markets, while pressure on costs will ease as greater flexibility allows optimal management of the workload. The biomanufacturing facility of the future will be like a giant Lego set; operational units, such as bioreactors, clarification systems, tangential flow filtration systems, purification and chromatography systems, will form the pieces, with pharmaceutical ‘players’ easily assembling, disassembling, and reassembling them to create any product, in any amount, at any time.

Towards Continuous Manufacture

Insight from Bernhardt Trout, Director & Principal Investigator, Novartis-MIT Center for Continuous Manufacturing

What are the benefits of continuous manufacturing?

Continuous manufacture, as we define it, is very much about achieving the ultimate process understanding, the ultimate process efficiency, and the ultimate product quality. The idea is not just to take existing technology and run it continuously, but to develop new technology. The aim is to develop a fully integrated process, including an integrated control system. The whole process is streamlined – it is more efficient, with reduced throughput times, smaller facilities and decreased costs, and quality is improved by avoiding potential issues with sterility and variation between batches.

What are the main barriers to implementation?

One potential barrier is the investment required to develop new technology. Another barrier, or at least perceived barrier, is regulatory approval for this new process. But I would say the number one issue is mindset. It’s a very conservative industry that can be reluctant to do things in a completely different way. Pharmaceutical manufacturing is lagging behind other areas, such as automotive and electronics manufacturing. There is a lot of inertia – of organizations, of procedures and of thought. As we know from Newton, to change an inert system, we have to apply force! That force has to come from top management. They have to be willing to invest and make the organizational changes required. Here, the biopharmaceutical industry has an advantage over small molecule drugs – as a newer industry, they are more open to newer technologies, but still suffer from the above problems.

How soon do you expect to see significant uptake of continuous processing?

It’s been slow but steady. Novartis is the leader in terms of investment in R&D for continuous manufacturing and in terms of timing.  Their focus is on small molecules, but the overall concept follows through to biologics. Genzyme, part of Sanofi, has been working on biocontinuous processing for some time. I think it will gradually increase, until the point where one company launches a fully validated, working continuous process – after that I think it will accelerate rapidly.

What other trends do you hope to see in pharma manufacturing in the future?

Here at MIT, we do a lot of outreach – both with the industry and with the public. We think it’s important for everyone to have a clear understanding of pharmaceutical manufacturing and its importance. When we think of automobile manufacturing we can envisage assembly lines and robotics, but few people easily envisage pharmaceutical manufacture. In the future, I hope to see a much stronger understanding of pharmaceutical manufacture, both for upper management – many of whom don’t have pharmaceutical manufacturing backgrounds – and the public as a whole.