Q. In a recent audit, we received an observation because we do not have a standard operating procedure (SOP) for the archiving of electronic records. We keep our electronic data and records on our live systems. Why would we need such a procedure?

A. The short answer is because the regulations stipulate this. “For new systems, a Validation Summary Report for each computerized system should be in place and state (or provide reference to) at least the following procedure for data archiving (processes and responsibilities), including procedures for accessing and reading archived data” (1). It is, however, sensible to look at the reasons behind this requirement and why it is also good business sense to have such a SOP in place. Data and records that are governed by the healthcare regulations must be retained and be available throughout the mandated retention periods for the respective records. In the case of clinical data, this can be 25 or more years, and for manufacturing records (paper or electronic), this is typically five or more years.

Over such a period of time, almost every computerized system undergoes modifications for a variety of reasons. These include patching the system (e.g., for security), installation of new software modules (e.g., for enhanced usability), system upgrades, system retirement, or system replacement. Any of these changes may or will affect the electronic records in the system. Depending on the impact, it can or will be necessary to remove the records from the system and store them in an archive.

Despite best intentions and good planning, there is always the possibility of an unexpected need to archive electronic records. That could be because of an unforeseen system failure or because the system performance falls below acceptable levels. It is not acceptable to wait until such an event occurs to write a procedure for the archiving of records and data; instead, it is essential to prepare the SOP well in advance.

Archiving electronic records is rarely trivial. Simply printing out the records is unlikely to either assure the entire record is captured or to be compliant with the regulations (paragraph 7.7.2 in reference 2). Archiving must take into consideration the regulations for automated systems and the guidance on data integrity. Especially:

If data are transferred to another data format or system, validation should include checks that data are not altered in value and/or meaning during this migration process (2)

Data may be archived. These data should be checked for accessibility, readability, and integrity (2).

Practical guidance has been published by various regulatory authorities (3,4) and industry associations (e.g., Appendix O1: Retention, Archiving, and Migration in reference 5).

In summary, having an electronic-records archiving SOP in place is not only a regulatory requirement, but it also makes sense from a business perspective. After all, you want to be sure that you can access your data and records throughout their lifespan and to be certain that the values and information therein is still correct and complete. Writing the SOP, however, is only a first step, implementing the process and validating it are the necessary and logical next steps.

 Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments 

Data Integrity and Compliance With Drug CGMP

Questions and Answers, Guidance for Industry

‘GXP’ Data Integrity Guidance and Definitions

Siegfried Schmitt is vice president, Technical at Parexel.

When referring to this article, please cite it as S. Schmitt, “The Difference between Electronic Records Retention and Archiving,” 

Articles

Ask The Expert

An SOP for electronic-records archiving is a regulatory requirement and good for business, says Siegfried Schmitt, vice president, Technical at Parexel. 

The Difference between Electronic Records Retention and Archiving

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,” 

Cover Story

Automation and digitalization work together in the digital plant.

Automating Biopharma Manufacturing

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?” 

Peer-Reviewed Research

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?

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.

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


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,” 

Development

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

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.

Feliza Mirasol is the science editor for 

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

Upstream Processing

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

Application of a quality-by-design (QbD) approach to process development is not limited to upstream and downstream operations. It should, in fact, be implemented for all aspects of drug development, including the design, development, and production of key raw materials. As such, QbD methodology has a role to play during the development of affinity chromatography processes and even prior to that in the development of the resins used in these processes. In both cases, a QbD approach can help minimize variability and lead to the development of robust manufacturing processes that consistently yield high-quality product.

The goal of a risk-based QbD approach is to identify the factors that will have the greatest impact on process performance (i.e., critical process parameters [CPPs] and critical material attributes [CMAs]) and how they may impact the quality of the drug substance. For affinity chromatography, in addition to resin attributes, the load ratio, pH, and conductivity are some of the factors to be considered.

One issue facing developers of affinity chromatography processes has in the past been measurable batch-to-batch variability in the affinity resins used. To overcome this problem, resin suppliers need to fully understand the relationships between resin manufacturing process parameters and the important resin characteristics that may affect resin performance, according to Gunnar Malmquist, a senior principal scientist with Cytiva.

That goal can be achieved, says Laurens Sierkstra, a business segment leader in Thermo Fisher Scientific’s BioProduction Group, with the use of a platform production technology. “Comprehensive platforms start with the identification and development of the affinity ligand and continue through all manufacturing steps required to produce the resin,” he notes. Without a platform, Sierkstra stresses that affinity ligands are then developed differently in different systems, which can affect the length of process development, compromise quality, and create inconsistency from lot to lot.

Applying a QbD approach is also highly effective in the development of affinity resins with minimal lot-to-lot variability. “The principles of QbD force an explicit focus on identifying the resin critical quality attributes [CQAs], which in this case are structural properties, and setting a control strategy that enforces process control,” Malmquist explains.

Cytiva has a long history of using the QbD framework for resin development, according to Malmquist, “allowing the development of a deeper understanding of structure-function relationships from resin design and connecting manufacturing process parameters to chromatographic performance, including robustness.”

All of Cytiva’s protein A resins since MabSelect have been developed using these principles, according to the company’s product manager for antibody capture, Josefin Bolik. Factors important for controlling physical/chemical properties in each manufacturing step are verified with design-of-experiment (DoE) studies. Verification, she observes, confirms the product will have design outputs that meet the product requirements, while validation confirms that the right product has been designed and that it will fulfill user needs.

Examples of affinity resins from Cytiva developed with this approach include MabSelect PrismA, which has improved alkaline stability and
binding capacity, and MabSelect VL, which has been designed specifically
for the purification of antibody variants and fragments.

Thermo Fisher applies a QbD approach to developing and optimizing its affinity chromatography resins, including the LambdaXP, CH1XL, FcXP, and KappaXP products. Its CaptureSelect technology, notes Sierkstra, incorporates high-throughput screening that enhances the performance of ligands (e.g., elution of the target molecule, stability under certain clean-in-place conditions, specificity of binding and binding kinetics, etc.). The designed ligands can then be manufactured, purified, and immobilized on a resin using the company’s platform. “By leveraging QbD in our technology and processes, the final product meets predefined performance and manufacturing criteria including minimal lot-to-lot variability,” he contends.

The greatest challenges in developing robust, reproducible, and high-yielding affinity chromatography processes are business-related, believes Kristina Pleitt, senior manager of systems design engineering in the BioProduction Group of Thermo Fisher Scientific. “Pressure to decrease timelines often forces process developers to reduce development scope,” she says.

“Fortunately,” Pleitt adds, “deep experience with affinity chromatography processes enables manufacturers to save development time without sacrificing yield and robustness.” The most basic form of affinity chromatography is the capture step using Protein A (ProA) affinity resins. The inherent selectivity of the ProA ligand gives a more or less built-in robustness, reducing the likelihood of variability as long as column packing reproducibility and the alkaline cleaning process are under control, Malmquist comments.

The ProA step, in addition, has been widely implemented for monoclonal antibody (mAb) therapeutics for more than 20 years, leading to a wealth of knowledge that is available to aid the development of robust processes, agrees Bala Thangaraj, director of downstream process development at Catalent Biologics.

Problems such as low capacity; the need to elute the antibody using an acidic buffer, which affects product quality (increased aggregates); and the absence of caustic stability, which is needed for cleaning between cycles, all of which existed in the earlier days of ProA use, have since been largely addressed through ProA ligand engineering, Thangaraj comments.

As a result, Pleitt points out that instead of taking time to identify target operating conditions, developers can use their general operational knowledge and conduct experiments that focus on potential CPPs that will improve their understanding of the design space.

Even so, a QbD approach is still useful. “The early identification of CPPs and their proven acceptable ranges (PARs) can be instrumental to the development of a robust chromatography process in general,” insists Alex Boulbrima, a principal scientist at Charles River Laboratories.

Some challenges in mAb affinity chromatography process development do, in fact, remain. The aggregation or reduction of the di-sulfide bonds between the heavy and light chains are typical examples of CQAs that continue to be problematic, according to Boulbrima. “Their monitoring must be a priority, as is the establishment of robust PARs and normal operating ranges (NORs) for the chromatography step to mitigate those CQAs,” he notes.

The risk ranking of process parameters also becomes different when implementing continuous mAb capture processes, according to Malmquist, because it requires more thorough characterization work to establish process parameter ranges that enable robust performance at extended cycle numbers.

For separation of antibody variants in the ProA step, there can also be various challenges that require a different approach compared to a regular mAb capture step. “For instance,” observes Bolik, “a gradient elution combined with ‘narrow’ process parameter ranges for conductivity and load ratio may be required.”

Affinity chromatography of new modalities

Newer antibody-based biologics may also require different affinity solutions, such as ProA ligands engineered to bind to different regions of the biomolecule. Even though more complex biologics may require different affinity solutions, these solutions are also inherently robust, Bolik assures. She does point out that if the affinity step provides separation of product-related impurities (e.g., through avidity effects), stricter requirements for process parameters such as elution pH, etc., may be necessary. Alternatively, the separation of these species must be ensured in the subsequent polishing steps.

For some non-Fc-based modalities, notes Thangaraj, some conventional ProA affinity resins can bind to variable regions of the heavy chain (VH region), enabling capture of antibody fragments. “While this approach can suffer from low capacity, adjusting the salt concentration can act as a helpful tool to address this issue,” he says.

In other cases, such as to aid purification of multichain bispecifics, resins need to be generated with specially designed ProA ligands engineered out of the VH binding region. Such mAbs with silenced Fc-regions may, more specifically, require the use of affinity towards VH3 or other antibody domains, Bolik adds.

Entirely different affinity resins, such as Protein L (ProL), can also be used to capture antibody fragments. However, due to the instability of fragments in comparison to mAbs, the loading factor, elution buffer pH, and hold time must be extensively studied.

For more complex biomolecules such as viral vectors, antibody drug conjugates, etc., Boulbrima says the biggest challenge remains the establishment of a broad and performant package of analytics, which is needed for the identification of specific CQAs that in turn help establish the correct CPPs and PARs.

For all newer modalities, an added challenge may be that a suitable commercially available affinity resin does not exist. If that is the case, Pleitt believes that while sourcing a custom affinity resin can add significant time and cost, doing so may be a favorable option because having an affinity resin as part of the process can also be beneficial.

The greatest benefit of employing a QbD approach for affinity chromatography process development is the creation of a robust process with a sound control strategy for relevant CPPs that impact quality, such as elution pH, linear velocity, and load ratio (loading capacity of the resin). That is important because, says Pleitt, affinity chromatography normally occurs towards the beginning of the purification process, and the outputs are inputs to the rest of the downstream unit operations, which means the process can ultimately impact product CQAs.

“Elucidation of the relationships between CPPs and CQAs leads to the definition of a robust control strategy for this step,” Thangaraj states. This relationship is well established for mAbs and Fc-based modalities, with loading factor and elution buffer pH (acidic) being the most common CPPs to affect CQAs and performance indicators, notably yield, according to Thangaraj. It is even more important for biologic drug substances for which traditional ProA capture steps are not applicable.

Affinity chromatography also benefits from the inherent robustness of the process, which helps deliver consistent unit operation outputs while allowing variability in process parameters and inputs, according to Pleitt. “The specificity, robustness, and available knowledge for many affinity resins are a great starting point for development and provide a solid foundation for building out process knowledge. Frequent use of affinity resins aids in selecting the most likely CPPs that should be the experimental focus. Streamlining the development and risk-based approach to experimentation helps accommodate the ever-present business pressures of time and cost, while maintaining compliance and ensuring sound knowledge of process performance,” she explains.

QbD, concludes Boulbrima, has helped greatly in justifying product specifications, process validation, and robustness. “Moreover,” he continues, “it has reinforced our knowledge with respect to process performance and the appropriate control strategies to be put in place.”

Resin considerations in process development

Application of a QbD approach to affinity chromatography development typically begins after resin selection has been made, generally due to the resource intensiveness and associated costs of QbD approaches, Thangaraj notes.

Even so, a QbD mindset should be applied at all stages of the development process, according to Pleitt. For instance, as discussed above, resin suppliers should apply QbD when designing resins and developing their own manufacturing processes. Of course, Malmquist observes, it also behooves drug developers to select resins that have good column packing properties and high alkaline stability to maximize the likelihood of a robust manufacturing process at scale.

Selection of the resin, says Boulbrima, is done based on performance studies, which he suggests might still qualify as a light QbD
early-identification activity. “Even during resin screening,” Pleitt adds, “an understanding of the desired performance and outputs is needed. While the overall process performance may be undefined, understanding the expectations for the unit operation from the start—clearance of various impurities, ability to accommodate variability in the feed stream, etc.—is important,” she contends.

A QbD approach involves leveraging development data to establish CPPs early in the development process, focusing on process characterization (PC) study parameters, identifying impacted CQAs, and minimizing rework, notes Marcia Kary, principal scientist, downstream process development with Catalent Biologics. “The PARs generated by the PC study give a more complete process understanding and ensure process control when later process changes or situations arise,” she says.

In addition, Malmquist believes a QbD approach allows developers of affinity chromatography processes to focus on the most important aspects of the step and pinpoint the CPPs that are important to control in order to ensure product quality.

Pleitt goes further, noting that ideally the increased process understanding gained by using a QbD approach should allow for more process flexibility and reduced emphasis on end-product testing. Today, she says, control strategies for biopharmaceutical production frequently involve tight constraints on process parameters and material attributes with extensive end-product testing.

“A QbD mindset enriches the process understanding and can help identify and characterize a wider design space. By linking parameter performance and material attributes to unit operation outputs, it helps process developers move away from the lowest level of control and makes it possible for them to focus on the inputs that truly impact the product,” Pleitt concludes.

Cynthia A. Challener, PhD, is a contributing editor to 

When referring to this article, please cite it as C. Challener, “Quality by Design for Affinity Chromatography,” 

Downstream Processing

Enriching process understanding enables robust process controls.

Quality by Design for Affinity Chromatography

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,” 

Manufacturing

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

BioPharm International, July 2022 Issue

The Difference between Electronic Records Retention and Archiving

Automating Biopharma Manufacturing

Do Modeling and Simulation Tools Really Benefit the Biosimilar Industry?

Evolution to a New Clinical Research Environment for Cellular Therapies

Plant-based Expression Systems are Gaining Mainstream Advantage

Quality by Design for Affinity Chromatography

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

Material Management and the Impact on Extractables and Leachables

The Road Ahead for the Pharma Cold Chain

Improved Formulations to Enable Stable Delivery of Biologics

FDA Advances Quality Initiatives to Combat Drug Shortages

Process Development Struggles with Molecular Diversity

How Can We Come Up Short So Often?