Having a clear clinical strategy early on can shave time off overall development projects.

Early Strategizing Tightens Development Timelines

With recent approvals of bispecific antibodies, these complex molecules are fast moving out of the research box and into clinical pipelines.

Bispecific Antibodies are Moving from Research to Clinical Development

Extensive work has greatly expanded the possibilities for fetal bovine serum sourcing.

Considerations for US Fetal Bovine Serum Sourcing

Thanks to technological advances, process chromatography challenges are surmountable, but increasingly complex therapies in the pipeline will demand more efficient processes in the future.

Advancing Process Chromatography in DSP

The complex nature of biologics creates challenges for GMPs in sterile manufacturing, and the EU’s Annex 1 is making an impact.

GMPs for Sterile Manufacturing of Biologics

Precompetitive consortiums seek solutions to industry-wide challenges.

Coming Together to Enable Cell and Gene Therapy Manufacturing

When considering whether to outsource work to a CRO, there are a number of factors to assess, including the type of work that may be outsourced, regulatory considerations, and needs for the study.

When Is It Appropriate to Outsource Bioanalysis Work to a CRO?

Jennifer Markarian is manufacturing editor of BioPharm International.

Automation—using machines rather than people to perform tasks—offers benefits to biopharmaceutical manufacturers in multiple facets of plant operation, such as transporting materials, taking samples, and controlling the process. Digitalization—replacing manual records with digital ones and using data in a variety of digital tools and connected systems—works synergistically with automated processes. Data collected from equipment that is connected via the industrial Internet of things (IIoT) and analyzed with artificial intelligence (AI), for example, allow the control system to know when a process is trending out of specification, or when a piece of equipment needs maintenance. The digital or “intelligent” plant makes use of both automation and digitalization.

“With the advance of data science enabling factors such as easy access to scalable memory and computing resources; our growing competence in collecting, storing, and contextualizing data; advances in robotics; [and] the quickly evolving method landscape driven by the open-source community, the benefits of automation and simulation are becoming accessible in the notoriously complicated realm of biopharma manufacturing,” says Marcel von der Haar, head of product strategy data analytics at Sartorius.

Business benefits of the digital plant include getting new products to market faster; faster changeover of products, which enables flexible and multi-product manufacturing; improved operational integrity, which includes predicting and correcting potential problems before they occur; and real-time release, which makes production faster and minimizes inventory, says Nathan Pettus, president of process systems and solutions at Emerson. Digital tools accelerate the pipeline and help commercialize products faster by easing technology transfer. “For example, cloud-enabled knowledge management software that manages product and process specifications through the entire drug development lifecycle is enabling biopharma manufacturers to minimize errors in the tech transfer process,” says Pettus.

Automation leads to improved product quality and compliance, reduced risk, and improved productivity, says Heather Coglaiti, global industry strategy and marketing lead for life sciences, Rockwell Automation. An increase in right-first-time occurrences leads to fewer deviations and investigations. Predictive or adaptive mechanisms to prevent equipment failure, as well as real-time asset management, help reduce operational risk, she explains.

“Automation, even partially digitized, reduces the human errors associated with batch-to-batch variability,” adds Dennis Brandl, BRL Consulting. For example, automated dispensing systems have less variability than manual dispensing. Automation also eliminates human error associated with manual data entry.

Automation provides consistency in performance, quality, and process, agrees Dushyant Arora, life sciences industry manager for Siemens Pharma USA. He explains that automation and digitalization enable online quality testing and review-by-exception, which can enable real-time release.

Automating flexible and intensified processes

Adoption of these technologies in biopharma is driven in part by the ongoing push for speed-to-market and the trend to flexible and multi-product manufacturing. Digital technologies are also a crucial part of continuous processing.

“As life sciences plants have moved away from manufacturing a single product and are focused more on developing a wider range of specialized treatments, the importance of flexible manufacturing has taken center stage,” explains Pettus. “Plug-and-play” capabilities of automation systems, which enable flexible manufacturing and faster technology transfer, are more important than ever, he says.

For scaled-down and distributed systems that use multiple, identical manufacturing lines located in one facility or at multiple sites, the ability to collect and share information across the enterprise is crucial, adds Pettus. “Today’s automation platforms leverage scalable ‘data aggregators,’ often based on software-as-a-service models and cloud-architectures. [This ability to scale allows] companies to use automation from the beginning, develop the right process, and then scale the solution as they build their business and infrastructure globally,” he explains. Pettus concludes, “At any scale, there is too much at stake to dismiss automation and digitalization, as they are truly critical pieces of the quality puzzle.”

Intensified and continuous processes rely on real-time testing for process control. “We are focusing our efforts for the ‘factory of the future’ on process intensification and connecting unit operations together, which is enabled by single-use technology, automation, and process analytical technology (PAT),” says Darren Verlenden, head of bioprocessing at MilliporeSigma, the US and Canada life science business of Merck KGaA.

MilliporeSigma’s good manufacturing practice (GMP) PAT platform for bioprocessing includes a Raman spectroscopy analyzer and software that can achieve in-line, real-time monitoring of process parameters and quality attributes. These data can be used to automate control of the bioreactor. In April 2022, the company acquired Lonza’s MAST platform, an automated, sterile bioreactor sampling system; upon closing, it will become part of MilliporeSigma’s BioContinuum platform. The GMP MAST system will help processors evolve from manual sampling to automated sampling, says Verlenden.

Digital transformation is an ongoing journey, says Verlenden. He adds that some customers may want to run a fully continuous, automated process, while others want to intensify and automate certain unit operations.

The digital biopharmaceutical manufacturing plant is the “facility of the future,” but it is also a reality today. Sanofi’s digital and paperless facility in Framingham, Mass., for example, won the 2020 overall Facility of the Year Award (FOYA) from the International Society for Pharmaceutical Engineering (ISPE). The company says that the manufacturing facility is 80 times more productive than a traditional facility and has a smaller environmental footprint (1). ISPE’s 2022 FOYA category award for innovation went to another digital plant located in Framingham, Mass.: CRISPR Therapeutics’ facility, which uses digital systems and automation for production and filling operations (2). Digital tools allow this facility to manage multiple production suites and products at different stages of development (2). Takeda Pharmaceuticals International’s vaccine facility in Singen, Germany won ISPE’s 2022 Pharma 4.0 category award for its use of digital technologies, which include an electronic batch record system, an embedded warehouse management system, and autonomous mobile robots to transport materials (3). ISPE’s Honorable Mention-award winner, Iovance Biotherapeutics’ autologous cell therapy facility in Philadelphia, uses digital tools, including electronic batch records and centralized equipment monitoring (4).

Walvax Biotech’s new COVID-19 messenger RNA (mRNA) vaccine plant in China is another example of an intelligent and digital plant; it uses Honeywell’s batch process control, building and energy management solution systems, and digital twins to monitor assets (5).

“As the need for speed and agility increases, biopharma production facilities need some way to better visualize and integrate batch processing across various equipment and systems,” says Shawn Opatka, vice-president and general manager, life sciences at Honeywell. He explains that the data capture, recording, and reporting systems used by Walvax will help maintain auditability as well as optimize production. Opatka says that data from the live process will be sent to the digital twin, where operators can proactively watch for problems and fix them before they occur.

“The application of AI is paramount and will continue to grow as many organizations progress in their digitalization journey,” says Opatka. “We see more biopharma customers interested in having plants with planning and production executed automatically and using advanced analytics.”

Using AI in predictive analytics to anticipate manufacturing problems—the predictive plant—is the next level of digital maturity after a connected plant, says Yvonne Duckworth, Industry 4.0 specialist, director of digital technology, and senior automation engineer at CRB. “Predictive analytics can reduce downtime and promote quality,” says Duckworth. She points to a real-life example of a vibrating agitator that unthreaded itself before the operators noticed; if a vibration sensor had been attached to the agitator, the control system would have flagged the vibration as a concern before it could have been seen by a human eye. “Some equipment vendors don’t yet offer this capability; some have vibration or temperature sensors available as options, and others offer a fully integrated predictive analytics platform,” says Duckworth. “Vendors have been challenged over the past year to have an answer to the question of predictive analytics capability.”

Another step forward on the digital journey is the use of digital twins, which are digital models of a physical system. Brandl says that digital twins have been used for the past 30 years in process industries where the chemistry of the processes is well understood. Only recently, however, enabled by AI and data availability, have digital twins been developed for biological processes, where there is no ‘first principle’ development possible, he says. “Automation brings in the data for machine learning to model the dynamic processes of cell growth and map it against the multiple dimensions provided by advanced sensors,” explains Brandl.

Digital twins are being used today in biopharma process development to optimize the process in a simulated environment. They can also be used for collaborating in real-time across the value chain and validating new lines and processes virtually, says Coglaiti.

“We will likely see biopharma manufacturers moving from using the digital twin primarily as a simulation and training component to making it a key part of the overall dynamic control of the process,” suggests Pettus. “Manufacturing models are becoming more well defined and well understood, and measurements that were virtually impossible to understand in the past are now enabled with various technologies such as spectral-based techniques. As the industry becomes more comfortable with this more complex, closed-loop control and includes the digital process response predictions with advanced control techniques, we will see the digital twin become even more relevant than it already is today.”

“Today, digital process twins based on statistical models, such as multivariate statistical process control, are increasingly widely applied to obtain predictive and even prescriptive insights into biological process development as well as GMP manufacturing,” adds Mark Demesmaeker, head of data analytics at Sartorius. “We are now moving toward the next step, which will combine data-driven methods and mechanistic concepts—such as growth kinetics and specific metabolite consumption rates in upstream processing, and fluid dynamics or neural networks in downstream processing—to obtain enhanced observability of highly complex cell culture processes or separation and purification steps. This will allow the industry to advance to a closed-loop model predictive control strategy in the coming years.”

Experts agree that there are some regulatory challenges to the concept of applying AI-based models to closed-loop controls. “The use of AI, or even machine learning in a regulated environment, still needs a more elaborated validation framework to manifest [the] great promise [of these technologies],” says Dirk Wollaert, digitalization lead at Siemens Pharma headquarters.

Pettus says that Emerson and others are working together in the BioPhorum consortium to develop strategies
to meet this challenge. “We are optimistic that a path forward for these remaining regulatory hurdles is already underway, particularly as we continue to work with BioPhorum, other similar organizations, and companies that are already engaging regulatory bodies around the world,” he explains.

Despite these many potential benefits, one of the obstacles to automation is the difficulty of calculating the return on investment of a project. Identifying the value is key, says Verlenden.

Duckworth agrees that cost can be a barrier. “Identifying the problem you’re trying to solve makes it easier to identify the savings,” she explains. Some are concerned about the cost and effort of revalidating an existing process, she adds.

“It is important for companies putting in a new facility to think about what approach they want to take from a digital technologies perspective,” adds Duckworth. “A lighthouse approach incorporates all the new technologies at the start. A phased approach, however, can be more beneficial if there are limited resources or a need for speed to market. In this case, we can design a robust network infrastructure which will allow for more advanced digital technologies to be added in later phases.”

Development-stage biotech companies that are moving to commercial manufacturing may not be as familiar with automation and the requirements for using computer systems in GMP environments, such as computer system validation, says Michel Claes, biopharma portfolio lead at Siemens. System integrators can provide guidance, he suggests.

In the past, connecting different types of equipment was a big challenge for automating bioprocesses, but this difficulty has begun to be addressed by modular systems and open-source module type package (MTP) communication protocols that standardize the connections.

“With MTP, organizations can easily add new equipment without having to worry about compatibility and need not spend weeks or months integrating equipment when moving from bench-scale to production-scale,” says Pettus.

Standard interfaces make it easier to integrate PAT sensors into automation systems, says Brandl. “Adding a new sensor for pH, oxygen, or carbon dioxide, for example, can be done at 10% of the cost that it was a few years ago,” he says. Another key development provides the ability to port automation logic across platforms, which is important for biopharma companies that have production in different parts of the world, says Brandl. “PLCOpen has provided the ability to use the same machine control strategies in different facilities using locally supported automation systems,” he explains.

Industry members have been working with the BioPhorum consortium to further pave the way for plug-and-play automation. A current issue is a lack of standardization for data integrity requirements, such as audit trails. In a 2021 paper, BioPhorum proposed a harmonized audit trail model, which is intended to stimulate development of a formal international standard (6).

Maintaining data integrity faces multiple challenges. “Organizations must centralize their data because traditional on-premises historians often lack the metadata and contextualization required to uphold data integrity,” suggests Petter Mörée, managing director for EMEA, Seeq. In addition, he says, data must be reliably stored and managed and available throughout its lifecycle.

Having the right workforce with the suitable skills necessary to incorporate and maintain digital technologies can be another challenge, says Duckworth. Recognition of the need for workers to have digital skills is part of the European Commission’s “Industry 5.0” vision, which seeks a human-centric approach to digital technologies (7) and incorporates sustainability into the way industries are moving forward.

Technology is driving rapid and significant change in biopharmaceutical manufacturing, with more to come, experts suggest.

“Most industry players have merely scratched the surface of what could become a fully automated and digitally twinned manufacturing process,” says von der Haar. “At Sartorius, we are convinced that the companies that adopt and master these methods will disrupt and guide the biopharmaceutical industry in the coming years, generating benefits ranging from drastically reduced time-to-market, lower process variability and failure rates, [and] resource efficiency gains.”

“Real time release, one-click tech transfer, autonomous plants, and self-adjusting processes are going to be important in our future,” says Pettus. “I would be very surprised if these four areas are not significantly developed and advanced in the coming three to five years. The life science industry is going to impact all of humankind over the coming two decades in ways similar to how the semiconductor industry has over the past 50 years.”

2. ISPE, “2022 Category Winner for Innovation,” 

3. ISPE, “2022 Category Winner for Pharma 4.0,” 

4. ISPE, “2022 Honorable Mention Winner,”

5. Honeywell, “Honeywell Collaborates With Walvax Biotech To Automate China’s First Digital mRNA Covid-19 Vaccine Plant,” Press Release, Feb. 1, 2022.

6. Biophorum, “On the Plug-and-Play Audit Trail to Connect Intelligent Pieces of Equipment,” Press Release, July 22, 2021.

https://ec.europa.eu/info/research-and-innovation/research-area/industrial-research-and-innovation/industry-50

Jennifer Markarian is manufacturing reporter for

When referring to this article, please cite it as J. Markarian, “Automating Biopharma Manufacturing,” 

Articles

Automation and digitalization work together in the digital plant.

Automating Biopharma Manufacturing

Mili Pathak is principal scientist, Process Science, R&D, at Intas Pharmaceuticals Ltd. (Biopharma Division), Ahmedabad, Gujarat, India.

Prashant Pokhriyal is associate scientist at Intas Pharmaceuticals Ltd. (Biopharma Division), Ahmedabad, Gujarat, India.

Ronak Patel is principal scientist, R&D, at Intas Pharmaceuticals (Biopharma Division), Ahmedabad, Gujarat, India.

Laxmi Adhikary, PhD, is senior vice-president, R&D, at Intas Pharmaceuticals (Biopharma Division), Ahmedabad, Gujarat, India.

The concept of end-to-end adoption of modeling and simulation tools for biopharmaceuticals process development is still seen with mixed views across industry professionals. The lack of standard analytics frameworks leads to suboptimal output and limits their widespread applicability. Additionally, the business impact of these tools is poorly understood because of the dearth of case studies on them. In this article, the authors present a business case study to investigate the returns from these tools. The authors also extrapolate the benefits to the overall drug development timelines and portfolio for the biosimilars industry.

Submitted: Jan. 25, 2022.
Accepted: March 22, 2022.

Mili Pathak*, PhD, mpathak38@gmail.com, is principal scientist, Process Science, R&D; Prashant Pokhriyal is associate scientist, Process Science, R&D; Ronak Patel is principal scientist, R&D; and Laxmi Adhikary, PhD, is senior vice-president, R&D; all at Intas Pharmaceuticals (Biopharma Division), Ahmedabad, Gujarat, India.

*To whom all correspondence should be addressed.

When referring to this article, please cite it as M. Pathak, et al., “Do Modeling and Simulation Tools Really Benefit the Biosimilar Industry?” 

The business impact of modeling and simulation tools is not well understood and requires clarification of their benefits to drug development.

Do Modeling and Simulation Tools Really Benefit the Biosimilar Industry?

Izaskun Elorza, MD, is the senior medical director for cell and gene therapy at Parexel.

Cellular therapies are a therapeutic option for thousands of people with cancer, genetic, and degenerative diseases. Immense resources are being invested into this therapeutic area as hundreds of academic research groups, biotech companies, and top pharmaceutical companies are working on cell therapies in their development pipelines.

Cellular products can show therapeutic effects based on innate cellular capabilities, although many gene-modified cellular products are being developed to enhance, change, or add new functions to cells. The current most successful technology for cell engineering is chimeric antigen receptor (CAR) expression on the patients’ T lymphocytes. This artificial receptor enhances the capacity of T cells to detect tumor cells, kill them, and activate the whole immune system.

The CAR-T trials show impressive response rates and survival outcomes in relapsed and refractory patients with B-cell malignancies and multiple myeloma, leading to growing new approvals by FDA and the European Medicines Agency each day. Recently, clinical trials showed the benefit of CAR-T in second-line therapy for lymphoma. Soon, multiple myeloma patients at early stages of the disease will be enrolled for trials with CAR-T targeting B-cell maturation antigen.

There has been tremendous improvement in the safety profile of CAR-T therapies because of increased knowledge of early side effects and because of international consensus guidelines for clinical management. Real-world data and well-designed follow-up methodology show similar anti-tumor efficacy and survival outcomes in the long term and a good safety profile without new toxicities in the long term. The clinical and technological progress that represents CAR-T has been made possible by the close link among companies, regulatory agencies, patients, investigators, and sites.

Contract research organizations (CROs) have been the glue to coordinate such strategic partnerships, supporting all the stakeholders and equilibrating their genuine interests. Furthermore, the global resources of CROs have given access to patients and companies across different countries. Adaptability is a critical advantage to working with CROs and contract manufacturing organizations, as is having access to a multidisciplinary expert group of people and resources that provide options when selecting the specific services needed at any point throughout the cell therapy development pathway. Having experienced and expertise in conducting clinical trials and the desire to support state-of-the-art therapies can overcome the main challenges seen today in cell therapy product development.

Clinical sites expertise and trial design

The primary challenge in cellular therapy is building trust in patients, advocacy groups, and investigators. Biotech companies and enterprises must show solid preclinical data and strong support throughout the trial. The design of a protocol is also crucial. The protocol should fit patients’ reality and have safety, tolerability, and quality of life at the frontline.

Many characteristics of cellular therapy, such as supply chain, apheresis, and infusion, impact the recruitment of patients in clinical trials. The Foundation for the Accreditation of Cellular Therapy, the Joint Accreditation Committee of the International Society of Cellular Therapy, and the European Society for Blood and Marrow Transplantation have created standard quality guidelines for appropriate clinical management of patients involved in cell and gene therapy (CGT) trials or treated with approved therapies. These standards include a guide for donor evaluation, apheresis procedure, and handling of cellular products. The centers accredited by these committees show multidisciplinary experience teams and blood bank resources. The number of CGT trials opened exceeds the number of accredited centers, however. As these institutions are large academic reference centers, they sometimes lack resources due to health necessities, as has happened with the COVID pandemic. On the other hand, many candidates enrolled in CGT trials are treated and then have follow-up appointments in middle-sized community centers with limited experience, resources, and access to CGT trials. The partnership among different health resources will be critical in recruitment and accessibility in clinical trials.

Cellular therapies are also studied outside of oncology and hematology, such as neurology and cardiology, from regenerative medicine with pluripotent cells to the anti-inflammatory effects of mesenchymal stromal cells. The local delivery of the cells is sometimes needed to improve these products’ efficacy, which is challenging for a clinical trial. The product is not only a bag or vial with cells but a part of a complex translational platform. The investigator and site need specific training on delivery tools because this approach can cause related toxicity added to the cellular product itself. This issue should be considered when designing the product maximizing the option for easy delivery and fast learning requirements and thinking in the post-commercialization period.

The quality of the trial design in terms of monitoring the patients and establishing reliable data management is paramount in cellular therapy clinical trials. The lack of deep characterization tools and methods often does not reveal rare but critical safety concerns and can caused regulatory holds to clinical trials.The mandatory long-term follow-up in clinical trials with retroviral-based cell therapy is 15 years. Furthermore, long-term safety and efficacy assessment trials are mandatory after the product´s authorization to protect patients and collect data for further therapy development. The plan to maintain contact with patients and community sites is crucial. Decentralized trial methods preserve the quality of patient follow-up and data collection improving the quality of life of patients.

Cell therapy is an exciting therapeutic area, rapidly evolving with clinical and manufacturing challenges. CAR-Ts’ clinical success has driven companies to develop more effective, safe, and persistent cellular therapies using other cell types, such as natural killer (NK) cells and macrophages, to treat other cancers, including solid tumors. The current use of retroviral vectors to insert genetic information within cells can cause oncogenic genetic changes. The advent of genome editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 has enabled alternative strategies to improve genetically modified cells’ safety, efficacy, and manufacturing.

Autologous CAR-T implementation has demonstrated to the industry and the world how fast a transforming therapy can become part of the standard of care for the unmet needs of patients. It is time to design the path from small-scale treatment to large-scale allogeneic therapies that can impact a broader patient population. Allogeneic cell sources, “off-the-shelf” therapy, from healthy donors or pluripotent stem cells (PSC), are still in early phases but are open to patients, encouraging investigators, and simplifying operational challenges. The waiting time during the manufacturing process of three to four weeks is a severe limitation of autologous CAR-T cell therapy products that have currently been approved. Cells from induced PSC, in comparison, can be manufactured without limits from a single clonal cell bank, replicated, and expanded, resulting in a consistent and well-characterized product.

Some companies contract external manufacturing services at the beginning of development to have access to fast, adaptable technology until finding positive results in terms of feasibility and safety from early clinical trials. In the late stages of clinical development, the internally manufactured product may make more sense to control production and costs. Other CGT developers only get part of their starting material—cells or viral vectors—from specialized manufacturing laboratories. So, a “make vs. buy” approach can change through time, with the available data from clinical trials and the resources or partnerships that the company can develop through the clinical development path.

Decentralized manufacturing will be another approach to scalability, thanks to technology becoming increasingly portable and increasing experience in this field. There are also projects to develop CAR-Ts in vivo, for example, using viral vectors or nanoparticles, transfecting patients’ lymphocytes directly in the body, and avoiding the need to collect cells and manipulate them in the laboratory.

The manufacturing complexity of cellular therapies is unique, mainly in cell therapies containing viral vectors. Companies need to demonstrate a strong understanding of their product and the target population and have a purposeful plan to analyze therapy performance through clinical studies. The regulatory agencies are very active in developing new guidelines about the quality of cellular products.An expert clinical, chemistry, manufacturing, and controls, and regulatory consultant is likely to benefit patients and cellular products, easing the translation of the product to clinical application with proper safety testing and traceability documentation.

The challenge is to standardize assays on individual products, and companies are often forced to identify the most fit-for-purpose methodology and present it to regulators for approval. The possibility of designing a standard manufacturing approach could accelerate cell therapy manufacturing, ensure homogeneity and quality, and make the regulatory pathway easier.

Society is impressed with what science and human tenacity can achieve. Cell products are a considerable change in the therapeutic paradigm and require a new insight into the research structure and the relationship between stakeholders. The human resources, infrastructure, and investment needed to bring these therapies to market must be coordinated so that the knowledge and capabilities of pharma companies, CROs, investigators, and patients are all brought to bear to address challenges in development. The goal should be to conduct more adaptative clinical trials, resist uncertainty, and create efficient strategies for fast scale-up to make cell therapy accessible as the standard of care. The regulatory agencies also support recommendations on collecting patient-reported outcomes, tailoring operational plans, and manufacturing high-quality products. Expectations for these therapeutics are high, and it is time to make cell therapies a real option for patients.

A new approach is critical for patients with malignant and chronic diseases looking for a curative and safer therapies that can offer a better quality of life.


Vol. 35, No. 7
July 2022
Pages: 16–17, 24

When referring to this article, please cite it as I. Elorza, “Evolution to a New Clinical Research Environment for Cellular Therapies,” 

Finding specific solutions to overcome uncertainty has led to the evolution of a new clinical trial research environment.

Evolution to a New Clinical Research Environment for Cellular Therapies

Feliza Mirasol is the science editor for 

While Chinese hamster ovary (CHO) cells are the workhorse of biologics production, other cell expression systems are starting to gain ground, such as plant-based expression systems. Though an older technology in and of itself, plant-based manufacturing has recently been validated in the mainstream biopharmaceutical industry, but there is still a lack of biomanufacturers using such platforms for good manufacturing practice (GMP) production.

In particular, a newer emerging platform, the plant-made pharmaceutical platform (PMP), has come into the mainstream spotlight with the February 2022 approval of Canada-based Medicago’s COVID-19 vaccine in Canada, COVIFENZ (plant-based virus-like particles, recombinant, adjuvanted) (1).

An important criterion for any expression system used to manufacture biologics products is the comparability of the end product with a validated expression system that is well known and widely used in the industry, such as mammalian CHO cells.

Plant cells are highly developed eukaryotic cells; each cell has the same machinery as a mammalian cell to express heterologous protein sequences accurately. Plants do, however, have slightly different post-translational modifications such as minor glycoform differences.

According to one industry source, if the glycoform on a particular therapeutic is a key to functionality, the glycoform can now be modified in the plant cell expression system to be as fully functional as the mammalian counterpart. This has been demonstrated in the literature for over a decade. One advantage in the plant system seems to be the consistency of the glycoform pattern expressed.

Plants also tend to produce a more homogenous product with post-translational modifications. Mammalian cells produce multiple glycoform patterns, which can be affected by culture conditions, including scale-up to larger reactor systems. Many biologics do not have any post-translational modifications.

Since the plant is a singular bioreactor that is grown the same way every time, consistency is achieved. To scale-up, simply grow more plants, this industry source says.

For most recombinant proteins, a plant-based expression system yields products that are highly comparable to mammalian/CHO systems, says Tom Isett, CEO of iBio. Isett also points out that, particularly in regards to monoclonal antibody (mAb) development, plants can deliver a more homogeneous N-linked glycosylation pattern. This characteristic provides greater assurance that the glycoform of choice is appropriately represented in the final product, likely improving efficacy, Isett notes.

“More simply put, it turns out that adding or removing sugars, or carbohydrates, to proteins in the development of antibodies can in some instances make them more stable and perform better. This process, called glycosylation, seems to be more easily controlled in plants than in CHO,” Isett states. “We typically see more homogeneous glycan types with plant-expressed antibodies. This is particularly important in the production of next-generation mAbs, biobetters, and fast-follower products.”

In addition, Isett points out that, for the development of mAbs for immuno-oncology, an afucosylated molecule (a mAb lacking the sugar, fucose) can yield enhanced potency via greater antibody-dependent cellular cytotoxicity (ADCC). Isett explains that his company uses a version of its plant-based bioreactor to deliver afucosylated molecules, “which have proven to be highly comparable, if not superior, to CHO expression systems.”

Because there is no limit to the size of a gene insert, plants can express both large and complex biomolecules that do not express well or cannot be expressed at all in conventional mammalian cell or bacterial expression systems, including immunoglobulin M molecules, says Leanne Williams, PhD, business development manager, Leaf Expression Systems.

Another benefit for plant-based expression of antibodies is that plants produce a vast range of stable and consistent post-translational modifications, including glycolysis. Although plants produce a slightly different glycosylation to mammalian systems, data have shown that these changes do not usually affect antibody functionality. “In the event that human glycosylation patterns are important or necessary for functionality, there are accessible plant lines that have been modified to produce human glycolysis patterns,” Williams states.

The approval of COVIFENZ makes a case for the use of plant-based manufacturing beyond just mAbs; rather, vaccines can now also be manufactured using a plant bioreactor system.

Isett points out that his company has used its plant-based technology (the FastPharming System) to rapidly produce subunit vaccine candidates. “In fact, at the outbreak of COVID-19, we were able to produce two spike-based vaccine candidates in just five weeks, a speed that rivals that of the mRNA [messenger RNA] platforms. This is consistent with the original DARPA [Defense Advanced Research Projects Agency] ‘Blue Angels’ project—upon which our facility was built—with the aim to be able to rapidly produce medical countermeasures in the event of a pandemic,” Isett remarks.

Isett says that iBio has continued to utilize plant-based expression technologies to produce a next-generation COVID-19 vaccine candidate. “Specifically, we believe that a vaccine that uses the more stable nucleocapsid protein of the virus can provide more durable protection against the frequently changing spike protein that commercially available vaccines attempt to provide immunity against,” he states.

In terms of production parameters, the upstream part of the company’s process (i.e., growing and transfecting the plants with the protein of interest) is much simpler and more robust than cell culture-based systems because fewer components are required, there is no need to maintain sterile boundaries, and there is no risk of exogenous viral contamination. Meanwhile, the downstream purification process is essentially the same in both mammalian and plant-based platforms. “That said, it’s the design of the antigen that will ultimately deliver us a more durable, effective, vaccine, than the first-generation versions that don’t seem to give us more than six months of immunity,” Isett says.

Vaccines are considered ideal targets for plant-made systems since the development time, time to clinic, and subsequent time to production can be much less than traditional mammalian systems. Although mRNA vaccine production has not necessarily been a large focus for plant systems, it has been demonstrated that plants are a strong platform for mRNA production, says an industry source. This achievement should portend well for plant-made production of mRNA vaccine candidates, the source adds.

Given the necessity of protein sub-unit vaccines for many applications, plant-based production is here to stay and will be part of the vaccine landscape for a long time even with the welcome success of mRNA vaccines. To achieve wide-spread immunity and to mitigate risk of new variants, it is important to develop these vaccine production systems globally, including parts of the developing world that cannot afford or support such efforts, the industry source notes.

The plant-based system works well, particularly for production of virus-like particle (VLP) vaccines, which includes COVIFENZ, adds Williams. “Production parameters between the systems suggest that plant-based expression processes offer a commercially viable option to conventional bioreactor-based processes, particularly when considering the ease of scale-up, which is achieved by simply increasing the number of plants, negating the need for complex scale-up processes required by traditional bioreactor systems,” Williams states.

She further explains that post-translational modifications (e.g., glycosylation patterns) are also more consistent in the plant systems because there is not the variation in culture parameters that occur in bioreactor scale-up processes. Williams also points to lower production costs in plant-based systems, saying that production time is predicted to be approximately 25% faster than a conventional bioreactor system. “In addition to the above points, a VLP vaccine is stable at 4 °C, which enables the vaccine to be transported more easily than the mRNA-based vaccines that are stored at either -20 °C or -70 °C,” she states.

Investment (e.g., equipment, technologies, facility, personnel) would be far less capital intensive for the upstream processing portion of plant-based biologics production, compared to investment needed to set up comparable upstream processing for mammalian cell-based systems (both single-use and traditional stainless-steel reactor facilities).

The ability to grow plants as reactors with high precision in automated and vertical hydroponic and aeroponic systems have been well developed, according to the industry source. This source also emphasizes that these plant manufacturing systems have no animal/human inputs or intervention, and, thus there are no concerns for adventitious virus contamination in these systems.

The upstream capital expenditure for a plant system is less than 35% of a traditional staged bioreactor train, whether single-use or stainless-steel, the industry source states. Furthermore, scale-up is not incremental in plant-based systems as additional capacity does not require a linear increase in robotics and personnel. Meanwhile, as explained earlier, downstream processes are comparable between plants and traditional bioreactors. Other advantages of the plant-made system include much lower energy consumption, lower water usage through recycling, and extremely low waste treatment costs, according to that industry source.

Furthermore, when comparing manufacturing with single-use systems, one must be mindful of the environmental impacts, points out Isett. Specifically, while single-use systems are considered by some to be more environmentally friendly than the cleaning associated with stainless-steek, at the end of the day, single-use systems use a significant amount of plastic disposables, Isett explains. He also notes that such significant plastic use likely contributes to biopharmaceutical industry being 55% more emissions intensive than the automotive industry.

Conversely, the key raw materials with a plant-based manufacturing system are considered “all-natural”: purified water, stone wool for the plants’ root substrate, and seeds, Isett lists. Isett says his company is still looking at ways to bring modern continuous purification bioprocessing techniques to the fore in downstream processing as well.

While afucosylated mAbs for immuno-oncology are undoubtedly well suited to having a plant-based production system, it has been demonstrated that plant-based technologies also have the ability to produce other recombinant proteins, says Isett. Isett uses the example of Safi Biosolutions, for which iBio was able to produce important cytokines and growth factors for that company’s bioproduction red blood cells and neutrophils in cell culture, with the aim to replace donated blood transfusions. Additionally, Isett points out that there are certain molecules that simply cannot be produced effectively in CHO cells, either because of their construct, or because aggregation and other issues occur with other expression platforms.

One significant technological advantage is the fact that plant cells, in most cases, are not affected by highly active human proteins, while mammalian cell-based systems can be affected by a build-up of a potent, heterologous protein, says the industry source. Plant systems are therefore ideal for producing highly active antibodies and antibody conjugates. Proteins can be compartmentalized in plant cells in the endoplasmic reticulum or trans-golgi spaces and can be secreted into the lamellar, cellulosic cell wall. Innovative downstream extraction and separation systems have been developed to take advantage of these properties, the source explains.

Widespread adoption of plant-based manufacturing technologies in the biopharmaceutical industry remains elusive, however. The biggest hurdle has been attracting capital investment to these platforms. The biopharmaceutical industry is slow to change, especially in production systems. Many biologics have been developed and demonstrated to be active by a relatively small number of academic laboratories and companies, and only a few have gone through the entire regulatory approval cycle, the industry source points out.

This source says that successes by companies such as Medicago and Protalix are welcome and showcase the platform; however, the plant-made pharmaceutical community, as a whole, has not put forth a unified effort for marketing the platform to the mainstream.The potential of the platform is still not widely understood, the industry source states.

On the regulatory front, both FDA and the European Medicines Agency are well informed about plant-made products and have been supportive and helpful in evaluating clinical trials and manufacturing systems, the source adds. Moreover, few, if any, clinical trials involving plant-made products have been put on clinical hold for toxicity; however, at this point in time, there are few, if any, contract development and manufacturing organizations that currently manufacture biologics for human clinical trials under current GMP compliance.

The COVID pandemic has played a role in bringing new technological platforms to the forefront, including a plant-made vaccine, baculovirus vaccines, and mRNA vaccines. In this relatively short period, these three platforms have gained a more mainstream prominence, the industry source adds. The hope is that this attention will result in investment and subsequent development of these systems for routine development and production of biologics.

The biopharmaceutical industry has traditionally been slow to innovate for a number of reasons, primarily patient safety/risk and quality/regulatory risk, according to Isett. The standard mammalian cell culture-based expression systems have been around for more than 30 years and continue to be perceived to be a relatively low-risk way to produce protein therapeutics. Furthermore, since upstream expression systems have achieved significantly high yields, the onus has been put on downstream processing to solve debottlenecking issues.

“That said, the question is whether we have ‘walked past’ quality and sustainability as well as speed as major unmet needs with traditional bioproduction. Let’s face it, in the midst of a terrible time for the biotech markets, now—more than ever—we need to find ways for developers of new therapeutics and vaccines to cross the funding ‘valley of death’ between preclinical and Phase II to find faster, less expensive ways to bring better new molecules to the clinic. The way to do that is with expression systems that expedite time-to-clinic and allow poor projects to fail faster, and good projects to proceed to IND [investigational new drug] application more cost effectively and with a greater probability of success,” Isett remarks.

Producing therapeutic and diagnostic products in plants is not new, says Williams. This technology has been around for the past 30 years, but it is not well established and is met with skepticism by many in what is a very highly regulated industry, she emphasizes. “This [skepticism] is by far the biggest hurdle plant-based expression systems have had to overcome. That said, the recent development of a successful COVID-19 vaccine has proved that the industry is open to change, and recognizes the need for a variety of production platforms in order to adapt to our growing and changing world,” she adds.

1. Medicago, “Medicago and GSK Announce the Approval by Health Canada of COVIFENZ, an Adjuvanted Plant-Based COVID-19 Vaccine,” Press Release, Feb. 24, 2022.

When referring to this article, please cite it as F. Mirasol, “Plant-based Expression Systems are Gaining Mainstream Advantage,” 

Industry adoption of plant-made biologics remains slow, but plant-based technology gains an advantage by mainstream exposure.

Plant-based Expression Systems are Gaining Mainstream Advantage

Anna Maria Bertasa is global marketing manager in the Healthcare dvision at Solvay Specialty Polymers.

 is processing engineer, NA life solutions technical team, in the Healthcare dvision at Solvay Specialty Polymers.

Many companies are using single-use technologies (SUTs) to replace traditional reusable stainless-steel equipment in biopharmaceutical manufacturing. This transition is largely due to the reduction of time and costs associated with teardown-reset-cleaning-validation cycles, the elimination of the risk of cross-contamination, and the flexibility to produce small batches or niche products. Another driver of SUT adoption is the ability to establish regional manufacturing capabilities close to customers without a major capital investment in infrastructure and logistics.

Plastics are used to manufacture the majority of SUT components, such as bags, tubing, filtration media, and filter housings; connectors, valves, and clamps; sensor housings and gauges; and final fill and storage containers. While plastics can deliver performance properties similar to those of metal, such as stiffness, strength, and impact resistance, they also surpass metal in several important ways.

Polymers offer greater design freedom and lower system costs through high-volume injection molding, or extrusion, as well as optical and radio transparency, flexibility, corrosion resistance, weight reduction, and designs with improved ergonomics. But not all polymers can meet the stringent—and evolving—requirements of biopharmaceutical SUTs. Those demands call for plastics with a higher level of performance.

Specialty thermoplastics can replace not only metal, but also lower-performing polymers, to add value to SUTs and help address emerging industry challenges. By improving compatibility with chemicals and sterilization methods, reducing the risk of extractables and leachables (E&L)
to increase the reliability and lifespan of SUT components, and expanding design and performance possibilities, these polymers can contribute to a manufacturer’s overall strategic objectives.

The baseline requirements for any plastic used in SUTs for biopharmaceutical processing include regulatory testing, biological safety, low E&L, chemical resistance, and the ability to be sterilized prior to use. However, for the best results, a polymer needs to deliver more than the minimum prerequisites. The following specialty polymers offer high performance properties and other attributes to meet the current and future needs of biopharmaceutical SUTs:

—this rigid, high-strength, semi-tough, transparent plastic offers higher heat resistance and better hydrolytic stability than polycarbonate (PC). It retains its good mechanical properties when exposed to steam autoclaving and other sterilization techniques. PSUs are used in a variety of membrane filtration applications and fluid handling components in bioprocessing systems.

—this transparent, flame-retardant polymer offers good toughness, strength, and hydrolytic stability. It withstands prolonged exposure to water, chemicals, and temperatures, retaining its transparency, mechanical properties, and dimensional stability in high-heat environments. Applications include monitoring and filtration devices and biopharma processing components, such as sight windows and quick-connects.

—this high-performance thermoplastic excels in high-heat/high-humidity environments. It offers impact strength similar to that of PC and better chemical resistance than PC or polyetherimide (PEI). PPSU also features inherent flame retardancy and long-term hydrolytic stability at elevated temperatures. It is compatible with all sterilization processes. Typical applications would be for higher performance sensor housings and fluid handling connectors and components.

—exceptional performance in multiple areas, including chemical, fatigue, hydrolysis, heat, wear, and abrasion resistance, makes PEEK an excellent candidate for components used in the most aggressive chemical environments.

—typically reinforced with high glass fiber loadings, PARA still delivers high flow that enables thin-wall molding. High strength and stiffness, combined with a smooth surface finish, make this material suitable for metal replacement in SUTs, such as powder transfer valves and tri-clamps.

Specialty polymers can often address evolving industry requirements for SUTs in biopharmaceutical processing more effectively than metal or lower-performing polymers. For instance, many commodity polymers are formulated with processing aids and other additives that can raise product safety issues related to E&L. In contrast, high-performing specialty thermoplastics can accommodate a wider range of use environments without relying on stabilizers and other additives. The result is a cleaner, purer end product, with improved E&L.

Cost control can be another differentiator for specialty thermoplastics. If metal parts require machining, welding, polishing, and other secondary operations, total system costs can rise compared to injection molding or extruding a plastic part. In some cases, cost advantages can be achieved through part consolidation, which is often easier with plastics thanks to their design flexibility. Reducing the total number of parts can save material and increase throughput by eliminating assembly steps. Designs of high aspect ratio parts, such as fill tubes, are easy to do with a high flow, injection molded resin, but costly to machine.

Although they are single-use components, SUTs often need to perform effectively through the production of multiple batches of the same biopharmaceutical without having to be replaced. The superior properties of high-performance thermoplastics can help extend the useful life of the SUT component. For instance, improved chemical resistance helps avoid premature stress cracking that can occur with lower-performing polymers as well as galvanic corrosion that can affect metal parts. Greater resistance to high temperatures and other environmental factors can also minimize degradation, such as yellowing or haze in transparent thermoplastics, to ensure consistent performance of SUTs, such as optical sensors.

From the standpoint of sustainability, specialty polymers can expand the range of SUT components that can be developed and implemented, helping to further reduce the need for clean-in-place/sterilize-in-place components that require significant amounts of water, energy, and materials. They can also enable designs that reduce raw material usage; high-stiffness, high-flow polymers allow for the use of thin-wall designs and functional integrations that conserve resources and contribute to light-weighting efforts.

To help the industry feel more knowledgeable and confident about the performance, purity, and regulatory compliance of specialty thermoplastics in SUTs, suppliers are generating additional data and test results for their materials. Data on such factors as X-ray compatibility and cryogenic performance for cell-gene therapies at very low temperatures (-150 °C to -180 °C) can help quantify the advantages of adopting PSU, PESU, PEEK, PPSU, or PARA for biopharmaceutical processing components.

Anna Maria Bertasa and James Hicks are global marketing manager and application development and processing engineer, NA life solutions technical team, respectively, in the Healthcare dvision at Solvay Specialty Polymers.

When referring to this article, please cite it as A. Bertasa and J. Hicks, “Specialty Polymers Add Value to Single-use Technologies for Biopharmaceutical Processing,” 

Specialty polymers demonstrate the advantages of single-use consumables in biopharmaceutical manufacturing.

Specialty Polymers Add Value to Single-use Technologies for Biopharmaceutical Processing

Andrew Feilden is the European E&L strategic director for Element.

In the world of extractables and leachables (E&L), one thing that is nearly guaranteed is that change will happen with the materials used in the container closure system. Management of these changes is the responsibility of the drug product manufacturers.

Changes can be external, where the supplier changes manufacturing, information, or availability of a component. It can also be internal, where the drug manufacturer changes the validated manufacturing process or use of the component. External changes can vary from small manufacturing changes that are within manufacturing tolerances, such as in-process changes to time, temperature, etc., to larger manufacturing changes, such as a site change. Larger or more significant external changes can happen, such as a change in the formulation of the material (e.g., additive change) or stopping the manufacture of that particular material. Internal changes can include changes in contact time with a single-use container or the addition of a second supplier of the material components. These internal or external changes are not an exhaustive list but give a flavor of potential changes that may occur.

Guidance for Industry: Changes to an Approved NDA or ANDA, 

FDA details recommendations to holders of new drug applications and abbreviated new drug applications, specifically on post-approval changes for drugs other than specific biotechnology and specific synthetic biological products (1). This guidance provides recommendations for post-approval changes in:

According to this guidance (1), these changes might require post-approval in accordance with section 506A of the US Federal Food, Drug, and Cosmetic Act and 

These documents outline the classification of a change (minor to major) and the regulatory requirements for handling these different change levels.

A minor change, according to FDA guidance, has “minimal potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product” (1).

 Title 21, FDA instructs that the applicant must describe minor changes in the next annual report (2).

In an FDA guidance, a moderate change has “a moderate potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product” (1).

Commonly, these changes require that the drug manufacturer submit a supplement called Changes Being Effected in 30 Days (CBE-30). This supplement will include information describing the effects of the change. The drug manufacturer must wait 30 days after submission of the CBE-30 before implementing the change and must not implement the change if FDA responds with a request for more information to support the change.

Finally, FDA states that a major change has “a substantial potential to have an adverse effect on the identity, strength, quality, purity or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product” (1).

These changes require that the drug manufacturer submit a prior approval supplement (PAS). The drug manufacturer must wait for FDA approval of the PAS before implementing the change.

Material changes can have an impact on both product quality and the patient. There are a few well-known examples. The most quoted example was during the period of 1998–2002 when there was an increase in the incidence of antibody-positive pure red cell aplasia in patients receiving subcutaneous administration of EPREX (epoetinum alfa). At the time, two simultaneous changes happened. Firstly, the drug product formulation was changed to include polysorbate 80; and secondly, the coated stopper was replaced with an uncoated one (3). Additional compounds were observed in the leachable analysis of the new product. However, these leachable compounds were only observed when the product contained both polysorbate 80 and used the uncoated stopper, but these new leachable species were not observed when both were used separately.

In the early days of E&L testing, prior to appropriate change management, a change in the composition of the material was first known upon a test being conducted and a new extractable profile—or worse, a leachable profile was observed. Because leachables typically take time to form, this observation implied that a change happened, potentially, many months prior. This first E&L observation was also before the seminal document by the Product Quality Research Institute on 

Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products in 2006

(4). This recommendation has set the scene for E&L testing in the years following. Despite this being only a recommendation, it was authored with FDA and Health Canada involvement.

Inhalation aerosols and sprays are deemed to have the highest likelihood of packaging component-dosage form interaction and the highest degree of concern based on the route of administration. As such, it is not too surprising that most of the early work on regulatory requirements focused on orally-inhaled and nasal drug products. It was groups such as the International Pharmaceutical Aerosol Consortium on Regulation & Science that initiated and built on supply chain interaction and understanding. The group’s initial work was published in the 2011 paper, “Recommended Baseline Requirements for Materials Used in Orally Inhaled and Nasal Drug Products (OINDP),” and a subsequent update was provided in 2017 (5).

It is also not necessarily the direct container closure system that can cause problems with patient safety and product quality. Around 2010, there were product recalls due to the wooden pallets on which product boxes were stored. A biocide used to treat the pallets had degraded, and one of its degradants—2,4,6-tribromoanisole (TBA) migrated into the products and tainted them. The TBA has a very low odor threshold, meaning that very small amounts can cause unpleasant musty and moldy aromas. A total of 55 million bottles of Tylenol were recalled in a six-month period in 2010 due to this issue (6). This incident resulted in several pharmaceutical companies ceasing the use of wooden pallets to transport products.

Material changes can have potentially more impact on biologics that are manufactured with single-use systems. A particular biologic can be impacted by small amounts of leachable species. The exact mechanism of this is unknown. The most quoted example of this is “Identification of a Leachable Compound Detrimental to Cell Growth in Single-Use Bioprocess Containers,” a research article by Amgen (7). Researchers found that a trace amount of a breakdown product of a common antioxidant, Irgafos 168, was detrimental to cell growth. The level of this antioxidant was far lower than typical screening levels that would be required due to typical toxicological concerns.

Additionally, it is well known that biologics/peptides are at significant risk from reaction with E&L. The biggest risk relates to covalent bond formation for which there are several well-known examples. One example includes the reaction of the common leachable from halo butyl rubbers. This leachable, the C

2 reaction with the protein, forming a new chemical species.

Acrylic acid, which can be used as the glue in syringes, is known to modify peptides either through the lysine side chain or through histidine by a Michael addition reaction. The level of modification was reported at 0.2–5% of a range of proteins (8).

Other reactions can happen, such as the Schiff base reaction of breakdown products of butylated hydroxy toluene and acylation reactions (9). It is often observed when materials undergo sterilization, which causes additives, such as antioxidants, to degrade and form potential reaction products. It is important to mention that if these antioxidants were not present, the polymer would very rapidly degrade, and the container closure would no longer be useable. It is, therefore, likely that any changes with materials used with biologics could have a more significant impact on patient safety (either because of safety or efficacy) than those with small molecules or medical devices. Further work is in progress to help identify potential issues with common leachables.

Cumulatively, this leads to the importance of understanding the materials used in container closure systems and manufacturing systems for biologics and peptides to avoid potential issues—rather than solving them after the event. Having appropriate data on materials used for biologics/peptides can assist in reducing the risk of interaction with leachables. Appropriate data includes extractable data obtained from studies that are undertaken on sterilized/treated materials under appropriate extraction conditions (where extractables can be correlated with leachables) with sufficient sensitivity. 

What does the future hold? As mentioned at the start of the article, change is inevitable, but there are some potential new changes coming. There is a push for greener materials and the reduction of single-use plastics. Will the additive packages change to allow polymers to be depolymerized back to the starting monomers so they can potentially be used as virgin materials rather than recycled? It is through an understanding of the likelihood and impact of change that potential patient safety can be understood and mitigated.

Guidance for Industry, Changes to an Approved NDA or ANDA 

 Title 21, Part 314, Vol. 5, Subchapter D (Government Printing Office, Washington, DC), accessed June 2022.
3. K. Boven et al., 

Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products 

(Sept. 8, 2006).
5. IPAC-RS, “Recommended Baseline Requirements for Materials Used in Orally Inhaled and Nasal Drug Products (OINDP),” 

(Feb. 9, 2017).
6. G. Miller and E. Teichert, “The Battered Brand: A Tylenol Recall Timeline,” 

67 (2) 123–134 (2013).
8. D. Liu et al., 


Volume 35, Number 7
July 2022
Pages: 41–43

When referring to this article, please cite it as A. Feilden, “Material Management and the Impact on Extractables and Leachables," 

By understanding potential material change, the impact on patient safety can be understood and mitigated.

Material Management and the Impact on Extractables and Leachables

Robert O. Williams III, PhD, is the division head and professor of molecular pharmaceutics and drug delivery at The University of Texas at Austin, College of Pharmacy; the Johnson & Johnson centennial chair in pharmacy at the University of Texas at Austin, College of Pharmacy; editor-in-chief of the AAPS PharmSciTech scientific journal; and the technology inventor/special advisor for TFF Pharmaceuticals.

There is a growing demand for biologics spurred by clinical success, favorable safety data, and the ability of biologics to target the underlying cause of disease. Progress in proteins, peptides, nucleic acids, vaccines, and monoclonal antibodies (mAbs) has allowed biologics to advance quickly, especially in recent years. According to an article in 

, 25% of new chemical entities approved by FDA between 2015 and 2019 were biologics (1). Perhaps the most striking recent example of the demand for biologics is the rapid scale-up and application of messenger RNA (mRNA) vaccines to treat COVID-19. Though progress has been swift, challenges have created barriers to global adoption due to complications related to formulation, thermostability, and drug delivery. 

Biologics originate from living organisms, have large molecular weights, and generally cannot be chemically synthesized. This means they are vulnerable to the environment and require extreme care to formulate, manufacture, and store (2). As biologics are large molecules with primary, secondary, tertiary, and quaternary structures, they are also sensitive and expensive to produce (3). While biologics are conventionally delivered intravenously in liquid form, liquid formulations exhibit chemical and physical stability problems. Conversely, biologics formulated as a dry powder are more stable and are less prone to degradation, but drug manufacturers must consider shelf stability as well as which excipients and formulation conditions will enable a longer shelf life. Additionally, the chemical and physical properties of the final product must be considered during formulation to fit the route of administration.

This article explores technological innovations that could overcome challenges in formulation and the delivery of biologics—especially for respiratory diseases where inhaled drug delivery offers a significant advantage—to address the need for scale-up of biologics to benefit a broad range of patients.


Overcoming the challenges of oral delivery of biologics

A major issue for respiratory and lung conditions treated via oral therapies is that a lower amount of drug reaches the lung with a higher amount delivered systemically, which can reduce effectiveness and lead to potentially life-threatening toxicities. Vaccines are one example of a biologic that when delivered directly to the respiratory system, rather than through systemic injections, can offer significant advantages and sidestep challenges of oral delivery. The lungs have a large surface area and thin peripheral epithelium, so the administration of vaccines directly to this area allows for faster onset of action (4). Additionally, vaccines administered by inhalation directly into the respiratory system can stimulate the mucosal membrane surface, an advantage for immunity as it triggers the memory T-cell immune response at the site of infection, which can allow for quicker neutralization of the virus and serve as a prevention strategy for infectious diseases (5).

While delivery of respiratory drugs, including vaccines, is a potential route to overcoming the challenges of oral delivery, vaccine formulation has its own challenges and requires appropriate development, manufacturing, distribution, and storage considerations. While vaccines are commonly refrigerated between 2–8 ˚C, they should ideally be stored at ambient temperatures with a long shelf life to reduce cost for both storage and distribution (6). Sensitive vaccines, such as mRNA vaccines, require even colder temperatures to preserve activity. However, vaccines in liquid form cannot be frozen, as this process induces stress to the mixture and can cause irreversible changes to protein shape and therefore function (6). Common vaccine adjuvants, such as aluminum salts, also cannot be frozen and require expensive cold chain storage for distribution (7,8). Excipients and other stabilizers can improve the stability of liquid vaccines, but reformulation via dry powders offers a more elegant solution.

How dry powder techniques can overcome limitations in biologics development and delivery to broaden routes of administration and global accessibility.