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Delivering successful new drugs

Published on 01/03/16 at 12:48pm

Pharma companies are struggling with challenges specific to their industry. Patents for many drugs, that had created massive amounts of revenue — have expired, and more will be expected to do so in the coming years. Regulators and the public are asking pharma companies to produce and deliver more complex product portfolios at a lower cost, while continuing to meet rigorous quality necessities.

In the face of such challenges, pharma manufacturing has been slow to change, due to chief operating officers who have normally concentrated on making sure their high-margin products persisted in stock and met quality demands. For as long as manufacturing costs were kept within industry standards, operating chiefs didn’t give much thought to them. Additionally, changes in manufacturing processes often have regulatory consequences.

When looking at the sector’s opportunities, challenges and needs in connection to trends, products and technologies, we can see a true sense of what may affect the sector in short-, medium- and longer term progress. 

Continuous manufacturing

The pharmaceuticals industry is commonly viewed as technologically advanced. However, when it comes to manufacturing, it seems to be trapped in the past. The existing approaches of drug making, which are arguably labour intensive and unproductive, are usually based on batch processing which has been active since the middle ages of the 20th century and make pharmaceuticals progressively liable to contamination.

However, a new approach called continuous manufacturing is on the approach, potentially transforming the pharmaceutical sector. This shift has the potential to make drug manufacturing more efficient, less expensive, and more environmentally friendly.

Smaller lot sizes of drugs means delivering tailored, more effective treatments for conditions will become progressively important. The complexity of supply chains will also increase as the manufacturing of drug will move offshore or closer to the end user.  A more collaborative approach to product development involving partnerships with other companies or research centres will also multiply sourcing expertise and bringing them together. Building quality control into the design stage, called Quality by Design (QbD), which requires a more responsive regulation will also mean fewer errors. 

The act of tailoring drugs to individual genetic signatures requires complex therapies and formulations which in turn will mould the manufacturing industry, lowering prices. Alongside the other issues, patents for blockbuster drugs have always been an intense issue. The future of this will change when the increase of reduced revenues and increased competition will arise, or when product patents expire – whichever comes first. The system will also need to fit the evolving needs of an ageing population, which will mean a higher volume of specific drug manufacturing. 

Industry-led initiatives

All these changes arguably will create wealth for the UK. Earlier this year the UK government began funding new manufacturing partnerships that will improve design processes and supply chain initiatives to lift the UK life sciences sector.  The ABPI and the UK BioIndustry Association (BIA) have welcomed a government decision to fund a project to develop new digital design and processes for medicines that has the potential to make them significantly better, faster and safer.

The Medicines Manufacturing Industry Partnership (MMIP) was launched last year by the ABPI and BIA to bring together key industry bodies, and now this is the first time the project has borne fruit in the shape of a big funding round. Some of the key names involved in the movement are Pfizer, GlaxoSmithKline, AstraZeneca and Bristol-Myers Squibb. 

Likewise, a newly-launched major collaborative project is set to transform the UK pharmaceutical industry by enabling the manufacturing processes of the innovative medicines of the future to be designed digitally. 

The ADDoPT (Advanced Digital Design of Pharmaceutical Therapeutics) project addresses a key challenge for the pharmaceutical industry; getting new innovative medicines to market in the quickest and most cost-effective way possible to ensure access for patients. The collaboration will pursue this goal by developing and implementing advanced digital design techniques that eliminate non-viable drug candidate formulations as early as possible, streamlining design, development and manufacturing processes. 

ADDoPT is four-year collaboration between government, industry and academia.Led by Process Systems Enterprise and supported by the MMIP, it involves pharmaceutical companies Pfizer, GlaxoSmithKline, AstraZeneca and Bristol-Myers Squibb, as well as leading UK universities, research centres, and knowledge-driven technology SMEs. 

Alison Clough, acting chief executive of the ABPI, comments: “We welcome the Government’s commitment to continuing to develop the UK’s life sciences sector. This project will help to put the UK in a position to make innovative medicines available to UK patients more quickly by futureproofing our advanced pharmaceutical manufacturing sector. By reducing the risks associated with the manufacture of medicines we can provide the UK with a competitive advantage in a globally significant sector.” 

Her MMIP counterpart at the BIA, chief executive, Steve Bates, adds: “This is a great result for UK medicines manufacturing and I look forward to seeing the new technology being applied to biologics so that we can continue to address unmet patient need with the most innovatively designed and effective treatments possible.” 

ADDoPT builds on UK excellence in big data, mechanistic modelling, process optimisation and control to establish a highly competitive UK knowledge value supply chain for the pharmaceutical sector. It will incorporate ‘digital design,’ which combines research insight and mechanistic modelling to provide links between raw materials, formulation, manufacturing processes and drug product quality. It spans all operations, processes and procedures during the development and manufacture of medicines, and their in vivo application. 

These kinds of novel products, processes and services will be the future of high value manufacturing in the UK making a considerable impact on the ageing and fast growing population in the UK. This means design for manufacturing will need to be made easier allowing them to be produced more quickly. The act of tailoring also means manufacturing for personalised medicines – diagnosis and drug treatments tailored for each patient – will need to speed up. To improve the process, the use of existing and new data need be better along with a better understanding of the customer’s needs which can be found through data. 

Key technologies and capabilities required within the sector to enable the products, processes and services to be implemented would need the following changes. Multifunction equipment would be important with quick turnaround. A continuous amount of processing across a variety of platforms and unit operations would also need to be implemented. An appropriate process of controls and associated software and measurement would be needed to allow quality control, flexibility and small batch, complex processing. 

Attention will also need to be given to single-use components to speed-up product changeover and cleaning validation whilst better construction materials for components used in labs and production will be used to reduce breakdown and improve equipment design. The importance of multi-dose/multi-pack formats for medication to be reconfigured according to required dose and new approaches in synthetic biology to create both existing and new molecules will also need to be looked at. 

As the involvement of technology becomes enhanced, electronic prescribing data to reduce lead-time for drug manufacture following patient diagnosis will also help in the manufacturing process. Technologies also introduce supply chain errors and addressing by reducing costs and sustainability whilst being environmentally friendly. 

The influences that could enable these innovations to take place would be better sustainability metrics to inform manufacturing options with greater engagement with other process sectors to promote knowledge transfer. Improved communication between scientists, business and regulators will also need to be established to enable regulatory issues to be considered from an early stage. This will create engagement between researchers and the industry to support better technology transfers from applied and basic research to robust manufacturing development and commercialisation. 

New problems, new solutions

Other companies are taking the lead in the UK, with new initiatives to solve traditional drug delivery problems. Staffordshire-based ceramics company Lucideon is turning its hand to creating pharma solutions, and one of its flagship products is an edible ceramic pill, designed for the pharmaceutical industry.

Making ceramic coated pills could help solve the problem of opiate tablet addiction – a huge and growing problem in the US (see box) – by stopping opiate addicts from leaching the addictive substances out of the drugs using alcohol.

“Ceramics can be very porous,” explains Tony Kinsella, Lucideon chief executive. “We put the drug into the pores of the ceramic, which means it can’t dissolve in whisky. It will only come out when the material hits the stomach.”

These ceramic pills can’t be compromised – if you heat them to release the drug, the temperatures required to break down the material will burn off the opiates. Lucideon forecasts that this abuse deterrent will help the business to reach £100m in sales by 2018, up from £15m today. The same technology can also be used to manufacture slow-release drugs, allowing patients to take one pill a week instead of several.

New drug-delivery capsule may replace injections

Given a choice, most patients would prefer to take a drug orally instead of getting an injection. Unfortunately, many drugs, especially those made from large proteins, cannot be given as a pill because they get broken down in the stomach before they can be absorbed.

To help overcome that obstacle, researchers at MIT and Massachusetts General Hospital (MGH) have devised a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed. In animal studies, the team found that the capsule delivered insulin more efficiently than injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” says Giovanni Traverso, a research fellow at MIT’s Koch Institute for Integrative Cancer Research, a gastroenterologist at MGH, and one of the lead authors of the paper, which has been published in the Journal of Pharmaceutical Sciences.

Although the researchers tested their capsule with insulin, they anticipate that it would be most useful for delivering biopharmaceuticals such as antibodies, which are used to treat cancer and autoimmune disorders like arthritis and Crohn’s disease. This class of drugs, known as “biologics,” also includes vaccines, recombinant DNA, and RNA.

“The large size of these biologic drugs makes them non-absorbable. And before they even would be absorbed, they’re degraded in your GI tract by acids and enzymes that just eat up the molecules and make them inactive,” says Carl Schoellhammer, a graduate student in chemical engineering and a lead author of the paper.

Safe and effective delivery

The team has tried designing microparticles and nanoparticles that can deliver biologics, but such particles are expensive to produce and require a new version to be engineered for each drug.

Schoellhammer, Traverso, and their colleagues set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the GI tract. Their prototype acrylic capsule, 2 centimetres long and 1 centimetre in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 millimetres long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the GI tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload. It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found that the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of insulin was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Traverso says. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

“This is a very interesting approach,” says Samir Mitragotri, a professor of chemical engineering at the University of California at Santa Barbara who was not involved in the research. “Oral delivery of drugs is a major challenge, especially for protein drugs. There is tremendous motivation on various fronts for finding other ways to deliver drugs without using the standard needle and syringe.”

Further optimisation

This approach could also be used to administer vaccines that normally have to be injected, the researchers say.

The team now plans to modify the capsule so that peristalsis, or contractions of the digestive tract, would slowly squeeze the drug out of the capsule as it travels through the tract. They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimise any safety concern.

The researchers concluded in Journal of Pharmaceutical Sciences: “Here, we demonstrate proof-of-concept experiments in swine that microneedle-based delivery has the capacity for improved bioavailability of a biologically active macromolecule. Moreover, we show that microneedle-containing devices can be passed and excreted from the GI tract safely. These findings strongly support the success of implementation of microneedle technology for use in the GI tract.” The research was funded by the National Institutes of Health.

Embracing developments such as these will be vital if the industry is to adapt to the pressures it faces today. The healthcare industry is unstable. Spending on healthcare has been mounting, and numerous countries have presented creativities intended to bring costs under control.

Access to skills and knowledge, a robust legal system for the protection of Intellectual Property (IP), and world-class manufacturing capability have contributed to making progress in the discovery and development of new medicinal products.

In the recent past, the industry has been a highly successful centre in the area of large molecules and biological innovation. Future investment in the pharmaceutical manufacturing capability to exploit this success has to be encouraged to continue the industry’s success.

Lilian Anekwe

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