EPM May 2016

Copyright: Betto Rodrigues

FIGHT THE GOOD FIGHT WHAT’S PHARMA REALLY UP AGAINST? PLUS EXPERTISE IN CONTINUOUS MANUFACTURING DRUG DELIVERY UPDATE PACKAGING

MAY 2016

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Contents May 2016 | Volume 16 Issue 3

Regulars 5

16

Features 14

COMMENT

FIGHT THE GOOD FIGHT

6

Lu Rahman looks at the challenges the industry faces combatting illness

NEWS ANALYSIS

11

29

OPINION James Thomas, Seren Partnership Negotiation offers advice on pharmaceutical negotiating

16 COVER STAR – THE SEQUEL Continuous manufacturng expertise from Colorcon and LB Bohle

34

19

CHEMICAL REACTION

MAKING SUCCESS

Mark Offerhaus, highlights how Micreos is using nature to fight bacteria

Michal Wlodarski, Camin examines the manufacturing challenge of antibody-drug conjugates

23 TOUGH LOVE

32

Schott explains the merits of chemically strengthened glass for storing medication

25 NOW YOU SEE IT… Omya looks at functionalised calcium carbonate and its use in orally disintegrating tablets and granules

29 WRAPPED UP Schubert-Pharma’s packaging process for Nephron Pharmaceuticals

32 SWEET SUCCESS Beneo describes how its galenIQ can deliver benefits in medicines formulation

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from the editor

Life on Mars Astronauts on drugs? With one member of the EPM editorial team having a particular fondness for Tim Peake, we were particularly interested to read about the latest events taking place on the International Space Station (ISS).

It’s one thing keeping abreast of the latest developments in the pharmaceutical sector on Earth so to read that researchers at the University of Southern California (USC) and NASA’s Jet Propulsion Laboratory have come up with idea of launching fungi into space to create new medicine, is incredibly exciting.

As I’m writing this, the fungi should be on their way into orbit, the idea being that under pressure changes can be triggered which can lead to the production of drugs such as penicillin. According to the American Association for the Advancement of Science (AAAS), some types of fungi produce molecules called secondary metabolites which can be used to make pharmaceuticals. Penicillin and lovastatin for lowering cholesterol, are two examples of secondary metabolites.

“The stressful environment of the International Space Station (ISS) could trigger changes in physiological responses (such as gene expression) and metabolism of a well-studied fungus called Aspergillus nidulans,” said Clay Wang, a professor of pharmacology and pharmaceutical sciences and chemistry at the USC School of Pharmacy.

“We’ve done extensive genetic analysis of this fungus and found that it could potentially produce 40 different types of drugs. The organism is known to produce osteoporosis drugs, which is very important from an astronaut’s perspective because we know that in space travel, astronauts experience bone loss,” he revealed.

This is an amazing project. Drug discovery in space is a vital step forward for the protection of astronauts and keeping them healthy on the ISS. It also allows space exploration to increase its boundaries safe in the knowledge that astronauts can be kept well should the need arise. However, the breakthroughs aren’t simply confined to space. According to USC scientists, based on current, Earth-based research molecules from Aspergillus nidulans could be used to fight cancer and Alzheimer’s. It’s inspiring stuff and highlights just how far drug development has come and will go.

Lu Rahman

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NEWS ANALYSIS

Roman god helps create pill for long term drug release Dual-sided Janus device means tablet can be attached to the lining of the GI tract while other side act as a repellent

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esearchers from MIT and Brigham and Women’s Hospital have designed a new type of pill that, once swallowed, can attach to the lining of the gastrointestinal tract and slowly release its contents. The tablet is engineered so that one side adheres to tissue, while the other repels food and liquids that would otherwise pull it away from the attachment site.

Such extended-release pills could be used to reduce the dosage frequency of some drugs, the researchers say. For example, antibiotics that normally have to be taken two or three times a day could be given just once, making it easier for patients to stick to their dosing schedule.

“This could be adapted to many drugs. Any drug that is dosed frequently could be amenable to this kind of system,” says Giovanni Traverso, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research, a gastroenterologist at Brigham and Women’s Hospital, and one of the senior authors of a paper describing the device in the April 6 issue of the journal Advanced Healthcare Materials.

Robert Langer, the David H Koch Institute Professor and a member of the Koch Institute, is also a senior author of the paper. The paper’s lead author is Young-Ah Lucy Lee, a technical assistant at the Koch Institute.

Sticking point Over the past several decades, Langer’s lab has developed many types of materials that can be implanted in the body or attached to the skin for long-term drug release.

To achieve similar, long-term drug release in the gastrointestinal tract, the researchers focused on a type of material known as mucoadhesives, which can stick to the mucosal linings of organs such as the stomach.

Scientists have previously explored using this kind of material for drug delivery to the GI tract, but it has proven difficult because food and liquid in the stomach become stuck to the tablet, pulling it away from the tissue before it can deliver its entire drug payload.

“The challenge with mucoadhesives is that the GI tract is a very rough and abrasive environment,” says Lee.

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To overcome this challenge, the researchers decided to create a dualsided device, also called a Janus device after the two-faced Roman god.

One side sticks to mucosal surfaces, while the other is omniphobic, meaning that it repels everything it encounters.

”

Researchers have created a new type of dual-sided pill that attaches to the gastrointestinal tract. One side of the pill sticks to mucosal surfaces, while the other is omniphobic, meaning that it repels everything it encounters.

Double up To overcome this challenge, the researchers decided to create a dualsided device, also called a Janus device after the two-faced Roman god. One side sticks to mucosal surfaces, while the other is omniphobic, meaning that it repels everything it encounters.

For the mucoadhesive side, the researchers used a commercially available polymer known as Carbopol, which is often used industrially as a stabilising or thickening agent. The omniphobic side consists of cellulose acetate that the researchers textured so that its surface would mimic that of a lotus leaf, which has micro and nanoscale protrusions that make it extremely hydrophobic. They then fluorinated and lubricated the surface, making it repel nearly any material.

The researchers used a pill presser to combine the polymers into twosided tablets, which can be formed in many shape and sizes. Drugs can be either embedded within the cellulose acetate layer or placed between the two layers.

Using intestinal tissue from pigs, the researchers tested three versions of the tablet — a dual-sided mucoadhesive tablet, a dual-sided omniphobic tablet, and the Janus version, with one mucoadhesive side and one omniphobic side.

To simulate the tumultuous environment of the GI tract, the researchers flowed a mix of food including liquids and small pieces of bread and rice along the tissue and then added the tablets. The dual-sided omniphobic tablet took less than 1 second to travel along the tissue, and the dual-sided mucoadhesive stuck to the tissue for only 7 seconds before being pulled off. The Janus version stayed attached for the length of the experiment, about 10 minutes.

Illustration: Christine Daniloff/MIT

Tejal Desai, a professor of bioengineering and therapeutic sciences at the University of California at San Francisco, says this approach could make it possible to deliver larger quantities of drugs through the GI tract.

“The ability to precisely engineer the adhesiveness of a particle opens up possibilities of designing particles to selectively adhere to specific regions of the GI tract, which in turn can increase the local or systemic concentrations of a The researchers may particular drug,” says Desai, who was not -also further pursue involved in the work.

“

Further tests

the development of tablets with omniphobic coatings on both sides, which they believe could help patients who have trouble swallowing pills.

The researchers now plan to do further tests in animals to help them tune how long the tablets can stay attached, the rate at which drugs are released from the material, and the ability to target the material to specific sections of the GI tract.

In addition to delivering antibiotics, the two-sided material may help to simplify drug regimens for malaria or tuberculosis, among other diseases, Traverso says. The researchers may also further pursue the development of tablets with omniphobic coatings on both sides, which they believe could help patients who have trouble swallowing pills.

”

“There are certain medications that are known to get stuck, particularly in the esophagus. It causes this massive amount of inflammation because it gets stuck and it causes irritation,” Traverso says. “Texturing the surfaces really opens up a new way of thinking about controlling and tuning how these drug formulations travel.”

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REGULATORY AFFAIRS

Rare diseases – EU regulatory overview and orphan drug development

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he last day of February every year is observed as Rare Disease Day. February 29 was chosen since it is a rare day! The objective of the day is to raise awareness amongst the public and decision makers about rare diseases and their impact on patients’ lives.

Benefits of the orphan designation include the following; • Incentives • Assistance in development including protocol assistance • Reduced fees for the license application depending on the type of sponsor • Access to centralised procedure for evaluation of the marketing authorisation application

Rare Diseases – EU overview A rare disease or orphan disease is a disease or disorder that affects a small percentage of population. Any disease affecting fewer than five people in 10,000 is considered as rare in Europe.

As per the published estimates, 6000 to 8000 distinct rare diseases affect or will affect 6 - 8 % of the population in Europe, which would be approximately 246 000 people. Many patients suffer from very rare diseases affecting 1 in 10,0000 or more people and many of them are children.

These diseases are mostly of genetic origin and cause chronic health problems or are life-threatening, creating psychological and financial stress for the affected families. Combined efforts from policy makers and industry are needed to deliver the health policies and expertise that will lead to improved diagnosis and access to care globally.

‘Orphan drugs’ are intended for the treatment of rare diseases that, under normal marketing conditions, the pharmaceutical industry would be reluctant to develop for economic reasons. However, these medicines are developed based on public health demand. Discovery of new molecules for a small patient population will be expensive and it will take long time (more than 10 years after the discovery of molecules) to market such drugs under the standard regulatory pathways.

The EU is promoting Rare Disease as a public health priority, and a range of incentives are being offered to industry to encourage the development of medicines for rare diseases.

Orphan Regulation (Regulation (EC) No 141/2000) that came into effect in 2000 established the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA). COMP is responsible for reviewing applications for orphan medicinal product designation.

• Market exclusivity rights when the license is granted Orphan designated medicines can benefit from funding available from the European Commission and other sources, including national-level grants offered by the member states for the development. Scientific advice offered by the EMA prior to the submission of an application for Marketing Authorisation on orphan medicines is called protocol assistance. Protocol assistance is offered at the reduced charges.

Orphan medicinal products enjoy 10-year market exclusivity rights, which are extended to an additional two years depending on the pediatric investigation plan granted.

Regulatory activities including protocol assistance, license application/ maintenance, inspections, annual fees and so on can be considered for reduced fees.

Orphan Medicinal Products – Way Forward On 7th March 2016, the European Commission launched a very advanced scheme called PRIME to accelerate the assessment of medicines for unmet public health needs. PRIority MEdicines (PRIME) scheme will, of course, enhances early scientific consultation facilitating early access of promising medicines.

In addition to the regulatory procedures and schemes available on the common EU platform, there are schemes and early medicines access procedures available nationally. It is therefore important that sponsors exploit all available sources of support in close collaboration with regulatory agencies.

The multilingual database ‘Orphanet’ provides information about orphan drugs and diseases. National-level plans are recommended to combat rare diseases, and the EU ensures the traceability of rare diseases through adequate coding. Since the implementation of this regulation, there has been significant enhancement in research and development initiatives.

Lini Subin, Senior Manager, Regulatory Affairs

Orphan Designation and Orphan Drug Development

Well versed in EU DC/MR and ICH national strategies, her specialities include dossier development for a variety of markets including Europe, Asia, Africa, Latin America, CIS countries and the US. She is also an expert in managing eCTD/NeeS conversions, and MA transfers.

The EMA plays a key role in the development and authorisation of orphan medicines. Sponsors need to submit for EMA review an application for orphan designation in order to benefit from the incentives. Based on the COMP’s positive opinion, the European Commission grants orphan status to medicines provided they meet set criteria.

With almost a decade of expertise in global pharmaceutical regulatory affairs and holding an MSc in Chemistry (Pharmaceuticals), Lini Subin is a knowledgeable strategist who understands the entire application lifecycle, from pre-approval to post-approval activities.

Based in India, her insightful knowledge of market trends gives her a unique perspective on implementing business development initiatives.

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9

OPINION

Talk talk James Thomas, Seren Partnership Negotiation offers advice on negotiating in the pharmaceutical industry

I

t is probably true to say that building trust is the pharmaceutical industry’s biggest challenge when dealing with its customer. The huge sums of money made by pharma companies don’t sit comfortably with customers despite the industry’s attempted justifications that only three in 10 drugs launched make any profit. The healthcare professional needs to successfully treat as many patients as possible within tight budget constraints, whilst the pharma industry needs to achieve a return on investment for the millions spent on R&D every year. There is clearly a conflict, but despite this they still do business through structured negotiation processes and regulatory guidelines.

Most value is gained through collaborative negotiations where there is a relatively high level of trust between both parties. Without this trust it will be challenging to work in partnership for the common good of patients. The resulting behaviours therefore become adversarial and competitive, with cost being the focus of attention.

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Here are some common negotiation mistakes made by the pharma industry: Negotiating too soon

This mistake is not unique to pharma. Before you earn the right to negotiate, you need to ensure the sales process has been thoroughly delivered. If the customer has not bought into your drug, even the best negotiator in the world is going to struggle to get the deal. It is therefore completely inappropriate to start negotiating terms such as price and contract length before the customer has agreed that your drug is one of the treatments of choice.

Inexperienced negotiators often fall into the trap of justifying the reasons why the customer should buy after the price has been put on the table.

They do this because they think they are strengthening their case.

However, the other party is thinking the complete opposite and considers justification to be a weakness. Why do they do this? Well there are a few reasons: Firstly, the salesperson may feel they have not convinced the buyer enough on the benefits of the product and so they continue to sell.

Secondly, they fail to realise that experienced negotiators are trained to reject the first offer, irrespective. Make sure that you have positioned your proposition effectively and understood what the other party sees as the true benefits.

Not understanding the balance of power

It is not unusual to enter a negotiation with the feeling that the other party has all the power. You may feel on the back foot and under pressure to get the deal and your behaviours will consequently reflect this. For example, if there are a number of competitors in the market that are similar to your offering, you will naturally feel you are in a weak position right from the start. Power is more often perceived than real so it is important to understand the factors that impact your ability to negotiate. These will include time pressure, circumstances in the businesses or the market place and the number of options available to the other party and you. This final point is particularly crucial because having options gives you more power to negotiate. In other words if your customer is dependent on your product then you are likely to have most of the power, whereas you have very little power in a market of copycat products. Consider therefore how you think through the factors that affect the balance of power before every negotiation.

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Before you earn the right to negotiate, you need to ensure the sales process has been thoroughly delivered

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Justifying price

Playing by someone else’s rules Other people’s rules restrict our ability to negotiate, so in a market as heavily regulated as pharma there is likely to be a lot of red tape.

You have a choice to follow the rules and toe the line or set the terms of engagement yourself.

Consider the impact of putting your proposal on the table first, rather than responding to the other party. It puts you in control and tends to put the other party on the back foot.

Pharma clients tell me that they often negotiate with committees or boards within organisations. I tell them they don’t – they negotiate with people. What is more concerning is that they don’t know the names of many of the committee members let alone have a business relationship with them. It is crucial therefore to recognise individuals’ interests and their motivations for making decisions. Make an effort therefore to identify each person in the decision making process and what is important to them. Granted, access to these possible is sometimes restricted but it is vital to understand the key players.

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Not knowing who you’re negotiating with

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The huge sums of money made by pharma companies don’t sit comfortably with customers despite attempted justifications that only three in 10 drugs launched make any profit

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RISING TO THE CHALLENGE OF ILLNESS

Fight the good fight Lu Rahman asks whether finding a cure for modern diseases is the only challenge the pharmaceutical sector faces?

S

ocial media is awash with pharma conspiratory theories. For anyone who hasn’t seen, the latest one doing the rounds is re-emergence of the MMR-autism issue fuelled by the publicity of a Robert de Niro-backed film.

Co-founder of the Tribeca Film Festival, de Niro backed the film directed by Andrew Wakefield, the doctor who made the original claims that there was a link between the jab and autism. Following outcry from the medical community de Niro pulled the film but not before the incident had re-awakened the argument that the vaccine could lead to autism.

An article by Laurie Tarkan in Fortune outlined the incident, saying that according to Autism Today, an organisation advocating research into autism: “Over the last two decades, extensive research has asked whether there is any link between childhood vaccinations and autism.

The results of this research are clear: Vaccines do not cause autism.”

Copyright: Betto Rodrigues

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For the medical and medtech communities this type of controversy is not only damaging to the health of us all but also detracts from the work being carried out to both protect and cure us from a range of modern illnesses.

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It was a similar scenario earlier this year as the Zika virus made headline news. While the World Health Organisation (WHO) and companies such as Sanofi and Novartis voiced the need to find a cure and / or vaccine for the virus, conspiracy theories were kicking in that the vaccine had indeed been created before the disease itself.

Gary Barnes writes on Truth Kings: “Which came first, the virus or the vaccine? Well in the case of Zika, it is starting to appear more and more likely that the answer is the vaccine. With rumors of a Zika virus vaccine on the horizon, it is beginning to seem as though the pharmaceutical industry was more than prepared for Zika virus fears to create an atmosphere of mayhem.”

Of course, this isn’t quite the truth and while the pharma sector has been working on a vaccine – Bharat Biotech International in Hyderabad, India was the first company to file a patent for a Zika vaccine and began working on the product months before the world was made aware of this health epidemic – it doesn’t mean the vaccine was created before the virus.

While the public is subjected to stories aimed at harming the pharma sector, the way in the industry rises to the challenge of tackling illness and disease is often overlooked. Of course scaremongering stories make better headlines than announcing that a Zika vaccine may only be months away. And what about Ebola? Isn’t it funny that we don’t see headlines such as Reuters’ ‘Experts warn complacency on Ebola may leave vaccine work unfinished’ plastered all over Facebook for Joe Public to get excited about?

In the article, written at the end of March, Kate Kelland, Reuters, wrote: “Great progress has been made in Ebola vaccine development in the last two years, according to a report by an international panel of infectious disease experts, but this ‘could grind to a halt as memories of the outbreak in West Africa begin to fade’.”

According to Jeremy Farrar, director of the Wellcome Trust: “The job is still not done…As Ebola infection rates come under control it's a huge concern that complacency sets in, attention moves to more immediate threats and Ebola vaccine development is left half-finished."

I may be being cynical but I’d put money on Ebola hitting the headlines again if someone were to write a salacious story about the origins of the disease or the harm a potential cure might bring.

While mainstream media teases its readership with potential horrific outcomes of new-launch drugs, where are the stories celebrating success? We grow up learning to celebrate the discovery of penicillin,

or Edward Jenner’s work to eradicate smallpox, and we think nothing of the polio vaccine being a regular staple in the quest to keep our children healthy. Meanwhile society is shocked to read of the rise of TB, outbreaks of scarlet fever. But have we ever seen anyone high-five the news that Novartis has made cancer and heart disease drugs affordable in Kenya or the news that Eli-Lilly has announced a breakthrough drug for the treatment of Alzheimer’s disease?

Last month EPM reported that the University of Manchester had been given £177,713 to fund the development of a Zika virus vaccine. It’s expected that the results will take around 18 months and may lead to multiple targets for other diseases.

Tom Blanchard, honorary senior lecturer at The University of Manchester, said: “We know that there’s an urgent need for this vaccine but we’ll be working carefully to deliver a product which is safe and effective and which can be quickly deployed to those who need it.

“

Have we ever seen anyone high-five the news that Novartis has made cancer and heart disease drugs affordable in Kenya or the news that Eli-Lilly has announced a breakthrough drug for the treatment of Alzheimer’s disease?

“If we can also use this vaccine on multiple targets then this will represent an exciting step forward in dealing with these kinds of outbreaks.”

In the last year we have come closer to a cure for cancer that works by attacking the ‘Achilles Heel’ of the disease, a breakthrough in diabetes care thanks to a probiotic pill and a blood test for Alzheimer’s which could lead to early intervention of the condition. Step back in to 2015 and GSK announced groundbreaking news that it had developed Mosquirix, a vaccine for malaria which had been given EU approval.

While there have been some initial stumbling blocks with the vaccine, GSK has been reported as revealing it had not profited from the product and that it was reinvesting money made back into research on malaria and other diseases.

”

The pharmaceutical sector regularly rises to the challenge of illness and disease. Perhaps as modern patients we have become complacent and expect a cure no matter what making breakthroughs in treatment less overwhelming than they should be? It’s evident that the public like a headline which sparks indignation but as companies invest considerable amounts of money tackling new disease and the rise of modern illness it’s unfortunate that the sector not only faces the challenge of finding new cures but of presenting them to a receptive and grateful audience.

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CONTINUOUS MANUFACTURING

Cover star – the sequel Following on from his article on continuous coating in EPM last year, Charlie Cunningham, Colorcon, describes how momentum continues to build for continuous processing - part 2

T

he advantages of continuous manufacturing for solid oral dosage forms include streamlined manufacturing steps, less material handling, reduced inventories, and increased process flexibility.

There is also potential for real-time release of products using QbD and PAT approaches. Integral to the design of these processes are reduced manufacturing footprints and significantly shorter process times with reduced in-process material.

Film coating is an important final step in tablet manufacture. Coating enhances tablet appearance and identification, masks adverse tastes and odours, aids in swallowability, provides additional protection to the dosage from moisture or oxygen degradation and offers ways to modify drug release.

With respect to the film coating process itself, not much has changed in the past decades. Traditionally, tablets are coated in large rotating, perforated drums, ranging in diameter at production scale from 48” (122cm) to more than 60” (152cm) with individual batch sizes up to several hundred kilograms. Coating times can vary from an hour or up to several hours, depending on the purpose of the coating (aesthetic vs. functional), the coating formulation or equipment.

Other factors affecting coating time include: the mixing efficiency of the pan; distribution of spray; thermodynamic balance (drying efficiency), alongside the formulation of the film coating (with respect to polymer viscosity), resultant solids concentration and drying properties.

In response to recent continuous processing initiatives, several coating equipment manufacturers are now offering improved, or completely new, continuous and semi-continuous coating equipment designs, which differ considerably from the traditional batch configurations. A common theme is a very rapid coating cycle time, which reduces exposure of the tablets to the coating environment and provides throughput flexibility; achieved by significantly increasing the frequency and uniformity of tablet presentation to the spray zone and speeding the drying process.

Some traditional film coating formulations have been shown to work well in these new machines however, there are limitations. The viscosity of the coating formulation limits the rate at which the coating can be effectively sprayed without resulting in a rough surface, and increases the process time needed to achieve the target coating level. Due to viscosity, most coating formulations are limited to application at less than 20% solids concentration. Application rates may also be limited as a result of the drying requirements of the coating.

As continuous manufacturing initiatives drive the redesign of coating equipment we also strive to innovate new coating formulation technologies. Coatings need to provide maximum flexibility for efficient use in traditional batch pans, as well as the new and emerging continuous

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and semi-continuous coating process equipment. New coating systems should offer the widest flexibility in solids concentrations, application rates and drying properties without compromise in coated tablet quality or final finish.

Colorcon is introducing an innovative coating system that is proving to meet these needs. Opadry QX, Quick and Flexible Coating System, was designed to expand the range of process parameters and application speeds that can be used, irrespective of coating equipment design. The development program for this new product included over a hundred field trials, across the globe, in batch (solid wall and perforated pans), continuous and semi-continuous coating equipment from a variety of manufacturers.

Throughout these trials, testing large variations in solids concentration, application temperatures and airflows, the coating results were remarkably consistent. The results confirm a greatly expanded window of process adaptability compared to traditional coating formulations.

Coating formulation design space for process adaptability At the 30th International Forum and Exhibition on Process Analytical Technology, Washington DC, collaborative work between GEA, Colorcon and Kaiser Optical was presented examining the process robustness of Opadry QX in the GEA ConsiGma coater coupled with real-time measurements of tablet critical quality attributes (CQAs) using a non-contact Raman Spectroscopic probe (Kaiser Optical).

The ConsiGma coater is designed for semi-continuous and rapid application of coating onto small 3kg sub-batches of tablets as the final step in a continuous manufacturing line. In this study, a 19- run trial Design of Experiments (DoE) was performed using Opadry QX with coating solids concentrations from 20% to 35%, over a range of coating temperature and application rates. CQAs of tablet coating weight gain, gloss, surface roughness, and color uniformity were measured. At the highest solids concentration and highest spray rates the targeted 3% weight gain was achieved in as little as 3.2 minutes. Across all trials, irrespective of process parameters used, CQAs fell within acceptable ranges. The on-line Raman data correlated well with off-line coating weight measurements and predictive models were generated for monitoring in real-time as the tablets are coated.

The GEA ConsiGma coater is just one example of recent advances in the coating equipment space. Opadry QX is an example of innovation in formulation technology helping to advance process flexibility and robustness over a range of coating technology. This adaptability allows Opadry QX to meet the unique challenges of today’s evolving needs for coating application.

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CONTINUOUS PROCESSING

Thought process Continuous processing will require a change in mindset for controls and automation, says Hubertus Rehbaum, L B Bohle

Talking point: According to Dr Hubertus Rehbaum, continuous processing for secondary manufacturing in pharma is a hot topic

C

ontinuous processing for secondary manufacturing in pharma is still one of the hottest topics currently discussed. Academia, industry and governmental institutions have embraced this development, working towards solutions from both the technological and regulatory perspective.

Continuous processing also has potential for more efficient and cost-effective manufacturing of tablets.

With the pharmaceutical industry being conservative, this paradigm change from batch to continuous requires a re-thinking for all the stakeholders that are part of the manufacturing process.

Challenges for machine suppliers Despite some pharmaceutical companies taking the engineering and implementation into their own hands, it is machine suppliers who are challenged to translate concepts and regulatory requirements into industrially viable solutions, setting new standards for future production of solid dosage forms. In this respect, one of the major tasks on the pathway towards fully continuous production lines is the significantly increased complexity for the automation system, with the necessary control logic embedded. For reference, key words such as model predictive control, traceability and supervisory control systems are often used in this context. Until now, the process machines for batch manufacturing rely on local PLCs and PID control loops, both familiar to the pharmaceutical industry. However, the complexity of full continuous production systems exceeds the capabilities of these well-established technologies, calling for new methodologies.

Instead of standalone PLCs with HMIs, different architectures with distributed control structures and more advanced software platforms take a leading role in controlling both the production process and moreover the final product quality[1]. Examples of such

implementations can be found in various test installations around the globe, either in pharmaceutical companies or on demonstration system of machine suppliers. Ahead of all, academia has presented pioneering solutions, implementing complex control logics with model predictive control on platforms such as Matlab[2].

Role of rapid prototyping If it comes to customising the control strategy for a new product, rapid prototyping platforms provide a highly valuable advantage in the early phase. For each product, the process chain implies constraints such as material properties, valid design spaces and critical control parameters, which are identified theoretically or empirically. Finally, the overall control strategy in the production line automation must take into account these constraints, leading towards customised implementations. In such implementations, the entire toolset of controls engineering must be available, reaching from simple decision trees over regular PID control loops towards non-linear, adaptive and model based control algorithms. Especially on rapid prototyping platforms, such implementation of complex control strategies are realised in a reduced time frame, speeding up the process development.

Of course, the development and implementation of a control strategy is not enough without the full understanding of the interrelations and restrictions of each process, sensors and machinery. For instance, one might consider using NIR spectroscopy to control the continuous feeding and blending of API and excipients. A commonly seen proposal is to use the NIR measurement as a feedback signal into an internal control loop to adjust the gravimetric feeder for the API, while keeping the other (excipient) feeders constant. In such scenario, it is crucial to ensure that the resolution of the NIR system in conjunction with the applied chemometric model is high enough to provide a stable control

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system. Unfortunately, while from a controls engineer perspective such control loop makes perfect sense, it will introduce a discrepancy between the product definition in the recipe and the recorded feed rates (mass flow) of all raw material streams. Instead, from a practical and regulatory perspective, the alternative solution is to rely on the accuracy of the gravimetric feeders, dispensing the pre-defined combination of raw material, but to use the NIR signal to identify temporary variations in the final blend in order to reject them if needed. As can be seen from this example, it is important to assess each element of the control strategy from different angles before taking a final decision.

The good news is that the above-mentioned technologies are readily available. Model predictive control, multilayered control architectures and rapid prototyping platforms are commonly used in related industries to the pharmaceutical field. Similarly, we can quantify the performance and reliability of process and sensory equipment, providing valuable input for the definition of control strategies. The greater challenge lies in the acceptance of these technologies and more importantly in the sharing of knowledge and experience. Pharmaceutical companies regulatory agencies, equipment suppliers and academia have to collaborate closely, in order to pave the way for continuous processing in secondary manufacturing and therefore improved quality for solid dosage forms.

Reference: [1] https://iscmp.mit.edu/white-papers/white-paper-6 [2] doi:10.1016/j.compchemeng.2014.02.029; Dr. Hubertus Rehbaum) .

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MANUFACTURING

Making success Michal Wlodarski, Camin examines the manufacturing challenge of antibody-drug conjugates

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raditionally afflictions such as cancer, autoimmune diseases and inflammatory disorders have been treated with small molecule compounds that lack cell-targeting and thus have profound systemic implications. A well-known example is a chemotherapeutic agent. These compounds often have detrimental non-specific effects which, together with their prolonged multi-dose administration and systemic exposure, yield severe side-effects. In addition such drugs often have very low therapeutic indexes where the window between the drug’s effective and toxic dose is narrow, making the optimal dosing a significant challenge for the clinicians, and ultimately deteriorating treatment outcomes and patient’s wellbeing.

Antibody-drug conjugates (ADCs) combine the functionality of biologic preparations with small drug molecule therapeutics to optimise treatment efficacy and thus improve outcomes and eliminate many of the problems associated with non-specific treatments outlined above. The key to this unique functionality is in the antibody-drug complex structure. An ADC is a multipart molecule consisting of a monoclonal antibody fused with a small molecule compound via suitable linker and spacer molecules. The antibody contains tumour-specific epitopes driving the API to the tumour tissue and away from the healthy cells. Upon binding with tumour antigens, the antibody-drug complex is internalised by the cancer cell where the antibody disintegrates and the drug molecules interfere with essential cellular processes to halt the cancerous growth.

Treatment revolution

Main antibody groups

ADCs have already made a positive impact within the oncology sphere and are soon to revolutionise autoimmune and inflammatory disorders treatments. Adcetris (brentuximab vedotin) marketed by Seattle Genetics in 2011 targets Hodgkin and systemic anaplastic large cell lymphomas while Kadcyla (trastuzumab emtansine) introduced to market in 2013 works against HER2-positive metastatic breast cancer (mBC) non-responsive to conventional treatment lines.

Drug development pipelines currently hold more than 250 potential ADC designs, with more than 30 different lead ADC products in clinical development.

Looking at marketed ADC technologies and those currently in development, small molecules conjugated to antibodies belong to two main groups: drugs that cause damage to the DNA and drugs that disrupt microtubule polymerisation. Common cancer chemotherapeutics such as doxorubicin, methotrexate, vinca alkaloids (auristatins and maytansinoids) as well as DNA-binding (eg calicheamicin) and tubulinbinding antibiotics (eg maytainsine) have also been successfully conjugated to antibodies. Notably, delivery in the form of ADCs allows to exploit the excellent potency of many cytotoxic agents with low therapeutic indexes by decreasing their systemic toxicities 100-1,000fold as compared to their unconjugated forms.

Given that many potent APIs suitable for conjugation have long been successfully commercialised and that monoclonal antibody development and production are well understood, the challenge in producing quality ADC products lays on the manufacturing side. Indeed, ADC development can be regarded as an area of manufacturing where very few companies offer all of the drugs’ pieces.

This makes for a complex supply chain and calls for diverse partnership collaborations between specialised biotechnology companies, typically larger co-developer pharma companies and contract manufacturing organisations (CMOs).

ADC assembly itself is challenging, requiring providers to simultaneously handle biologic materials in aseptic conditions and manipulate highly potent small molecules under containment.

Demand for experienced CMOs is therefore strong. Global CMO market is currently consolidating under heavy maturation forces that include changes to regulatory environment, changing client expectations, and small profitability margins for smaller (< US$ 25m) players. Consequently, in next few years we are likely to observe some of the smaller companies pursuing their competitive value by establishing strong technical niches. ADC assembly presents as one of such niches, one that is bound to attract investments across a wide range of disease areas where drug-target specificity is central to effective therapy.

Small molecule compounds are covalently attached to the antibody via a linker molecule that in some preparations (eg Adcetris) is accompanied by a spacer, crucial for providing enough room for the enzyme to cleave the bond and release the drug inside the target cell. Other methods of drug release include linker hydrolysis at low pH, cleavage of the linker through a redox reaction, and proteolytic degradation of the antibody. Stability of the linker and spacer molecules is central to efficacy and safety profiles of ADC preparations as it ensures delivery of the API load to its target, whereas the choice depends on the treated condition as a consequence of the unique biochemistry of target cells.

Cysteine and lysine are two most common naturally occurring amino acids suited to serve as drug binding sites on the antibody (usually IgG1 or IgG3).

The major advantage of using cysteines is the relatively mild condition for the partial reduction of antibody’s inter-disulphate bonds and relatively high efficiency of the conjugation step. In case of lysines, the primary amine on lysine side chain forms a suitable reactive group for conjugation.

Importantly, lysines do not commonly reside in the complementarity determining region of the antibody, which minimises possible interference with antigen recognition that is necessary for specific binding. However, with almost 40 lysine amino acids suitable for conjugation by having their side chains exposed on the IgG surface and much lower numbers with conjugated small molecule compounds (typically 3-4), resultant preparations could result in highly heterogeneous mixtures.

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Best performance For the best performance in vivo, however, the drug needs to be evenly distributed on the antibody. This is because a well-defined loading can make an ADC easier to purify and characterise, and possibly more stable and functional as a therapy. It is generally agreed that three to four drug molecules per antibody offer most optimal performance as too high numbers may lead to short ADC serum Antibody-drug conjugates half-life and increased hydrophobicity and thus reduced solubility. Loading (ADCs) combine the consistency is expressed with the number functionality of biologic (usually as the drug-to-antibody ratio, preparations with DAR) and positions of drug molecules small drug molecule conjugated to single antibody. Successful therapeutics to optimise conjugation should also allow to maintain antibody’s pharmacokinetics, antigen treatment efficacy binding capacities, and sufficiently complex thermostability.

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Site-specific conjugation technologies designed to manufacture more homogeneous ADCs are currently under development. Three main approaches exist and include taking advantage of an antibody’s natural structure and the widespread distribution of lysine or cysteine amino acids (eg Seattle Genetics’, ImmunoGen’s technologies), employing mutagenesis or non-natural amino acids to create defined high-affinity linkage sites on an antibody to attach drug molecules (Catalent’s SMARTtag, Innate Pharma’s tagging technologies), or both by using the natural bonding sites but improving binding efficiency and product performance (Meditope Biosciences’ SnAP, Igenica’s SNAP, and PolyTherics’ ThioBridge technologies).

Site-specific conjugation Catalent’s SMARTteg technology aims for site-specific conjugation to create homogeneous ADC structures in terms of drug loading and positioning. This approach involves introducing natural five-amino acid sequences into the antibody as linkage points equipped with a chemical handle. From there, a formylglycine-generating enzyme recognises the sequence tag and selectively converts it into a unique aldehydecontainig residue suitable for joining with existing or novel linkers at defined locations. The company successfully tested more than 50 such combinations against multiple targets. Innate Pharma’s new conjugation technology uses a bacterial transglutaminase enzyme where singlepoint mutations in an antibody generate two to four enzyme-recognition sites. The enzyme then attaches a pre-synthesised drug-carrying linker the company has designed to couple specifically at these sites in order to consistently manufacture ADCs with an average DAR of three.

Meditope Biosciences’ ‘meditope’ technology combines what antibodies have to offer with useful genetic engineering. A naturally occurring pocket of space in the Fab region of antibodies can be altered to accommodate another molecule, typically a small peptide, called a meditope. Importantly, using the company’s patented SnAP technology, any antibody can be ‘meditope-enabled’ by removing several amino acids from that pocket of space. Antibodies enabled in this way remain fully functional and can carry an API load attached to the meditope itself. Igenica’s SNAP method on the other hand involves engineering site-specific amino acid changes in the native antibody to enable flexibility in choice of linkers and toxins. The company complements this approach with iTab (in vivo anti-tumour Antibody) and sTAg (surface Tagged Antigen) methods to identify promising antigens and generate novel antibodies of high therapeutic potential.

Polytherics’ ThioBridge method uses a bis-thiol alkylating reagent to form a three-carbon bridge to which an API load is conjugated while maintaining antibody’s original structure and stability. The company is actively collaborating with drug discovery units of other developers to test a range of drug-linker combinations. Its patented conjugation process enhances conjugate’s solubility profile by reducing ADC aggregation and assembles products of suitably narrow DARs. Another novel technology is the ‘lock and release’ approach developed by ADC Biotechnology where an antibody is immobilised on a solid surface and conjugated prior to its release in a soluble form. The process is suitable for any antibody-linker-drug combinations and can be scaled up by running on columns in a flow mode.

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With numerous examples of drug-antibody Site-specific conjugation complexes and various conjugation technologies in pre-clinical and clinical technologies designed development phases as well as promising to manufacture more commercial success of the field’s pioneers, homogeneous ADCs this therapeutic technology area is are currently under expected to grow and diversify significantly development. in the near future. Areas of extensive development will include antibody-drug complex design, formulation protocols, and manufacturing (assembly) methods. Consequently, given the fast technical advancement in aseptic handling of small molecule compounds, dynamic CMO market restructuration, and evolving CMO-biotech partnerships, this technology market segment is expected to exceed US$ 5bn in sales by 2018 becoming a key component of cancer, and likely autoimmune and antiinflammatory therapeutics.

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DRUG DELIVERY

Tough love In cartridges with chemically strengthened glass, life-saving medication can be safely stored and ready for application, says Schott

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here are times when the packaging used with a drug has to function perfectly.

The movie hero James Bond experienced this in ‘Casino Royale’ when his martini was neither stirred nor shaken, but rather poisoned. He only had a few seconds to inject a life-saving medication into his carotid artery. Bond survived, thanks to an injection pen that was immediately ready for use and his co-star, Vesper Lynd, who miraculously recognised within only fragments of a second where the missing cable was Schott Cartridges BR, on the defibrillator.

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With expensive or toxic drugs can be processed, transported, and administered safely– even in rough environments,” Andrea Wesp, Schott

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Even if this was Hollywood, the example shows that there are in fact situations in which break-resistant packaging can make the difference between winning and losing.

Sometimes, even between life and death. This is true when break-resistant packaging is used in areas of war and natural disaster where the conditions are harsh.

”Pharmaceutical companies are also extremely interested in having break-resistant cartridges for storing drugs that are particularly expensive or highly toxic,” explains Schott product manager Andrea Wesp. Toxic medications? ”Yes, especially for treating cancer. Here, the highest safety precautions must be taken to protect employees on the production lines during the manufacture and packaging of these substances. The same applies during transportation of the drug and when administering it to the patient.”

Cartridges are glass bodies inside pen and auto-injectors that hold the drug.

To mechanically harden the glass to suit these types of situations, Schott has now developed chemically hardened cartridges. Two aspects were particularly important here: “We wanted to retain the original geometry to make sure that the new cartridges still work with standard pen systems,” explains Wesp. Simply shaping the walls to be thicker was therefore out of the question. ”Chemically hardening the glass proved to be an alternative that would not affect the integrity of the drug,” she adds.

The goal was to avoid an undesirable reaction between the glass surface and Even if this was Hollywood, the contents that could impair the drug’s there are situations in effectiveness.

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which break-resistant packaging can make the difference between winning and losing

The answer was to further develop a glass hardening process that has been the industry standard for many years. These efforts proved to be successful at the US development lab in Pennsylvania, where Schott researchers optimised a proven ion exchange process for use in pharmaceuticals.

The cartridges bathe in a potassium nitrate solution during this process, whereby the sodium ions in the surface layer are exchanged for larger potassium ions from the solution. This gives the glass greater stability. Tests have shown that the cartridges hardened in this manner are three times as resistant to mechanical stresses. They can be used in auto-injectors, needle-free injection devices and pen and pump systems.

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Resistance training: Chemically strengthened glass cartridges from Schott are significantly more resistant to mechanical stress than conventional primary glass containers

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TABLET PRODUCTION

Fast paced: ODTs and ODGs are particularly convenient for children or elderly patients as well as people who want to take their medicine ‘on the go’

Now you see it…

Omya takes a look at functionalised calcium carbonate and its use in orally disintegrating tablets and granules

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ith functionalised calcium carbonates, pharmaceutical manufacturers can produce orally disintegrating tablets that offer high mechanical strength while disintegrating twice as fast as comparable products.

As orally disintegrating tablets (ODTs) and orally disintegrating granules (ODGs) disperse in the mouth without the use of water, these dosage forms are particularly convenient for children or elderly patients, and the delivery format of choice for people who want to take their medicine ‘on the go’.

The challenges

Porous but strong

The development of ODTs is a demanding process and requires two seemingly contradictory product attributes: high porosity for fast disintegration and high mechanical strength to prevent the tablets getting damaged. The preferred technique to prepare ODTs is by direct compression. However, the disintegration capacity of ODTs produced in this way is limited by the size and hardness of the tablets.

Functionalised calcium carbonate (FCC) is manufactured from high purity calcium carbonate, which undergoes a surface recrystallisation process to create a structured molecule. This process can be controlled to obtain desired specific surface areas of 30–180 m2/g, a particle size distribution between 2–30 µm and porosities of higher than 60%.

FCC’s particles are characterised by an external lamellae structure and an internal network of interconnected pores. This structure actually facilitates the production of granules and, subsequently, tablets that feature both high porosity and high levels of hardness — properties that are normally inversely proportional.

When compressing ODTs, the main concern is ensuring a porous structure that enables adaquate water absorption. High pressures result in harder tablets, which increases the disintegration time.

Consequently, ODTs with optimal disintegration characteristics are often more friable and small – and only have a low API (active pharmaceutical ingredient) load capacity. Further challenges in ODT formulation include cost-intensive production processes such as lyophilisation and a lack of physical resistance in the packaging. With Omyapharm functionalised calcium carbonate, the mineral producer Omya has developed a next-generation excipient that can overcome these challenges.

What’s special about Omyapharm is that, during dry granulation in the roller compactor, FCC’s lamellae interlock. This provides plenty of surface contact points that lead to greater tensile strength at pressures that are lower than those needed for other excipients. In turn, low compression pressures preserve the porosity in the granules, allowing higher API load capacities and, most importantly, shorter disintegration times. After milling and sieving, the orally dispersible granules are ready to be mixed with APIs and can be directly compressed into ODTs.

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Exceptional compressibility

Huge market potential

In a study, researchers examined the compressibility of tablets made using FCC granules and compared them with tablets made with either FCC in powder form, plain calcium carbonate, mannitol or microcrystalline cellulose (MCC).

The scientists analysed the tensile Further challenges in strength and porosity of the tablets ODT formulation include across a broad pressure range. At cost-intensive production low compression pressures, the tensile processes strength of tablets formulated with FCC powder or FCC granules was higher than that of tablets formulated with mannitol or calcium carbonate and was comparable with that of tablets formulated with MCC. The FCC tablets also had a higher porosity than those using the other excipients tested.

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In a second step, researchers also analysed tablets formulated with paracetamol and one of the following: FCC powder or MCC. They concluded that, despite the presence of an API, the porosity of the FCC tablets decreases significantly less than that of tablets formulated with MCC when the compression pressure increases. FCC is able to maintain its powder form while accommodating API loads of up to 40%.

FCC’s direct compressibility into granules and its high porosity allow faster water uptake, resulting in a disintegration time that’s twice as fast as the market reference product. As such, it enables ODGs to disintegrate in two seconds. Loaded with API and pressed into tablets, FCC products disintegrate in less than 10 seconds.

Standard market ODTs are manufactured using expensive processes such as freeze drying to achieve fast dispersion rates. The high porosity of ODTs formulated with FCC means that disintegration is rapid and even, thus there’s no need to use cost-intensive production equipment. Current market formulations also require special packaging because of the inherent friability of the tablets. With their high mechanical strength, ODTs formulated with FCC as The high porosity of an excipient can be filled in regular bottles and blisters, which significantly reduces ODTs formulated with FCC the cost of packaging. Moreover, thanks means that disintegration to FCC’s mineral origin, manufacturers is rapid and even can enhance their products and provide novel functionalities without getting further regulatory approval for existing formulations. Addressing these issues, FCC is a very promising excipient that could revolutionise the ODT market.

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PACKAGING

Wrapped up

Clean sweep: Sterilisation cassette loading. After sterilisation the products are separated as they are removed from the sterilisation cassettes

Schubert-Pharma develops a new packaging process for Nephron Pharmaceuticals

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ephron Pharmaceuticals is a global manufacturer of generic respiratory medications and a pharmaceutical contract manufacturer. The company is headquartered in Orlando, Florida. For a new production facility in South Carolina, Nephron was on the lookout for a supplier and service provider for secondary Following the filling process in the primary machine, the packaging packaging line processing – taking products from the filling system to process begins with the TLM machine taking over the blow-fill-seal blocks (BFS) and sorting them in sterilisation the pallet – and ideally, coordinated from cassettes, which are then grouped on a a single source. The company opted for sterilisation pallet.

Schubert-Pharma.

Feeding products into the TLM tray loader

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A TLM-P4 depalletising / palletising robot Nephron was on the lookout In the new facility, Nephron planned to puts the cassettes in place. No other for a supplier and service package what would be an entirely new supplier could offer a suitable handling of product for the company: an injection provider for secondary the products before autoclaving, palletising agent to be filled in a new type of vial – packaging line processing – them in cassettes and on sterilisation pallets. using polypropylene for the first time, taking products from the TLM-F4 four-axis robots can easily take instead of polyethylene. Nephron didn’t on product handling, while also enabling filling system to the pallet yet have any direct experience in handling future product sizes to be processed without this product in the secondary packaging requiring complex format adjustments. system. Furthermore, the products had Both picking up the products by robot and to be sterilised in an autoclave – another process step with which the company wasn’t familiar. And finally, the providing the completed pallets for autoclaving take place in a way products would have to be fitted with a shrink-wrap sleeve prior to that is laser-supported and fully automatic, which is why this process packing, instead of a labelled pouch or a separate label, like other step – like virtually the entire packing process – does not require manual intervention.

Nephron products.

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For these reasons, the new partner’s expertise in engineering consulting and project management would play a key role. In the end, SchubertPharma delivered two packaging lines to Nephron, each one comprising four individual machines – a TLM tray loader, a TLM vial separater, a TLM For the actual sterilisation, the cassettes spend 20 minutes in the cartoner and a Schubert TLM case packer. All functional components autoclave chamber, where any microbials are killed at temperatures of were based on the TLM modular system. close to 120 degrees Celsius.

A gentle separation process

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After sterilisation the products are separated as they are removed from the sterilisation cassettes. For this purpose, the existing blocks of four must be separated so that individual BFS vials can be made available.

While competitive machines ‘mechanically split’ the blocks of four, this step is positively controlled in the TLM product splitter using moulded change parts and is therefore extremely gentle on the product. The BFS blocks are removed from the cassettes row by row and placed directly into the separating station. Through a shearing motion, the separating tool separates the block into individual BFS vials.

The line management system and track & trace functionality With increasingly stringent regulatory requirements with regards to serialisation, Schubert-Pharma also developed an implementation concept for an intelligent line management system (LMS) with integrated track & trace functionality for Nephron. Schubert-Pharma first adapted Nephron’s interfaces in their factory-wide data management system (Manufacturing Information System, MIS) and then developed the required software. The system receives randomised serial data for the product carton from the MIS, groups them together in the shipping carton and The high porosity of ODTs communicates it back to the MIS at the formulated with FCC production location.

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means that disintegration is rapid and even

Robot handling: Four-axis robots handle the products, while enabling future product sizes to be processed without requiring significant format adjustments

“We are more than satisfied with the line and with Schubert-Pharma’s project management,” says Jonathan Burgess, R&D engineer at Nephron Pharmaceuticals in Orlando. “It was especially important for us to have a permanent contact person at Schubert and to remain in touch through the entire process. The products, as well as individual process steps, such as sterilisation, were new to us. We wanted an expert advisor throughout the entire process to guide us in selecting individual components. Schubert-Pharma took on this role brilliantly. The main reason we chose Schubert-Pharma, however, was that we would be able to build the entire secondary packaging line using the TLM modular system’s seven basic components, which had already proven themselves in several other projects. With its TLM technology and consulting expertise, Schubert-Pharma was the perfect partner for this assignment. We would be very happy to work with Schubert-Pharma again anytime in the future.”

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Once the product blocks are separated, the individual BFS vials are inserted in product carriers or pucks. A special feature in this process step is that the products are deposited in the pucks headfirst. A sensor checks that the cassettes have been completely emptied, and then they are palletised for reuse. A complete batch from the autoclave can be handled in the staging Further challenges in area where the pallets come and go. In ODT formulation include two intermediate downstream steps, the cost-intensive production products are checked for proper sealing processes (vacuum check) and then labelled with a shrink-wrap sleeve.

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Sleeving the vials for further use intensive consulting and customer project support. Looking for the optimal sleeve technology, SchubertPharma together with Nephron reviewed several qualified vendors, and finally a recommendation was made. For labelling using a shrinkwrap sleeve, a printed plastic tube is cut to the required lengths and the resulting plastic elements placed over each individual product. By heating the plastic, it shrinks to the contours of the products.

Delivery to the case packer The next step is cartoning the vials. To this end, the product needs to be removed from the puck and grouped in the appropriate count for the intended carton sizes. The TLM top-load cartoner is the ideal solution for cartoning ‘standing’ vials with different heights and numbers in the carton. The TLM machine covers a range of formats and enables trouble-free adaptation, even to future carton sizes which may unknown today

Part of the process: The BFS blocks are removed from the sterilisation cassettes in rows and placed directly into the separating station

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FORMULATION

Sweet success Beneo describes how its galenIQ can deliver multiple benefits in medicines formulation

T

he taste of a medicine is an important compliance factor for certain patient groups, including children, the elderly, those with chronic conditions and even in the growing field of veterinary medicine. Choosing the right filler-binder can enhance overall palatability significantly.

With galenIQ the German company Beneo says it offers an excipient that can achieve this in a range of applications.

Taste test: galenIQ reduces the bitter taste of APIs and masks the unpleasant taste of ingredients

Sugar-like sweetness

The sachet trend

galenIQ is the pharmaceutical grade of Beneoâ&#x20AC;&#x2122;s Isomalt, a disaccharide alcohol derived from beet sugar. Its source material is the main reason why galenIQ has a sweetness and taste profile that is very close to sucrose. With its well-balanced sweetness, the fillerbinder has no significant off-tastes or aftertaste. galenIQ reduces the bitter taste of APIs, masks the unpleasant taste of ingredients such as plant extracts and contributes to a palatable pleasant taste profile and mouthfeel in the final pharmaceutical or nutraceutical product.

Due to its cost effectiveness and time-saving benefits dry blending of all ingredients without further processing is the most favoured method of drug preparation. Dry blends can be used in compression and compaction processes or simply filled into capsules, bottles or sachets.

The â&#x20AC;&#x2DC;sachet trendâ&#x20AC;&#x2122; is already becoming evident, with line extensions of well-established brands increasingly moving into sachets and stick pack packaging. Dry blends facilitate a convenient and fashionable form of drug delivery. When developing these powder mixtures for oral application, it is important that bulk excipients fulfil the necessary requirements, such as excellent flowability, low hygroscopicity, high physical stability during mixing and high dilution potential and content uniformity, to name just a few.

A recent comparative study has shown that galenIQ is able to considerably suppress the bitterness of a quinine hydrochloride solution.

In comparison to maltitol, mannitol and sucrose, the addition of galenIQ (grade 721) in concentrations as low as 3 to 6% w/w led to a significantly higher reduction in bitterness.

A range of grades galenIQ is primarily considered to be a soluble filler-binder for tablets and powdered products. However, the past 10 years have proven it to be a truly multi-functional excipient: It has been used to coat solid dosage forms, as a component in hot melt extrusion processes and, most importantly, it has improved the taste of many medicines, even in liquid applications.

The galenIQ product range comprises different grades that serve a variety of dosage forms. Besides the agglomerated grades 720 and 721 for direct compression and dry blend applications, the 800 series offers special powder grades of different solubilities and particle size distributions for wet granulation, roller compaction and other agglomeration processes. Sieved grades for starter pellets (galenIQ 960), for pan coating and syrups (galenIQ 981) as well as for medicated confectionery (galenIQ 990) complete the range.

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Technological benefits With well-defined particle size distribution, galenIQ 720 and 721 are designed to provide outstanding flow and mixing properties. galenIQ is the perfect excipient for easy tableting because of its compactability and high dilution potential. At the same time only low compaction forces are required to achieve a high tablet hardness. Agglomerated galenIQ is a white, odourless and water soluble material with a special morphology.

The porous and large surface areas enable high concentrations of active ingredients to be incorporated without compromising the flow properties of the final mixture. These surface structures also prevent segregation, even in very low dose blends, throughout the whole process, thus ensuring the homogeneity of the mixture and subsequently the required content uniformity.

Regulatory approvals Isomalt (galenIQ) is monographed in leading pharmacopoeias (USPNF, Ph. Eur, BP) and is approved in both Japan (JPE) and China (with an Import Drug License).

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A recent comparative study has shown that galenIQ is able to considerably suppress the bitterness of a quinine hydrochloride solution

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Trend setter: The ‘sachet trend’ is becoming evident, with line extensions of well-established brands increasingly moving into sachets

Drug store: galenIQ is considered to be a soluble filler-binder for tablets and powdered products

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CHEMICAL REACTION It’s important to keep on top of the latest services, companies and innovation.

EPM’s Chemical Reaction highlights a technology, service or business we think would be worth keeping an eye on…

Fighting talk Mark Offerhaus, founder and CEO Micreos highlights the implications of antimicrobial resistance and the ways in which Micreos is using nature to fight bacteria

EPM: Who are you and what do you do?

MO: Micreos is a pioneering biotechnology company based in the Netherlands; our main focus is developing targeted antibacterial products for use against various species of bacteria.

We’ve developed a product where the active ingredient is based upon principles and mechanisms derived from nature and developed over millions of years by the natural enemy of bacteria, phages. Because this working mechanism is unrelated to that of antibiotics, the treatment has the potential to be used as an alternative to, or in conjunction with antibiotics to help alleviate the mounting pressure of bacterial resistance.

EPM: Describe your latest innovation?

MO: Micreos’ latest innovation is Staphefekt (SA.100), an endolysin (enzyme), which specifically targets and kills Staphylococcus aureus, including the Methicillin resistant strain, MRSA. Staphefekt is the first endolysin registered for human use.

Study results show that both MRSA and MSSA are equally susceptible to Staphefekt, and that Staphefekt is equally efficient at killing both strains1. What’s brilliant about Micreos’ technology is that because of its specificity Staphefekt does not harm the beneficial skin flora, whereas antibiotics can’t differentiate. This makes Staphefekt suitable for long-term daily use without the common side effects associated with antibiotics.

EPM: What projects have you been focused on recently?

MO: Recently Micreos has focused on projects with the eczema and rosacea patient organisations in Germany and The Netherlands.

The study had two key findings.

The first was that whilst 74% of the eczema patients needed corticosteroids for their eczema, after using Gladskin, over 50% reported a reduced need for corticosteroids. The second finding showed that around 80% experienced a reduction of the typical symptoms such as itchiness, redness and infection, and the vast majority saw this improvement within days, far quicker than we had expected.

We are also preparing double blind placebo controlled clinical trials, together with Prof Pasmans (Paediatric Dermatology Erasmus Medical Centre Rotterdam), and developing compounds which target other bacterial species.

And finally we have just completed an additional funding round, securing 12 million for the clinical development of Staphefekt for a range of inflammatory topical problems.

EPM: What does it mean for the pharmaceutical sector?

MO: We know that the spread of antibiotic resistant infections around the world is a growing problem.

Antimicrobial resistant infections are estimated to cause 10 million deaths per year by 2050, so it is essential that alternatives to antibiotics are developed.

Staphefekt is a step in the right direction as it has the potential to be used as long-term maintenance therapy – where antibiotics are not suitable – thereby preserving antibiotics for when we really need them.

As each infection is preceded by colonisation, Staphefekt acts as an intervention tool that can help prevent development of severe infections for those who are at risk, for example people with skin barrier problems due to skin conditions.

We provided the Gladskin eczema and rosacea products - with Staphefekt SA.100 - to over 600 patients.

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Q & A

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Nature’s way: Mark Offerhaus, Micreos discusses antimicrobial resistance how Micreos is using nature to fight bacteria

EPM: Plans for the future?

MO: This year we are focusing on the clinical development of Staphefekt SA.100, including GMP production and preclinical work, for new indications such asatopic dermatitis, folliculitis and diabetic wound infections. We plan to register pharmaceutical products for these indications over the next five years.

In the meantime many people can already benefit from our first products for topical skin problems, ranging from simple acne and skin irritation to eczema and rosacea.

The impact these have for these people is very gratifying, yes, it makes our day!

1) Herpers BL, Badoux P, Pietersma F, Eichenseher F, Loessner MJ. Specific lysis of methicillin susceptible and resistant Staphylococcus aureus by the endolysin Staphefekt SA.100. 24th European Congress of Clinical Microbiology and Infectious Diseases, Barcelona 2014

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