EPM Jul/Aug 2021

www.epmmagazine.com PHARMA & TECH TEAM-UP

THE ETHICS OF PRECISION MEDICINE

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INNOVATION THROUGHOUT THE INDUSTRY

July/August 2021

THE IDEAL INSPECTION

NATOLI EXAMINES THE IMPORTANCE OF VISUAL TOOL INSPECTIONS FOR FINAL TABLET QUALITY.

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Contents

July/August 2021 | Volume 21 Issue 4 REGULARS 5: EDITOR’S DESK

Why collaboration outside of pharma is key for the industry.

6: A SMALL DOSE

A brief round-up of some of the latest development in the industry.

10: OPINION

Why new approaches to pricing and reimbursement in Europe are needed for patients to benefit from gene and cell therapies.

13: IN THE NEWS

A short selection of stories from the world of science.

14: COVER STORY

Natoli examines the importance of visual tool inspections for tablet quality.

30: TALKING POINTS

Stories to consider and what to look out for in EPM over the coming weeks.

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FEATURES 8: PERSPECTIVE ON PHARMA

Exploring a collaboration between tech and pharma.

16: CAPSULES & COATINGS

How industry 4.0 is helping to transform capsule manufacturing.

20: CONTAINMENT & CLEANROOMS

Digital modelling and the benefits it offers when designing cleanrooms.

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22: CLINICAL TRIALS

How technologies are helping advance clinical trials.

24: PRECISION MEDICINE

The key ethical challenges of precision medicine.

26: INDUSTRY INSIGHTS

How one company helped pharma continue operating throughout the pandemic.

28: BIOLOGICS

The importance of accuracy and precision in bioassays.

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TECH TALK

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ollaborations across the pharmaceutical industry are nothing new. Regularly, we see companies, big and small, team-up so that knowledge, portfolios and intellectual property can be shared.

Think of the start-up being acquired by the pharma giant because of its promising therapeutic. Or the biotech with an artificial intelligence (AI) algorithm that can sift through data in the search of promising candidate medications.

Pharmaceutical companies are always on the search for new talent. The intensive

time and costs associated with drug discovery and development often mean it’s easier, or at least from a business perspective, less risky, to invest in promising companies that bring with them a wealth of knowledge or a therapy with encouraging data behind it.

You only have to look towards the coronavirus pandemic and the University of Oxford, who decided to collaborate with AstraZeneca, so the pharmaceutical company could help develop and distribute the university’s Covid-19 vaccine.

EDITOR’S DESK Whilst these types of collaborations are fairly standard across the industry, new opportunities are emerging for companies who are willing to look outside of the umbrella of life sciences. Now, pharmaceutical companies are looking towards the technology industry to assess how they can work together.

Indeed, in this issue alone we cover how pharmaceutical

companies are utilising technologies in the search for better working practices and even to position themselves at the forefront of infectious disease breakouts.

If there’s one thing that’s stood out to me within these stories, it’s that data is becoming a defining factor in helping pharmaceutical companies move forward.

The pharmaceutical industry isn’t short of data, but factors such as patient privacy and access continue to act as obstacles to companies wanting to make better use of the years of historical and clinical data they’ve amassed.

Anonymised clinical data means that it’s very difficult for pharmaceutical companies to extrapolate on anything outside of a specific set of questions. For instance, this means that companies wanting to understand how a therapy is performing once on the market may not be able to see if there are any underlying factors affecting adherence.

Real-world data which can be linked to clinical data will be key for pharmaceutical companies wanting to gain a better understanding of how and if their products are working for patients.

However, with tech giants such as Google, Amazon and Apple all entering the healthcare sector, the pharmaceutical industry may be on the back foot when it comes to amassing and analysing real-world data.

Collaborating with technology companies outside of pharma will be a priority for those wanting to get a step ahead of the competition. If not, a world of new and emerging opportunities could be missed.

6

A small dose

Coriolis Pharma strengthens service offering

CHIESI CONTINUES TOWARDS SUSTAINABILITY THROUGHOUT PANDEMIC

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hiesi has continued its journey towards becoming the first fully sustainable pharmaceutical company throughout the pandemic, as highlighted in its recent Annual and Sustainability Report 2020.

Chiesi continues to report on how it operates across its

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iopharma service provider Coriolis Pharma is expanding its advanced therapy medicinal products (ATMP) development facilities in order to strengthen its business.

The company is reconstructing an existing building near its headquarters in order to expand its laboratories.

Coriolis is aiming to have the facilities operational towards the end of 2021, where they will host the formulation development of ATMPs. This will include cell culture activities, particle characterization and identification, analytical ultracentrifugation and a lyophilization development centre for ATMPs. “Already in 2018, we started strengthening our scientific expertise

and offering services for ATMPs and are now pleased to see that this segment experiences a significant growth,” said Dr Michael Wiggenhorn, CEO of Coriolis Pharma. “That is why we are expanding our capacities in this area with new lab facilities under biosafety level S2.”

ATMPs can currently have a very short shelf life (hours to days) and require extremely cold storage conditions if they are to be preserved.

Whilst the sector is strong, Coriolis states that ATMP formulations are still far from advanced. The company believes a tailored formulation development programme, which includes potential lyophilisation, could improve the development of ATMPs.

business. The company has developed a methodology to assess its business impact, by analysing products, processes, its global value chain and corporate citizenship, all in alignment with the United Nations 2030 Agenda of Sustainable Development Goals (SDGs).

Last year saw all of the company’s Italian

sites, which represent around 80% of its total energy consumption, be powered by 100% renewable energy.

2020 also saw the company’s total energy consumption decrease by 15% compared to 2019, driven mainly by a reduction in energy use from its fleet of cars, due to the pandemic.

Chiesi has signed a new contract for its

Novo Holdings launches neurodegenerative company

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ife sciences investor Novo Holdings has launched Muna Therapeutics, a neurodegenerative company looking to develop first-inclass small molecule therapeutics.

Novo Holdings launched the company with $73 million of Series A funding, backed by the likes of Sofinnova Partners, Droia Ventures and LSP Dementia Fund with participation from Polaris Partners, Polaris Innovation Fund, Sanofi Ventures, V-Bio Ventures and VIB. The company was founded in 2020 by professor Simon Glerup and his team from Aarhus

University, Denmark, in collaboration with Novo Seeds, the earlystage investment team of Novo Holdings.

Muna then teamed up with K5 Therapeutics, co-founded in 2020 by professor Bart De Strooper from VIB-KU Leuven Belgium.

In Europe, neurodegenerative diseases such as Alzheimer’s affect over 7 million people, with that figure expected to double every 20 years as the population ages.

Muna has developed an all-in-human target discovery and validation platform, based on insights into molecular pathways in different human brain cell types

that underlie disease pathology and resilience to neurodegeneration.

Muna will use the funding to advance its small molecule programmes focused on repairing neuronal dysfunction, resolving neuroinflammation and restoring neuroprotection and resilience to disease.

The company is hoping to advance its programmes towards Investigational New Drug (IND) applications.

Muna will be based in Copenhagen and Leuven and is led by pharmaceutical executives CEO Rita Balice-Gordon and COO Anders Hinsby.

Rita Balice-Gordon,

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2021 and 2020 energy supply from a new wind farm located in the Puglia region, Italy.

Chiesi’s Parma sites use electricity which comes from high-quality renewable sources, with 2.6% being generated from its own plants.

This year, the company states it intends to complete the transition to 100% renewable electricity at all of its manufacturing sites.

Chiesi says that its strong financial year of 2020, in which revenues increased by 11.8% compared to 2019, will provide it with an opportunity to continue

diseases like Alzheimer’s and Frontotemporal Dementia that devastate cognition and quality of life of patients as well as caregivers. Our team is committed to leveraging our collective expertise to deliver impactful disease modifying small molecule therapeutics to patients as rapidly as possible.”

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chief executive officer of Muna Therapeutics, said: “We are delighted for the support and backing from Novo Seeds and this world class investor syndicate.

We are in an era of rapid advancement in understanding how to slow or stop the relentless progression of neurodegenerative

targeting sustainable practices.

Chiesi has aims to become carbon neutral by 2030 in regard to direct greenhouse gas (GHG) emissions and indirect GHG emissions from purchased electricity and heat by 2035. The company is planning to reduce emissions from its inhalers by 90% through the introduction of a potential low global warming propellant.

“The pandemic has changed the world with full force in what were already transformative times. Within this context of adversity and

the need to manage the unknown, I am grateful for the organisation that we have demonstrated to be. The mobilisation of Chiesi’s people has gone beyond the scope of our business and attested the values we share together. Our shared value approach, as a certified B Corp and a Benefit Corporation, demonstrates that the values we stand for represent the solid foundation our company needs for the challenges of our time” said Ugo Di Francesco, CEO of Chiesi Group.

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PERSPECTIVE ON PHARMA:

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n June this year pharmaceutical company Boehringer announced a collaboration with Lifebit, a technology company specialising in the collection and analysis of big data within life sciences, with an aim of helping companies discover new drugs and improve patient outcomes.

The partnership will see both companies working together to detect and report on global disease outbreaks. Lifebit is to use its REAL platform, which uses advanced analytic capabilities to automatically notify users of relevant outbreaks, such as transboundary disease spread or the emergence of pathogens, such as Covid-19.

The platform is essentially a way of harvesting data from available real-world evidence.

This could be social media posts, news outbreaks and scientific articles such as those on PubMed. The data are then monitored continuously in the hope of assessing where and when the next infectious disease outbreak may occur or is occurring.

“So, for example if a regional newspaper in a far-flung country identifies that there is a new EPM speaks to technology company Lifebit about its collaboration with Boehringer to report on infectious disease outbreaks.

What a tech partnership means for pharma virus spreading throughout their animal or human population, we can pick that info up and the system can synthesise that information into an insight for Boehringer,” Tom Sharrock, AI engagement manager at Lifebit, told EPM over a Zoom interview.

The emergence of the partnership during Covid-19 - when pharmaceutical

companies have expedited efforts into developing vaccines and therapies against what is essentially a new disease - points to an industry that understands the need for collaboration.

Despite the fact that pharmaceutical companies developed vaccines for Covid-19 in such a short time compared

to normal, the industry was still caught off guard. Certainly, Boehringer understands that in order to effectively develop or reposition drugs against new or emerging pathogens, then a clear data-driven approach is needed.

“I think Boehringer is trying to become more innovative. They realise that in order to move

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There are already cases where we’ve identified particular geographical regions, such as individual parks in a city, where actual disease outbreaks have been pinpointed down to a particular location through social media.

fast in the market they need to adopt a different strategy and that’s what they’re doing. This is an alliance which will allow both companies to deliver great outcomes for patients at the end of the day,” says Dr Maria Chatzou Dunford, CEO and cofounder of Lifebit.

The partnership will offer Boehringer both short-term and long-term opportunities.

In the short-term, the real-time data Lifebit provides on how a disease may be spreading and which drugs – if any - are being used to treat it, will enable Boehringer to either accelerate or decelerate its existing efforts.

For instance, if there aren’t any drugs being used to fight an emerging disease, then the data could allow Boehringer to look through its own portfolio

and assess whether it has any potentially effective therapies to position into the affected regions and territories.

In the longer-term, having clear and accurate data that show what kinds of diseases have become more prevalent will enable Boehringer to potentially invest in those disease areas, or understand how it can maximise its return-on-investment.

Data then is at the heart of this collaboration. Whilst the pharmaceutical industry is built on clinical data that affirm the efficacy of drugs, the partnership between Lifebit and Boehringer is indicative of two industries (pharma & tech) working together to gain a clearer picture of how data can inform a pharmaceutical company’s practices.

During our conversation, Dr Maria Chatzou Dunford tells me about the laborious nature of data collection when it comes to infectious disease surveillance and how what is offered by the likes of the World Health Organisation (WHO) can be superficial.

Data offered by global agencies, she tells me, doesn’t currently offer a total understanding of a disease. It might say where it’s spreading but it won’t go into why or how it’s affecting animals or humans and what drugs are being used for it.

For a scientist presented with a new disease, just knowing where it’s spreading isn’t enough. Where does a researcher start if they don’t have an idea about the chemical structures of a pathogen or any clinical data?

As Dr Maria Chatzou Dunford puts it: “A treasure map is totally useless if you don’t have a big red mark that says dig here. Our

9 system not only gives you the treasure map but also gives you a clear path saying, ‘dig here’.”

In the years to come, this partnership should allow Boehringer to position itself into disease areas where it knows it can be effective.

If there’s any doubt into the use of Lifebit’s technology to identify emerging diseases or infectious disease outbreaks, Sharrock explains just how beneficial real-time data such as those on social media can be.

“For a scientist to pick up that there could be a potential outbreak would take a matter of weeks at the minimum. Then to actually publish that data would take a number of extra months.

By monitoring social media, you jump ahead to get a better real-time view,” he explains.

“There are already cases where we’ve identified particular geographical regions, such as individual parks in a city, where actual disease outbreaks have been pinpointed down to a particular location through social media.”

Of course, a social media post doesn’t have the veracity of something like a scientific article, but Lifebit’s solution is an example of how the life sciences industry can be informed by real-time data found across the likes of Twitter and Facebook.

Going forward, Dr Maria Chatzou Dunford believes theirs is a partnership which will be replicated across the pharmaceutical industry.

“I think Boehringer is very smart to realise that there is a new pharma coming and they are embracing that very well. I think other pharma companies will eventually also either perish or adapt,” she says.

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Opinion

To date, no country has fully adjusted its processes to adequately reflect the peculiarities of gene and cell therapies.

CELL & GENE THERAPIES: THE PRICE ISN’T RIGHT Author: CHRISTOPHE HILBERT - senior manager of Access, Value, and Evidence Strategy, Europe at bluebird bio

Why new approaches to pricing and reimbursement in Europe are needed for patients to benefit from gene and cell therapies.

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t the dawn of gene and cell therapies, it appears that our healthcare systems are not keeping pace with scientific progress. While continuous research and development has led to the rise of a new class of therapies, some of which hold curative promises, healthcare systems continue to rely on processes that were designed for previous generations of chronic treatments when making reimbursement decisions. It is thus crucial to ask whether relying on these legacy processes may put existing innovation at risk, stifling future innovation in Europe and preventing patients from having access to potentially life changing therapies?

HEALTH TECHNOLOGY ASSESSMENT AND PRICE NEGOTIATION: THE MISSING LINK For national healthcare systems to evaluate a drug product and its worth, national pricing and reimbursement processes typically consist of two steps: A Health Technology Assessment (HTA), followed by a price negotiation. Simply put, an “HTA measures the added value of a new health technology compared to existing ones”1. HTAs play a key role in informing the price negotiation. However, in the case of gene and cell therapies, randomised controlled trials, which are regarded

by HTA frameworks as the gold standard2,3, may not be feasible or ethical. This

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OPINION

means it can be challenging to do an HTA and create a strong link between these two cornerstones of access, leading to situations where the HTA outcome is not factored into the price negotiation – or only loosely linked to it. This inevitably leads to a price that does not accurately reflect the therapy’s true value.

WHEN SCIENTIFIC REALITY COLLIDES WITH PRICE NEGOTIATION One area where we see this disconnect is in the evaluation of innovative therapies with curative intent by national systems.

Whereas regulatory and scientific bodies like the European Medicines Agency consider that the effect of some of these therapies is expected to be life-long, this perspective is not always shared by national healthcare systems.

Although it is somewhat understandable that healthcare systems may initially struggle to appropriately value therapies with expected life-long effect (there is no scientific data yet which spans human lifetime), it also does not make sense to base decisions on a random time frame (e.g., 15 years) as part of price negotiations. This is especially the case when discounting can be used as a simple financial tool to reflect a life-long effect.

WHAT YOU SEE IS WHAT YOU GET: HOW CLINICAL TRIALS AND ANNUAL COST CONSIDERATIONS GET LEVERAGED TO CHRONIFY DISEASES To date, no country has fully adjusted its processes to adequately reflect the peculiarities of gene and cell therapies.

In the eyes of some healthcare systems, it is a case of “what you see is what you get”. In fact, it is not uncommon to hear that the duration of clinical trials should inform value definitions, whether they are one-time treatments or chronic therapies. This means that the value of a potentially curative one-time therapy in relation to a life-long permanent therapy must therefore be based on the observation period of clinical trials. This also suggests that a life-long effect can only be monetized when the new therapy has been available on the market for a lifetime.

The pharmaceutical industry is often criticised for prioritising profit over public health objectives, investing in chronic treatments instead of new curative therapies. It seems ironic, then, that as one-time therapies reach the market, health systems are measuring value by the duration of clinical trials.

This might not only mean the end of one-time therapies; it also implies the continuation of higher cost burdens from the longterm treatment of chronic diseases.

INTRINSIC DIFFERENCES BETWEEN GENE AND CELL THERAPIES Gene and cell therapies are complex and often conflated, with the differences between them overlooked. However,

these differences are critical in understanding mode of action, durability of effect (whether lifelong or not), as well as clinical and economic value. There are also significant differences between gene therapies – including whether treatments take place inside or outside the body, and their delivery method using different types of vectors. All these factors need to be appreciated when assessing value and price.

PREVALENCE VS INCIDENCE: A QUESTION OF COMMERCIAL VIABILITY Another issue that healthcare systems must consider when determining value is the characteristics of the patient population.

For example, whereas certain severe genetic diseases have a defined pool of prevalent patients with a lower incidence of new patients, oncology products usually target variablesized prevalent patient pools with a constant, non-negligible incidence rate. This has important economic implications on commercial viability. Given those therapies aimed at severe genetic diseases will have a pool of prevalent patients to treat but only low incidence of new patients, manufacturer revenues will rapidly decrease as the innovation is applied. The situation is different for oncology products: once an established therapy, revenues are expected to remain steady, or even grow as populations age. This is one of the elements determining the commercial viability of, and future research into, innovative therapies. To interpret the example from the viewpoint of healthcare systems, replace “revenue” by “budget impact”.

OUTLOOK FOR A BETTER FUTURE While today’s pricing and reimbursement processes are still struggling to properly value gene and cell therapies, there is hope. For one, there is acknowledgement of the need to recalibrate current systems across the entire healthcare ecosystem – from industry, trade associations, patient groups, health economists, politicians, and payers. The topic of reform and adapting current HTA systems is being widely debated at national and pan-European levels, and is the focus of many academics and expert health economists working to address barriers such as uncertainty, discount rate, societal value, and budget impact. Hopefully, initiatives such as the EU’s Pharmaceutical Strategy for Europe will help drive this much needed change so that we begin to see a world where gene and cell therapies will consistently become available to patients.

The clock is ticking, however, regarding effective reform, raising concerns over whether gene and cell therapies will ever have broad access in Europe. One question remains: what can be done to accelerate the adjustment of pricing and reimbursement processes to properly value these innovations across Europe and increase the treatment choices available to rare disease patients?

REFERENCES 1. https://ec.europa.eu/health/technology_assessment/overview_en Accessed June 2021 2. BMJ 2010;340:c332 https://doi.org/10.1136/bmj.c332 3. https://www.eunethta.eu/wp-content/uploads/2018/03/Methods_for_health_economic_evaluations.pdf Accessed June 2021

13

IN THE NEWS

BMA says Covid-19 inquiry should not wait as it begins its own pandemic review

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s we wait for the government’s public inquiry to begin, the British Medical Association (BMA) has started its own ‘Lesson learned’ review into the Covd-19 pandemic.

The BMA will publish a call for evidence for stakeholders soon, gathering evidence from members across the UK to inform its review. The evidence it gathers will directly inform its submission to the public inquiry.

The “Lessons learned” review will focus on five areas which include: the protection of healthcare workers from Covid-19; the impact of the pandemic on healthcare workers; delivery of healthcare during Covid-19; the public health response to the pandemic; the impact of the pandemic on population health.

The BMA has said it believes the public inquiry should start immediately, whilst memories of the pandemic are fresh in the minds of those who work on the frontline.

Dr Chaand Nagpaul, BMA council chair, said: “The public inquiry into the country’s handling of the pandemic will probably take years to gather evidence and publish its findings – so we should not be

waiting to uncover the reasons why the UK has suffered the highest death toll in Europe or the seventh highest in the world as well as the devastating impact on our health service and its staff.

This work is especially critical right now as

we sit amidst a rapidly growing third wave of infections that threaten our health service and the long-term health of our nation.

“In the absence of any meaningful action from government, we will speak with our members and other

stakeholders; pose the key questions they need to answer and produce clear recommendations for the government.

Drawing upon lessons learned we will call on ministers to put into place measures, so the NHS is adequately

Did you know?

DEATH TOLL The UK’s public inquiry into Covid-19 will start in Spring 2022.

Recent efforts by MPs to begin the inquiry sooner were rejected in the House of Commons.

The UK has the world’s 7th highest death toll.

prepared of any future pandemic or unexpected surges in demand, together with proper support and protection of its healthcare staff. We will also outline areas where the inquiry needs to interrogate witnesses - who will be compelled to give evidence.”

Professor Helen Stokes-Lampard, chair of the Academy of Royal Colleges, added: “We fully understand and support the need to examine everything that has happened during the pandemic and if the government plans to delay the inquiry, there is a strong argument for gathering evidence while events are still fresh in people’s minds. The medical profession has been on the front line of the battle against Covid-19 for too long and the lessons learned should be shared as soon as practicable. This has particular urgency now as we are in the midst of a rapidly escalating third wave, with the likelihood of more destructive variants of infection and further waves to follow, which will in turn heap further pressures on our health and care systems.”

14 WHY INSPECT PUNCHES AND DIES? Tooling inspection procedures generally encompass a check of all critical dimensions, but frequently a visual inspection of the punches and dies may be overlooked. Even though a dimensional inspectional of the tooling may find the punches and dies to be within specification, a thorough visual inspection may find punch tip and die bore wear that could be responsible for tableting defects observed during production. An inspection of the critical punch dimensions should be performed periodically, but a visual inspection of the punches should be performed each time a tool set is removed from the tablet press.

We believe there are three dimensions that should be considered in a dimensional inspection of an upper or lower punch. Checking other dimensions is either unnecessary because it rarely changes and therefore isn’t worthy of the time and expense of measuring, or they cannot be properly measured with typical equipment and is better served by a visual inspection.

The three dimensions include the following: 1. Working Length is considered the most critical punch dimension as it largely determines tablet weight, thickness, and hardness.

Tolerances should be determined by comparing the working length to the length of the other punches within the set, rather than comparing it to a specific value. Uniformity of punch working lengths is the key.

As long as the punches are the same length (within the specified tolerance of each other) it doesn’t really matter

COVER STORY

THE IDEAL INSPECTION

Natoli examines the importance of dimensional and visual tool inspections and their direct relationship to final tablet quality. how they compare to a specific predefined length.

2. Cup Depth should be calculated by subtracting the measured working length from the measured overall length. Cup depth is not considered a critical dimension with regards to controlling tablet weight.

3. Overall Length is not critical, except that it is necessary to accurately calculate Cup Depth. Therefore, do not assume a standard European (EU) overall length of 133.60mm for every punch.

However, it is important to understand that the overall length of the lower punches is responsible for tablet ejection and smooth take-off.

Understanding that the consistency of working length between punches in a tool set is primarily responsible for the resulting weight, thickness, and hardness of the tablets, solidifies it as the most important dimension

in your tool inspection programme. When inspecting working lengths, the upper and lower punches should be separated and inspected for variances independently of one another. The majority of all new upper and lower punches are engineered and manufactured to a standard tolerance of 0.05mm T.I.R. (Total Indicator Reading). This means that, within a set of upper or lower punches, the difference between the working lengths of the longest and shortest punch would be no more than 0.05mm T.I.R. For in-process (used) tooling, it is recommended that you periodically inspect the punches to ensure working lengths do not exceed this tolerance. The lengths of the lower punches are a bit more critical than the upper punches because theylargely determine how uniformly product fills the dies. Deviations in the amount of product in the dies may affect tablet weight and hardness.

The working length of the punches should be measured for deviation from punch-

to-punch rather than to a calculated number. You should measure working lengths using a digital indicator mounted on a sturdy steel post fixed to a granite base. This relatively inexpensive basic measuring equipment provides the same accuracy as an elaborate inspection system that can cost $50,000 USD or more.

VISUAL INSPECTION OF PUNCHES Tooling inspection procedures often overlook wear to the edges of punch tips. Many factors can cause tip wear, including poor design of tablets and tooling, abrasive formulation characteristics, improper steel selection for an application, and improper press setup. While inspection technicians typically pay attention to the punch cup’s face, typical surface degradation is generally not responsible for tablet defects such as capping, lamination, and flashing. These tablet defects are more often related to wear on the punch tip’s outer edge and land, the narrow flat surface around the perimeter of the punch cup.

While proper inspection can help to prevent many common tableting defects, punch-tip inspection often only checks the size of the tip by measuring it with a micrometer or calipers. Since the measuring anvils, i.e., contact surfaces of these instruments are 3 to 6 millimeters wide, they actually can only check for the largest dimension. Wear to the very edge of the punch tip is relatively small and is undetectable using traditional measuring equipment and techniques, and unassisted visual inspection may not easily observe it either. Some form of magnification, such as a horizontal optical comparator

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UPPER EXCESSIVE FLASHING

DIE

LOWER EXCESSIVE FLASHING - WEAK TABLET EDGE DUE TO PUNCH TIP WEAR.

or a stereo microscope, is necessary to properly and thoroughly inspect the punch tips for edge wear.

If excessive tip wear is discovered on punches, then also checking for the presence of J-hook is recommended. This type of tooling defect can be detected by checking the inner periphery of the punch cup with a fingernail. J-hook will cause the fingernail to catch the inward curled metal at the cup edge. Without repair, this condition can lead to capping and lamination of tablets. To remove J-hook from a punch, a quick buffing of the punch cup can be performed to remove this, but will not repair any of the damage on the outer perimeter of the punch tip. Excessive wear to the outer edge of the punch tip can cause flashing and possibly cause binding of the upper punch tip in the die.

For lower punches, checking the back edge of the tip for sharpness is another visual inspection that will have to be done so the relief is functioning as designed. If the back edge has become worn or rounded, it will not clean out the die bore on the downstroke. To check the sharpness of this area, you can drag this against your fingernail, and it should shave some of the nail.

If this area isn’t sharp, this could lead to lower punch tip binding in the die bore due to build-up of product. This condition can cause excessive friction, heat generation, sticking and picking, and excessive wear to the back angle of the lower punch head.

DIE INSPECTION (BOTH VISUAL AND DIMENSIONAL) Inspecting the dies of a tool set begins with a visual check for wear rings in the bores. Simply holding a die up with a bright light on the opposite side of the bore and reflecting the light throughout the entire bore will highlight any wear rings that may be present or beginning to form. Depending on the abrasiveness of the formulation being compressed, the definition of this wear ring can vary from fairly faint to clearly visible during this visual inspection. A premium wear resistant steel such as PM15V or utilising a carbide/ ceramic lined die would be a viable option to address this type of wear and extend the service life a die set before replacement would be necessary.

To determine the extent of any die wear seen visually, the use of a split-ball bore gauge connected to an indicator or a digital handheld gauge could be employed to measure the wear ring(s)

within the die bore. If the dies have visible wear and are still producing acceptable tablets, you may deem the measured wear as acceptable. Allowable wear within a die bore depends on the characteristics of the powder, which varies product to product. With each compressed tablet, the wear will continue to increase and eventually affect final tablet quality and hinder smooth operation of the punches and press. Flipping the die over to compress tablets in the other half of the die is an option if the die only has wear in one end of the bore.

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Author: JOHN NORMAN -Technical Service Representative for the Tooling and Tablets division at Natoli.

CONCLUSION Regular and frequent inspections of punches and dies, for dimensional consistency within the set and visually for wear, can prevent issues from arising during tablet manufacturing. Inspecting working lengths within a punch set to confirm they are within the specified tolerance range for your company, will help ensure consistency in resulting tablet weight, thickness, and hardness. Visual inspection of the punch tip’s outer edges and die bores can prevent common tableting defects, such as capping, lamination, and flashing. For the best results, include a detailed inspection in your Standard Operating Procedures (SOP’s) so each tooling technician inspects the punches and dies in the same way.

We believe there are three dimensions that should be considered in a dimensional inspection of an upper or lower punch.

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CAPSULES & COATINGS

Transforming capsule manufacturing

WITH INDUSTRY 4.0

ACG on the journey it has been on since 2017 to implement Industry 4.0 technologies into its capsule manufacturing lines.

INDUSTRY 4.0 & INFLECTION POINTS The inflection point of a curve is the point where the curve takes a considerable change in trajectory. The change can be either upward or downward.

The same is true with business performance. To move in an upward trajectory from an inflection point, organisations need to make certain strategic, decisive choices. In today’s world, technology driven transformation powered by Industry 4.0 technologies is one such preferred choice.

Progressive organisations have made this choice to come up with new business models, enhance customer experiences, build smart products and services, and transform operations. ACG started its Industry 4.0 journey in 2017 with a focus on transforming operations.

INDUSTRY 4.0 AT ACG, A CASE IN POINT It was a busy day at ACG’s capsule manufacturing facility.

The maintenance team received an email and SMS alert on the increasing trend in the energy consumption in capsule manufacturing machines in one of the production halls. The machine learning algorithm had analysed and detected an anomaly in energy consumption, considering the machine operating data, production data, energy consumption data, local weather data, benchmark data from similar machines and SKUs (stock keeping units).

Industry 4.0 is a huge change initiative encompassing technology, process, and people.

As soon as the anomaly was detected, auto root cause analysis was triggered to give clear and actionable insights to the end user.

In this case, the root cause was the malfunctioning of heating coils.

These heating coils were drawing more than normal current in the context of the SKU under production. While the symptom was about abnormal energy consumption, malfunctioning heating coils have a significant impact on product quality. Suitable alerts were generated showcasing the anomaly, root cause, and possible corrective actions based on standard operating procedures. The maintenance team swung into action to replace the heating coils thereby preventing any impact on product quality. This is one of the examples of how Industry 4.0 can add value to manufacturing operations.

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Today, ACG is well on its way in the Industry 4.0 journey with a range of appropriate solutions deployed across functions spanning planning, production, maintenance, service and supply chain, powered by technologies such as industrial IoT, machine learning, computer vision, advanced automation, augmented and virtual reality.

THE JOURNEY Reducing machine breakdowns and enhancing OEE (overall equipment effectiveness) in capsule manufacturing was the key business driver with which the Industry 4.0 journey started. Pilot projects began with focus on condition monitoring, breakdown analysis, and condition-based maintenance of

capsule manufacturing machines.

Initial days were spent on solving problems ranging from sensors, connectivity, data ingestion to the IoT platform, streaming, data management, data analysis and so on. There has been no ‘looking back’ since then.

Today, more than 1,000 machines are connected to our industrial IoT platform streaming more than 30,000 parameters real-time, spanning process data, energy data, machine condition data, alarms, alerts and more. What started as a condition monitoring initiative has evolved into a range of Industry 4.0 initiatives cutting across production planning, condition monitoring, predictive maintenance, energy optimisation, process capability, quality, safety, operator augmentation, remote service and more. These solutions are powered by Industry 4.0 technologies such as industrial IoT, advanced analytics, machine learning, computer vision, mobile robotics, augmented and virtual reality.

PEOPLE AND CHANGE MANAGEMENT – THE FIVE CS Industry 4.0 is a huge change initiative encompassing technology, process, and people.

Effective people and change management practices have helped us steer our Industry 4.0 journey in the right direction. Our change management is focussed on five Cs – Clarity, Consistency, Commitment, Capabilities, and Consequences.

To bring in clarity and consistency, we conducted several training sessions and workshops to create awareness about Industry 4.0 and its relevance for our business.

To drive commitment and accountability, a ‘hub and spoke’ organisation was created with clear ownership and goals aligned with our annual performance appraisal process. Review and governance mechanisms were

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set up with the top leadership of the organisation. Our rewards and recognition programme helped further improve motivation and commitment.

Building, deploying, and adopting Industry 4.0 initiatives requires a spectrum of technology and domain capabilities. Active collaboration with start-up ecosystems, continuous improvement cells and hands-on training sessions are helping us develop the required skill sets.

We engaged with leading EdTech companies for online training on Industry 4.0 technologies. With a constantly changing technology landscape, skill management is a continuous endeavour.

Industry 4.0 is about transformation and change, and there are consequences to any change. This brings in concerns and perceptions on the pains and gains. We conducted workshops across the organisation to address these perceptions and concerns, elaborate on the impact of change, and articulate the business value gained from Industry 4.0 initiatives.

ACG will continue to focus and improve on change management practices to ensure effective adoption and value realisation from Industry 4.0 initiatives.

THE WAY FORWARD So far, our Industry 4.0 journey has yielded significant benefits in reducing downtime, enhancing OEE, reducing lead time, optimising energy consumption, enhancing capacity, reducing defects, improving first pass yield, reducing set-up times, and much more.

While the current focus is on transforming operations, ACG is expanding into building smart connected products and services, developing delightful customer experiences, and creating digital led business models. The future is bright. The future is digital.

Authors: KARAN SINGH - managing director, ACG, BALAJIKASIRAM SUNDARARAJAN - group chief digital officer, ACG, SELWYN NORONHA - CEO, ACG Capsules

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Why glass primary container serialization is a clear winner Track-and-trace barcodes are a familiar sight on pharma packaging, providing traceability for drugs and medical devices all the way from the manufacturer to the patient. The unique identification offered by barcodes makes product recalls more efficient and accurate, as well as helping

to prevent issues ranging from medication errors to counterfeiting.

But relying on the secondary packaging for this crucial traceability means it only lasts up to the point when the contents are removed.

And it gives no individual identification of items during the production process. So,

if a problem is identified on the production line, manufacturers are often unable to define which products might have been affected. They are then forced to adopt a policy of over segregation or full batch write-off – leading to lost revenue and, potentially, drug shortages.

Until now, there has been no individual identification of primary glass containers for parenteral use. That’s why Stevanato Group set about tackling the challenge of how to mark glass containers that have a glossy, non-absorbent surface that is often curved.

Under these conditions, it’s difficult to achieve high legibility and optimum ink adhesion at high speed on a production line.

Benefits of primary container serialization The option of uniquely coded primary containers would

make tracking possible throughout the filling and finishing processes. This will enable data-driven analysis to identify issues and drive faster, enable more detailed root cause analysis and process optimization.

If particulates are discovered in an unmarked glass container during the highspeed production process, the container will be rejected. However, the reject will be mixed up with items rejected for other reasons – so it will be time-consuming to find the specific containers affected by particulates. With a unique barcode on each glass container, the search becomes quick and easy.

Primary container serialization can also help if a problem is identified after production. Determining which filled product has been affected can prove a challenge – that is why

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there is often a tendency for manufacturers to over segregate or write off the whole batch. A unique identifier on each primary container will reveal the date and time at which each container was filled – so a defined segregation policy can be used, based on real data. If contamination is found, for example, the manufacturer will know which containers were on the production line at that time.

Another benefit of primary container serialization is that it makes it possible to automate the batch reconciliation process which is used to prevent mix-ups when production switches between different filling processes. Manually counting tens of thousands of containers is timeconsuming, whereas individual barcodes enable the process to be automated and radically speeded up.

Unique identification codes on each glass container can be associated with the production data exchanged by each machine allowing for a detailed analysis of the batch to

facilitate manufacturing improvements. Knowing the precise date and time each container was filled, for example, or how long the process took, can help to improve the production processes well as delivering a detailed batch report.

The unique Stevanato Group approach At the start of the project nine different marking technologies were considered. The need to handle unique serial numbers and barcodes at high speed meant a digital marking process was required. It was crucial that container integrity was not affected – and the effect on manufacturing lines needed to be minimal.

Other requirements included the fact that the marking process needed to withstand all the pharmaceutical sterilization processes, and the barcodes have to be readable by standard serialization cameras and applicable to all container formats and sizes.

The result was the selection and development of a

digital printing process for Stevanato Group’s novel primary serialization solution, with inks that could withstand the various temperatures involved on all production lines. A GS1 ECC 200 2D data matrix barcode is printed on the primary containers after the forming stage – giving each glass syringe, cartridge and vial its own ‘fingerprint’.

The machine-readable barcode allows each container to be tracked during every manufacturing process – from forming through to filling and automated inspection. The addition of manufacturing data at each step delivers significant process and quality benefits for both glass container producers and pharma companies.

Industry validation The benefits of having a unique code for primary parenteral drug containers during filling, inspection and packaging operations

have been validated across the industry. When the PDA conducted a survey of its members to get their views on traceability, 68% of respondents said they had considered using marked containers. The potential use cases quoted ranged from avoiding mix-ups with filled containers to reject tracking in automated inspection processes.

The International Society for Pharmaceutical Engineering (ISPE) is also supporting the Stevanato Group approach, and a working group was set up with the initial aim of creating a discussion document that could be used for implementing unique identification of primary glass containers.

For more information, see the discussion paper – Unique Identification on Primary Containers to Drive Produce Traceability & Quality – published earlier this year by the ISPE.

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CONTAINMENT & CLEANROOMS

DIGITAL DESIGNS How digital modelling is helping with the design of cleanrooms.

D Author: JOE MURPHY product & process development lead at Connect 2 Cleanrooms

epending on whether it is a pharmaceutical manufacturer or a principal contractor, clients have different expectations when it comes to cleanroom design. End users expect to see plans and elevation drawings to help them visualise a facility and satisfy that each element is present and positioned

correctly. If the end-user has appointed a principal contractor that lives in the design and construction world, expectations are much higher.

No matter what the expectations are, each client needs the same level of service—one that delivers compliance to regulations and successful interfaces between the new cleanroom and its surrounding facility.

Whilst 2D and 3D models are beneficial to allow clients to visualise their project and conduct virtual reality walk-through tours to test the layout and workflow, there’s now so much more that can be done with the help of digital modelling.

Cleanrooms are complex systems that require a combination of a hygienic envelope and HVAC system design to create a controlled environment appropriate for processes. To

make sure that cleanrooms are fit for purpose, teams of Autodeskcertified design engineers should carry out designs following the latest Building Information Modelling (BIM) standards and workflows. In 2016, the UK government mandated compliance with BIM level 2 for any public sector construction project and since then this standard has become the default. Working to an agreed standard allows full collaboration and coordination with any other contractors involved in a facility build, resulting in greater accuracy and higher quality results.

Say, for example, as part of a new facility fit out you have a cleanroom specialist appointed to build a cleanroom and a construction company building a mezzanine. Both companies can amalgamate their BIM models—or import one into the other—to create a federated model. Clash

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detection can be performed on this federated model to create accurate interfaces between the two elements of the fit-out.

Not only does this improve accuracy, but it also shortens overall project timelines as it reduces finish-to-start dependencies. In this example, when working with a federated model, the installation of the mezzanine doesn’t need to be complete before the design of the cleanroom can start.

Some cleanrooms are installed into large warehouses with little or no interfaces with the surrounding environment.

But some cleanrooms need to be installed into areas where space is at a premium.

These cleanrooms may need to incorporate HVAC ducting into tight ceiling voids or align windows and doors with existing openings.

Point cloud surveys can 3D scan the current environment of facilities to create an exact digital model. A proposed cleanroom design can then be imported into the 3D scan to clash detect and verify that the design operates in line with the planned process and its surrounding environment. With this advanced level of planning

and design, prefabrication of certain components of a build can be made off-site to avoid working within restricted spaces when on-site.

When working to BIM level 2 everything you draw isn’t just a representation of an independent system, it’s a live model with information that sits alongside it. When these models get client approval, the data on the parts required for the build can be automatically fed to procurement teams to source.

These Design for Manufacture and Design for Assembly (DfMA) principles mean there is no need to manually create a bill of materials. Instead, exporting data from the design package straight to the Enterprise Resource Planning (ERP) software is a one-step process.

This automation reduces the chance of human error and provides a reduction in the processing time of around 80%.

The enhanced data provided in a BIM model means that as well as providing an operations and maintenance manual in the client handover, you can also provide a live model of the facility. Why would we

do this? The answer is risk analysis. These BIM models can be used to track failures and any required maintenance.

Data is then fed back into a database so decisions can be made by facilities managers on maintenance schedules.

Another type of modelling that is incredibly beneficial for cleanrooms is airflow mapping.

Furniture layout, temperature and humidity, and heat gains from equipment can all have a big impact on the way air moves through a cleanroom.

Airflow modelling allows you to analyse the airflow and all the contributing factors that affect it, to see how particulate is moving. You can even isolate different particle sizes, depending on which sizes are of concern to the process.

Visualising how clean the air is at the critical point of a process allows you to optimise the airflow path. Better airflow patterns can be achieved

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by positioning the air supply immediately above critical parts of the process and the strategic positioning of air return grilles.

Of course, many manufacturers will need to be compliant, not only with ISO 14644-1, but also GMP guidelines. When working towards GMP compliance, there needs to be a documented Design Qualification (DQ) process. DQ verifies that the proposed design of the facilities, systems, and equipment, is suitable for the intended purpose. It starts right from the conceptual design phase of the project. Digital modelling helps to qualify that the performance of a cleanroom is in accordance with the parameters stipulated in the User Requirement Specification (URS).

This approach mitigates the risk of non-compliance with a URS and avoids delays and modification costs at later stages of the project.

There’s now so much more that can be done with the help of digital modelling.

22

CLINICAL TRIALS

THE FUTURE OF

CLINICAL TRIALS How new technologies are driving the advancement of clinical trials.

O Author: DR NICK SCOTT RAM managing director of life sciences at Sensyne Health

ver the last 10 years, we have seen huge advances in genomics broadly and CRISPR genome editing specifically, diagnostics, biomarkers, imaging, stem cell research, targeted cancer therapy and immunotherapy. Against this background of innovation we are now also rethinking approaches to randomised clinical trials to try and overcome the associated time, cost, patient recruitment and efficacy challenges which can often hinder our understanding about potential new investigational therapies.

Early changes in improving clinical trials often saw the use of data science and technology as a key driver from new ethical and regulatory frameworks changing the way researchers use data to inform drug discovery and development, to new technologies, reducing the need for mass patient participation and greater targeting amongst patient populations during clinical trials. All this against an extraordinarily challenging

Synthetic control arms could significantly contribute in transforming clinical development by helping pharmaceutical companies improve clinical trial design and success rates.

period of a global pandemic has driven the healthcare and life sciences industries to improve patient care and dramatically speed up more inclusive and targeted drug development.

It’s probably safe to say that during the pandemic we’ve seen an historic accelerated and collective clinical trials process, prompting global cooperation for vaccine research and

the distribution for the SARSCoV-2 virus in under a year - a pace never before possible. The success of multiple vaccines already being currently rolled out across nations, has proven it is possible to create treatments with the aid of new technologies and medical innovations. From quickly

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identifying the protein that affects an immune response, to scaling up the manufacturing process from tens of doses to millions - as well as being able to rapidly design clinical trials and recruit patients. Access to data and tools such as artificial intelligence (AI) and machine learning (ML) has been invaluable.

Traditionally, the average time for a new treatment to go from initial discovery to market is anywhere between 10 and 15 years, with clinical trials alone taking up to six or seven of those. This process could cost on average $40,000 per patient or more depending on how rare the disease area being investigated is.

As we look to the future, conducting clinical trials through a multidisciplinary, collaborative

and innovative approach will help speed up and improve the development of vaccines, drugs and other treatments.

THE FUTURE IS IN SYNTHETIC CONTROL ARMS There are many challenges associated with traditional clinical trial approaches. Factors such as speed, accuracy, costs, failure rates and diverse patient population recruitment in combination with the biological complexity of diseases, can prevent the evolution of trials.

Synthetic control arms could significantly contribute in transforming clinical development by helping pharmaceutical companies improve clinical trial design and success rates. Specifically, they could help overcome patient stratification challenges, reduce the amount of time it takes to develop medical treatments, and improve patient recruitment by allaying patient concerns about receiving a placebo.

They could also enable the management of large diverse trials while providing the opportunity to reduce both the time and costs associated with clinical trials, and gain a better understanding around the efficacy of investigational treatments.

Essentially, synthetic control arms utilise both real-world and historical clinical trial data to model patient control groups, removing the need to administer placebo treatments to patients, which can be detrimental to their health, negatively affect trial enrolment and patient outcomes. This approach can be particularly useful for rare diseases where patient populations are smaller and/or where lifespan is short due to the aggressive nature of the disease. Deploying this technology throughout clinical trials and taking the step to bring trials closer to the patients can hugely reduce the

inconvenience of traveling to research sites and the burden of undertaking consistent medical tests. Time spent on recruiting representative patients during the trial process can also be much more efficient.

For clinicians, applying machine learning, and artificial intelligence in particular, during the clinical trial process means previously collected data sets can be analysed at a much faster pace, often with greater efficiency and more reliability. At a time when clinical trials are undergoing huge amounts of digital transformation, integrating synthetic control arms into medical research offers new and exciting opportunities that can revolutionise drug development.

With the number of available data sources continuing to increase, these synthetic control arms could become the fastest and safest way for pharma companies to use real-world data for research into diseases with large enough patient populations.

Leveraging real-world data to drive synthetic control arms and applying AI and ML technologies to analyse it, offers the promise of more efficient, safe and fast-paced trials. It poses the opportunity for researchers to quickly achieve more homogeneous patient populations and gain meaningful insights. The use of essentially a virtual patient enables them to test which drugs are suitable for certain patient cohorts, and allows them to “fail” as many times as they need in order to find the right drug for the right patient, taking a step closer to truly personalised healthcare and improved patient outcomes.

REGULATION AND SYNTHETIC CONTROL ARMS While using patient data effectively presents the

23 opportunity to deliver a healthier future, it also raises important considerations regarding ethics, privacy and transparency. It’s critical that the industry along with other key stakeholders work with regulators to determine how patient data can be analysed to support getting medicines to patients more quickly, while still maintaining trust over the way that data is used, and which meets the highest data security and governance standards.

Patients will always have ownership of their data. They need to know and have the right to know what their data is going to be used for and have a clear understanding of the positive impact this will have for research and the patient care landscape as a whole.

There is now an ongoing mindset shift towards applying this kind of advanced technology in the pharma and healthcare sector, partially triggered by the pandemic and the rapid development of the Covid vaccines. With greater amounts of patient data now being collected through the use of remote monitoring technologies, electronic medical records and consumer health devices, researchers will be able to develop drugs and treatments with far more targeted, cost and time effective results.

Through using existing technology combined with close partnerships with hospitals and healthcare providers, application and access to data will revolutionise medical research, not to mention improve diversity, safety and efficiency.

The pandemic brought about an urgency to speed up the way we develop vaccines – and clinical trials were a huge part of this. Now, looking to the future, we must continue to innovate and make trials as quick, safe and effective as possible.

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PRECISION MEDICINE

THE ETHICAL CHALLENGES OF PRECISION MEDICINE The key ethical questions of precision medicine and what the industry needs to do to overcome them.

P

recision medicine could transform healthcare as we know it. But putting it into practice is far from simple and some serious questions have been raised already about ethics.

WHAT IS PRECISION MEDICINE? Healthcare has been transformed in recent years thanks to the explosion of genomic data and the rise of precision medicine.

Precision medicine is an emerging approach for disease treatment and prevention that considers individual variability in genes, environment, and lifestyle. Its potential lies in medical practitioners being able to provide a tailored approach to medicine, rather than a onesize-fits-all solution.

It may sound futuristic, but it has already been applied to real life scenarios with great success. However, to meet its full potential, there are still several challenges medical professionals need to overcome – one of which is the ethics of its application.

COMMUNICATING INCIDENTAL FINDINGS When it comes to implementing precision medicine, a key grey area is what practitioners should do with incidental findings.

Incidental findings aren’t new to modern medicine. In fact, medical imaging such as x-ray

and CT scans often reveal anomalies that are unrelated to what they were originally looking for. This is no different in databank research where additional findings can reveal potential health or reproductive issues for the individual.

Whilst communicating incidental findings is general practice in genetic research, as it stands, there is no legal duty of sharing additional research findings with patients. Various questions remain as a result. For example, what type of findings should practitioners and researchers communicate? The significance of findings is not always clear.

Incorrect findings also occur, and they have the potential to lead to unrequired expenses on healthcare. Should practitioners therefore agree on which specific incidental findings should be communicated, or should communication of findings be mandatory across the board?

The answer to the latter might not be clear cut when we consider communicating conditions or diseases for which there are no known treatments available. Practitioners must consider the psychological repercussions in these cases: is it still advisable to tell someone they have an increased risk of developing a disease, when nothing can be done? Does the individual still have a right to know or is the knowledge only harmful at this point?

The answer is that this must be addressed early on. Genetic sequencing warrants an informed consent process. It is at this initial stage that clinicians should discuss the possibility that any type of genetic testing may yield additional findings and agree whether the patient or their family - wants to receive such findings.

GENETIC DISCRIMINATION As precision medicine becomes a mainstream form of healthcare, practices also need to be put in place to prevent individuals from being discriminated against based on their genetic make-up. Without this protection, individuals who are discovered to be at risk of certain diseases, or carriers of deleterious genetic variants, could find themselves vulnerable to discrimination from the likes of employers who could decide to recruit only “healthy” talent, or insurers who could offer products based on individuals’ genetic profiles.

In fact, there have already been growing calls to restrict life insurers’ access to genetic test information, as there are concerns that genetic discrimination may discourage people from participating in genetic testing and research.

The only way we can address those fears is by creating protections on the genetic information insurers are allowed to access, and ensure that genetic discrimination is

outlawed in the same way it is for sex, disability and race.

THEOLOGY AND GENETICS Another factor to consider is the interplay between genetics and theology. Genetic research – whether that is IVF, genetic engineering, or gene therapy - has often raised ethical questions for religious communities. Religions such as Catholicism, for instance, do not support treatments like IVF and there are minorities of various faiths that have expressed concerns about predictive medicine in the past.

Mainstream Islamic scholarship is actually more permissive than many other religions when it comes to genetic or cellular level interventions. Islamic scholars have also taken a progressive stance on incidental findings, not only encouraging them to be reported, but saying healthcare professionals are obliged to do so if the detected finding causes a life-threatening and actionable disease.

This support for personalised medicine has been reflected in the wider Muslim community; in fact, a recent national survey showed that 71% of Qataris said they would be willing to donate a sample for the Qatar Genome Project.

Nevertheless, as precision medicine is incorporated into mainstream healthcare, practitioners around the world

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will need to improve the public’s understanding of genetics and empower communities that may otherwise be sceptical of this area of science.

THE NEXT PRIVACY BATTLEFIELD Perhaps the biggest area for concern from a public perspective is data privacy.

We’ve seen first-hand from some of the privacy violations from social media companies that data ownership is an important and sensitive topic for individuals.

Precision medicine demands that individuals contribute their

medical histories and genomes to big data research pools, and it is understandable that the public is therefore concerned about the risk of data being exposed. When it comes to personal information, genomic data is as sensitive as it gets.

Questions have also been raised around who owns the genetic data – the medical professionals or individuals - and therefore, whether researchers need to alert participants whenever their data or specimens are used. With data stored for long periods of time, it is impossible to anticipate all future uses of data and information at

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the start – adding an extra layer of complexity.

Perhaps one of the more surprising solutions to the problem of privacy and ownership is blockchain, since blockchain does not reveal anything specific or personal about the user and cannot be traced back to them.

On the other hand, individuals are given complete control of their own data and are even able to monitor its usage.

THE FUTURE OF PRECISION MEDICINE In an age of personalised medicine, access to genetic data is a valuable commodity for medical professionals. However, if pharma and healthcare industries are to expand their use of genetic information successfully, they will need to address these ethical challenges and give individuals peace of mind.

Author: DR SAID ISMAIL - director of Qatar Genome Programme

The best way we can achieve this is through more standardised best practices. It is important that any new regulations are balanced preserving sensitive biological information for the individual, whilst avoiding unnecessary red tape that could stifle innovation in the field.

The ethics of precision medicine isn’t just an area of debate in theology and philosophy. It is in fact critical to the development of medical practices and their associated laws. We therefore cannot afford to ignore it if precision medicine is to take off at a global scale.

When it comes to personal information, genomic data is as sensitive as it gets.

26

INDUSTRY

insi

hts

HELPING OUT How one company found itself in the right place at the right time to help the industry operate throughout Covid-19.

I

n March of 2020, businesses all over the world panicked as countries went into lockdown due to the spread of coronavirus.

For the life sciences industry, the pressure would have been immense. The global necessity not just for coronavirus test kits and diagnostics, but for the thousands upon thousands of healthcare products that are essential to the wellbeing of patients all across the globe, means that the life sciences industry is not one that can simply stop operating without consequence.

“Every company had to respond quickly when the pandemic originally happened but none more so than the pharmaceutical industry. There was a very sudden increase in demand for services and at the same time – as with everyone else – a decrease in the ability to provide them,” said Devon Copely, CEO of remote communications company Avatour.

When the pandemic hit, Copely found that Avatour was in a position where it could help the pharma industry continue to operate.

Avatour provides a platform for remote site meetings, where an operator uses an inexpensive 360° camera to guide participants, wherever they are, through a tour of a location. For pharma, this means that companies can remotely connect with inspectors to complete

And the benefits may be more widespread than people think.

Avatour’s ability to conduct remote site inspections ultimately means that quality personnel are travelling less. It isn’t just money that companies are saving either it can give employees a better work/life balance. As Copely puts it: “It’s people being able to go home and have dinner with their kids.”

Author: Article and interview by Reece Armstrong

For Copely, Covid-19 represented a shift in the way that pharma companies viewed the adoption of technology. internal and external audits of their production facilities.

For Copely, Covid-19 represented a shift in the way that pharma companies viewed the adoption of technology. With key quality personnel restricted from travel due to coronavirus, pharma companies quickly realised that they needed another way to conduct audits and assessments that didn’t require an in-person visit.

“There was a panicked search for alternatives and options. For us, with the Avatour product, we had very recently launched the product and quite honestly we were kind of in the right place at the right time,” Copely admits.

Since then, Copely has seen a progression in how Avatour’s customers looked at how they could be using technology. What started out as an initial panicked search for technology that could enable businesses to run under Covid-19 restrictions, quickly turned into companies reassessing how technologies could benefit their organisation in a number of different capacities moving forward.

That reduction in travel has other benefits too. With the EU Commission aiming to reduce greenhouse gas emissions by 55% by 2030 compared to 1990, the onus is on industries such as pharma to become more sustainable and reduce their impact on the environment. Already we are seeing the likes of companies such as Merck, Chiesi, AstraZeneca and others take hard stances on sustainable working.

Copely hopes that companies like Avatour, which offer alternatives to travel through remote video conferencing, can be one part of the industry’s solution towards becoming more environmentally friendly.

Going forward it will be interesting to see if the adoption of technology in pharma continues at an accelerated pace after Covid-19. One thing is for certain though, Covid-19 has forced pharma to rely on tech in ways it never before imagined. What happens next is up to the industry.

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BIOLOGICS

Think lean The importance of accuracy and precision in bioassays and how it can help boost manufacturing efficiency.

A

Author: ANN YELLOWLEES founder of Quantics Biostatistics

n essential part of the pharmaceutical manufacture of many biologics is a bioassay to measure batch potency. The fundamental requirements for the assay are that it should meet the required accuracy and precision criteria.

LOOKING TO LEAN Whilst the pharmaceutical industry is, in general, investing in the ideas of lean manufacturing to reduce waste and improve efficiency - “to do more and more with less and less” - little or no attention has been given to the bioassay that is an essential part of batch release.

An assay may be in use for years and is often a hidden factor that significantly increases costs and resource use. So, what is the scope for “leaning” a bioassay in routine use to contribute to efficient manufacturing?

LEANING A BIOASSAY In bioassay development, the final method is normally locked when adequate precision and accuracy have been achieved, formally documented as part of the statistical validation step.

Once validation is complete, the assay may remain in use in the same format for many years.

During development, assays often evolve in a complex way. In the hunt for acceptable accuracy and precision many different designs are tried out,

and there are many choices to be made. This can include: the number of doses; dose spacing; replicates within and across plates; statistical models; system and sample suitability criteria, as well as many different biological design choices.

To quote E.B. White, “There’s no limit to how complicated things can get on account of one thing always leading to another” and in bioassay development the result is often an assay that fulfils the primary objective but is far from optimal.

THINGS TO CONSIDER It should go without saying that for efficient manufacturing, the assay should also only pass samples that should pass, and fail those that should fail.

This is a problem because bioassays are statistically (and biologically complex) and the pass / fail criteria are usually dependent on probabilities, or “p values”, typically set at 0.05.

Consider an assay that has one such test on the reference and one on the sample. These are independent and, on average, ~10% of samples that should pass will be recorded as failing. It is the way the math works; it is called Type 1 error. (It is a bit more complex

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Little or no attention has been given to the bioassay that is an essential part of batch release. if the tests are correlated.)

How many suitability criteria do you have?

To avoid deviations in the pass / fail criteria, manufacturers should ensure that only strictly necessary system and sample suitability criteria are used. Aim for 99% pass rate of samples in usual ranges (USP 1032).

Be as simple as possible from a laboratory point of view – Reduce plate “real estate” Unnecessary replicates and plates will lead to more laboratory errors and assay or sample failures. More than one plate will

increase maths type 1 failures as the number of suitability criteria applied increases.

Therefore, the lab should be ensuring that there are no unnecessary replicates / doses / plates in the design.

MAXIMISE THROUGHPUT AND REDUCE LABORATORY REQUIREMENTS Removing unnecessary replicates and plates will allow more samples per plate and higher throughput. Therefore, minimise the plate real estate required per sample.

REDUCE QUALITY ASSURANCE (QA) AND QUALITY CONTROL (QC).

A simple laboratory process is easier for QA/QC, but the resulting increased throughput increases QA/QC burden.

However, automated QA/QC can speed production release and reduce QA costs. Look to choose appropriate software that is suitable for automation and consider fully automated continuous real time validation systems if available.

HOW AND WHEN? Once the biology is stable and well characterized, it is time to re-evaluate the design – think about leaning your assay before validation. Stop, step

Other Considerations: …BE SIMPLE TO “TECH TRANSFER”.

A simple assay is also much easier to transfer. … BE STRAIGHTFORWARD TO MONITOR Simple assays make it easier to determine whether a sample is failing the assay, or the assay is failing the sample.

29 back and review whether all the elements of your design are actually required before continuing.

By this stage, there is usually lots of data available and a biomathematical approach can use techniques such as variance components analysis and simulation to optimise the design with respect to plates, doses, layouts and replicates.

Often little or no further laboratory work is required.

Many suitability criteria are mathematically related to each other, and a competent biomathematician can reanalyse development data sets to look at the passes and fails with different criteria and in almost every case reduce the number of proposed tests significantly. NB: USP General Chapter 1032 states:” …it is advisable to accept large fractions of these control ranges (99% or more) and to assess system suitability using only a few uncorrelated standard response parameters.”

LEANING IN PRACTICE WHAT CAN BE ACHIEVED? Doubling throughput and cutting assay failure rate by 30-50% each would not be unusual. As an example, Public Health England asked Quantics to lean an assay for them. The results were presented at the BEBPA conference in 2018. There was a lot of historical data so no further laboratory work was required. Leaning the assay resulted in a reduction of the number of doses required from eight to four; the throughput was doubled. So, if you are about to validate your assay, now is the time to stop and ask… is this lean?

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Talking points Open Oprhan launches infectious disease spin-out

O

pen Orphan has launched the spin-out organisation, Biotech Poolbeg targeting the infectious disease market.

Poolbeg Pharma’s lead asset is a first-in-class, small molecule immunomodulator for severe influenza. POLB 001, as it’s known, is already positioned for phase II trials and if successful, Poolbeg states it can address unmet need for effective treatments against severe influenza.

Poolbeg has a number of data platforms that are designed to discover new therapies and predict diseases. The company’s Vaccine Discovery Platform takes data from the human challenge model in an effort to discover new vaccines. More so, its PredictViral Biomarker platform can be used to predict severe disease and potentially help guide parts of the industry on how infectious diseases are treated. Poolbeg will use a capital light business model to develop assets through to Phase II quickly.

If its therapies are successful, then the company will look into monetising them through licensing deals with larger pharmaceutical companies.

Speaking to EPM, Jeremy Skillington, CEO of Poolbeg Pharma said that the company’s focus is to develop “infectious disease therapies more efficiently and effectively.”

WHO TO SET UP COVID VACCINE HUB IN SOUTH AFRICA

T

he World Health Organisation (WHO) will set up the first Covid mRNA vaccine technology transfer hub in South Africa.

The hub will enable manufacturers to receive training and any necessary licenses to the technology required to develop mRNA vaccines for Covid-19. WHO and partners will bring in the production know-how, quality control and necessary licenses to a single entity to facilitate a broad and rapid technology transfer to multiple recipients.

WHO will work alongside a consortium of South African organisations including Biovac, Afrigen Biologics and Vaccines, a network of universities and the Africa Centres for Disease Control and Prevention (CDC), to set up the hub.

Biovac and Afrigen will provide development and manufacturing work for mRNA vaccines for Covid-19, whilst the universities will provide mRNA-know-how, with Africa CDC offering technical and regional support.

“This is great news, particularly for Africa, which has the least access to vaccines,” said Dr Tedros Adhanom Ghebreyesus, WHO director-general.

“Covid-19 has highlighted the importance of local production to address health emergencies, strengthen regional health security and expand sustainable access to health products.”

OUTSIDE EPM

R

achel Shelley, head of medical technologies, IDA Ireland, explains why medtech is well placed to lead in ‘lights-out’ manufacturing, and how companies in Ireland are being helped towards this.

Make sure to read the full article on www.med-technews.com

BE SURE TO LISTEN TO The latest episode of The MedTalk Podcast sees EPM editor Reece Armstrong speak to Paul O’Donohoe, scientific lead, eCOA and Mobile Health at Medidata about how digital technologies are affecting clinical trials in the pharmaceutical industry.

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