The Evolving Landscape of Oral Solid Dosage Forms

Drug Solutions Podcast

Industry experts discuss the need for stricter environmental controls.

Automating Aseptic Processing Reduces Contamination Risk

The right processes used with the right excipient combinations address evolving formulation needs.

Development of Coprocessed Excipients

Elemental impurity analysis of drug products is primarily aimed at ensuring patient safety.

Ensuring Patient Safety Through Elemental Impurity Analysis

When considering whether outsourcing to a CRO, one must consider the type of work, regulatory considerations, and study needs.

When to Outsource Bioanalysis Work to a CRO?

Is AI a panacea for pharma’s productivity gap?

Big Pharma in the Balance

The Criticality of Training in Aseptic Processing

Pramote Cholayudth previously was the managing director of the Professional Conference Center, Ltd. He currently is a validation consultant to Biolab Co., Ltd., in Thailand. He is the founder and manager of PM consult, cpramote2000@yahoo.com.

Relative standard deviation (RSD) limits were used in content uniformity in the past (before 2007). From a statistical point of view, RSD is one of the only few statistics that describes the term “uniformity” best. In a simulation study conducted by the author, both acceptance value (AV) and RSD distributions have a typical relationship where it was found that AV and RSD charts, when applied for continued process verification (CPV) purpose, can be constructed concurrently on the same chart frame to demonstrate their common overlay view. While RSD calculation is much more simple, RSD charts may also be applied to confirm the validity of AV charts in CPV exercise.

Submitted: May 23, 2022
Accepted: June 8, 2022

Pramote Cholayudth, cpramote2000@yahoo.com, is the founder and manager of PM Consult. He is an industrial pharmacist with more than 40 years of experience. He is a guest speaker on process validation to industrial pharmaceutical scientists organized by Thailand’s FDA.

When referring to this article, please cite it as P. Cholayudth, “Application of RSD Charts for Content Uniformity Data in Continued Process Verification,” 

Articles

This article is focused on introducing a control chart technique using relative standard deviation (RSD) statistics (i.e., RSD chart); in other words, a coefficient of variation chart for continued process verification. 

Application of RSD Charts for Content Uniformity Data in Continued Process Verification

Unexpected occurrences, such as the COVID-19 pandemic, have shone a light on the already existing issue of global accessibility to medicines through traditional means of manufacturing. As technology improves, the industry looks toward how to improve the landscape of medicinal accessibility. Point-of-use manufacturing may have the potential to change the distribution and accessibility of medicines throughout the world, but not without considering some of the challenges that may arise. 

 spoke with Peter Walters, director of advanced therapies at CRB, and Maik Jornitz, president and CEO of G-CON, to explore some of the benefits, challenges, and logistics of point-of-use manufacturing.

The flaws of a new manufacturing approach

What are some of the major challenges/obstacles to consider when approaching point-of-use manufacturing of drug products?

 Point-of-use manufacturing solves the problem of patient adjacency and therapy transport logistics, but typically introduces the problem of a distributed manufacturing model. The design capacity of a point-of-care facility is most often smaller than that of a central production center, and, as a result, the cost effectiveness of having a fully effective support infrastructure must be evaluated. It is typical for functions like QC/EM [quality control/environmental monitoring] testing, warehouse, engineering support, etc. to be stripped from the building and outsourced or supplied from other sites. As a result, it can be difficult to provide and ensure the same degree of quality, consistency, and compliance in a point-of-use facility compared to a centralized manufacturer. While you have possibly solved the issue of patient access and therapy transport, you have introduced logistical issues with maintaining supply chain and support (engineering, maintenance, calibration, etc.) logistics.

: The past of point-of-use or point-of-care manufacturing has shown certain weaknesses when reviewing cGMP [current good manufacturing practice] compliance and aseptic processing safety. There were many examples which showed flaws, [such as] contamination control strategies, [where] low costs were the focus instead of high quality. These past experiences need to be overcome, [which] can only be done when the new wave of point-of-care systems are of high quality and in compliance with regulatory requirements. For example, process spaces or units still need to have the appropriate cleanroom classification, material, and personnel flows and gowning. Any cleanroom installed base at the point-of-care requires to be of sufficient quality instead of a cheap fix.

How has the COVID-19 pandemic impacted point-of-use manufacturing, in your opinion?

 Yes, it has; from mobile sample/test units to compounding and filling units to be able to fight the pandemic spread and drug shortages. The pandemic highlighted that we can be more flexible within our processing systems and bring the processing towards the point-of-use. In our experience, it has been very encouraging to see the industry, regulators, and suppliers come together to work on processing solutions, which allow much faster and more flexible capacity build-up.

The availability of COVID-19 vaccines in countries not manufacturing a vaccine directly has been challenging and has caused many countries to revisit their philosophies for providing capacity for therapy supply in-country. Some smaller countries have begun government-sponsored facilities for bringing vaccine and critical therapy innovation within their borders to manage against a repeat of the COVID-19 pandemic situation.

: How can point-of use-manufacturing facilities improve accessibility to vaccines and other drugs in certain countries?

 Many pharmaceutical therapies, especially when it comes to sterile injectables, have transport and storage logistics that involve cold chain complications. When trying to manage transport between different countries, factoring in customs and inspections timing, the effective shelf life and efficacy of a therapy can be dramatically impacted by just trying to deliver cross-border. Further, factor
in that most countries producing a
vaccine are likely going to prioritize their own citizens first. The brutal truth is that smaller countries may find themselves waiting in the queue for therapies to arrive, with reduced usability once they do. In many cases, the ability for these countries to have point-of-use manufacturing centers enables them to begin supplying patients faster and more effectively.

: How can modular facilities/point-of-use drug manufacturing impact manufacturing capacity/scalability?

: The design capacity of a point-of-care facility is typically smaller than that of centralized production facility. The facility is intended to serve a local patient population instead of a global population. Therefore, the scale of production for a point-of-use facility is going to be smaller by design. While smaller production [is] at an individual level, at a global view you can leverage a number of these distributed facilities to make an impact on patient populations.

 How can a controlled environment be maintained in a modular facility in different climates/smaller production space to ensure consistent drug quality?

: It all depends on the technology deployed. It is much more difficult to control the environment in a modular facility unit, which was meant for other purposes, for example, transport containers. Cleanrooms are purpose-built, with high quality to be assured that the injectable coming out of such unit is safe for the patient. Mobile units we delivered need to have the right robustness in containment to [ensure] that the processing of the medicinal drug is safe in any outside environment. That starts with temperature, pressure, and humidity controls, which means the air handling units needs to be appropriately scaled, [and] insulation needs [to be] correctly specified and personnel/material flows controlled so outside air cannot penetrate the processing space. This can only be done with high-quality designed and constructed cleanroom systems.

: There is, at this point, an established history of fully modular manufacturing spaces being able to provide robust cleanroom environments to support GMP processing. The design team would need to account for the site location requirements, and, if the point-of-use facility is intended to be mobile and relocatable, the span of site requirements it may encounter.

 What engineering considerations must manufacturers be aware of prior to approaching point-of-care manufacturing in a modular facility setting?

 Modular builds are fast to erect but come with their own set of design complications. Spaces must adhere to certain dimensional restrictions for shipping purposes, which can implicate how many cleanroom suites and how large they can be. Modular builds can be completely free-standing outside, but this would need to be factored in from the start of design. One prime benefit of the modular approach for point-of-care spaces is that they can be disassembled and relocated to different sites, as befits the point-of-care need.

: The processing environment requires to be protected in the same way as any other processing space. In [certain] instances, one can see a drift into low quality environments, which requires strict regulatory reviews as there may be weaknesses in containment and stable environmental conditions. That means the design and build of these modular facility settings requires detail and experience to meet the quality and regulatory demands.

 spoke with Peter Walters, director of advanced therapies at CRB, about point-of-use manufacturing for cell and gene therapy.

 How can point-of-use drug manufacturing impact the cell and gene therapy industry?

 Point-of-use manufacturing could have the potential to improve the personalized cell therapy industry. These therapies suffer from transport logistical issues in moving patient cells from the clinic to the manufacturing facility, and then back again. This transport causes delays to the delivery of the therapy to the patient, introduces cold chain and sheer sensitivity shipping hurdles, and lengthens the time the cells are forced to be stored in a non-ideal state. All of these ultimately contribute to lowering the efficacy of the therapy and the chances the patient will have a successful recovery. Moving the manufacturing activity adjacent to the patient could dramatically reduce these issues, potentially improving the therapy’s effectiveness.

: What technological
improvements have occurred that have helped to progress point-of-use
manufacturing?

: The technology improvements happened twofold; single-use process technology enabled closed processes and mobile cleanroom units to deploy such processes to different location or being cloned to a multitude of locations. In addition, the volumes processed, for example in cell therapy, are much smaller, which
allowed process intensification and the processing within single-use
assemblies within smaller footprint mobile cleanrooms. If the volumes would not have gone down and we would still live in a world of 20,000L volumes, point-of-care processing would not [be able to] happen.

 The industry push towards Pharma 4.0 and the widespread adoption of automation and digitalization helps drive toward consistent and digitally documented manufacturing. One of the biggest hurdles for a distributed manufacturing model is how to maintain and ensure quality and consistency from site to site. The use of concepts like electronic batch records, online process monitoring, and automated quality testing would go a long way to providing quality assurance and helping negate site to site nuances.

 What, in your opinion, do you foresee as being important trends that will impact point-of-use manufacturing in the near future?

: Three factors will determine the use of point-of-use manufacturing; scalability, controls, and quality. With the possibility of mass-production of mobile progressing units, we can bring costs down and therefore scale such platforms much faster. Controls are needed to keep these processes and units under the robust containment options needed, as well as potentially reduce the human contamination impact. Quality is a must and it starts with the design and construction materials used. Ultimately, the quality benefits will outweigh the cost of bad quality, and that will save patients’ lives.

: To enable point-of-use manufacturing to go from talking point to reality, facilities are going to need to utilize robust small-scale processing solutions that are automated and digitally integrated. To make the business model viable, manufactured therapies will need to be handled and produced with the same level of quality and care from site to site. Use of automated processes, testing, and digital monitoring will be essential in ensuring quality and consistency across the manufacturing network. 

When referring to this article, please cite it as A. Leon, “Advancing Accessibility through Point-of-Use Manufacturing,” 

Point-of-use manufacturing may lead to a big change in the accessibility of medicines globally. 

Advancing Accessibility through Point-of-Use Manufacturing

Gary Kruppa, PhD, is vice-president of Proteomics, Bruker Daltonics.

Single-cell technologies are transforming our understanding of human health and disease. Single-cell genomics and transcriptomics are mature disciplines that can be used to study more than a million single cells (1). However, human

biology cannot be understood through the analysis of DNA and RNA alone. It also requires the study of proteins and protein modifications, lipids, and metabolites.

Proteins are biochemically active and also serve as signaling molecules. As a result, it is not surprising that approximately 95% of drugs are targeted at proteins. However, protein molecules cannot be amplified like DNA or RNA to perform single-cell proteomics measurements. Thus, novel and highly sensitive technologies are required that can decipher this complexity at the single-cell level and contribute to our understanding of emergent issues surrounding health and disease (2).

Protein function is frequently modulated through post-translational modifications, such as phosphorylation and ubiquitylation, that can change the functional course of the cell with fast kinetics. Processes such as endogenous proteolysis and glycosylation are known to play a role in oncological mechanisms (3,4). In addition, gene expression is affected by so-called bursts in expression, which results in additional variations that would be automatically normalized by post-translational regulatory processes in the case of proteins (5). Furthermore, alternative splicing of RNA transcripts can result in additional protein variants. Single-cell proteomics technologies are now entering the mainstream thanks to the pioneering work of a relatively small group of dedicated scientists and the emergence of extremely sensitive mass spectrometers. Typical estimates of the protein content of individual cells are in the order of 200 picograms (which is one-billionth of a milligram). In a recent study, qualitative and quantitative information for up to 1400 proteins was obtained from single cells using an unbiased single proteomics approach that did not require complex isobaric labeling chemistries to boost the peptide signals (6). Cluster analysis of the data could distinguish cell types and cell cycle stages, despite the technology not specifically targeting known and verified markers.

This microheterogeneity in seemingly homogenous cell populations plays a key role in decisive pathways pursued by biological systems. The underlying microheterogeneity is caused by variations in genes and their expression, and understanding these variations at the single-cell level helps to identify the few cells that act as a seed for cancer development, for example. Studying DNA and RNA molecules within the cell is one of the most common approaches to single-cell biology and has also helped motivate the measurement of proteins at the single-cell level. Exponential advances have been achieved in single-cell DNA and RNA sequencing technologies and, depending on the application, a variety of sequencing techniques can be employed for these studies (2).

With the help of such advanced technologies, studies involving the measurement of the single-cell transcriptomes of more than a million individual cells are now feasible (1) and have revealed previously unseen biology as well as highlighted the heterogeneity of single cells—thereby opening up new areas of biology and medicine. A common enabling factor in all these approaches is the ability to amplify DNA and RNA molecules to virtually any desired amount, bringing these molecules into a detectable or quantifiable range (7).

Unbiased proteomics of single cells have been performed in recent years by specialized research groups involving nano-fluidics that are not yet readily adopted by the general research community. These applications often focus on minimizing the loss during sample preparation and multiplexing samples to boost signal intensity (8,9). Despite these solutions, however, the field still has need of innovations that can boost the sensitivity of the mass spectrometer.

The development of parallel accumulation and serial fragmentation (PASEF) (10) provided a spectroscopic technique used with liquid chromatography coupled to mass spectrometry (LC–MS)-based proteomics to improve sequencing speed and sensitivity. PASEF makes efficient usage of the ion beam and, together with intelligent precursor selection of ions eluting from a trapped ion mobility spectrometry (TIMS) cycle, achieves rapid MS/MS identification speed. In addition, the ions are focused in space and time within the TIMS cell, resulting in a significant boost in the sensitivity. This enables the analysis of low sample amounts, in the range of low nanogram peptide loads.

TIMS measurements also provide collisional cross-section (CCS) values and separation of isomeric species that are mobility offset but mass aligned and alleviate ratio compression in multiplexed quantification approaches. The introduction of these 4D-proteomics capabilities has bridged the gap between the requirements of the most demanding proteomics approaches—such as clinical research proteomics, companion diagnostics research, and personalized medicine research—and the solutions effectively available on the market.

Next-generation sequencing technologies now represent a multibillion-dollar industry (11) that promises to help deliver personalized medicine and precision therapeutics, which will help tackle complex and heterogeneous conditions, such as cancer and Alzheimer’s disease.

Single-cell protein technologies have the potential to transform our understanding of cell biology at the macromolecular level and answer fundamental questions regarding protein dynamics, cell differentiation trajectories, and mechanisms of disease. These processes act at the nano- and microscopic level but fundamentally influence higher-order macroscopic behavior. Hence, it is vital that these processes are understood at the highest possible spatial resolution.

 566, 496–502 (2019).
2. G. Chen, B. Ning, and T. Shi, 

, April 5, 2019.
3. L.A. Liotta and E.F. Petricoin, 

 116 (1) 26–30 (2006).
4. M.A. Connelly, et al., 

 15, 219 (2017).
5. G.K. Marinov, et al., 

 24, 496–510 (2014).
6. A.D. Brunner, et al., 

 12.22.423933 (2020).
7. C.F.A. de Bourcy, et al., 

 9 (8) e105585 (2014).
8. D.Hartlmay, et al., 

 60, 1–9 (2021).
10. F. Meier, et al., 

 17 (12) 2534–2545 (2018).
11. Markets and Markets, 

Single-cell Analysis Market by Cell Type (Human, Animal, Microbial), Product (Consumables, Instrument), Technique (Flow Cytometry, NGS, PCR, Microscopy, MS), Application (Research, Medical), End User (Pharma, Biotech, Hospitals)—Global Forecast to 2026


Volume 46, Number 7
July 2022
Pages: 20–22

When referring to this article, please cite it as G. Kruppa, " Innovations in Single-Cell Proteomics Drive Advances in Disease Research," 

Single-cell analytical technologies can deepen the understanding of cell biology and, therefore, disease mechanisms.

Innovations in Single-Cell Proteomics Drive Advances in Disease Research

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,” 

Automation and digitalization work together in the digital plant.

Automating Biopharma Manufacturing

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 46, Number 7
July 2022
Pages: 48–51

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

Colder Products Company’s AseptiQuik G DC Series Connector is designed to connect and disconnect tubing aseptically through a single, sterile connection. The latest in the company’s AseptiQuik G line of genderless sterile connectors, the product can make quick sterile connections and disconnections in both sterile and non-sterile environments without requiring any ancillary equipment.

The AseptiQuik G DC connector’s “FLIP-CLICK-PULL” assembly is designed to help users transfer liquids easily. After transfer is complete, a simple two-step disconnection process maintains system sterility. AseptiQuik G DC connector hose barb termination sizes include quarter inch, three-eighth inch, and half-inch sizes.

The AseptiQuik G DC connector is a single, sterile connection technology that can connect and disconnect tubing aseptically.

Aseptic Tubing Connector

HEMCO’s UniFlow Radioisotope Fume Hood 

HEMCO’s UniFlow Radioisotope Fume Hood is designed to meet strict requirements for lab work involving radiochemicals. The product is constructed with a welded one-piece seamless type 304 stainless-steel interior fume chamber with all corners coved for easy cleaning. The work surface is welded to the fume chamber liner and reinforced to support weight loads associated with isotope work, such as lead barriers and equipment.

The fume hoods come in 48-inch, 60-inch, and 72-inch widths and can be outfitted with various accessories such as service fixtures, electrical service options, cabinets/tables, and suitable exhaust blowers to safely remove hazardous fumes or particulates. LED lighting and a vertical slide tempered glass sash are also included.

The ROSS Mixing/Melting and Holding Tank System can generate up to 10 psig internal pressure to produce potent and reactive materials. 

Radiochemical Fume Hood

Steriline’s Robotic Nest Filling Machine

Steriline’s Robotic Nest Filling Machine is designed to aseptically process injectable drugs in a more efficient, safe, and flexible manner than traditional alternatives. By minimizing human intervention, the machine aims to produce a higher quality product with fewer operator mistakes.

The machine automatically adapts its process to recipes that have been registered in its database. Once a specific container is registered in this database, special sensors in the machine can detect the type and capacity of the containers. These sensors can also identify any non-compliant pieces and manage them without technician intervention, reducing waste and downtime.

The machine is capable of processing vials, ampoules, cartridges, syringes, and bags, and can handle toxic or non-toxic products in both liquid and powder form. It can be equipped with laminar air flow, open and closed restricted access barriers, and isolator barrier systems.

Steriline’s Robotic Nest Filling Machine is designed to minimize human intervention in aseptic processing of injectable drugs. 

Robotic Injectable Drug Processor

ROSS Mixing/Melting and Holding Tank System

The ROSS Mixing/Melting and Holding Tank System is a custom-designed machine that can produce highly potent and reactive materials at 350 °F and up to 10 psig internal pressure. The system includes a pressure-rated sealed enclosure with an operator-friendly safety glovebox and two mixers each equipped with a two-wing anchor agitator, Teflon scrapers, and jacketed six-gallon vessel.

A specially designed elevator system enables the mixers to be lowered to a maintenance position and raised to an operating height which allows for gravity feed from the melter to the holding tank. It also comes equipped with a hot oil heater and chilled water cooler.

Fully Enclosed Mixing/Melting System

On June 30, 2022, Getinge announced the release of its new DPTE-EXO with Sleeveless DPTE-BetaBag, which offers more secure aseptic transfer. According to a company press release, the product it a first-of-its-kind alpha port that comprises an external opening and an integrated funnel. The design is aimed at securing automated aseptic transfer and improving operational efficiencies.

The new port addresses the need posed by the biopharma industry’s rising demand for throughput and automation as well as stricter good manufacturing practice requirements. The combination of a motorized external-opening alpha port with an optional funnel provides operational efficiency by reducing manual intervention. This design also frees up time for the operator. The product is a fully validated and interlocked system and, with the dismountable funnels, offers a total transfer solution from the outside to the process area. Having the external opening significantly reduces the risk of contamination, and the connectivity offers a greater degree of traceability and data analysis.

“As the industry evolves, the next generation of pharmaceutical manufacturing needs greater flexibility of the batch’s size to switch production quickly from one drug to another,” said Anneke Evers, senior director, DPTE Sales & Market Support, Getinge, in the press release.

“DPTE-EXO with Sleeveless DPTE-BetaBag supports the efforts to build safe, automated, and compliant filling lines. It’s easy to use and has several smart controls governing its safe and efficient door opening and closing and funnel movements. It also integrates a specific program with an open door and funnel position suitable for the barrier system bio-decontamination cycle,” Evers also said in the release.

Getinge’s new DPTE-EXO with Sleeveless DPTE-BetaBag is an alpha port with an external opening and an integrated funnel for automated aseptic transfer.

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