Trends come and go in our industry, as is the case in every industry. What would you say is currently the single largest trend in bioprocessing?
TK: The biggest trend is that bioprocessing is going smaller scale. With so many blockbuster drugs coming off patent, large pharma companies purchasing smaller biotechs, and greater focus on orphan drugs to remain profitable, the large production facilities to produce one product line are nearing extinction.
NH: The single largest trend in my view is the move to everdecreasing batch sizes. Once upon a time companies with the ability to manufacture in bioreactors of 12k L and beyond were respected and lauded as companies that were relieving industry capacity constraints. Now the focus is on small batch sizes of highly potent drugs such as antibody-drug conjugates, plasmid DNA, or cell therapies. Outbreaks such as Ebola have shown the need for vaccines to be manufactured quickly and closely to the source of an outbreak rather than in large, centrally located global facilities.
MW: The single largest trend in our industry at the moment continues to be when and where to use single–use technologies as a manufacturing solution. Many companies struggle with the appropriate level of implementation and we are searching for a best-inclass end-to-end solution. The technology is fantastic in many areas, but it must make sense for processing situation based on bioprocess applicability and cost of goods.
MH: The largest trend in bioprocessing is the continued move towards single-use manufacturing technology. While many of these technologies are not new themselves, continued innovation in this area coupled with industry becoming more comfortable with the technology has opened the door for entirely disposable manufacturing. Many processes are now capable of converting to fully disposable from bioreactor through to aseptic filling. Many companies are now creating technology centers where the knowledge and experience is at a point that enables full-fledged implementation. Leveraging this technology has so many described benefits and will be an asset to the industry as we are forced to become more flexible to meet the needs of an increasingly diverse product portfolio.
JM: Diversity in engineered molecules but standardization in process development methods and integration of quality by design.
Thinking back over the past 5 years, how has the landscape of bioprocessing changed since 2010?
TK: Outsourcing has tremendously changed the landscape. It is not just manufacturing that is being outsourced, but also research and development. With cost pressures on the rise and a greater need to ensure a successful commercial product launch, companies have removed the risk from their assets lists and are focused more on distribution of more targeted drug products. There is a need to evaluate a lot of smaller patient pool products versus the blockbusters that served the masses and allowed costs of non-successful attempts to be covered.
NH: As above.
MW: The idea of biosimilar or bioequivalent products being approved by regulatory bodies was a hot topic as a result of the Biologics Price Competition and Innovation Act of 2009 and the Affordable Care Act of 2010. In 2010, we saw many large drug company mergers fueled by potential biologic pipelines. We just recently witnessed the first biosimilar or bioequivalent product approval by the FDA. Approximately 40 drugs (30% biologics) were approved in 2014, an increase from average of the previous decade. Once the first biosimilar product gained approval, the industry will have a blueprint in terms of expectations and should fuel many follow on approvals. Currently, about half of the top–selling drugs are biologics, a dramatic increase since 2010. Economic pressure will increase over time as biologics become a larger source of therapies tackling some of what once previously thought of incurable diseases.
MH: In the last 5 years, biosimilar products have become a reality. Regulatory guidance has been issued and some of the major markets have now begun approving biosimilar products with the FDA’s first approval coming quite recently. While this has been expected for some time, the patent holders have enjoyed a bit of a reprieve from this reality as firms pursuing follow-on biologics have struggled to demonstrate comparability and with the bioprocessing technology itself. This new reality will now apply more cost pressure to an already competitive environment and force firms to become leaner and cut out more waste from manufacturing processes.
JM: (1) The use of CMOs by all sizes of companies; processes are developed, manufactured in several locations/countries (global business). (2) Expansion of European/American pharma into Asia. Emerging companies in India, Korea, China, especially vaccine and insulin production. (3) In chromatography, Simulated Moving Bed is gaining interest to reduce purification costs. Chromatography membrane devices have been accepted to replace sorbents in polishing and large molecule purification. (4) In final filling, the move from RABS and open handling of final filling suites to closed isolators which have several different advantages. Modular design of manufacturing areas so that multiple products can be made with the same general equipment set up—ie, combination filling machines, etc, that have PP/time pressure and piston pumps on it, reduced cost of maintaining a larger Grade A/B area, reducing risk of sterility failures because the system is truly closed. Removal of direct contact of the operational staff with the drug product.
What were some of the major trends that have come and gone since then?
TK: The fast and loose development of new products by small biopharma companies. With large pharma purchasing these smaller companies, they are applying their rigorous quality systems to new product launches. It has gone from just getting something close from a supplier to ensuring consistency and traceability through the supply chain and bio-process.
NH: As above.
MW: In 2010, the industry was challenged with implementing many new systems not readily accustomed to in pharmaceutical manufacture. Namely, Quality by Design (QbD), Risk Management, and Process Analytical Technologies (PAT). Many of these items are now truly part of the bioprocess development and manufacturing environment, enabling science-based and data-driven decisions in a historically risk adverse environment.
JM: As above, move away from RABS systems to closed gased isolators for improved sterility assurance and system integrity. In chromatography, Expanded Bed Adsorption has disappeared.
What would you say are the biggest challenges facing bioprocessing today?
TK: Securing the supply chain and reducing risk plus gaining a better understanding of what the critical quality attributes are in bioprocessing. It used to be that the process was generally controlled under one roof, but now with outsourcing being more prevalent, additional due diligence is required on items that used to be taken for granted.
NH: The bioprocessing industry is maturing and manufacturers are beginning to consider some of the challenges in ever greater detail. For example, the benefits of single-use technologies are now well understood and completely disposable facilities have been built; however, the issue of how single-use quality and supply chain risks will be managed, maintained, and monitored is only now being addressed to any significant level. This is a major challenge for the industry. How many tiers through the chain are being adequately managed? What does dual sourcing really mean? How is traceability maintained as supply chain complexity increases and what are the cost implications of mitigating these risks? Never before have the pharmaceutical industries suppliers been so responsible for ensuring the supply of quality life-saving drugs to patients.
MW: Generally speaking, the challenge of improving and incorporating GMP design into process and process delivery systems with newer technologies while the industry looks to maintain economical stewardship around the cost of products. Specifically, as more biologic processes gain market approval, manufacturers will require improvements in bioprocessing technologies in order to handle challenges with process yield, protein stability, and regulatory scrutiny concerning safety and efficacy.
MH: Biotechnology was created from the innovative minds of some extremely creative and special people. The bioprocessing industry has had the daunting task of bringing innovative therapeutic ideas from the lab bench to large-scale manufacturing in a safe and compliant manner. While bringing protein therapies into manufacturing facilities through approval to the market has been very challenging in the past, it is becoming increasing difficult as companies begin to move off-platform into some very exciting new areas. Tissue therapies, gene therapies, dual affinity antibodies, antibody drug conjugates, and therapeutic vaccines to name a few are becoming a reality. The biggest challenge in bioprocessing today is designing facilities and processes to handle a more diverse set of product platforms. Facilities of the future will need to be nimble, flexible, and largely disposable to meet the needs of this innovation explosion.
JM: (1) Sterility assurance of aseptic process formulation and filling. (2) Meeting unclear regulatory expectations for implementation of single-use technologies. (3) Reducing variation in product quality, remove/prevent protein aggregation and misfolded molecules.
Let’s shift to looking forward. What do you think we can expect to see in the next 5 years in the bioprocessing arena for pharmaceuticals?
TK: With drug shortages becoming more prevalent, there will be greater focus on biosimilars and generics. New players will emerge in the market as a result in this shift. Existing players will focus more on the orphan drug pipeline in order to remain profitable and serve the needs of the market.
NH: The emergence of cell therapy medicines is going to have a huge impact on the bioprocessing arena over the next 5 years. Some of the early products being developed are having an enormous impact on the lives of patients. Bioprocess scientists and regulatory experts will need to apply their skills, honed in the recombinant protein industry, to the challenges of cell therapy manufacture. These include very small batch sizes, new techniques such as the thawing of cryopreserved medicines that have significant impact on quality and tiny patient populations. Small patient populations make the statistical proof of safety and efficacy ever more challenging while also reducing the market size for these drugs. The development of new economic models may be required if development costs increase to accommodate ever more rigorous testing while future revenue streams are squeezed by having more patient-specific drugs.
MW: With the industry’s first approval of a biosimilar product, I think we’ll see an increased focus on automated high throughput and rapid bioprocess development. I think we’ll see some real innovations in this area utilizing a host of technologies that could include novel biologic platforms, more extensive use of robotics for repeatability and throughput, inline analytical measurements, and computer systems able to construct and analyze massive amounts of data before a process is moved to a large-scale manufacturing environment.
MH: To meet the need of the increasingly diverse product platforms that will start to become commercialized, manufacturing processes and facilities will become more and more flexible. There will be an increased focus on building facilities that can be changed over quickly, mobile disposable wheel-in and wheel-out manufacturing equipment will be needed, and manufacturing space management will be a required aspect of any construction project. This will be especially true for larger companies where diversity of the product portfolio continues to expand.
JM: (1) Standardization and simplification of bioprocesses, eg, less chromatography steps. (2) Full single-use processes integrating pre-packed columns or chromatography membranes. No specific needs/ expertise for the operators such as packing columns. (3) As single use becomes further adopted for formulation and filing—more emphasis on the systems quality and manufacturing aspects—supplier inspection for visible particles, POU leak testing, and also more detailed information on the components that are used in the fluid contact parts.
What are some recently improved methods or other improvements you’ve noticed that have been implemented in the field of bioprocessing?
TK: Single-use systems and automation of bioprocessing. Mundane tasks that had been performed by PhD’s are being replaced with equipment that can run tests or production runs without the need for holding down buttons. As a result of freeing up this non-value-added processing time, the PhD’s can focus on thinking of new products and applications and fully utilizing their brain power.
NH: Whether companies are manufacturing cell therapies, antibody-drug conjugates, or vaccines, there is a great need to ensure the safety of operating staff from coming into contact with these potent molecules while also protecting the product from environmental contaminations. In the early days of single-use bioprocessing, little consideration was given to containment or closed system processing. Nowadays manufacturers are much more interested in the concept, especially if it means that facility costs can be significantly reduced through having lower room air handling classifications. Closed systems processing seems like the only way to ensure the sterility of cell therapies that cannot be filter sterilized; however, it has significant benefits with more traditional biopharmaceutical products in operations such as bulk drug substance filtration and container dispensing where the need for vertical laminar flow cabinets can be eliminated.
MW: I’ve seen a positive movement in the industry concerning analytical and manufacturing technologies. Analytical assays are becoming more quantitative with greater accuracy and precision, including improvements in rapid methods such as microbiological detection and identification. The use of disposable probe technologies is moving our industry in a positive direction. I think we all would like to see continued progress concerning biophysical comparability testing technologies in order to demonstrate biosimilarity.
MH: In recent years, the often discussed yet underutilized asset of rapid microbiological methods has started to take hold. Fear of these new technologies themselves along with the method validation and regulatory hurdles of implementing them for previously approved products has really stifled their uptake. There has been increased pressure on the bioprocessing industry from regulatory agencies in recent years to tighten microbial control on the non-sterile steps in upstream manufacturing processes. Using rapid methods as a detection tool enables real time feedback on microbial status of media and buffer solutions prior to committing valuable product to the next step of the process. These tools are a real step forward in improving microbial control in bioprocessing.
JM: (1) Exploration of continuous processes for biopharmaceuticals. (2) New concept in biochromatography leading to combining several steps. (3) 100% inspection of the final primary packaging—for particulates using vision systems—that are trained to intuitively detect defects and selflearning systems for final inspection as well.