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UNDER PRESSURE

Natoli breaks down the misconceptions of maximum compression force

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Contents May 2019 | Volume 19 Issue 3 REGULARS 5: EDITOR’S DESK Reece Armstrong looks at why global cohesion is necessary to fight growing health epidemics.

6: A SMALL DOSE A brief round-up of some of the latest developments in the industry.

10: OPINION Why digital transformation is key for pharma.

13: ANALYSIS How packaging can support pharmaceutical innovation.

14: COVER STORY Natoli break down the misconceptions of maximum compression force in tooling.

FEATURES 21: ANTICOUNTERFEITING Interviews and insights into stopping counterfeit drugs in the supply chain.

27: BIOPROCESSING Advanced technology and the latest innovations in bioprocessing.

35: LYOPHILISATION The growing need for lyophilisation technology and new approaches for freeze-drying.

46: FROM THE FACTORY Why single-use technology is key for complex manufacturing environments.

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BETTER TOGETHER

Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE.

Recent news that the UK has increased its spending on fighting global neglected diseases places it at the forefront of international efforts to fight ailments such as malaria and tuberculosis.

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EDITORIAL editor reece armstrong reece.armstrong@rapidnews.com

Figures from the 11th annual G-Finder report show that global funding targeting research and development (R&D) for neglected diseases is now at its highest ever level, the first time since 2009.

deputy group editor dave gray david.gray@rapidnews.com head of content, life sciences lu rahman, lu.rahman@rapidnews.com publisher duncan wood

The UK was only second to the US in terms of funding, increasing the amount it spends on combatting neglected diseases by $87 million.

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Volume 19 Issue 2 © Mar/Apr 2019

While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed.

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More important might be the international efforts to tackle health concerns in developing countries

And while many accuse big pharma of chasing profits, the biopharma industry was shown to be one of the largest supporters of fighting neglected diseases. Indeed in 2017, biopharma’s funding was the third largest, coming only behind the USA’s National Institutes of Health (NIH) and the Gates Foundation.

Highlighting these commitments might seem congratulatory,

EDITOR’S DESK but as the report shows, there simply isn’t enough being done to fight neglected diseases across the world.

The World Health Organisation (WHO) recommends governments spend 0.01% of their GDP on researching the health needs of developing countries, yet in 2017 not a single nation met this target.

Perhaps more worrying is the fact that philanthropic funding is still reliant on a handful of organisations such as the Gates Foundation and the Wellcome Trust, which accounted for 95% of charitable contributions in 2017.

Still, the increase in funding is certainly welcome but more important might be the international efforts to tackle health concerns in developing countries. It’s these types of efforts which are needed for the prosperity of global health, especially when concerns surrounding anti-microbial resistance (AMR) and the safety of vaccines are on the rise.

AMR might be another area where the UK has previously led the way, but a lack of international cohesion could see the issue get worse before it gets better.

This is why developments such as the Global Antimicrobial Resistance Surveillance System (GLASS) are so important. Launched in 2016 to standardise the way countries collect data on AMR, GLASS was recently updated with a technical notice providing guidance on the use of molecular diagnostics in AMR testing.

It’s hoped that the notice will help health authorities make informed choices on the use of molecular tests in an attempt to gain a clear global look at AMR. Without global efforts, health concerns such as AMR and un-vaccinated citizens are bound to get worse. A lack of informed data and standardised tests that can assess where we are as a planet in terms of health will only widen healthcare disparity between counties.

6

A small dose

Smart pill bottle designed to improve safety

Researchers have developed a smart pill bottle to help fight the problem of prescription drug abuse.

A team at the King Abdullah University of Science and Technology (KAUST) 3D printed a lid that used light-emitting diodes to know how many pills have been dispensed. More so, the bottle uses sensors that prevent it from being tampered with and which can recognise the temperature and humidity inside.

If someone tampers with the bottle, or if it becomes too warm or moist, a control module can recognise the signals and deliver warnings to mobile phones.

The bottle was developed as part of further work by KAUST on creating affordable

electronic sensors to be used in health settings.

High costs associated with electronic manufacturing has meant that sensors aren’t available to lowincome populations that suffer from epidemics where they could be useful.

The team at KAUST has now developed a lowcost stretchy sensor that has a range of touchsensitive applications.

Professor Muhammed Hussain, who is leading the research said: “This sensor development that is easy to build also opens up broader possibilities for researchers. "If you give researchers a 'do it yourself opportunity,' there is a good chance they will use it to expand the horizon of electronics and empower humanity with better technology."

EUROPE’S LARGEST DRUG A collaborative platform is set to initiate 185 new drug discovery projects in Europe over the next five years.

The European Lead Factory (ELF) will help universities, research organisations and SMEs access compound libraries and screening facilities to translate earlystage fundamental biological research into credible and investable starting points for drug discovery campaigns.

With a project budget

of €36.5 million and 20 partners in seven countries, the ELF will push forward the transformation of potential drug targets to new medicines in the new European Screening Centre: unique library for attractive biology (ESCulab) project.

To help start drug discovery campaigns, the ELF will screen medically relevant drug targets from European researchers, small and medium-

sized enterprises and the pharmaceutical industry against the ELF library of 550,000 unique chemical compounds.

Jon de Vlieger, coordinator of the ESCulab consortium at Lygature, said: “It’s truly exciting to continue the onboarding of new and innovative proposals for screening and provide high quality starting points for drug discovery to academics and SMEs throughout Europe. In

COLD CHAIN PACKAGING HELPS BRING CANCER MEDIC TO AFRICAN CHILDREN Cold chain packaging is helping bring oncology medicines to children in Tanzania thanks to a partnership between packaging provider Softbox and charity International Health Partners (IHP).

Through the partnership, medicines are delivered to TLM, the charity’s Tanzania-based aid partner which helps run an oncology programme for children in Dar es Salaam. Softbox’s collaboration with IHP will see it deliver a third shipment containing

500 medicines to Tanzania, bringing the total deliver to 1,900.

“Softbox’s donation has enabled us to send these muchneeded medicines to those who desperately need it,” said Colleen Harrisson-Dodds, IHP’s logistics director.

“The pharmaceutical companies we work with recommended Softbox’s packaging, and we are very pleased with the result. This is an ongoing programme, and we hope to continue delivering this medicine

to our partner hospital in Tanzania, as they have no other access to it and many more patients are in need.”

Kevin Valentine, general manager of Softbox, said: “We are proud to be working with IHP to help achieve the safe temperature control transportation of these life-saving medicines.

Knowing our packaging is helping these children to have a healthier and happier life is very rewarding, and we are very proud to be part of this fantastic initiative.”

7

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G DISCOVERY PLATFORM SET FOR SUCCESS an effort to broaden our scope we are not only looking for target-based approaches, but now also enable phenotypic screens.”

The ELF has already attracted two pharmaceutical companies to join, with Servier and Grünenthal as well as the Medicines for Malaria Venture (MMV), a leading product development partnership in the field of antimalarial drug research and development.

CINES

Tim Wells, chief scientific officer at MMV, adds: “We are thrilled to participate as ESCulab and the European Lead Factory represent a chance for new partnerships for MMV, both with the EU through IMI and with a variety of highly creative companies.

These partnerships give access to a novel, high quality chemical library that we believe is important to be screened against high priority malaria targets.”

Catalent expands softgel capabilities Major pharma player Catalent has announced it is to expand its integrated turnkey softgel capabilities at its facility in Eberbach Germany.

The company will undertake a $14 million expansion, set to be completed by mid2020, and which will include two new softgel encapsulation lines dedicated to Catalent’s proprietary Vegicaps technology.

Catalent state that the expansion is being

driven by an increased global-demand for animal-free consumer health products. The investment includes new printing technology, a state-of-the-art vision inspection system, expansion of the facility’s softgel coating capabilities, and the addition of further packaging capacity.

“The Eberbach facility is our biggest softgel development and manufacturing facility in Europe with a capacity of more than 10 billion softgel

capsules per year,” said Raoul Bernhardt, general manager of the Eberbach facility. “This investment reflects the importance of the site and will enable us to better serve our customers with increased volumes and turnkey services.”

8

A small dose

MERCK BIOTECH TEAM-UP TO accelerate global drug discovery Pharma company Merck has teamed up with biotech player DyNAbind to help distribute fragment-based DNAEncoded Library (DEL) kits to accelerate drug discovery.

Through the partnership, Merck hopes that it will help accelerate global drug discovery through increased navigation of early discovery workflow.

results in days rather than months.

of the fragment or fragment-pair hits.

The kit also includes customer access to a secure analysis portal.

Hosted by Merck, this portal enables deconvolution of the DNA sequence to reveal the chemical identity

Unlike traditional highthroughput screening methods which require sophisticated robotics equipment and specialised biochemical assays, DELs offer a low-footprint solution

that can be used in any laboratory with regular molecular biology equipment.

DyNAbind’s Dynamic Libraries are built on a DNA architecture that allows the formation of randomised, transient pairs of chemical

structures. These pairs reshuffle in solution until stabilised by binding to the target protein, offering in situ generation of additional copies of the most strongly binding pairs for better signal-tonoise ratio and reduced false positive hits.

DyNAbind’s DEL kit contains over 370,000 paired arrangements of molecular fragments and provide improved signal-to-noise ratios and reduced false positive hit rates. This means that companies can expect

FIRST FULLY-INTEGRATED RETINAL GENE THERAPY COMPANY LAUNCHED The first fully-integrated retinal gene therapy company with clinical, manufacturing and delivery capabilities has been launched thanks to a new merger.

Biotech company Gyroscope Therapeutics has merged with medical device company Orbit Biomedical to focus on the precise and targeted delivery of gene and cell therapies into the retina.

The company will operate under the Gyroscope name and its next phase will involve bringing medicines to patients.

Khurem Farooq, chief executive officer of Gyroscope Therapeutics, said: “It is an exciting time to join Gyroscope with our first clinical study in patients with geographic atrophy due to dry AMD underway.

By joining forces

with Orbit, we can combine our expertise in developing gene therapies and our highquality manufacturing processes with a surgical platform that can support accurate, safe and consistent delivery of medicines that will hopefully cure eye diseases that today leave people blind.”

Chris Hollowood, chief investment officer of Syncona and chair of Gyroscope,

added: “Gyroscope is one of the first companies globally to move gene therapy out of rare diseases through the delivery of natural regulatory proteins. As retinal gene therapy progresses to more prevalent conditions, delivering a therapeutic in a way that ensures higher consistency of dosing, whilst allowing patients to receive a less invasive treatment, is key to

widespread use and clinical effectiveness.

The merger ensures Gyroscope now has all the platform capabilities it requires to develop and deliver its therapeutics commercially. This marks an important step in fulfilling founding academics, David Kavanagh and Andrew Lotery’s vision of widespread use of genetically defined treatments for dry AMD.”

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10

Opinion

Although multiple lessons can be learned from Theranos’ failure, one is abundantly clear: digitising processes and data is essential for control and transparency throughout the product development life cycle.

HOW TO AVOID THE THERANOS EFFECT In the wake of the Theranos disaster, Dave Edwards, executive vice president of MasterControl, explains why digital transformation is key if pharma companies are to achieve transparency throughout product development.

N

ot long ago, everyone was clamouring over Theranos. Founder Elizabeth Holmes drafted a captivating pitch, courted investors and even partnered with Walgreens to open blood testing centres in California and Arizona.

Theranos seemed too good to be true, and it was.

Holmes and former-Theranos president Ramesh Balwani misled the public through a systematic lack of transparency. The company did not have peerreviewed evidence showing the safety and effectiveness of its machine, and soon holes were poked in Holmes’ narrative, leading to the company’s ultimate demise.

Although multiple lessons can be learned from Theranos’ failure, one is abundantly clear: digitising processes and data is essential for control and transparency throughout the product development life cycle. For manufacturers, digitising can offer a competitive advantage through understanding customers’ propensity to buy and enable streamlined operational processes and optimised demand forecasting. Greater efficiency is additionally attained through more actionable data, visibility to identify and address problems quickly, and predictive maintenance programmes that get products to market faster.

REFERENCES 1 https://www.mckinsey. com/industries/retail/ our-insights/the-how-oftransformation

www.epmmagazine.com

5 Best Practices for Successfully Inciting Digital Change To embark on a successful digital transformation project, manufacturers should adhere to the following best practices: 1. Audit legacy systems and assets. Analyse existing systems, processes, tasks and assets, including those already leveraging digitisation. Survey processes including material requirements planning tools for inventory control, materials management and procurement planning, manufacturing execution systems, shop floor control solutions, enterprise resource planning (ERP) and supervisory control and data acquisition (SCADA) systems. These all have overlapping functionality, so identifying commonalities will establish a digital thread that connects and integrates systems and provides a cohesive data record.

2. Foster a culture of open mindedness.

Manufacturers must recognise employee fears and educate them on the realities of digital transformation. Discuss which automated tasks are activities employees don’t want to undertake, like pulling and loading data. By introducing predictive algorithms, employees can make better decisions and free up time for more rewarding, interesting and higher-valueadd activities.

3. Start small but work fast. Begin with a paperless pilot in one department. If a paper-based system is in place for maintaining device history records (DHRs), consider replacing this system with a closed-loop manufacturing execution system offering faster detection and prevention of problems, along with improved investigations to find and correct root causes. Improved data consistency across plants and the supply chain can be realised, and intuitive dashboards for key metrics enable continuous improvement.

4. Gather user feedback continually.

Take advantage of your subject matter experts, and make it clear their input is essential to successfully digitising. Asking how and where they think processes can be refined is a crucial step, not just as you embark on a digital transformation initiative, but throughout the project.

5. Invest in training. Employees should be wellequipped to perform their daily tasks without interruption or confusion, receive training for new updates throughout a digital transformation initiative and have continual access to user-friendly support resources and digital transformation leads.

Don’t make the mistake of inciting digital change and walking away; expecting employees to adjust and blindly incorporate new processes won’t result in success.

Long-Term Relevance Requires Digital Transformation According to IDC, digital transformation efforts will reach an estimated $1.97 trillion by 2022, but despite enthusiastic spending, past research indicates 70% of large-scale digital transformation projects fail. Organisations often neglect to engender company-wide support, don’t set clear, achievable goals or consider the unique needs or goals specific to their business and make the mistake of digitising too quickly.

As technology advances and customer demands intensify, current systems including inefficient, insecure and costly paper-based and hybrid processes, are falling short. It’s imperative the manufacturing floor is digitally transformed and connected to quality to avoid the Theranos trap, while also remaining competitive and thrive in an age of data-driven intelligence and smart manufacturing.

If a paper-based system is in place for maintaining device history records (DHRs), consider replacing this system with a closed-loop manufacturing execution system offering faster detection and prevention of problems, along with improved investigations to find and correct root causes.

11

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13

ANALYSIS

HOW CONTRACT PACKAGING SUPPORTS PHARMACEUTICAL INNOVATION Dale Pittock, sales director of Valley Northern, explains how contract packaging can support pharmaceutical innovation.

I

n 2016, the global contract packaging market was worth $26.54 billion, and is expected to reach $47.28 billion by 2022. This compound annual growth rate (CAGR) of 10.1% is expected to be driven largely by growing demand for pharmaceutical contract packaging.

record legitimate medicines as they traverse from manufacturer to patient.

New regulatory changes like serialisation are driving manufacturers to outsource packaging to contractors that have the relevant infrastructure and expertise to ensure compliance.

While this tightened regulation is great for patient safety, it poses interesting challenges to pharmaceutical manufacturers.

Not only is there an additional phase to add to the packaging process, which will necessitate changes to production lines, labour and machinery, there is also a dramatically increased data management burden.

In addition, innovation in the types of medication being brought to market is facilitating packaging innovation at a rate and scale that requires costly changes to packaging lines.

The threat posed by counterfeit medication has challenged the industry for years, and regulation to protect people from black market medicines has had to advance to remain effective.

This is what drove the European Commission (EC) to start work to amend Directive 2001/83/EC to address these concerns under the Falsified Medicines Directive (FMD) in 2011.

The updated FMD aims to protect patients by reducing the chance of counterfeit drugs entering an established supply chain. It will introduce a system to track and

Under the new directive, manufacturers need to add safety features to every pack of medication, including a tamperproof security seal and a barcode.

Regulatory compliance alone seems reason enough to be driving growth of contract packaging.

However, there are other benefits to manufacturers choosing the right contract packer.

Each of these new types of drug has new packaging, labelling, storage and shipping demands.

Contract packaging specialists that make sure they are cognisant of the latest drug technology developments will be able to adapt their systems, processes and production lines to easily accommodate the corresponding innovation in packaging.

For example, many of these new medications rely heavily on

packaging that separates required doses or equipment for different steps the patient must follow to take them safely. Additionally, this type of medication is heavily reliant on coldchain storage and distribution.

As well as new drugs, contract packagers must also be aware of any new trends being driven by pharmacies or end users. For example, the industry is currently experiencing a shift away from large count bottles for tablets and capsules.

Businesses in this sector that prove the value on offer to pharmaceutical manufacturers, will free up the sector to invest more funds into drug research and development and drastically reduce the time to market.

Where possible, contract packagers need to keep things simple and hassle free. One easy way to do this is to choose suppliers that work with them in a straightforward way.

It’s a complicated business, but there is no doubt that the pharmaceutical industry is going to become heavily reliant on outsourced packaging. Packaging firms that adapt to stay ahead of changes in the regulatory and technology landscapes will be vital in the advancement of modern medicine by solving challenges that distract drug companies from development of new treatments.

14

COVER STORY

UNDER PRESSURE In this article, John Norman, mechanical drafter and designer for Technical Service Support at Natoli Engineering, breaks down the misconceptions of maximum compression force.

I

t is common for tablet manufacturers to exceed the maximum compression force ratings of their tooling to form a quality tablet. This situation usually arises when an issue with the formulation or powder causes the press operator to exceed the recommended force range of the tooling in an attempt to produce an acceptable product. However, going beyond the prescribed tooling rating may result in premature tool wear or failure and possible damage to the press. With proper formulation development and tablet design, the tablet press operator should be able to manufacture quality tablets without exceeding the tooling’s maximum compression force rating.

Tablet compression tooling manufacturers establish maximum compression force ratings to prolong tool life and avoid premature tool failure. These manufacturers assign a rating to each set of punches that identifies the maximum compression force recommended for that particular set of tooling. Press operators may exceed the recommended force for a short period of time, but if the punches are run continuously at a higher force, the service life of the tooling will decrease and could result in tool failure.

By providing accurate maximum force ratings, tooling vendors help tablet manufacturers protect their punches and tablet press from damage. This article describes the variables that are analysed by reputable tooling vendors when providing the maximum force rating for their tablet compression tooling.

A better understanding of how this rating is calculated will help tablet manufacturers design a tablet that can be efficiently and successfully manufactured.

FACT VS. FICTION There is often a misconception among tablet manufacturers regarding the maximum compression force rating

for punches and how that rating is determined. The misconception is that the force rating provided by the tooling vendor is determined by only one variable, such as the material of the punches. This, however, is not the case as the calculations to determine a maximum force rating include many variables and any changes to the tablet or tool design could influence this value.

With every tool design being custom, the allowable force rating is tailored to each individual application. There is not a common compression force rating that is applicable across a range of products.

Steel selection, heat treatment of tooling, and tablet configuration all play roles in determining the allowable compression force rating assigned to an individual set of tools. The use of Finite Element Analysis (FEA) software has become common among tool vendors to help analyse tooling designs and help provide more accurate maximum compression force ratings.

TOOL STEEL SELECTION Steel selection is one of the primary factors in determining the maximum force rating of tablet compression punches.

There are many tool steels available, all of which have unique physical attributes benefitting different tabletting applications. The two most important material properties in determining compression force are yield strength and impact toughness. Yield strength is the maximum stress a material can withstand before experiencing plastic deformation. Impact toughness is the maximum energy that a material can absorb from an impact or shock before fracture. These mechanical properties can be found on published data sheets for all typical punch and die steels.

Another critical material property to consider when selecting tool steel is the wear resistance. Wear resistance is the

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Reputable tooling vendors supply the maximum tip force ratings with all tablet and tooling drawings.

ability of the material to withstand the abrasiveness of a product's granulation.

Most tooling vendors offer a large variety of steel choices for punches and dies, enabling them to recommend a steel that is compatible with the compression force required, and combats the abrasive, sticky, or corrosive properties of the granulation being tabletted.

When selecting a tool steel, it is important to consider the characteristics of the formulation, the tablet and tool design, and compression force required.

Choosing the proper tool steel based on the tabletting application is a critical step to prevent problems during production.

All steels have a different chemical composition. Standard steels, such as S7 for punches and D3 for dies, provide a good combination of wear-resistance and toughness. If the product is abrasive, tooling manufacturers may recommend using tool steel that can withstand higher wear, such as D2, A2 or DC53 for the punches. For severely corrosive formulations, high-chrome steels, such as 440C or M340 are viable options.

High-chrome steels are also used to mitigate sticking issues. When selecting a material for your application, confirm with your tooling vendor that the punches will withstand the force necessary to compress your tablet and combat any anticipated production issues.

During the manufacturing process, the punches are heat treated to transform the tool steel into a hardened state. Reputable tooling vendors know that the heat-treating process is one of the most critical steps in manufacturing high-quality tablet compression tooling.

When the punch material hardens, the elements in the alloy of the steel develop their unique characteristic properties of toughness, wear resistance, and corrosion resistance.

There are many steps during the heattreating process that help alleviate the residual stress that arises from machining performed prior to heat treat. Proper elimination of this residual stress in the material allows the steel to withstand a higher compression force and significantly decreases the chance of premature tool failure.

TABLET DESIGN Tablet design characteristics also directly influence the maximum compression force which the upper and lower punches can withstand. Size, cup depth, cup configuration, and land width are the primary tablet design variables that will affect the allowable force rating.

Adding land or increasing the land width of an existing design is one way to strengthen tooling and increase the force rating. Land is the area between the edge of the punch cup and the outside diameter of the punch tip. The addition of land to a tablet design not only helps improve the maximum force rating of the punches, but also increases the wear characteristics of the inner edge of the punch cup and reduces the severity of nicks on the outer edge of punch tips as illustrated in Figure 1. When the tablet designer incorporates sufficient land, they have the option to add a generous blend radius at the intersection of the cup radius and land to eliminate any sharp transition between the two surfaces. Land plays a vital role in achieving a higher tip force rating when the tablet design has a deep or compound cup design and is considered necessary on these designs.

Deep cup and compound cup configurations typically result in a steeper slope at the edge of the cup and negatively impact the allowable tip force rating for the tooling. Deep or compound cup configurations, can create near vertical surfaces at the cup edge and the addition of land adds inherent strength to the tooling. Compound cup designs have a greater angle of flexing force and result in an overall lower allowable force rating due to the smaller cup radius near the tip edge. Changing a tablet’s cup configuration or shallowing the cup depth can help increase the strength of the tool, increasing the maximum compression force rating. Knowledgeable tablet designers can suggest slight modifications to a tablet design, such as a slight increase in the outer radius of a compound cup, to increase the maximum compression force rating without drastically changing the tablets geometry, function or appearance.

Reputable tooling vendors supply the maximum tip force ratings with all tablet and tooling drawings. These ratings

15

16

COVER STORY

take into consideration that the punch tips will experience wear over time. When calculating the maximum tip force rating, tooling vendors safeguard their tooling, by utilising a factor of safety (FOS), to extend the service life and prevent premature failure. It is essential to understand that tooling may initially withstand more force than what is recommended, but if operated continuously at a higher force its life may be significantly shortened.

Maximum compression force ratings are determined by conducting multiple FEA sets emulating the same force being applied to the tooling as it wears throughout its lifetime. The solid 3D models in Figure 2 depict how tooling design affects the strength of the punch tip.

FIGURE 1

The maximum compression force rating provided by tooling vendors should also take into consideration that tooling experiences a build-up of residual stress, in addition to wear, over its life cycle. It is normal for the maximum compression force a tool can withstand to decrease over time due to residual stresses that build-up inside of the tip during use. With tool wear occurring during each compression event, this also reduces the maximum force the punch tips can withstand over their lifetime. As a punch wears, the maximum compression force that it can withstand is reduced. The compression force that a tool can withstand when producing the first tablet is going to be higher than the force it could withstand when compressing the one millionth tablet. Tooling vendors are capable of providing acceptable tip force ranges for new and/or worn tooling through the use of FEA software.

Ask your tooling vendors if their tooling is designed and engineered for continuous high cycle loading.

FIGURE 2: Figure 2: FEA analysis performed at 30kN of force on an 8mm standard concave cup design. These images illustrate how the amount of land on tablet compression tooling affects the maximum tip force rating. A decrease in land increases stress and can negatively impact the allowable compression force rating.

MICRO-TAB TOOLING Micro-tab tooling is gaining popularity in many industries.

Understanding the allowable force this type of tooling can withstand is critical. Generally, the term microtab tooling refers to tablets that are four millimeters (5/32�) in diameter or smaller. The compression force rating when using micro-tab tooling is normally not determined by the cup geometry, but rather the possibility of bending of the very small punch tips.

When designing micro-tab tooling, tool vendors should obtain the maximum fill requirement from the tablet manufacturer and recommend using the shallowest fill cam possible to maintain a tablet that meets all the required parameters.

Knowing the maximum size of the fill cam helps the tooling vendor design the best tool configuration for the application. When the selected fill cam is shallower than the standard fill cam for that tablet press, the tooling vendor can design the tooling to have an undercut die, and a shortened lower tip straight to strengthen the lower punch tips. This tooling design helps increase the allowable maximum compression force rating for micro-tab tips. To utilise this tool configuration, the tablet press

will also need to be equipped with effective lower punch retainers or filler plates.

The maximum compression force rating provided for a tooling set could be different between tooling vendors. This difference may be explained by vendors having different factors of safety (FOS) built into their force calculations. The FOS is the ratio of the calculated stress to the yield strength of the material.

If the tooling has a FOS of two, that means the force applied generates stress in the tool steel that is one-half the yield strength of the material. With all the variables that go into manufacturing high-quality tablet compression tooling, the allowable maximum compression force is dependent on each of them and could change if any of the variables are altered.

The factors that determine the maximum allowable compression force for tablet tooling can vary based on the steel selection, heat treatment process, tablet and tool configuration, and tooling wear.

With a better understanding of these elements, tablet manufacturers can establish parameters for their tooling that increases tooling life and prevents premature tooling failure.

18

DATA

Stop the clocks Chris Whitehead, managed platform product manager at SolutionsPT, looks at the importance of disaster resilience and the solutions available to help protect pharmaceutical manufacturers from the loss of critical data and interruptions to production.

C

hanges to intellectual property (IP) protection laws have left pharmaceutical manufacturers facing fierce competition and urgently looking for ways to streamline production, boost productivity and minimise downtime whilst adhering to a strict regulatory framework. With many pharmaceutical plants now moving towards continuous operation, the threat of disruption to production looms large and is costlier than ever before.

increase efficiency and protect plants from downtime.

As a tightly regulated sector in which downtime equates to potentially huge financial losses, manufacturers in the pharmaceutical industry typically experience comparatively less unplanned downtime than those in other sectors. However, when disruption does happen, it is much costlier, leading to potential drug shortages, fines and compliance failures.

Unlike other industries, pharma has not always had to pay close attention to manufacturing costs.

With generous margins and limited competition, the high price tag of finished drugs often compensated for any inefficiencies in production.

However, the intellectual property (IP) landscape in pharmaceuticals has changed. New competitors are emerging, increasing the pressure on manufacturers to fast-track new drug innovation, increase the speed at which they introduce new drugs to market and claw back profits with improved margins and better operational efficiency.

Pharmaceutical manufacturers are heavily regulated in terms of traceability and batch serialisation, and, as such, any downtime during a batch run will almost certainly ensure the entire batch has to be discarded as there would otherwise be no continuity in the batch data. Waste such as this has huge cost implications in terms of materials, time and profit.

As a result, innovators in the pharmaceutical industry are quickly waking up to the fact that, as manufacturers, they must go back to basics and adapt and improve their processes in the same way automotive and fast-moving consumer goods (FMCG) businesses have before them. The first task is to embark on an improvement campaign to

Threats to continuity do not only impact those who manufacture by batch. Many of the industry’s manufacturing leaders are exploring continuous manufacturing as a route to increase quality, process throughput, and profit.

Pharmaceuticals that are made using continuous manufacturing are moved non-stop within the same facility. This new approach is delivering significant benefits to pharmaceutical businesses but from an operational perspective, it is also creating a reliability challenge. During

batch production, quality testing would normally be carried out at regular intervals. However, during continuous manufacture, the production process doesn’t stop, so reliability and product quality must always be guaranteed.

Machinery failure is a common cause of downtime in pharmaceutical manufacturing, but increasingly one of the most pressing issues is cyber security. The 2017 attack on Merck saw a ransomware attack hit every location within the company, including its industrial control systems. The pharma giant suffered a total worldwide disruption of its operations and had to halt production of new drugs - negatively impacting on the company’s bottom line.

It is estimated that 96% of ransomware victims lose access to their data for more than one-day, heavily impacting production. With such a heavy reliance on OT systems to maintain uptime and productivity within the pharmaceutical space, it is essential to have disaster resilience and business continuity systems in place to ensure minimal impact across the plant, should a ransomware attack strike.

From a patient safety perspective, pharmaceutical manufacturers have a public responsibility to ensure that the production of drug substances and final drug products are not disrupted. Beyond the

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need to ensure the uninterrupted supply of vital medicines, drug companies have a responsibility to mitigate threats to their business operations and assets, which is why building disaster resilience into the pharma manufacturing environment, rather than relying on back-ups, is essential.

Traditional backup solutions are often not specifically designed for operational technology (OT) systems and may present issues.

For example, they often only perform a cyclic redundancy check (CRC) check on the backup data which doesn’t provide assurance that systems could be fully recoverable. In addition, these backups are often only tested in a recovery scenario by support teams.

The latest managed disaster resilience services can highlight anomalous file level changes through continual monitoring.

Backups are rigorously tested on a defined schedule by recovering the system in an ‘offline state’ while checking key services, dependencies and where applicable, integrity of critical databases and data sets. With ‘hot standby’ technology, systems can be quickly recovered with minimal of downtime on primary or backup hardware. Initial infection and lateral movement can also be tracked and contained, ensuring that critical pharma processes can continue while support teams investigate the outbreak and remediate the effects.

Compliance demands, a highly competitive environment and the delivery requirements of a complex range of end customers, including hospitals, insurance firms, supermarkets and pharmacists, means that operations continuity is crucial in pharmaceutical manufacturing.

As a result, having a good b business continuity and disaster

resilience process in place is essential and this isn’t just about having the ability to retrieve files but knowing how soon you can carry on production.

Pharma businesses need to ensure they don’t leave disaster resilience too late. It is essential to plan for what will happen when the worst happens and to test that plan out on a regular basis. Then, when something does go wrong, you’ve been through the procedures, you’ve been through a disaster resilience shake-down test and the people and the teams are all in place, so everyone knows what needs to be done to get things back up and running as quickly as possible. If this is something that your operation would struggle with, considering an externally managed service could be the solution.

When disruption does happen, it is much costlier, leading to potential drug shortages, fines and compliance failures.

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34th International Exhibition for Fine and Speciality Chemicals

26 – 27 June 2019 | Messe Basel, Switzerland

Europe’s most renowned industry hotspot

eciality p s d n a Fine a l s fo r chemic ndustries i various

Meet suppliers and experts from around the globe and find bespoke solutions, new approaches and innovative substances for your enterprise. fine chemicals • agrochemicals • pharmaceuticals • adhesives & sealants • paints & coatings colourants & dyestuffs • flavours & fragrances • pulp & paper chemicals household & industrial cleaning • leather & textile plastics additives • food & feed ingredients cosmetics • polymers • surfactants water treatment • petrochemicals electronic chemicals and much more Top conferences and workshops offer valuable insights into ongoing R&D projects!

• • • • • •

Agrochemical Lecture Theatre Chemspec Careers Clinic Pharma Lecture Theatre Regulatory Services Lecture Theatre RSC Lecture Theatre Innovative Start-ups

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ANTI-COUNTERFEITING

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Bringing the fight to fake drugs With drug counterfeiters increasing in number and determination, it’s crucial to be able to spot fraudulent medicines to stay safe. Here Scott McDougall, co-founder and registered manager of The Independent Pharmacy outlines five technological advancements that are taking the fight to fake drugs.

IDENTIFICATION FEATURES A medicine’s packaging should include a wide range of identification features, and some are more obvious than others.

REFERENCES 1 D, T. (2019). RFID in the pharmaceutical industry: addressing counterfeits with technology. - PubMed NCBI. [online] Ncbi.nlm.nih. gov 2 (2019). Fake drugs kill more than 250,000 children a year, doctors warn. [online] the Guardian.

Covert features include holograms, intricate guilloches, and colour changing inks. These elements are immediately visible (although some may require close examination to spot) and are useful for quickly identifying counterfeits during the supply chain.

Covert features are harder to describe, and with good reason.

These are hidden elements that are only detectable with special equipment, or if you know where to look.

This strategy is also used during the minting of currency. The new £1 coin released by the UK’s Royal Mint, for example, contains a number of hidden security features, detectable only by dedicated (and restricted) technology.

The markings on medicines work in the same way. For example, a medicine’s packaging might contain a chemical tag in the form of special ink. This holds a chemical signature that can only be spotted using technology specially designed for the task.

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ANTI-COUNTERFEITING

terms, this means blockchain data is nearly impossible for forgers to manipulate.

But how can blockchain technology make the supply of pharmaceuticals safer? As a drug moves through the supply chain, blockchain tech timestamps a product at each stage, ensuring its security.

Criminals can duplicate packaging, and the feel and look of authentic medicine. In fact, some are so skilled that it’s hard for even doctors to tell the difference.

However, by providing concrete proof of what medicine has been delivered, who transported it, and who manufactured it, through the application of blockchain technology to the supply chain, it will make it harder to counterfeit drugs.

SPECTROMETERS Spectrometers are hand-held devices which detect the chemical composition of a medicine. Each type of spectrometer is unique, tailored for different purposes depending on the situation, from space exploration to marine biology.

But spectrometers are also vital in the fight against fake drugs.

Every product created by pharmaceutical manufacturers has its own colour profile (or spectral fingerprint). This comprises the unique colours of each element used to make up the drug, acting as a method of quality control and patent protection.

Spectroscopy is used to identify the colours of drugs and highlight where they differ from those recorded by pharmaceutical companies – much like a crime lab would review a fingerprint to see if they can find a match in their records.

Spectrometers aid the battle against fraudulent drugs by identifying them before they enter the black market, eliminating the risk of fake medicine being purchased by unsuspecting customers. How? Because government agents can use a hand-held spectrometer to test drugs found in seaports or airports.

RADIO-FREQUENCY IDENTIFICATION (RFID) RFID tracks people and objects by using radio waves. It works via a system that uses software combined with an antenna, reader and tag. The latter element is added to an object to provide a unique ‘identification tag’ that transmits a data code and provides a way of tracking it.

Each RFID tag holds an electronic product code. So in terms of confirming medicine legitimacy, this code can be used to provide a record of when the drug was created and moved, along with details on the manufacturer. The information on the tag can be tracked, traced, and secured by the manufacturer – making the tag near impossible to counterfeit, unlike a barcode.

QUANTUM IDS Researchers at Quantum Base (a tech start-up at Lancaster University) have combined quantum technology to develop an identity tag for drugs and weed out illegitimate products.

In essence, quantum material only one-atom thick is combined with the surface of a product. When these materials are excited by bright light, they radiate light.

This action offers two data points: the properties of the emitted light, such as their colour, and the nature of the dwindling signal after the flash. The data points form a unique quantum ID that can be easily verified, i.e. pharmacies would be able to match the quantum ID with its assigned product.

But can these tags be copied by fraudsters? Potentially not. The tag’s unique code means that criminals would need to ‘atomically engineer a clone to be successful – a task that is decades from being practical’.

This technology means you can test that the drugs you’re taking are what they claim to be. Because of this, it’s been claimed that ‘RFID implementation is the most promising technology to quickly combat counterfeit drugs’1.

Covert and overt identification features, blockchain, spectrometers, RFID, and quantum IDs aren’t just examples of great tech, they’re tactics that save lives.

DID YO

U KNO

W? Over unknow 250,000 chil dren ingly medica tion ev taking coun terfeit e r fatal 2. y year T w help sa echnology ca hich can pro n be feg ve risks fa uard people fr leveraged t o ke med o m the overt id ic entifica ines pose. C potential o tio vert an spectro d meters n features, b lockch , RFID, aren’t ain, a nd qua just ex ntum ID amples they’re s of gre tactics that sa at tech, ve live s.

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ANTI-COUNTERFEITING

Faking it

European Pharmaceutical Manufacturer editor Reece Armstrong sits down with Neil Gleghorn, CEO of labelling provider Kallik, to discuss compliance challenges for manufacturers and the threat of counterfeit medicines.

WHAT ARE THE CURRENT COMPLIANCE HURDLES FACING PHARMACEUTICAL MANUFACTURERS AND PACKAGERS? The major challenge faced by most organisations is the proliferation of isolated stove-pipe systems that artificially limit levels of collaboration and insight that can potentially impact the accuracy of labelling and artwork content. Information sharing, transparency and traceability are often limited by obsolete systems and processes that can have a direct effect on levels of compliance.

There is also a reluctance to change amongst some of the larger manufacturers due to the perceived risk of introducing new technologies, however, without taking this step organisations are at risk of becoming uncompetitive and unable to attract a modern workforce.

WHAT ARE ON THE POTENTIAL IMPLICATIONS OF BREXIT ON LABELLING IN PHARMA? It is currently acceptable for drugs and devices manufactured outside of the UK and sold into the UK to carry the EU address of the Marketing Authorisation Holder (MAH) to distribute products in the UK, but this may not be the case if a no-deal Brexit is reached.

Simply, these products would need to carry a UK address, and post transition could even be required to carry UK and EU MAH addresses. Changes such as these can have a major downstream impact on supply chain operations.

Getting all partners adequately prepared for an unknown set of labelling changes is creating major headaches for the healthcare industry right now. Furthermore, as we move beyond the transition period (assuming there is a deal) we’re likely to see more changes to labelling as the EU and UK could go their separate ways when it comes to future legislation.

DOES THE RECENT FMD LEGISLATION DO ENOUGH TO ENSURE COUNTERFEIT MEDICINES AND PRODUCTS WON’T REACH ANY STAGE OF THE SUPPLY CHAIN? The FMD legislation is a step in the right direction but its success in eliminating counterfeit medicines and products will ultimately come down to the robustness of the solutions put in place by the industry. Given the challenging implementation timescales for FMD, many organisations have implemented stand-alone serialisation and traceability solutions at the point of print and packaging as opposed to upstream labelling and artwork creation to achieve compliance. Where pharmaceutical companies have a limited number of print and supply chain partners it’s feasible to put in place localised processes to maintain serialisation integrity, but this becomes far more difficult for global industries using potentially hundreds of supply chain partners across their print and packaging operations.

A better approach is to manage variable labelling content within the labelling and artwork solution as opposed to down at the factory floor as this removes the risk and overheads associated with managing serialisation data at a local level. It also simplifies the onboarding of new supply chain partners and provides global oversight of which products were manufactured and shipped from which partner in which territory.

The net result being a much more robust solution with increased traceability that also simplifies audit reporting and proof of compliance.

WHAT THINGS DO MANUFACTURERS OVERLOOK WHEN IMPLEMENTING A STRATEGY FOR LABELLING COMPLIANCE? Often manufacturers overlook the need for simplifying collaboration, providing greater process transparency and ensuring that audit reporting is an embedded part of the solution as opposed to being an add-on. The need for board level sponsorship and buy-in across the key stakeholders tends to be overlooked with individual business functions attempting to install localised solutions that simply fail to connect to one another resulting in poorly designed processes and minimal gains from investment. We believe that labelling is a board level topic and for it to be successful there needs to be enterprise-wide buy in and user adoption. Executive level

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sponsorship is needed because a proper labelling strategy will drive change and will require the business to grasp the opportunity it presents to rationalise their labelling estate and deliver real downstream productivity gains.

WHAT ARE SOME OF THE UPCOMING TECHNOLOGIES THAT YOU THINK WE CAN EXPECT TO SEE IMPLEMENTED FOR LABELLING IN PHARMA? I’d expect to see an increasing shift towards the adoption of web-based technologies. Cloudbased solutions can simplify the onboarding of new supply chain partners and production plants, and make it easier to scale up and down during periods of growth or contraction without the associate costs of on-premise solutions.

Technologies that provide greater levels of autonomy and decision support without risking noncompliance such as Rules Logic Engines and greater use of more modern, intuitive UI technologies are likely to feature more across labelling solutions. The key point here is ensuring that everything becomes connected, eliminating the need to share, review and approve labelling content via uncontrolled email, spreadsheets and documents.

HOW IMPORTANT IS TRACEABILITY DURING LABELLING AND WHAT CAN BE DONE TO HELP MANUFACTURERS KEEP TRACK OF THEIR PRODUCTS? Certainly for the pharmaceutical industry it’s needed to comply with the Falsified Medicines Directive, but the need for traceability is not limited to the supply of medicines. It also equally applies to the supply of medical devices, chemical products and cosmetics and potentially extends into other industries.

We view labelling content as being the master source for product traceability. Traceability also goes much further than the requirements set out in the FMD as it also applies to medical devices, although not to the same level of granularity as serialisation.

Legislation and regulation such as the US FDA UDI and the EU MDR require that medical device products can be identified and traced from healthcare providers back to the original manufacturer and by managing variable data such as LOT and Expiry within the labelling and artwork management solution makes it easier to trace products back to source.

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The FMD legislation is a step in the right direction but its success in eliminating counterfeit medicines and products will ultimately come down to the robustness of the solutions put in place by the industry.

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BIOPROCESSING

PUTTING THE PRO IN BIOPROCESSING Claire Hill, solutions support manager at IDBS, explains why advances in technology could be key for helping manufacture cell and gene therapies.

A

s innovations in the biopharmaceutical industry continue to push the boundaries of established scientific and engineering practices, the need for faster and more effective process development is greater than ever.

REFERENCES 1 https://www. cellandgene.com/doc/ intricate-supply-chaincomplicates-gene-therapymanufacturing-0002 2 http://www.cobrabio.com/ News/November-2018-(1)/ Cobra-Biologics,-PallCorporation-and-the-Celland 3 https://uk.reuters.com/ article/us-novartis-kymriah/ rare-manufacturing-glitchraises-concern-overcar-t-therapies-studyidUKKCN1MB334 4 https://www.biophorum. com/cell-gene-therapyphorum-acceleratesprogress/ 5 https://www.fda.gov/ NewsEvents/Newsroom/ PressAnnouncements/ ucm629493.htm

This is especially true for cell and gene therapies, one of the most exciting yet challenging growth areas in recent years.

While the therapeutic potential is clear, the technical challenges of manufacturing and the costs involved are still severely limiting.

Compared to other products such as monoclonal antibodies, cell and gene therapies are produced in very low volume batches using highly manual processes. An integrated development platform that can connect disparate data sources, support automation, and deliver process and product insight is essential for these niche products to start moving into the mainstream.

In 2019, it seems like hardly a day goes by without news of a new merger, acquisition, manufacturing facility, or other significant investments in cell and gene therapy. The potential to develop treatments for previously incurable conditions is a strong motivation and the recent approval of three gene therapies shows that the promise is starting to become a clinical reality.

Yet, while the therapeutic potential is incredibly appealing, the manufacturing process is

fraught with difficulties. Within the field of cell and gene therapy there is a wide range of different product types and methods of administration. While some products have the potential to be manufactured using established bioprocessing methods, such as suspension culture bioreactors, others like Chimeric Antigen Receptor T-cell (CAR-T)Â therapies involve highly manual processes that are very different from traditional biomanufacturing.

on dedicated manufacturing staff to support 24/7 operations. Many companies are investigating the use of healthy donor cells to create allogeneic CAR-T therapies with far greater potential to scale up manufacturing, reduce costs, and ensure better continuity of supply.

However, this approach has yet to demonstrate sufficient clinical efficacy, and using cells that aren’t patient-derived raises concerns about the immune response which must be addressed.

The two CAR-T products currently on the market, Kymriah and Yescarta, are autologous therapies which means that the patient’s own cells form the basis of the treatment. At a high level, the general process for autologous CAR-T therapies involves removing white blood cells, including T-cells from the patient, and then sending the cells to a manufacturing facility for processing where a new gene is inserted to help the T-cells recognise and destroy cancer cells.

Once enough modified cells have been attained, the cells are purified and tested before being sent back to the clinic and administered to the patient.

It seems likely that both autologous and allogeneic CAR-T therapies will be needed, both requiring efficient and cost-effective manufacturing solutions. One of the most promising approaches for autologous therapies is the use of closed, automated systems such as the CliniMACS Prodigy (Miltenyi Biotec) that can be operated directly in a clinic or hospital.

There are several limitations to this approach. The circular supply chain presents a number of logistical problems and the waiting time while manufacturing takes place- currently about twothree weeks can be an issue for critically ill patients1. Also, because the processes are predominantly manual, there is a heavy reliance

For allogeneic CAR-T therapies as well as gene therapy vectors such as lentiviruses and adenoassociated viruses, the use of continuous manufacturing platforms could greatly improve efficiency, while reducing manufacturing costs and improving quality. Cobra Biologics, Pall Corporation and the Cell and Gene Therapy Catapult recently received an Innovate UK grant to develop in-process analytical techniques and continuous manufacturing approaches using the Pall Cadence BioSMB system to significantly improve purification yields for adeno-associated viruses2. >>>

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The stakes could not be higher; the need for better manufacturing technologies and process steps was highlighted when a patient died in an early-stage CAR-T trial, due to a single leukemia cell accidentally being processed along with immune cells3. To overcome the current hurdles there needs to be a concerted effort across scientists, clinicians, engineers, and regulatory agencies. Still, effective data collection and analysis throughout process development and manufacturing is a challenge even for traditional biopharmaceuticals.

The compressed timelines and the complexity of gene therapy products only exacerbate this problem. Finding and reusing data from previous runs is difficult, if not impossible, and in many cases the most valuable information is buried away in spreadsheets and documents.

An integrated development platform that enables automatic batch recording and connects directly to instruments and material tracking systems is needed in order to achieve valuable process and product insight in a timely manner. Ensuring quality is embedded into the process from the beginning is essential for patient safety and also helps avoid wasted effort. The platform should be flexible enough for early process development and also support automation including the use of robots.

As in traditional bioprocessing, however, one of the biggest challenges is standardising data across various technology platforms. There are initiatives such as Allotrope, for analytical data and existing standards such as OPC and the ISA-88/ISA-95 object

The potential to develop treatments for previously incurable conditions is a strong motivation and the recent approval of three gene therapies shows that the promise is starting to become a clinical reality.

models for manufacturing, but true plug-and-play interoperability has yet to be achieved. Industry consortia such as the newly formed Cell and Gene Therapy Phorum are needed in order to promote knowledge sharing, establish best practices, and define industry standards4.

While there is still a great deal of work to be done, the potential for cell and gene therapies to radically transform healthcare now seems to be a question of ‘when’, rather than ‘if’. The FDA has announced plans5 to issue new guidance later this year and the growth in global investment will hopefully soon lower production costs and ultimately improve the safety and availability of these therapies for the patients who desperately need them.

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BIOPROCESSING

Who: Watson-Marlow Fluid Technology Group What: Explains why its silicone gaskets were the perfect choice for a new container system

Watson-Marlow Fluid Technology Group (WMFTG) explains why its silicone gasket technology was selected for use by container systems provider PuroVaso.

Case study

How: Through a unique combination of value and performance

GASKET-CASE

AT A GLANCE BIOCLAMP SELECTED FOR PUROVASO, A HANDLING DEVICE FOR POWDERS AND TABLETS. SILICONE GASKETS ALSO CHOSEN AS PART OF A TOTAL HERMETIC SEALING SOLUTION. HUNDREDS OF BIOCLAMP UNITS AND GASKETS WILL LIKELY BE REQUIRED.

31

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The product

Gaskets prove ideal

PuroVaso, a new product on the market for handling powders and tablets, is using BioPure BioClamp and BioPure silicone gasket technology on its containers. BioPure is an established brand of the Watson-Marlow Fluid Technology Group (WMFTG).

To complement BioClamp, PuroVaso has also opted to use BioPure 4” silicone gaskets.

According to the company, these were selected in preference to silicone gaskets from other manufacturers based on their GMP compliance.

Depending on sales, potentially hundreds of silicone gaskets and BioClamp fittings will be acquired over the product life of PuroVaso.

PuroVaso was designed to overcome a specific problem. The manual handling of pharmaceutical products can often be difficult due to the weight of the container. PuroVaso, however, offers a product-to-container weight ratio that ensures operator handling limits are driven by product weight, not the weight of the container. The result is a unique combination of value and performance.

Why BioClamp fits the bill In order to fit any valve type with a tri-clamp connection, PuroVaso engineers had to think carefully about the choice of union clamp fitted to the containers, opting for the BioClamp.

“We selected BioClamp as it was the most suitable solution,” confirms Steve Boswell, director at PuroVaso. “Influencing factors included weight, suitability for use in pharmaceutical applications, quality, GMP compliance, appearance, and having a trusted partner in WMFTG. In addition, BioClamp performed well in tests and was pricecompetitive compared with stainless steel alternatives.”

The patented BioClamp, which is moulded from reinforced Nylon 66 USP Class VI, is an extremely popular union clamp that is specifically designed to meet the needs of busy bioprocessing and pharmaceutical laboratories.

PuroVaso is using both 4” and 6” BioClamp neck fittings to ensure hermetic sealing between the PuroVaso container and valve. The design is deliberately generic to allow its use with any choice of valve.

BioPure silicone gaskets are FDA approved and come with industry-leading validation. They are manufactured and packed in BioPure ISO Class 7 cleanrooms which provide a controlled atmosphere with pressurised air locks and stringent checks. Each cleanroom has at least 30 complete air changes per hour with particulate counts monitored and recertified every six months.

High-purity, platinum-cured silicone gaskets are precision engineered to achieve a smoothbore, contamination-free fluid path under clamping compression. The gaskets have also been evaluated for extractables using a multisolvent approach in line with BPOG guidelines.

Both flanged and unflanged size options are available.

To facilitate full traceability, BioPure silicone gaskets feature permanent lot numbers produced by laser etching, while BioClamp has moulded-in lot numbers.

PuroVaso was designed to overcome a specific problem.

The manual handling of pharmaceutical products can often be difficult due to the weight of the container.

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BIOPROCESSING

ON THE RUN

European Pharmaceutical Manufacturer editor Reece Armstrong sits down with Andrew Bulpin - head of process solutions at the life science business of Merck - to discuss the industry and the company’s new platform for ‘contiGuous’ manufacturing in bioprocessing.

WHAT’S THE CURRENT STATE OF THE BIOPROCESSING INDUSTRY? The industry is at a very interesting turning point. The number of different modalities and therapies on the market, as well as globalisation, has picked up the pace over the past several years. Chronic diseases are prevalent and the onus is on the industry to help develop treatments that are more effective, safer and to do so more quickly.

Next-generation processing is gaining traction in the industry because of the significant impact it will have on bringing therapies to patients. The manufacturing template for monoclonal antibodies needs updating, as the same templated manufacturing process has been used for 30 years and the manufacturing equipment is also ready for updating. This manufacturing evolution will intensify the manufacturing template down to a continuous process involving just a few steps.

This intensification brings benefits of smaller footprints for equipment and the manufacturing facilities, requiring less capital. There are additional efficiencies gained in the flexibility of producing drugs in smaller batches versus big, stainless steel vats.

However, this is a journey and we cannot do it alone. This manufacturing evolution requires a triangular collaboration between suppliers, biomanufacturers and regulators - and sometimes even beyond by including academia and industry associations.

ARE THERE ANY REGULATORY BARRIERS TO NEW BIOPROCESSING TECHNOLOGIES? Bioprocessing is heavily-regulated, which has created a conservatism within the industry. Adoption of new technologies and novel approaches are slow as a result.

There is a hesitation to be the first to go to the FDA with a new manufacturing approach. In many cases, the established players in the industry have a certain culture and risk aversion. Nevertheless, it’s clear to me that the benefits of next-generation bioprocessing are there.

One of the major challenges is precedence from a regulatory standpoint. Nobody wants to be the first company to put in a new manufacturing process and get that through the regulatory agencies, hence there is a natural inertia to bring innovation into manufacturing. The FDA now encourages the industry to adopt continuous processing for small molecules and eventually, the continuous approach to manufacturing biologicals will gain more ground. However, any delay in getting a molecule to market can cost a company millions of dollars, so you can understand the caution on being an early adopter of an innovative manufacturing approach. Continuous processing offers clear benefits. Collaborative consortiums such as the Biophorum Operations Group (BPOG) and The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) can

help advance the technology and innovation so there is more acceptance.

COULD YOU EXPLAIN A BIT ABOUT MERCK’S APPROACH TO CONTINUOUS MANUFACTURING AND THE BENEFITS ITS BIOCONTINUUM PLATFORM OFFERS TO MANUFACTURERS? This manufacturing evolution brings with it process challenges.

Manufacturers are looking to suppliers for integrated solutions as they think holistically about their process and visualise future scale up. The industry is buzzing about continuous processing because it will have a significant impact on how our customers bring therapies to market, delivering them to patients faster and more costeffectively than ever before.

When we think about Merck’s role in leading the manufacturing evolution, we start with process intensification by updating and upgrading outdated unit operations, then connecting these processes to run in a connected and then continuous, flow-through fashion ultimately, reaching “contiGuous” manufacturing – a process that is continuous, connected and digitally-enabled with all the suitable software and automation, run as an orchestrated production train.

ContiGuous takes continuous processing to the next level by going beyond just connecting the individual unit operations to include the orchestration and management of all the processing

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steps (materials, production, testing and analytics) with an industryleading streamlined and optimised approach. Our vision is that the entire process is controlled, orchestrated and digitally managed through one manufacturing execution software system.

Merck is ideally positioned to offer contiGuous bioprocessing because we own all of the unit operations and are designing the BioContinuum Platform to achieve contiGuous bioprocessing - the seamless physical and digital integration of our BioContinuum Platform building blocks.

WHAT ARE THE DIFFERENCES BETWEEN MERCK’S APPROACH TO ‘CONTIGUOUS’ MANUFACTURING AND CURRENT CONTINUOUS MANUFACTURING TECHNOLOGIES AND THEIR IMPLEMENTATION? While continuous processing is the future of drug manufacturing, customers face challenges today in terms of speed-to-market, facility flexibility or cost of goods sold (COGS). A fully connected, fully continuous process is not

This manufacturing evolution requires a triangular collaboration between suppliers, biomanufacturers and regulators.

necessary for customers to see benefits. That’s why we’ve designed the BioContinuum Platform to feature next generation technologies that provide incremental process benefits now, with a mind to the continuous process of the future. Our unique holistic approach to process intensification allows us to realise benefits of process intensification over the entire process, not gained by focusing on one area at a time.

IS THE LAUNCH OF THE BIOCONTINUUM BUFFER DELIVERY PLATFORM EVIDENCE OF A WIDER STRATEGY FOR MERCK IN REGARD TO CONTINUOUS MANUFACTURING? The BioContinuum Buffer Delivery Platform is one of those building blocks and a perfect example of the high degree of connectivity that contiGuous biomanufacturing can achieve. The BioContinuum Buffer Delivery Platform is a highly accurate and precise buffer dilution system that utilises buffer concentrates and in-line dilution delivering buffer directly into the system. This streamlines the buffer delivery step and reduces the

process footprint by eliminating the massive buffer holding tanks.

HOW PREPARED IS THE PHARMA MANUFACTURING INDUSTRY FOR DIGITALISATION? For certain, future innovation lies with analytics and process monitoring. Initially, that will evolve to be at-line, but progressively as more technologies advance and the industry moves towards continuous manufacturing, analytics will evolve to be included in-line.

Improvements in the manufacturing template and expression levels allow production on a much smaller scale, while delivering higher yields and more potent drugs.

The manufacturing facility of the future will be highly digitalised (cybernated), multi-product or multi-modality facilities. Artificial intelligence and algorithms will not only control production, but also run better processes.

Both BioContinuum Platform & BioContinuum Buffer Delivery Platform are trademarks of Merck.

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LYOPHILISATION

Coming in from the cold Zak Yusoff, pharmaceutical freeze-drying applications manager at SP Scientific discusses why a quality by design (QbD) approach is key to achieving optimal lyophilisation of limited and expensive biopharmaceutical drugs.

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istorically, scale-up has been accomplished largely empirically, relying on multiple runs and prior experience.

Although this approach can result in quicker regulatory approval, it also increases the risk of vial rejection within and between batches leading to increased costs. Difficulties also arise when scaling up the development and manufacturing process. As the demand for better yields and higher quality of biopharmaceuticals intensifies,

optimising the lyophilisation process throughout the product’s life cycle plays an important role in providing a quality, successful biological product.

The US Food and Drugs Administration (FDA) strongly recommends a QbD approach to drug manufacturing, suggesting quality should not be inspected solely at the end of production but must be designed into the entire manufacturing process.

Although implementation of this

idea may appear a daunting task, and futile at the earlier stages of product development, controlled lyophilisation in the laboratory that can be transferred to full commercialisation will avoid the need for repeated optimisation of the lyophilisation conditions at each stage. As part of a QbD approach, Process Analytical Technology (PAT) tools can be used to improve the freeze-drying process by defining critical parameters and a range within which an acceptable product is obtained. >>>

One of the biggest freeze-drying scale-up challenges is changes in the degree of supercooling before freezing.

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LYOPHILISATION

CONSIDERING CRITICAL PARAMETERS OF LYOPHILISATION WHEN SCALING UP Even after the product formulation has been optimised, using different freeze dryers for each stage of the lyophilisation process can alter the freezing behavior of a product.

processes to use smaller amounts of initial product. This is especially relevant with biopharmaceuticals that are usually available in limited quantities. A more labourintensive option is to characterise the lyophiliser for minimum controllable pressure, max sublimation rate and heat transfer coefficient (Kv) measurement.

One of the biggest freeze-drying scale-up challenges is changes in the degree of supercooling before freezing. The lower the temperature at which the product nucleates (freezes), the higher the rate of supercooling, leading to increased cake resistance and smaller ice crystals. This can result in performance differences and, in many cases, increased drying times.

ACCELERATING SCALE-UP WITH COMPATIBLE EQUIPMENT AND TECHNOLOGIES Combining many of these scale-up options into a range of equipment that can be used for freeze-drying products from early stages of development to full commercialisation could enable transfer of conditions more easily. SP Scientific’s Line of Sight approach consists of a suite of tools (technologies and equipment) that can be employed at each stage of development and production. The Line of Sight strategy has been to use QbD approaches and equipment design to create an expanded design space for products as early as the formulation and cycle development stages enabling better transfer across equipment when scaling-up.

Currently, if the raw materials for the lyophilised product are scarce or very expensive, fractional load experiments can be performed using only part of the freeze dryer shelf area: an inefficient utilisation of resources. The introduction of a new generation of small capacity freeze dryer, such as the seven vial LyoCapsule freeze dryer, can overcome these limitations and enable multiple optimisation conditions to be tested on a small number of samples.

Another parameter that can differ between lab and commercial scale dryers is the heat transfer coefficient from the heating surfaces to the product creating batch heterogeneity. For the most efficient processing, it is desirable to operate at the highest possible shelf temperature and at a chamber pressure that still maintains the target product temperature during primary drying. Variations in resistance to mass flow during primary drying can occur between lyophilisers due to differences in nucleation temperature and equipment design. Therefore, it is important to optimise the mass flow rates in early primary drying to maintain the heat removal capacity of the condenser.

SOURCES LyoFlux® is a registered trademark of Physical Sciences Inc., Andover, MA, USA and used by permission.

Tempris® is a registered trademark of iQ-mobil solutions GmbH, Holzkirchen, Germany and used by permission.

STRATEGIES FOR OPTIMAL SCALING UP OF FREEZE-DRYING PROCESS There are several strategies that have been employed to overcome these challenges. The simplest relies on using historical experience of a particular freeze dryer as a product is scaled up.

It is also possible to scale down

Transfer of lyophilisation conditions between freeze dryers is efficient by applying the same methodologies throughout the process. New generation technologies, such as ControLyo

technology to control nucleation, SMART-MTM to calculate freezedried cake resistance and product temperature, Tempris wireless sensors to measure product temperature, or Tunable Diode Laser Absorption Spectroscopy (LyoFlux TDLAS) to measure water vapour concentration and flow velocity, are enabling organisations to freeze-dry a specific product providing consistent product quality.

CONCLUSION A QbD approach provides optimal process conditions through greater knowledge of the entire process which enables the development of a design space for the process and product. Once this design space is determined the product should be acceptable within this range under the FDA’s QbD definition.

If we view the product and process development for freeze-dried parenterals as an integrated process, rather than as a collection of independent activities, then it makes sense to follow a QbD method even at the early stages of formulation development.

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LYOPHILISATION

The big freez In this article, Karen Bossert, vice president of operations at CDMO Particle Sciences, reviews the use of lyophilisation in pharma and the growing market need for this technology, as well as how practical expertise and operational experience help obtain the best results for pharma’s most advanced drug developers.

MANAGING SHELF LIFE AND OTHER CRITICAL DELIVERY TARGETS Lyophilisation is a practical, commercially validated method to stabilise formulations and therapeutic molecules. The process relies on the control of pressure and temperature within the lyophiliser to remove liquid from formulations containing thermally sensitive active pharmaceutical ingredients (APIs) or formulation components. The resulting solid exhibits greater stability than the aqueous solution and can be stored for longer periods at potentially higher temperatures compared to its liquid precursor and may include ambient conditions. This technology has been particularly useful for large molecule developers - a growing segment of the pharmaceutical industry. With lyophilisation, fragile biologics no longer require expensive complex logistics such as rigorous cold-chain custody validation regimes and constant documentable refrigeration at the dispensary level.

THE MARKET’S GROWING NEED As API and formulation stability challenges become more common, growing numbers of pharmaceutical and biotech manufacturers view lyophilisation as an enabling technology for the next generation of therapeutics.

Over the past five years, there has been a marked increase in the use of lyophilisation in pharmaceutical and biopharmaceutical manufacturing – around 13.5% growth each year. This growth is being driven by many factors, including the complexity and variety of drug formulations that are coming through the pipeline.

Lyophilisation is a mature commercial process, and multiple blockbuster drugs (including biologics such as Enbrel, Herceptin, and Rituxan) were made possible due to sterile lyophilisation. Currently, around 16% of the top 100 pharmaceuticals are lyophilised, including a third of all biologic drugs and half of all new injectable/infusible drug approvals. In the future, market analysts predict that a quarter of all biotechnology and pharmaceutical products will undergo lyophilisation.

A BETTER STABILISATION STRATEGY Lyophilisation offers parenteral drug developers great utility because it results in a stable powder for injection that is easily packaged and transported as a finished product. However, lyophilisation can also be used to generate stable intermediates during drug product development and manufacturing.

A lyophilised stock of sensitive API has a longer shelf life, which is useful for APIs that lack the stability to be processed in an aqueous state. Lyophilisation can generate a powder with flowability for milling or powder fills, or it can simply be used to remove residual solvent from a material.

INHERENT COMPLEXITIES REQUIRE COMPREHENSIVE APPROACH While lyophilisation offers clear advantages, the process itself still requires good science, bestpractice operations, and optimised equipment to ensure lyophilisation processes meet the molecule’s requirements without compromising its therapeutic goals. This demands significant investment in time, money, and staff resources:

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ze • Specialised knowledge required: Lyophilisation cycle development and scale-up relies on a thorough understanding of the freezing and sublimation processes. This requires extensive characterisation of the drug product as well as studies to understand the effect of packaging and batch size on processing.

• Additional contamination risk: Many lyophilised products are not amenable to terminal sterilisation and must be manufactured under aseptic conditions to maintain product sterility. This is a major challenge that requires extensive validation and monitoring of equipment and procedures to execute.

• High capital investment: R&D development of a lyophilisation cycle can take place with pilot scale equipment in small batches. However, largescale lyophilisers and the associated cleanroom facilities to accommodate sterile fill-finish cost millions of dollars to install and maintain.

Developing, scaling, and validating a lyophilisation cycle is challenging, and many small and large pharmaceutical companies choose to place their lyophilisation processes in the hands of CDMOs for clinical and commercial manufacturing.

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Although there is a clear and growing demand for lyophilisation in the market, providing expert lyophilisation capabilities demands more than installing the newest state-of-the-art equipment and systems.

RECOGNISING HIGH PERFORMANCE LYOPHILISATION SERVICE PROVIDERS Although there is a clear and growing demand for lyophilisation in the market, providing expert lyophilisation capabilities demands more than installing the newest stateof-the-art equipment and systems.

From analytical and quality support to validation and regulatory guidance, it is vital to ensure that contract development and service providers offer critical supporting services, including complex formulation expertise and experience with analytical method development and validation. These skills allow CDMOs to meet target product profiles and effectively verify product performance before and after lyophilisation.

For example, a growing number of drug products rely on complex formulation approaches such as encapsulation in polymeric microparticles or liposomal platforms. These products often provide poor stability in their native states and rely on lyophilisation to be commercially viable. Without a formulation team skilled in excipient selection and an analytical group who can consistently characterise product performance, a CDMO cannot formulate the initial solution/suspension, design the

lyophilisation process, and ensure that the final drug product is truly ready for market.

THE FUTURE, BASED ON A DRY CONCLUSION Lyophilisation is rapidly gaining ground as more and more drug products benefit from this manufacturing process. With the increase in complex molecules and unstable compounds in the drug development pipeline, it is likely that the demand for expert capabilities implementing this method will only increase.

From a commercialisation perspective, any drug developer considering lyophilisation must ensure that they have the necessary capacity and capabilities, whether in house or outsourced.

Any CDMO partner brought in to assist in a project must possess more than just a “freeze dryer” to get the job done. They must have formulation and analytical expertise along with experience developing, scaling, and validating lyophilisation cycles to ensure a project has a chance of success.

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TABLET PRODUCTION

TINY BUT MIGHTY Dr Niklas Sandler, chief technology officer at Nanoform, explains why the use of nanonisation and artificial intelligence (AI) can help pharmaceutical manufacturers unlock added value for bioavailable nanoparticles.

N

anonisation, the process of manufacturing nanometerscale particles, is a powerful technique for increasing the bioavailability of drug substances by enhancement of dissolution rates and solubility. It is estimated that half of all drug substances currently working their way through pharma pipelines exhibit poor solubility. This can all too easily result in failure during clinical development, as poorly soluble compounds are absorbed less efficiently into the body.

Overcoming the problem of low solubility by simply increasing dose is often not an option, as it can either be practically unfeasible or result in increased side effects.

Nanoparticles have a clear advantage over microparticles in terms of bioavailability, which can best be explained by the difference in relative surface area between particles on the nanometer versus the micrometer scale. A 100-fold decrease in the size of a cubic particle will increase its surface area to volume ratio by 100 times. This dramatically increases the particle’s exposure to solvent and leads to an observed increase in dissolution rates, directly correlating to increased solubility and better absorption into the body.

One drug on the market for which this increased relative surface area was crucial for successful commercialisation is aprepitant, used in the treatment of chemotherapy-induced nausea.

Aprepitant is a largely non-polar compound that shows very poor

solubility in water and is absorbed through a small section of the upper gastrointestinal tract. It was only through the manufacture of nanoparticles that the drug could be made sufficiently soluble to take advantage of this narrow absorption window.

However, the manufacture of these nanoparticles required a complex milling process, which is unreproducible for many drug substances in development, and introduces numerous excipients into the final drug formulation.

New technology must therefore be investigated as a means to better overcome the industry’s formulation challenges and help enable more promising drug candidates to reach the market.

BRINGING TOGETHER ADVANCED TECH, EXPERT KNOWLEDGE AND MACHINE LEARNING Recent advances in nanonisation technology, such as controlled expansion of supercritical solutions (CESS), can reproducibly generate pure drug particles, free from excipients. In the CESS process, drug substances are dissolved under high pressure in supercritical CO2, and then recrystallised through a controlled step-wise reduction in pressure.

After careful optimisation of parameters, the methodology enables unprecedented control over the thermodynamic processes of particle nucleation and growth.

A deeper understanding of the specific parameters that are likely to lead to successful nanonisation

of a given drug compound will allow further gains in qualityby-design, and help pharma companies to focus on winning compounds.

Manufacture of effective nanoparticles requires knowledge at the cross-section of biology, chemistry and physics. A significant facet of this is understanding how a given candidate for nanonisation sits in chemical space, and the numerous physical and chemical properties that will affect its performance in experiments.

These properties are many and varied, including the overall size of the molecule, its functional groups, and its hydrogen bonding network.

As drug substances go through the nanonisation process, the reaction data collected can be used to help elucidate the interplay between different molecular properties and how they influence nanoparticle manufacture. However, due to the sheer number of variables that can affect overall nanonisation success, a machine learning AI approach has the potential to be extremely beneficial in truly understanding how a molecule will behave.

Smart integration of AI machine learning systems can complement advanced technology and expert knowledge with their ability to deliver the insights needed for process optimisation.

AI FOR ALL AI solutions that are currently being rolled out within the pharma industry are typically based on machine learning algorithms using

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big data. However, for optimising drug particle nanonisation, this approach has limited use. Firstly, the input data is generally taken from many different sources and used in such a way that its accuracy can be difficult to verify. Secondly, the scale of the datasets required is something that even the largest pharma companies struggle to acquire.

An alternative approach is therefore to leverage sparse data AI, which can allow for process optimisation with far fewer experimental data points.

With sparse data AI, smaller data sets are directly augmented with detailed expert knowledge to allow for the probabilistic prediction of factors, such as how a given molecule will behave under certain circumstances. The approach is a promising way to help identify the compounds that are most likely to be successfully nanonised, and the conditions that will best facilitate the process.

A deeper level of understanding about factors influencing the nanonisation process allows more precise design of nanoparticle attributes, in turn allowing more formulation challenges to be overcome.

In order to expand this understanding, sparse data AI can use available in vivo and in vitro experimental data to ground and guide in silico experiments that investigate how various parameter settings affect different molecules. This will enable more rapid decisionmaking about which molecules are likely to succeed, and provide good indication of the process parameters likely to be successful. As a molecule moves through the iterative stage of process optimisation, AI can be further used to drive decisions about parameters like temperature, flow rate and pressure, in order to achieve optimal nanoparticle products.

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HELPING DRUG CANDIDATES REACH THE CLINIC The use of state-of-the-art machine learning to predict a drug substance’s nanonisation success will help pharma companies unlock added value in their preclinical, clinical and late phase programmes. By delivering constant process improvements through consistent learning, the technique is poised to help in the reliable production of high quality, highly soluble, highly bioavailable nanoparticles. In turn, this will help solve the industry’s challenging particle manufacturing problems and enable more molecules into the clinic. Through the application of expert knowledge, cuttingedge technology and sparse data AI, advanced nanonisation processes have the potential to minimise problems with solubility and double the number of drugs reaching the market.

A deeper understanding of the specific parameters that are likely to lead to successful nanonisation of a given drug compound will allow further gains in qualityby-design, and help pharma companies to focus on winning compounds.

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COATINGS & CAPSULES

One step

ahead

Sanket Sanjay Sapate, research analyst at Adroit Market Research explains the benefits of microencapsulation and the challenges it presents to drug manufacturers.

M

icroencapsulation is an advanced delivery system which involves storing particles of an active agent in a protective shell made of polymeric compounds to form particles sized in micrometre to millimetre range.

The main objective of the process is to protect the active agent in uncertain conditions and prevent its degradation.

Within the pharmaceutical industry, the technique is used to prevent enzymatic degradation of active agents when entered in the body. It is also one of the major benchmarks for controlled release dosage forms. Microencapsulation has evolved as a replacement for sustain release patches owing to dosage convenience possessed by microencapsulation products.

Currently, major challenges faced by drug manufacturers include the taste of drugs, drug disintegration in undesired pH, hygroscopic nature of drugs, and many more. In the case of bitter drugs, encapsulation offers superior coating over the drugs to improve taste and ease the administration of tablets & capsules. Whereas in the case of hygroscopic drugs, a capsule protects the drug molecules from water and prevents undesired reactions between drugs and moisture.

Large number of research activities are being done across the globe to gain maximum advantage of the technology.

One of such was done in 2018 in which insulin-producing cells were transplanted into diabetic patients. Encapsulation protects the cells from T1D autoimmune attacks and creates a suitable biological environment for cell function and survival.

Microencapsulation involves placing the islet cells in its own capsule whereas macroencapsulation involves many cells placed in one device. However, as of now, an array of limitations are present, such as a continuous supply of healthy islets. Currently, cadavers are the only source of islets which are limited in numbers.

Additionally, the susceptible nature of islets, which means they need oxygen for survival, makes it is difficult to maintain a healthy state of cells. Furthermore, fibrosis is a major worry and is the most common area of concern while transplanting islets.

The major companies in the market are involved in strategic partnerships with end-user industries such as pharmaceuticals, home & personal care, agrochemicals, food additives and many more.

High investment in research & development in order to improve the efficiency of existing characteristics is likely to be a key factor for the market growth. AnaBio introduced new microencapsulation technology which involves liquid creatine in the systems such as sports drinks, gummies, and gels. Previously, creatine, when added in water, decreased the effectiveness in the body. To overcome this challenge, the encapsulation system was designed to protect the molecules and reduce its instability in water.

The development made by AnaBio is expected to increase the adoption of creatine in sports nutrition products.

To end with, microencapsulation has been a boon to pharmaceutical research. Continuous development in dosage forms with increasing complexities in drug molecules has resulted in the adoption of capsulation technology to protect APIs. With a large number of drug approvals, there will be a continuous requirement of suitable dosage forms to maintain the efficacy of the APIs where encapsulation technology is expected to act as a frontier in the coming years.

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COATINGS & CAPSULES

AN EVEN COAT The film coating process requires a balance of the complex interactions between the tablet substrate, coating system, coating process and equipment. In this feature Jason Teckoe, technical director, EMEA at Colorcon discusses the importance of choosing the right formulation and managing the coating process to ensure process efficiency while delivering a perfect tablet finish.

TABLET FILM COATING SCALEUP & TECH TRANSFER A frequent challenge for manufacturers is scaling up to different coating equipment while maintaining reproducible coating quality. It’s common for issues not predicted earlier in development to become apparent in real-world settings.

A key part of technology transfer is scale-up, with studies to take the optimised, already-developed process and transfer it to various equipment types and sizes… often at other manufacturing sites. In some cases, it can involve further optimisation of parameters specific to the manufacturing site or a particular piece of equipment. Also, as older processes or equipment are improved, coating parameters sometimes change. This is not uncommon when shifting from a conventional type of coater (solid-pan) to a perforated pan (auto-coater), or when transitioning from batch coating to larger scale continuous or semi-continuous coating equipment

IDENTIFYING CRITICAL PROCESS PARAMETERS OF FILM COATING There are several variables, often inter-dependent, that can influence both the coating process and the quality of the final coated substrate. During scale up, you’ll need to identify all the critical process parameters.

The objective is to understand the importance of each parameter to achieve your required quality and functionality at the desired scale of operation.

These critical parameters need to be controlled within limits that allow the final process to be operated routinely in a manner that yields an optimal product within acceptable time & cost constraints.

REDUCING RISK DURING TABLET COATING SCALE-UP Achieving a perfect finish for your coated tablet comes down to ensuring the right coating formulation and process parameters are used, whatever the scale.

One of the major differences amongst coating machines is air flow capacity. For example, in the Asia Pacific region and some parts of Europe, coating equipment tends to have much lower airflow than that in North America. Other regions still use many conventional solid wall pans, which have low airflow and poor temperature control. The coating formulation needs to be flexible and robust to withstand these types of variables and still result in a uniform, highquality final appearance that does not vary from batch to batch.

At Colorcon, we’ve conducted multiple studies to identify and characterise the impact of varying key coating process parameters on critical quality attributes for all our formulated coating systems.

This helps manufacturers to be confident their process will be reliable through scale-up and transfer, even across different types of equipment.

Opadry QX – a recent Colorcon technology advance – is designed to simplify tech transfer and scale-

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up as it can be easy to use across a wider range of process variables.

Where many coatings require narrow windows of operation, Opadry QX delivers excellent results across much wider ranges.

In addition to being forgiving across variable parameters, it is effortless to work with and delivers better coating consistency with process efficiency.

And, with quick application to protect from the rigours of the film coating process, Opadry QX is enabling manufacturers to easily coat temperature sensitive actives.

Designed for use across a wide range of equipment, with tablet bed temperatures as low as 30°C, the high solids levels mean a perfect coating finish is completed in 40% less time. This exceptional process adaptability means coating scale-up and transfer to production is simpler, saving time and valuable resources, while still delivering a premium quality finish.

The commercial impact of the process and equipment flexibility means that pharmaceutical companies can easily transition the manufacture of drug products across sites, and continents, overcoming challenges often met with equipment differences.

Capital investment may also be deferred through more efficient equipment utilisation as production needs increase.

Achieving a perfect finish for your coated tablet comes down to ensuring the right coating formulation and process parameters are used, whatever the scale.

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FROM THE FACTORY

ALL THE SINGLE SOLUTIONS Chargepoint’s senior product manager Ben Wylie explains why single-use technology might be key for complex manufacturing environments.

W

ith the growing demand for medicines that have complex manufacturing requirements, pharmaceutical companies must introduce aseptic and high potency manufacturing processes into their operations. Effective containment during high potency manufacturing is important to protect the safety of operators, while aseptic processing measures must protect the drug product from contamination. Any contamination during the manufacturing process can have a substantial financial impact, not to mention possible implications within the supply chain.

In response, pharmaceutical manufacturing environments are evolving with new technologies. These include smart monitoring capabilities which give manufacturers an automatic / reliable method of understanding the health

status of process and transfer devices to better control risk and ensure consistent integrity throughout the lifecycle of the system and its critical components.

2019 is no exception with the rise of hybrid, single use technology now being adopted within pharmaceutical manufacturing processes.

Whilst single use technologies need to deliver the same level of performance as some of the more traditional stainlesssteel solutions, the reality is that this is often not the case.

A new hybrid solution now includes disposable versions of Split Butterfly Valve (SBV) technology, which enables high performance contained and sterile transfer of pharmaceutical powders.

Responding to the challenges of today and tomorrow, pharmaceutical manufacturers

also need solutions that are pre-validated, ready to use and deliver repeatable and reliable performance levels. They must also be easily integrated into existing processes and perform to the highest level of containment and sterility assurance.

Hybrid single use SBV systems are lightweight and cost effective, delivering containment and sterility assurance performance whilst eliminating the time and cost associated with cleaning, maintenance and validation of the disposable half, something that will increase productivity and reduce downtime.

Transfer Solutions Today, more pharmaceutical companies than ever are utilising multiple manufacturing locations. Consequently, more drug products and APIs are being moved between facilities. Assuring the integrity of these expensive, sensitive powders whilst in transit is a challenge that is currently met with common packaging solutions that, while they meet the needs for transportation, often give facilities a headache

when it comes to filling, sealing, handling and emptying in line with containment or sterility requirements. One method that works well for facility A, may not work so well for facility B or vice versa.

Together, the SBV and transfer bag form a high performance, single use package for the contained and sterile transfer of pharmaceutical powders between manufacturing process steps or even facilities.

Furthermore, single use options can also reduce the time and investment required to get facilities and process lines up and running. These solutions can be a method for contained powder transfer within facility A (drug supply), but can also be used as a product’s primary packaging and container closure for transportation to facility B (for drug product formulation for example).

A hybrid system, including a single use version of the passive mating half of SBV technology, ensures users can take advantage of the benefits of single use transfer technology without compromising performance or convenience.

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