Demand for biological manufacturing is growing faster than capacity growth, and Emil Ciurczak forewarns the need for tighter quality controls in biosimilars production.
CPhI Worldwide – the world’s largest pharma event, taking place in Frankfurt, Germany (5-7 November, 2019) – releases the second part of its annual report focussed on biologicals.
Fittingly, in 2019 BioProduction – which features five concurrent streams of content covering the entire spectrum of biopharmaceutical development and production – will run alongside CPhI Worldwide for the first time, bringing together the entire pharma and biopharma supply chain.
In the report, experts Dawn Ecker, Director of bioTRAK® Database Services with BPTG (BioProcess Technology Group, BDO USA, LLP), and Emil. W. Ciurczak, President of Doramaxx Consulting, explore the near- and medium-term trends in the industry. In particular, the report forecasts the biologics industry’s ability to meet and keep pace with future manufacturing capacity concerns, as well as evaluating the current state of quality control in bio – with an emphasis on concerns about CQAs (critical quality attributes) in biosimilars.
Dawn M. Ecker, having analysed the global biopharmaceutical industry’s production, predicts that Europe will possess the world’s largest biologics manufacturing capacity within the next four years – a feat currently owned by the USA. Europe’s capacity is growing more quickly year-on-year, and it is expected to increase by 15% come 2023. This growth is helping loosen capacity constraints in the continent in the short term. Asia is also identified as likely to have substantial growth until 2023, with 9% growth per annum. One of the key drivers behind the recent growth in building new capacity has been a number of notable government initiatives and tax incentives in countries such as Ireland, Singapore, and South Korea.
Ecker explains that the growing manufacturing demand – driven by the increasing number of commercially approved biologics – will see the sector significantly expand volumetric capacity. However, much of the new capacity coming online is from CMOs and hybrid companies, who will in turn increase their respective market shares in biologics manufacturing. “Our analysis shows the 2018 mammalian cell culture supply to be nearly 4,400kL and we predict it will grow to nearly 6,400kL by 2023, a 5-year growth rate of 8%. Currently, product companies control over 70% of the installed mammalian cell culture capacity, but this is predicted to drop to 65% by 2023, with CMO capacity increasing 6%, and hybrid companies increasing 1%, respectively.” Commented Ecker.
In the current forecast parameters, one of the key variables that could potentially lead to greater shortfalls in available capacity would be a high rate of approvals for certain bio-drugs. Such biologics include those that are being used to treat Alzheimer’s disease and cancers, and they may achieve regulatory approval and financial backing from healthcare organisations sooner than expected. “Should several of these large-demand products (e.g PDL/PDL-1 checkpoint inhibitors for broad cancer treatments) obtain regulatory approval and adequate reimbursement by healthcare oversight organizations, a significant increase in demand for manufacturing capacity could occur quickly, potentially leading to a serious capacity shortage.” Adding further variables to this prediction, Ecker suggests that projected increases in volumetric demand remain ‘volatile’, seeing as the sector could tilt towards producing ‘more potent products, such as ADCs or bispecific bodies’, which require substantially less product demand.
One product group contributing to future capacity demand are biosimilars, Emil Ciurczak explores the impact of the increasing number of biosimilars becoming available, as well as the long-term implications of slight differences in manufacturing approaches. He argues that biosimilar production accentuates the risk of potentially hazardous side products, as, unlike generics, biological impurities could include unknown proteins. As the biology behind rare diseases become more transparent, the biologics developed to treat such diseases – and their synthesis routes – are becoming more complicated. This has significant implications for quality assurance, as both the production and degradation (once in the body) of these molecules can produce a plethora of potentially toxic by-products.
“All impurities in APIs are critical, but with biological impurities (often proteins, not seen previously), the stakes are potentially higher. Not only are there potential long-term carcinogenicity and mutagenicity dangers, but, with unknown proteins, there are also potential immediate allergic reactions. Long-term use of bio-drugs, such as insulin, which could be used for decades, could be of high risk without proper quality control, as even the smallest impurity could do harm to the patient over these extended periods of time.” Comments Ciurczak.
He also highlights that biosimilars are just as hard to commercialise as the original products, due to the fact that generic and initiator companies may utilise different biosynthetic pathways, which could result in the formation of different ‘exotic’ by-products. Ciurczak explains “Competition has arisen for production of biologics from secondary companies, producing the ‘same’ active molecule, but from a different synthesis/bio-expression route. While the major active ingredient may be identical to the patented one, any biological process expresses numerous proteins, each particular to the mode of expression…the most problematic feature of any biosimilar will be the side products and potential side effects.”
Looking ahead, Ciurczak predicts that regulators will seek to harmonise their guidances and rules regarding the assessment of critical quality attributes (CQAs) for biologics, with the common goal of expediting production time and therefore time-to-market. He states that we are already seeing such changes beginning to take place – with regulators ‘peaking over each other’s shoulders when writing guidances and rules’, and newer documents becoming increasingly standardised.
CPhI Brand Director Europe, Orhan Caglayan, commented “Our experts suggest that biologics manufacturing is evolving in conjunction with the development of new and exciting bio-products, which we hope will be of fantastic benefit to sufferers of rare diseases. These findings are particularly striking given the introduction of the BioProduction Congress at this year’s event, which will concentrate on the manufacturing and processing of biopharmaceuticals. There has never been a better time for all players within the biopharma space to attend CPhI Worldwide, as the Congress promises to keep you up to date with the latest trends across the biologics supply chain. In particular, the forecast manufacturing capacity constraints may well put CDMOs under pressure, and meeting supply chain partners early at events like CPhI and BioProduction will be essential to securing your supply chain and advancing with products more expeditiously.”
Summary of trends
Dawn M. Ecker, Director of bioTRAK®
Database services with BPTG, BDO USA, LLP
Trends Overview 2019-2023
- Demand for biologics manufacturing by volume is projected to reach over 4,200kL, a 5-year growth rate of over 10% per year (just over 2,500kL in 2018).
- If Alzheimer’s drugs and PDL/PDL-1 checkpoint inhibitors are approved, demand could be much higher resulting in capacity shortages.
- Global biologics manufacturing capacity will increase to 6,400kL by 2023 from nearly 4,400kL in 2018
- CMO/hybrid companies increase their control of capacity from 28% in 2018 to 36% in 2023
- By 2023, Europe will have capacity at least equivalent to North America. Capacity in Asia continues to grow.
- Half of products in late phase development (Phase 2, Phase 3) can be met by a single 2,000 or 5,000L bioreactor.
- Overall capacity should experience some loosening in short-term constraints but may tighten after 2023. With the majority of capacity remaining in-house, it may be difficult for companies with products in development, but without internal manufacturing, to access capacity at the right time and under the right terms.
Emil. W. Ciurczak, President of Doramaxx Consulting
Quality control overview
- The increasing complexity of biologics must see a parallel increase in quality control due to the nature of the products and manufacturing processes
- Biological systems used to manufacture biologics require greater environmental control and an aqueous solution compared to standard chemical reactors
- Analytical tools for real-time quality control of biologics manufacturing are only starting to surface now
- Impurities and by-products from biologics manufacturing are likely to be more harmful than those forming from pharmaceutical products
- Clinical and nonclinical data can be used to rank product qualities in order of importance when performing risk assessments on biosimilars
- Biologics possess much more complex synthetic and degradative pathways, which could produce a wider range of by-products that must be accounted for in risk assessment