Category Archives: Manufacturing

Method to predict drug stability could lead to more effective medicines

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Researchers have developed a new method to predict the physical stability of drug candidates, which could help with the development of new and more effective medicines for patients.

Researchers from the UK and Denmark have developed a new method to predict the physical stability of drug candidates, which could help with the development of new and more effective medicines for patients. The technology is being developed for use in the pharmaceutical industry in order to make medicines that are more easily released into the body.

The researcher’s method solves an old problem: how to predict when and how a solid will crystallise. Using optical and mechanical measuring techniques, they found that localised movement of molecules within a solid is ultimately responsible for crystallisation.

Solids behave differently depending on whether their molecular structure is ordered (crystal) or disordered (glass). Chemically, the crystal and glass forms of a solid are exactly the same, but they have different properties.

Molecules in the glass form are more readily absorbed by the body because they can dissolve more easily

One of the desirable properties of glasses is that they are more soluble in water, which is especially useful for medical applications. To be effective, medicines need to be water-soluble, so that they can be dissolved within the body and reach their target via the bloodstream.

“Most of the medicines in use today are in the crystal form, which means that they need extra energy to dissolve in the body before they enter the bloodstream,” said study co-author Professor Axel Zeitler from Cambridge’s Department of Chemical Engineering & Biotechnology. “Molecules in the glass form are more readily absorbed by the body because they can dissolve more easily, and many glasses that can cure disease have been discovered in the past 20 years, but they’re not being made into medicines because they’re not stable enough.”

After a certain time, all glasses will undergo spontaneous crystallisation, at which point the molecules will not only lose their disordered structure, but they will also lose the properties that made them effective in the first place. A long-standing problem for scientists has been how to predict when crystallisation will occur, which, if solved, would enable the widespread practical application of glasses.

“This is a very old problem,” said Prof Zeitler. “And for pharmaceutical companies, it’s often too big of a risk. If they develop a drug based on the glass form of a molecule and it crystallises, they will not only have lost a potentially effective medicine, but they would have to do a massive recall.”

In order to determine when and how solids will crystallise, most researchers had focused on the glass transition temperature, which is the temperature above which molecules can move in the solid more freely and can be measured easily. Using a technique called dynamic mechanical analysis as well as terahertz spectroscopy, Prof Zeitler and his colleagues showed that instead of the glass transition temperature, the molecular motions occurring until a lower temperature threshold, are responsible for crystallisation.

These motions are constrained by localised forces in the molecular environment and, in contrast to the relatively large motions that happen above the glass transition temperature, the molecular motions above the lower temperature threshold are much subtler. While the localised movement is tricky to measure, it is a key part of the crystallisation process.

Given the advance in measurement techniques developed by the Cambridge and Copenhagen teams, drug molecules that were previously discarded at the pre-clinical stage can now be tested to determine whether they can be brought to the market in a stable glass form that overcomes the solubility limitations of the crystal form.

“If we use our technique to screen molecules that were previously discarded, and we find that the temperature associated with the onset of the localised motion is sufficiently high, we would have high confidence that the material will not crystallise the following manufacture,” said Prof Zeitler. “We could use the calibration curve that we describe in the second paper to predict the length of time it will take the material to crystallise.”


Green Leaf Farms receives expanded cultivation site approval

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US manufacturer of cannabis products has begun operations in a state-of-the-art facility.

Green Leaf Farms, a US-based manufacturer of medical and recreational cannabis products, has received approval for expansion of its state-of-the-art facility and commencement of operations in an additional cultivation site.

Both sets of permits were tied together, the company said, due to the complexity of the structural and mechanical engineering that was needed to integrate the operations.

Based in Denver, Green Leaf Farms is a Division of Player’s Network (PNTV). The company took home the approved building permits for Phase Three development of its production and cultivation build-out, and officially began operations in an 8000 ft2 cultivation room. The site was completed last November.

According to PNTV, the expanded building has been designed to develop new products that will differentiate Green Leaf Farms in the emerging legal marijuana industry.

The expansion includes a state-of-the-art cleanroom, genetics lab, development laboratory, an extraction facility, a commercial kitchen, product development space, automated water purification including custom dosage and nutrient centre, a bio-testing facility, curing, packaging, and media centre.

“These design approvals will allow Green Leaf Farms to complete its build-out and become what I believe will be among the most advanced marijuana production and cultivation facilities in the world,” said Mark Bradley, CEO at PNTV.

“We have combined technology with an amazing, creative workspace that will encourage innovation, product development, differentiation and operating efficiencies.”

Green Leaf Farms has announced that further details of the expanded cultivation and manufacturing facility will be disclosed in due course.


Carrying the torch for scientific glassblowing

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Walk into a chemistry lab anywhere in the world and you are bound to find an array of glassware being used for all manner of experiments.

Glass has many properties that make it useful for scientific applications, such as good chemical resistance and being transparent and good for heat transfer.

But, despite the important role glass plays in science, the skill to develop the glassware is in decline. Scientific glassblowing has now been classed as an endangered craft by The Radcliffe Trust.

Becoming a skilled glassblower can take as long as a decade according to Radleys Workshop Foreman Paul Robson.

He has been glassblowing for 40 years but his interest in the profession goes even further back. He said: “It was a demonstration with the scouts that kind of stuck with me. Later I attended a course at Braintree Technical College.”

Talking about the craft, Paul said: “It has been in decline because things have changed. The demand for glassware has declined because of alternative materials being available and new chemistry techniques being used.”

“Training has changed, too, and there are no more courses at colleges. You have to go to a local company and learn on the job.”

To help tackle the issue, Radleys has just started its own training programme. Radleys foundations lie in glassblowing and it is still an important part of their business.

Craig Joyce is the first apprentice to join the training programme at Radleys, which takes about 3–5 years. He fell into the job by chance when he was looking for a change after years spent mostly working in customer services at bars and restaurants.

The position caught his eye when he was job hunting. He said: “It looked really interesting. I’ve always liked making things and I like doing DIY at home. I originally worked as a workshop assistant for 6 months before I was offered the apprenticeship.”

Now he is several months into the apprenticeship and is enjoying using his new skill. He said: “I think it’s amazing what you can do with glass and I really can’t speak highly enough of my mentor. I enjoy coming to work every day.”

Craig’s scientific glassblowing apprenticeship combines following a detailed training programme with actually manufacturing items and components for sale. He routinely makes test tubes and adaptors and is building the skill through training to make more complex equipment like jacketed coil condensers.

“It can be very frustrating if you don’t do something right. You can burn yourself, or the item you’re working on can easily crack, or break. You have to be patient, have your eye on the ball and pay attention to minute details.”

But he is spurred on by the thought that the glassware he produces helps scientists all over the world do critical work.

“I like to think what I’m doing makes a difference,” he said.

As well as working on orders from their glassware catalogue, Radleys also deals with bespoke requests from scientists who need a specific piece of glass to help them solve a problem. Paul said: “The bespoke requests are very technical, you have to be determined because it can take a long time to finish what you are making.”

Being dexterous and having the ability to concentrate are just some of the qualities scientific glassblowers need. “You have to be a certain sort of person; perseverance and concentration are important,” Paul said.

You also need to get your head around more technical aspects such as engineering tolerances. Scientific glassblowing doesn’t leave much room for error. If you are not precise, you could end up producing a piece of equipment that isn’t fit for purpose, or is unsafe to use.

Trainees start of by mastering basic techniques, such as joining two pieces of glass, which in itself can take a while. A lot of the process involves benchwork, which’s done by hand with a flame. This gives them a hands on feel for how glass reacts. For example, when it’s molten hot, it follows gravity.

They then learn how to put all that they’ve learnt together. Everything they make needs to go into an oven to be annealed at 570 °C.

They use the raw material Borosilicate, also known as lab glass, or Pyrex glass to laypeople. The glass is usually imported from Germany because they are world leaders in producing it.

A lot of Radleys glasswork involves making reaction vessels for pharmaceutical or polymer companies. Paul’s work as Workshop Foreman also includes dealing with health and safety, technical issues and quality assurance. He leads a team of eight glassblowers.

During his time as a foreman, he has noticed it has become difficult to find trainees. “There is so much scope for other things. Manual skills aren’t at the forefront of young people’s minds.”

But even with the rise of automation, the human touch is still needed for glassblowing. Paul said: “You can use machines for holding hot stuff but you still need a person to do the job.”

Paul estimates there are fewer than 300 glassblowers in the UK. The British Society of Scientific Glassblowers is one of the places the small community can turn to for support.

“They help if we are stuck and they have a good library of resources, including videos,” Paul said. At the society’s latest symposium, Radleys won best in show.

If you think you’ve got what it takes to become a scientific glassblower, and are interested in starting your career with us, then please get in touch. Radleys are always on the lookout for talented people to join our expanding business, from trainees to expert glassblowers.


Symbiosis Pharmaceutical Services opens US office

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Symbiosis Pharmaceutical Services, a Scottish contract manufacturing organisation (CMO) has opened an office in North America in response to continued demand from US-based biotechnology companies for its vial filling expertise.

The sterile filling specialist’s commercial site in Cambridge, Boston, MA, supports clients on both the East and West Coast, as well as giving the CMO a base for reaching new customers in this territory. The company is currently on a recruitment drive to strengthen its US commercial team.

Increased demand for both liquid and lyophilised formulations in injectable dosage forms at Symbiosis has been driven mainly by biotech firms looking for an outsourcing partner with small-scale aseptic manufacturing capabilities to support clinical trials.

Colin MacKay, CEO at Symbiosis Pharmaceutical Services, said: “Given Cambridge [Boston] is the epicentre of the global biotech community, it was the ideal location for us to open an office in the US. So far it has been a great success and we foresee that continuing as we continue to reflect the demand from US-based biotechnology firms looking for small-scale aseptic manufacturing resources.”

“Back in 2015, we took the decision to strategically focus on the North American market after we identified a surge in funding for early stage biotech companies, which are exactly the type of drug development company that are best suited to seek our manufacturing scale and specialist capabilities.”

“As expected, our expertise in filling biologic and small molecule products, combined with our ability to offer rapid access to sterile manufacturing slots, has been very well received by pre-clinical and phase I-II biotech and pharma companies, which has helped to fuel our steady growth.”

“Since strengthening our US-focused personnel and developing our relationships with networks like ISPE and MassBio, we have significantly grown our US client base, which is projected to account for around half of our revenues in 2017. Opening the office on the US East Coast has added to the success of the company’s growth strategy.”

For the last 12 months, Symbiosis has grown revenues by 40% and has also continued to recruit steadily, increasing staff by 30% to meet demand for its aseptic fill/finish service.

MacKay said: “At a macro level, demand for biologic and highly potent products is likely being driven by the increased emphasis on the development of treatments for small patient populations in the case of orphan indications, new oncology products requiring containment capabilities and novel tailored personalised medicines.”

“Those kind of products require specific GMP manufacturing skills for the small-scale production of sterile batches for clinical trials, hence the clear uptake in demand for what we do at Symbiosis.”


Sterling invests £6m in new milling micronisation and solid form facility

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Contract development and manufacturing organisation (CDMO) Sterling Pharma Solutions is investing £6 million into a new facility at its UK site to strengthen and expand its milling, micronisation and solid form capabilities.

The 40 acre site in Dudley, North East England, will meet growing demand for pharmaceutical API particle size control technology and expand Sterling’s laboratory capabilities to provide a full solid form offering including polymorph screening, salt selection, particle engineering and crystallisation scale-up.

Four new milling areas will house a range of new technologies, including mechanical milling, spiral jet milling and small lab scale trial mills. Supporting the CDMO’s expertise in handling potent and hazardous materials, the facility will also provide containment to handle OEB 4 classified molecules and offer ISO 8 cleanroom environments.

Kevin Cook, CEO at Sterling Pharma Solutions, said: “From our UK facility, we are building a global active pharmaceutical ingredient (API) services business with customers in the US, UK, Europe and Asia. This latest investment is an important step in bolstering our offering so we can cater for growing market demand, including the need for high potency capabilities to reflect the global drug pipeline.”

“We are proud that we can take products from proof of concept to commercial scale manufacturing all on one site and the new facility will strengthen our current offering by adding additional milling, micronisation and solid form capabilities.”

Established in 1969, Sterling’s site has a strong heritage in API services and a successful track record of compliance with both the MHRA and FDA. The investment forms part of a 15 month strategic development plan totalling almost £12m, which will also see the expansion of the CDMO’s GMP kilo laboratories and pilot plant.

Expected to be operational by mid 2018 the milling, micronisation and solid form facility will create more than 15 jobs in the next 18 months, bringing Sterling’s total workforce to around 400 employees.

Kevin continues: “Our strong growth can be attributed to a number of factors, including the emerging pharma sector in the US and big pharma demand for the complex and hazardous chemistries we provide. We have focussed our strategy on the diversification of our customer and product base, and have recently expanded our presence in the Asian markets including Japan. We will continue to invest to ensure we meet the diverse needs of our customers globally.”


New project to bring world-class medicines ‘smart’ packaging capability to the UK

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The Centre for Process Innovation (CPI), the UK’s technology innovation provider for process manufacturing, announced it has begun the first phase of its ‘Medicines Smart Packaging’ project.

This phase of the North East Local Enterprise Partnership (LEP) funded project, known as SmartMed, will begin the process of crystallising the needs for innovation in the smart packaging of medicines and medical devices leading to the creation of an innovation capability.

The healthcare sector is in the midst of change, driven by multiple factors including longer life expectancies, a rise in chronic disease and a shift in the pharmaceutical industry towards advanced and personalised therapies.

There is also an increasing number of people taking multiple medicines, putting pressure on the NHS to be able to track exactly where drugs are going and when patients are taking them.

With the Secretary of State for Health, Jeremy Hunt’s target for digital-led NHS treatment by 2018, there is increasing expectation on the sector to use technology, such as smart packaging, to address these issues.

Using smart packaging would also benefit organisations such as distribution companies, who could track and monitor medicines throughout the supply chain, as well as pharmaceutical companies who could use sensors to monitor environmental conditions during storage and delivery including temperature, humidity and damage, to ensure that medicines are effective when they reach the patient.

Smart packaging for medicines could feature printed sensors that can also be used to help with patient compliance. This is a major issue for healthcare, because patients that do not take their medicines as prescribed not only risk their health, but also contribute to significant economic losses for healthcare providers such as the NHS in the UK.

“From manufacture to clinical supply to patients, digital technologies and new types of material have the potential to revolutionise the way in medicines are packaged and therapies of all kinds are delivered. Innovation in this area can help to improve both the effectiveness and experience of treatments for patients,” said Richard Baker, Head of Policy and Strategy at the North East LEP.

“The North East has established strengths in technologies like printable electronics, product formulation and digital application which, if brought together, could make a step change in medicines delivery and also develop approaches of value to other industries such as food and consumer products. We are delighted to be working with CPI and other partners on this project, which will aim to ensure that the North East takes a leading role in this area.”

The Medicines Manufacturing Industry Partnership (MMIP), a partnership between the UK government and industry, has endorsed the creation of a national centre of excellence in packaging for medicines.

This will support the development of the next generation of packaging technology and the associated smart devices required for new and novel medicines, including specialist packaging needed throughout the manufacturing supply chain.

The proposed world-class centre of excellence would allow medicine manufacturing and medical technology companies to build their niche capabilities and differentiate themselves in the global marketplace, securing activity and creating jobs.

CPI will be hosting a series of workshops to speak to the pharmaceutical industry, distribution companies, NHS, pharmacies and patient groups to assess their need for these innovations and the proposed capability creation.

CPI is happy to hear from any companies or groups that may be interested in taking part in these workshops, please contact for more information.

“The project will focus on defining and crystallising the user requirements leading to a significant and globally recognised innovation capability in the North East, helping UK companies to stay at the forefront,” says Alex Cole, Centre for Process Innovation.


Fluence Analytics launches new patented protein and polymer stability monitoring product

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New Instrument Continuously Analyzes Protein and Natural Polymer Aggregation.

Fluence Analytics, a manufacturer of realtime, industrial and laboratory monitoring systems, today announced the launch of ARGEN, a patented protein and polymer stability monitoring product. By utilizing continuous light scattering measurements, ARGEN yields a unique information stream which reduces discovery and formulation and development times. For more than a year, Fluence Analytics worked with university partners, biopharmaceutical companies and industry leaders during beta testing to improve ARGEN’s measurements, user experience and software features.

ARGEN is engineered for precise, individual control of thermal and mechanical stressors of each of its 16 independent sample cells. By continuously analyzing the state of samples, ARGEN provides novel time series datasets with quantitative insights into the early detection of aggregation, degradation and particle formation. ARGEN allows users to swap samples in and out during experiments without affecting ongoing measurements in other cells. ARGEN data can also optimize lower throughput, standard characterization tests such as SEC.

“ARGEN’s proprietary technology was honed through years of laboratory experimentation and development,” says Michael Drenski, CTO of Fluence Analytics. “Today, ARGEN is the only instrument on the market that allows for the simultaneous, stressor dependent testing of 16 samples. This capability significantly accelerates research and development efforts for biopharmaceuticals and other materials.”

ARGEN uses Total Intensity Light Scattering to characterize the stability of proteins, polymers and other natural products by measuring changes in molecular weight. The instrument includes commercial control and analysis software that enables users to configure, monitor and manipulate experiment conditions in real time. The software also offers the ability to analyze past or current experiments and determine the aggregation rate of any sample.

“ARGEN is an excellent complement to historically mainstream techniques for monitoring and quantifying aggregation in the pharmaceutical industry and has become a mainstay in my laboratory,” says Prof. Christopher Roberts of U. of Delaware. Prof. Roberts’ group was an early adopter of ARGEN, using it to study proteins.

“I have searched more than a decade for an analytical tool to provide insight into both the mechanism and rate of protein aggregation. ARGEN is the first instrument that I have used which can detect early-stage aggregation in real time while providing aggregation information under both thermal and interfacial stress,” says Dr. Danny Chou, President of Compassion Biosolution. “Today, ARGEN is the most versatile protein analytical tool of which I am aware.” Dr. Chou is a veteran of the biopharmaceutical industry with more than 15 years of experience in protein formulation development, protein analytical technology and drug delivery.


Sanofi invests €170 million in vaccine production facility in France

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Sanofi is investing €170 million in expanding a vaccine manufacturing site in Val de Reuil, France.

The new facility will allow Sanofi Pasteur, the vaccines global business unit of Sanofi, to expand supply of VaxigripTetra® to up to 70 countries in six continents. The new quadrivalent influenza vaccine contains two A strains and two B strains of influenza virus, as per the World Health Organization recommendation.

The new Val de Reuil facility will  be the only site of its kind in France and Sanofi Pasteur remains the sole influenza vaccine producer in the country.

This investment is one of several major capital expenditures Sanofi has made in recent years to improve and expand its vaccine production capacities across France, the United States and Mexico.

Sanofi plans to complete the expansion by 2021, subject to relevant health authority approvals, and will begin producing vaccines in this new facility in 2022.

Philippe Luscan, Executive Vice President, Global Industrial Affairs, Sanofi, said: “This project brings together the expertise of our people with our leading industrial know-how and illustrates our commitment to manufacturing excellence solutions. Our investment underlines Sanofi’s intent to strengthen our industrial capacities in France as a major centre of influenza vaccines production for worldwide markets.”


FDA rejects Mylan and Biocon biosimilar, citing manufacturing issues

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A biosimilar from Mylan and Biocon has been rejected by the FDA because of manufacturing issues at a production plant in India.

The companies have filed a biosimilar of Amgen’s long-lasting white blood cell booster Neulasta (pegfilgrastim) with the FDA – but the regulator has rejected it, citing issues with the manufacturing site.

In a short statement Biocon, which partners with Mylan to produce biosimilars in the US, said the filing is due to be updated with data from the facility after recent modifications required by the FDA.

The FDA’s rejection letter did not raise any technical questions, Biocon noted.

It added that it did not expect the rejection to impact on the commercial launch timing of the biosimilar in the US.

In August, Biocon withdrew filings of two biosimilars in Europe, versions of Roche’s breast cancer drug Herceptin (trastuzumab) and Neulasta, because of regulators’ concerns over the manufacturing facility in Bangalore.

EU regulators required “corrective and preventive” actions at the plant before it is able to supply drugs to the EU market.

Inspectors from France’s regulator had been conducting a pre-approval inspection of the plant, which produces biosimilars of Herceptin, Neulasta, and Sanofi’s Lantus (insulin glargine).

The FDA also raised concerns earlier this year after inspectors found a range of problems including environmental monitoring and cleaning procedures.

Neulasta has been off-patent in the US for two years this month, but is still Amgen’s second-biggest seller after its inflammatory diseases blockbuster, Enbrel.

In the second quarter sales were down 5% compared with the same period last year, to $937 million because of lower demand.


Improving healthcare has led to a higher salt requirement

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The number of dialysis treatments is increasing across the globe, mainly due to an increasing number of patients and improved healthcare in many developing countries.

The main market for pharmaceutical grade salt lies in dialysis solutions. Supply has struggled to keep up with demand, which led to AkzoNobel expanding its production site in Denmark.

AkzoNobel’s Specialty Chemicals business completed the expansion of its production site, which supplies pharmaceutical grade salt to the healthcare industry, increasing capacity by 60%.

Located in Mariager, the products supplied by the facility are used as an active pharmaceutical ingredient in various applications, including intravenous solutions, insulin and baby food.

“Our facility produces the purest salt in the world,” said Nils van der Plas, General Manager of AkzoNobel’s Salt business, “this expansion will now enable us to serve a strong growing market worldwide.

“Following a year of detailed engineering, construction and testing, the Mariager site is now well positioned to continue capturing the organic dialysis market developments. This specific market is growing globally by 7 to 8% per year and is expected to continue growing at this pace for at least another generation.”

In addition to dialysis, pharmaceutical grade salt is also used as a base material for liquid medications and dietary formulations.