EPM November/December 2018

BIG DATA IN CONTINUOUS BIOPROCESSING

THE LATEST IN BREXIT

HIGHLIGHTS OF 2018

December 2018

BRIDGING THE DIVIDE

Catalent discusses the methods that can be used to bridge the discipline gap when classifying a drug’s solubility

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Contents

December 2018 | Volume 18 Issue 8 REGULARS 5 EDITOR’S DESK

The growing threat of antimicrobial resistance (AMR) and why it’s time for governments to step up their game.

6 A SMALL DOSE A brief round-up of some of the latest developments in the industry, including a potential new way to treat cancer, a recent collaboration on drug discovery and a preview of Pharmapack 2019.

9 ANALYSIS The UK’s medicines supply situation in a no-deal Brexit scenario and how data is advancing continuous bioprocessing.

14 OPINION Find out if the pharmaceutical supply chain is ready for true medicine traceability in this article by Zebra Technologies.

16 COVER STORY Catalent discusses how to bridge the divide between disciplines when classifying a drug’s solubility.

34 TECH TALK In our last ever Tech Talk Novarum looks at how to mitigate risks for mHealth apps.

FEATURES 19 SECTOR HIGHLIGHTS Some of the biggest names in pharmaceutical manufacturing give their highlights of 2018.

22 HIGH POTENCY FACILITIES Safety and integrated mobile solutions and the principles of roller compaction in highly potent active pharmaceutical ingredients (API).

27 MERGERS & ACQUISITIONS Is heightened due diligence needed for pharmaceutical manufacturers during mergers and acquisitions?

28 SEPARATION TECHNOLOGY How manufacturers can use total organic carbon (TOC) analysis to delivery reliable results.

31 CONTAINMENT How wireless integrity testers can help manufacturers secure sterility.

32 REGULATORY AFFAIRS Helpful tips on regulatory guidance from a new life sciences conference.

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RESISTANCE ISN’T FUTILE It’s no secret that antimicrobial resistance (AMR) is one of the biggest threats to modern medicine. Though unlike the multitude of sleepless nights caused by a fear of conditions like cancer and dementia, AMR seems to barely register on the general public’s list of worries.

Tel. +44 (0)1244 680222 Fax. +44 (0)1244 671074 Web: www.epmmagazine.com

EDITORIAL editor reece armstrong reece.armstrong@rapidnews.com deputy group editor dave gray david.gray@rapidnews.com

In the UK in particular, political activity addressing AMR seems to have decreased in the past five years, despite widespread concern from the life sciences industry. It’s probably fair to say that the UK government has been slightly preoccupied since around June 2016, but it’s still worrying just how little attention is being paid to AMR.

head of content, life sciences lu rahman, lu.rahman@rapidnews.com publisher duncan wood

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Volume 18 Issue 8 © December 2018

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Unlike the multitude of sleepless nights caused by a fear of conditions like cancer and dementia, AMR seems to barely register on the general public’s list of worries.

A recent report by the Health and Social Care Committee highlighted the lack of visible political leadership in regard to AMR. Indeed, the report states that there have been no inter-ministerial meetings held to discuss AMR by the UK government in the past 15 months.

The statistics surrounding AMR should be enough to spur

EDITOR’S DESK government into action all over the world. As it stands, AMR infections currently kill around 700,000 people around the world, every year. If this sounds bad now, in the next 30 years, deaths related to AMR are expected to overtake the global toll of both cancer and diabetes, rising to over 10 million a year by 2050.

To exemplify the matter further, a collection of 36 life science organisations have called on the UK government to address the chronic underfunding and shortage of scientists that are working towards new antibiotics.

Not that steps aren’t being taken to tackle AMR. Recently, the UK government announced over £10 million to be used to progress a number of AMR initiatives. Around half of the funding will be used to develop new diagnostic methods targeting ‘super gonorrhoea’. The funding will also be used to find new ways to diagnose AMR and to ensure that antibiotics are being used appropriately. Still, if the addition of a superhero moniker to gonorrhoea doesn’t keep you awake at night, I don’t know what will.

It isn’t just government however. Consider the charity and celebrity-led campaigns which are designed to raise awareness for a multitude of conditions and diseases. AMR has no such backing, a fact which isn’t surprising when diseases such as cancer have such personable and visible effects on patients and their families. Even worse has been the exit of big pharma from the AMR stage, and there are now only six major players involved in developing new antimicrobial treatments.

Hopefully when the government’s updated AMR strategy is released in 2019, we’ll see clarification and actionable ways to tackle this growing threat. Until then, if you come down with a cold during the Christmas holidays, maybe think twice before asking your doctor for that antibiotic.

Happy holidays.

6

A small dose

A new strategy to treat cancer

What’s on at PHARMAPACK EUROPE 2019

P

harmapack Europe 2019 is set to showcase the latest innovations when it returns to the Paris Expo Porte de Versailles from 6 - 7 February next year.

Pharmapack 2019 is expected to play host to over 410 exhibitors and 5,290 attendees from more than 100 unique countries over two days, making it the most international edition to date.

R

esearchers have discovered a new way to reactivate genes that have been epigenetically silenced by cancer.

The show’s conference agenda will be delivered by industry expert speakers, discussing the current pharmaceutical packaging market trends along with an overview and analysis on regulatory changes in the EU and US markets.

Visitors can expect major themes, including patient adherence, challenges in usability, regulatory

updates, new biologicals and biosimilar drug delivery devices to be featured throughout conferences.

Pharma industry leaders will be

NEW METHOD DEVELOPED TO DETECT ANTIBIOTIC RESISTANT BACTERIA IN A MATTER OF MINUTES

A team at the Fels Institute for Cancer Research & Molecular Biology at Lewis Katz School of Medicine at Temple University (LKSOM) discovered how to reactivate genes by inhibiting the DNA transcription regulator CDK9.

The team found that reactivating genes leads to restored tumour suppression gene expression and enhanced immunity against cancer.

Researchers performed a live cell drug screen with genetic confirmation to identify CDK9 as a target, then developed and tested a new inhibitor drug - MC180295. They found the drug to be highly selective and could potentially avoid side-effects associated with inhibiting the cell cycle. In addition, the drug showed broad effectiveness against cancer both in vitro and vivo.

R

esearchers at UC Berkeley have found a way to identify bacteria that are resistant to particular classes of antibiotics in a matter of minutes.

The DETECT test is able to recognise the molecular signatures of antibiotic-resistant bacteria in the urine

samples of patients with urinary tract infections (UTI).

Importantly, the test doesn’t use expensive instrumentation and can even be used in a doctor’s office.

It works by identifying specific enzymes (betalactamases) in urine samples or in other

words, the molecules “that are actually breaking down the antibiotics,” according to Tara DeBoer, postdoctoral fellow at UC Berkeley.

DETECT uses an enzymatic chain reaction to boost the signal from beta-lactamases by a factor of 40,000,

7

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exhibiting at the 2019 Technical Symposium, highlighting ways to tackle the challenges associated with new approaches. This will include eight casestudy demonstrations to allow for a better understanding of implementing strategy when selecting, integrating and managing solutions.

allowing the test to detect the enzymes in urine samples. Using DETECT, if a patient tests positive for a UTI they can then be treated with a more powerful antibiotic or a different therapy.

The team are now working on developing the test so it can be used to detect antibiotic resistant bacteria in blood samples.

“Drug-resistant infections are a silent pandemic that actually kill more people every year than Zika or Ebola,” said Lee Riley, professor of epidemiology and infectious diseases in the School of Public Health at UC Berkeley. “The faster you can start the right drug, the better the chances of survival or avoiding complications.”

In particular, there will be a presentation delivered

by Nicolas Perrin, branch manager at Antares Vision France, where he will discuss a disruptive approach, moving beyond serialisation, to optimise performance of the value chain.

Once again, the Pharmapack Awards will be hosted alongside the show and will celebrate the latest innovations coming from the pharmaceutical packaging industry. The awards’ two categories – Health Product

& Exhibitor Innovations – are judged by a jury of independent industry experts, with the awards being presented on 6 February.

All of the innovations submitted for the Pharmapack Awards are showcased in the Innovation Gallery – the exhibition’s comprehensive overview of recently launched products.

Moreover, there will be hour long Innovation Tours delivered by industry experts to highlight exceptional exhibitors throughout the innovation gallery.

In the centre of the show, visitors will find the 2019 Start-up Hub, a platform dedicated to young companies developing new and innovative technologies across pharmaceutical packaging, labelling, drug delivery device design and engineering.

Exhibitors will be able to take part in the Start-up Pitch to highlight their products to a panel of experts and an audience of industry professionals.

Lastly, the International Meetings Programme is

a complementary online service which allows exhibitors and visitors to pre-arrange mutuallybeneficial meetings for the event.

Visitors can expect to see the latest innovations and exciting products when Pharmapack Europe 2019 runs from 6 - 7 February next year.

New collaboration aims to boost use of bioanalytical technology for drug discovery

A

new collaboration between the Medicines Discovery Catapult and AstraZeneca has been announced to help boost the use of acoustic mist ionisation mass spectrometry (AMI-MS) within drug discovery.

The collaboration enables UK small and medium-sized enterprises (SMEs) to access state-of-the-art bioanalytical technology through research partnerships with the Catapult.

Traditional mass spectrometry is used to determine the mass, structure and number of molecules, but is limited by the rate at which samples can be introduced to the instrument. AMI-MS uses sound energy and can analyse up to three samples every second, or over 100,000 samples every day.

Dr Peter Simpson, chief scientific officer of the Medicines Discovery Catapult, said: “It is important

for us to enable UK SMEs to use hard-toaccess sophisticated bioanalytical technologies. For the first time, using the power of sound energy, this state-ofthe-art technology gives our partner SMEs the potential to better understand and more rapidly advance their promising drug candidates.”

Dr Jon Wingfield, principal scientist, Innovative Medicines and Early Development

(IMED) Biotech Unit at AstraZeneca added: “We are investing in ground-breaking science to help lead the way in mass spectrometry screening.

Our collaboration with Medicines Discovery Catapult will not only enable us to engage with the wider scientific community but will also allow us to unlock the potential of acoustic mass spectrometry within drug discovery.”

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9

NEWS ANALYSIS

INDUSTRY’S BREXIT WORRIES START TO SHOW Reece Armstrong examines the impact a no-deal Brexit would place on medicines supply in the UK.

A

nother edition means another Brexit development. Well perhaps development is a bit of a strong word considering how many things seem to be up in the air at the moment.

The latest Brexit news comes from logistics export, Tudor International Freight, who warns businesses trading with the EU to brace for disruption if the UK leaves the EU without a deal.

Indeed, with the UK set to leave the EU in less than six months, the notion of leaving without a deal is a “very real” possibility, warns managing director David Johnson.

If this all sounds a bit complicated it’s because we know that Brexit has been, if anything, smooth sailing.

Other developments came from a Health and Social Care Committee held in October, which aimed to look at the impact of a no-deal Brexit and featured representatives of the pharmaceutical industry, as well as a number of MPs. The session made it clear that there are major concerns surrounding the delivery of medicines into the UK. What keeps Martin Sawyer, executive director, Healthcare Distribution Association, up at night is the complicated, integrated supply chain that currently exists between the EU and the UK.

“On average, 50% of the medicines in most of our depots have been through the EU before they get to UK warehouses, and this whole integrated supply chain that we rely on was clearly set up after we joined the EU. It is only in the last 20 years that it has been put in place. It is very sophisticated—twice a day delivery “just in time.”

Logistical issues are made more complicated by the coldchain storage required for the transportation of certain medicines and biologics. Mike Thompson, chief executive, Association of British Pharmaceutical Industry (ABPI) pointed out that “there are no cold-chain facilities at the border ports” and that is why “we rely on real frictionless trade to be able to move medicines quickly.”

Of course, plans for a no-deal Brexit have been put in place since last December, with members of the ABPI being requested to “build an extra six weeks’ stock,” according to Thompson. Whilst commendable, there are no illusions that stockpiling medicines will be an effective solution to any potential shortages in the UK.

Worse still, there are not enough cold-chain warehouses in the UK to cover the stockpiles that are being created, meaning the government is now having to build additional cold-chain units to house the extra medicines.

If this all sounds a bit complicated it’s because we know that Brexit has been, if anything, smooth sailing. Thankfully, a focus on ensuring patients are having their medicines delivered when needed was a point raised many times during the committee.

“Our main concern is to ensure that we can continue to deliver the medicines that patients need, both here and on the continent, through this period. That is the thing we have been working hardest to do,” Thompson said.

But whilst the sentiment is appreciated, the vagueness of the current situation means that we’re heading into Brexit with a looming worry over how likely it is patients will be able to receive their required medicines – something which should be considered unacceptable for a country of relative modernity.

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11

ANALYSIS

Data, machine learning and the road to continuous bioprocessing Martin Smith, chief technology officer of Pall Corporation, explores how data is finally unlocking the door to continuous bioprocessing in medicine manufacture.

T

he journey from tried and tested batch manufacture to continuous bioprocessing has been a long and gradual process.

It began around two decades ago when manufacturers started to shift from stainless steel systems to single-use components, eventually leading to the introduction of modular systems – but the pace of change has been slow.

Pharmaceutical manufacturers have historically been wary of departing from batch processing – largely because of perceived risk of contamination and control issues, large investments of capital already made in stainless steel plants, and lingering concerns around regulatory barriers to process change.

Now, finally, things are changing.

Our burgeoning ability to harness the power of data is giving us means by which to demonstrate the remarkable cost-efficiency, consistency and scalability of continuous bioprocessing, while eradicating the perceived disadvantages of regulatory risk and compliance challenges.

With increased cost pressures, greater competition and public criticism for medicine shortages, manufacturers have had to stop and consider the huge potential benefits that continuous processes can bring. Investing in continuous manufacturing methods is now critical to longevity, profitability and survival, as well as the key to finding a more efficient way to ensure the right patient receives the right medicine, at the right time.

PLAYING CATCH UP A wide range of industries have experienced the benefits of continuous for many years, including increased efficacy and reliability, reduced capital costs and failure rates, and improved process control.

Data and technology have expedited the pace of change within industries such as food and automotive. While automotive manufacturers have been embracing Industry 4.0 for many years now, including utilising AI, robotics and data analytics technologies as a matter of course, these transformative technologies are still nascent in biopharma.

The pharmaceutical laboratory has remained largely unchanged for decades; only now is the industry genuinely talking about the ‘Lab of the Future’ with real conviction.

This has hindered the sector’s move to continuous processes.

As was the case with single-use components, pharmaceutical manufacturers want the reassurance of hard data and evidence of scalability before they make a change. But since adoption of cutting-edge technology has been slow, data on continuous exists on a very small scale, making it a challenge to demonstrate production-scale viability. This cycle has been hard to break.

CONTINUOUS CHROMATOGRAPHY Nothing demonstrates value of the continuous approach more than the possible improvements it can bring to chromatography.

Chromatography systems have been critical in the production of new medicines for many years.

The technology is well established and many manufacturers have been reluctant to go against the status quo, but the potential for huge cost savings are driving a major shift to continuous chromatology.

Chromatography is usually the most cost-intensive aspect of downstream bioprocessing.

Protein A sorbents used in the primary capture step, for example, can cost over $10,000 per litre.

However, by optimising the number of columns needed to operate this process, manufacturers can enable reductions in buffer and decrease the volume of sorbent used by up to 90%. This vastly improves the efficiency of consumable use, while also reducing the need for large tanks, buffer-storage bags and other equipment – all of which takes considerable cost out of the manufacturing process.

Of course, this is often easier said than done. Column numbers and configurations need to be optimised on a case-by-case basis, and every bioprocess is different.

Many different factors including binding capacity (which permits reduction of buffer consumption), productivity (which enables minimisation of sorbent use) and workflow (which minimises time) impact the decision and need careful consideration to achieve the best results.

To determine column numbers and configurations effectively, you need

12

ANALYSIS

data. At Pall, we have developed a number of tools to calculate the optimal column numbers from any given parameters, enabling us to predict the best configuration for a particular situation.

UNLOCKING THE FUTURE Data analytics and monitoring, as well the application of cuttingedge automation have a key role to play when it comes to regulatory issues too.

There are several perceived risks that have hindered uptake in the past. In continuous processing, for example, unit operations mostly run for longer periods than in batch systems, which raises questions about bioburden management and process consistency. There are also concerns that the use of more complex instrumentation in continuous bioprocessing could generate additional risk of equipment failure.

These fears, while understandable, do not bear scrutiny. From a regulatory perspective, continuous processing is inherently no riskier than batch processing – indeed,

the current regulations make no distinction between batch and continuous processing. And on the subject of complexity, the sophisticated nature of continuous systems reduces risk, rather than creating it: the quality of data that manufacturers can generate around process parameters using these advanced instruments makes it infinitely easier to show consistent operation within acceptable ranges.

These robust datasets can speed up the process for clinical approvals and have the potential to form the foundation of a new approach to regulation. Instead of the classic model of regulators approving each stage of batch processing, we could see the emergence of a more seamless, integrated drug approval process, improving speed to market.

Most importantly, it is patients that will ultimately feel the true benefit of an industry-wide shift to continuous bioprocessing. Where traditional batch processing could take up to seven weeks, continuous bioprocessing could deliver the same product in just one week.

This vast improvement in the speed at which biopharmaceutical companies can evaluate the viability of a new product, produce clinical trial material and reach potential failure points will help tackle some of the world’s most pressing medicine shortages.

This, coupled with the remarkable financial benefits manufacturers can realise, makes going continuous a question of when not if, and something the industry can no longer afford to ignore.

Nothing demonstrates value of the continuous approach more than the possible improvements it can bring to chromatography.

14

Opinion

No country is immune from this scourge, with traffickers primarily targeting anti-cancer drugs which can carry an annual treatment cost of more than $50,000.

WHY THE PHARMA SUPPLY CHAIN NEEDS TO BE READY FOR TRACEABILITY In advance of new European measures to help reduce counterfeit medicines, Wayne Miller, healthcare director EMEA at Zebra Technologies, asks if the pharmaceutical supply chain is ready for true medicine traceability.

M

ore than 400,000 pharmacies in Europe will be impacted by European Directive 2011/62/EU, ratified by the European Parliament in 2016 and effective in February 2019. The intent of this measure is to prevent the introduction of illegal medicine into the legal supply chain. This means pharmaceutical industry players must consolidate their medicine traceability practices to fight a rise in medicine counterfeiting. What lessons can be learnt from this supply chain revolution?

According to the World Health Organization, about 700,000 deaths worldwide every year are caused by the sale of counterfeit medicines. No country is immune from this scourge, with traďŹƒckers primarily targeting anti-cancer drugs which can carry an annual treatment cost of more than $50,000.

To counter this trend and alleviate patient concerns, the pharmaceutical industry has already established several defensive procedures which will be reinforced with the Parliament’s Directive. But how ready is the entire pharma supply chain to apply this new regulation?

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THE PHARMACEUTICAL INDUSTRY IS COMMITTED TO PATIENT PROTECTION One result of Directive 2011/62/EU is the introduction of a unique serial number to be applied to the packaging of all medication. Known as serialisation, this labelling process has set a race against time for all branches of the global pharmaceutical industry including laboratories, manufacturers and pharmacies who must integrate it to help ensure the meticulous monitoring of all medicines, from their manufacture to their sale in pharmacies.

Updating production lines and installing appropriate coding equipment is a complex task. It requires first-rate technical abilities and machines which can deliver high-quality printing. Similarly, serialisation introduces substantial production investments for most companies in the pharmaceutical industry, as revealed in a KPMG survey published in May 2017.

Europe’s pharmacies will also have to adapt by procuring 2D barcode scanners, which are critical in checking the compliance of any medicine sold.

The result is a major upheaval throughout the supply chain, where monitoring of this new unique number is vital both upstream and downstream.

TRACEABILITY IS VITAL IN FIGHTING COUNTERFEITING This substantial investment is a critical support in fighting counterfeit medicines and vaccines.

In fact, anti-counterfeiting and safety procedures will continue to play a significant role in the folding carton packaging sector. According to a report by the Smithers Pira design office titled “The Future of Folding Cartons to 2022”, traceability solutions represent one of the four major advances in technology set to transform the market by 2022.

Indeed, once it is possible to identify where a medicine package has come from, the risk of getting a counterfeit product is drastically reduced.

An increase in traceability procedures should help scale down a massive global counterfeiting industry, estimated by the World Economic Forum to exceed $200 billion worldwide in 2017.

SERIALISATION PROVIDES A MEANS TO SECURE EVERY LEVEL IN THE SUPPLY CHAIN That which holds true for the pharmaceutical industry also applies to other sectors like the food, textiles and leather goods industries, which are also facing increasingly sophisticated counterfeiting schemes.

In certain food industry scandals, serialisation would have helped in identifying fraudulent products or batches bearing inaccurate labels.

Thanks to a unique identification code, specific to each unit being sold, the origin and composition of a product could easily be ascertained. Using a basic 2D barcode flash, distributors would be able to follow their listed products in real time anywhere in the world. In the example of a bacterial contamination, distributors could react quickly to prevent it reaching consumers.

This trend involves the entire supply chain.

Beyond printing and monitoring hardware, it also requires software to be integrated into the production line to generate unique codes that can be adapted to the MES (Manufacturing Execution System) and ERP (Enterprise Resource Planning) widely used by enterprises. With this in place, all that remains is applying the unique code to the primary package using printers that can produce a code which will remain legible throughout the product’s lifecycle.

BOOSTING PRODUCT TRACEABILITY: A KEY OBJECTIVE FOR OTHER SECTORS The serialisation set to come into effect within the pharmaceutical industry should help monitor the supply chain and fight the spread of fraudulent medicines and vaccines. The process may also provide some additional benefits including a more accurate view of stocked products with better historical data of the origin and quality of the purchased goods. These benefits could also apply to other sectors confronted with the hazards of counterfeiting.

Serialisation represents an opportunity to modernise current traceability systems.

Through this win-win model, any action taken against parallel markets would be significantly enhanced by controlling the supply chain and the application of data-driven best practices.

No country is immune from this scourge, with traffickers primarily targeting anticancer drugs which can carry an annual treatment cost of more than $50,000.

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16

COVER STORY

BRIDGING THE Stephen Tindal, director of science and technology at Catalent Pharma Solutions discusses what methods can be used to classify a drug’s solubility and bridge the divide between disciplines during development phases.

C

ommonly in the drug development process there is a disconnect between the chemical development of a molecule in the medicinal chemistry phase, and dosage form selection. This is more apparent in smaller research companies that focus on the earlier stages, where there may not be the resources to have extensive expertise across disciplines to guide development with a view to the longer term needs of the molecule.

The portion of new chemical entities (NCEs) that are being progressed through the pipeline by smaller companies is increasing and at the same time, nearly one-third of drug candidates are failing in preclinical studies. So for smaller companies, choosing the correct development partners who can provide the expertise, as well as resource and expertise in areas where the companies may be lacking is increasingly important.

REFERENCES 1 Serajuddin AT: Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007; 59:603-16 2 Butler JM, Dressman JB: The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci. 2010; 99:4940-54.

One of the major areas where the disconnect between disciplines is most apparent is in the development candidate’s solubility.

For the medicinal chemist, the focus is on achieving optimal in vitro potency of the molecule, however this is often at the expense of its biopharmaceutical properties.

Molecular weight and the solubility of molecules are often pushed towards the limits of what would be acceptable under Lipinski’s Rule of Five, and the questions of what salt form or polymorphic form the molecule may take – which can have a have a major influence on both solubility and manufacturability – are often overlooked.

All the actions taken by the medicinal chemist to finely balance the structure, activity, and property requirements of candidate molecules are with little thought as to how this may affect the final drug product, and how the drug will be dosed to patients.

different pH conditions) is often absent. Changing a salt form in later stages of development is difficult without significantly increasing timelines and costs as a new salt form requires repeat biological, toxicological, formulation, and stability tests to be undertaken.

For a formulation scientist, ensuring bioavailability in the drug, as well as stability and manufacturability of the dose are key scientifically; but beyond that, looking at the drug delivery mechanisms and what the route of administration and potential pill burden of the drug product are as important. Formulators will almost always look to increase water solubility, with experience teaching that most drugs’ solubility are too low and this has led to an industry-wide progression of unoptimised drugs or increased development timelines.

The choice of salt form not only affects the solubility, but also the molecular weight of the API, which in turn, affects the weight of the drug product which needs to be carried by whatever drug delivery system is chosen. This is not necessarily an issue in a powderfilled capsule, but in any other formulation with a drug loading of less than 100%, the excipient loading becomes a multiple of the molecular weight increase provided by the salt and the drug loading. This means a larger pill and potentially more pills for the patient to swallow.

If a formulator comes to a project when an API’s salt form and polymorphic form have been decided (based purely on efficacy in the assay), solubility enhancement techniques can lead to delays, especially if the solubility of the salt form is still not high enough or if the solubility increase must be countered by an increase in molecular weight.

A 2007 study1 found that early in the development process, salts are selected based on ease of synthesis and crystallisation, cost of raw material, etc. Unfortunately, focus on downstream processes (physical and chemical stability, processability into dosage forms, solubility, and dissolution rate at

Overcoming this disconnect, where issues are addressed one function after the other rather than simultaneously, needs the development of the final dose form to be considered alongside API optimisation. A formulator has solubility enhancement tools outside of traditional chemistry, including the use of excipients, so by working alongside medicinal chemists, these can potentially eliminate the need for a salt form.

The Developability Classification System (DCS) proposed by Butler and Dressman2 is useful to help guide technology selection, but is not widely used. This classification separates drugs into four classes

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DIVIDE One of the major areas where the disconnect between disciplines is most apparent is in the development candidate’s solubility.

17 Most NCEs would be classified as DCS 2a/2b (dissolution rate or solubility limited). For class 2b compounds, employing particle size reduction alone or dosing as a solution (for example in polyethylene glycol) would not be expected to increase solubility, and solubility-enhancing technologies like amorphous dispersion, lipid formulation, or perhaps co-micronisation should be considered instead, as these technologies are likely to have a far greater impact on the SLAD. For formulators, the DCS is a powerful tool, and by involving them in the later stages of candidate screening alongside medicinal chemists, allows the earlier determination of which salt form, formulation, dose form and drug delivery technologies are appropriate for human clinical trials. This parallel approach, rather than the traditional step wise process of enhancing potency and then finding a formulation that suits the molecule, can lead to acceleration of development projects, saving time up front and potentially, long, costly optimisation work later in clinical development.

based on their jejunal permeability and the volume of simulated intestinal fluid (SIF) needed to dissolve an entire single dose (see Figure 1). DCS also calculates the Solubility Limited Absorbable Dose (SLAD), above which no more drug is expected to dissolve during the transit time through the small intestine, and this is used to split DCS Class 2 into molecules with dissolution rate limitations (DCS Class 2a) and solubility limitations (DCS Class 2b) to oral bioavailability. When reviewing DCS, it is important to remember that dose means the maximum dose taken by a patient at one time (not the highest strength dosage unit), and this number is increased during ascending dose studies.

Figure 1: DCS classification chart

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SECTOR HIGHLIGHTS

EPM speaks to some of the leading names in pharmaceutical manufacturing to find out what the key moments have been for them in 2018.

JONATHAN GAIK, TIFIC, DIRECTOR, NATOLI SCIEN ING EER GIN EN LI TO NA

pened breakthroughs this year hap One of the biggest pharma ijuana. mar from ived der first product when the FDA approved its l (CBD) but idio nab can ing tain con tion The product is an oral solu translate ss that this approval did not the FDA was careful to stre y small Man s. ent pon com er oth or its into approval of marijuana starting are y the and that contain CBD, companies make products panies com of lot a r, eve How . tablets to look at manufacturing CBD l solid ora with nce e little or no experie nity who want to make tablets hav ortu opp e hug a with ted ng presen . doses. Manufacturers are bei tion duc pro let as they move into tab to work with CBD companies

ETTORE CUCCHETTI, CEO - ACG INSPECTI

ON

The track & trace industry is currently going through a complete overhaul, in light of the EU FMD regulations. The approach of a centralised repos itory with localised verification data centres is well-t hought through. ACG Inspections foresees technologie s like blockchain, IIoT and machine learning playin g a key role in securing the pharmaceutical supply chain from counterfeit goods. And we expect that - in future - all countries will come together to standardise track & trace implementation and information exchange. Track & trace will move from a need to have the technology to must-have technology in the complete pharmaceutical production.

STACEY VAUGHAN, SENIOR DIRECTOR, STRATEGIC MARKETING, PHARMA, WEST PHARMACEUTICAL SERVICES

West is seeing notable requests for components supplied in port bags indicating that more companies are transitioning to fully enclosed isola tors, restricted access barrier (RAB) or closed systems. In concert with this requ est, the European Medicines Agency (EMA) Annex 1 “Manufacture of Sterile Med icinal Products” has given the industry further guidance on use of barrier technolo gies.

While there is no direct requirement for manufacturers to use it, the Annex infers by the statement “RABS, isolators or closed systems, should be considered in order to reduce the need for interventions into the grade A environment and minimise the risk of contamination” that barrier tech nology should be being adopted.

20

SECTOR HIGHLIGHTS

TIM FREEMAN, MANAGING DIRECTOR, FREEMAN TECHNOLOGY

try continues to be the A significant focus of the pharmaceutical indus rties and process prope ial mater of t impac strive to understand the -line and in-line off parameters on product quality attributes. Both rt scientists and suppo to d utilise be can measurement techniques the most suitable e ensur to ative imper it’s but task, this in engineers continuous of ts fi bene tial poten properties are measured. The ted, however accep and ssed, discu y widel been have e manufactur process given a in times nce in this environment, where reside ledge know t robus a ds, secon in ured meas be operation may is even more important. of all relevant material and process variables uction of quality Great progress has been made since the introd be further acquired. to by design (QbD), but there is still knowledge

DR ANDREAS M ATTERN, DIRECTOR PROD UCT MANAGEM ENT PHARMA, BOSC H PACKAGING TE CHNOLOGY

The pharmaceutica l industry is witnes sing important developments in biological agents, for instance for the treatment of cancer or orph an diseases.

These call for flex ible equipment th at can handle ever smaller batch es, while adaptin g to new products and pack aging formats qu ickly. Moreover, the development of continuous ma nufacturing equipment for or al solid dosage (O SD) is opening new potential for optimum API dosa ge and faster time-to-market. 20 19 will also see an increase in industry 4.0 solut ions especially ad apted to the strict regulations of the pharmaceut ical industry.

BEN WYLIE, SENIOR PRODUCT MAN AGER, CHARGEPOINT TECHNOLOGY

Increased demand for drug manufac turing using high potency active pharmaceutical ingredients (HPAPIs) and sterile manufacturin g requirements have created containm ent challenges for manufacturers.

From ensuring operator safety, to protecting drugs from cross contamination, the need for more innovative containment strategies was high on the agenda for 2018 . Smart wireless monitoring technology has been introduced to improve confidence in containment solutions. This type of technology has made it possible to receive crucial equipment usag e data quickly and remotely, and provides continuous audit trails , allowing maintenance and operating teams to make decision s on effective maintenance and proactively manage the health statu s of their containment equipment.

ANITA PAZ, INNOVATION CONSULTANT, TJOAPACK

In recent years, the pharmaceutical industry has started to explore how improving the to way they gather and analyse data could help t adven the with And, . chain y suppl the streamline data, there of serialisation legislation and its associated to access legacy are even more opportunities for companies tional performance. opera information and gain more insight into supply chain more and more see will we rd, As we move forwa their operations. partners adopt machine learning to optimise ing and packaging This will be the case particularly for manufactur registration and ction produ l digita whom for ers, provid e servic an organisational in-process control can improve operations at level. line at l contro y qualit smart e ensur level and

DANIEL TEDHAM, MANAGING DIRECTOR, WASDELL MANUFACTURING A DIVISION OF THE WASDELL GROUP

ed on mass The pharmaceutical industry is no longer focus drug production and a ‘one size fits all’ approach. The novel oping devel to ed devot ly heavi pipeline is now more demand the ng meeti and ses disea rare for ents treatm busting for personalised medicine. The pipeline for block is not as ations popul t patien high ecting aff ents treatm instead prominent as it was 20 years ago, with the focus cts. produ h biotec e volum r smalle ds moving towar see Therefore, throughout 2019 I would expect to tions. condi rarer for ghs further breakthrou

JOE HAUGH, CEO OF ZENITH TECHNOLOGIES The outsourcing of automation services under managed service contracts has seen significant growth this year. One of the bigge st industry challenges is finding sufficient talented engin eering resources that are able to innovate and introd uce technologies to transform life science manufactur ing whilst preparing them for the digital future. As we move into 2019, the use of data is going to become increasingly important.

The industry currently collects data from a wide range of sources and there are a number of projects seeking to connect all of these sources so that companies can ultimately get the best out of the data they collec t to make tangible business improvements.

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22

HIGH POTENCY FACILITIES

On a roll

David O’Connell, director of scientific affairs at PCI Pharma Services, discusses the principles of roller compaction – particularly in the development and manufacturing of oral solid dosage forms containing highly potent active pharmaceutical ingredients (API).

G

ranulation is a process in which primary powder particles adhere to each other, resulting in larger, multi-particle entities; ‘granules’. When performed without adding liquid binders, it is called dry granulation: the powder blend is compacted by applying a force, causing adhesion and size enlargement.

The subsequent granules can be processed into tablets, capsules and powder in bottle/sachets.

Dry granulation can be manufactured in two ways: slugging, where a large compact is formed and broken down into granules; or roller compaction, where material is compressed into a ribbon prior to breakdown. Dry granulation is required for products when wet granulation may be an unsuitable manufacturing method, such as moisture or heat-sensitive compounds.

WHAT IS ROLLER COMPACTION? Roller compaction is a method of powder compaction of dry powders into a solid mass known as the ribbon. This process is achieved by feeding powder through a set of directly opposed, counter-rotating rollers. The process avoids the use of liquids and high temperatures.

The ribbon is broken down into a specific granule size via a milling system, such as an oscillating mill.

The purpose of dry granulation is to increase the bulk density of powders and particle size to ensure a better flow of distributed material; an important factor in the manufacturing of tablets and capsules using production equipment.

The most important parameters in the dry granulation process are powder feeding, compaction pressure applied, and the gap diameters. The powder is fed into the rollers and – depending on the feed rate of powder, gap diameter and force – the powder will be ‘compacted’ into a pre-defined ribbon thickness. To ensure an end result of suitably uniform granule properties, a precise process control is critical. This is determined by the pressure at which the powder is forced through the rollers.

BENEFITS OF ROLLER COMPACTION OVER WET GRANULATION AND OTHER DRY GRANULATION TECHNIQUES The benefits of roller compaction over wet granulation depend on the compound itself. In a moisturesensitive compound, for example, wet granulation could prove unsuitable in terms of inducing potential impurities. In contrast, the roller compaction process does not require a liquid binder and could be a more suitable option.

In addition, should a compound be heat-sensitive, wet granulation with a drying stage would not be appropriate and roller compaction would the suitable option.

Other forms of dry granulation exist such as slugging. Slugging is large compact produced on a tablet press prior to milling to granules. This method may cause some inherent challenges such as powder flow not being sufficient for compaction, leading to inconsistent compaction results.

This method of dry granulation is

being used less, particularly given that roller compaction is able to offer an effective alternative.

Another advantage of roller compaction is that pilot batches can occur on the same machine as commercial batches. This mitigates scale-up issues that can occur during GMP bulk production.

DIFFERENT TYPES OF ROLLER COMPACTION AND ADVANTAGES The two main categories of roller compaction are essentially based on the gap between the rollers.

The first being fixed gap rollers and the second described as ‘floating’, meaning it is possible to change the distance between the rollers depending on the powder properties. The generally accepted opinion is that a ‘floating’ option is more advantageous.

A fixed gap can lead to production of inconsistent ribbon due to inconsistent powder flow. With a floating gap option, the distance between the rollers will alter depending on the amount of powder provided, the force applied then remains constant, ensuring that fluctuations in the granules are minimised, resulting in a more uniform or homogenous granulate.

Following compaction, the ribbons are milled with a sizing mesh which limits the upper particle size.

Oscillating milling provides a gentle process to avoid creating fines. The granules can be further processed into either a tablet or capsule dosage form with increased confidence of dose uniformity.

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THE PHARMACEUTICAL LANDSCAPE IS CHANGING WITH FOCUS ON SPECIALISED POTENT MEDICINES, HOW DOES ROLLER COMPACTION WORK WITHIN THIS ARENA? The pharmaceutical landscape continues to evolve with more products being deemed potent.

The reason for this being that as the biological activity and specificity of the API increases, the dosage strength decreases.

Potent molecules require specialist handling in order to protect the workforce over-exposure.

Personal protective equipment (PPE) is being replaced with contained engineering solutions.

With this in mind, identification of a fully contained roller compaction should form part of any decision process – whether a company is looking for a CDMO, or to build internal capabilities.

At PCI, a decision was made to invest in technology to safely process multi-API potent compound within a purpose-built facility. The facility utilises fully contained engineering solutions, eliminating the need for PPE and able to manufacture with OELs down to 0.01Âľg/m3. As a service provider, PCI responded to the potent development landscape offering best-in-class solutions.

Within 12 months of opening the facility, however, customers were requesting potent dry granulation.

PCI installed a fully contained roller compactor to meet this growing need.

The roller compactor was designed within a negatively pressured isolator with spilt butterfly containment valves for material in and out via IBCs. In terms of cleaning when processing is complete, the roller compactor contains numerous spray nozzles that are used to wet down the contamination prior to a machine strip down and placement into a parts washer.

In summary, there are many different types of granulation techniques available. The choice of which method is ultimately selected will be reliant on multiple factors including the physio-chemical characteristics and potency of the compound. In each instance, it is important to use all known information and experience to make the most informed decision to give the greatest chance of success for any development project.

The pharmaceutical landscape continues to evolve with more products being deemed potent.

The reason for this being that as the biological activity and specificity of the API increases, the dosage strength decreases.

23

medtech | digital healthtech | medical plastics manufacturing | software | inspection and metrology regulation | design | early stage innovations pharmaceutical manufacturing

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25

SAFETY FIRST Mike Knapp, director at Peacock Engineering discusses how pharmaceutical manufacturers can use integrated mobile solutions to improve safety in highly volatile environments.

W

hilst compliance and safety are paramount to every pharmaceutical organisation, the industry still experiences unfortunate accidents. The recognition that working with volatile components or in an unstable environment means that organisations need to think not only about health and safety, but also how to incorporate adequate warnings and flags into research and manufacturing processes.

Technological advances may provide the answer to resolving this conflict; indeed, identifying technology usage features as one of the top 10 issues within the industry. Emerging technologies around artificial intelligence (AI) and automation offer significant opportunities within a digitised supply chain by Emerging reducing manufacturing technologies costs and increasing compliance. around artificial

intelligence (AI) and automation oer significant opportunities within a digitised supply chain by reducing manufacturing costs and increasing compliance.

Predictions around the savings and potential growth vary, however technology could help accelerate growth by up to 5%. This would generate an average of ÂŁ10bn new revenue over the next decade, helping to counteract the cost of bring new drugs to market.

However, investing in new technology cannot be seen in isolation.

Pharmaceutical industries that are looking to achieve a competitive advantage through technology will be looking at integrating technology

into a business transformation programme, where they look at operating models, production processes and supply chain.

All of these need to be closely aligned to health and safety ensuring that technology is able to both demonstrate and adhere to the required compliance.

One key area for consideration is Enterprise Asset Management (EAM). There are a number of asset management systems which are used by pharmaceutical and chemical organisations involved in drug manufacturing.

Advances in technology means that combining AI (through predictive analytics) and automation with an asset management system can provide a real competitive advantage. Predictive analytics, or machine-based learning, could provide a health and safety revolution particularly for those organisations using toxic and flammable materials. By calculating the interaction scenarios between volatile components, it is possible to create a warning system that forecasts issues before they occur.

Being able to work in an explosive environment requires specialist technology to allow an integrated asset management system to function effectively. Many systems do not have adequately robust mobile solutions that allow seamless integration into the main asset management system.

This results in a reliance on paper-based processes or off-line mobile solutions that duplicate effort and time.

Having a mobile system that allows engineers and technicians to maintain production lines in a volatile environment has a number of benefits. As well as improving eďŹƒciency (through the removal of duplicated entry) it improves health and safety standards.

Mobile systems such are now designed to operate in explosive environments, so that engineers can report and work in real-time.

This means that an organisation can have one database rather than a separate asset management system and computerised ATEX system.

This means there is only one central database, allowing all reporting and information interrogation to be automated.

Advances in technology mean the opportunities around predictive analytics and automation for pharmaceutical and chemical organisations are now a reality. Companies are able to incorporate these into their asset management systems so that their systems and processes are fully integrated and robust. This means that organisations are able to more effectively deal with health, safety and compliance as well as the more complex issues of financial constraints or ageing plant in declining areas.

Regardless of which system is used though, having an asset management system that has a fully integrated mobile solution is key to ensuring that the company is able to address these issues and to gain a competitive advantage in the marketplace.

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27

M&A

Pay your dues Jennifer Lopez, director, solutions delivery at Maetrics discusses why heightened due diligence is needed for pharmaceutical manufacturers during mergers and acquisitions.

M

ergers and acquisitions (M&A) within the global pharmaceutical industry are prolific; in fact, pharmaceutical companies probably face more M&A activity than any other industry. Typically the main driver for changes in the pharmaceutical industry is the everManufacturers increasing prices of drug-development; should not a lot of companies underestimate how as fail to keep up with M&A can cloud the demanding costs of R&D to find visibility into the new and innovative supply chain, which compounds for the market. However, as ultimately brings the pharmaceutical more risk for the industry expands, companies involved. European and US-based manufacturers are creating increasingly globalised supply chains which increases the potential risk for manufacturers to mismanage their compliance procedures.

HIGH QUALITY COMPLIANCE IN PHARMACEUTICAL MANUFACTURING In 2017, the US Food and Drug Administration (FDA) reported a significant increase in the number of warning letters issued to pharmaceutical companies, compared to 2013 levels; highlighting an increase in violation of Current Good Manufacturing Practices (cGMPs).

In pharmaceutical plants worldwide many areas of non-compliance have been highlighted including, but not limited to, systematic data manipulation, failure to exercise sufficient controls over computerised systems to prevent

unauthorised access to data as well as failure to dispose of qualityrelated documents appropriately and violations associated with contamination, hygiene and quality management systems.

Many companies are outsourcing parts of the manufacturing process in order to boost their capacity, improve overall speed-to-market and to attempt to capitalise on the availability of new suppliers in Asia.

However, manufacturers have found that it is getting even more difficult to keep sufficient visibility and control over this activity, ultimately meaning that quality issues arise.

diligence has taken place. In fact it is pre-acquisition due diligence which is crucial to acquirers when deciding whether to accept a deal.

Manufacturers should not underestimate how M&A can cloud visibility into the supply chain, which ultimately brings more risk for the companies involved. In many cases the deep analysis of manufacturing operations, often made by the acquiring companies, limits the ability of personnel to perform supply gap analyses, supplier assessments, and to manage any quality issues that may arise, all of which will have an effect on ensuring compliance.

COMPLIANCE DUE DILIGENCE A proactive approach is needed to tighten up compliance procedures, ensuring a higher level of inspection readiness and also delivering commercial benefits such as a greater understanding of demand and capacity as well as an improved ability to assess and react to disruptions. Mergers and acquisitions are known to complicate supply chains and increase risk in the global pharmaceutical sector as areas of non-compliance are often not identified nor appropriately managed. It’s also been reported that at least 75% of companies that acquired a new business over the last year failed to execute proper due diligence.

MITIGATING RISK Whether or not a pharmaceutical manufacturer is planning an M&A with another company, it is clear that there is an urgent need for pharmaceutical companies to bring their quality, safety and risk management controls into line with regulatory requirements. It is important that manufacturers tighten up compliance procedures, which will not only ensure a higher level of inspection readiness, but will also deliver widespread commercial benefits such as a greater understanding of demand and capacity and an improved ability to assess and react to disruptions.

The importance of having a compliance team involved from the get-go is paramount in order to be fully equipped to assess the potential risks that may come from the take-over. Ultimately it will be the responsibility of the purchasing company to ensure complete due

The key to success for manufacturers is to ensure wellplanned, well-documented and successfully executed supplier and quality agreements are in place, critical components to control the quality of the final manufactured product.

28

SEPARATION TECHNOLOGY

THE PURSUIT OF PURITY Total organic carbon (TOC) analysis remains a key backbone of the pharmaceutical production process. Here, Peter Morgan - technical product specialist at Elementar UK explains how TOC analysers help to deliver reliable results for drug makers, and how new advances are keeping them at the forefront of the quality assurance (QA) process.

I

n a sector as stringently regulated as the pharmaceutical industry, defensibility of data is everything.

The safety of even the most common production processes can never be taken for granted; the reliability of an organisation’s results, and the purity of its products, needs to be constantly demonstrated and documented to retain regulatory accreditation.

It is within these demanding circumstances that total organic carbon (TOC) analysis has emerged as a quality assurance (QA) gold standard, with regulators such as the US Food and Drug Administration (FDA) and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) adopting it as a best practice method for evaluating organic contaminants throughout the pharmaceutical industry.

TOC analysers offer a proven way for manufacturers to guarantee the microbial integrity of therapies and prevent cross-contamination between product batches.

Moreover, the latest technological improvements mean they are now able to do so in a way that is more efficient and reliable than ever, at a time when QA in drug development has arguably never been more pivotal.

TOC ANALYSIS - MORE IMPORTANT THAN EVER? One of the key reasons why TOC analysis is coming to the forefront of pharmaceutical manufacturing is the recent move away from exclusive blockbuster drugs, towards a model where more

companies are producing a wider variety of medications.

In the past, most therapies would be manufactured exclusively by their patent holders using dedicated production processes, but recent waves of patent expiries have opened up the market to a glut of contractbased manufacturers producing multiple generic products within the same facilities, using the same equipment. At the same time, growing interest in personalised medicine means that the era of the one-size-fits-all therapy may be coming to an end, requiring an even more significant diversification of production approaches than has been seen so far.

As such, regulators are paying closer attention to product quality than ever, in order to ensure that production standards are being upheld and that compliance with their guidelines is being stringently documented. This paradigm shift has meant that reliable industrystandard verification methods like TOC analysis have an unprecedented opportunity to offer a reminder of their value.

PROVEN BENEFITS OF TOC ANALYSIS TOC analysis has two primary applications in pharmaceutical production: for identifying and facilitating the removal of carbon impurities found in the products themselves, and for verifying the effectiveness of the cleaning work carried out between production batches.

The instruments operate by releasing the carbon contained within the sample in question by oxidising it, either by breaking it down through the use of UV/ persulfate decomposition, or by placing it inside a high-temperature combustion furnace. This converts the carbon into carbon dioxide gas, which can then be identified using an IR detector.

Pharmaceutical manufacturers usually find that the UV/persulfate digestion method delivers the greatest benefit - drug production usually deals with relatively pure samples, without many instances of the kind of large solid mass that environmental scientists rely on furnace combustion-based TOC analysers to break down.

In this context, the digestion-based approach proves to be cheaper and more efficient, as well as offering lower detection limits due to the fact that larger sample sizes can be analysed.

The use of TOC analysis in cleaning validation has been shown to deliver particularly considerable value for drug makers, allowing manufacturers to ensure that any containers or vessels used in the production have been decontaminated thoroughly before the next batch is produced. This can be done by testing the final rinse solution of washing water for TOCs, or by analysing a swab sample.

This method offers a number of benefits - it has been shown to prevent microbial build-up on equipment and stops the transfer

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of bio-burdens between products, enhancing lot integrity in a way that is quicker and more precise than other methods; moreover, because it is not ingredient-specific, it is ideal for situations where more than one type of impurity might be expected NEW INNOVATIONS SOLVING EXISTING CHALLENGES As with any pharmaceutical industry methodology, TOC analysis remains a work in progress, with new solutions continuously emerging to solve the remaining challenges that manufacturers still face when carrying out this kind of work.

One common issue is the fact that most pharmaceutical production sites usually rely on UV/persulfate decomposition-based analysers, which makes it diďŹƒcult to carry out any analysis that would require a combustion-based system. For instance, when analysing a large, solid swab sample that cannot be effectively dissolved - without investing in a separate piece of equipment that would only be used in specific circumstances.

Growing interest in personalised medicine means that the era of the one-size-fits-all therapy may be coming to an end.

29 However, technological innovations are now helping to bridge that gap: the acquray system, for example, is a newer UV/persulfate system that provides an add-on combustion furnace module, allowing labs to carry out occasional solid analysis using the same IR detection methods as the core digestionbased unit. As the market continues to evolve, new functionalities of this kind will continue to be added to TOC analysers to further improve their eďŹƒciency and reduce the amount of laboratory downtime to a bare minimum.

In this way, TOC analysis remains well positioned to continue meeting the demands of pharmaceutical manufacturers, even as the sector continues to diversify and embrace new operating models. Production strategies may change, but the importance of quality, purity and traceability is something that drug makers simply cannot allow to fall out of fashion - and TOC analysis is still one of the best ways of ensuring that doctors and patients can remain confident in the safety and effectiveness of their medicines.

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CONTAINMENT

31

Pass the test Getinge discusses how wireless integrity testers make it easy to secure sterility

I

t is both necessary and well-known that pharmaceutical manufacturers have to comply with rigorous rules and regulations when producing life-saving drugs and medicines. But in order to secure sterile transfer integrity in the manufacturing and transport of components, even more new solutions are required.

Not only to meet demands to keep trace of the system’s lifecycle and its components, but also to account for normal wear and tear.

These were the steps Swedish Life Science group Getinge took into consideration when developing its new Transfer Leak Tester. Here, Didier Papin, systems developer and Paolo Liverani, product line manager at Getinge, explain the process.

“The importance of checking the integrity of the gloves or the equipment, in addition to the isolator itself, is well known in the industry.

But what is not equally well known is that it is possible and highly recommended in certain guidelines to also check the rapid transfer ports and/or Beta parts included in the barrier system for aseptic and containment applications. In both cases, it is important to be able to detect breaches in sterility and give the requested evidence – traceability – to the inspecting bodies and regulators.”

When visiting customers, Getinge had noticed end users’ concerns about providing evidence of the integrity of transfer systems.

Regardless of the transfer system used, not all customers take into consideration age and ordinary tear and wear – with potential consequences such as unexpected downtime in manufacturing or impact on operator safety, in the case of toxic and cytotoxic substances.

Several other factors might also affect the performance of systems used to measure and test transfer integrity. One is the use of cumbersome tools to fasten the transfer integrity tester to the transfer ports. Another more critical factor is the risk of uneven pressure in the flexible pipes if handled incorrectly by operators (low pressure at the start of a test cycle in combination with moving pipes).

That is why the new Getinge GLT – Glove Leak Tester – and TLT – Transfer Leak Tester – are not only pipeless, they are also wireless, paperless and use lightweight plugs equipped with inflatable gaskets allowing for easy fastening to glove ports or to flanges of both DPTE Alpha and Beta parts.

This negates the need for specific tools to fasten the testers using

a particular torque. Instead you just push a button, and the gasket inflates securing an air-tight seal.

“This makes the TLT and GLT operator-friendly, convenient and easy to use, both when transferring between different sites and on fixed installations – whatever the orientation of the port tested.

They secure repeatability and are reliable instruments in the Maintenance Management System ensuring the system’s performance over time and allowing the enduser to recognise when it is time to change system parts. The TLT and GLT are designed to keep track of the lifecycle of product and components in the customer’s records with compliancy to the FDA CFR21 PART 11 and GAMP5 standards according to the latest orientations. In short, they make life a little bit easier for the validators,” concludes Paolo Liverani, product line manager at Getinge.

Regardless of the transfer system used, not all customers take into consideration age and ordinary tear and wear.

32

REGULATORY AFFAIRS

Reece Armstrong takes a look at the regulatory guidance which emerged from a new UK conference for developing life science companies.

GETTING ON TRACK WITH REGULATION AT BIOFORWARD E

arlier in October, emerging companies flocked to BioForward, a new conference held at the University of Birmingham and organised by not-for-profit membership group OBN. The one-day conference featured a range of panel discussions designed to provide emerging life science organisations with the knowledge they need to bring products through development stages and ultimately to market.

Of particular note was the ‘Get Your Regulatory Strategy on Track from the Start’ session, which detailed useful strategies for early-stage companies needing to navigate regulatory compliance.

Chaired by Johnathan Rohll, head of business information at OBN, the session also featured Jo Burmester, director of global operations at PharmaSchool, Roy Ovel, chief commercial officer for Optipharm and Katrin Spaepen, director strategy at Veeva Systems.

and which regulatory pathways need to be taken.

On that clinical strategy, Ovel emphasised how companies should be quick to realise that drug development costs quickly spiral past one or two million pounds. Importantly, Ovel remarked that alongside reliable science, companies need to be clear on what their product is, as this will instil confidence in investors.

“If you have your first draft of funding, make sure whatever you promise, you can deliver on or overdeliver on. If you lose credibility as a management team, you lose face,” Ovel said.

Burmester echoed this sentiment, highlighting the need for companies to understand the value of their product to help drive development processes and dictate what rules to follow once companies start on the regulatory pathway.

Unsurprisingly, Brexit became a big topic of conversation towards the end of the session, though the speakers matched the government’s vagueness on knowing what changes are going to occur. Burmester likened the outcome to a ‘Deal or No Deal’ scenario, the former of which being the most preferable as the UK would then stay part of the EU’s regulatory system for medicines and medical devices.

If this doesn’t happen, Burmester’s understanding is that the “MHRA will cut and paste the EU regulation into the UK as a stopgap,” she stated. “Whatever happens, we’ll still be using the same rules for clinical trials and GMP for manufacturing. The big question is if we get a deal with the EMA.”

The session covered a lot of ground, highlighting areas where early-stage companies are most likely to make mistakes when it comes to drug development. The speakers identified potential pitfalls such as finding the right investor and knowing what your exit strategy is, a point Ovel remarked as something which defines “where you’re going as an organisation.”

Burmester meanwhile discussed the things companies need to consider for developing a robust clinical strategy.

Companies need to understand the market and think from both the patient’s endpoint and the regulator’s. Burmester pointed out that that the Medicines and Healthcare Products Regulatory Agency (MHRA) should always be contacted if companies are unsure about their product. Specifically, on things such as where you’re going to start clinical trials

Make sure whatever you promise, you can deliver on or overdeliver on.

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34

TECH TALK

WHEN YOUR mHEALTH APP GOES WRONG… In our last Tech Talk of the year, Dr Neil Polwart, Novarum founder and BBI Group head of mobile, discusses how to mitigate risks for mHealth apps.

M

obile health (mHealth) apps can often bring with them potential risks that are overlooked, but unlike traditional pharmaceutical products, they can also engineer solutions to mitigate product risks.

All medical device software is categorised according to its potential to cause patients harm. Generally, the greatest perceived risk arises from fundamental algorithm issues which should be subject to the most scrutiny and validation during development.

However, developing robust underlying science is only the start of providing a useful and valuable mHealth solution.

How your software handles errors, as with how your organisation handles software failures can be the difference that makes or breaks your offering.

Notice the distinction between errors and failures; we expect errors such as invalid user data and lost internet connections, but all these issues can be managed by good software design.

Software failures happen when we either encounter an error the system was not designed to cope with, or the system design is simply inadequate for the job it is being asked to do.

However, for most users, ordinary bugs like a button not appearing on the screen can be the most frustrating and common, compared to major things such as security breaches.

Ideally those issues would be detected before you go to market. However, with an everincreasing range of hardware to test on, covering every eventuality with physical testing is a herculean task.

It is almost inevitable that an issue with your software will occur, requiring you to release a new version. Fortunately, your software team will be very familiar with such regression issues and will hopefully have created a suite of tests to help spot the issue before your new version gets released.

These, together with an array of tests run on each individual software component every time

the software gets built, integration testing to ensure it is all put together correctly as well as frequent code reviews by different developers should all help to spot and prevent problematic code from reaching the market.

Good mHealth apps will include a mechanism for managing app versions. In some cases, the operating system, app stores or mobile device management software running on all of a hospital’s devices might do this for you, but it is such a critical part of managing software failures that it usually makes sense for the app to be able to check it is up-to-date and alert the user if not.

If your app relies heavily on the device hardware, you may even check if the app is running on an approved list of devices and either warn or prevent the user from proceeding depending on the associated risk.

Together with a programme of frequent maintenance, gathering user feedback and responding to it, you may think these issues will ensure that disaster is avoided.

That overlooks the biggest source of failure in any software product though – the user. You will often have conducted usability trials, perhaps ensuring that the workflow is logical, watching users operate the app and that the expected behaviour is intuitive. You may even have integrated some analytics to identify problem areas in the app and maximise usage.

One overlooked area is that most users want a simple “good” or “bad” type outcome, but of course health is rarely so black and white. Naturally, humans are bad at quantifying risk and understanding probability, so even when results are presented as percentages or odds they may not be well understood.

Some recent mHealth headlines have been made not necessarily by any failure of the app, but rather by a failure to communicate the risk and significance of the data presented – issues such as this can be managed through well thought out user studies at an early stage.

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