CHANGING THE WAY MEDICINES ARE CREATED TO BEAT COVID-19 AND FUTURE PANDEMICS AND ENSURE WE MAKE DRUGS PEOPLENEED, NOT JUST WHAT MAKES THE MOST PROFIT.

New initiative aims to return to days where patients came first, and physicians led the charge

A panel of eminent healthcare experts (see APPENDIX) have come together to change the way medicines are created, spurred on by the industry’s chaotic response to the CoViD-19 pandemic which has revealed disjointed and chaotic supply chains, over-reliance on overseas products and raw materials, a reluctance to work with UK businesses, inadequate forward planning, duplicated and sometimes flawed clinical trials, chronic PPE shortages compounded by breakdown of transport links and an inability for government to comprehend the scale of use; even the manipulation of statistics to massage figures. These have drawn attention to a medicines (pharmaceuticals) system that for many years has put profits before benefits and is now on life-support  

The problem starts when molecules can be patented then shelved to prevent competition. Drug discovery uses a ‘shotgun’ approach, making trials onerous, expensive and time consuming. Promising drugs are held back to maximise profits from existing products. Only a handful of medics are involved in a drug development process, so healthcare professionals only see a new drug when their drug rep calls. They have no opportunity to give guidance on what patients actually need. 

Difficulties like these are compounded by major pharma companies outsourcing nearly all their product development, manufacturing and distribution capability over the last 40 years, while moving offshore (mainly China) to save on the cost of their raw materials and intermediate products. 

The problems are epitomised by the hundreds of companies currently competing against each other to manufacture a vaccine, with huge financial gains for the winner. These mRNA ‘fast track’ vaccines using assembled genetic code rather than immobilised virus originated in early 1990s, but have never been approved for use in humans due to safety concerns and poor profit potential. No-one has ever succeeded before in developing a coronavirus vaccine, despite the huge profit to be made with a cure for the common cold. No-one can predict whether a vaccine will emerge that may or may not be of use, or one that if rushed, may do more harm than good. Yet government strategy seems to be reliant on such a vaccine being successful. 

Recently the UN Chief, Antonio Guterres called for global collaboration within the pharmaceutical industry, stating – “We need an ambitious effort to ensure that international stakeholders operate through a harmonized, integrated and leveraged approach to maximize the speed and scale needed for the universal deployment of such a vaccine by the end of 2020.”

The time is right for our panel of eminent healthcare experts to facilitate change and breathe new life into an ailing system.

How will we achieve this? 

 Hedley Rees, CEO of life science supply chain management consultancy, PharmaFlow, and Wiley author on the topic, says: I completely agree with the UN Chief Guterres.

“We want to start by showing that the current business models have not helped the majority in the past; why are we in a race and not helping each other”?

We will create educational packages for students wanting to apply their STEM skills and pursue a career in medicines starting at GCSE level. Then we have packages through A-Level, undergraduate, graduate, up to existing medics, scientists, pharmacists and engineers – we aim to instil a culture of collaboration and integration into this crucially important industry.

We will lobby decision-makers, government, learned bodies and trade organisations. We will explain how to unravel complex supply chains, highlighting the focus on patents not patients, and the harm and damage this is causing. We will show them a completely different way that has a proven track record of working. 

Hedley aims to bring back the old ways of medicinal discovery, where patients were put first, alongside the input from medics with all the benefits of modern science and technologies – erasing the ‘blockbuster for profit’ model that is showing less and less returns, and replacing it with tried and tested methodology for providing drugs that target real illnesses, diseases and ailments. 

The team of experts have proven track records in all aspects of pharma, including materials, manufacturing, clinical trials, testing, quality and marketing, as well as experience of expert systems, production control, the latest technologies etc., and can drive the project in whatever direction is most appropriate to help pharmaceutical companies make medicines that benefit society and by doing so become major income streams. 

A KICKSTARTER CROWDFUND HAS BEEN LAUNCHED TO HELP BRING THIS PROJECT TO LIFE.

Travelling back in time to ‘meet’ Dr Alexander Fleming, August 1928

Using Kickstarter as the funding mechanism, Hedley aims to raise £35,000. This will provide him and his highly experienced team the funds and the time to create digital educational packages that will take medicines back to the future, to the days of collaboration, but with new technologies, knowledge and ways of thinking, The Kickstarter crowdfund has been launched to help bring this project to life.

VIEW KICKSTARTER

Notes to Editors

Contact: h.rees@pharmaflowltd.com or call +44 7734 961726 for further details.

About Hedley Rees, CEO PharmaFlow, author of Wiley’s Supply Chain Management in the Drug Industry; Delivering Patient Value for Pharmaceuticals and Biologics and Taming the Big Pharma Monster, leader of this important initiative.

Hedley Rees is an author and CEO of PharmaFlow Limited, a UK based consultancy specialising in operations and supply chain management within life science.

Hedley held senior positions at Bayer UK, British Biotech, Vernalis, Ortho-Clinical Diagnostics (formerly Johnson & Johnson) and OSI Pharmaceuticals (now Astellas).

His skill set covers the range of competencies from strategic procurement, production and inventory control, distribution logistics, information systems and improvement.

Hedley is a zealous advocate of the regulatory modernisation frameworks of FDA’s 21st Century Modernization (Janet Woodcock MD) and the International Council for Harmonisation (ICH). He graduated from the University of Wales as a production engineer and holds an Executive MBA from Cranfield University School of Management. Hedley lives in Bridgend, South Wales.

• People treated as individuals with prevention, diagnostic and therapy needs.
• If medicine needed, healthcare professionals (HCPs) involved at the start.
• Involve all the professions needed to develop a medicine AT THE BEGINNING.
• Remove the brick-wall between discovery and development, to make it one group titled ‘DESIGN’.
• Group develops prototypes to be tested for suitability for patients and HCPs.
• Supply chains should be designed strategically, making them simple and streamlined.

Is quality by design (QbD) in pharma only for gifted scientists?

These days in pharma development circles, hardly a day goes by without mention of quality by design (QbD). Who is doing it properly? Is it too expensive? What is the business case? Can small companies afford it? How do we get executive management interested?

You could be forgiven for believing QbD is some kind of complex hybrid mix of rocket science and nuclear fusion, territory reserved for the scientifically gifted only. This is not the case of course, and in this article I hope to convince you so, especially if you are one of the scientific cognoscenti wrestling with the issues and opportunities of QbD.

What did the regulators Intend?

Many will be familiar with the famous Modernization words of Dr Janet Woodcock, Director CDER at FDA [1], now seemly lost in the mists of time, pleading for:

“A maximally efficient, agile, flexible pharmaceutical manufacturing sector without
extensive regulatory oversight.”

Nearly 20 years on, who would argue we are even close to that goal? Certainly no-one I talk to. The reason to me is clear—the industry has totally missed the intention behind the words—to make your products in the same way as those companies demonstrating outstanding outputs from their production systems. Yes, production systems; and this is where we are stuck.

Science doesn’t understand the notion of making products for customer markets. It is, of course, a vitally important part of the mix, but it is not the cake itself . . . the production system makes the cake and delivers it to customers. So if you are wrapped up in design space, process validation, process analytical technology, design of experiments, etc, spare a thought for the rest of it. The regulators intended it that way.

Importance of the production system (PS)

A word about a Production System (PS). The Toyota Production System (and others similar) was spawned from the work of Shewhart, Deming and Juran et al in the late 50s and 60s, helping those companies introduce increasingly effective ways to produce products for customer markets that were “fit for purpose.” When the NUMMI study in the 1980s investigated what they had achieved, they discovered a completely different way of working compared with the hitherto mass production paradigm.

These findings subsequently became reported in the western world as Lean Production and were recorded in the now famous book “The Machine That Changed the World” [2]. There were several absolutely fundamental differences between this way of working and what the lean fraternity  dubbed the process village—producing to a “batch and queue” mentality. Firstly, they were fanatical about understanding what their customers “value for money” needs were—what they were willing to pay for, and importantly, what they were not.

Then they aligned the PS to deliver that value and relentlessly eradicated the non-value adding activities; and this is where the critical lesson for Pharma and QbD lay—they designed an end-to-end value stream for a defined product family in early development; this was operated in close synchronization across the value stream and processes/equipment were joined up. By joining their processes, it took away the cosy blanket of being able to run a machine to bulk, oblivious to the need of the downstream process.

They had to solve the problems where, for example, the components fed from an upstream activity (and that could be a third party supplier) contained defects that could not be accommodated by the downstream operation. That meant also, involving and developing their suppliers, and even their suppliers, so that the PS improved continuously over time, resulting in the superior quality, cost and delivery leadtime performance we have come to expect from the best companies in the field.

In summary, they created a tight system of people, processes and technology working in unison and joined up from beginning to end. Interestingly, much a Deming’s work was on the subject of systems [3] and yet we see little of it in the Pharma world.

What Does This Mean for QbD?

It means that it is not enough to attempt to optimize the existing paradigm of mass production that exists in this sector; it needs a fundamental shift in mindset. For example, if a product has been developed using materials that have some basic incompatibility with the downstream process being PAT’d (PAT = process analytical technology), the answer does not necessarily reside in better
technology on the line; it may lay in involving the supplier at the development stage to identify a better characterized material. This is a supplier relationship issue and is an example of how “the system” is such an important element. If we now take the example above, the critical need for a systems approach to QbD begins to emerge. Because of the interconnected, interdependent nature of Production Systems, cause and effect are rarely in the same place [4]. The effect of high defect rates, for example, can often be traced back to issues locked-in very early on in development.

When we trace back to those early days in development, we often see thinking processes devoid of downstream considerations.

What Needs to Change?

The systems world tells us that effective change for the better (Kaizen in Lean parlance) can only be achieved by attacking cause rather than effect. So, what is the cause? In my opinion it is the fact that, historically, Pharma has had a deeprooted mind-set that aims to answer the question: “How can I invent a miraculous new treatment for an unmet medical need?” To redress the effect of
this (total ignorance of the process of bringing products to customer markets) the industry needs to answer the question: “How can I make a difference to this person’s life so that they will come to me rather than my competitors?” When asking that question, you instantly focus on the source of your long-term success, satisfying patient needs; and then you do what every other successful
sector does to stay in business—align the entire organization with delivering the customer value position. How many drug development organizations are thus focused? Not many, if any, I suspect.
This is where the change has to take place, in early stage drug development, where all the manufacturing data begins to become hard coded—processes, suppliers, specifications, analytical methods, etc., and registered in the CMC package (CTD Module 3). Those downstream of this can only ever be grappling with the “foliage” of the problem. In the famous words of Henry David Thoreau:

“For every thousand people hacking at the leaves of evil, there is one striking at the roots.”

If you haven’t already done so, why not join me, make your way down to the long-term source of QbD success?

References

1. Pharmaceutical cGMP’s for the 21st Century – A Risk-Based Approach. FDA
website
2. James P Womack, Daniel T Jones and Daniel Roos, “The Machine That Changed the World, Simon & Shuster, New York, 2007.
3. W Edwards Deming, The New Economics of Industry, Government, Education, 2nd Ed
4. Hedley Rees “Supply Chain Management in the Drug Industry: Delivering Patient Value for Pharmaceuticals and Biologics, J. Wiley, NJ, 2011 PP 357 – 362.

Officionardos of Quality by Design (QbD) in Pharma should be moving their line of sight, at least initially, away from the compounds they are studying, on to those using the medicines they help develop and produce – healthcare professionals (HCPs).

Note, patients aren’t mentioned. When you are a passenger in an aircraft, you don’t feel you want to have helped with the development of it, you trust the manufacturer has consulted enough pilots. It could be the same in Pharma, with HCPs co-developing the medicines destined for market. Here is a simple diagram that explains the principle:

• Disease treated holistically; prevention/diagnosis/therapy are inextricably linked.
• If medicine is required, we need early engagement of a representative number of HCPs with deep knowledge of the indication (disease state)
• Involve more stakeholders at concept stage.
• Include payers, commercial manufacturing, suppliers, patient groups and charities (if relevant to VOC.)
• Integrate the ‘discovery research’ and ‘development’ functions into a single design function, working closely with final product manufacture and supply.
• Make prototyping an essential responsibility of design, to cut attrition rates, reduce time to market and significantly reduce testing in animals.
• Plan supply chain architecture strategically, optimising quality, cost and speed to market, by striking alliances with key suppliers and other supply chain partners.

So, if you work in the field of QbD, try shaking hands with the HCP fraternity!

If you wish to learn more, you will find it in TAMING THE BIG PHARMA MONSTER

Published by Hedley Rees

Managing Director PharmaFlow Ltd, UK

The penicillin story is well known. For those that need reminding, the mother of all antibiotics was discovered in 1928 by Alexander Fleming. On his return from holiday, he noticed that in one of his agar plates, bacteria had not grown. He obtained an extract from the mould in the plate, naming it ‘penicillium‘. The rest is history…or is it?

…actually, no. The REAL story goes like this[i].

Fleming did not have the wherewithal to properly identify the mould strain or make it in any quantity. It took a team at Oxford University, headed by a gentleman named Howard Florey, to purify enough penicillin to run pre-clinical (1939) and clinical (1941) studies. They were a great success, but they didn’t know how to make sufficient quantities to supply the market.

In 1941, Florey and a fungal expert, Norman Heatley, visited the US to mull over the problem. The scenario was put to a microbiologist named Andrew J Moyer, an expert in moulds, working at USDAs Northern Regional Research Laboratory in Peoria, Illinois. He and his team came up with the idea “to culture the penicillin in a mixture of corn steep liquor and lactose, thereby greatly increasing the yields and production rate.”[ii]

Moyer applied for a patent in May 1945, which was awarded three years later.[iii] He was inducted into the National Inventors Hall of Fame in 1987.

So why did the myth persist?

An article in The Times reported the breakthrough in Oxford, but failed to mention Fleming or Florey. Fleming’s boss wrote to The Times, extolling his virtues and Fleming talked freely to the press at the time. Florey didn’t say a dicky bird to the press. So the real account of it was never told.

To paraphrase, the whole story goes like this:

• Fleming discovered a mould he called penicillium, but couldn’t characterize it.
• Florey’s team in Oxford isolated and purified enough to make test quantities, but they couldn’t make it any more than gram quantities
• A J Moyer’s team devised the commercial process to make penicillin in exponentially greater quantities, and patented THE PROCESS NOT THE MOLECULE.

So what is the takeaway here? Patenting a process seems fair, as a lot of work had gone into proving it could work. Until then, awarding patents for molecules is bad for patients, if no effort has gone into collecting evidence the molecule could get to market.

The other important takeaway is if Fleming, Florey’s team and Moyer’s team had been together from the start, it would have taken roughly three years from start to finish, instead of the fifteen years it actually took – five times faster!

Fast forward to the industry as it is today. Based on his discovery, Fleming would have patented as many molecular structures as he possibly could, in the hope that one of them was the magic bullet. His chances of finding it would have been almost zilch; one in 10,000 according to the US Government Accountability Office. He would have selected 250 of those molecules and got five to testing in the clinic (the other 245 go in the bin). The one that got to market would probably not have been penicillin, rather a poor relation with the bones marketed out of it.

Let’s reflect on this then.

If Fleming HAD patented his discovery, penicillin and all its many derivatives would not have seen the light of day. He didn’t have the faintest idea how to identify the active ingredient (molecule) or make it for patient use.

Ask yourself, based on the evidence above, does it REALLY make sense to award patents to molecules? How many other ‘penicillin’s’ remain unavailable to the world because a patent stopped others  having a go with that same molecule?

We have to change patent law. find out more in Taming the Big Pharma Monster, by Speaking Truth to Power

References:

[i] Gaynes R. The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use. Emerg Infect Dis. 2017;23(5):849-853.

https://dx.doi.org/10.3201/eid2305.161556

[ii] “Historical Patents – The Automobile and Penicillin”, Article One Partners

https://www.articleonepartners.com/blog/historical-patents-the-automobile-and-penicillin/

[iii] “Method for production of penicillin: US 2442141 A”, Google

http://www.google.co.uk/patents/US2442141