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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

Our knowledge is available 365 days for you. Count on our multidisciplinary teams to exchange knowledge, ideas, and experience to develop and improve your project. As a specialist integrated CDMO we are dedicated to helping you bring new and off-patent drugs to market faster. Challenge us   Our scientists attend the leading events of the pharma industry throughout the year where they share their knowledge and present their innovative work.   Did you miss the articles on Pharmaceutical Technology, Drug Development & Delivery, On-Drug Delivery or Chemistry Today? You are still in time to read them. Access them here:        Moving Beyond Particle Size Control Contributors: João Henriques (Group Leader, R&D Drug Product Development) Mafalda Paiva (Group Leader, Analytical Development)   Improving Bioavailability & Solubility: Each Molecule Is Unique - Emerging Platforms Address Extreme Compounds Contributor: João Henriques (Group Leader, R&D Drug Product Development)       Semi-Automation in Inhaler Testing - Exploring the Potential & Practicalities Discussion with João Pereira (Team Leader, R&D Analytical Development) Raquel Borda d' Água (Associate Analytical Chemist, R&D Analytical Development; Copley)    Where Continuous Flow can help in today’s Pharmaceutical Industry Panel Discussion with Rudi Oliveira (Scientist, R&D Process Engineering and Scale-up)               Did you miss our presentations at DDF, RDD, DDL or AIChE? You are still in time to join. Access them here:         Technology & Innovation Performance Enhancement Strategies for Low Solubility APIs – do more with less Authors: Mafalda Paiva & João Henriques   Workshop Presentation Fully Integrated DPI Development From API To Device Authors: João Pereira, Beatriz Noriega Fernandes     Predictive Scale-Up/Scale-Down for Production of Pharmaceuticals Reaction Kinetic Model Application to Speed up Development Author: Filipe Ataíde   Presentation and Paper Spray-dried composite formulation for lung sustained release Author: Beatriz Noriega Fernandes  


Our knowledge is available 365 days for you

Aug 09, 2021

Hovione staff donating hand sanitiser to a St John’s Ambulance crew. Hovione donated 65MT free of charge to over 150 institutions with the help of charities, local community groups, private nursing homes, local hospitals, sporting clubs, and An Garda Síochána, who dispensed the sanitiser in Templemore Training Centre into smaller bottles for HSE-run nursing homes across the country. Dr. Paul Downing, general manager of Hovione in Cork, reflects on the values driving the company’s years of global success.   When news of a global pandemic broke Hovione, a contract pharmaceutical manufacturing company which helps bring new and off-patent drugs to market, adapted and responded almost immediately. The sudden spike in demand for medicines and for Covid-19 specific treatments required unique mobilisation efforts across the entire Hovione network. “We needed to execute major capital expenditure projects at our sites, maximise operational efficiency, hire additional talent and quickly identify an external partner to expand our overall capacity”, explains Dr Paul Downing, General Manager of Hovione’s manufacturing plant in Cork. The company, which employs 250 people in Cork and approximately 1,800 more at its other three sites spread over three continents with facilities in Lisbon (Portugal), Macau (China) and New Jersey (USA), has over 60 years experience in the development and compliant manufacture of Active Pharmaceutical Ingredients and Drug Product Intermediates. Hovione began manufacturing hand sanitiser on site in March 2020 for the protection of their team members. Very quickly, they saw public demand grow and in keeping with the company policy of ‘Corporate Citizenship’ this led Hovione Cork to appoint a project team to bring the manufacturing of hand sanitiser to distribution. The hand sanitiser was made readily available for donation to help protect various facilities and institutions across Ireland. The first batch of hand sanitiser was collected for use at St. Stephen’s Hospital in Glanmire in Cork on April 20th. Hovione supplied the sanitiser across Ireland to nursing homes, care facilities, charities and hospitals. The company worked closely with An Garda Siochana to safely distribute hand sanitiser to the HSE — “we organised 65 metric tonne of hand sanitiser to be distributed freely nationally and within the community locally to GAA clubs, churches and other community-based organisations. Dr. Downing says: “It gave all of us a sense of purpose during a difficult time.” Hovione distributed hand sanitiser free across all of their plants to support the local communities of each country they manufacture in. Dr. Downing explained that when the supply crisis ended in July 2020 the companies who would normally make these sanitising products were back in production so “we stopped and focused on other things”. He said it was a great privilege to be a part of “this truly global response where we witnessed the pharmaceutical supply chain working together in an unprecedented fashion to treat patients and save lives. I think the global pandemic showed us how important and resilient the life sciences sector is”. Hovione Cork which took over Pfizer’s former Loughbeg site in Ringakiddy in 2009 plays a significant and strategic role within the Hovione network. The company has seen rapid growth over the last 12 years expanding its production capacity to occupy three separate production buildings at the site.   Last September, in the middle of the Covid pandemic, Hovione announced a partnership with US-based Ligand. This was to support manufacturing of antiviral Veklury for Covid-19 which meant the company needed to significantly ramp up the production output of Captisol leading to the announcement of 48 new jobs for Cork in October 2020. Dr. Paul Downing explained that Captisol is used in the formulation of Gilead’s Covid-19 treatment Veklury and Hovione is the sole producer of this key enabling excipient. To meet Captisol demand associated with Veklury, Hovione was producing in one month the quantity it normally produced in a year. Going forward Dr. Downing said Hovione has an ambitious plan to be the Number 1 innovative, integrated pharmaceutical solution provider to the global pharmaceutical industry by 2028. “Our mission is to passionately turn any challenge into a solution by collaboration with our partners to develop great medicines. That is a company corporate goal so that requires all our facilities to grow and expand so this expansion plan is across the whole Hovione network including Lisbon, New Jersey, Macau and also obviously Cork”. The company — which was founded by Ivan Villax with his wife Diane Villax in Lisbon, Portugal in 1959 — recently celebrated 62 years in existence. “In short we give our customers what they cannot find elsewhere”, says Dr Downing who explains that customers come from the sectors of biotechnology, medium, speciality and large pharmaceuticals and generics pharmaceuticals. Hovione he says has a unique value proposition. “We have more than 15 years of experience in pharmaceutical spray drying and have produced hundreds of batches for clinical trials and commercial supplies”.   Sustainability is hugely important Hovione was one of the first companies to sign up to Business in the Community Ireland’s new Low Carbon Pledge in 2018 to commit to cutting their carbon footprint, report annually on their progress and develop a credible roadmap towards a net-zero economy. “Here at Hovione we continue to try and be contemporary, practical and pragmatic. We have a large footprint of a site here so we are investigating if we can install solar power. “We continue to challenge ourselves in reducing our industrial footprint in terms of energy consumption, water consumption and waste generation so this Ligand product for instance that we worked on is very water-intensive and we did a lot of processing improvements in parallel to this huge ramp up to actually reduce energy, reduce solvent, reduce waste and reduce water. Sustainability is at the forefront of what we do and it starts at the very beginning with our R&D in Portugal.”  Dr.Downing says he notices when recruiting younger staff, in particular, they are asking ‘what is your sustainability philosophy, what are you doing to reduce your impact’ so you know it has to be real, it can’t just be gestures”. These concerns he says are embedded in Hovione’s core values and purpose — “sustainability is fully integrated into our business strategy”. Overall Hovione’s steadfast growth is the result of an integrated synergy that allows the company to serve both the global markets and also to respond to specific customer demands when necessary. The company has a solid legacy of Corporate Social Responsibility — in 2018 Hovione became a Certified B Corp — becoming the first facility in Ireland to have received this Certification. The company’s ‘Safety First, Quality Always’ culture is also something staff are very proud of — “we nurture it each day so that we don’t take it for granted”. In the coming years Dr. Downing said the company will continue to invest in additional capability and hire additional team members, launch and validate more new products. He points out that the company is an active member of Biopharmachem Ireland, Cork Chamber as well as Business in the Community Ireland. Hovione sponsors and supports local community initiatives as well as establishing crucial links with the academic and training institutions through its support of STEM — initiatives to encourage take-up of subjects such as science, technology, engineering and mathematics — as well as MTU student placements and the Cork Training Centre. “We are the first Chemical/Pharmaceutical Company integrating this innovative community of companies that use the power of business to solve social and environmental problems. As a Certified B Corporation we want to contribute to redefining success in business meeting the highest standards of social and environmental performance, setting out team members for success and personal satisfaction and aspiring to use the power of markets to solve social and environmental problems.”    Promoting career growth, diversity and inclusion “We employ 250 people and currently have 18 nationalities onsite”, says Dr. Paul Downing, general manager of Hovione’s manufacturing plant in Cork. Hovione, he says, is a fast, challenging, and dynamic environment with great opportunities for people with all skill sets at whatever age. Because the market demands different products, you can work on multiple products and multiple projects at the same time. That gives people a real diversity of experience. “We like to have a balance between promoting from within and recruiting from outside, so if someone has the desire to move within the organisation, these opportunities arise”. He says that Hovione is constantly developing its talent pool, and is a big supporter of and encourages apprenticeships for young people where they are given the opportunity to gain some very substantial and important skills, allowing them to take up roles as electricians, fitters, quality-control analysts, instrument technicians, as well as automation technicians. The apprenticeship programme not only provides participants with the necessary technical and professional skills, but it also provides valuable teamwork experience. “What we do find is that people can have very strong technical and academic skills, but their team collaboration skills require us to invest in further training. “These skills would be automatically instilled in participants in the apprenticeships programmes. “In complex and large organisations like ourselves, the interpersonal skills and an ability to work in small teams is important.”  Hovione works with Skillsnet and other local academic institutions to help build capabilities that can take advantage of the many career opportunities available. “We continue to work with Munster Technological University, Cork Education and Training Board, University College Cork. “We do college site tours and Masters students’ placements. We work with the IDA on the IBEC EOP programme which, before Covid-19, would see graduates spend six months with us and six months with our sister facility in Portugal, mostly working as process engineers or QC analysts. “We are starting to think of ways to get more diverse employees, so just before the pandemic hit, we partnered with Ireland’s national autism charity AsIAm. “They are working to create a society in which individuals with autism are empowered to reach their own personal potential and fully participate in society. “We believe that there may be certain areas within our sector which are very data-intensive like QC, like engineering, which may present opportunities. We were audited to see if we were an autism-friendly workplace. “We had to change a few things around, including adapting our cafeteria to ensure it had appropriate lighting and noise levels. Some of my team were given training and we hope to do some work with AsIAm post-Covid, and continue to celebrate diversity and inclusivity in the workplace.”   Read the article at      

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Hovione meets increased demand during Covid

Jun 21, 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

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