Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

Bio/pharmaceutical manufacturers have been required to pivot in recent times because of a number of factors, including the shifting focus of drug development to next-generation modalities, pressurized supply chains, increasing adoption of digitalization, and intensified efforts to be more sustainable (1). One event that has thrown up hurdles and required novel solutions in response has been the COVID-19 pandemic, which has had an influence on all aspects of industry across the globe.

Despite the disruptions and uncertainties caused by the pandemic, the bio/pharmaceutical manufacturing sector has advanced and evolved, balancing the fluctuations correspondingly to mitigate risk and allow for further progression. According to research, for example, the bio/pharmaceutical manufacturing market should witness compound annual growth in the region of 11% between 2022 and 2027 (2), thanks in part to advancing manufacturing technologies.

“There have been a couple of significant shifts in the industry,” stresses Dan UpDyke, strategic marketing manager, Life Sciences, Rockwell Automation. “In years past, it was typical to build purpose-built, single product facilities. These would have fixed vessels and be designed with rigid processes to deliver repeatable results but had limited flexibility. As drug development has shifted to highly specialized treatments with smaller patient populations, the need for flexible and scalable systems has become a focus leading to solutions such as single-use technologies.”

Precision medicine and other next-generation modalities, such as cell and gene therapies, have been a focus for the bio/pharmaceutical industry over the past decade, remarks Bryan Deuber, senior director, Business Development and Strategic Partnerships, Andelyn Biosciences. “In response, outsourced development, manufacturing, and testing organizations have adjusted their models to accommodate the flexibility of serving both relatively small-batch manufacturing and larger indications,” he states. “Many therapeutics behind the recent growth require an extremely skilled workforce, state-of-the-art technologies, and advanced consumables, including plasmids and viral vectors.”

These new modalities and platforms—messenger RNA (mRNA), cell and gene therapies, and so on—also require delivery in multiple dosage forms, such as autoinjectors, syringes, and vials, and new patient distribution models, specifies Sridhar Krishnan, vice president, The Catalent Way at Catalent. “Manufacturers must be able to integrate this wide range of needs into their operations,” he says.

“Most recently, biopharmaceutical manufacturing has been impacted by pressures on supply chain,” specifies Antonio Crincoli, vice president of Engineering, Pharma and Consumer Health, Catalent. “The expectation from customers is for consistent, resilient, and predictable supply chain performance, at a high quality and a reasonable cost.”

Although Jade Byrd, director of Industry Marketing at Agilent Technologies, also points to the drive toward better risk management by the manufacturing community because of the scrutiny over supply chains over recent years, which is reducing the risk of drug shortages, as a key trend, she believes that the most impactful change is the move to continuous manufacturing. “The same number of doses can be produced in much smaller facilities, leading to both reduced costs and less waste,” she says.

“The pandemic had a major impact on pharmaceutical manufacturing, forcing organizations to think differently about treatment manufacturing,” continues Nathan Pettus, president, Process Systems and Solutions, Emerson. “COVID brought supply chain issues to light, and that revelation created a push for more regional manufacturing, instead of making everything in one place. By creating more regional manufacturing hubs, many pharmaceutical manufacturers are significantly de-risking their supply chains to minimize disruptions.”

For Shankar Gupta, chief sales officer, ACG, it is the globalization of the bio/pharmaceutical industry that has led to the advent of new manufacturing hubs with rising cross border sales. “Encouragingly, this growth has brought with it a real focus around quality and inspection,” he adds.

However, according to Thomas Schmidt, marketing director, Digital Solutions, Agilent Technologies, despite the existence of lean Six Sigma and quality-by-design initiatives to ensure better product quality for some time already, these tools have not always been used to their full potential, perhaps as a result of the change management they require.

“Regulatory expectations are increasing,” emphasizes Krishnan, “and as a result, manufacturers must look to meet the highest regulatory standards to be able to supply to all markets. Accordingly, there is a focus on quality management systems that ensure data integrity and governance, and that digitization occurs with appropriate validation, also, where necessary, that there is segregation of operating systems to eliminate risk of corruption.”

Customers are also placing greater importance on speed-to-market for products and flexibility of supply, notes Crincoli, meaning that manufacturers must be capable of quickly deploying or transitioning manufacturing assets to meet market needs. “It is therefore beneficial if facilities and equipment are designed to handle multiple products or dose forms. Similarly, there must be the ability to quickly move from development to commercial operations through scaling up or scaling out,” he says.

In fact, the speed at which COVID‑19 vaccines were created and manufactured demonstrated to the world that it was possible to launch new products at pace, confirms Pettus. “While much of that speed was enabled by emergency authorization regulation changes and special funding, life sciences companies have now seen what is possible, and they want to find additional ways to safely develop and manufacture other essential treatments much faster,” he states.

Another big movement for bio/pharmaceutical manufacturing has been investment in the digital transformation, adds UpDyke. For many years, technology innovation has been slow, with equipment and processes becoming “standard,” until recently when the business value of digitalization is being realized, he affirms.

Focusing on the fact that companies are looking to operate in more regionalized facilities, work with a greater number of contract development and manufacturing organizations (CDMOs), and develop more niche markets, Pettus points out that they will have many more batches to track and products to manage. “The massive amounts of data generated by these information-intensive methods will need to be contextualized so manufacturers can glean innovative and more efficient ways to ensure they are operating in a cost-effective, reliable, and quality-compliant manner,” he says.

A useful tool that will empower manufacturers to take advantage of additional data not previously collected is process analytical technology (PAT), which enables inline monitoring and real-time release, Pettus continues. “With the application of these technologies—instead of performing sampling processes, waiting for in-process testing before proceeding to the next step, or waiting for final batch test results to proceed with or release the batch—much of the critical process parameter and critical quality attribute data can be collected in real-time during the manufacturing process,” he states. “When critical steps are performed during manufacturing, teams have results before the process step or even the batch is complete, ultimately moving them to more efficient real-time control and closer to real-time release.”

“PAT and an emphasis on process understanding have been embraced by the majority of pharmaceutical manufacturers, and there are several case studies where both artificial intelligence (AI) and machine learning (ML) have led to improved quality or increased yield, even in good manufacturing practice (GMP) facilities,” adds Byrd. However, there are still regulatory hurdles impeding adoption of more modern techniques, she asserts. “[Although] this [situation] has improved over the past several years with the incorporation of engagement possibilities like the Emerging Technologies Team at FDA and the Innovation Task Force at EMA [European Medicines Agency],” Byrd notes.

In concurrence, Schmidt also emphasizes the importance online and at-line analysis has become in recent years. “Our customers want results much closer to product manufacturing and not always in the traditional lab,” he remarks.

Ensuring all equipment is running efficiently and effectively is another pertinent area to balance, according to Pettus. “By monitoring key characteristics of the equipment and the process, potential problems are identified, and appropriate actions can be planned to ensure emerging potential issues are resolved before they cause production problems,” he says. “And with regards to that planning, real-time scheduling software helps manufacturing and support teams to not only make the most of equipment time and production availability, but to also automatically reorganize schedules when there is an aberration—such as a supply chain issue, equipment failure, or other delays—to help ensure on-time production for improved delivery times and profitability.”

“Business continuity is key to any reliable supply chain, which includes ensuring all of a company’s facilities and equipment are available and operate as intended, to meet the flexible demands,” emphasizes Crincoli. In addition, it is just as important for manufacturers to build and select a strong, high quality, supplier base for raw materials and consumables, he adds.

Improvements in manufacturing efficiency can be made through comprehensive quality management systems that focus on digitization, reduce human errors, and improve data integrity, notes Krishnan. “These steps are backed up by having an operational excellence strategy, and a continuous improvement system, but whatever systems are in place, the most important step is a continuous investment in people, and the training of employees,” he says.

Pettus also highlights process and knowledge management software, which collates, contextualizes, and standardizes process steps and critical data across the entire lifecycle, as a useful tool for ensuring manufacturing efficiency from process development to full-scale manufacturing. “Ultimately, these are the technologies that will unlock one-click technology transfer in the future, which will be a key component of faster product launches, including individualized treatment,” he adds.

“Time can be saved using modular facilities and equipment that can be assembled offsite, and rapidly deployed,” continues Crincoli. “There is more equipment available with the ability to manufacture multiple forms (i.e., vials or syringes) on the same line, and employing single-use equipment can reduce cycle times while improving the overall speed of manufacturing campaigns. Time can also be saved, for example, when expediting a commercial launch, using strategies such as scaling out rather than scaling up, and again, utilizing continuous manufacturing where it offers an advantage.”

The importance of continuous manufacturing is growing, affirms Pettus, who agrees that it can help eliminate the scale-up issues that were common with the “one-size-fits-all” product development and commercialization process. “Instead of scaling up, continuous manufacturing capacity is increased by scaling out,” he states. “Organizations can use the same continuous manufacturing technology in their product development, clinical trial manufacturing, and commercial manufacturing. As demand increases, they can simply copy the technologies to new manufacturing facilities to increase output or bring manufacturing closer to a population in need, without the additional burdens of scaleup design and its associated technology transfer complications.”

Gupta is also in agreement about the exponential growth of continuous manufacturing and adds that further balance within bio/pharmaceutical manufacturing is being found in terms of opportunities as well. “Customers today are demanding higher quality at a lower cost,” he says. “Therefore, the playing field has levelled for manufacturers, offering scope and opportunity for new players from emerging markets.”

For emerging therapies, such as cell and gene therapies, more work is needed to balance the complexity of processes required to ensure the risk of errors is minimized, Pettus stresses. “Organizations need to find ways to improve the complicated technology transfer process, which is full of opportunities for errors,” he says. “A decentralized manufacturing model will be important for individualized therapies because they will need to be consistently manufactured closer to the patients, all over the world.”

Although, Deuber reveals that despite initial tools being derived from academia and ultimately not suitable for scale-up purposes, within the past five years much work has already been done by industry leaders in the design of advanced instruments to enable drug developers to improve the quality and manufacturability of innovative new medicines, such as cell and gene therapies. “There have been improvements throughout drug development, from molecule screening to purification,” he says. “For viral vectors in particular, suspension platforms have gradually replaced adherent processes to ensure scalability as the cell and gene therapy space expands to include further indications.”

Finally, Byrd iterates the importance of viewing equipment, software, and technology suppliers as valuable resources throughout the value chain, thanks to the expertise they can provide to guide risk assessments and selections of technologies on what is fit -for-purpose. “Vendors often engage with regulators to help them understand the underlying mechanisms in the products they provide and therefore assist industry to gain acceptance for deploying more modern manufacturing approaches that maximize the quality and efficiency of manufacturing processes and reduce costs,” she asserts.

“In an industry that is justifiably risk averse, change needs to be balanced with assuredness,” concludes UpDyke. “As new initiatives come along, there is a lot of work done to understand regulatory, quality, and reliability impacts. A lot of peer review and collaboration, such as the work done through BioPhorum [a global collaboration of industry leaders and subject matter experts], helps to ensure that new solutions are fully vetted and understood.”

Pharmaceutical Manufacturing: Trends Shaping the Future

. Industry Report, March 2022.
2. Mordor Intelligence. 

Pharmaceutical Manufacturing Market—Growth, Trends, COVID-19 Impact, and Forecasts (2023–2028)

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.


Vol. 47, No. 4
April 2023
Pages: 16–20

When referring to this article, please cite it as Thomas, F. Balancing Change and Certainty in Manufacturing. 

Articles

As new manufacturing processes and technologies are introduced to meet demand and overcome challenges, understanding also needs to improve to ensure the right balance is achieved.  

Balancing Change and Certainty in Manufacturing 

For some time now, the bio/pharmaceutical industry has been under increasing pressure to deliver efficient therapeutic products at pace and reduced costs. Global factors, such as the COVID-19 pandemic, rising rates of inflation, geopolitics, and novel therapeutic modalities, are compounding industry pressures and leading companies to renew their focus on operational strategies (1).

Faster speed-to-market, lower operational costs, improved product quality consistency, and better process control are just some of the key benefits that can be provided to the bio/pharmaceutical industry through process intensification (2). However, despite there being considerable research in certain fields where continuous processes have been implemented, there is limited information on end-to-end continuous systems, perhaps as a result of the separation between synthetic and formulation sections (3).

When approaching drug development via intensified/continuous processes, there are some important formulation considerations to take into account, such as the particle characteristics of both the API and the excipients, confirms Thomas Durig, senior R&D director, Life Sciences, Ashland. “Continuous manufacturing relies on automated, mechanical, gravimetric feeding to dispense the right proportions of the various components. Powder ‘feedability’ and flowability are therefore paramount,” he says. “Particle characteristics such as size, shape, bulk density, surface area, cohesiveness, electrostatic charging tendency, surface roughness, stickiness, and hygroscopicity can all affect successful continuous manufacturing.”

Additional care should be taken over determining whether the drug can be formulated using excipients that allow for direct compression or roller compaction (dry granulation), which are the current best-established continuous processes for oral solid dosage forms, emphasizes Durig. “If wet granulation is required, one must consider the rate limiting and potentially destabilizing step of drying the granulation, so a further consideration would be whether the product could be produced via melt granulation (i.e., twin screw hot melt extrusion), this can obviate these limitations of wet granulation. There are a lot of advances being made in this aspect by leading companies and academic institutions,” he notes.

“Process intensification and continuous unit operations are fast becoming the new normal in biologics manufacturing, as they enhance productivity through the efficient use of production suites,” adds Paresh Vadgama, fellow scientist, Biologics Product Development, Catalent. “Though the biopharmaceutical industry has successfully implemented processes for drug substance (DS), its application for drug product manufacturing is still nascent. Biologics, being complex and highly sensitive molecules, have selected excipients added to protect them against various environmental factors during production and transportation,” he says.

Other than considering the molecular stability and drug product presentation needs, Vadgama notes that understanding of other factors, such as the DS dilution ratio, product compatibility with contact parts, and risk of exposure to environmental factors, is also required. “In addition, specific dosage form needs, including particle size and its distribution for suspension, or residual moisture for lyophilized powder, as well as stability-indicative analytical methods for real-time quality monitoring, should also be considered,” he states.

There are many formulation challenges that pertain to intensified processes, Vadgama continues. “One main issue to consider is the risk of a high titer or a high density/intensified fed-batch producing concentrated solutions,” he explains. “Such solutions may be too viscous to handle during filtration and filling operations. Moreover, these circumstances offer the potential for aggregation due to the absence of a stabilizer. Amino acids, such as arginine hydrochloride, or salts, including sodium chloride, can be added at the upstream stages of bioprocessing to protect protein molecules.”

Monitoring the attributes of a product in real-time during continuous process control and product quality monitoring has always been challenging, Vadgama stresses. “However, performing at-line rapid analysis using standard techniques of multiple sterile samples collected along the process flow, could potentially resolve such challenges,” he states.

Moving to downstream processes and the aggregation risk of shear-sensitive molecules can be problematic as this makes them difficult to handle in high-speed filling machines, Vadgama adds. “Optimizing stabilizer and/or surfactant ratio during formulation development can help to reduce the negative impact of mechanical interfacial stresses,” he explains. “In addition, scale-down modeling using computational fluid dynamics can be best suited to studying molecular behavior while undergoing anticipated processing conditions.”

“Generating multiple drug product batches from a single drug substance batch in a continuous mode is also very difficult,” Vadgama emphasizes. “Factors such as diverse dosage forms, product batch size, and variable market forecasts play a significant role.”

To mitigate the risks posed by the aforementioned challenges without negatively impacting the microbiological quality, Vadgama points to a few different strategies, such as splitting the DS batch or diverting material and parallel product manufacturing in dedicated good manufacturing practice suites. “The key to success is to ensure end-to-end, detailed process and raw material movement mapping and synchronization between various teams,” he says.

“Some of the specific challenges [when formulating for intensified processes] are the need for ‘feedable’ excipients and the risk of variability that would render gravimetric feeding/dispensing and process control very tricky,” asserts Durig. “Potential solutions [to these challenges] include ensuring that the process can handle the inherent variability in powder characteristics that impact feedability, and choosing only formulation components in which the powder properties are optimized, well-understood, and controllable.”

Pointing to some examples of excipients that are optimized for continuous manufacturing, Durig highlights two options available from Ashland, Benecel DC HPMC (hypromellose)—an existing, approved excipient—and Polyplasdone Plus crospovidone—which is pending approval. “[These products] are important because they are surface-optimized excipients that also include glidant and lubricant,” he states. “These factors enable powder feeding of otherwise poorly flowable and controllable finely divided solids as well as good tablet compaction.”

Continuous tablet coating can also pose a challenge to formulators as a result of the drying/mass transfer of water in the formulation, which can take an order-of-magnitude longer than the other close-coupled process times, reveals Durig. “The consequence is that drying can be rate limiting,” he says.

Some possible solutions to help with continuous tablet coating issues include advanced coaters, such as the ConsiGma coating modules (GEA, Germany), or continuous coaters, such as KOCO (L.B. Bohle, Germany), adds Durig. “However, here too, process time limitations exist. These can be overcome with purposely designed ultra-high solids, ultra-high spreadability coating products such as Ashland’s Aquarius Genesis film coatings,” he says.

In June 2022, the US Center for Drug Evaluation and Research’s (CDER’s) Office of Pharmaceutical Quality (OPQ) published an article regarding the results of a self-audit that they performed about the regulatory approved products that had been manufactured using continuous processes versus those that had been batch manufactured (4). Specifically, confirms Ana Ladino, Global Regulatory Affairs director, Life Sciences, Ashland, the OPQ looked at the time to approval and market entry, manufacturing process changes reported in annual reports, manufacturing-related post-approval application supplements, and pre-approval inspections. Based on its self-audit, FDA concluded that continuous manufacturing technology has regulatory advantages and economic advantages, and that its use should be encouraged in the development and manufacture of drug substances, she notes.

Less than a year later, in March 2023, the International Council for Harmonisation (ICH) published the Step 5 version of its Q13 guidance on continuous manufacturing (5), which expands upon the guidance set out by FDA back in 2019 (6). “ICH’s Q13 guideline, soon to be effective in the EU [European Union], is the first step towards harmonizing scientific and regulatory principles covering batch definition, control strategy, process validation, and stability studies,” asserts Vadgama. “Key regulatory messages for continuous manufacturing from this guidance include: that the dossier should summarize process integration for each unit operation, along with input raw material attributes, feedforward, and feedback process controls; process dynamics should be well understood with respect to changing inputs or operational conditions or transient events, which in turn would require deeper formulation robustness studies; the mode of manufacturing can be converted from batch to continuous, with appropriate control strategies and comparability exercises, even after product approval; details of the real-time release testing model to measure protein content, residual moisture, and protein stability are to be provided as applicable.”

Improving speed of product development and reducing costs are the two main drivers for businesses to adopt intensified processes, Vadgama stresses. “However, the technology still needs to evolve for it to be suitable for broader implementation within the drug product space,” he says. “Several non-technical limitations may explain this phenomenon: for example, initially, high capital investment is required to automate equipment, innovate process analysis/control technologies, and standardize practices across sites. But increased productivity, higher facility utilization rates, and lower labor costs would, given time, drive production efficiencies and savings.”

When approaching continuous production as an integrated unit operation, there could be some impact on the organizational structures of the purification and formulation areas as the distinction between these facets will become blurred, Vadgama continues. “Such changes can alter working practices, due to transitioning from a batch production mindset,” he explains. “In the drive for process excellence, emphasis should be given to operational control and regulatory compliance; therefore, receiving the full support of top executives and management is vital.”

Focusing on the supply chain, it is important to note that continuous operations require an uninterrupted supply of raw materials of consistent quality, Vadgama adds. “Single-use, disposable components form the backbone of the supply chain for continuous manufacturing workflows,” he summarizes. “Diversifying supply, better long-term inventory planning, and quality assurance teams being able to thoroughly qualify vendors can help remove the risk of supply chain issues.”

“Industry and stakeholder perceptions regarding the risk of adopting newer state-of-the-art manufacturing technologies are obstacles that must be overcome,” warns Durig. “The pharma industry tends to be conservative about adopting new manufacturing and formulation technologies.” Using twin-screw melt granulation as an example, he points out that despite the advantages such a technique can offer when compared with wet granulation approaches to continuous manufacturing, perceptions still exist that the technology could have an adverse effect on API stability.

“These perceptions and the obstacles they present to new technology can be overcome through trial and investigation. Continued education and collaboration among industry stakeholders, drug product manufacturers, equipment manufacturers, excipient companies, and academia are required,” Durig concludes.

1. Dukart, H.; Lanoue, L.; Rezende, M.; Rutten, P. Emerging from Disruption: The Future of Pharma Operations Strategy. McKinsey and Company, Oct. 10, 2022.
2. Yazdanpanah, N. Continuous Manufacturing in the Pharmaceutical Industry. 

, March 2021.
3. Domokos, A.; Nagy, B.; Szilágyi, B.; Marosi, G.; Kristóf Nagy, Z. 

, 25 (4), 721–739.
4. FDA. An FDA Self-Audit of Continuous Manufacturing for Drug Products. 

, June 28, 2022.
5. EMA. EMA/CHMP/ICH/427817/2021 

ICH Guideline Q13 on Continuous Manufacturing of Drug Substances and Drug Products

. Step 5 version, March 3, 2023.
6. FDA. Quality Considerations for Continuous Manufacturing; Draft Guidance for Industry; Availability. 


Vol. 47, No. 4
April 2023
Pages: 24–26, 44

When referring to this article, please cite it as Thomas, F. Formulating Drugs for Continuous Processing. 

Despite the advantages intensified processes can offer developers, there are still some obstacles to overcome before broader application of new technologies will be implemented.

Formulating Drugs for Continuous Processing

The biopharmaceutical market is experiencing continued growth—forecast to reach $769.45 billion by 2030 (1)—driven by factors such as an aging population and the increasing prevalence of chronic diseases. Additionally, thanks to the ability of biopharmaceuticals to treat diseases that were once considered ‘untreatable,’ there is a greater acceptance of these therapies across the board within the industry.

Biopharmaceutical drugs, however, are intrinsically unstable and predisposed to degradation and may require processes that can maintain the product’s stability during storage and transport. “Protein-based biologics are susceptible to various stresses such as temperature excursions, pH shifts, shear, interfacial adsorption, moisture, organic solvents, and so on. Some biologics are less stable in their liquid state and may undergo hydrolysis, thereby, leading to protein aggregation and/or denaturation. Moreover, the storage and transport of bulk products in their liquid or frozen state increases the need for cold chain shipping requirements and validation,” confirms Ashutosh Sharma, researcher, Pharmaceutical and Molecular Biotechnology Research Centre, SETU Waterford (Formerly, Waterford Institute of Technology), Ireland. “To combat some of these challenges, freeze-drying of biologics is deemed suitable for many products.”

Freeze-drying, or lyophilization, of therapeutic products is a well-established technique within industry. The batch freeze-drying process is commonly used for a variety of biologics, such as enzymes, antibodies, fusion proteins, nanobodies, vaccines, hormones, and gene therapy products, according to Sharma. “Some advantages of freeze-drying include improved stability and shelf-life of labile biologics, reduced chemical decomposition and cold chain requirements, and low residual moisture content post-processing,” he says.

According to market research, the global market for lyophilization services for biopharmaceuticals is expected to grow at a compound annual rate of 10.1% between 2022 and 2030 (2). This growth is undoubtedly reflective of the increasing demand for biopharmaceuticals that is being witnessed by industry as a result of the therapies’ high specificity for treating widespread diseases, as well as their improved interactions with cellular receptors and other biomolecules, Sharma notes.

“Being high-value products, ensuring a high standard of safety, quality, and efficacy of [biopharmaceuticals] is of utmost importance,” says Sharma. “As per a review by Gervasi 

 (3), nearly 34% of biologic products are lyophilized formulations in the European market. Two key drivers for this technique are to improve and increase the shelf-life of biologic drug products and to reduce complexities associated with cold chain requirements of liquid and/or frozen bulk products while the technique itself has its own challenges.”

When freeze-drying drug products, there are several fill/finish unit operations in addition to lyophilization, such as freeze-thawing, time out of refrigeration, vial filling, and so on, that need to be considered which could potentially impact the products’ critical quality attributes (CQAs), Sharma stresses. However, focusing on conventional lyophilization, which is one of the major unit operations for freeze-dried products, there are a few key challenges that should be noted, he states.

“Firstly, long processing times that could vary from days to weeks with high capital costs and high energy consumption leading to reduced efficiency in the overall process [are a significant challenge],” Sharma says.

Then, there is the potential for some biologics to experience cold denaturation during the freeze-drying process, Sharma continues. “The requirement for appropriate formulation components including cryoprotectants and lyoprotectants as well as their impact on the overall glass transition temperature and melt temperature is very essential at the formulation development stage prior to lyophilization,” he says.

Other concerns pertain to the heat and mass transfer, as well as scaling up of the process—all of which are under discussion (4–6)—which can be dependent upon the dryer designer, container closure, load condition, and product formulation, Sharma emphasizes. “Vials situated on the edge of the shelves dry faster than vials present in the center due to radiation from the chamber walls which causes issues of vial-to-vial heterogeneity,” he says.

“Moreover, being a static process, [lyophilization] increases the risk of rejection of the entire batch in case of process failure. A batch process is limited to processing small volumes of unit doses which increases the requirement for a large number of vials,” Sharma specifies. “Human intervention during the process can increase the risk of contamination despite current good manufacturing practices (CGMP).”

Furthermore, Sharma points out that the reconstitution of certain high concentration freeze-dried protein cakes can prove problematic and lengthy when compared with free-flowing powders that are produced by alternative drying techniques.

And these challenges are also evolving in the wake of the continued advancement and increasing complexity of the biopharmaceutical therapies in development. “To meet the needs of patients, some biologic products are required in multiple dose strengths. Each dose strength requires a completely different lyophilization cycle with additional qualification and validation for different fill/finish unit operations, primary packaging components supply chain, sterilization and clean validation, container closure integrity, and so on, thereby, increasing the complexity of this technique for certain drug products,” Sharma states.

“To combat some of the challenges associated [with] conventional lyophilization, alternative drying technologies are gradually gaining popularity for the manufacturing of biopharmaceuticals,” asserts Sharma. By way of example, Sharma highlights some of the continuous processes and technologies that are currently under development, such as the Spin-freeze-drying of unit doses technology developed by RheaVita and Ghent University (7), or the continuous freeze-drying of suspended vials that has been developed and described in patent from 2018 (8).

Another alternative approach that has gained some interest within industry has been Electrostatic spray-drying developed by Fluid Air (9), which has the ability to improve drying efficiency with reduced thermal stress, Sharma continues. “Moreover, [aseptic] Spray-freeze-drying by IMA Life and Meridion Technologies (10) and PRINT Technology by Liquidia Corporation (11) are also promising technologies that enable particle engineering for the production of dry powder-based products,” he adds. Further innovative drying techniques have been detailed in a paper by Sharma 

“Along with some of the continuous and alternative drying technologies described above, process as well as product characterization are essential requirements as per CGMP,” Sharma says. “Product and process characterization can be achieved by using process analytical technologies (PATs) and offline characterization techniques. These technologies allow to identify and evaluate critical process parameters and CQAs and may also aid in establishing a correlation between the two.”

Numerous advanced techniques, including near infrared spectroscopy, Raman spectroscopy, infrared thermography, mass spectrometry, and wireless probes, have been evaluated as PAT tools for lyophilization and alternative drying technologies for biologics, Sharma explains. “In addition, other advanced characterization techniques such as solid-state hydrogen deuterium exchange–mass spectrometry and solid-state nuclear magnetic resonance provide more insights on protein-excipient interactions in the solid-state,” he states.

“Overall, these techniques will aid in improving the existing process by providing more insights and better understanding of both the process and the product,” Sharma concludes.

Biopharmaceutical Market by Product Type (Monoclonal Antibody, Interferons, Growth and Coagulation Factors, Recombinant Proteins, Hormones, Vaccines, Cell and Gene Therapies, and Others), by Therapeutic Application (Oncology, Immunology, Cardiovascular Diseases, Neurological Diseases, Metabolic Diseases, Blood Disorder, and Others), by End User (Hospital and Retail Pharmacies, Biopharma Companies, Diagnostic Labs, and Clinical Research Organizations)— Global Outlook and Forecast 2022–2030

. Market Report, Aug. 8, 2022.
2. InsightAce Analytic. 

Global Lyophilization Services for Biopharmaceuticals Market

. Market Report, Aug. 3, 2022.
3. Gervasi, V.; Dall Agnol, R.; Cullen, S.; McCoy, T.; Vucen, S.; Crean, A. Parenteral Protein Formulations: An Overview of Approved Products Within the European Union. 

, 131 (October), pp. 8–24.
4. Patel, S.M.; Pikal, M.J. Emerging Freeze-Drying Process Development and Scale-up Issues. 

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5. Barresi, A.A.; Pisano, R.; Rasetto, V.; Fissore, D.; Marchisio, D.L. Model-Based Monitoring and Control of Industrial Freeze-Drying Processes: Effect of Batch Nonuniformity. 

, 28 (5), 577–590.
6. Sharma, A.; Khamar, D.; Cullen, S.; Hayden, A.; Hughes, H. Innovative Drying Technologies for Biopharmaceuticals. 

 (accessed Jan. 16, 2023).
8. Trout, B.L.; Pisano, R.; Capozzi, L.C. Freeze-Drying Methods and Related Products. WO2018204484A1, 2018.
9. Fluid Air. Electrostatic Spray Drying. 

www.fluidairinc.com/processes/spray-drying

 (accessed Jan. 16, 2023).
10. IMA. Continuous Aseptic Spray Freeze Drying. 

IMA.it/pharma/paper/continuous-aseptic-spray-freeze-drying/

 (accessed Jan. 16, 2023).
11. Liquidia. PRINT Technology. 

www.liquidia.com/products-and-pipeline/print-technology


Vol. 47, No. 4
April 2023
Pages: 32–34

When referring to this article, please cite it as Thomas, F. Accepting Alternative Approaches to Freeze Drying. 

Alternative approaches to freeze-drying are gaining popularity and will help to overcome some of the challenges associated with conventional lyophilization.

Accepting Alternative Approaches to Freeze Drying

As we enter the second quarter of 2023, the revised pharmaceutical legislation for Europe is still, at the time of writing, unpublished. The latest delay to the publication of the new pharma reform, which is the third postponement, came towards the end of March 2023, much to the dismay of members of the European Parliament (MEPs).

MEP and member of the Renew Europe Group, Véronique Trillet-Lenoir, urged the president of the European Commission in a letter issued shortly after the delayed publication was revealed to publish the legislation. In her letter, Trillet-Lenoir indicated that the commission has given into industrial pressure to further postpone the legislative revisions, and she stated that the lack of justification for the delay and the fact that no alternative date for publication has been provided is simply “unacceptable” (1).

“This legislation is key to ensure the fair and equitable access of medicines to all patients, to all Europeans,” she wrote (1). “Today, we are urging you [Ursula von der Leyen] to publish this important legislative package no later than April 2023 to allow the legislative process to start.”

However, there have been glimpses to what might be in store for industry as, at the end of January 2023, the internally circulated proposed reforms were leaked and were met with trepidation by industry. The European Federation of Pharmaceutical Industries and Associations (EFPIA) expressed particular concern about the leaked reforms, which it warned would “irretrievably sabotage” the European Union’s pharma industry (2).

“Whether it is naivety, blind optimism, or a more conscious decision for Europe to rely on innovation from the [United States] and Asia, there should be no doubt that in its current form, this proposed legislation will be extremely damaging to the competitiveness of Europe’s industry and to our region’s strategic autonomy,” specified Nathalie Moll, EFPIA director general, in the reaction press release. “It will have a negative impact on jobs, investment, the European research eco-system, growth, patient access to new clinical trials, and availability of the latest treatments for decades to come.”

With no defined date for publication of the EU’s pharma legislation reforms, the question now becomes whether or not these revisions can be appropriately reviewed before the 2024 European parliamentary elections.

1. Trillet-Lenoir, V. Twitter Post, @VTrillet_Lenoir, 23 March 2023.
2. EFPIA. EFPIA Reaction to Leak of the Proposed Pharmaceutical Legislation. 

When referring to this article, please cite it as Thomas, F. Legislative Hold-Up. 

A further setback to the publication of the pharmaceutical legislative changes in Europe may mean time is running out for appropriate review before 2024 parliamentary elections.

Legislative Hold-Up

In this episode of the Drug Solutions podcast, Felicity Thomas, European/Senior Editor, talks to Rhonda Henry, President of Emmes’ BioPharma Group, and Adam Mendizabal, VP and Director of Emmes’ Cell and Gene Therapy Center, about the role contract research organizations (CROs) play in cell and gene therapy development. Rhonda and Adam will discuss the key factors and solutions driving growth in the CRO market with a particular emphasis on cell and gene therapies entering development pipelines, and will address some of the challenges facing the industry and best practices to ensure these limitations are overcome.

Rhonda Henry is the President of Emmes’ BioPharma Group

. She holds a B.S. in nursing from the University of North Carolina, Wilmington. Rhonda joined Emmes with 30 years of clinical research experience holding a number of leadership positions in clinical operations, patient centricity and strategic partnerships at PPD.Before her entry into clinical research, Henry served as a nurse at New Hanover Regional Medical Center. In 2020, she was named to the PharmaVOICE 100 list of most inspiring people working in the life-sciences industry. She has been active in a number of non-profit organizations, including her current position as chair of the board of directors for The Carousel Center, a nationally accredited child advocacy center serving New Hanover, Brunswick, and Pender counties.

Adam Mendizabal, PhD is the VP and Director of Emmes’ Cell and Gene Therapy Center

. He joined Emmes in 2002 and has progressively increased responsibilities from a Biostatistician and Sr Investigator to his current role leading the expansion and of the cell and gene therapy clinical trial portfolio at Emmes. During his time at Emmes, Adam has co-authored publications across different therapeutic areas that have focused on cell and gene therapies. He received his Bachelor’s degree in Biological Sciences from Rutgers College in 2000, a Master’s degree in Statistics from Rutgers University in 2002, and a PhD in Epidemiology from The George Washington University in 2014.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Podcasts

In this episode, Rhonda Henry and Adam Mendizabal from Emmes discuss the role CROs play in cell and gene therapies undergoing clinical trials at all stages.

Drug Solutions Podcast: How CROs Adapt Themselves in the Ever-Changing Landscape of Cell and Gene Therapies

There are myriad factors influencing the drug delivery market, such as the rising prevalence of chronic conditions, an ageing population, and technological advancements in drug development, leading analysts to predict continued growth in the sector at a compound annual rate of 3.7% between 2022 and 2030 (1). A significant driver of growth within drug delivery has been highlighted as the advancement of the biopharmaceutical industry, which is giving rise to new and innovative drugs for previously untreatable or incurable diseases and, hence, the need for ways to deliver these novel therapies.

To learn more about influential drug delivery trends, market drivers, aspects of drug delivery that require greater research, and how partnering with an outsourcing company can help in this sector, 

® spoke with Torkel Gren, senior director, science and technology officer, and Uwe Hanenberg, head of product development, Oral Solid Dose, both at Recipharm.

 Over the past decade, what, in your opinion, have been the most influential developments in alternative drug delivery formulation?

 The most influential development in recent years has been the advance in solid lipid nanoparticles that allowed the development of mRNA [messenger RNA] vaccines to tackle COVID-19. [This advancement] opens up the opportunity to develop many new pharmaceutical products with increased efficacy in the future. There is plenty of potential to harness mRNA technology to create exciting new vaccines and other therapies to tackle previously untreatable conditions over the next decade.

 What trends in alternative drug delivery formulation do you think may be seen during the next decade?

 There will be increasing investment in new delivery technology for targeted and or simplified drug delivery. The effect/side effect ratio of a large number of drug substances can be significantly improved when delivered directly to the site of action. Administration by injection will play a key part here, alongside other delivery routes—topical, pulmonary, and ophthalmic, for example.

Integration of dosing with smart devices will also be a major theme in the coming decade as a means of increasing patient adherence. By monitoring biodata, such as blood glucose, these systems can provide both patient and HCP [healthcare professional] with valuable information to ensure that medication is used optimally to meet the unique needs of individual patients.

It is expected that the next decade will see advances allowing oral delivery of a greater number of biologic formulations. Efforts are already being made to develop a platform technology to support absorption of orally administered biopharma treatments, with exciting potential to further improve patient convenience.

 Could you elaborate on any of the market factors that are driving growth in the alternative drug delivery formulation sector?

 Rising demand for new biologics has created the need for special formulations for these treatments. It is important to note that the term ‘biologics’ refers to a large number of different modalities, from monoclonal antibodies, nucleotides, CAR-T [chimeric antigen receptor T] cells, and microbiome products. These all have their specific scientific challenges, each requiring a different formulation approach.

Interest in improved treatment for small indications has also contributed to greater demand for alternative drug delivery, as these often call for some special drug delivery solutions.

 How have these drivers changed over recent years?

 The trend toward more advanced biological treatments with a higher potential to cure the disease rather than just its symptoms has implications for drug delivery. Technologies that ensure an effective treatment by improving the stability of the active ingredient and that can be administered easily (e.g., orally) are drivers and will enhance patient compliance This could increase the demand for specialized drug delivery solutions in the coming years.

 Are there any areas in alternative drug delivery formulation approaches that still require a significant amount of research?

 [There have been] impressive developments in new biological medicines in recent years, with a number of new therapies entering the global market. However, the cost of these products has undermined their impact on public health and wellbeing. More work needs to be done to reduce development and manufacturing costs of these biopharma treatments while optimizing their efficacy.

New drug delivery technology may help solve this problem in the future. Better formulation approaches, for example, have the potential to improve stability, resulting in longer shelf life and reduced need for cold storage. This can cut distribution costs significantly, especially in countries with warm climates and limited infrastructure. Currently, biologics that have exceeded their shelf life or been transported outside their allowed temperature interval have to be disposed of—which is also very costly.

The fact that most biologics today need to be administered by injection is also contributing to their relatively high overall treatment cost, as this usually means they must be administered to patients by HCPs. There is some interesting work on alternative administration routes (orals, buccal, and pulmonary, for example), but it is likely that injection will continue to dominate in the future, due to the unique stability and absorption characteristics of biopharma. Injectable delivery systems, such as auto-injectors, which allow self-administration by the patient in the home, can help reduce costs by eliminating the need for a trip to a clinic to be treated by a HCP. Depot formulations allowing monthly dosing instead of daily injection can also reduce the burden on HCPs and clinics.

 What is the role of an outsourcing partner in the alternative drug delivery formulation market?

 Many different types of drug delivery technologies will be needed for different modalities, administration routes, and markets. As such, it is almost impossible for pharmaceutical companies to fill all their needs in-house. Outsourcing drug development and manufacturing to contract development and manufacturing organization partners can address this issue. By working with partners that have experience in a particular alternative technology, companies can benefit from specialist expertise and infrastructure, helping to smooth their development journey.

Pharmaceutical Drug Delivery Market (by Route of Administration: Oral, Pulmonary, Ocular, Nasal, Injectable, Topical, and Others; by Application: Cardiovascular, Diabetes, Cancer, Infectious Diseases, and Others; by End Users: Hospitals, Ambulatory Services, and Home Healthcare)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2021–2030


Vol. 35, No. 3
March 2023
Pages: 14–15

When referring to this article, please cite it as Thomas, F. Influencing Change in Drug Delivery. 

Advancements in therapeutic modalities are necessitating change in drug delivery to help negate some of the expense of development and manufacturing.