Recent events have underlined the need for pharmaceutical innovation and are encouraging more inventive and holistic approaches, reports Brian Attwood.
The European Patent Office’s annual reports reveals that, within the United Kingdom and the process industries, the pharmaceutical sector has maintained its place as a major source of innovation.
In all it was responsible for 293 new patents last year. That was a substantial increase from the impressive 268 filed over the previous 12 months, representing an overall increase of 9.3%.
Granted, that’s a fraction of the number of global pharma- ceutical patent applications in 2019 which topped 7,697 – with the USA contributing more than 3,000 and achieving a year on year rise of 145 or 4.4%.
Yet the UK achieved more than double the worldwide percentage rise (of 4.4%) as well as outperforming stalwarts such as Switzerland and Germany.
Far from denting this achievement, the likelihood is that the battle to combat Coronavirus will prompt more investment suggests Paul Chapman, partner at leading intellectual property firm Marks & Clerk: “As the ongoing Coronavirus pandemic demonstrates, innovation is key to the pharmaceutical sector... to meet the challenge posed by novel pathogens, such as Covid-19.
“Today, the challenges faced by the pharma sector are quite different to those it was faced with even a few months ago. As economies across the globe come grinding to a halt, the pharma industry has been thrust into the spotlight.”
Covid versus cliff
A key challenge is that, as demand for pharmaceutical products attributable to a new and unforeseen pandemic grows, so the industry must contend with the ever-present limitations on supply presented by the so-called ‘patent cliff ’.
This phenomenon occurs when patents for blockbuster drugs expire but no new drugs come on the market to replace their role. The result, says Daryl Thompson, director of Scientific Initiatives and founder of Global Research and Discovery Group Sciences, is that pharmaceutical companies experience an abrupt decrease in revenue, reducing overall innovation globally, including the crucial research into new methods to prevent and treat illnesses.
“The patent cliff represents a significant crisis in pharmaceutical innovation. The primary cause of the crisis is that most techniques for modifying natural molecules to pharmaceutical grade products are essentially played out.”
Most of the methods to make drugs, he asserts, have already been published in scientific papers or rationalised in long expired patents and these methods can render the development of new, novel compounds unpatentable.
“Previous strategies for increasing the potency of a natural compound to pharmaceutically therapeutic levels... typically included standard practices such as altering functional groups, the addition or substitution of halogens and or the inclusion of lipid structures,” he continues.
“The challenges faced by the pharma sector are quite different to those it was faced with even a few months ago. As economies across the globe come grinding to a halt, the pharma industry has been thrust into the spotlight
Paul Chapman, partner, Marks & Clerk
Unfortunately, these effective techniques are undermined due to lack of patentability due to prior disclosure, says Thompson. Consequently, there is a heavy financial impact with the medium cost of bringing a single new drug to market today pushing close to US$1 billion.
His company is adopting a different route, partnering the Singaporean eDevelopment subsidiary Impact Biomedical in the creation of the research solution Quantum. The aim, he describes, is to boost the efficacy and persistence of natural compounds and existing drugs while maintaining the safety profile of the original molecules.
“Instead of modifying functional groups, as is typically done presently in drug discovery, this new technique alters the behaviour of molecules at the sub-molecular level. We will be moving past macro-molecular techniques and going deeper into the sub-atomic. Here we can look at molecular modification from the perspective of quantum physics.
“Quantum molecular modifications approach this problem from the perspective of manipulating the sub-atomic electron balance as a whole in consideration of the sum of both kinetic and potential energies within the molecular state.”
While the claim that this could permit a virtually endless array of methods to allow new drug discoveries might sound ambitious, the partners say they expect to deliver the first six Quantum molecules to research institutes “within three business quarters”.
Thinking inside the box
Innovation in pharmaceuticals need not focus always on being outside the box, however. Recognising the primacy of research in underwriting innovation, Aston Particle Technologies (APT) boosted its capabilities by investing in a means to overcome the challenge involved in scaling up small powder blending projects into commercially realisable approaches.
Says APT’s founder and CTO Professor Afzal Mohammed: “One of the challenges when working with conventional powder blending technologies is that there is almost no correlation between small and large-scale equipment, which means most development work takes place on a larger scale.”
While working in collaboration with automation consultancy GB Innomech, the latter firm succeeded in reproducing APT’s one-step particle engineering technology on a small scale: to enable ‘challenging’ active pharmaceutical powders to be dry powder coated onto carrier particles.
This was done by designing two benchtop systems to prepare small quantities of blended powders for use in its formulation development projects for pharmaceutical companies. The systems can be used to prepare up to tens of grams of blended materials but use exactly the same process technology, conditions and recipe-based control system as the company’s two kilogram pilot-scale production unit.
When a development partner selects which formulations to progress, APT can transfer the process conditions into its pilot-scale system to start producing the blended material in kilogram quantities for more extensive R&D studies, outlines Mohammed.
“The new units will enable us to work at a smaller scale, on a larger number of commercial projects and to more closely align our formulation development activities with the needs of our pharmaceutical industry partners. As a result, we can also develop multiple prototype formulations and at an earlier stage when pharmaceutical companies have typically only got small quantities of key ingredients available,” says Mohammed.
Small quantities can be made for proof of principle studies before a pharmaceutical company buys in bulk quantities or scales up its synthesis of specific ingredients.
Digi-pros and cons
As in every process sector, it is the effective harnessing of Big Data that will allow incremental changes in pharmaceutical production. This is of particular relevance with regards to transitioning from batch production – whereby goods are produced in multiple, separate units that require downtime for quality controls – to uninterrupted continuous manufacturing.
Traditional quality by testing (QbT) approaches involve testing the material being processed after every manufacturing stage to ensure that the critical quality attributes (CQAs) are in line with specifications, stopping to collect samples and conduct testing. This cannot be reconciled with the principles of continuous manufacturing, says Martin Gadsby, director at Optimal Industrial Technologies.
By contrast he says: “Quality by Design (QbD) relies on the principle that product quality should be designed into the process, rather than tested in stages and corrected afterwards.
“A responsive system, featuring real-time monitoring of product CQAs and adjustment of critical process parameters (CPPs), allows plant operators to obtain consistent and quality compliant products while reducing the likelihood of re-work or rejects.”
Process analytical technology (PAT), continues Gadsby, provides structure for measuring product quality in real time.
PAT typically uses a range of spectral (multivariate) and univariate data sources together with prediction engines to make real-time product quality predictions. These are at multiple points within a continuous process in order to achieve a holistic, QbD quality system. Analytics are performed online and in real time, as the process takes place, so there is no need to stop production to perform quality testing.
Fortunately, batch processing can accommodate QbD and PAT, enabling manufacturers to test first on relatively small and simple processes before opting for wider adoption.
However, there are particular aspects that cannot easily be solved in a digital embrace, cautions Chris Johnson, managing director of ceramics bearings supplier SMB Bearings: “Plant maintenance is no easy feat, particularly in complex facilities like that of pharmaceutical production.”
He cites the computerised maintenance management systems (CMMS) now being deployed to store and analyse condition monitoring data for predictive maintenance. Vibration analysis might be employed to monitor the performance of a bearing on an industrial mixer integral to the production of pharmaceutical products.
“Taking data acquired during vibration analysis, the CMMS can intelligently predict when the bearing might fail by extrapolating the performance over several future batches of production. This intelligence can allow engineers to tackle the problem – in this case, a deteriorating bearing – and replace it before its failure causes unplanned downtime,” outlines Johnson.
Plant maintenance is no easy feat, particularly in complex facilities like that of pharmaceutical production
Chris Johnson, managing director, SMB Bearings
Maintenance engineers may discover the range of equipment on the factory floor would require hours of training for them to completely understand every detail. In pharmaceutical manufacturing, this challenge is heightened by regulations, as well as the presence of corrosive and chemical ingredients.
Thus, cheaper stainless steel bearing might replace a ceramic product of the same diameter, because steel bearings tend to be cheaper, these varieties are more likely to be held in inventory in order to reduce downtime length.
“In highly corrosive environments, choosing the correct material is incredibly important. While full ceramic bearings offer outstanding levels of corrosion resistance, some steel varieties cannot withstand the aggressive environments that are commonplace in pharmaceutical manufacturing, including those that operate inside an industrial mixer,” warns Johnson.
Hardness and speed are also relevant factors. Ceramic bearings tend to be up to 30% harder than steel, which improves their durability. However, the material is also much more brittle, meaning ceramic varieties cannot handle the same loads as steel versions. Do CMMSs factor in the properties of different bearing materials when analysing and forecasting equipment health, queries Johnson?
“Computerised software might be beneficial for planning factory maintenance, but engineers cannot rely on digital tools to effectively maintain complicated facilities. Pharmaceutical production certainly falls into the category of complicated manufacturing and while regulation in the industry is incredibly rigorous, we need to ensure component maintenance is too.”
