THE WORLD OF AI & CANCER
OUR LATEST ORAL SOLID DOSAGE SUPPLEMENT
THE FUTURE OF GENE EDITING
g n i d i Avo S
E S I R P SUR
Natoli Engineering details a robust tablet formulation strategy from development to production.
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Contents Nov/Dec 2019 | Volume 19 Issue 8
REGULARS 5: EDITOR’S DESK
Reece Armstrong looks forward to Christmas in the only way he can – by comparing politics and pharma.
6: A SMALL DOSE
A brief round-up of some of the latest developments in the industry.
The role pharmacies play in fighting antimicrobial resistance.
16: COVER STORY
Natoli Engineering details a robust tablet formulation strategy from development to production.
20: IN THE NEWS
A short selection of stories from the world of science.
FEATURES 8: PERSPECTIVE ON PHARMA
How an AI platform could revolutionise how we develop cancer drugs.
18: IN PROFILE
EPM speaks to ACG’s Ettore Cucchetti about his journey into pharma.
21: WHAT’S TRENDING
Following CRISPR, what’s next for the future of gene editing?
25: ORAL SOLID DOSAGE SUPPLEMENT The latest advancements and technologies from the oral solid dosage sector.
46: FROM THE FACTORY
How to tap into the hidden data of a pharma manufacturing plant.
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The UK’s fractious politics over the past three years has threatened to undermine our position as a leader in the AMR field.
ith the UK heading into a December General Election, citizens across the country are all wondering which stuffed turkey will be in Number 10 come Christmas. As someone who’s been uninspired with the state of politics for some time now, it’s difficult not to be pessimistic about party pledges and promises. After all, the past decade or so has seen political figures range from cartoonish to outright villainous, and the state of the UK has never been as fractious as it is now. In some ways it’s similar to the pharma market – cartoonish villains and all. Martin Shkreli, who infamously raised the price of the anti-parasitic drug Daraprim by 5,000%, is now behind bars for securities fraud, paying example to how accountability in the life sciences market is apparently hard to come by. More so, controversy followed when it was announced earlier this year that Mylan CEO Heather Bresch would be retiring with
EDITOR’S DESK a hefty paycheque after 28 years at the company. The first woman to run a Fortune 500 pharma company, under Bresch’s tenure Mylan faced a string of controversies, the biggest of which included raising EpiPen prices by over 400% - a questionable move given the company’s mission to improve patient access to
medicines. However, much like in politics those doing good work rarely get a mention. Take antimicrobial resistance (AMR) for instance. Most people tuned into the world of life sciences understand that this is one of the most pressing health issues facing the entire planet, but progress has stymied due to pharma companies pulling out of antibiotic development initiatives. And the UK’s fractious politics over the past three years has threatened to undermine our position as a leader in the AMR field. This year though saw Pfizer UK launch a number of programmes to help address issues around AMR. After showing support for NICE’s plan to trial a new subscription model for antibiotics, the company announced it would remove sales incentives for anti-infectives. Instead, salespeople at Pfizer UK are being measured via management-based objectives (MBOs), with a particular focus on generating access to medicines and promoting the appropriate use of antibiotics. Of course, as a leading supplier of antimicrobials, it’s in Pfizer’s best interests to be at the forefront of AMR developments – but that’s my cynical side talking. However, it’s efforts like Pfizer’s that show pharma companies aren’t entirely profit driven and can be, in fact, a bastion for progress and goodwill. Now if only our politicians would act the same then we’d all have happy holidays. Merry Christmas.
A small dose Oxford biotech raises £2M to tackle AMR
iotechnology company Oxford Drug Design (ODD) has raised £2.2 million in funding to help advance its drug discovery programme.
RECIPHARM SET TO BECOME TOP FIVE CDMO
ontract development and manufacturing organisation (CDMO) Recipharm is set to become a leading inhalation company through a new acquisition. Recipharm will acquire global drug delivery and device company Consort Medical in a bid to become a top five CDMO. Through the acquisition, Recipharm hopes to enlarge its organisation to become a best-in-class technology based CDMO, enabling it to compete more effectively within a wider part of the value chain. In particular, Consort’s drug delivery technologies are complementary to Recipharm’s capabilities in the development and commercial supply of both inhaled and sterile injectable finished dose forms. Pharmaceutical companies are currently looking to reduce their
costs through a focus on core research, development and sales capabilities. This means they’re frequently turning to partners with the necessary technologies to support them through the drug development and manufacturing process. Recipharm has submitted a cash offer of £505 million to acquire Consort. Commenting on the transaction, Christopher Brinsmead CBE, chairman of the board of Consort, said: “Consort’s leading technologies and market positions provide innovative solutions and products to a blue-chip customer base. We believe that Recipharm’s businesses are highly complementary to our own and the board intends to unanimously recommend the offer from Recipharm which represents a 39% premium to our share price”.
The spin-out from Oxford University will use the funding to further its drug research and discovery efforts, focusing specifically on its latest project to develop cutting-edge solutions that tackle critical issues of anti-microbial
resistance (AMR) in humans and animals. The company’s latest project aims to discover and develop novel small molecule drugs, traditional Chinese medicines (TCMs) and TCM components for the treatment of bacterial infections in pigs using an approach that minimises the risk of development of resistance to antibiotics used for the treatment of people.
The research, taking place at the University of Portsmouth, is being led by microbiologist Dr Roger Draheim. He said: “There is a degree of urgency to overcome increased resistance to many commonly prescribed drugs and it is very exciting to be working on developments that could directly limit the initial generation of resistance at its source. This funding also further lends credibility to our in-house small molecule high-throughput in vivo screening strategies.” Paul Finn, CEO of Oxford Drug Design said: “This latest funding further validates our computational designled focus that has enabled rapid progress in building our pipeline of novel antibiotic programmes. We are excited to be working with partners in the UK and China to develop a novel solution to the major challenge of supporting animal health without contributing to the rise of AMR in human infections, with potential benefits food production and human health worldwide.”
most inno Switzerla
Trinity College to use e-learning to advance students’ pharma knowledge
overtaken Germany as that Switzerland has across Europe – and delivery is accelerating innovation in drug highlights that Innovation Index from the Pharmapack Provisional findings shows. market, new research innovative drug delivery as Europe’s most overtaken Germany witzerland has
executives – notably according to industry ‘innovation potential’ Spain) saw increases in UK, France, Italy and (Switzerland, Germany, European markets states. All six major market, the research solutions entering the devices and packaging being driven by new Innovation is largely drug delivery market. Europe’s most innovative
in terms of FDA a remarkable few years Markets, said: “It’s been director at Informa Silvia Forroova, brand overall gains. showing the biggest and Switzerland (10%) United Kingdom (5%) year-on-year, with the has increased by 4% innovation potential leader. On average, States as the world closing on the United
ovative drug delivery market and overtakes Germany as
GE Healthcare to expand factory in a box
E Healthcare Life Sciences is to expand its “factory in a box” offering to increase the availability of biotherapeutics across the world. GE will work with Pharmadule Morimatsu to expand its off-theshelf KUBio modular facility portfolio. Pharmadule will provide engineering design, construction, installation, and validation services, based on GE Healthcare Life Sciences’ proprietary design. The two companies will work together to introduce additional modular platforms in 2020 to allow biopharma manufacturers to quickly scale-up vaccines, viral vector-based therapies and other novel modalities.
GE Healthcare Life Sciences launched its first off-the-shelf KUBio modular facility in 2012 for the biomanufacturing of monoclonal antibodies. Since then it has been expanded to support the production of vaccines and viral vectors. Olivier Loeillot, general manager BioProcess at GE Healthcare Life Sciences, said: “We are combining our decades-long expertise in biomanufacturing with Pharmadule’s proven excellence in modular construction to support the growth of the biopharmaceutical industry. What biomanufacturers need is fast access to reliable technologies, costeffective investments, and speed to market. KUBio offers all this,
while continuing to extend and adapt to the dynamics of the market.” Helen Zhang, CEO of Pharmadule, added: “Joining expertise with GE Healthcare Life Sciences is an important milestone. Through this collaboration, we will leverage our capacity to execute effective projects from conceptual design to a qualified modular facility and support the expansion of the KUBio biomanufacturing facility offering. This fits very well with our modular concept, which includes global turn-key delivery, from early design through fabrication and installation up to operational qualification on site.”
rish company Innopharma Education has partnered with Trinity College Dublin’s School of Pharmacy and Pharmaceutical Sciences to give students the very latest knowledge from the pharmaceutical industry. The partnership will see Innopharma Education donate e-learning materials worth €20,000 to Trinity, giving students access to the latest information. In return, Trinity’s students and academic team will provide valuable input and feedback into the continued development of Innoskills.com Innopharma Education’s new e-learning platform for the pharmaceutical industry. With modules covering topics such as Process Analytical Technology, Bioprocessing and QA & GMP, Innoskills. com provides industry grounded technical skills that many university students don’t always have easy access to. Professor John
Gilmer, head of Trinity’s School of Pharmacy, said: “It is very important to this School that our graduates are equipped with the very latest industry thinking and knowledge that ensures their employability in the industry. As Ireland’s pharmaceuticals industry continues to grow, our aim is that Trinity’s graduates continue to be the most sought after by employers here in Ireland and all over the world.” Eve Conboy, head of Innoskills. com, said: “Trinity’s School of Pharmacy and Pharmaceutical Sciences is in the top 25 of Pharmacy schools globally, so we’re very proud to have their students use our e-learning modules. Their students and academic staff have given us very important feedback, and are helping us to refine and develop our product. Feedback from students so far has been very positive – they are gaining important and valuable industry skills.”
PERSPECTIVE ON PHARMA Can this AI platform change the future of cancer treatments?
s a disease, cancer is perhaps both a patientâ&#x20AC;&#x2122;s and a clinicianâ&#x20AC;&#x2122;s biggest
For patients, a diagnosis of cancer often means undergoing invasive surgery to cut out whatever tumour resides inside them, alongside months or even years of body-wrecking chemotherapy. Often it means a death sentence. For clinicians, cancer acts as almost a final frontier, an unbeatable and mythologised disease at which surgery and chemotherapy are used in the hope of beating it. And while recent years have seen the emergence of immunotherapies target cancers, the truth is that treatment for the disease has largely remained the same for decades. Lantern Pharma wants to change that. Founded in 2014, Lantern Pharma wanted to discover new ways to utilise precision medicine and biomarkers to rescue cancer drugs that PANNA SHARMA, CEO of clinical stage oncology biotech Lantern Pharma, speaks to EPM about how his company's artificial intelligence platform could help revolutionise drug development and ultimately change the way we treat cancer.
Lantern Pharma decided on a different approach to clinical trials; one that would involve using artificial intelligence (AI) and biomarker signatures to understand how patients respond to specific drug classes.
“I really thought that this was a company that could be a game changer because they weren’t just a technology and service provider, they were also biotech,” Sharma mentions. RADR - which stands for Response Algorithm for Drug Positioning & Rescue – works by leveraging big data and genomics to analyse millions of data points from clinical trials to determine how drugs will work with tumour samples. What this means for clinical trials is that RADR is able to identify patients that will respond better to certain therapies, ultimately de-risking trials for drug development companies. “The platform today can very exquisitely tease out who’s going to respond and who’s not going to respond and generate a fairly, smart, practical, genetic signature. And we get that genetic signature from all the way down from the 20,000 genes, to 2,000, to 20-50,” Sharma explains. Whilst RADR sounds impressive, the platform is only a fragment of what the company is wanting it to be. The platform currently holds around 100 million data points of specific drug tumour interactions, but the company wants it to be bigger - much bigger. “Our goal is to be at about 300+ million [data points] next year, a billion the year after. At that point it’ll be a fairly unique platform. We’ll be able to not only understand which patients respond to the majority of drug classes, but we’ll also be able to start identifying which combinations of drugs can
work best in different tumour dynamics,” Sharma says. More than this, Sharma hopes that by using RADR, drug development companies will be able to start designing clinical trials in a more efficient way. “If you can generate the assay or the lab test that can look for a certain biomarker, a certain genomic sequence, or a certain protein like PD-L1, and you can test for that or more importantly you can enroll based on that, well that totally changes the way you should think about the trial,” Sharma explains. Of course there’s another usecase for RADR and that is for helping reduce the excessive costs pharma companies currently face when conducting
I think the future of leadership in pharma and the success of those organisations is going to be based on incorporating patient data more directly and providing transparency into pricing and therapy eﬀectiveness.
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The AI platform the company eventually developed - ‘RADR’ - is one of the big reasons CEO Panna Sharma was attracted to the company.
had failed in late stage trials. Oncology continues to remain pharma’s biggest market but its success in clinical trials can be devastatingly low.
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PERSPECTIVE ON PHARMA
clinical trials. Ultimately, if successful, this could mean cheaper drugs becoming more accessible to patients; because despite all of the advances in technology and emergences of the likes of AI, pharma is yet to see any cost returns. Drugs are still overly expensive, so much so that patient advocacy groups regularly criticise the industry and, in the UK, NICE and the NHS are constantly battling to approve drugs that are cost effective. “We live in an era where drugs have gotten obnoxiously more expensive and everything else in multiple other industries has gotten cheaper. Computers, computing power, clothes. The only thing that’s gotten more expensive is real estate and drugs - pharma and healthcare in the United States. Ridiculously expensive,” Sharma says seriously. “The opportunity here is to leverage all the advances from the computing and data industry and fundamentally change the cost curve – so that $2 billion cancer drug can hopefully be brought down to $200 million or $100 million and hopefully enable greater lifesaving care.” When questioned on whether pharma companies will continue to charge extortionate prices for their products - despite his company’s aim of drug development costs being reduced - Sharma is perhaps more optimistic than some. “I think the future of leadership in pharma and the success of those organisations is going
to be based on incorporating patient data more directly and providing transparency into pricing and therapy effectiveness,” he says going on to mention how this kind of activity is already occurring in the rare disease community. It makes sense. Diseases such as spinal muscular atrophy and cystic fibrosis now have treatments that can vastly improve the lives of patients but at massive costs. So while progress in pharma never comes cheap, the industry must take a step forward towards more responsible pricing, and more transparent conversations surrounding those prices. But how is all of this going to change the way we treat cancer? Imagine that if in 10 or 15 years, a patient diagnosed with cancer could be ‘genomically profiled’ as Sharma puts it, so that instead of having to undergo surgery or needless chemotherapy, the oncologist would know which drug or drug combinations would work best against their tumour and prescribe them accordingly. That’s exactly what Lantern Pharma is targeting with a clinical trial investigating the efficacy of a drug to treat prostate cancer. In collaboration with The Clinical Translational Research and Innovation Centre (C-TRIC), Lantern Pharma is investigating how its drug LP-184 can be used to reduce tumour growth in patients with advanced prostate cancer – with an ultimate aim of bringing
the therapy to market. The unique quality of the trial however comes from the way it is being undertaken. By taking fresh biopsies from the patients’ tumours, Lantern Pharma is hoping to ‘gain real insight into the biology of the disease,’ Sharma says. It’s fairly uncharted work, as Sharma explains, that enables the company to follow patients to see how they respond to the drug. This way, if a patient isn’t responding to their current standard of care, the data gathered will enable Lantern Pharma to guide clinicians towards other treatments that may be best suited to their cancer. “In many ways this is the way to start pioneering and thinking about very importantly personalised medicine. I think this is how a lot of future cancer treatments will be done,” Sharma says.
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Opinion Community pharmacists have some of the most significant opportunities to intervene and prevent unnecessary antimicrobial use.
A PHARMACYâ&#x20AC;&#x2122;S ROLE IN ANTIMICROBIAL STEWARDSHIP Author: Adrian Pittock - marketing director of Valley Northern
Antimicrobial stewardship (AMS) strategies form a vital filtration system for our healthcare system but what many donâ&#x20AC;&#x2122;t consider is the vital role pharmacists play in promoting antimicrobial stewardship to ensure the future of treatment for infection is sustainable.
nly certain objects can fit through a filter, such as a sieve or fine mesh. Liquid and small particles will pass through while other particles are stopped in their tracks. The same idea should be applied to prescribing antimicrobials. Certain people need, and therefore, should pass through the filter and receive this treatment, whereas others should be held back by the filter, to try other treatment options before resorting to antimicrobials. Inappropriate use of antimicrobials, such as antibiotics, is the key driver in the spread of antimicrobial resistance (AMR), meaning that infectious microbes are no longer killed by the treatment. Additionally, with the discovery and production of new antimicrobials slowing down, there is greater concern
for the sustainability of our current supply of treatments. Ultimately, steps need to be taken to preserve the antimicrobials we already have, which rely on a reinforced filtration system across the entire healthcare sector. NATIONAL BACKING The National Institute for Health and Care Excellence (NICE) defines AMS as “an organisational or healthcare-system-wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness.” It encompasses everyone in healthcare. Professor Dame Sally Davies, the UK's former chief medical officer, said in the 2013 Chief Medical Officer’s report: “Antimicrobial resistance poses a catastrophic threat. If we don’t act now, any one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can’t be treated by antibiotics”. This alarming notion shows the importance of reinforcing the antimicrobial filter. NHS England released a Commissioning for Quality and Innovation (CQUIN) guidance in 2016, which was a financial incentive for pharmacies to reduce the indiscriminate or inappropriate use of antibiotics and review antibiotic treatment within 72 hours of administration. The CQUIN framework is intended to reward excellence, encouraging a culture of continuous improvement. Rebecca Carter, a neuroscience specialist pharmacist based in Oxfordshire, believes a key strategy to achieving CQUIN targets is education. “I would advise focussed training in areas where over consumption of antimicrobials is high, to help them to identify areas in their practice where they may be able to use alternative agents, or increase their knowledge of antimicrobial stewardship.” RESPONSIBILITY Community pharmacists have some of the most significant opportunities to intervene and prevent unnecessary antimicrobial use, as patients often go to their community pharmacist first to seek expert advice. This is an opportunity to quash any misconceptions surrounding antimicrobials, as well as to educate the community on infection prevention strategies, including good hygiene, hand washing and vaccinations. Pharmacy labels are available to affix to pharmacy bags to enhance existing communication strategies.
Often, conversations in a pharmacy may be forgotten by the time the customer gets home, but pharmacy labels continue to get the message across for much longer. Labels such as ‘complete entire course’ will continue to speak volumes for as long as the label is visible. These labels resonate with customers as they take their prescription home, away from the busy pharmacy environment. Additionally inﬂuenza vaccinations should be proactively marketed to vulnerable groups, saving on antimicrobial resources in the long-term. By simply sticking a label on pharmacy bags stating ‘ﬂu jabs are available here’, this message is clear. Small changes such as using pharmacy labels can complement AMS efforts greatly. ALTERNATIVES If prescribers aren’t sure if antimicrobials are required, delayed (back-up) prescriptions are an alternative to immediate antimicrobial prescribing. It encourages other treatment as a first step, but allows a person to access antimicrobials without another appointment if their condition gets worse. However, a survey in the British Medical Journal found that 72% of the general public were unaware of this delayed system. With this delayed way of prescribing likely to increase further to complement AMS strategies, patients may require reassurance and advice from their pharmacists as they may have expected to receive antibiotics. With changes like this ongoing, community pharmacists not only need to keep up-to-date with the most recent guidelines, but create a pharmacy environment indicative to AMS. Pharmacies are an ideal place to display AMR and infection prevention leaﬂets. When patients bring their antibiotic prescription to a pharmacy, this is an important opportunity for pharmacists to have discussions about what has caused the infection, alternative treatment and the risks of taking antibiotics. Additionally, pharmacists can act as reinforcement within the antimicrobial filtration system, asking questions that GPs may have already asked but are worth asking again. Questions could surround current medicines, hygiene and allergies. All pharmacists can play their part in slowing down emergence of AMR and conserve precious healthcare resources. Without pharmacists' supportive efforts, a gaping hole would be present in a vital filtration system.
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AVOIDING SURPRISES Author: Robert Sedlock - director of technical training and development for Natoli Engineering
Natoli Engineering discusses some of the important raw material characterising techniques to provide readers with a robust tablet formulation strategy from the development arena to the manufacturing environment.
ablet compression is an established manufacturing process with numerous applications in pharmaceutical, nutritional, food, cosmetic and other industries. Compressing a block of particles into a single compact is a combination of art and science. With today’s technology, science is prevailing.
Figure 1- Sticking Index
Underestimating the tablet design, formulation development and manufacturing process, could certainly cause significant problems at some stage of the product’s life. Many common tabletting defects arise due to the failure of fully understanding the raw material properties and how they are subjected to the tabletting process.
weight variation and compaction pressure issues during the tabletting process. ProSolv grades provide the highest BFE values and the API’s provide the lowest BFE values, according to the chart. This is typical, as most API’s have ﬂow and compactibility issues, and ProSolv is an excipient that formulators add to the blend to improve ﬂow and compactibility.
DISCUSSION Powder Rheology Powder ﬂow is a fundamental attribute required for successful tablet manufacturing. The powder must ﬂow from the tablet press hopper to the feeder system and fill the die cavity in a homogeneous manner. If the powder doesn’t have sufficient ﬂow properties, the resulting tablet weights will not be uniform, causing many issues, including API (Active Pharmaceutical Ingredient) content uniformity and tablet density variation, which leads to dissolution issues and other tabletting challenges.
Powder permeability is another fundamental property affecting the tabletting process. Entrapped air in the powder blend reduces the interparticulate bonding and reduces the final tablet tensile strength, which leads to tablet failures, like capping. High permeability indicates less air entrapment during the tabletting process and fewer tablet defects.
Utilising powder rheology equipment, like the FT4 from Freeman Technologies, gives scientists insight on the powder properties and helps identify potential issues on the tablet press. First, you must understand the environment of each stage and what measurements are available.
Image 1- Presster
Basic ﬂowability energy (BFE) is one of the experiments to consider before tabletting. This fundamental test will give insight on the ﬂowability of the materials. This is defined as the energy required to initiate the powder ﬂow. High energy indicates poor ﬂow of the powder, which causes
Another FT4 measurement is the sticking index. While not mentioned above, sticking is one of the most common tablet manufacturing issues. Moreover, at the manufacturing stage, formulation changes require a process following SUPAC (ScaleUp and Post Approval Changes) guidelines, which can be time consuming and halt production. Tool manufacturers offer punch tip coatings and special steel types to combat sticking issues but having insight of the formulation at early stages allows the scientist to modify the formulation and select the proper tools for a successful process. Punch sticking results from the adhesion behaviour of the powder blend to the punch. This is quantified using the adhesion and cohesion behaviour of the powder. Adhesion behaviour
was quantified using the ratio of the wall friction angle to the angle of internal particle friction. A higher sticking index indicates the higher sticking tendency. Figure 1 shows that IBU has the highest sticking tendency and adding Prosolv increases cohesiveness, which reduces adhesiveness and sticking. There are other factors that cause punch face sticking, like excessive particle fines, high moisture content, worn tooling and punch tip configuration, but the sticking index is another fundamental powder test before tableting. Material Deformation Properties & Compaction Emulation Characterising the mechanical properties of raw ingredients is another vital test in developing a robust tablet formulation. Compaction emulators (Presster Image 1) are a material sparing compaction machine (<1 gram) that offers sophisticated instrumentation measurements. The emulator characterises the mechanical properties of the raw ingredients and emulates the manufacturing tablet process by matching the compression times of the desired manufacturing tablet press. Below is a chart of the available instrumentation, the measurement type and the analysis advantage. CONCLUSION Characterising powder rheology and mechanical properties provides science-based data for the tablet development process. Unwanted surprises at manufacturing scale are minimised by understanding powder rheology and utilising compaction emulators at development scale. Special acknowledgements to Freeman Technologies, JRS Pharma and Pratap Basim, Dr. Rutesh Dave at Natoli Institute / Long Island University Arnold and Marie Schwartz College of Pharmacy in Brooklyn, New York.
Table 1- FT4 Measurements Stage
High stress condition, reduced porosity, gravitational ﬂow
Shear Properties, Wall Friction, Compressibility, Permeability
Moderate stress, dynamic condition, forced ﬂow
Basic Flow Energy, Flow Rate, Compressibility
Low stress, dynamic condition, gravitational ﬂow
Aeration, Specific Flow Energy, Permeability
Very high stress, forced ﬂow, material deformation
Compressibility, Permeability, De-aeration, Basic Flow Energy
Upper & Lower PreCompression Force
Upper / Lower Pre-Compression Roller Force Transducer
Identify the required Pre-Compression force to reduce capping, lamination and increase tablet strength
Upper & Lower Main Compression Force
Upper / Lower Main Compression Roller Force Transducer
Identify the required Main Compression force to provide a robust tablet and identify the upper and lower punch forces as a function of the punch penetration.
Upper & Lower Punch Displacement
Punch Carriage Upper & Lower Punch Displacement Transducer
Record the real time in-die tablet thickness and identify deformation properties by measuring Heckel and Work curves
Ejection Cam Transducer
Identify ejection issues and optimise powder lubrication levels
Radial Die Wall Force
In-die Strain Gage Transducer
Measure radial die wall force during compression and residual die wall force after de-compression
Take-Off Bar Transducer
Identify sticking issues
Punch Carriage Proximity Switches
Emulate the manufacturing velocities for scale up
Table 2- Presster Instrumentation
IN PROFILE WITH
ACG's Ettore Cucchetti ACG’s Ettore Cucchetti sits down with EPM to explain his journey into pharma, the success of a major company milestone, and the challenges and opportunities serialisation presents. How did you get into the pharma industry? I first entered the pharma industry in 2015 when I started with ACG. I was head hunted whilst working for a technology company in Switzerland, so it meant a transfer to Mumbai in India. Ettore Cucchetti: CEO ACG Inspection at ACG
I have always focused on technology, mainly around quality and regulation, so moving into inspections in the pharma industry
was a natural and appropriate progression. Whilst traceability as a topic within the industry goes back to the 1980/90s, and we have also seen the evolution of tracing from analogue to digital, pharma is certainly behind other industries when it comes to using tech. Being at the forefront of new technologies and innovations is what really attracted me to working in this industry and to this role at ACG.
This year ACG completed its 1000th track and trace line installation, what does this milestone mean for the company? It’s a very important milestone, but one that comes with a lot of responsibility. We are relied upon by over 1,000 pharmaceutical businesses to keep track and trace lines functioning globally with trillions of data managed by us for the better future.
Could you discuss your role at ACG? Inspections was the youngest of the business units within the group when I started. My objective was initially to reorganise the management structure and to develop a comprehensive growth strategy for the unit.
ACG has a large global presence, are there any differing serialisation challenges that you’ve come across? There are many challenges when it comes to serialisation, including the varying regulations from country to country. Challenges can also arise when it comes to relaying and implementing these regulations to individual customers. Each customer has their own business model, supply chain structures and contract manufacturing organisation (CMO), so there are various nuances and idiosyncratic features to consider. It means customisation is key when it comes to working with any customer – every customer is unique, even if one company is operating across a number of territories.
Currently my role as CEO is to focus on introducing new technologies, sourcing new talent, and opening and acquiring new facilities. It’s already been busy — just recently we opened ACG’s Swiss ‘Centre of Excellence’ supporting the company’s continued global expansion. The office will be the headquarters for logistics, development, data, service support, factory acceptance test (FAT) and project management for ACG Inspections in Europe. So far it has been a journey of growth, and we’re excited about what lies ahead.
The data flow is huge. Success boils down to proximity and communication and how a company like ours responds and manages the master data.
We have a long, long road ahead to safeguard human life and ensure a better future. How big a threat is counterfeiting to the pharmaceutical supply chain? The threat cannot be underestimated. The statistics around fake and available overcounter products are frightening - whether it’s contamination, incorrect formulations or issues in the manufacturing process. A secure pharmaceutical supply chain is key when it comes to protecting customers and fighting counterfeiting. It gives the benefit of recourse of the products and can pinpoint exactly where the product has come from. Has contract manufacturing and outsourcing contributed to serialisation challenges and counterfeits? Absolutely. Whether large international pharmaceutical brands or more locally-based ones, they will all use contract manufacturers – bringing everything into the mainstream data ﬂow is a huge task. The financial investment to support track and trace is considerable. This is an ongoing and continuous journey. Regulations are and will always keep changing, and hopefully improving, as criminals and counterfeiters become more sophisticated. We have a long, long road ahead to safeguard human life and ensure a better future. What should manufacturers be focusing on next? Now the regulation has passed, the time has come to focus on
data, and this will be the next major step. Predictive consumer behaviour and industry 4.0 are only around the corner. The whole process is very challenging and hence very rewarding. We discover new ideas and challenges on a daily basis. Only now are we being given the opportunity to address efficiencies in the supply chain. Many companies struggle to grapple with the huge investment required when it comes to serialisation, but I firmly believe we need to look at the bigger picture and the benefits this will bring when it comes to data management. Conversely, what are some of the industry’s problems and challenges? Communicating to the customer why they need to implement these technologies given the huge financial outlay and continued investment. This is the first step towards digitisation and being receptive to what it can offer will bring many benefits to the industry. Following 2019’s milestone, what’s next for ACG? We are working on our new ‘centre of excellence’ in Switzerland. This has been a very thoroughly thought-through journey. There was a lot of consideration about where to create and build the centre to best serve the next generation. We chose Switzerland because of the type of competency we were looking for and the ease of doing business there.
P R O F I L E
IN THE NEWS
Apple launches app to advance clinical research
Is anti-ageing Britain’s next big industry?
ech giant Apple has launched a new app to help advance medical discoveries and develop the next generation of health products. The company’s Research app is available on both the iPhone and Apple Watch and marks yet another step for Apple’s push into the healthcare market. Apple has also announced that US customers can enrol in three clinical studies via the app focused on women’s health, heart and movement, and hearing. The studies are being conducted in partnership with academic and research institutions and will use Apple’s products to capture data during everyday activities. The idea is that by recording activities such as workouts, headphone usage and menstrual cycles, these data can be used to inform the future production of healthcare products and interventions. “Today marks an important moment as we embark on research initiatives that may offer incredible learnings in areas long sought after by the medical community,” said Jeff Williams, Apple’s chief operating officer.
n entire market dedicated to slowing down the effects of ageing could be Britain’s next biggest industry. Speaking to a House of Lords Science and Technology Committee, Richard Faragher, professor of Biogerontology at the University of Brighton said that today’s scientists have the knowledge and potential to reverse or slow down ageing. With this expertise available in the UK, it could mark the beginning of a ‘formidable’ industry. The meeting between members of the House of Lords and academics was intended to garner information into how
science and technology can enable healthier living in old age. One of the major barriers we face against ageing are senescent cells – rogue cells which start secreting damaging chemicals into the body. And whilst younger bodies can deal with these rogue cells fairly quickly, older bodies take longer to get rid of them.
“If you delete senescent cells in these mice they ran about three times as hard and as fast as their little mates who are still full of senescent cells.” Professor Faragher equated the results to a person of eighty years old jogging as if they were thirty. Committee chair Lord Patel jokingly volunteered for such an experimental treatment.
“If government leads, funds basic research properly, establishes the full translation pipeline that our clinical and pharmaceutical colleagues (are proposing), if we do these things then this country could build up a formidable industrial base in this area,” professor Faragher added.
Professor Faragher said if senescent cells were eliminated then the result could be dramatic: “We know this is a major ageing mechanism because in experimental animals where it has proved possible to delete these cells these animals showed enormous increase in their health.
Did you know?
23% of people aged between 50 – 64 have three or more long-term health conditions.
By 2023 England is expected to have 1.54 million people aged over 85.
An 85-year-old costs the NHS five times more than the average 30-year-old patient.
CRISPR GENE EDITING CRISPR might have taken the world by storm but what’s next for gene editing technology?
e’re going to make the most of the time we have together,” Alexandra’s mother said to her. When Alexandra* was born, in the 1950s, her life expectancy was 12 to 13 years, like that of other babies born with β-thalassemia. From childhood, her mother told her to make the most of life but prepared her to not expect too much – like finishing or even starting high school, going to university, or getting married. β-thalassemia is a genetic blood disorder, where the β-protein chains of haemoglobin in red blood cells are either present at lower than normal levels or not synthesised at all. Individuals with β-thalassemia can suffer from severe anemia and other serious medical issues such as bone deformities, broken bones, and an enlarged spleen. Patients are treated with regular blood transfusions, but this can lead to the build-up of iron in the body, which can damage the heart and endocrine system.
SPOTLIGHT ON CRISPR Since CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing was discovered in 2012, it has been taking the world by storm and generating excitement among diverse audiences including scientists, people suffering from currently untreatable diseases, patient advocates and the general public. CRISPR was one of the biggest and most important science stories in 2019. To put this into context, in 2011 there were fewer than 100 published papers on CRISPR. Today, there are almost 30,000 and that number keeps growing. With the first clinical trials underway and a broad range of possible applications for CRISPR, including disease-vector control as well as agricultural science, I wanted to reﬂect on the successes achieved to-date and share my predictions for where the technology is heading. Given the hype and progress made in a
relatively short timeframe, I believe we will be hearing a lot more about CRISPR in 2020 and the years to come. WHAT IS CRISPR GENE EDITING? CRISPR gene editing is a technique being investigated by scientists to make permanent and precise changes to DNA in animals and plants. It is promising since it offers scientists the possibility to target and then edit a single, specific stretch of DNA more precisely, quickly and cheaply than was previously possible. However, while the technique is relatively simple, powerful and precise, it is not perfect. The goal of CRISPR gene editing is to target, and then edit, specific stretches of DNA. However, cleavage may occur at
Author: Ashley Jacobi, senior staff scientist at Integrated DNA Technologies (IDT)
<1> U.S. Centers for Disease Control and Prevention (CDC). Real Stories from People Living with Thalassemia. 2019. https:// www.cdc.gov/ncbddd/ thalassemia/stories.html (accessed November 2019). <2> https://scholar. google.com/scholar?as_ylo=2018&q=crispr&hl=en&as_sdt=0,9 <3> Zhang, X. H., Tee, L. Y., Wang, X. G., Huang, Q. S., & Yang, S. H. Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol. Ther. Nucleic. Acids. 17 (4), e264 (2015). <4> Vakulskas CA, Dever DP, Rettig GR, Turk R, et al. A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells. Nat Med. 2018;24:1216–24.
unintended sites with similar sequences to the target site. These are known as off-target effects (OTEs) and may account for more than 50% of editing accomplished with wild-type (WT) Cas9, the most widely used CRISPR enzyme. There is always a risk that off-target editing may lead to unintended, adverse consequences. A NEW CAS9 ENZYME Numerous attempts have been made by scientists to improve the specificity of the Cas9 enzyme, including our team at Integrated DNA Technologies (IDT). By devising an unbiased bacterial mutagenesis screen to isolate Cas9 variants, we at IDT were able to develop a high-fidelity Cas9 enzyme, known as HiFi Cas9. HiFi Cas9 offers highly specific cleavage with minimal OTEs and on-target nuclease activity in line with that of WT Cas9. The results of this work were highlighted through the application of HiFi Cas9 in human stem cells, published in Nature Medicine in 2018. Due to its activity and specificity, HiFi Cas9 is ideal for use in clinical studies. This led IDT to partner with Aldevron to supply a Good Manufacturing Practice (GMP) grade of the enzyme for clinical use. The enzyme has also been singled out for use by researchers in their proposed clinical trials. One such researcher is Dr Matthew Porteus, professor of Paediatrics (Stem Cell Transplantation) at Stanford University, who has been using it in his preclinical studies and intends to use it in his proposed Phase I sickle cell disease (SCD) clinical trial. The trial is investigating the potential for CRISPR to correct the SCDcausing point mutation to the human beta-globin gene (HBB). Another researcher, Dr Katy Rezvani, professor of Medicine (Stem Cell Transplantation) at the University of Texas MD
Anderson Cancer Centre, has also been using HiFi Cas9 in her translational cancer research and is looking to use it at GMP grade in protocols being developed for potential use in oncology clinical trials. While unknowns remain, we are beginning to see the first therapeutic applications of CRISPR being tested in human trials. CLINICAL APPLICATIONS OF CRISPR In 2018, news broke that the first cancer immunology clinical trial using CRISPR had been opened at the University of Pennsylvania; this was quickly followed by trials launched in 2019 for SCD and β-thalassemia. SCD and
β-thalassemia are prime targets for CRISPR editing since there are no viable current treatments available and each disease is caused by a single-DNA base mutation which, in theory, could be corrected using this technology. However, assessing the success of these trials and treatments, as well as any side effects, will take many years as we are only just beginning to scratch the surface of both the potential and clinical applications. WHERE MIGHT THE FUTURE TAKE US? As we build our understanding of the technology, and fully understand the opportunities it may afford us, as well as begin to
CRISPR and other gene editing therapies oﬀer patients suﬀering debilitating diseases hope that someday there will be a curative therapy for them. uses, how will we maintain public support once more clinical trials are being launched and outcomes from early-stage trials begin to emerge? CRISPR and other gene editing therapies offer patients suffering debilitating diseases hope that someday there will be a curative therapy for them. However, as we have seen with other scientific advancements, it will be critical for consumer awareness and education to keep pace with scientific progress to ensure people remain open to CRISPR’s potential and confident that enough regulatory oversight is being applied.
see the outcomes of early clinical trials, I would anticipate that we begin to broaden its use from diseases caused by single-DNA base mutations to more complex diseases. Furthermore, we might start to see applications being developed for in vivo use. These in vivo therapies might start out as highly targeted and localised treatments, for example therapies delivered to a specific site like the eye but could eventually become systemic in-vivo treatments. This will, of course, take many years of testing.
presentation at the Cold Spring Harbor Laboratory in October this year, there was much excitement about the potential of “prime editing.” While this technology is exciting, it is still somewhat in its infancy, compared with the current predominant CRISPR technology. It will be important to evaluate its strengths and weaknesses and assess OTEs. No doubt there will be other discoveries that will show potential, but it remains to be seen which ones will lead to eventual therapies and other real-world applications.
We will also likely witness the advent and application of other similar technologies. Following a
MAINTAINING MOMENTUM While there is currently much hype about potential therapies and
The dialogue will require participation from all strata of society: scientists, ethicists, patients, patient advocates, caregivers, journalists and policymakers. Only with a concerted effort will the technology continue to make progress at its current rate. The benefits cannot be understated, and neither can the risks if we fail to learn from previous shortcomings or fail to facilitate meaningful and informed conversations and debates. As leaders in the innovation and provision of CRISPR technologies, we are invested in supporting and encouraging endeavours aimed at raising awareness, education, and discussion regarding CRISPR technology among both multidisciplinary experts and the general public.
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| ORAL SOLID DOSAGE SUPPLEMENT
RD F UTH
Essential stories detailing the latest advancements in the oral solid dosage sector.
ORAL SOLID DOSAGE SUPPLEMENT
ALWAYS ON MY MIND Why spray drying should be on every formulator’s mind when trying to overcome solubility issues.
Author: William Wei Lim Chin, technical specialist, Science and Technology at Catalent
evelopers and manufacturers are frequently turning to spray dried dispersions (SDDs) as a means of overcoming the solubility challenges presented by many new medicines. Spraydried dispersions have some unique characteristics, and there are some important formulation and processing parameters to be considered when creating an amorphous solid dispersion (ASD) and incorporating ASDs into common dosage forms.
For formulators, solubility is a persistent challenge to delivering the therapeutic benefits of a treatment, and one that, if not properly addressed in the early stages of development, can be costly, both in terms of time and money to solve later. It is estimated that nearly 40% of the new chemical entities (NCEs) screened by pharmaceutical companies fail to progress to later stages of development due to poor aqueous solubility.1 This puts an onus on formulators to improve the bioavailability of poorly soluble drug molecules to ensure that life-changing drugs are not abandoned and can reach their true potential, and the patients who need them. Since many of these insoluble drugs exist in crystalline form, creating an ASD using spray drying technology is one approach to improve solubility. Amorphous forms are intrinsically more soluble than crystalline materials, as there is no crystalline lattice energy to be overcome. An SSD is an amorphous molecular dispersion of a drug in a polymer matrix, created by dissolving drug and polymer in an organic solvent and subsequently atomising this liquid feed into very small droplets within a hot drying gas, leading
to ﬂash drying of the droplets into solid particles. This single-step, continuous process is very robust and stable and offers multiple opportunities for formulation development of dosage forms. PROCESSING PARAMETER CONSIDERATIONS FOR SPRAY DRYING Creating the ideal spray dried particles requires control over the critical processing parameters that inﬂuence radial distribution of the active pharmaceutical ingredient (API) and polymer components.2 During the rapid drying phase, the components tend to adsorb and diffuse on the surface of the droplet. Solvent evaporation, a balance between the solvent’s vapour pressure and partial pressure, causes the droplet surface to recede, leading to diffusion of components towards the interior. To avoid phase separation, evaporation must occur before the API crystallises, and this can be controlled by optimising the spray rates, feed solution concentration and processing temperature. By varying the parameters of the spray drying, it is also possible to engineer smaller particle size (typically between 1-5 µm) for inhaled drug products. The process allows for the formulation of products that may have unusual or difficult characteristics, including products that are difficult to handle, or are hygroscopic. Spray drying also offers advantages for materials that are particularly temperature sensitive, as the rapid drying involved in the process helps ensure the product is not degraded during processing. FORMULATION CONSIDERATIONS FOR SPRAY DRYING In the development of an SDD, it is crucial that the product is stable.
The nature of the polymer used in the process must be considered to ensure that it is chemically stable with the API, while also being miscible and improving the supersaturation of the API in aqueous media. Selecting polymers that have a high glass transition temperature (Tg) could ensure that the rate of phase separation and crystallisation is substantially reduced. Though most polymers are relatively inert, some are hygroscopic or acidic and therefore inappropriate for compounds prone to hydrolysis or acid degradation. Similarly, the choice of solvent is important as it must provide sufficient solubility and chemical stability for both the API and the chosen polymer. A wide range of organic solvents are suitable for spray drying, and often a combination of solvents can be the most appropriate. DOSAGE FORM FORMULATION It is important to note that any instability previously observed in the crystalline form of the API will likely be more pronounced in the amorphous state. Specifically, hygroscopicity is usually worse in an amorphous form due to the hygroscopicity of some polymers, and the high surface area of the ASD particles. Reactivity with acids, bases, and oxidisers is also generally worse due to the high energy state of the amorphous material. Once a physically and chemically stable SDD has been developed, formulating this into a solid dose form is the next step – which could be either a tablet, capsule or an alternative format. Excipients for dose form formulation however, must be selected and tested for compatibility with the spray-
dried powder. Excipients that can provide the best chemical stability are often those that are pH neutral, low moisture content, and low hygroscopicity, such as mannitol as a tablet excipient and hydroxypropylmethyl cellulose (HPMC) capsules instead of gelatin for hard shell capsules.
poor aqueous solubility, spray drying is becoming an important part of development “toolkits”, and investments across the industry are being made in increased capacity and expertise to ensure the technology is accessible to allow drugs to be taken through to commercialisation.
For compounds that are pHsensitive, excipients with pH buffering capacity, such as citric acid and sodium bicarbonate, can have a stronger stabilising effect on ASDs than on a crystalline API, and additionally, solid dosage forms can be coated with materials such as polyvinyl acetate (PVA) for further moisture protection.
REFERENCES 1 Roots Analysis Business Research & Consulting, Pharmaceutical Spray Drying Market, 2nd edition 2018-2028. 2 Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008 May;25(5):999-1022. Doi: 10.1007/s11095-007-9475-1
It is important that formulation development efforts focus on fast-disintegrating dosage forms, otherwise the increased solubility of the spray-dried API can be quickly negated by its poor release into the body. It may be necessary to introduce aggressive disintegration approaches in the dose form if initial attempts produce long disintegration times, or slow dissolution rates. All in vitro formulation development work needs to be confirmed with in vivo studies whenever possible, and comparison studies carried out between the neat dispersion suspended in water along with the formulated dispersion in a relevant model, to ensure poor disintegration is not leading to lower than expected exposure levels. CONCLUSION Typically, spray drying is unlikely to be a formulator’s first choice to overcome solubility issues, as other approaches such as salt forms, co-crystals, and micronisation require less technical expertise and are economically advantageous. However, developing an ASD should be considered if other approaches do not offer the desired solubility. With more molecules being developed with
In the development of an SDD, it is crucial that the product is stable.
IN THE NEWS
PACKAGING SOLUTIONS APPROVED FOR HIV PREVENTION MEDICINE
ptar’s packaging solution for oral solid dose drug delivery has been approved for a HIV prevention medicine, the company has announced.
VR paves the way for continuous manufacturing
irtual reality (VR) may be helping pharmaceutical companies experience the benefits of continuous manufacturing thanks to a new offering by GEA. GEA’s Continuous Experience room, demonstrated at this year’s CPhI,
The company’s Activ-Blister packaging protects oral solid drug products with a type of polymer that can be customised specifically for a drug developer’s formulation. It is designed to protect drugs through moisture protection, and oxygen and odour scavenging. The oral solid dose drug was developed by a leading pharmaceutical company in the HIV treatment and prevention space and represents the first FDA approval of Aptar’s Activ-Blister packaging solution.
enabled visitors to use VR to take a closer look at the company’s continuous manufacturing technologies. In particular, visitors got the chance to examine ConsiGma, a multipurpose platform designed by GEA to transform powder into coated tablets in
development, pilot, clinical and production volumes in a single compact unit. Dr Jim Holman, GEA New Development & Innovation Pharma, explained: “GEA designs and manufactures a wide range of complex equipment and cuttingedge machinery. Virtual reality (VR) allows us to present those technologies in a comprehensible way and greatly facilitates processes such as operator training and the breakdown or disassembly (and reassembly) of plant for cleaning and maintenance.” Arco Hamelink, vice president global
sales, pharma solids, added: “We see VR as an enabling tool that we can use to communicate the benefits of our solutions to both existing and future customers and demonstrate the full potential of platforms such as ConsiGma without actually having a finished line in place.” “In fact, with VR, we can provide guidance and train users to successfully operate complicated pharmaceutical manufacturing systems long before the hardware has actually been delivered and installed.”
DRINKING STRAW MAKES TAKING MEDICINE EASIER
new drinking straw has been designed to help make it easier for people to swallow medication. The XStraw has been designed to help people take a safe, pre-portioned oral drug to ensure they receive a precise dose each time. The straw is used alongside a beverage to help the user ingest their proper drug dosage. The straw was designed by DS Technology but uses
a porous filter solution from Porex to keep drugs in place. The filter works by absorbing liquid only when the user begins to suck on the straw, preventing medication from clumping together and changes position to indicate when the drug has been consumed. The device is designed for those who may struggle to take medication, such as children or elderly people. “With more than 50%
of people young and old having problems taking pills, the XStraw becomes a gamechanger for anyone seeking a simple and intuitive method for administering an exact dosing quantity,” said Dr Elke SternbergerRützel of DS Technology. “Through our partnership with Porex, we’re able to offer patients of all ages an effective way to ingest their medication safely and properly.”
ORAL SOLID DOSAGE SUPPLEMENT
A WAY OUT
of the assessment maze? Merck oﬀers a practical view on the implementation of the EU Excipient Risk Assessment Guidelines.
T Author: Frithjof Holtz, Advocacy & Surveillance Life Science Regulatory Management at Merck KGaA
hey are often inconspicuous, but just as often indispensable: excipients are far more than passive additions to active pharmaceutical ingredients (APIs). Their critical role in drug production has become the focus of many debates – and of regulatory authorities who are demanding more stringent quality management in excipient production and use. Whether speaking of antiadherents or binders, a high quality of the more than one thousand different excipients is essential for drug and patient safety. Regulatory authorities are increasingly demanding stricter quality management in excipient production and use, which affects both excipient suppliers and pharmaceutical manufacturers. Since March 2016, excipient users in the EU are legally mandated to implement GMP requirements of the EU Excipient Risk Assessment Guidelines. However, while regulations regarding GMP for APIs clearly define what is required for compliance, the EU guidelines never intended to be more than their name suggests: guidelines offering tools and a framework. From the manufacturing authorisation holder’s point of view, the guidelines are lacking a clear implementation prescription. They neither provide detailed instructions nor a clear definition of appropriate GMPs for excipients. This remains the responsibility of the manufacturing authorisation holder and can be quite a challenging task.
THE EU GUIDELINES AND THEIR CHALLENGES The good news is that no one needs to develop their own GMPs from scratch. In fact, they can follow several well-established, voluntary industry standards such as USP General Chapter 1078, EXCiPACT and NSF/IPEC/ANSI363-2016, or the IPEC-PQG GMP Guide. Together with the IPEC Europe “how to“ document, the latter gives a good initial guidance. It offers a clearly arranged step-by-step overview of how to comply with the EU Excipient Risk Assessment Guidelines, which will be sufficient in many cases. But what about those excipients that could potentially pose hazards to patients? They certainly require application of more exhaustive control mechanisms. Moreover, the voluntary standards are not binding, which often confronts manufacturers and users of excipients with nearly unsurmountable challenges as to how exactly they should perform their risk assessment. The large number of excipients that need to be formally assessed, as well as the scope of the supporting documents can also be quite overwhelming. LEARNING FROM REAL EXPERIENCE To simplify the task and to enable effective learning through practical experience, Merck conducted a real-life case study based on a defined number of pharmaceutical products and excipients. The initial question was “what do medicinal product manufacturers need to consider during risk
assessment?” Two lists of criteria, i.e. from the manufacturing or supply perspective and from the application point of view, identify risks related to excipients based on the EU guidelines. Based on these lists, five different quality areas were defined for risk assessment: quality management system, manufacturing of excipients, supply chain, route of administration and function of the excipient. Prior to the actual assessment process, the medicinal products were examined in order to identify all excipients and their respective use. In the end, 24 excipients were investigated and assessed in a step-by-step approach. A FOUR-STEP ASSESSMENT PROCESS The first step consisted in translating the EU guidelines into a supplier questionnaire to assess the supplier qualification. The incoming information was harmonised and bundled in a spreadsheet. Next, the team developed an excipient risk ranking template covering all elements of the EU guidelines, using ICH Q9 Quality Risk Management as guidance. The template provides a risk score from low to medium to high for each individual excipient, both regarding each single criterion as well as the overall risk score. According to the previously defined minimum requirements derived from documents such as the IPEC GMP Guide and EXCiPACT, the supplier risk was determined in step three. The final
step consisted in creating a risk profile for each supplier based on a gap analysis. The goal was to identify effective mitigation options, such as an update of the Quality Assurance Agreement or intensified incoming goods control. RESULTS AND FURTHER CHALLENGES In the overall ranking, none of the 24 assessed excipients were classified as high-risk. However, excipients can still have high single risks, for instance regarding storage monitoring and packaging, dosage form and permanent intake, which need to be closely looked into. The gap analysis at the supplier end led to 14 excipients classified as low, and 10 as medium risk. The identified gaps included a potential for microbiological or endotoxin/pyrogen contamination, which can be mitigated through additional quality control testing in the manufacturing authorisation holder’s laboratory. Other gaps concerned environmental control and control of storage/ transportation conditions including cold chain management and packaging integrity. While translating the relevant points from the EU guidelines into a supplier questionnaire was already rather complex, finding an appropriate procedure for risk prioritisation proved to be the largest challenge. The sheer amount of data was overwhelming. Here, suppliers can contribute to a good process by following established guidelines, fulfilling information needs and providing timely documentation, ideally in electronically transmitted packages. Once defined, the risk assessment process must be transferred into daily business and kept up to date. A WAY OUT OF THE ASSESSMENT MAZE A good excipient risk assessment procedure contributes decisively
to product and patient safety – and facilitates regulatory inspection processes for excipient manufacturers and users. However, the more stringent regulations have also increased the workload for manufacturing authorisation holders: as the case study shows, a structured excipient risk assessment process requires a large amount of resources. Cross-functional teams, an open and structured communication between drug manufacturers and excipient suppliers are just as important as a strong commitment and awareness from management. Online programmes such as Merck’s Emprove provide further support. Tried and tested tools including comprehensive documentation packages simplify processes and help
drug manufacturers master the challenges of timely information, structured communication and “inspection-friendly” documentation. The dossiers cover all relevant EU guidelines with clear references to the respective chapters. This way, the tools help to efficiently implement a compliant and sustainable risk assessment process – and offers pharmaceutical manufacturers a way out of the assessment maze.
From the manufacturing authorisation holder’s point of view, the guidelines are lacking a clear implementation prescription.
ORAL SOLID DOSAGE SUPPLEMENT
Who: Artur Jakubiak, international sales director at Adamus. What: A handy guide for manufacturers wanting to increase their tablet press capacity.
How: By examining the different factors in tablet press set-up.
STOP THE PRESS T
oday in the race towards the maximum tablet press output, two different approaches are observed - that process efficiency can be inﬂuenced by the modification of the machine features or by applying compression tooling with special design. Obviously, by buying a larger tablet press with a larger turret pitch diameter, the effect of the increasing capacity is easily addressed but is usually connected with high investment costs. Changing design parameters in the existing tablet press - such as the stations number or turret rotation speed - is usually connected with quite deep interference in the tablet press construction and/or control system. The effect of the stations numbers in the turret can be seen in Table 1. Increasing the number of stations can be connected with a decrease in the die outer diameter, as well as a decrease in the maximum tablet diameter available to produce.
In the case of the tablet having a diameter (for round tablets) or a larger axis length (for shape tablets) of 11 mm or less, by changing the turret from D type to B/BBS type you can increase the production capacity of the tablet press by 185%. Another way which has a huge impact on production capacity through increased output and reduced production time is through applying multi-tips tooling to existing machines. Additional benefits include less maintenance and a reduction in press setup-time calculated per production batch. The fewer tablet presses needed to satisfy required output leads to less ﬂoor space, which gives more product volume processed per square meter. All these factors
translate to reduction in overall plant running costs. When using multi-tips, theoretically, the number of tablets per turret rotation could be multiplied by the number of tips. However, usually turret rotation speed has to be reduced due to increasing numbers of die bore to fill (right powder distribution) and the capacity increase factor can be smaller as a result. The inﬂuence of the tips number on capacity of Kilian Synthesis 500 can be seen in Table 2. These data should be treated as indicative only, as the real factor values strongly depend on the formulation to be compressed. Generally, there is no need for any special tablet press modifications when applying multitips. Tablet presses must be in good working condition with no significant wear in punch guides, keyways and die pockets. The upper punch table in the turret must have a keyway in the guide to ensure exact alignment with the tooling - as in the case of using any shape tooling. The lower punch guide does not require a keyway because the tips are guided by the die, but a keyway helps in the setting process, especially for tooling with higher tips number. Additionally, it should be considered that even if tips are guided by the die, during the contact of the punch head with the compression roller, the punch has a natural tendency to turn. Certainly, this rotation is restricted by the die and this leads to developing a stress between tips and die wall. As the stress is repeated many times during the compression cycle, finally it ends with the premature fatigue breaking of lower tips. Such stress can be eliminated by the keying of the lower punch or using a rotating head. The formulation being compressed should be investigated to cope with the increased fill requirement and granulation ﬂow. If product is not ﬂowing well, a solution could be to modify the fill shoe paddles or reduce the machine
Die outer diameter [mm]
Maximum Tablet diameter [mm]
Maximum tablet output
1 020 000
Maximum tablet output [tablets/hour]
Tablet output per station [tablets/hour]
speed to allow enough time for filling to take place. Two different designs of multi-tip punches are generally available. One is an assembly design where individual tips are fastened into the punch shaft directly or by cup. The second is a monoblock design of punches machined out of a single piece of steel. Choosing the type of configuration, the size of the tablet and the tool type (number of tips per punch size) have to be considered. Due to the more complicated machining operations, multi-tip monoblock tooling has been regarded as more expensive than an assembly design. However, current technological developments bring price equalisation to both constructions. Many companies prefer to use monoblocks because they are easier to set up and can be cleaned much more easily than assembly construction tooling, which must be disassembled for cleaning. One of the most interesting benefits of an assembly construction is that the tips are removable, making the replacement of damaged punch-tips possible. Of course, replacement a damaged tip for a completely new one is risky, as the wearing of the remaining tips can lead to differences in the working lengths in assembly, which eventually
Capacity increase factor
may cause the rejection all tablets produced in the station. That is why circulating the spare tips during the set lifetime to keep the same wearing level is of great importance. With the solid monoblock design, broken tips in this case require the replacement of the complete multipunch. The latter is much more expensive than replacing a single damaged punch tip.
Table 1. Romaco Kilian KTP 720X press capacity (based on data published by producer)
Table 2. Capacity increase factor for different multi-tips
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What lies in store for the future of research tabletting equipment.
n the last 15 years the offer of research tabletting equipment has evolved at an increasing pace, catching up with the evolution of production presses.
Reaching all the desired goals of formulation scientists on a research press had previously been impossible until the beginning of the century. The technical constraint implied a trade-off in order to get strong and accurate data like force | displacement | die wall pressure out of a small sample at a high compression speed, and in a clean and easy manner. Historically, research equipment has been evolving around slow single-punch equipment, â&#x20AC;&#x153;eccentric pressesâ&#x20AC;?, which are easy to instrument and well adapted to early stage. This is the oldest and still frequently used solution you will encounter in every laboratory and university in the world. The most famous being the Korsch EK0/XP1 family which have been heavily copied around the world. With a single punch, this type of equipment can produce tablets suitable for consumption. The compression event being relatively slow ensures good tablet cohesion, hiding potential issues appearing at high speed. As development was advancing, formulation scientists were then moving to a downsized rotary press (8-10 punches), if enough powder was available, usually after several years of process. They were trading speed of compression for accuracy of data acquisition. In that trade-off, the speed sensitivity information is invaluable and so is measuring the benefits of pre-compression on tablet quality. In addition, small rotary presses can produce small to medium size batches fairly rapidly using similar punches than production, but not with a tablet quality comparable to large scale production speed. The most famous being the RIVA Piccola and Korsch XL100. Both these machines can create tablets fitted for consumption and despite their limitations, these technologies represent the largest share of R&D tablet press market in volume. In both cases, copies and exotic sourcing provides equipment for the most cost conscious customer with various success. Alternatively, scientists and academic researchers went one step further, trading ease of use and good manufacturing practices (GMP) against an even higher speed of compression and a very consequent budget with hydraulic-actuated equipment. Still, these solutions were not satisfactory, and some companies tried to fill the gap with interesting concepts with various new benefits but also new trade-offs. Some laboratory and academics went with custom-made concepts designed to fit their needs but which were not always easy to maintain in the long run.
Author: Bruno Villa, general manager at MedelPharm
ORAL SOLID DOSAGE SUPPLEMENT
Reaching all the desired goals of formulation scientists on a research press had previously been impossible until the beginning of the century.
The appearance of standard, easy to use, mechanical equipment combining ease of use, quality of instrumentation, high speed tabletting, and small batch production has convinced scientists of this new approach at an affordable budget. The STYL’One Evolution has fulfilled this vision with an even more complete offer, of instrumentation for research, of accessories for production and ﬂexibility for marketing creativity. Research scientists enjoy high precision measurement with scalable sensitivity for multilayer tamping, different force feeding system for the most difficult ﬂowing powder, production rotary press simulation as well as dry granulation/roll compaction simulation for ensuring robustness of formulation. The same equipment is used with production in mind including external lubrication capacity or weight regulation with tablet rejection. c These batches of 10 or 20,000 tablets per day are real prototypes of a press running at 400,000 tablets per hour bearing in mind that 50 punches produce 50 times more than a single one! However, these batches are useful in orphan drugs production or oncology with full containment application. Using a similar concept and based on the technology of “Electro mechanical actuated equipment”, we now see a new generation of more affordable, benchtop equipment answering the needs of USP 1062 requirements and replacing both the historical single punch eccentric press and small rotary research press efficiently. Being even more affordable and easier to handle, this equipment can be expected to rapidly replace the classic solutions in quality-driven formulation laboratories. The only limitations are the production capacity of a single punch press and medium speed of compression. What do we have to expect in the near future? This niche market of research tabletting instruments is evolving fast, pushed by innovation and competition. We expect new players entering that segment now that the demand for these new technologies has been created and acknowledged. Meeting the stringent requirements is still a challenge to be overcome. We also see growing interest for purely mathematical models (DEM/FEM). Computers following “Moore’s’s law” will offer even more calculation capacity for these models making them more detailed and available to a larger group of scientists. At one point in time, however, we will be back to square one: powder has to be put into a die to make tablets to confirm the mathematical model.
Tabletting taken to the next level â&#x20AC;&#x201C; automation not only increases efficiency, but also patient safety. Developing beyond your expectations!
Author: Karen Rossington, Contec
How the GMP Draft Annex 1 will impact cleaning and disinfection.
leaning and microbial contamination control are critical focus areas in the pharmaceutical industry. Robust cleaning and disinfection programmes are needed to meet the required cleanroom microbial grades, to prevent cross contamination and microbial contamination of products. Indeed incidents of contaminated products entering the supply chain with devastating consequences have happened in the last eight years. The manufacture of medicines in the EU is governed by EudraLex Vol 4 Good Manufacturing Practice and each country in Europe takes the legislation into their own guidance.
rewritten and now features new and expanded topics, with the concept of risk management embedded throughout. Thousands of comments were returned from industry and industry groups in response to the draft. CONTAMINATION CONTROL STRATEGY One of the main documentary requirements of the new draft is the requirement for a holistic contamination control strategy (CCS).
ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS EU Annex 1 specifies guidance for the manufacture of sterile medicinal products and was first issued in 1989. With no complete review of the annex having been carried out for over 10 years, a complete rewrite was needed. The annex needed to catch up with both changes in sterile manufacturing technology and significant updates in regulatory expectation.
This document, either in one master document or separate related documents will reflect a site-wide strategy for minimising contamination. Whichever way is chosen, it must be a “living” document, which is kept up to date throughout the life cycle of the facility. For established facilities it probably already exists even if across separate documents and the manufacturer should try to include links and references in order not to rewrite all qualification documents. New facilities should start the CCS as early in the process as possible. Ideally it would form part of the design process and be included in URS and DQ documents.
Therefore, in December 2017 the European Commission via a GMP/GDP working group produced a draft of Annex 1. The document was completely
The draft states that “a contamination control strategy should be implemented across the facility in order to assess the effectiveness of all the
control and monitoring measures employed.” The main elements will include amongst others, design of plant and process, equipment and facilities, process risk management and cleaning and disinfection. CLEANING AND DISINFECTION The references to cleaning and disinfection have been expanded. The terminology of “cleaning” has been replaced with “cleaning and disinfection”. The text notes that “for disinfection to be effective, cleaning to remove surface contamination must be performed first”. This clarifies current best practice that cleaning and disinfection are two distinct activities trying to achieve different things. Cleaning is the removal of non-viable contamination and disinfection is “the process by which surface bioburden is reduced to a safe level or eliminated.” Many common and well used disinfectants leave significant residue on a surface, which can subsequently have a detrimental effect on the effectiveness of the disinfectant used. This is acknowledged in the new draft - “cleaning programs should be effective in the removal of disinfectant residues.” There are disinfectants available which do leave minimal to no residue, or which have residues which are free rinsing or easily removable.
ROTATION Regulatory guidelines are currently not aligned on the subjection of rotation and the number of disinfectants which need to be used. The US FDA, Japan and the Brazilian Health Regulatory Agency don’t specify and expect it to be based on a review of EM data. EU GMP annex 1 previously stated that “more than one type of disinfecting agent should be employed” and this is repeated in the draft. In line with other regulatory guidance the phrase “include the periodic use of a sporicidal agent ” has been added.
to be effective for the duration of their in-use shelf life.” This will be relevant not only for dilutions made from concentrate but also RTU trigger sprays and presaturated wipes. Efficacy testing will be required for not only the unopened product at the end of shelf life but also for the product during its in-use period. It’s expected that work will be carried out on isolates and surfaces that are specific to the individual facility. The draft annex includes the phrase “taking into consideration appropriate contact time and the manner in and surfaces on which they are utilised.”
If the risk management approach of the rest of the guide is applied, the number and frequency of disinfectants to use would be decided upon reviewing the trends of the environmental monitoring programme and periodic auditing of the cleaning and disinfection process, rather than an edict to rotate two different disinfectants. Discussions with two MHRA inspectors confirmed that if environmental results/ trends are under control, there would be no stipulated need to have achieved this using a rotational disinfectant programme.
This point is reinforced further: “Disinfectants should be shown to be effective when used on the specific facilities, equipment and processes that they are used in.” As well as standard lab testing on EN surfaces and with ATCC organisms, it is now clearly stated that work needs to be carried out on surfaces from the facility. The disinfectant needs to be shown to be effective against house isolates, these can change seasonally but will be shown by EM trends. Annex 1 now clarifies that “if microorganisms are detected in a grade A or B zone, they should be identified to species level."
Many facilities will routinely use a broad-spectrum disinfectant in rotation with a sporicide kept for intermittent or action point use. This is mainly due to the corrosive or aggressive nature of many sporicidal biocides rather than any concern over resistance. The more recent availability of highly effective cleanroom sporicides with no classified hazard may change this approach. DISINFECTANT QUALIFICATION The draft version of Annex 1 gives some clear guidance about the validation of disinfectants; “disinfectants should be shown
Consideration should also be given to the identification of grade C and D contaminants, this requirement should be defined in the CCS.” It continues to state that “disinfectants and detergents used in Grades A and B should be sterile prior to use.” SO WHAT NOW? The annex is still at a draft stage and there has been a call for a further consultation phase. The Implementation Working Group met in September and it's likely an amended draft will be sent out for another consultation. However, there is a widely held view that the general direction of travel shown in the document will not change. It would be prudent to plan ahead with any disinfectant validation with these core principles in mind as it is likely that many will appear in the finished document.
Many common and well used disinfectants leave significant residue.
TESTING & INSPECTION — SPONSORED WHITEPAPER
Whitepaper Conﬁrms Sepha VisionScan is Non-Destructive Leak Test Method
r Dorian Dixon, packaging specialist and senior lecturer in the School of Engineering at Ulster University, has published a new whitepaper that confirms the Sepha VisionScan is a non-destructive method to test the integrity of pharmaceutical blister packs. A stability study was conducted to test the hypothesis that there is no significant increase in the moisture status of tablets inside a blister pack inspected by the VisionScan test method, compared to blister packs in the control group. These findings will interest those in the pharmaceutical packaging industry as the non-destructive claims of the Vision with Vacuum method are now backed up by independent, statistical data. This gives companies that are considering alternative solutions to destructive methods including blue dye, a validated and deterministic solution that will enable them to reduce production cost, as the packs that passed the test can be returned to the line and material and product disposal / incineration cost will be vastly reduced.
SEPHA VISIONSCAN The VisionScan, developed by leading engineering company Sepha, tests the integrity of blister packs using vision and vacuum technologies. The method works by creating a vacuum around a blister pack while a high-resolution imaging system monitors changes in individual blister pockets. Any difference in pocket shape which deviates from the expected behaviour when establishing the vacuum, or during the dwell time of the vacuum, indicates leakage of air from the blister pack. The tool-less system can identify leaks in individual pockets down to 7µm and offers manufacturers a nondestructive, deterministic, reliable and repeatable solution. STABILITY STUDY To test if blister packs inspected with the Sepha VisionScan are in any way comprised by the test method itself, a stability study was conducted by independent research company Relequa. Using its Moisture Profiling™ technique, the company investigated the barrier performance of blister packs made with different material
types, by measuring the moisture levels of the tablets over a 12-week period. A breach of seal integrity will expose the tablets to external humidity which will result in higher moisture uptake. Xylitol tablets were sealed inside blister packs with three different material types including: 1) PVDC coated PVC blister sealed with aluminium 20µm hard lidding material. 2) Aclar® (PVC/PE/PCTFE) blister sealed with aluminium 20µm hard lidding material. 3) Aluminium cold formed blister sealed with aluminium foil (Alu/ Alu) comprising of a polyamide/ aluminium/PVC laminate. For each material type, the blister packs were split into a group of packs inspected with the Sepha VisionScan and a control group not inspected with the VisionScan. All samples were then aged for 12 weeks at two elevated humidity conditions (25°C/60%RH and 40°C/75%RH). At different time points, tablets were removed from both the inspected and control blister packs and tested for moisture uptake. At the same time, positive control
packs with 15µm sized defects were tested to measure the effect of exposure to air on the moisture level of the tablets. RESULTS The results of the stability study show no significant difference in moisture uptake between the inspected and control blister packs of any of the three types. The tablets from all the blister pack types did show changes in moisture status over time, but the change was consistent for both inspected and control blister packs and were within the expected moisture transmission rate of the materials. For the positive control, it can be seen the WVEP was typically unreadable indicating the tablets had absorbed very high levels of moisture. CONCLUSION The above results show that the Sepha VisionScan leak test method, does not compromise tablets inside the inspected blister packs and confirms the Vision with Vacuum method truly is nondestructive. Dr Dixon comments: “In my previous whitepaper, a study showed that the Sepha VisionScan can identify 100% of defective pockets across a range of blister pack types. Adding the results of this new study proves
that the Sepha VisionScan is non-destructive and can offer a significant contribution to the quality control process of pharmaceutical packaging”. Sepha’s Head of Sales & Marketing, Paul Smith adds: “Although we have full confidence in our technique and system it is great to see the findings of the study confirm our hypothesis. Packaging integrity testing is an essential part of the packaging process, being driven by USP 1207 guidelines, CGMP and ASTM standards. While traditional, destructive methods are still within these guidelines, we see a trend in more companies looking for alternative solutions that have less environmental impact in terms of waste and that can reduce cost in terms of lost products, lost packaging materials and disposal/incineration cost. This new evidence can help these and other pharmaceutical companies as it proves the method does not negatively affect the product inside, enabling manufactures to reuse the products that passed the test and put them back on their line”. The whitepaper can be downloaded on: https://sepha.com/news/whitepaper/
TESTING & INSPECTION
A test of character How this new microscopy-based method can improve drug-polymer miscibility analysis.
new microscopy-based method – thermal analysis by structure characterisation (TASC) – saves time, improves sensitivity and significantly reduces the amount of material required for drug-polymer miscibility analysis. TASC looks set to become a standard screening test in early drug development. THE PROBLEM OF SOLUBILITY New chemical entities emerging from high-throughput screening programmes often exhibit unfavourable solubility properties, with some estimates suggesting that ‘approximately 60–70% of drug molecules are insufficiently soluble in aqueous media’1. Issues with poor solubility can also be seen with pipeline candidates once they progress through the formulation and the drug development pathway towards the clinic. As a result, the problem of solubility has been extensively studied, and formulators and drug development scientists are focused on finding novel ways to counter this undesirable characteristic. It is also no surprise that regulators have published a series of helpful definitions – for example, both the US and British Pharmacopoeias (USP and BP) define the solubility of drugs in seven categories, ranging from ‘very soluble’ to ‘practically insoluble’. In addition,
according to the Biopharmaceutics Classification System (BCS), drugs fall into one of four categories (I – IV) based on their solubility and intestinal permeability properties. DRUG – POLYMER FORMULATIONS Polymers are widely used in pharmaceutical solid dosage forms as functional excipients to create matrices in which the drug can be dispersed. Such ‘so-called’ amorphous solid dispersions (ASDs) have been shown to significantly improve the absorption of some poorly soluble drugs in comparison to the crystalline form of the drug2. The role of the polymer is to stabilise the amorphous form of the drug by reducing its molecular mobility and hence preventing it from crystallisation. In recent decades, ASDs have become a common formulation strategy to increase the bioavailability of poorly water-soluble compounds.
Authors: Duncan Stacey, sales & marketing director at Linkam Scientific & Sheng Qi, reader in pharmaceutics at the School of Pharmacy, University of East Anglia
To successfully formulate such products for drug solubility enhancement, the drug needs to be highly miscible with the polymer3. However, the preformulation stage of screening suitable polymers is often a lengthy process, requiring the use of a range of semi-empirical, theoretical and experimental methods. Drug–polymer miscibility is a critical parameter that has been shown to affect, for example, physical stability during storage, and dissolution rate of the final formulated product. The prediction of drug–polymer miscibility using theoretical considerations has been widely reported in the literature, and many experimental screening methodologies have been developed to assess individual drugs.
Assessment of drugpolymer miscibility is 20-40 times faster using TASC than with the conventional DSC methodology, opening up the possibility for highthroughput screening.
TESTING & INSPECTION
Nevertheless, there remains a significant need for additional rapid and sensitive analytical approaches that can be applied early in the drug development process – where the amount of drug material is often severely limited. Now, a new, simple hot stage microscopy-based method – (TASC) – has been successfully used to screen the miscibility of drug-polymer combinations. A NEW ANALYTICAL APPROACH TASC is a recently developed thermal imaging tool that can be used to study behaviour such as melting and thermal dissolution. As applied in the study described in this article, it is used to investigate changes in the features of crystalline drug particles as they are heated on a microscope slide in a linear fashion and melted on a thin layer of the polymer of interest. Dr Sheng Qi and her group at the University of East Anglia (UEA) have a strong interest in ASD development and were seeking a new method for estimating drug-polymer miscibility. They have used TASC to develop this new application working closely with Linkam and professor Mike Reading. For all the experimental work, a Linkam MDSG600 motorised heating/freezing stage, was used, connected to a Linkam imaging station equipped with reﬂective LED light source and a 10x magnification lens. The stage is motorised in X and Y directions by precision microstepped motors that give micron repeatable position resolution and position recall. This enables a sample to be mapped, and positions of interest located so that temperature-controlled experiments can be carried out
at those points. The accuracy and control of temperature (from < -195°C to 600°C) means that users can characterise ﬂuid inclusions to better than 0.1°C and hold a stability of 0.001°C. The new TASC method was compared to what is currently the most widely used method – differential scanning calorimetry (DSC). DSC measures the melting point depression of a crystalline drug due to the presence of a polymer, reducing the chemical potential of the drug at melting. This reduction in chemical potential is an indicator of drugpolymer miscibility. Although the method has proven to be reliable, it has several drawbacks for routine screening. First, it is extremely time consuming and the accuracy of the estimation of miscibility is extremely dependent on the heating rates. A complete description of the experimental protocol and a full discussion of the results can be found in a recent publication 4, 5. To verify the relevance and comparability of the new method, a large number of TASC data sets detailing the measurements of the crystalline drug particles melting on top of thin films of a wide range of typically used polymers - in solid dispersion formulations, was generated. The full TASC plots of all drugpolymer pairs were analysed using principal component analysis (PCA) instead of comparing the depressed onset of melting as a single point measurement. The PCA results confirmed the ability of TASC to sort the drugpolymer combinations based on the degree of the melting depression, which is directly related to the miscibility of the
drug in the polymer and validates TASC as a useful and practical screening method of drug-polymer miscibility. CONCLUSION A new, rapid drug-polymer miscibility screening method based on TASC can give scientists the ability to quickly eliminate unsuitable candidate excipients. TASC is 20-40 times faster than conventional DSC methodology for detecting melting point depression. Important for early formulation and development stages, the new method provides actionable data from significantly less drug – only 1/1000th of the amount of material is needed to make the analysis. Compared to the current DSC methodology, the new TASC analysis also showed an increase in sensitivity.
1. Gupta et al., Formulation Strategies to Improve the Bioavailability of Poorly Absorbed Drugs with Special Emphasis on Self-Emulsifying Systems. ISRN Pharmaceutics: 2013; 2013 2. Jermain SV, Brough C, Williams RO. Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update. International Journal of Pharmaceutics. 2018;535(1):379-92. 3. Frank DS, Matzger AJ. Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality. Molecular pharmaceutics. 2018;15(7):2714-20. 4. Alhijjaj M, Belton P, Fábián L, Wellner N, Reading M, Qi S. Novel Thermal Imaging Method for Rapid Screening of Drug-Polymer Miscibility for Solid Dispersion Based Formulation Development. Molecular pharmaceutics. 2018;15(12):5625-36. 5. Thermal Analysis by Structural Characterization (TASC) as a novel method for assessing heterogeneity in complex solid pharmaceutical dosage forms 6. Alhijjaj, M., Reading, M., Belton, P. & Qi, S., 3 Nov 2015, In : Analytical Chemistry. 87, 21, p. 10848–10855
Counting the cost of blue dye testing
Packaging integrity testing is an essential part of the blister packaging process, being driven by USP 1207 guidelines, cGMP and ASTM standards. In line with new regulatory guidance, the Sepha VisionScan offers a deterministic and objective, cost saving alternative to traditional and probabilistic methods like blue dye. The non-destructive VisionScan method does not impact the integrity of inspected blister packs, enabling manufacturers to reuse the products that passed the test. To learn how the VisionScan can help you reduce cost, reduce waste and improve the quality control process of your blister packaging line, call us on +44(0)28 9048 4848 or visit sepha.com
WHITE PAPER New study proves Sepha VisionScan is non-destructive Download on sepha.com/news/whitepaper
FROM THE FACTORY
Hiding all away Why tapping into the hidden data of a manufacturing plant might not be as diﬃcult as perceived, if the latest manufacturing operations management (MOM) solutions are deployed correctly. Author: Gero Lustig, global business manager, pharma and life sciences ABB
fter reaching the patent cliff, many pharma companies are now turning towards improving their overall competitiveness. Today there is an increased focus on bringing products to market quicker while maintaining profitability in a regulated environment. Achieving these goals is helped with the arrival of smart sensors and digital control systems. These devices give access to an abundance of data. The challenge facing manufacturers is a lack of know-how for converting this data into usable information. This creates a scenario of data richness/ information poverty. What is often missing is the ability to connect the data in a manageable way, without the need to maintain individual interfaces. This is the art of digitalisation. Many solutions for the pharma industry are not fully integrated, requiring
high efforts in engineering and synchronisation of data between the manufacturing execution system (MES) and distributed control system (DCS). Especially in GMP productions this has a crucial inﬂuence on time to market, quality and profitability. The key to unlocking this hidden potential in a factory is to ensure that the interface between enterprise, manufacturing execution and control systems is a standardised solution - one that conforms to ANSI/ISA95 or ISA-95 standard. A very promising approach is a message-based interface which provides a powerful way to build an ecosystem, as opposed to point-to-point techniques. A message-based communications system sends and receives instructions and data such as quality, setpoint and consumption between the MES and the production equipment and is open to include other equipment
and components in a digital ecosystem. DISTRIBUTED CONTROL SYSTEM (DCS) A DCS enables compliance with the FDA’s 21CFR Part 11 through electronic batch recording, dual signature access, verification and audit trails, as well as certification, modelling and calibration tool integration. These solutions meet both GxP and nonGxP requirements. A DCS provides a consistent method for accessing enterprise-wide data and for interacting with multiple applications from any connected workstation in the plant or office. Powerful information management software collects, stores, retrieves and presents historical, process and business data to enhance the usefulness of data from all operations. MANUFACTURING OPERATIONS MANAGEMENT (MOM) MOM is a comprehensive, scalable and modular software suite maximising visibility, knowledge and control throughout the complete manufacturing domain and thus includes the elements of the MES, complementing
the real-time DCS. By turning large amounts of industrial data into actionable information, MOM software helps daily operations improve, by ensuring subsequent shifts run more efficiently than the last. MOM supports stakeholders working in the plant and business side of a company, by collecting, storing, combining and translating data from business, control and monitoring systems into actionable information. Such users work with the overall plant operations in the areas of data analysis, reporting, production planning/execution, quality and asset management. SUMMARY Few digital systems in manufacturing are fully integrated. Companies, suppliers and customers are not closely linked and departments don't always communicate with each other effectively. Yet the need for agile manufacturing where production can be adapted to meet specific customer demands, can only be achieved if everyone is talking the same digital language. MOM can deliver this through its end-to-end visibility of an entire production process.
4 - 6 March 2020 | Bangkok, Thailand Your Regional Pharma Forum
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DON’T TAKE THE BAIT.
Some tablet press OEMs use scare tactics to keep customers from using non-OEM replacement parts. At Natoli, we work hard to ensure that the quality and integrity of our parts meet—or exceed—OEM specifications. We spend hundreds of manhours each year testing the quality of our parts. We ensure your high expectations are met with premium products, substantial savings, and unbeatable delivery times.
Contact us today! NATOLI ENGINEERING COMPANY, INC.
natoli.com • email@example.com • +1 636.926.8900