New technologies such as artificial intelligence (AI) could revolutionise pharmaceutical manufacturing but only if regulators change to prevent hindering future innovation.
Drug Manufacturing
According to Bikash Chatterjee, president and chief science officer (CSO) at Pharmtech Associates, technologies including pharma 4.0, the Internet of Things (IoT) and AI could ultimately deliver huge shifts in how we discover and develop medicines – even if the short-term applications may not bring the results people are striving for.
The statement comes as part of the CPhI Worldwide 2019 Annual Report, which includes a number of experts commenting on the state of global pharmaceutical manufacturing.
“There is no doubt we will see broader adoption of IoT on the shop floor and in the distribution portion of the supply chain in the short term. The biggest impact operationally, I believe, will be seen in the clinical trial management stage of the drug development lifecycle, over the next five years. However over the next decade, AI could have a transformational impact on molecular selection and design,” Chatterjee writes in the CPhI Worldwide 2019 Annual Report.
In particular, Chatterjee envisages AI being used to deliver significant changes in therapies by 2040, when ‘it will be standard practice in the design of drug therapies, their processes and in the treatment of disease’. He predicts that ultimately this will mean personalising dosing and drugs regimens designed around each patient’s genetic markers and circumstances.
However, in order to achieve this drug developers and AI companies need to understand each other better if they are to expedite the process of disruptive technology adoption.
Exploring the cost of manufacturing and the current high levels of regulatory infringements Girish Malhotra, president of EPCOT International, believes that regulators should use powers to remove Abbreviated New Drug Applications (ANDAs) for repeat offenders.
“With USFDA being short staffed, even the use of ‘risk-based inspections’ may be insufficient to catch less than quality/cGMP producers,” Malhotra says. Adding “repeated non-compliance to FDA’s requirements and guidelines should be a cause to forbid shipments to the United States.”
Additionally, he suggests a 90-day approval process, which will necessitate that companies filing applications have complete command of every facet of manufacturing, product quality, and labelling.
Taking this a step further, he also advocates enforcing mandatory deposits (circa $200,000) for first deviation from FDA’s expectations, with forfeiture of the deposit and, ultimately, being barred from importing into the United States should further problems occur.
Fundamental to Malhotra’s regulatory proposals is the proposition that governing bodies should stick to enforcement - not preach to the market on how best to implement manufacturing processes.
“The FDA should refrain from suggesting to companies what types of manufacturing processes (batch or continuous) they need or practice, instead they should concentrate on helping ensure manufacturing processes are repeatable using continuous improvement principles,” Malhotra added.
Within biologics, the report forecasts the 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.
In the report, expert Dawn Ecker, director of bioTRAK Database Services 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.
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.
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 as those for Alzheimer’s disease and cancers.
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 organisations, 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.
Biosimilars too may contribute to future capacity demand with Emil Ciurczak, president of Doramaxx Consulting, arguing that biosimilar production accentuates the risk of potentially hazardous side products. 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.
Looking ahead, Ciurczak predicts that regulators will seek to harmonise their guidance 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.
Another area the report highlights is the growing opportunities for CDMOs in cell and gene therapies, as well as the needed capacity expansions to meet China’s burgeoning demand.
Michael E. Ultee of Ulteemit BioConsulting forecasts that manufacturing in biopharma is now entering a new age of advanced processes whereby the overall cost of production could potentially begin to fall. He says that in five-year’s time with the new processes now being applied, “manufacturing will become more efficient and cost savings will be delivered. Furthermore, economic pressure from biosimilars will push manufactures of these types of therapeutics towards lower costs.” In fact, Ultee suggests that many of the manufacturing challenges with biosimilars have been overcome and that hurdles to wider patient access are chiefly due to patent walls and litigation.
In advanced therapies, a lack of cell and gene expertise is now already causing potential issues in the clinical progress of many therapies, and there is a scramble for the most capable development partners, despite many CDMOs investing in capabilities. “There is already a shortage of CDMO services for this type of work. The high valuations shown by recent acquisitions of CDMOs, such as Brammer Bio and Paragon Bioservices, bear this out. I expect the shortage to continue for the next few years until more development and manufacturing scientists are trained in this new discipline and CDMOs expand their offerings,” adds Ultee.
The implications of these new targets is that there will be a realignment over the next one to three years in the areas of cancer and rare-disease therapies – with a greater focus on cell and gene therapies rather than recombinant proteins.
China’s market too is noted in the report as being on the rise. Vicky Qing Xia of BioPlan Associates notes that by 2021 at a CAGR of 16%, the biologics market in China may reach $50bn. Similarly, regulatory reforms – such as the MAH pilot – are seeing a bio services market growing even faster at above 30%, and forecast to reach $1.4bn by 2021. Qing Xia attributes this growth to several advanced players (primarily serving western customers) – notably WuXi Biologics, MabPlex, CMab and JHL biotech.
However, Qing Xia also believes there may be a good degree of flux in the market predictions, particularly as new products transition between clinical and commercial supply, adding: “Many of the VC-backed developers would seek IPO, and Chinese investors are known to value fixed assets such as land, facility over IP and product portfolio. We see many developers outsource pilot-scale production, but they would then plan to build their own facilities when their project goes to late clinical stage.”
Tara Dougal, head of Content at Informa, says: “What our expert’s analysis shows is that we are at a really significant point for the supply chain, as new technologies help bring about improved manufacturing processes. It is also a big focus at both CPhI Worldwide and BioProduction this year and much of our content and, of our course, networking opportunities are designed to empower both exhibitors and attendees to meet partners that will help them prepare and deliver new solutions to help the industry expand in the next few years. Additionally, P-MEC is also showcasing all of the global technologies to help deliver new manufacturing methodologies and sustain the growth predicted in contract services for both solid dose and biological drugs.”