What are some recent industry issues that are affecting the growth of the biopharmaceuticals market?
Felipe Burns, Ph.D., Associate Manager at Cambrex: We have recently seen a big transformation in the approach to moving the regulatory process ahead by using digital platforms as companies seek to achieve regulatory and process excellence. The United States Food and Drug Administration Title 21 CFR Part 11 compliance states that companies using electronic systems for documentation and signature control must provide assurance that the electronic documents are authentic and confidential. This means that manufacturers need to have robust computer systems in place and complete validations to meet Title 21 CFR Part 11 and other globally updated guidelines on the same topic.
Undoubtedly, as manufacturers embrace more automation and digitization, it is invaluable to have computer systems that can be shared with partners and contract research organizations (CROs). There is a great deal of time savings and a streamlining of documentation (no physical paper trail), however there are also challenges that come with this approach. As each company will be operating on preferred software and systems, antiviral programs can impact flexibility and there are wide range of antiviral programs to choose from. Additionally, Lightweight Directory Access Protocol (LDAP) and automatic backup programs can interfere with the functionality of analytical software.
Anticipating what potential antiviral programs CROs will be using (given the amount of choices) is not a simple assumption.
As a result, certain bioanalytical assays, instruments, methods, and programs can make it challenging to meet current guidelines and impact the biopharmaceutical drug product manufacturing process. Complicated or data rich bioanalytical assays such as cell-based impedance assays, certain enzyme kinetic assays, and next generation sequencing can fail to meet all current expectations, yet there are scientific and statistical needs with this type of data which are not compatible for every requirement or expectation. The modulation of a risk-based approach complete with documented justifications are required to reach the next phase of the process; this will support meeting 21CFR Part 11 and other current guidelines and requirements until the bioanalytical systems can catch up with small molecule systems that have been doing this for years.
Bernie Clark, Vice President of Marketing & Strategy, Catalent Biologics: The biologics market as a whole continues to thrive with few headwinds impacting near-term growth. COVID-19 has obviously created a number of challenges for the industry in the short-term, as the immense need for therapies and vaccines has driven a lot of new and accelerated product development, in addition to drugs already approved or in clinical trials being repurposed. Emerging modalities, such as antibody-drug conjugates (ADCs), and bi-/multi-specifics are also growth drivers, with activity in the ADC field increasing over the last couple of years, including several approvals and partnership announcements. Another emerging modality is mRNA-based therapies, which is a trend that has been amplified by the COVID-19 pandemic.
Regional dynamics also play a part in understanding market demand and growth, as while North America still makes up the largest percentage of the development pipeline that feeds the commercial market, Asia-Pacific is growing fast, with large concentrations in India, China, Japan and South Korea.
Charles Christy, Head of Commercial Solutions, Ibex Dedicate, Lonza Pharma & Biotech and Abdelaziz Toumi, PhD, Head of Commercial Solutions, Ibex Design & Develop, Lonza Pharma & Biotech: New challenges have brought on accelerated approval pathways such as FastTrack and Priority Review. There is increased pressure to quickly deliver therapies for the patients who need them most which in turn puts pressure on process development. In the past, it was enough to design a process to bring the molecule to tox in phase 1 and fix it later in phase 3. Today’s timelines request the CMC process to be right first time. The COVID-19 pandemic has increased the emphasis on speed to market, disrupting supply chains (virtual), supply of raw materials, and access to quality capacity which causes delays in clinical trials.
As market demand continues to rise for more potent and effective therapeutics, biologic pipelines are evolving from standard antibody formats to next-generation biologics (NGBs). This shift requires a deeper understanding of the biological mode of action early on. This understanding is strengthened by advancement in science, access to data and sequencing, to name but a few.
Other issues include:
- Pressure on pricing caused by a robust increase in funding within the biopharmaceuticals market, coupled with demand for access and affordability
- Increased understanding of disease pathways and companion diagnostics
- Strong growth in different modalities such as bioconjugates, vaccines including mRNAs and combination therapies i.e. oncology
- More targeted therapy, clinical trials are becoming more personalized (personalized medicine), drug usage is evolving
Priyanka Gupta, Head of Market Entry Strategy, Protein Segment, Sartorius Stedim Biotech: As new molecules are being developed, there is a lot of pressure on manufacturers to fulfill the varying demands of a diverse pipeline. Cost of development is increasing while manufacturers are facing increased pressure to lower the cost of drugs. Also, as an emerging market competes for the same indications, manufacturers are feeling greater urgency to be the first in the market, but at the same time, they still need to keep the cost of their drugs low as well as follow stringent regulatory protocols. All of this uncertainty is putting a lot of pressure on the biopharma industry to come up with unique and innovative ways to develop, produce and manufacture drugs.
Ronald A. Rader, Sr. Technical Director, BioPlan: The major issues affecting growth of the biopharmaceuticals market are attributable to industry response to the COVID-19 pandemic, and most of this involves dealing with rapid growth rather than serious problems. Industry response includes over 380 related vaccines currently in R&D worldwide. Most of this COVID-related R&D appears to be in new and in addition to ongoing R&D. However, the pandemic is diverting resources from mainstream R&D and this will have some negative impacts, including clinical trial delays slowing product development. The extent to which COVID-related projects are resulting in slowing of R&D with other classes of products remains to be seen.
A major potential threat to the biopharmaceuticals market is price controls in the U.S., with both political parties promising “drug price reforms” during the recent election cycle.
Kristin DeFife, PhD, Sr. VP & Site Head, Ajinomoto Bio-Pharma Services: Certainly the pandemic has impacted market growth from interrupted supply chains, clinical site closures, travel restrictions, and a backlog of care. Further, our client companies have slowed manufacturing outsourcing for early stage products as they take a wait-and-see approach. This landscape has shifted focus away from targeted, potent and orphan drug development to development of COVID-19 therapies and vaccines.
What is your view of the current biosimilars market? Has it grown as fast as expected? If not, what have been some of the impediments to its growth?
Clark: The biosimilars market has grown as expected in some markets, notably those outside the US. In the US, and to some extent still in Europe, market growth is limited by patent expiry and process patents that are extending coverage for some innovators. For those products that are off patent, in some cases better alternatives have been approved or the standard of care has been modified. This means there is less incentive for the market to adopt a biosimilar of these innovators; for example, for many HER2+ breast cancer patients, treatment includes both Trastuzumab and Pertuzumab, and only Trastuzumab has biosimilar options.
Christy and Toumi: The current biosimilars market is a tale of two cities. In Europe and India, we see tremendous growth with a clear framework in Europe. However, there has been slow adoption in the US because there is not a clear framework or strong support from the government.
Gupta: Although a lot of companies are developing biosimilars, not many biosimilars have made it to the market. First and foremost, there are hundreds of companies competing to produce biosimilars for the same 10-15 innovator products. So, the competition to be firstto-market is very high, as the company that is first-to-market with a competitively-priced biosimilar will take most of the market share. Secondly, the companies that are producing innovator drugs are lowering the cost of their own drugs in emerging markets, making it difficult for biosimilar companies to produce drugs that have an even lower cost of production. Third, since the major challenge for any biosimilar company is to first prove the biosimilarity of their product to the innovator, they need to invest time and money into tackling this hurdle while simultaneously speeding up their production to make it to the market first. All and all, there is a lot of biosimilar development taking place, but biosimilarity, the cost pressures, and the regulatory hurdles in various regions are major challenges for all of the biosimilar companies.
Rader: The current worldwide biosimilars/biogenerics market has grown as fast as expected in all significant markets other than the U.S. Biosimilars have become mainstream products, competing well with reference products, in Western Europe and other non-US major markets; and biogenerics are very much the dominant products in developing countries. Patent disputes and settlements continue to delay U.S. market launch of most FDA-approval biosimilars. The U.S. market remains restricted in terms of diversity of marketed biosimilars, including in comparison with Western Europe. Otherwise, there is some continued resistance among U.S. healthcare professionals and even payers/insurers to adoption of some biosimilars, with this often varying by product and disease area.
DeFife: We have seen an increase in biosimilars coming to us from our biopharma clients, and we expect to see this trend continue, as the biopharma industry sees adoption and FDA approval of these products, which has lagged behind the EU. We expect uptake to intensify as more molecules come off patent in specialty areas like oncology.
Specifically, how has the growth/acceptance of wearable devices to deliver biopharmaceutical products helped the market segment grow?
Clark: Wearable devices are still not widely applied for most products, so I would say the impact on the overall market segment is limited at this time. However, wearable devices obviously have some growth potential for products that need to be delivered on a daily basis.
Hans-Christian Mahler, Head of Drug Product Services, Lonza: Biopharmaceutical products parenteral delivery to treat diseases systemically, i.e. these products are administered by injection, infusion or implant into the human body, for example via intravenous (IV) or subcutaneous (SC) route. A number of biopharmaceuticals in the market and in clinical development are developed as vials for IV administration.
Prefilled syringes, autoinjectors or wearable devices such as patch pumps are increasingly developed and commercialized, especially in indications that benefit from SC delivery - either due to pharmacological reasons or to allow patients to self-administer. Autoinjectors and syringes are however, currently limited to administration of 2.25 mL. The dose and volume of most subcutaneously delivered biopharmaceuticals is significantly higher than 2.25 mL, so wearable devices like patch pumps for SC injection or SC infusion will become more and more important.
However, there are only a few technically advanced device options, so it is difficult to combine the “drug” with the “device” to make a drug/device combination product. The lack of device options creates challenges navigating development, manufacturing, testing and regulatory considerations.
This is why Lonza Drug Product Services and Ypsomed have announced their partnership to enable pharmaceutical companies to develop and commercialize patch-pump (Ypsodose R) based combination product therapies, with Lonza DPS contributing its expertise in the development, manufacture and testing of sterile products.
Rader: Wearable devices, including injection systems and simply skin patches, for delivery of biopharmaceuticals remains a relatively small market, and one dominated by a few insulin products. I do not agree that these medical devices have significantly “helped the [biopharmaceuticals] market segment grow.”
Companies that develop biopharm products face many challenges. What sort of basic framework/structure/organization should a company have in place to ensure success?
Burns: Depending on the phase of development, finding the right balance of quality, efficiency, and cost control is critical for the drug development process regardless of the type of end drug product. When we look at the trends towards digital document control via Electronic Lab Notebooks (ELNs) or Laboratory Information Management System (LIMS), we see the importance of having a complete computer system validation process. The more information manufacturers can provide on the computer system validation front (pre-generated computer system validation protocol drafts), the easier it will be for smaller firms to meet basic expectations for bioanalytical cGMP data. However, it is vital that the Electronic Lab Notebooks (ELNs) or Laboratory Information Management System (LIMS) are flexible enough to capture the unique need of biopharmaceutical methods, which can be immensely diverse in their data management needs. There will undoubtably be struggles to meet the efficiencies desired while maintaining the ability to effectively document the wide variety of analytical approaches used to support biopharmaceuticals.
Clark: It is important for small/virtual biotech companies with only one or a small number of molecules in their pipeline to understand the importance of dedicating resources to development and manufacturing. Since they will not typically have their own inhouse facilities, they will need to use partners that can help them progress programs from the discovery phase to clinical trials and beyond. Unless the leadership team has expertise in CMC, it is often helpful to find an experienced consultant to help partner them with contract providers that match their needs, and then help manage the relationship as the program progresses. Mid to large pharma will likely have a different strategy, dependent on how much development and manufacturing capability they have in-house. Those companies typically have a team dedicated to working with external partners, and their drivers to outsource could be because of a variety of reasons such as: desire to manufacture in a new region that addresses a follow-on market; leveraging a partner for specialized expertise not available in-house (such as development of a non-traditional antibody or novel technologies); or securing additional capacity for risk mitigation or coping with a surge in demand.
Christy and Toumi: Ensuring success needs to be routed in strong science, great investors and great partners.
A growing number of molecules in the pipeline are expected to be owned by small and virtual biotech companies. An increasing number of these companies will want to take their molecule to market but will lack the in-house expertise to do so and therefore need to consider outsourcing.
While small and virtual biotech companies focus on science and biology, it is critical that they choose the right partners and build an ecosystem with a limited number of interfaces. It is equally important to satisfy their investors. Partnering with a CDMO that can align development and funding milestones can add value at every stage of development and offer procurement powers and legal frameworks to smaller biotechs.
For all biotechs, strong advisers are key to ensure that your first milestones are designed with commercialization in mind. This helps improve overall program speed while increasing efficiency. The importance of CMC at every stage should not be underestimated.
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Andrew Bulpin, Head of Process Solutions, MilliporeSigma: Biomanufacturers are facing unprecedented pressures to increase productivity and deliver biotherapies faster and cheaper to the market. They are being asked to deliver higher efficiencies, while navigating the complexities of regulations, budgets, internal structure, and decision-making.
Industry 4.0 is expected to dramatically transform biopharma by combining automation, data and analytics into a single environment with the manufacturing facility. These approaches and technologies can help increase quality, flexibility and speed, while reducing errors and costs. To achieve these benefits, biomanufacturers must enable the following principles:
- Interconnectivity – where machines, sensors, and other devices are connected to the people tasked with monitoring a process for effectiveness and efficiency.
- Information transparency – This interconnectivity allows the immense amount of data and information collected from all points in the manufacturing process to aid functionality and help identify areas that can benefit from innovation and improvement.
- Decentralized decisions – Sharing information across networks leads to decentralized decisions, the ability to combine local and global information at the same time, driving better decision-making and increasing overall productivity.
- Technical assistance from systems and automation designed with remote support capabilities by the supplier will help operators make informed decisions and solve urgent problems on short notice.
DeFife: Many biopharma companies adopt a strategy to partner with CDMOs for the development and manufacture of their products, which can provide speed-to-market and access to expertise that may not exist in-house in regards to the latest CMC and regulatory expectations. The key framework the sponsor company needs in this scenario is a clear understanding of their internal gaps and their actual outsourcing needs. Through discussions with their prospective CDMO partner to ensure strategic alignment will facilitate understanding if the partnership is tenable at the relationship level. This is key because technical challenges will invariably arise during the development process, and a strong, aligned relationship will drive success.
In the next few years, what do you anticipate as critical industry issues that will drive market growth?
Burns: There are so many opportunities in this market right now and for the future. Companies are looking to ensure resilience as priorities shift in supply chain management during COVID-19 times, while keeping a broader view of what the future will hold and how to properly prepare. As the industry becomes more automated and digitized, pre-generated computer system validation protocol and hardware validation protocol drafts will help manufacturers to better support customers. Computer systems are being highly scrutinized, and some firms will not accept bioanalytical GMP instrumentation solely on poor responses to basic aspects of computer system software data integrity issues listed in their user requirement specifications and in 21 CFR part 11.
Clark: The overall biopharmaceuticals market should continue to thrive with some standout modalities, such as cell and gene therapies driving disproportionate growth. As more cell and gene therapies advance in the clinic and gain approval, that segment will comprise an increasingly larger portion of the overall biologics market. Combination therapies may also start to significantly impact growth.
We are seeing combination therapies today in some COVID trials, evaluating antibody cocktails or an antibody paired with a small molecule etc., but other examples of combination therapies being explored include ADCs combined with other oncology therapies to help improve patient outcomes. All of these trends are exciting developments for our industry as it stands today, and will fuel future growth as promising new technologies are explored.
Christy and Toumi:
- Treatments for major populations (vaccines, chronic diseases), increased prevalence of chronic disease, and an aging population
- Rise of the middle class in China and other emerging economies, major investment in emerging economies (e.g. Brazil, China, India, etc.)
- Globalization of healthcare and related investment
- Pre-investment in manufacturing capacity and human capital to respond to future pandemics
- Current technologies are reaching maturity. With the desire to bring new therapies faster and cheaper to market, regulators are supporting new technologies such as continuous capture. We are close to a tipping point where a lot of new technologies will be implemented thanks to funding to invest in R&D and data availability.
- Industrialization of newer therapy platforms (mRNAs, bioconjugates) in the same way that microbial and mammalian have become scalable and robust. New therapy platforms will follow a faster technology maturation and adaptation.
Bulpin: Single-use and continuous processing, the diversification of different modalities, and industry consolidation for both vendors and pharmaceutical companies will have a significant impact on the future of biomanufacturing. The industry is buzzing about continuous processing because it will have a significant impact on bringing therapies to market, delivering them to patients faster and more cost effectively than ever before.
The industry is moving towards intensified, connected, and continuous bioprocessing. Continuous biomanufacturing will play an integral role in better integrating up and downstream operations over the next five years as manufacturers look to suppliers for integrated solutions as they think holistically about their process and visualize future scale up. Our customers expect that, in 5 years, 40-50% of their processes will incorporate continuous capture and flow through polishing technologies.
Gene therapy manufacturers are eager to develop a mAb-like process template that will help them increase upstream and downstream productivity while avoiding bottlenecks during process scale up.
Gupta: Some of the critical drivers that need to be addressed moving forward include: 1) the development of different modalities that are non-monoclonal antibody, where establishing a platform is not really possible, 2) advances in cell and gene therapy and the development of the technology needed to produce these highly potent and effective treatments, 3) personalized drugs, when cost of drug is critical, 4) intensified processes that are semi-to fully continuous, and 5) Building more sustainable, single-use modular facilities that can cater to these varying pipeline demands.
Rader: Biopharmaceutical market growth, amounting to billions of dollars in new sales, in the next 5 years will be dominated by COVID-19 vaccines, along with dramatic growth in the gene and cellular therapy areas. Problems will mostly involve dealing with success, including meeting demand. We expect growth in development of pandemicrelated products, including biodefense, with COVID-19 showing how vulnerable societies are to pathogenic threats; and development of other infectious disease products, including those addressing antibiotic resistance. The market will continue to deal with critical issues including biosimilars variably adopted in different markets high costs of biopharmaceuticals; rapid growth of biopharmaceutical manufacturing in developing countries, such as China and India, initially mostly to meet domestic market needs but eventually targeting major markets; and more biopharmaceuticals coming to market reflecting the overall pharmaceutical industry shift away from small molecule drugs.
DeFife: We anticipate that an increased focus on sustainability, reducing waste, and protecting the environment will play an even larger part in the CDMO industry over the next few years. The CDMO industry is already reacting to biopharma clients looking to partner with CDMOs who are embracing greener, safer and more efficient manufacturing operations from an early stage.
Biopharma outside of the COVID-19 market will have to find a way to ensure access to critical raw materials and components that are currently being directed towards governments under programs like Operation Warp Speed. The lead times for fill finish components now undoubtedly is longer than the operating runway of some innovator companies.
Many industries learned how quickly strategic and innovative shifts could be made that, pre-pandemic, would have involved pilot studies, staged rollouts, and slow uptake. Retaining the lessons learned and application to driving growth can, in fact, accelerate biopharmaceutical market growth as economies emerge from the pandemic.