Press Room

Responsible for 39% of the nation’s total annual exports, the Irish pharmaceutical sector continues to expand its capabilities   Ireland’s life sciences sector is internationally renowned for its operational and innovational excellence, with 19 out of the top-20 global pharmaceutical and biopharmaceutical giants having a presence in the country. Overall, more than 85 pharmaceutical companies are currently operating in Ireland and the sector employs over 42,500 people. And this talent base is constantly expanding, thanks to continuous new investment into the sector. “We are the world’s third-largest exporter of pharmaceuticals and we have a good reputation for strong regulatory compliance and quality. Our regulators are seen around the world as some of the leading lights in setting standards. As a result, pharmaceutical companies in Ireland go beyond compliance, which gives them a competitive advantage,” says Paul Downing, general manager of Hovione, the leading international contract development and manufacturing organization (CDMO) that specializes in fully integrated innovative services for drug products, product intermediates and substances.    PAUL DOWNING GENERAL MANAGER, HOVIONE “Pharmaceutical companies in Ireland go beyond compliance, which gives them a competitive advantage.”   With state-of-the-art manufacturing facilities in Ireland, the US, Portugal and China — all of which have high regulatory compliance — Hovione has a global employee base of nearly 2,500 people and in its 63-year history has had more than 41 regulatory inspections from authorities such as the US Food and Drug Administration with no product recalls and no warning letters being issued. Something that Downing is exceptionally proud of. “We’re an expert organization with capabilities in technology transfer and new product introductions and, from a CDMO perspective, we’re recognized as a world leader in spray drying,” he says. “We’re also a progressive company and we go above and beyond compliance; we always want to learn and give our customers more, because customer satisfaction is at the heart of everything we do.” Hovione began its operations in Cork in 2009. Since then, it has quadrupled its Irish assets, client base, sales and employees, which has given it the right ecosystem to take on large customer projects. As with any industry, the digital revolution is changing all facets of the pharmaceutical business and Hovione itself has implemented a host of new digital tools at its Irish facilities in recent years. “One example of this is an electronic laboratory notebook, which is a digitalization of our core activities in research and development and our quality control laboratories. That has driven efficiency and standardization,” says Downing. “As a company, we have other global initiatives, including a plant data management system, which is a central hub for all our data on trends and information that allows us to analyze and share that data. “In addition, we’ve started to adopt a manufacturing execution system and are automating electronic batch records. That’s the journey we’re on. Here in Ireland, there are lots of advocates for industry 5.0. We’re watching that brief to see how it evolves and whether we can tap into that as well.”   Future growth of the biopharma industry Ireland’s pharmceutical sector began to become an international presence in the 1960s after the arrival of pharma giant Pfizer, which was followed by names like Merck, MSD, SmithKline, GSK, Eli Lilly, Bristol Myers Squibb, Alexion and Regeneron — and by 2021, the sector was generating over $85 billion a year from its exports. Investments continue to flood in to the tune of around $1-$2 billion annually, and this could soon increase, as the association that represents Ireland’s biopharma and chemical industry, BioPharmaChem Ireland —part of the wider trade body Ibec — has recently launched a five-year strategy to further develop the sector.    "We’re prioritizing skills and talent,” outlines Matt Moran, director of BioPharmaChem Ireland. “For example, we have established an apprenticeship program, which we work on with the government, that is non-traditional and vocational. In the past, companies would normally have employed university graduates, but now there is an opportunity for school leavers to work in the industry and acquire qualifications at the same time. We also operate an industry-led Skillnet training initiative, through which we arrange for training programs to be delivered to the industry to fill skill gaps. The association is also prioritizing the continued growth and competitiveness of all the sub sectors of the industry, including active pharmaceutical ingredients, biotech and finished products, states Moran, who adds: “Some of the newer areas we’re exploring at the moment are pharma 5.0, which involves empowering employees as well as deploying technology, sustainability in manufacturing, cell and gene therapies and very advanced therapeutics. We also want to grow our indigenous base of startups and to expand our footprint to include additional aspects of the industry, such as global business services, clinical research and more engagement research. That’s the future.”   Read the full article at    


Excellence in pharmaceuticals

Jun 30, 2023

Hovione has expanded its continuous tableting capacity with a state-of-the-art manufacturing facility at its site in Loures, Portugal. Portuguese pharmaceutical contract development and manufacturing company Hovione has built a state-of-the-art continuous tableting manufacturing facility at its existing site in Loures, Portugal, to expand its continuous manufacturing offering and services. The company invested $70m to develop the facility, which is part of its broader $170m investment programme to increase its production capacity by around 25% by 2023. The investment will enable Hovione to develop differentiated and empowering capabilities and assets to meet customers’ specific requirements for manufacturing oral dosage forms. The new drug manufacturing facility came online in September 2022.   Details of the pharmaceutical facility expansion Hovione Loures was expanded with a manufacturing building and eight-lab quality control facility. The company also upgraded its labs with the tools required to support the drug product lifecycle to ensure competency and capacity through research and development (R&D) to the production stage. In addition, it established an experienced, multi-disciplinary global team in continuous tableting to further improve its capabilities. Hovione has designed a commercial continuous tableting platform that facilitates key control requirements and offers operational ease, mechanistic modelling, and appropriate process analytical technology to its customers. The features of its quality system include automated in-process controls, real-time release deployment, and compliant digital infrastructure. These are designed to support the release of continuous tableting products. The company’s technology offers features and benefits such as faster development of simpler processes, rapid manufacturing of variable demand, strong control strategies and high process quality standards.   Details of Hovione’s existing site in Loures Hovione’s existing manufacturing plant at Loures has been operational since 1969 and has been continuously upgraded by adding new facilities. The plant was first approved by the US Food and Drug Administration (FDA) in 1982 and is inspected regularly. The manufacturing plant supports the development, piloting and full commercialisation of drug substances and product intermediates. It has an extensive capacity of 430m³ of vessels, ranging from 50lt to 14,000lt, along with a complete range of spray dryers with sizes ranging from lab-scale to industrial sizes. The site also features highly potent active pharmaceutical ingredient (API) handling, cryogenic, hydrogenation, corticosteroid, and potent spray-drying capabilities. It is staffed by highly skilled and experienced process development and analytical development teams that assist with the drug substance and particle engineering disciplines. The plant and the quality control labs operate 24 hours a day, seven days a week. The Loures site has been certified by the Health, Safety and Environment Management System in compliance with OHSAS18001 and ISO14001. It is also a certified Authorised Economic Operator.   Marketing commentary on Hovione Established in 1959, Hovione is an integrated contract development and manufacturing company (CDMO) with more than 60 years of experience. It offers services for drug substances, drug product intermediates and drug products. The company currently operates four FDA-inspected facilities in the US, China, Ireland and Portugal, as well as development laboratories in Lisbon, Portugal, and New Jersey, US. The opening of Hovione’s first manufacturing plant in Loures, Portugal, in 1969 was followed by its second manufacturing site in Macau, China, in 1986. The company subsequently opened plants in New Jersey in 2001 and Cork, Ireland, in 2009. Under the company’s $170m investment programme, Hovione is investing $50m in its manufacturing facility in East Windsor, New Jersey. This expansion will add two spray dryers to the facility and triple its capacity, as well as expand its capacity for research and small-scale API production. The company is investing a further $50m to add a spray dryer and upgrade its high-potency API production in Cork, Ireland, as part of the investment programme.   Read the full article at      


Hovione’s Continuous Manufacturing Facility, Loures, Portugal

Oct 10, 2022

In this episode of the Drug Solutions Podcast, Feliza Mirasol, science editor, discusses the changing parameters for oral solid dosage forms as driven by APIs and new chemical entities with Deepak Thassu, vice-president R&D and Regulatory Submission, LGM Pharma, and Marco Gil, senior vice-president of Sales & Marketing, Hovione.     Oral solid dosage forms are a dynamic, ever-changing landscape, driven primarily by more highly potent new chemical entities (NCEs) that require particularly specific formulations. In this Drug Solutions Podcast episode, Deepak Thassu, vice-president R&D and Regulatory Submission, LGM Pharma, and Marco Gil, senior vice-president of Sales & Marketing, Hovione, discuss how, in addition to NCEs, older, more established APIs are finding renewed life because these APIs are continually enhanced to have higher potency at lower doses, changing the way their formulation is handled. Looking toward the future, the bio/pharma industry is also tackling the issue of converting large-molecule (biologic) drugs into orally administered dosage, rather than parenteral administration, for increased patient compliance. Among the issues discussed are: The latest developments in oral solid dosage technology and methodologies What remains the biggest challenges in formulating APIs for oral solid dosage administration How the industry is tackling the issue of enhancing bioavailability through better oral solid dosage formulations/technologies, etc. Some “best-practice” approaches to formulating oral solid dosage products   You might be interested in: Learning more about our optimal solutions for complex drug products Making your drug soluble with Dispersome® technology    


Drug Solutions Podcast: The Evolving Landscape of Oral Solid Dosage Forms

Jun 21, 2022

Supply chain discipline has paid off for contract development and manufacturing organizations amid an ongoing crisis by Rick Mullin   The time to repair the roof is when the sun is shining,” said President John F. Kennedy in his 1962 State of the Union address. The metaphor rang true during the Cold War as an admonition to guard against complacency in times of prosperity. More broadly, it registered as the kind of sensible advice that people during all times frequently ignore. At its outset, COVID-19 proved a case in point, as a containable outbreak spread relentlessly despite years of warning from public health authorities of an imminent pandemic. Yet the crisis also went on to showcase instances of preparedness, foremost of which was the rapid development and deployment of effective vaccines. The pharmaceutical industry emerged as a hero of the pandemic. Less obvious but just as important was the rapid response of the pharmaceutical services industry, which does much of the heavy lifting for drug companies, working behind the scenes to coordinate the shipment of raw materials, produce active pharmaceutical ingredients (APIs), and formulate finished products within a complex international supply chain. The sector had been on a 10-year profitability streak before 2020 and has done even better during the pandemic. It navigated challenges posed by COVID-19 on the strength of previous improvements to supply chain management and a yearslong campaign of diversifying services and expanding manufacturing capacity. Those proactive measures put the industry in a strong position when the storm hit early last year. Indeed, industry watchers say the drug services sector displayed enviable resilience over the past 18 months. “There were issues—I don’t think there were any questions about that. But I think we knew how to deal with it,” says James Bruno, president of the consulting firm Chemical and Pharmaceutical Solutions. Unforeseen transportation holdups caused problems early on, as did rattled production schedules when companies found they suddenly needed to produce large volumes of APIs such as remdesivir and dexamethasone on a very short timeline. But companies were able to work out the supply chain snags, Bruno says.   Related: European Consortium Seeks Autism Drugs Roger Laforce, an industry consultant based in Switzerland, notes that as vaccines advanced toward emergency approval last year, several service companies, often called contract development and manufacturing organizations (CDMOs), were in a position to make vaccines happen. The big Swiss firm Lonza, for example, relied on a 2018 investment in prebuilt manufacturing shells at its facility in Visp, Switzerland, to meet a tight deadline for bringing production of the active messenger RNA ingredient in Moderna’s vaccine on line. “People who’ve invested in operational excellence—having good supply chain operations and good management practices around their inventory—have actually been able to do pretty well,” says Wayne Weiner, who heads the consulting firm PharmaTech Solutions. “The other thing CDMOs have done a good job at is managing protection for their workers—keeping them safe so they could actually come in and run the plants.” The pandemic also served to illustrate a dilemma that CDMOs have been bringing to the attention of governments in the US and Europe to little avail—heavy dependence on China for antibiotics and other generic drugs. The global drug supply chain emerged as front-page news when the Donald J. Trump administration considered a “buy American” executive order for pharmaceuticals, and the US government allocated funds to support domestic production of critical drugs. The European Commission also turned its attention to domesticating drug supply. And even as the Joe Biden administration attempts to undo much of the legacy of the Trump administration, the focus on the drug supply chain remains.   ABSORBING THE SHOCK “The CDMO is the shock absorber for the pharmaceutical industry,” says Guy Villax, CEO of Hovione, a Portuguese CDMO with facilities also in China, the US, and Ireland. “Whenever there is a problem, they ask us to fix it.” When an unforeseen requirement for large-scale vaccine manufacturing emerged last year, for example, “the CDMOs got their act together,” Villax says. And they did so under duress. Villax says that 150 workers at Hovione facilities have tested positive for COVID-19 since the pandemic began. “Every single person has recovered,” he says. There were transportation snags, especially in China, when the pandemic hit, but those were sorted out before long. And business is “very good,” Villax says. “I remember in April and May of last year, I had a torrent of calls from journalists really keen that I could give them evidence so they could write stories to show that the supply chain was a catastrophe and all the pharmacies would be empty in a short time,” he says. “In fact, none of that happened. I think the supply chain is somehow really resilient.” One reason for the industry’s preparedness was its ongoing investment in new production capacity well before the pandemic hit. Hovione came into 2020 with a new research center in Lisbon, Portugal, and plans to open a manufacturing building in Loures, Portugal, with new reactor capacity, Villax says. And the firm plans further capacity increases. The Swiss CDMO Siegfried is among the firms that landed contracts serving vaccine makers. Marianne Späne, chief business officer, says Siegfried had to build a new production line from scratch at its site in Hameln, Germany, to fill and finish vials of Pfizer and BioNTech’s vaccine. While the company had fill-and-finish capacity, “we had never done vaccines, and in record time we were able to build it up, to validate the process,” she says. Bringing production on line was a matter of close collaboration with Pfizer and BioNTech, Späne says, adding that Siegfried also has a contract to provide Novavax with fill-and-finish services for the vaccine it is developing. And as it did before the pandemic, Späne says, Siegfried is continually expanding capacity for small-molecule drug manufacturing at all its sites—in Switzerland, Germany, France, Spain, the US, and China—often by debottlenecking or streamlining processes to increase output. The CDMO is the shock absorber for the pharmaceutical industry. Whenever there is a problem, they ask us to fix it. - Guy Villax, CEO, Hovione   Read full article at C&    


How the drug services industry found itself prepared for a pandemic

Sep 27, 2021

When running manufacturing equipment continuously, rather than in batch mode, operators should consider what cleaning practices need to be adjusted. FDA’s draft guidance for continuous manufacturing of small-molecule, solid oral drug products notes time between equipment cleanings can depend on a variety of factors, such as running time or amount of product (1). When considering equipment running continuously, cleaning might be automated with clean-in-place (CIP) elements or involve full disassembly with manual cleaning, say Paul Lopolito, senior manager, and Beth Kroeger, senior manager, in Technical Services at STERIS. “Using cleaning agents or cleaning tools requires a cleaning validation to demonstrate removal of these elements to acceptable limits. The calculation of accepted limits may utilize traditional uniform carry-over models or non-uniform residue or stratified residue models,” say Lopolito and Kroeger. These models are used because residue can become concentrated as it moves through the connected equipment (2). Other considerations with continuous manufacturing are addressing microbial issues and process intermediate degradant residue. “These residues may present a cross-contamination risk to the next lot or batch of product. If these hazards exist, then it is warranted to perform the appropriate level of cleaning and cleaning validation to mitigate the risk,” they conclude. Most lines for continuous manufacturing of solid-dosage drugs today are cleaned in a “clean-out-of-place” mode, but a complete CIP solution would improve cleaning turnaround times, notes José Luís Santos, director of Hovione’s Continuous Tableting Center of Excellence, who suggests that end-users would need to work closely with equipment vendors to develop such a system for a full process train. Hovione’s contract development and manufacturing facility in New Jersey has been running continuous solid-dosage drug manufacturing equipment for a few years and working to streamline the manual cleaning process. “The magnitude of the task of changing over a continuous manufacturing rig from one product to the next is very large,” explains Santos. “From a unit operation standpoint, there are no major differences from batch equipment, and in most cases the equipment is exactly the same at the unit operation level. The differences between continuous and batch have to do with the transition sections in between [the integrated] unit operations. Depending on the actual setup of the continuous rig, these transitions can be comprised of large pipe sections, in some cases with pass-through connections between floors. Also, such transitions might comprise large number of PAT instruments to measure, for example, powder level or quality attributes of the material being processed. Thus, continuous rigs have additional parts to be cleaned. If the continuous manufacturing line is entirely ‘clean-out-of-place,’ the extra equipment also poses the added challenge of keeping track of many equipment components of all different sizes as they move through the cleaning operation and subsequent reassembly; the learning curve associated with these operations may be much longer than comparable operations of individual batch manufacturing units.” Santos notes that, “While in batch, each unit operation is operated independently, in separate rooms, and typically staggered in time; in continuous, the full set of equipment is used during manufacturing, typically with higher asset utilization. Hence, from a planning standpoint, the cleaning of continuous rigs requires significantly more resources, effort, and cleaning capacity (e.g., additional wash rooms and footprint for parts staging and storage) to address the full set of equipment without impacting productivity of the area or overall equipment effectiveness (OEE).” A cleaning best practice applied at Hovione was to allocate enough resources to address the manual cleaning process—including a large team of operators and enough space to do the cleaning—and then to optimize with shop-floor operational excellence tools, says Santos. “In our experience, the use of Lean [management tools] brought not just the acceleration of the operation, but also an increase of the comfort levels of the team members involved with the cleaning. An otherwise huge challenge could be decomposed into smaller, more manageable, blocks of work, with a clear visibility of how the work was progressing during each day of the operation,” he explains. Another best practice is to maintain control of the organization of equipment components from disassembly through assembly. “For example, use specific bins to contain disassembled components from specific (predefined) sections of the line so that those components, which make up those specific line segments, stay together throughout the cleaning process. Organization is critical to reduce lost and mixed-up equipment components among thousands of such components,” Santos explains.   Considerations for cleaning biopharmaceutical process equipment In biopharmaceutical manufacturing, process intensification can change the way the equipment is used and thus affects cleaning methods. Beth Kroeger and Paul Lopolito, senior managers for Technical Services at STERIS, shared some points to consider in an interview with Pharmaceutical Technology. Click to read: “Considerations for Cleaning Biopharmaceutical Process Equipment”. PAT considerations Process analytical technology (PAT) sensors in the equipment are a crucial part of continuous manufacturing systems, but, in some cases, such as near infrared (NIR) probes, they may be fragile and require special handling during assembly and disassembly, notes Santos. He adds that it is important to use the PAT vendor’s procedures for proper cleaning and maintenance. “Having additional instruments to address concurrently with cleaning of the manufacturing equipment is logistically quite demanding, requiring close communication and planning in order to keep operations running efficiently. Developing and controlling standard procedures with the right level of details and mistake-proofing become even more critical in the context of preventing damage to such sensitive components during handling and cleaning.” “When cleaning equipment with internal sensors, consideration should be given to the material of construction to ensure compatibility with the chosen cleaning agent. Typical substrates may include glass, titanium, or polymeric material,” note Lopolito and Kroeger. If using a CIP cleaning method, they recommend working with the PAT vendor to check compatibility to determine if there will be any impact to the sensors through chemical exposure, high-pressure steam, foaming, build-up of residue on the probes, or through any interaction of materials. Another concern with sensors in a CIP process is determining how well the cleaning and rinse solution flows in and around the sensor and whether there is a significant change in the flow dynamics through the piping. “Coverage testing can be confirmed using riboflavin, and flow dynamics can be assessed through computer modelling, Reynold’s number calculations, or inspection with a borescope,” they explain. It may be possible to use the existing PAT (which measures process variables when the process is running) to also monitor a CIP cleaning process, says Lopolito. “An example would be an ultraviolet (UV) or Fourier Transform Infrared (FTIR) spectroscopy sensor (to monitor drug active) that can also be used to detect trace levels of cleaning agent in rinse water and stop the rinse process when a target limit is achieved within a specified time,” he explains. FTIR is also being investigated as an approach to cleaning verification, using a handheld instrument to detect and quantify surface contamination (3). One of the challenges for manual cleaning is the difficulty of standardizing across a wide range of equipment components with different degrees of product exposure or adhesion, notes Santos. “New technologies such as handheld FTIR can certainly bring a level of simplicity to this process, either in terms of an in-process control to determine the endpoint of cleaning of a component or to eliminate dependence on analytical samples altogether,” he concurs.  


Cleaning Continuous Manufacturing Equipment

Jun 02, 2021

Particle engineering is a vital tool in overcoming many formulation challenges, and technological advances are enabling developers to achieve the full potential of pipeline molecules.     Particle engineering plays a vital role in optimizing a drug’s effectiveness. The size of a particle will have an effect on the delivery of a drug, the route of administration—particularly in cases where an inhaled formulation is being developed—and will impact the rate at which a drug is metabolized in the body. “In formulation and development, both active and excipient particles can be engineered to tailor the performance/efficacy of the drug product,” confirms Jamie Clayton, operations director, Freeman Technology (a Micromeritics company). “A relatively simple example would be controlling the particle size of an active to influence dissolution rate and by extension bioavailability.” Additionally, particle size, along with other properties, influences bulk powder properties, Clayton continues. “Therefore, particle engineering is equally important for achieving desirable bulk powder properties, properties associated with the consistent manufacture of a drug product of acceptable quality, for example, a tablet with the required hardness,” he says. “With drug particles or particle assemblies being the crucial component of solid dosage forms, which represent the vast majority of all medicines, it has become clear that ‘drug particles are of the essence’ when designing quality, safe, and efficacious medicines,” agrees Peter York, chief scientist at CrystecPharma.   Critical attributes, such as a drug’s solid state, particle size, and morphology, all impact a drug’s bioavailability, remarks João Henriques, group leader—Drug Product Development, Hovione. As a vast proportion of the development pipeline is now incorporating compounds with low aqueous solubility and permeability, addressing bioavailability is forming a significant part of development approaches.   “Particle engineering plays a pivotal role in addressing bioavailability issues,” says Henriques. “By modulating the solid state, particle size, or morphology, one can increase both the solubility and dissolution rate of a drug. The former is generally required when dealing with solubility-limited compounds and can be achieved by particle engineering techniques, such as spray drying and nano-milling.” Furthermore, for downstream operations, particle engineering will dictate the processability of a drug, adds Henriques. “Even in the absence of bioavailability challenges, particle engineering can be used to mitigate processing problems, from avoiding segregation to improving flow and compactability,” he reveals. “Particle engineering is therefore an essential tool for formulators to enable successful pharmaceutical development programs of challenging drugs.” “The importance of particle engineering and particle size analysis take on an even stronger role in the development of therapeutics with more novel routes of delivery, such as inhalation,” York notes. “Here, the particle properties not only dictate the pharmacokinetic performance of the drug, but also the amount of drug that reaches the targeted site of administration.”   Common challenges A major challenge with particle engineering is access to the information needed to guide the process, Clayton explains. “The goal is to determine robust correlations between manipulable particle properties, process variables, and critical quality attributes of the drug product,” he adds. “Bulk powder properties are often vital in elucidating such correlations, but with a wide range of analytical techniques to choose from, it can be difficult to identify those of most value.” Recently published collaborative studies have demonstrated the drive for industry to refine analytical strategies (1–3), Clayton continues. “These [studies] focus on the potential of material property databases to accelerate the identification of critical material attributes, support process optimization, and improve supply chain management. Such work is equally helpful for those learning how to efficiently gather information to support particle engineering,” he confirms. “A particle engineering technology should ideally be built upon an understanding of the mechanical, physical, and/or chemical events taking place during particle formation,” adds York. “For drug substances, the requirements of good manufacturing practice (GMP) and regulatory specifications must be embedded into the engineering and operation of the process.” Traditionally, particle size reduction methods are approached in a ‘top-down’ way, so, reducing the size of larger crystalline drug particles uses high-energy impact mills, York explains. “This method continues to be widely used as a ‘first approach’ in solving the dissolution challenge; however, the high energy applied, and uncontrolled fracture and breakage of particles frequently imparts negative features to the milled drug particles such as changes in the solid state and causing highly charged, static particles, which are difficult to process downstream,” he says. “These factors, as well as the need for particle engineering tools that address not only the issue of low drug dissolution, but also potential physicochemical and biopharmaceutical challenges, have provided the basis for innovation in drug particle engineering and new concepts and approaches in drug particle design and delivery.” To ensure the desired characteristics have been achieved through particle engineering, it is necessary to employ analytical tools, highlights York. “Whilst particle size and size distributions are a key property to be measured, the wide range of effects of particle size reduction methods on drug substance structural chemistry necessitates additional analytics to determine whether the process has led to any detrimental changes in solid state, physicochemical properties and, in the case of biotechnology substances, the biochemical and potency characteristics,” he states.   Other common challenges encountered with particle engineering and size analysis are related to process scale-up, asserts Mafalda Paiva, group leader—Analytical Development, Hovione. “Particle size methods are product and size specific, and method development should be performed with lead process candidates,” she says. “A change in process scale is often accompanied by an increase in size that can translate to challenges in measuring the desirable primary particles. Attention is required when analyzing this data, for instance, employing an orthogonal technique such as scanning electron microscopy (SEM) to ensure the employed method is still fit for purpose.” Further challenges can arise with particle engineering as a result of solid-state changes, emphasizes Paiva. “The use of particle engineering can often lead to changes in the solid form,” she reveals. “These [changes] may be as simple as residual amorphization upon high energy milling operations and the emergence of different polymorphs after spray drying.” The hurdles associated with new drug candidates are numerous and varied, particularly when accommodating different routes of delivery, York continues. “By far the major current challenge is the low aqueous solubility of drugs, which constrains the dissolution and thereby subsequent bioabsorption of drug particles when administered to patients,” he notes. “Incorporating micron sized drug particles in the medicine provides a high surface area and drives up the rate of solution of the drug, which in some cases is sufficient to provide an efficacious product.” Henriques concurs that low aqueous solubility of new chemical entities represents the most common challenge facing formulators that requires the use of particle engineering. “The increasing number of BCS [biopharmaceutical classification system] class II compounds means that the interest and demand for such technologies is also increasing,” he says. BCS class IV actives, which have both low solubility and low permeability, represent one of the toughest formulation challenges, remarks Clayton. “Gastroretentive (GR) oral solid dosage forms can be the answer, with floating, sustained release tablets the most common approach,” he adds. “Engineering such tablets is a complex task and calls for an array of analytical insight, with particle morphology, blend flowability, and porosity information all of proven value (4).” Another trend of note, highlights York, is the increasing prevalence of biotherapeutics entering the development pipeline. These compounds are typically more sensitive to high energy processing techniques that are used in conventional particle engineering, he explains. “Emerging technologies enable particle engineering to be conducted in low temperature and chemically benign environments, providing opportunities to engineer particles of biological substances with high levels of retained biological activity and targeted particle properties to enable specific target product profiles to be achieved,” York stresses.   Novel and alternative approaches There are many established particle engineering techniques that are being used for commercial supply of API programs, Henriques specifies. Techniques such as spray drying, hot-melt extrusion, and co-precipitation are commonly encountered, but there are also new methodologies emerging within academic and industrial initiatives, he comments. “One [such technique] is the use of mesoporous silica for the impregnation of APIs,” says Henriques. “[This technique is providing formulators with the opportunity to overcome] some of the limitations of amorphous solid dispersions and is providing opportunities for the formulation of challenging compounds.” A lot of interest over the past 20 years has been given to alternative approaches to ‘top down’ particle formation technologies, such as hot-melt extrusion and nano-milling, emphasizes York. “However, the converse strategy of ‘bottom-up’ particle formation techniques has proved a particularly fruitful area for particle engineering. In this approach, a solution of drug substance is subjected to a drying or solvent extraction process to yield drug particles, ideally in a single step operation,” he notes. “Manipulation of targeted particle characteristics, such as particle size, by means of varying process conditions delivers the ambition of particle engineering.” An example of an innovative approach that is finding success in terms of drug particle engineering includes supercritical fluid (SCF) based technologies, which are available through specialist service providers, such as CrystecPharma, York states. “In supercritical anti-solvent (SAS) configurations, where the supercritical fluid (typically carbon dioxide due to its low critical point) acts as a powerful antisolvent, the solvent from a feed of drug solution is rapidly extracted in a pressure vessel, and dry drug particles precipitate almost instantaneously,” he notes. “The versatility of this technology is impressive in terms of excellent intra- and inter-batch reproducibility, as well as the ability to ‘tune’ the characteristics of the engineered drug particles, for example size, solid state and surface properties. Also, the low processing temperatures possible using supercritical carbon dioxide enable particles of delicate biotech drugs, from peptides to monoclonal antibodies, to be produced.” Additionally, SCF is being used for wider process and formulation simplification, beyond ‘pure’ drug particle engineering, York continues. “Composite dry particles containing a second drug and/or functional additives can readily be manufactured in a single step—a feature termed in-particle design. Here, solution feed lines containing drug and/or excipients, in addition to the primary drug solution, feed into the pressure vessel to form dry composite particles upon contact with the SCF,” he explains. “Each particle contains a final composition equivalent to that of the sum of the solutes in the feed solutions. The scope and options provided by this feature are vast, and excipient inclusions can be diverse with tunable composition ratios. Added excipients could, for example, be for aiding drug stability, dissolution, absorption, or for modulating drug release profiles.” The quantification of particle morphology—both particle size and shape—provides more in-depth information than just measuring size alone, a fact that is highlighted when developing a GR tablet, asserts Clayton. “Flowability data adds value here because the agents used to impart buoyancy tend to compromise flow properties,” he says. “Dynamic flow properties measured with a powder rheometer were helpful in identifying optimal formulations. This application also highlights the value of mercury porosimetry, which provides detailed information about pore size, pore size distributions, pore volume, and other metrics, thereby elucidating buoyancy behavior (4).” “In modern pharmaceutical product development, particle engineering has moved beyond the simple concept of particle size control. Innovative technologies and approaches to particle design and engineering allow molecules to meet their full therapeutic potential, while streamlining development processes, simplifying formulations, and building novelty into products,” York concludes. “In addition to providing opportunities for enhanced intellectual property, cost of goods savings and added process efficiencies, a thoughtful approach to particle engineering can enable the development of therapeutics that better serve the needs of patients and healthcare providers.”  


Moving Beyond Particle Size Control

Jun 02, 2021

As the European Commission prepares a new pharmaceutical strategy, manufacturers seek financial support and technology investment by Rick Mullin NOVEMBER 27, 2020 | APPEARED IN VOLUME 98, ISSUE 46   When the COVID-19 pandemic exposed weaknesses in the pharmaceutical supply chain in the US—in particular its dependence on products outsourced to Asia—the government responded forcefully. The Trump administration led with an initial grant of $354 million, with a possible $458 million to follow, for a newly formed company, Phlow, dedicated to manufacturing critical active pharmaceutical ingredients (APIs) domestically. Next came a letter of intent for a $765 million loan to Eastman Kodak to convert a specialty chemical plant at the company’s headquarters in Rochester, New York, into an API manufacturing complex dedicated to “reshoring” pharmaceutical chemicals from China and India. Now it’s Europe’s turn. The European Commission (EC) has been studying the global supply chain, setting itself a year-end deadline for delivering a drug and health-care strategy. Proposed road maps solicited by the EC from manufacturers of APIs and finished drugs illustrate differences between the US approach and Europe’s possible path to self-sufficiency in pharmaceutical manufacturing. In a meeting in April with the European Union conference of presidents, the EU’s health and food safety commissioner, Stella Kyriakides, raised the matter of supply chain vulnerabilities exposed by the COVID-19 pandemic. Kyriakides cited “structural weaknesses in the EU’s medicines supply chain and a high dependence on non-EU countries for active pharmaceutical ingredients” and recommended that supply chain issues be addressed in an EU strategy. The EC solicited public comment on the proposed strategy in June. Judging from the recommendations put forward by European associations representing drug and pharmaceutical chemical firms, the commission’s approach will differ significantly from the tack taken by the outgoing Trump administration. Rather than spending millions of euros launching made-in-Europe ventures, the EC will likely leverage a sizable established manufacturing base. Likewise, industry guidance for Europe’s plan places greater emphasis on making its supply chain more secure rather than less global, while maintaining and expanding the region’s manufacturing footprint. Adrian van den Hoven, general director of Medicines for Europe, an association of generic-drug and API makers, stresses that reshoring cannot be viewed as simply resuming the manufacture of products that have been outsourced to China and India. “It’s a question of making it sustainable to invest and continue to invest in Europe,” van den Hoven says. “We still have a pretty robust industrial footprint in Europe, with a lot of capabilities.” But growth has flattened in recent years, he adds, as manufacturers in countries like India have taken market share.     Medicines for Europe’s proposals to the EC include a change to generic-drug pricing, which individual countries currently set at the lowest possible levels to reduce the cost of subsidized health care. The association proposes a scheme that would allow prices to be negotiated from the bottom up based on a supplier’s cost of goods, regulatory costs, and other considerations. For hospital and retail purchases, van der Hoven says Medicines for Europe favors “multi-winner tenders,” in which buyers are required to purchase from several suppliers as opposed to awarding contracts to the lowest bidder, a practice that has fueled consolidation among drug suppliers. The group also advocates government support for technology development. Van den Hoven points to Europe’s almost $900 billion COVID-19 recovery package, “The commission has made it clear that some of the funding will be available for technology investment by our sector,” he says. Medicines for Europe also advocates global coordination of drug supply as opposed to rampant reshoring. “It is important that we maintain critical technologies in Europe,” van den Hoven says. “That said, we don’t believe we can or should produce everything in Europe.” That view is seconded by Luis Gomes, senior vice president of operations at the Portuguese API firm Hovione. He’s also chairman of the Pharmaceutical Activities Committee of the European Fine Chemicals Group (EFCG), an industry association. “I think the commission has an understanding that it needs to strengthen the production of pharma products in Europe in order to reduce the dependence and vulnerability of the supply chain,” Gomes says. “I think regulators need a kind of road map to pursue what I would call meaningful pharmaceutical production reshoring in Europe. That starts with priorities.” The EC must arrive at a list of critical APIs that need to be manufactured in Europe, Gomes says. Those no longer made in Europe can be reintroduced, thus increasing the domestic manufacturing base. “And it’s not only APIs one cares about,” he says. “You are also dependent on supply of intermediates and building blocks. You need to look at the supply chain from an end-to-end perspective.” Pharmaceutical chemistry presents a significant hurdle given that many of the reactions involved have disappeared from Europe in the wake of the region’s Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation and other environmental tightening over the past 2 decades. For example, REACH required expensive environmental controls on reactions such as nitration, fluorination, and bromination, which are critical to making certain drug ingredients. “I think REACH created an incentive for production of these chemicals to move to other places, especially Asia, but that doesn’t mean they cannot be manufactured again in Europe,” Gomes says. Like Medicines for Europe, EFCG sees a need for the government to invest in green technology. Financial support will also be needed to establish European production of critical drugs and drug ingredients now made exclusively overseas. Maggie Saykali, director of resins and fine chemicals at the European Chemical Industry Council (Cefic), says in an email that her trade association also has been in discussions with the EC regarding vulnerabilities in the pharmaceutical supply chain. Cefic is preparing a report with recommendations at the commission’s request. “One of the pillars of our roadmap is selective reshoring of the critical technologies needed for the molecules for which long-term supplies must be guaranteed,” Saykali writes. “In order to be sustainable in the long run, this selective reshoring needs support for process innovation, expansion of existing EU production facilities and enforcement of a level playing field for the highest-quality safety, environmental, and social standards.” Sources agree that continuous manufacturing technology will play a role in developing efficient and green manufacturing. They also agree that the Research Center of Pharmaceutical Engineering’s Center for Continuous Flow Synthesis and Processing (CC Flow) initiative at Graz University is the center of continuous technology development in Europe. C. Oliver Kappe, scientific director of CC Flow, says that his lab is not communicating directly with the EC on the development of a reshoring strategy but that several of its partners are contract manufacturers and members of associations such as EFCG. Kappe says the lab plans to set up a facility near Graz, Austria, that will pilot the manufacture of both APIs and finished drugs in a fully continuous fashion. Continuous manufacturing could help avert crises such as drug shortages during pandemics in Europe, Kappe argues. He notes that CC Flow has worked on a process for manufacturing remdesivir, a COVID-19 treatment developed by Gilead Sciences. It also has collaborated with a similar center in the US, the Medicines for All Institute at Virginia Commonwealth University. Medicines for All is a partner in Phlow, the company launched by the Trump administration to repatriate generic drugs. While Europe has taken a few pages from the US response to the COVID-19 pandemic—the EU recently announced it would create a biomedical research agency comparable to the Biomedical Advanced Research and Development Authority, the US government agency that launched Phlow—the European path will inevitably differ. Observers note that Brussels is coordinating 27 independent countries’ efforts, ensuring a more protracted process than experienced in Washington. One EU country has floated a Phlow-like venture with a view toward securing domestic supply of acetaminophen. The government of France is sponsoring a partnership with the French drug firms Sanofi and Upsa and the French API maker Seqens to establish domestic supply of the analgesic, which currently comes mostly from China. Seqens manufactures bulk acetaminophen there. Upsa and Sanofi manufacture most of the finished drug used in France, but they source API from China. The plan, still at a preliminary stage, would have Seqens add capacity for the API in France. Van den Hoven at Medicines for Europe likes the hospital and health-care-facility purchasing strategy adopted by Phlow and its partner Civica Rx, a nonprofit launched in 2018 to help manage generic-drug prices and prevent shortages for member institutions. But he questions the US government’s decision to spend up to $800 million establishing a new company to foster domestic manufacturing of APIs. “It’s an incredible amount of money,” he says. “In Europe, we can do it for a lot less.” He points to Sandoz’s deal with the Austrian government to invest more than $175 million at its site in Kundl, Austria, Europe’s last large antibiotics plant. “This is really small change for a production site that supplies half of Europe with penicillin,” van den Hoven says. On Nov. 25 the EC issued its Pharmaceutical Strategy for Europe, which outlines a raft of initiatives the commission will put forward for approval by the European governing bodies. The strategy, which is not finalized, addresses many of the manufacturing issues raised by industry associations, including pricing policies and investment in green technology. But it lacks details on regulatory changes impacting the use of continuous process manufacturing, and it does not suggest the creation of a list of critical APIs. Van den Hoven says the commission is still fielding input from industry pending a finalized plan. Europe’s drug manufacturers are awaiting further direction from the EC just as the world braces for a surge in COVID-19 infections that may reignite supply chain anxiety. Van den Hoven notes, however, that the first wave of the pandemic was marked by a cooperative response globally. For instance, Europe expedited the export of drugs used in intensive care units to the US despite crisis-level demand for the same drugs at home, he says. “The political climate is a little tense right now,” van den Hoven says. “But at some point people are going to have to go back to cooperation again.”   Read the full article on C&EN website  


Europe’s drug supply chain gets ready for a makeover

Nov 27, 2020

Experts Share Their Opinions on How the Custom Manufacturing and Research Industry can Tackle the Impact of the Covid-19 Pandemic and a Demanding Economic Climate   20.10.2020 - The coronavirus crisis caused by the Covid-19 pandemic has uncovered problems that have been smoldering beneath the surface of the pharmaceutical industry — including CMOs/CDMOs and CROs — and need to be addressed. That supply chains are vulnerable to disruption when major development, production and transportation hubs are blocked or shut down has become painfully obvious. The ongoing pandemic is putting pharmaceutical R&D strategies to the test and also challenging manufacturing planning and supply chain management. Particularly in this industry segment, the supply chain is global, complex and interconnected. Each link must be strong enough to ensure that the road from lab to final drug product is as smooth as possible, even under the most difficult circumstances. In addition to the pandemic, the growing threat of a no-deal-Brexit amid old and new trade conflicts and increasing protectionism, is putting even more stress on companies operating in the pharma sector. In cooperation with Wombat Capital*, a cross-border investment bank, CHEManager asked executives and experts of CMOs, CDMOs and CROs operating in the pharmaceutical sector to share their opinion on current challenges for their industry and how these challenges may influence changes in their market and opportunities.   Expert Interview: Jean-Luc Herbeaux       16.10.2020 - So far, the pharmaceutical industry — including CMOs/CDMOs and CROs — has responded well to the outbreak of the Covid-19 pandemic. However, the coronavirus crisis has uncovered problems that have been smoldering beneath the surface and need to be addressed. That supply chains are vulnerable to disruption when major development, production and transportation hubs are blocked or shut down has become painfully obvious. The ongoing pandemic is putting pharmaceutical R&D strategies to the test and also challenging manufacturing planning and supply chain management. Particularly in this industry segment, the supply chain is global, complex and interconnected. Each link must be strong enough to ensure that the road from lab to final drug product is as smooth as possible, even under the most difficult circumstances. In addition to the pandemic, the growing threat of a no-deal-Brexit amid old and new trade conflicts and increasing protectionism, is putting even more stress on companies operating in the pharma sector. In cooperation with Wombat Capital, a cross-border investment bank, CHEManager asked executives and experts of CMOs, CDMOs and CROs operating in the pharmaceutical sector to share their opinion on current challenges for their industry and how these challenges may influence changes in their market.   What in your opinion and from your perspective are the main impacts of the coronavirus pandemic on the drug supply chains? Jean-Luc Herbeaux: While Covid-19 placed some strain on global supply chains and logistics, the pharma industry overall showed surprising resilience considering the severity of the situation. The pandemic highlighted the strong reliance and dependence of drug and medical product supply on China and India and the limitations of such a supply model. It caused governments to look at pharmaceutical manufacturing in a more strategic manner, including potential repatriation, to guarantee access to life-saving medicines to cater to the most extreme demands. A new type of “nationalism” promoting preferential (or even exclusive) access to therapies and vaccines has emerged in the meantime and it has the potential to greatly disrupt the established global manufacturing and supply models.   Many Western CDMOs have already shifted operations back to the USA and Europe as intensive business activity in China has driven up labor costs. In addition, national policies, trade-related developments such as Brexit and the US-China dispute and impacts of pandemics are likely to require repatriation of at least part of the supply chain in many countries. Could CMOs/CDMOs be beneficiaries of restructured supply chains? J.-L. Herbeaux: CMOs/CDMOs have a chance to benefit from the repatriation trend, which already started some years back. The first wave of relocation, which started some 4 or 5 years ago, stemmed from quality and regulatory considerations. This repatriation was very beneficial to CDMOs with assets and quality systems in good standing as they were able to gain access to business which had escaped them up to that point. The new wave seems to be driven by countries and their citizens coming to terms with the fact that most of their medical supplies are from foreign countries and entities. The recent Covid-19 crisis has revealed the limits associated with reliance on third party country supplies and the ongoing Covid-19 vaccine and therapy “nationalism” further exacerbated the sentiment that repatriation of pharma assets is now a strategic priority. We ought to recognize that the Covid-19 pandemic is extreme in terms of impact and medical supply needs. It has overwhelmed the global supply chains in unprecedented ways and no economically sound supply strategy could have prepared us for an event of such global proportion. In these special times, there is a risk of overheating and of wrong capital investment decisions. Investments need to make sense not only for the short term (i.e. in Covid-19 times) but also for the long haul (once the world returns to a more normal reality). In this overheated environment, experienced western CDMO´s with flexible assets and operating models and with meaningful engineering capabilities are probably the best bet for this industry. They know how to ramp up and run assets in an effective and nimble manner and make best use of these assets now and in the future thanks to their ability to accommodate an ever-changing portfolio.   What do you think the impact of the repatriation of the drug supply chain will have on the M&A activity in the CMO/CDMO industry? Do you think that this would create an impact on valuations? J.-L. Herbeaux: The pharma industry is very likely to weather the Covid-19 crisis better than other sectors and accordingly, one can expect valuation to go up at a time when investors may be looking for safe heavens. The demand-supply balance for M&A candidates in the USA will also drive multiples. One can foresee that the high availability of cash and short-term hype may result in some misguided investment decisions in parties and/or assets, which do not represent mid to long-term value. In the pharma CDMO space, assets are important but not sufficient. The right-to-win stems from established competencies in quality, regulatory and manufacturing service excellence and these attributes take time to develop.   Has the inability to hold face-to-face meetings with prospective clients and conduct client visits to sites affected your new business development since the outbreak of the coronavirus pandemic? J.-L. Herbeaux: New business development has become more difficult as travel restrictions have curtailed opportunities for face-to-face interactions. Physical closeness is known to help individuals (or groups of individuals) form interpersonal relations and develop trust. Proximity and face-to-face communication are therefore particularly important for first-time interactions. We see this clearly in our commercial activities: it is a lot easier to maintain or even further established relationships than to develop new ones. Add to this the need for pharma companies to audit new partners and you will understand why existing partnerships are preferred to new ones at this moment.   The CMO/CDMO industry has managed to support efforts to develop vaccines and therapeutics for Covid-19 despite already being at a high level of utilization. What made that possible? J.-L. Herbeaux: From what is published, there is significant cash being deployed to ramp up vaccine production and capacity repurposing or reactivation is also on the agenda. Some of this cash came from governments and public organizations to secure supply. As for Hovione, we are involved in several steep capacity ramp-up exercises and these have been made possible by very strong partnerships with our clients and suppliers. Everyone understands that these are extraordinary times, and all agree that only shared commitments can result in success. The rest is fueled by a sheer desire to save lives. We push our organizations, systems, and processes to new levels of speed and productivity relying on decades of experience, expertise and best-in-class practices. Under these extreme conditions, CAPEX, resources, and associated capacities are deployed faster and products become available in record time. This is what leading and agile CMOs do for a living: deal with the cross-functional and cross-discipline complexity associated with production ramp-up and compress timelines.   For the biopharma CMO/CDMO industry, the pandemic crisis has created great opportunities. What is your opinion on whether and to what degree the CDMO industry will enjoy long-term benefits from its role in tackling the current crisis? J.-L. Herbeaux: One may assume that the public opinion of the pharma industry will have improved during the last months and that any company, including CDMOs, which contributed to solving or alleviating the Covid-19 humanitarian crisis, would have a chance to boost its image externally but also with its own staff. There is little which can compete with being a contributor to tackling a global health crisis and saving lives. Leading CDMOs have certainly showed that they can be trusted and that supply chains supported by CDMOS/CMOs are robust. Moreover, their demonstrated ability to step up and make capacity available on short notice, absorbing much of the complexity associated with reaching new levels of supply, has positioned CDMOs at the core of the industry’s journey to provide therapies and vaccines to billions of individuals. The co-dependence between CDMOs and Pharma companies is stronger than ever, and this should increase the propensity of pharma to outsource.   One of Hovione’s facilities is located in Macau, China. How was the site in particular and your business in China in general affected by the outbreak of the coronavirus pandemic? J.-L. Herbeaux: Macau is a good example of Hovione’s success in controlling the risks associated with Covid-19. Extensive measures were quickly put in place to protect the team members and to ensure the continuity of our manufacturing operations. Many of the raw materials for Macau come from mainland Chinese suppliers and the site was also able to secure its supply chain. The site was even able to adapt to repair specialized equipment with its own staff as technical visits from suppliers were not possible. Our other sites, which have also been running without interruption or disruption, learned from the Macau response and organization. Best practices were quickly rolled out globally under the leadership of a global task force. All our sites are now operating safely according to this new reality. One of our most important decisions has been to offer free testing to our employees with an elevated risk profile, e.g. as they return from holiday.   The race is on to develop treatments and vaccines against Covid-19, and so is the need to assure supply of these potential drugs and vaccines. Pharma companies are leveraging their internal manufacturing networks but also partnering with CMOs/CDMOs. What supply and manufacturing strategies/alliances are in play? J.-L. Herbeaux: The Covid-19 pandemic has engendered an all-out search for treatment options. Many hundreds of compounds for prophylactic and therapeutic use have been tested in the race against this deadly disease. No drug candidate or route of administration has been neglected and innovative formulation concepts are given due consideration under the assumption that regulatory authorities will likely grant accelerated approval to treatment options which show positive clinical outcomes. The patient population is considerable, and the urgency is absolute. The manufacturing capacities for the few treatments that have demonstrated some efficacy (or promise of efficacy) to date are being ramped up to scales and with speeds which transcend anything the industry had seen so far. Pharma companies have sought the help of their partners to ramp up raw material supply and custom manufacturing services to help them deal with this colossal challenge. In times of pressing requirements, strong partnerships are key and unsurprisingly pharma companies have tended to reach out to their existing partners – especially those who demonstrated the ability to meet complicated supply challenges involving new asset deployment and commissioning. We, at Hovione, are part of this select group of CDMOs working closely with partners on both new formulation concepts and steep upscaling of industrial production capacities.   “Emerging”, “virtual” and other small (bio)pharmaceutical companies are driving the discovery and development of new drugs but are mostly dependent on the availability of financing – which could become more restricted due to the economic downturn cause by the economic and epidemiologic disruptions to the global economy. As emerging biopharma companies are important customers of CMOs/CDMOs, how is this going to affect your business? J.-L. Herbeaux: As a leading CDMO known for helping pharmaceutical companies of all sizes bring new and off-patent drugs to market, Hovione is of course dependent on the health of the biotech industry and its pipeline. So far, our business has remained extremely vibrant as our customers do not appear to be short of cash and pipeline projects are progressing as per plan. The last 3 years have been good in terms of biotech financing (the biotech sector in NASDAQ is at an all-time high). So, one may contend that biotech companies’ strong cash positions will allow them to weather the storm as long as the crisis does not perdure and investments do not stop abruptly. After a few months of increasing disruptions in clinical trials due to Covid-19, data now suggest that clinical trial disruptions have started to recede. Most trial disruptions appear to be due to suspension of enrollment – not financials.   Read the full article at CheManager      


The Coronavirus Crisis: Challenges and Opportunities for CMOs, CDMOs and CROs

Oct 20, 2020

Special Feature, from page 63 to 71   Hovione: Particle Engineering for Small & Large Molecules Hovione has strategically decided to explore niche areas that are difficult to tackle and can benefit from its expertise in particle engineering. Examples include the oral delivery of Amorphous Spray Dried Dispersions and the manufacturing of dry powders for inhalation. Historically, Hovione has mainly focused on small molecules and their pre-formulation, by means of particle engineering, to overcome solubility limitations or to render them suitable for inhalation. In recent years, Hovione has experienced some challenges with large-molecule particle engineering, but intends to increase its activity in this area. “The delivery of large molecules is leading us to novel areas of aseptic particle engineering that we will be introducing in our portfolio,” says Teresa Alves, PhD, Senior Director, Science & Technology, Hovione. Dr. Alves adds that there are opportunities to apply lessons learned with small molecules to large molecules. “We see a trend in the increased delivery of biologics by inhalation, particularly dry powder inhalation, including the delivery of peptides, proteins, hormones, DNA, RNA, etc. We are also actively working to process low bioburden biologics to solve difficulties that our clients experience in limited shelf life, high viscosity, and new areas of administration.” Márcio Temtem, PhD, Site Manager, R&D services, Hovione, explains how the company’s sponsors have benefitted from Hovione’s experience in spray drying. “Spray drying scale up runs with minimum work at scale,” he says. “This is what we call Development by Design. By relying on stasticial and mechanistic models, databases, and scientific know-how, we can save API and time required for CMC process development. We have successfully applied these tools to biologic molecules, namley proteins, antibodies, and fragments of antibodies, and some of these solutions have evolved to commercial manufacturing.”     Read the DD&D issue  


Outsourcing Formulation Development & Manufacturing: Specialized Capabilities for Small & Large Molecules

Jun 01, 2020

Based on research from Industry Standard Research's Contract Manufacturing Quality Benchmarking annual online surveys, more than 125 contract manufacturers were evaluated on 23 different performance metrics. Research participants were recruited from biopharmaceutical companies of all sizes and were screened for decision-making influence and authority when it comes to working with contract manufacturing suppliers. Respondents only evaluated companies with which they have worked on an outsourced project in the past 18 months. This level of qualification ensures that quality ratings come from actual involvement with a business and that companies identified as leaders are backed by experiential data. CMOs have an opportunity to win these awards in up to three groups of outsourcing respondents - Big Pharma, Small Pharma, and Overall (combined Big and Small Pharma). According to Life Science Leader magazine, in the 2020 CMO Leadership Awards, Hovione wins the following categories: Champion in the Expertise category  Exceeds customers expectations in the Capabilities Compatibility Quality Reliability and, Service categories Outside of the core metrics of capabilities, compatibility, development, expertise, quality, and reliability, the Individual Attribute Awards identify common themes sponsor companies consider when choosing a supplier. And Hovione was recognized in  Accessible Senior Management Innovation On-Time Reputation Right First Time State-of-the-Art Strength of Science           See the Award's Issue        


2020 CMO Leadership Award

Apr 10, 2020

Biologics raise unique formulation and development challenges, and industry is still on a learning curve to get the best out of these diverse and complex therapies. The global biologics market has experienced significant growth over recent years and, according to market research, is expected to continue to grow in the near future, potentially being worth $625.6 million by 2026 (1). Advancement of the sector is projected to be driven by an increase in prevalence of chronic conditions, technological advancements, mergers and acquisitions, more market approvals, and the development of more efficient biologics (1). However, biologics raise unique challenges in formulation and development, not least as a result of the large size of the molecules but also due to other characteristics of the complex API. According to Fran DeGrazio, vice-president, Global Scientific Affairs and Technical Services, West Pharmaceutical Services, the size of biologic drug products is particularly challenging when approaching drug delivery. “To be most effective, biologics must typically be injected directly into the bloodstream,” she says. “Additionally, biologics are sensitive to their environment and can easily aggregate or denature, leading to problems such as the formation of particles, which may then be injected into the patient.” “Biological molecules are not only larger in size but also more complex in structure when compared with small molecules,” concurs Constança Cacela, director—RD Analytical Development, Hovione. “This structural complexity can lead to challenges in ensuring stability during processing and long-term, which may result in potential losses of activity and increased immunogenicity.” Circumventing phenomena, such as denaturation, aggregation, and other forms of structural change, are of key importance when processing and developing formulations with biological molecules, Cacela further explains. “These aspects of biologics are responsible for an increased difficulty, requiring advanced technical expertise,” she says. Administration: Moving from IV to SC? When developing large molecule formulations, and depending on the delivery route, there will be different challenges to address with implication on the respective excipient selection, explains Eunice Costa, director—RD Drug Product Development, Hovione. “For injectables, concentration and viscosity of subcutaneous formulations are the main points to address and optimize, whereas for oral enzymatic and acidic degradations low absorption needs to be addressed as well,” she says. “Finally, for nasal, the challenge is mainly related with the low absorption while inhalation is targeting the lung.” There has been an upswing in the proportion of drugs in the pipeline to be administered via a subcutaneous (SC) delivery route, with biomolecules that are currently administered intravenously (IV) being formulated for SC instead. “Major issues associated with SC administration for biologics are the small volumes that require high concentrations of the API,” Costa adds. “The need for high concentrations results in increases of viscosity and challenges in maintaining isotonicity of the liquid formulation as well as in preventing aggregation. Moreover, viscous formulations are difficult and painful to administer. Addressing these issues includes careful optimization of the excipients in the formulation.” For DeGrazio, there are multiple approaches available for developers of formulations to be administered subcutaneously. “One approach is through optimization of the drug formulation design,” she asserts. “This can be accomplished using technologies that help the drug meet deliverability criteria for SC injections.” Another approach includes using a suitable delivery device. “An example of this approach may be drugs that are delivered to the patient through wearable injector devices,” DeGrazio continues. “Typically, a combination of both formulation optimization, and an appropriate delivery device, facilitates the transition from IV administration to SC.” Alternative routes The size of biologic drug products—ranging from 3000 atoms to more than 25,000 atoms—has meant that the primary route of administration is via injection, states DeGrazio. “Size is a challenge for crossing the barriers into the body using other routes,” she says. “The oral route is preferred for any drug product. However, due to the sensitive nature of active ingredients, they will not survive the acidic pH and digestive enzymes of the stomach. This would be just the initial challenge, the next would be absorption into the bloodstream.” However, there are several benefits in developing biologic formulations for alternative routes of administration, argues Cacela, with probably the most obvious one being improved patient adherence. “In the development pipeline, there are increasing programs in the areas of oral, inhalation, and nasal, with the first one generally being considered as the optimal route,” she says. To overcome the enzymatic and pH-dependent degradation of drugs in the stomach, in addition to permeability issues and the potential for degradation via first pass metabolism, formulation strategies, such as enzymatic activity inhibitors, permeation enhancers, enteric coatings, and carrier molecules, can be employed, Costa reveals. “The increased focus on inhalation delivery reflects the benefits offered by this route of administration,” Costa continues. “Delivery by inhalation bypasses the harsh conditions in the gastrointestinal tract, allowing the administration of lower doses with reduced side effects, particularly for respiratory drugs delivered directly to the site of action.” For systemic delivery, administering drugs to the lungs can also allow direct absorption into the bloodstream, leading to a more rapid onset of action, Costa explains. “The main challenges for inhalation include ensuring that the drug reaches the lung (e.g., delivery efficiency), a limited array of excipients available to interact and stabilize large molecules that are safe in the lung, as well as the lack of permeability to very large biomolecules,” she says. “Overall strategies include optimal design of the inhaler device, study of the interactions between excipients and biomolecules, biomolecule engineering (e.g., fragmented antibodies, anticalins) with the purpose of maximizing efficiency.” Nasal delivery, historically, has tended to be used for local delivery of drug substances. However, Costa adds that more recently it is becoming recognized as an interesting route for direct access to the brain. “It has been actively pursued for biologics, in particular peptides, due to the ease of administration,” she states. “As opposed to inhalation, one of the major limitations of this route is the relatively limited low surface area available for absorption. To increase absorption, mucoadhesive polymers are commonly added to the formulation.” Cacela emphasizes that an overarching technological solution, useful for overcoming the limitations for the various delivery routes discussed, is the use of particle engineering. “Through the preparation of optimally sized and shaped particles, the bioavailability of the drug can be improved,” she says. “As an example, nanoparticle-based delivery systems, such as lipid nanoparticles, are used for improving penetration of large molecules. In addition, these systems provide protection to the drugs, which is particularly relevant for large molecules administered orally.” A common technique used to engineer particles is spray drying, which Cacela states is the most commercially advanced solution capable of preparing stable and effective formulations. “Despite being generally used for oral small molecules, its benefits can be easily expanded to other systems and routes of administration,” she adds. “The anticipated forecast growth for spray drying services being applied to biologics (2) is a strong indicator of that.” Reformulation and self-administration trends SC administration of biologics, in particular antibodies, is a strategy being employed by industry to improve patient comfort and provide pharmacoeconomic benefits (3), highlights Cacela. Highlighting another example (4), she adds that in some cases using SC administration can result in improved safety due to reduced adverse effects. “Besides the aforementioned benefits, reformulation of existing biologics may also be of potential value for the originators as a means of life-cycle managements,” she says. In agreement, DeGrazio notes, “We are definitely seeing the trend towards reformulation as part of lifecycle management to enable self-administration. New biologic drug products in competitive therapeutic categories are being introduced in self-administration systems. This is one of the main reasons for the growth of drug-device combination products in the marketplace.” The move toward self-administration is being driven by a number of factors, DeGrazio continues. “One of the most significant is the potential cost savings if the delivery of a drug product can be done at home, versus in a hospital or clinic,” she says. “Additional reasons include improved quality of life for patients and product differentiation in a therapeutic category.” Mitigate risks, save costs The costs associated with any medical therapy are being scrutinized by regulatory bodies, governments, and patients. Biological therapies, due to the molecular complexity and associated challenges during development means that they come with a high price tag. “One of the best ways to impact costs is by mitigating risks early in the development process,” asserts DeGrazio. “Many drug product formulators think that all problems can be solved through their ability to adjust and optimize a formulation. However, not all formulators have a broad understanding of the impact of aspects beyond the drug formulation, aspects of which they need to be cognizant.” Highlighting some examples, DeGrazio notes that formulators must be aware of the potential impact primary packaging may have on the biological drug product. Additionally, whether or not it is possible to use the drug product with a delivery device is an important consideration. “Both packaging and device options are essential when looking at improving the patient experience,” she adds. “The route chosen regarding drug pricing must not inhibit innovation and must ensure economic sustainability,” warns Cacela. “However, R&D effectiveness may be improved and, therefore, have an impact on the final cost of biologics.” To improve R&D effectiveness, Costa explains that industry is using many different approaches. “Approaches such as preclinical models that more closely resemble the human conditions to be treated, reducing late-stage (Phase II and III) attrition rates and cycle times during development by using a better model,” she says. “New tools and technologies arising from the digital transformation era, such as the application of artificial intelligence algorithms to experimental and clinical data, further improve R&D effectiveness.” Specifically looking at formulation, Costa reveals, “As more biomolecules are screened models can be improved allowing for in-silico screening and reducing the chances of failure later on in clinical development.” Still on a learning curve For Cacela there is still much to learn and more development required in both the delivery and formulation of biologics. “Besides this, the diversity of these drugs and therapies is very large and it is difficult to find a common solution even within a same class of biomolecules,” she states. “Therefore, the coming years will be marked by advances in the delivery of novel biologics, as well as biosimilars, with new solutions, new excipients, and new delivery support molecules.” “We have learned that the drug formulation itself can have a detrimental impact on the function of a delivery device, such as a prefilled syringe system,” adds DeGrazio. “By understanding issues early in the development process, however, downstream problems can be avoided. Partnership with suppliers who are familiar with such challenges can be of great benefit. An openness to engage, and learn from each other, can benefit effective drug development and the patient.” References 1. Reports and Data, “Biologics Market By Product (Monoclonal Antibodies, Vaccines, Recombinant Hormones/Proteins), By Application (Cancer, Infectious Diseases, Autoimmune diseases), By End use (Hospitals, Clinics, Diagnostic Centres), and Region, Forecasts to 2026,” Market Report, (October 2019). 2. Research and Markets, “Pharmaceutical Spray Drying Market (2nd Edition), 2018–2028,” Roots Analysis, (April 2018). 3. K. Papadmitriou, et al., Facts Views Vis. Obgyn., 7 (3) 176–180 (2015). 4. P. Moreau, et al., Lancet Oncol., 12 (5) 431–440 (2011). Article Details Pharmaceutical Technology Vol. 44, No. 1 January 2020 Pages: 33–35 Citation When referring to this article, please cite it as F. Thomas, “Fresh Thinking in Biologic Drug Formulation,” Pharmaceutical Technology 44 (1) 2020.   Read the article on Pharmaceutical Technology's website  


Fresh Thinking in Biologic Drug Formulation

Jan 02, 2020

In this article, João Ventura Fernandes, PhD, Director of Technology Development and Licensing, and Peter Villax, Chief Executive Officer, both of Hovine Technology, look at the trends shaping the development of dry powder inhalers. Inhaled drug delivery is established as the primary choice for airway disease treatment and continues to hold high potential for systemic drug delivery. Since its invention in the 1950s, the pressurised metered dose inhaler (pMDI) has been the inhaled therapy “gold standard” for airway diseases such as asthma, as a result of being easy to use, multi-dose and inexpensive to manufacture. However, its drug delivery performance remains dependent on patient co-ordination – often leading to high drug losses – and environmental concerns have emerged with respect to the use of propellant-driven pMDI technology. Although initial chlorofluorocarbon (CFC) propellants have been discontinued due to their impact on the ozone layer, their hydrofluoroalkane (HFA) replacement propellants are unfortunately potent greenhouse gases – 2,000 times more potent than carbon dioxide. The global battle against climate change arising from greenhouse gas emissions may drive regulators to subject pMDI technology to carbon emission restrictions. Without major technological breakthroughs in finding alternatives which are not greenhouse gases, pharmaceutical companies may lean towards the use of alternative inhaler technologies.   Read the entire article      


Hovione Technology: Dry powder inhalers towards effective affordable sustainable respiratory healthcare

Nov 01, 2019

Transformative investments, and capacity expansions abound at CPhI North America Pharmaceutical services firms attending the CPhI North America trade show in Chicago earlier this month were virtually unanimous in reporting another year of strong growth in a business that has seen no direction other than up for nearly a decade. Investment continues apace, as do acquisitions, with many firms claiming their manufacturing assets are at or near full capacity. Tied as it is to the drug industry, the sector has long defied traditional economic cycles. Contract manufacturers of active pharmaceutical ingredients (APIs) have also added services, developed expertise in complex chemistry, and generally taken risks to grow businesses in the direction required by customers developing the drugs of the future. Results this year indicate that many of these risks have paid off. And ongoing investments hint at another round of risk taking on new technologies and service models. "Business is buoyant, the strongest it's been on record," said Denis Geffroy, vice president of business development for the Northern Irish firm Almac Sciences. "We are approaching 20% growth this year, which is really surprising because we've been growing 15-20% for the last 10 years." Several factors explain yet another year of strong results, Geffroy said. "First, I like to think we are doing a good job. But the market has improved, especially in the US," he said, citing a steady flow of venture funding for biotech start-ups. Meanwhile, customers continue to bring their outsourcing back to Europe from China, a shift that accelerated with a Chinese crackdown on environmental regulations starting in 2017. Almac Sciences is experiencing strong growth and is operating near full capacity. The firm plans a major expansion. Almac has also benefited from a commitment it made to biocatalytic services beginning in 2010. "We are staying ahead of the game, using enzymes not only for chiral molecules," Geffroy said. "About 20% of the compounds we make have got an enzyme somewhere, either in a final step or in an intermediate step." The 2015 acquisition of the Irish firm Arran Chemical was key to developing the service, he added. At the time, he told C&EN that Almac was "hitting the wall" on biocatalysis capacity. The company is hitting the wall again, according to Geffroy, this time in its core API business. "We are growing so quickly, we are at full capacity at the moment, which is a bit frustrating," he said. "We need more capacity, and we now have the approval from the board to start building an API plant next door to our current plant." The $20 million facility is expected to open in 2021, yielding a fivefold jump in the firm's capacity to make highly potent APIs. The Portuguese firm Hovione is also expanding. "We acquired a new piece of land in Portugal, a greenfield site, 10 times larger than the site we have," Marco Gil, senior director of commercial services, told C&EN. At the 40-hectare site, a half-hour drive from Hovione's headquarters plant in Loures, outside Lisbon, the firm will add API capacity while expanding in new areas such as flow chemistry and finished-drug production. The company is already expanding in Loures, where it recently established a continuous tableting line. Spreading out at the new site will give Hovione a chance to broaden its services and establish a full line from early-stage development to commercialization, all in the Lisbon area, according to Gil. In France, Minakem is building a lab for cytotoxics used in antibody-drug conjugates at its site in Louvain-la-Neuve, Belgium, where it is also installing a high-performance liquid chromatography column, according to Jean-Marie Rosset, vice president of sales and marketing. And the company, last year, completed and $11 million API-capacity expansion in Dunkirk, France. "We are facing capacity constraint," Rosset said, noting that Minakem is also pursuing an acquisition. "We have been looking for 18 months." The company may acquire R&D or pilot manufacturing assets in the US, he said. Rosset said that prospects look good for the year ahead. "We have a lot of stuff in the works that will require scale-up," he said. "The problem is where to put these products. But that's a good problem to have-better than empty capacity." Helsinn finds itself in similar straits, according to Sandra Moro, business development director. The company is in the midst of a $20 million project at its Biasca, Switzerland, headquarters to install large-scale cytotoxic manufacturing capability.                           We believe in the one-site shop with chemistry, particle engineering, and final product. Marco Gil, senior director of commercial services, Hovione The project will free up smaller-scale capacity, Moro said, allowing Helsinn to take on more of customers' early-stage work, such as oncology projects that have been fast-tracked by regulators. "We can go from Phase I to Phase III," she said, referring to stages of drug development, "but we currently have very few early-phase compounds-56% of our compounds are commercial." Tight capacity has not stifled growth, however. Helsinn's revenues increased about 20% for the second year in a row last year, Moro said. It's not only European firms that are investing. India's Hikal also has achieved 20% annual growth in recent years, according to Anish Swadi, head of business development and strategy. The company is also in need of capacity. "We are investing $55 million into assets and infrastructure," Swadi said; this investment will support the company's pharmaceutical chemical and crop protection divisions, which share core chemistries. The new capacity will expand continuous manufacturing and biocatalysis capabilities, he added. Some of the firms that disclosed expansions at CPhI did so on top of large acquisitions. Executives from such firms discussed integrating internal and external investments to create full-service offerings for their drug-industry customers. Catalent recently announced a $1.2 billion acquisition of the gene-therapy specialist Paragon Bioservices, setting itself up in an increasingly competitive new field in drug development. Separately, the company is investing more than $200 million to expand its monoclonal antibody (mAb) and other large-molecule production capabilities in Madison, Wisconsin, and Bloomington, Indiana. It's adding fill-and-finish and associated analytical and packaging capabilities as well, to "take your mAb from preclinical all the way to commercial," said Elliott Berger, vice president of global marketing and strategy. Although Catalent doesn't manufacture pharmaceutical chemicals, it is looking to bolster its presence in small molecules, where bioavailability-enhancing techniques are of increasing importance. Acquisitions over the past 5 years-including Micron Technologies in 2014, Pharmatek Laboratories in 2016, and Juniper Pharmaceuticals in 2018-have brought in spray drying, formulation, and other services downstream of API production. At the Chicago event, Catalent announced a $40 million expansion of oral-dose capabilities and the addition of spray drying in Winchester, Kentucky. And the company is also ready to invest heavily in its newest business, Berger said, noting that Paragon is building two commercial production facilities in Baltimore and expanding its relationship with Sarepta Therapeutics, a key customer for its adeno-associated virus vectors. "We have financing secured for larger than the acquisition to fund that," he said. At CPhI, Lonza announced what it calls a "first in human" service: a combination of API and finished-drug development, formulation, and manufacturing targeted at the 70% of compounds in development that have solubility challenges. According to David K. Lyon, a senior research fellow with Lonza, the service draws on both internal assets and those acquired in recent years, such as Micro-Macinazione, a Swiss micronization specialist that Lonza bought in 2017. Other assets are as far afield as Bend, Oregon, where Lonza does solubility work; Guangzhou, China, where it manufactures APIs; and Edinburgh, Scotland, where Lonza operates a liquid-drug formulation facility. Lonza is cuing up these assets to crack the bioavailability case at Phase I and expedite commercialization, especially of fast-tracked projects, Lyon said. It aims to reduce development time from 52 weeks to 32 weeks for customers seeking to file an investigational new drug application with the US Food and Drug Administration. The small-molecule specialist Cambrex is also putting recent acquisitions together. The company brought in early-stage API development when it bought PharmaCore in 2016 and added early-stage API capabilities and sites in the US and Scotland when it acquired Avista Pharma Solutions last year. It also bought Halo Pharma, a finished-drug producer, for $425 million last year. Cambrex is now better positioned to address the changing needs of innovative drug companies, according to Matthew Moorcroft, vice president of marketing. Meanwhile, Cambrex continues to invest in large-scale API production. It completed an expansion of its high-potency API plant in Charles City, Iowa, last year. The company is now ramping up continuous manufacturing capabilities at its Highpoint, North Carolina, facility-the former PharmaCore-and its factory in Karlskoga, Sweden. "To make a long story short, we are excited about what we've done over the last 6 months," Moorcroft said. "Now it's all about delivering."     Read the article      


In the drug services industry, growth has no end in sight

May 20, 2019

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