Mitigating and containing contamination of drug products manufactured under sterile conditions is an essential part of quality control in a pharmaceutical facility. This is particularly true for biologics. A facility that is aging may contribute to the challenges of ensuring the quality of drug products. But how long do biopharmaceutical manufacturing facilities last and what is considered aging?

According to Francesca A. McBride, director of Regulatory Compliance, and John Chapman, senior architectural technologist and subject matter expert, both at Jacobs, the original facility design, material, and personnel flow in facilities that date back to the 1990s and early 2000s may not be to the same standard as newer facilities and, therefore, may be perceived as obsolete.

The lifespan of a facility, however, depends on a variety of factors that include the date the facility was built, the type of products manufactured, preventive maintenance performed, and the flexibility to adapt to new purposes, according to industry experts. “Some facilities go offline if a product becomes obsolete or demand has diminished. [Whereas], if demand stays strong, the lifespan can be quite long. While the average life span of a facility is in the region of 12–18 years, there are facilities that have been in operation for over 20 years without a shutdown, thanks to strong market demand,” says McBride. “The lifespan of a facility can also be extended by switching processes, or if required, retrofitting the facility to manufacture an alternative product than it was originally designed to manufacture.”

Maik W. Jornitz, president and CEO of G-CON stresses that facilities may be viable for 20 or more years with constant preventative maintenance. “In addition, the question is whether the facility has the flexibility to be repurposed in case the product lifecycle runs out and a new product entity is admitted,” he says.

A commitment to maintain a facility is key to its longevity, notes Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. This maintenance includes equipment replacement, updating process validation, and using appropriate analytical methods for new therapies.

Manufacturing biopharmaceuticals in a facility that is older may create quality issues such as equipment breakdown and contamination risks. Older facilities may use older technology not in alignment with the advances of biopharmaceutical products, according to Schniepp. “Challenges in using an aging facility to produce new products could include difficulty in performing suitable process validations for the product due to antiquated manufacturing equipment. Another impact is the availability of change parts. Older manufacturing lines tend to break down more frequently and replacement parts may not be available
due to discontinuation. If we take a broader approach to aging facilities, we would also include antiquated methodology for analyzing the new biopharmaceutical products for patient safety and product quality,” she says.

For quality control, facilities must be able to adapt to changing requirements, according to McBride and Chapman, including staying up to date with automation and key process operations. “From a control standpoint facility operators need to also consider if there are risks related to environmental cleanliness that put the product at risk. This will vary depending on whether it is an open or closed process. For example, for solid dosage manufacturing, some of the steps are open with the addition of raw materials, so failure to maintain environmental cleanliness would put the product at risk. Self-culture operations, on the [contrary], is a closed process, so environmental contamination is lower risk,” says McBride.

“If the facility [is] not maintained frequently, the PDA [Parenteral Drug Association] aging facility survey found that the facility utilities, including wall finishes and air filtration, and the processes start causing problems,” says Jornitz.

According to a study performed by a PDA task force, the investment in post-approval changes may inhibit an organization’s interest in investing in new technologies (1). “Respondents agreed that the time required for post-approval changes can be considerable, 32% described time frames of up to two years, 62% said that they can take from two to 10 years, and 3% related that they take more than 10 years. A total of 92% of respondents estimated the regulatory costs for such changes to be below $110,000” (1).

This lack of upkeep or modernization can impact cleanrooms especially. A quality control risk assessment should consider the materials used to construct the cleanroom, according to Jornitz, because traditional construction materials can elevate the risk of mold contamination. “As has been experienced, some of the older cleanroom materials are hygroscopic and when damaged can cause major mold contamination issues, so much that in instances the infrastructures had to be either refurbished or were shut down,” he says. “Other experienced contamination risks in utilities could be biofilm formation in water systems or contamination within the duct or mezzanine levels. Key to avoid such contamination potentials is preventative maintenance and equipment upgrades.”

Risk assessment should be performed if a facility produces more than one product on a line, explains Schniepp, to minimize the potential for cross contamination. “In addition, the product flow (how the product moves through the manufacturing line) may not be ideal for the product and could expose it to potential viable and non-viable particulate contamination,” says Schniepp. “In some cases, the actual construction materials in the cleanroom may be degrading and difficult to clean, which also impacts the product. Manufacturing lines not using current protective barrier technology or single-use systems offer more exposure to the product through human interface.”

Schniepp stresses that aging facilities may cause more concern regarding microbial contamination. “This is generally because the materials of construction are not state of the art and could be degrading. Some of this degradation may go unseen or undetected during cleaning, creating areas that might harbor microbial growth. The cleaning regimen for the facility should be reviewed and effectiveness tracked through the microbial monitoring program,” she says. Microbial monitoring programs may also need to be more robust.

Jornitz also points to outdated aseptic filling lines as a potential problem for quality control in aging facilities. “If the fill line breaks-down or is not functioning as specified, the impact on quality can be detrimental. This critical processing step needs the highest attention level,” he says.

Adhering to a well-planned maintenance strategy can reduce the impact on cleanrooms, say McBride and Chapman. “Wear and tear and the reliability of older systems such as HVAC [heating, ventilation, and air conditioning], purified water/steam, and clean-in-place (CIP) systems are also a consideration in aging facilities,” says Chapman. “For cleanrooms, HVAC is a critical component, providing a reliable source of clean air. Durable, easy-to-clean finishes are also essential to maintaining a valid cleanroom. As the finishes age, tiny voids can begin to occur, making cleaning more difficult. The joints and seals between dissimilar materials will need more scrutiny and maintenance to ensure viability. There is also now increased regulatory focus on airlocks going into and out of process suites and the operations in the clean areas. Therefore, the facility design and operational strategy in aging facilities may no longer meet the regulations,” he stresses.

Jornitz warns that an HVAC system that does not function properly can impact the entire cleanroom infrastructure because of the centralized nature of HVAC systems. “Maintenance of the centralized HVAC system means also shut-down periods to start up the facility afterwards with time consuming requalification efforts. New cleanroom infrastructures see a higher segregation level all the way to autonomous HVAC units for individual cleanroom units,” he says.

Ductwork in the HVAC system can degrade over time, specify McBride and Chapman, impacting filter supply. “It’s important to perform routine maintenance on these systems including regular inspections and annual rebalancing and checking of the HVAC system. HEPA filters also need to be replaced regularly—the frequency will depend on usage and the fan systems,” McBride says.

Considerations must be made when adapting facilities previously utilized for small-molecule drugs or other types of manufacturing, to produce biopharmaceuticals. “A full risk assessment is conducted to examine and ensure suitability. Once approved, these facilities are adapted to ensure they fully comply with all relevant requirements and regulations related to biopharmaceutical manufacturing to ensure optimum quality control. This method prolongs the lifespan of a facility and expedites access to life enhancing medicines and therapies,” says McBride.

Chapman points to quality risks when adapting certain types of facilities, such as warehouses. “The building exterior envelope is typically less robust for excluding exterior elements, and the structure is rarely robust enough for the loads imparted by suspended larger HVAC, piped services, power and data, etc. Furthermore, the use of pre-manufactured cleanroom wall and ceiling systems is very prevalent, and these ceilings can be used to support nominal foot traffic, imparting additional structural loads. Either the systems are bolstered or compromises in distribution or maintenance would be introduced,” he says.

Cutting and patching of floors to install liquid waste systems and other underground services presents problems, according to McBride and Chapman. “Subsequent application of monolithic floor finishes [is] more susceptible to cracks or distress over or along the resulting concrete joints. Exposing the earth inside a space that will eventually house classified cleanrooms introduces additional risks to the cleaning and validation,” Chapman says. HVAC design as well as power, data, ceiling height, and liquid and/or gas services are other considerations.

In addition, continue McBride and Chapman, older buildings may have gypsum board wall systems that generate a significant amount of dust when built, modified, or repaired. “Care must be taken to seal HVAC systems and thoroughly clean following each instance to avoid contamination,” Chapman stresses.

Preventive maintenance and recapitalization are important factors for ensuring quality control in aging facilities, points out Jornitz. Upgrading equipment can limit the number of surprises and keep processes in control. Equipment should be updated when it shows weakness or is breaking down, Jornitz points out, and outdated equipment should be replaced if it cannot be maintained. “Some process technologies can function for decades when well maintained, but if one cannot get the spare parts any longer, one runs into the risk [of having] a break-down without a possibility to fix it. It is essential to have frequent site and process analysis and reviews on the equipment used to create capital investment plans and keep all equipment up to date,” he says.

Older systems may need more attention and maintenance, according to McBride and Chapman, especially pressure seals and joints between materials. “Durable, monolithic surfaces provide easily cleanable conditions. As a facility ages, it is normal for natural settling and movement from use and weather to create openings and cracks which can harbor contaminants. Facility finishes such as flooring can also experience wear and tear over time. This can diminish their robustness and ability to uphold the required level of cleanliness. In this case, the surface must be replaced to eliminate the risk of contamination. Newer materials provide inherent chemical defenses; however, these would not be available on older facilities without retrofit. Air pressure differentials between spaces of differing classifications is another line of defense; as the room envelope ages, the gaps and seals naturally lose pliability and effectiveness,” Chapman says.

Equipment, such as parts washers, autoclaves, restricted access barrier units, or isolators, should be assessed and maintained to ensure quality, adds McBride. “Naturally, wear and tear occur over time, whether that’s on surfaces or pressure seals, and on occasion, certain equipment may be deemed beyond further repair, and must instead be replaced to ensure optimum quality.”

Updating equipment should depend on the type and the process it’s being used for, explains McBride. Updates to software and sterilization procedures also impact the need to update equipment. “For any biopharmaceutical products manufactured on a commercial level, a license application must be submitted to FDA which describes in detail the equipment used. FDA must be notified of any changes made to equipment that have direct impact on the product manufacturing,” says McBride. She stresses that equipment upgrades, however, are not always sufficient. “Upgrading equipment in an aging facility can often present problems with facility infrastructure. A full facility upgrade after a 15-year timeframe will ensure both infrastructure and equipment are up to scratch and reduce the risk of non-compliance with new requirements.”

When dealing with manufacturing of biopharmaceuticals in an outdated facility, good manufacturing practice procedures must be in place, emphasizes McBride, and manufacturers should develop a 15-year lifecycle program. “Regular employee training and swiftly and coherently communicating any procedural updates or changes are also key steps to ensuring all individuals are aligned on best practices. Frequent maintenance assessments within an aging facility are also encouraged,” she says.

“Another part, not to be forgotten, are the people who run the facility and processes, as they also age and new people require the proper training to have the same capabilities as the experienced team members. Too often the human factor is forgotten and that can add a major risk to the processes whether well maintained or not,” agrees Jornitz.

Shanley, “PDA’s First Aging Facilities Survey Sees Regulatory Obstacles to Modernization,” 


Vol. 35, No. 12
December 2022
Pages: 12–15

When referring to this article, please cite it as S. Haigney, “Controlling Quality in Aging Facilities,” 

Articles

Cover Story

Manufacturing biopharmaceuticals in an aging facility may create quality issues such as equipment breakdown and contamination risks.

Controlling Quality in Aging Facilities

Viral clearance (VC) studies are mandatory for biologic drugs, which are pharmaceutically derived from human and/or animal sources such as cell line-derived recombinant proteins, blood products, vaccines, and critical medical devices. In these studies, the potential of removal and/or inactivation of adventitious and endogenous viruses of certain steps of the manufacturing purification process is addressed in a small-scale approach. Though regulatory guidelines are in place, the design of such a VC study is often not as straightforward as expected. The current guidelines do not keep up with the fast pace of the industry in terms of acquired knowledge, evolvement of new product categories, new methodology, and new production modes, which often leaves room for interpretation. In addition, there are other challenges and pitfalls that need to be taken into consideration when performing VC studies. This article will cover VC studies, their challenges, and the quickly evolving biologic drugs industry.

The first recommendation addressing the VC for biologics produced in cell lines was published by FDA in 1993 (1). Followed by the first VC guideline from the European Medicines Agency (EMA) in 1995, which covers all the categories of medical biological products for human use, with the exception of live viral vaccines, including genetically engineered live vectors (2). After almost 30 years, the reference guidelines do not cover the non cell line-derived biologics, which are also not addressed in raw-material-specific guidelines, including the urine-derived medical products (3) or the human blood plasma products (4). The reference guideline cell line for cell line-derived biologics from the International Council for Harmonisation (ICH), the ICH Q5A (5), was initially released in 1997, revised two years later, and is currently undergoing a long overdue revision. Meanwhile, several other guidelines and recommendations have been released. Despite these documents being in place, for manufacturers to decide on a VC study scope, they still must consider many aspects as guidelines are often only valid in certain countries.

In general, the regulatory guidelines ask biomanufacturers to prove the potential of at least two separate process steps independently. As a consequence, a combination of solvent/detergent and/or low pH treatment followed by a chromatography and virus-retentive filtration is being addressed. When it comes to the virus panel to be tested, the guidelines highly recommend addressing the known or suspected contaminates while covering all biophysical properties in terms of RNA or DNA, enveloped and/or non-enveloped viruses. Therefore, each VC study must be reviewed on a case-by-case basis to evaluate the risk factors associated with each tested product, including raw materials.

In the past 20 years, VC knowledge and data has accumulated especially for Chinese hamster ovary (CHO)-derived recombinant products. Additionally, considerations to reduce the VC study scope (e.g., standardized protocol ASTM E2888-12R19) for low pH treatment has been taken into account in which, under certain requirements, a 5 log10 clearance for murine leukemia virus (MuLV) can be claimed. However, the increase in knowledge and recommendations are only in place for certain territories, which raises the uncertainty and challenges in the industry regarding VC study scopes.

One challenge in VC studies is the demand of a scaled-down version of the process step. When scaling down is accomplished successfully, and its validity is demonstrated, a second challenge follows in that this established scaled-down version has to be communicated to a VC testing team. This team works in a laboratory setting, which is separated from the production site to prevent contamination of manufacturing processes. Often times, the VC studies are carried out by an external contract research organization. Therefore, a good understanding of the process and efficient communication between the manufacturer and the VC testing team are crucial for a seamless VC study.

Recently, as the industry optimizes their manufacturing processes to increase profit, new challenges have arisen. For instance, product concentrations are massively increasing in manufacturing. This increases the general risk of aggregation, especially upon addition of a high-titer virus spike that is being added for VC testing. In many cases, this also requires additional adjustments of common de-coupled VC study set-ups to inline process. This is a specific process where pre-filtering is employed directly before the chromatography or virus-retentive filter, which, due to the more sensitive material, cannot be de-coupled. Even though data obtained in recent years indicate that some pre-filters do indeed have the potential to remove viruses, the potential cannot be claimed. Authorities argue that integrity tests for these filters are not in place. Hence, the impact of the pre-filter on its own has to be addressed in addition to the inline set-up.

Another aspect is that biomanufacturing is transitioning from batch-mode processing to continuous processing (CP). This transition, of course, bears an exceptional challenge when it comes to establishing a scaled-down model and calls for innovative alternatives, which results in specifically tailored scaled-down models for VC testing purposes that should take into consideration the integration of linked-unit operations. Additional key issues for both increased protein concentrations and CP in manufacturing include the increases in volumetric throughput and product load across a retentive filter, which will cause virus breakthrough once critical thresholds are met. Thus, suitable sizing and scaling of the retentive filter is of paramount importance to accommodate the increased load.

Maintenance of a high standard of purity is a requirement of any biotherapeutic products. Many of the biotherapeutic products utilize cell culture for production, which increases the risk of contamination. Therefore, it is crucial for VC to be part of the known three principles—selection, testing, and reduction—to prevent the transmission of pathogens, in addition to sourcing and testing. Recently, it was shown that no manufacturer is immune to contamination events (6). In this study, though only 18 cases of contamination were reported in 35 years (6), contamination is still a real threat to all industries, including gene therapy. Contamination can occur in all stages of a product lifecycle. According to Barone 

, most of the contamination in CHO-cell-derived products originated from raw materials or intermediate components, while most of the contamination in human/primate cell lines originated from manufacturing operators or the cell line itself (6).

What about gene therapy products? What is the source of contamination? Considering the adeno-associated virus (AAV) system as an example, cell lines and helper viruses can be the potential source of contamination. Therefore, biological starting materials for gene therapy products are considered key in the assessment of viral safety testing and VC. The adventitious agents can be introduced into the manufacturing process using those biological starting materials, reagents, and raw materials such as animal-derived serum. Moreover, over the past decade, there is a steady increase in investigational new drug (IND) filings of gene therapy products. Because of the backlog for manufacturing, which is a result of limited manufacturing facilities, gene therapy products are increasingly manufactured at multi-product facilities. This situation increases the possibility of unintentional introduction of adventitious agents into the manufacturing process due to cross-contamination at multi-product facilities and raises several questions: what is the best course of action for manufactures to employ? Are there any specific guidelines that can be followed to evaluate if VC studies are needed, and how they can be applied? Unfortunately, there are no current and specific guidelines to direct the gene therapy industry to the required steps to follow regarding VC validation. Based on regulatory agencies, especially FDA, the current available documents might be used as reference guidelines. Some of these documents include the ICH Q5A 

Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications

The principles of ICH Q5A cover topics that can be applied to gene therapy products. For instance, according to the ICH Q5A document, contamination could arise from the cell line starting material by use of contaminated cell substrate or by endogenous contaminants, which can be applied to some gene therapy products. Systems that use baby hamster kidney (BHK) cells with potential retrovirus-like particles (RVLPs); systems that use human embryonic kidney 293 (HEK293 cells) with potential adenovirus contamination; and systems that use Spodoptera frugiperda 9 (SF9) cells with potential rhabdovirus contamination are examples of cell-line-derived contamination risks. Other sources of contamination include raw materials serum/medium, process-related components, such as helper viruses (e.g., baculovirus and adenovirus), and manufacturing operators or the facilities themselves.

It must be kept in mind that VC is not required for all early stages of gene therapy products as it is in recombinant protein products. If there is no risk of copurification of a helper virus or of an adventitious virus (e.g., from the cell line, such as an endogenous retrovirus or rhabdovirus, or from raw material), then a VC study might not be required in the early stages in such cases. The risk assessment for adventitious agents should be performed by each sponsor on a case-by-case basis to assess if VC is needed.

On the other hand, VC is required in certain conditions. The baculovirus/SF9 system can be used as an example of how to address some of the challenges that a system faces under a VC evaluation. Although the helper virus is not a human virus, and the system is mainly serum-free, there is a potential of detecting contaminants in the final product. There are two common sources of contaminations: Sf-rhabdovirus (Sf-RhV) and the baculovirus helper virus itself. Sf-RhV was one source of contamination that was reported in Sf9 cells (7). Small amounts of Sf-RhV particles in the final product may be immunogenic and can cause inflammation. Meanwhile, regarding the baculovirus helper virus, residues of this helper virus were detected in the final product, and those residues also have the potential to activate the innate immune system. Therefore, a VC study should be applied in this case.

One of the challenges in VC studies arises when it is applied to Sf9/baculovirus products because high residues of baculovirus are detected in, not only the harvest material and affinity chromatography load, but also the affinity product and anion exchange chromatography load material. These high residues of virus can impact the sensitivity of VC assays (either in a cell-based assay or in a quantitative polymerase chain reaction [PCR]). It is difficult to overcome the high-endogenous-virus-level background without applying significantly high non-toxic/non-interfering dilutions, which, consequently, will impact the titration limit of detection. This background might be higher than the total load titer of the baculovirus model that is spiked in the load material during the performance of the VC study.

One of the options to overcoming this issue is to use the residues of baculovirus in the tested material as the target virus to be removed or inactivated by the evaluated steps in the VC study, instead of spiking an additional baculovirus in the material.However, the obstacle here is that all the titration assay systems that are used by VC vendors are validated based on their own cell banks and virus banks. Each SF9/baculovirus system’s manufacturer must first establish a validation study at the VC facility to validate the titration assay for their specific baculovirus on the vendor’s cell system. This validated assay can be used mainly in the detergent treatment and affinity chromatography steps in VC studies.

What about other gene therapy viral vector systems, such as lentivirus and herpes simplex virus (HSV)? While it is still applicable to evaluate inactivation steps (e.g., detergent and heat treatments, and a nano-filtration step with certain sizes, such as 30–35-nm filters) in VC studies for AAV systems, these steps cannot be considered with gene therapy products using enveloped virus systems that are larger sizes than AAV. Chromatography steps might be the only options that can be employed to evaluate the downstream processes.

Because the possibilities of applying virus clearance steps during production are limited for many types of gene therapy products, the viral safety of these products should be ensured with the application of a combination of measures, including selection and control of starting materials, raw materials, and equipment. One possible solution involves the prevention of contamination at the upstream level, such as, for instance, implementing methods to remove or inactivate viruses in media or components (e.g., ultraviolet-C, irradiation, high temperature, nanofiltration), development of media that do not require animal/human-derived raw materials, and use of closed systems to avoid contamination by environmental sources, where applicable.

The most common downstream steps in gene therapy products that can be evaluated for VC studies are summarized in 

Finally, the viral safety of each gene therapy must be ensured; this procedure is summarized in EMA’s 

Guideline on the Quality, Non-clinical and Clinical Aspects of Gene Therapy Medicinal Products

“Contamination with extraneous viruses and residues of viruses used during production, such as production and helper viruses needs to be excluded as far as possible … Rigorous testing of seed and cell banks, intermediates, and end products for the presence of adventitious virus needs to be conducted in accordance with principles outlined in ICH guideline Q5A (R1)” (8).

The guideline highlighted the importance of testing raw materials of biological origin thoroughly or manufacturing them by production processes that can remove/inactivate adventitious and endogenous viruses. Therefore, when applicable, VC studies should be considered to validate these production processes to determine the reduction factors for each of the tested steps (8).

Points to Consider in the Characterization of Cell Lines Used to Produce Biologics

 (CBER, 1993).
2. EMA, EMA/CPMP/BWP/268/95, 

Note for Guidance on Virus Validation Studies

 (Feb. 14, 1996).
3. EMA, EMA/CHMP/BWP/126802/2012, 

Guideline on the Adventitious Agent Safety of Urine-Derived Medicinal Products

 (May 26, 2015).
4. WHO, “WHO Guidelines on Viral Inactivation and Removal Procedures Intended to Assure the Viral Safety of Human Blood Plasma Products,” 

, 2004 Annex 4 (March 1, 2004).
5. ICH, Q5A(R1) 

Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

, Step 4 version (1999).
6. P.W. Barone, et al., 

 38 (5) 563–572 (2020 ).
7. P.H. Ma, et al., 

 88 (12) 6576–6578 (2014).
8. EMA, EMA/CAT/80183/2014, 

Tareq Jaber, tareq.jaber@crl.com, is associate director, and Anja Tessarz, Anja.Tessarz@crl.com, is associate director RGDB, SME Viral Clearance; both at Charles River Laboratories.


Vol. 35, No. 12
December 2022
Pages: 18–21,33

When referring to this article, please cite it as T. Jaber and A. Tessarz, “Viral Clearance Studies: Challenges and Beyond,” 

Downstream Processing

The design of viral clearance studies must keep pace with the quickly evolving biologic drugs industry.

Viral Clearance Studies: Challenges and Beyond

Industry 4.0, conceptualized by the digitalization-led convergence of digital, physical, and virtual assets, brings a paradigm shift in the totality of operations across the value chain. While many industries are already leveraging the value and benefits of digitalization in manufacturing operations, the biopharmaceutical industries are slowly gearing up in this direction with an industry vision of Biopharma 4.0. Biomanufacturers are investing heavily in building next-generation capabilities toward intensified, connected, and continuous manufacturing to remain competitive and address current and future market needs on speed, quality, agility, value, and sustainability.

Biomanufacturers are taking steps to leverage digitalization, automating the collection, processing, and analysis of data gathered from multiple pieces of production equipment and moving toward Biopharma 4.0 principles. Initiatives are directed at connecting and integrating different operations digitally to provide for centralized data access. Advances in data analytics are affording proactive and predictive capabilities, providing greater process understanding and insights into process deviations and reducing the risk of variability and batch failures while increasing efficiency and quality consistency. Automation systems are reducing manual interventions for greater operational safety and less risk of contamination. There are also opportunities for digitalization solutions related to quality, data integrity, and regulatory compliance.

Irrespective of biomanufacturers’ goals for operational efficiency and building the capability to support next-generation bioprocessing, digitalization is inevitable. Digitalization is a key enabler for such transformational capabilities in biomanufacturing; therefore, the adoption of automation and digital technology is no more a choice but a necessity to remain competitive in the market.

Biopharma manufacturing presents enormous opportunities for benefit from thoughtful application of digitalization solutions, according to Matt Panning, senior director of manufacturing at Humacyte. “Controlling product quality, reducing costs, and improving time to market are always important factors in manufacturing. Biopharma manufacturing specifically can often involve small production runs for rare or personalized medicines and/or highly complex processes that require tight controls to ensure product quality and acceptable yield. The costs associated with more traditional infrastructure investment in capital and systems development, as well as the costs of not leveraging the data available from manufacturing, are all very good targets for digitalization solutions,” he observes.

“The benefits of digitalization in biopharma manufacturing are multidimensional across the value-chain of operations. They start with a holistic view of plant operations, facilitating more eyes to control and monitor CPPs (critical process parameters) and CQAs (critical quality attributes) and also include access to centralized contextualized data to gain valuable insights through advanced analytics, such as batch prediction coupled with automated reporting from and across the batch. Real-time access to process data coupled with AI/ML [artificial intelligence/machine learning] [to potentially] support batch release in real-time and significant time savings by minimizing error-prone, manual tasks and enabling easier collaboration across the organization through digital workflows are additional positive impacts. Overall, digitalization helps the organization to achieve operational excellence to meet the market demand on time, speed, quality, agility, and sustainability,” adds Braj Nandan Thakur, global product manager of process automation and analytics for MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany.

The potential benefits of such digitalization, says Cenk Undey, global head of data and digital for pharma technical development with Roche and Genentech, a member of the Roche Group, include process optimization and continuous improvement to drive cost-of-goods-manufactured (COGM) down and increase staff productivity and safety, while improving environmental sustainability. One of the first improvements, he notes, is the removal of ‘paper’ from the manufacturing process, otherwise required as a system of record. “Digitalization of batch records, equipment-use logs, and such are good examples that help reduce manual data transfers,” he comments.

Operations that heavily utilize process automation are often easy to integrate and mine, but some operations that are often paper-based can be more difficult, Panning remarks. He notes, however, that even some of the paper-based operations can be worth the investment to digitalize if they lead to significant yield or quality improvements through better process understanding and analysis.

Improved process and product insights at a much lower cost result in better manufacturing processes with faster development timelines, contends Jesse McCool, cofounder and CEO of Wheeler Bio, a new biologics contract development and manufacturing organization (CDMO) located in Oklahoma City focused on small-batch, agile drug substance manufacture. For instance, using data acquired in the past combined with dozens of data parameters obtained in real time, it is possible to elaborate through cloud domains and AI which of those parameters can be the best lead or process conditions to obtain a predefined response or target, according to Vincenza Pironti, senior pharma services R&D staff scientist at Thermo Fisher Scientific. “These benefits are applicable for all steps of the process involving all the unit operations present in a biopharma company,” she says.

Digitalization can, overall, impact the very basic philosophy of the biopharma industry and that is access to life-saving therapy in a faster yet compliant manner with proven quality at an affordable price. As a desired outcome of digitalization, while patient safety is of paramount interest, operator safety and sustainability cannot be ignored, Thakur summarizes. “Real-time process monitoring can give insight into process parameters and deviations and reduce the risk of oversight, non-compliance, and batch failures. Predictive analytics can anticipate process deviations earlier and optimize operations to deliver consistent quality. Digitalization can also increase flexibility in biomanufacturing processes by becoming more agile to reconfigure processes and respond to new modalities. Finally, implementing digitalization in biomanufacturing can deliver the goal of faster, improved quality, more cost-effective, safe, and effective therapeutics to patients, irrespective of modalities or steps,” he concludes.

There are other factors that can impact the level of benefits realized through digitalization. There may be process-specific nuances that differ between upstream and downstream operations, Thakur observes. “For example,” he explains, “if one looks upstream, where the harvest parameters are crucial to the downstream outcomes, there is the added challenge of accommodating the unknown variations during the process. While some variations can be measured, for others the real impact may not be known until later in the process. This introduces the need for constant measurement through the duration of a run which can span multiple days, during which significant online data [are] generated along with the offline data for the period of the run.”

Digitalization can help here, Thakur comments, because it enables monitoring of variability due to different sources—the genealogy of the raw materials used and continuous reviews of the quality profile (such as the glycosylation profile and charge distribution for antibodies) using advanced sensor technologies, process data analytics capabilities, and advanced analytical models.

Another big difference between upstream and downstream is referred to as the process time constant, such as in biologics drug substance manufacturing, according to Undey. Downstream operations are much faster and end more quickly—sometimes a phase lasts a minute versus weeks—for a process in a bioreactor. “In addition, while the types of data collected are very similar, more types tend to be evaluated for quality control (QC) samples obtained downstream for quality attribute analysis for lot release compared to those for upstream in-process control (IPC) samples collected for process performance variables,” he says.

Upstream, there can be further differences in digitalization for batch/fed-batch processes versus intensified processes performed in a smaller footprint. Integrated continuous manufacturing (CM), meanwhile, requires fully connected data flows between upstream and downstream operations (such as the harvest, chromatography, and ultrafiltration/diafiltration steps) with surge tanks as well as process analytical technology (PAT) sensors for ensuring process and product quality control across the CM process operation, according to Undey.

As with any major change in operational activities, there are hurdles that companies must overcome when moving to digitalized bioprocessing. One of the first that must be overcome is linked to natural human resistance to change. Steps that can be taken to minimize this issue, says Pironti, include creating a new mindset inside the organization to build necessary skills in the workforce and new roles for monitoring the progress and the outcomes resulting from the introduction of digital tools. Performance of gap and risk assessments should help identify specific needs and enable development of appropriate action plans.

Another human challenge noted by McCool is found in the intellectual interface between process scientists (subject matter experts) and data scientists (modeling experts). “I think it is quite difficult for most data scientists to contextualize bioprocess data without having a deep knowledge and tangible experience of the real-world physical systems they are modeling. Therefore, it is crucial to have a very good collaborative approach for model-based operations where process scientists and data scientists work together on a regular basis. Additionally, this structure needs executive sponsorship at the highest levels in the company for a disciplined ML strategy to emerge and be sustained,” he explains.

On the technical side, companies can find it challenging to select the right digital technologies and integrate them into their ecosystems, according to Thakur. “An existing facility comes with the challenge of integrating digital technologies into its legacy systems and existing infrastructure, while a new facility can build a new solution but faces the dilemma of choosing already-known technologies instead of innovative ones to reduce the risk and complexities of validation,” he says.

Adding to this difficulty is the lack of a unified out-of-the-box digital solution that applies across the biomanufacturing workflow and universal standards for software interfaces, which means biopharma companies must work with multiple vendors and systems to ensure that all these digital technologies are compatible and can be integrated together. “Standardization across the organization and across sites globally can be challenging as local digitalization needs can differ from global needs. When digital technologies are implemented in pockets of an organization or as a pilot to demonstrate value, the challenge remains in scaling up digital technologies to the wider enterprise. Last-but-not-least is the challenge of articulating the value realized from investments in digital technologies,” Thakur observes.

Lack of ubiquitous data standards across the industry, adds Undey, was confirmed by the domain experts from industry, academia, and suppliers during the Integrated Continuous Biomanufacturing conference that took place in Sitges, Spain in October 2022. “Different manufacturing technologies often have different data standards, and therefore, data integration requires further investment on the part of the biopharma company. Additionally, manufacturing digital systems are typically not plug-n-play, so each time we introduce a new piece of equipment or analyzer/sensor, effort is required to make its data integrated with the rest of the labs and plants,” he says.

Lack of standardization raises other questions as well. Assuring data integrity can be challenging while digitalizing large amounts of data from different sources and integrating them across multiple platforms. “Despite being an advantage overall, the use of multiple service providers who each deliver and manage their own solutions to a manufacturer can present the manufacturer with a significant problem when it comes to ensuring that all of the data maintains integrity across all of those platforms,” Panning comments.

In addition to controlling primary data sources, there are issues around handling the impact of software updates on data validation. “Manufacturers, not their service providers, are liable to understand and control their data collection, processing, and retention are maintained when these routine updates happen. And when two or more of these services are linked, which is often the case when a manufacturer sets up their own customized solutions, it makes keeping up with all of the changes that much more difficult,” Panning explains. The rate of change across the industry and regulatory agencies further heightens such concerns.

Accessing comprehensive data is another important issue facing biopharma companies looking to digitalize their manufacturing operations. According to McCool, Michelle K. Lee, founder and CEO of Obsidian Strategies and former AWS and Google executive, remarked in a MLxBio5 conference in San Francisco on Oct. 21, 2022 that companies are really only using approximately 10% of the data that gets generated (1). “The real work for any company looking for digital transformation is getting access to all the data being generated in their company,” McCool contends.In addition, he notes that more than half of the time spent developing ML models is spent wrangling, processing, and cleaning up data—activities that are ripe for automation by smart middleware solutions.

Furthermore, the biopharma industry, McCool observes, is not yet data-rich like other industries, even for commercial production, let alone clinical operations. “Bioprocesses are fraught with complexity, real-world processing interactions, and regulatory constraints that make predictive modeling fundamentally challenging. When this truth is considered along with the fact that data points are very expensive in bioprocessing ($6–$10 million for a Phase I manufacturing batch), it is obvious why data strategies currently remain limited,” he states. He reiterates that the solution, at least in part, is to have an accurate scaled-down model of bioprocesses coupled with automated workflows and smart middleware that lowers the cost of collecting and analyzing data points.

The level of adoption of advanced digitalization in the biopharma sector is fairly low, but that is changing. Most mid-to large size biopharma companies, says Undey, digitalized batch records in the early to mid-2000s to remove, or significantly reduce, paper records from manufacturing floor operations, although old paper-based recordkeeping may still exist in various spots due to organic growth and investment prioritization reasons. Process automation that integrates widely across a site and use of data analytics to better understand and control processes is expected at this point, according to Panning. He also notes that the use of service providers for licensed software has exploded in the past decade or so.

Even so, Panning believes the industry is still grappling with how to apply more traditional pharmaceutical models to the new models that are evolving today. In addition, McCool believes that currently manufacturers are making do with 21st-century digital tools and automation that are not sufficient. “To really penetrate into the heart of what is going on with their systems and achieve deeper understanding than is currently possible, process scientists need predictive modeling, digital twins, and AI augmenting their abilities,” he insists.

Full data integration across the plant is rare, Undey agrees. “A cross-industry forum led by BioPhorum group has created a maturity model for biomanufacturing digital plants to gauge the need and the level of digitalization and automation. The study found that for most plants, ‘connected plant with data integration’ is sufficient, while some fully autonomous/adaptive plants may make more sense to drive COGM down, depending on the production volume and staffing considerations,” he notes (2).

The COVID-19 pandemic has, however, put pressure on biopharma companies to pursue digitalization more quickly. “In an unprecedented way, biopharma companies, industry stakeholders, and regulatory agencies collaborated to accelerate the adoption of digital technologies for faster development and manufacture of vaccines and therapeutics and to facilitate day-to-day operations,” Thakur says.

As a result, today large biopharma companies look at digitalization as a transformation lever that helps them keep the core knowledge, architecture, and designs internally while working with strategic partners to execute the tactical technology implementation, according to Thakur. Smaller firms, however, often adopt digital capabilities that help them solve operational and compliance needs in the short-medium term while giving them a competitive edge in terms of operational efficiency, business intelligence, and customer collaborations so they can meet aggressive timelines. Contract service providers leverage digitalization strategies that afford them greater flexibility and scalability and the ability collaborate with their customers and regulators.

The pandemic, adds Pironti, prompted an incredible acceleration in digitalization of biomanufacturing—from lead selection to the generation of prediction modeling for the manufacturing process, to prevention of possible deviations through monitoring storage and distribution data. “These digital assets can be the starting point for further implementation of digital tools,” she observes.

Indeed, Undey underscores the fact that several companies have been making steady progress with digitalization of their bioprocessing operations. Example solutions he highlights include plantwide real-time process monitoring, predictive maintenance of equipment, PAT, cobots for warehouse ops, various “Industry 4.0” applications such as the Industrial Internet-of-things (IIoT), integrated MES/ERP/laboratory information systems (LIMS), applications of AI and ML, and advanced process control solutions. “The adoption of these technologies is driven by their technological maturity and availability in the marketplace (with robust suppliers), regulatory acceptance and experience, and ability to meet key business needs,” he states.

Digitalization is an exciting journey that continues to evolve within the biopharma industry as manufacturers continue to improve performance and strive for greater efficiency and quality, all with the goal of meeting current and future patient needs. “We should remember that digitalization of biomanufacturing is a means to that end to help drive utmost efficiencies and COGM down, ensuring supply to patients,” Undey emphasizes.

Areas within digitalization where further developments can be expected, according to Undey, include further capabilities for remote monitoring and support technologies and more advanced applications such as miniaturized wireless sensors, machine-learning programs for predictive plant-performance management, intelligent decision-support systems, and digital twins. “It is not a matter of if, but a matter of when. We are excited to help create that future and embrace it to harness the power of data and digital across the product-advancement value chain to better serve our patients,” he states.

Within change lie both opportunity and challenge, and that is true for digitalization of biomanufacturing, Panning observes. “Digitalization has enormous potential for our industry and will only continue to grow in its applications. Picking the right solutions, at the right time, and following through with proper resourcing during the change-management process are the keys to successful implementation,” he comments.

The adoption of digitalization in bioprocessing is, Thakur believes, happening at a very rapid pace, with Industry 4.0 technologies evolving at an even more rapid pace. The challenge for biopharma manufacturers is to keep themselves in step with this transformation. “For now, biopharma is more of an adopter than a pioneer in these applications. That, however, is going to change in the coming years. With the advancements in precision medicine, new modalities, and novel therapies like cell-and-gene to name a few, the space of biologics is going through a change that will demand a lot more precision and accuracy from these digital technologies that other industries may not demand of them,” he says.

The reason is simple, according to Thakur—biopharma touches lives like no other industry, and as the space of biologics starts rapidly evolving, the demand for innovation and technology will also be unprecedented. “This pace cannot be met by biopharma manufacturing organizations alone. Instead, it will require an ecosystem of technology companies, digital providers, manufacturers, regulators, governments, entrepreneurs, and life-science leaders alike, who will come together to transform the way biopharma will evolve in the coming decade. A lot more is yet to come, and this is just the beginning!”

M. Lee, Obsidian Strategies, “Seven Lessons for Successful Machine Learning Deployments,” Presented at the 5th Annual Machine Learning Meets Biology MLxBio5 Conference, San Francisco, Oct. 21, 2022.

E. Anttonen et al., “The Development of a Digital Plant Maturity Model to Aid Transformation in Biopharmaceutical Manufacturing,” White Paper, BioPhorum Operations Group. 


Vol. 35, No. 12
December 2022
Pages: 24–33

When referring to this article, please cite it as C. A. Challener, “Digitalization of Biomanufacturing: A Status Update,” 

Manufacturing

Digitalization of bioprocessing is slowly bringing benefits to the biopharma industry.

Digitalization of Biomanufacturing: A Status Update

This past year has been marked by continued efforts to develop, regulate, and distribute important therapies and vaccines to treat lethal and rare diseases, including the still-dangerous COVID-19 virus. Despite generally high praise for biopharmaceutical companies in advancing these efforts, industry was unable to block the adoption of price controls for prescription drugs, a policy that risks limiting research in some areas. At the same time, the tense political environment leading up to the November mid-term Congressional elections blocked agreement on many important legislative and regulatory initiatives for FDA, delaying until the very last moment reauthorization of critical user fee programs to support the agency. Despite the anxiety generated by that cliff hanger, FDA succeeded in maintaining an efficient oversight and approval program for new and important therapies and issued multiple new guidances, renewed field inspections, and launched a range of initiatives to support public health.

The delay in Congress renewing user fees for drugs, biologics, generic drugs, medical devices, and biosimilars hampered FDA planning and put multiple new programs on hold. Uncertainty over future funding made it difficult to attract much-needed new staffers to the agency. And the need to drop from the fee bill a host of legislative proposals put in limbo important measures to strengthen FDA’s accelerated approval process, update regulation of new 

 diagnostics, and enhance FDA’s authority to regulate cosmetics.

At the same time, the Biden administration succeeded in pushing through legislation to limit price increases on certain drugs and to authorize negotiations on leading medicines covered by the Medicare program. While advocates predict that the policy will yield billion-dollar savings in the years ahead and plan to press for curbs on high launch prices, biopharma companies claim it will discourage biotech innovation in areas facing uncertain long-term return on investment. Meanwhile, industry pushed back against expansion of the federal 340B program, which authorizes steep discounts on drugs distributed to certain hospitals and clinics and also joined efforts to question rebate and coverage practices of Pharmacy Benefit Managers (PBMs) that play a key role in how drugs are covered and made available to patients (1).

A preferable strategy for pharma in curtailing drug prices is to achieve more efficient and less costly clinical trials, a goal that has prompted a range of industry and FDA initiatives to modernize biopharma research operations. The pandemic supported wider use of remote and online systems to enroll study participants and oversee treatment and patient status, with digital technologies becoming more widely used for patient monitoring. These approaches also appeared effective in advancing diversity among study participants, where remote site visits may facilitate enrollment of individuals facing difficulties traveling to clinical sites.

The ongoing surge in R&D for cellular and gene therapies prompted a reorganization and expansion of FDA offices overseeing these products and efforts to clarify and update regulatory policies in this area. The importance of FDA providing individualized advice for these cutting-edge therapies highlights the critical need for the agency to attract experts to its staff able to oversee and encourage new methods and innovations.

Continued shortages in both new and long-used drugs and medical products fueled FDA efforts to encourage industry adoption of advanced manufacturing systems and support for regulatory programs designed to ensure production of high-quality treatments on a continual basis. Similarly, the expansion in innovative biotech therapies and vaccines highlighted the importance of modern production methods able to quickly ramp up production of new treatments. FDA continued to advance several initiatives to improve product quality, including proposals for a Quality Management Maturity program for drugs and biologics; appropriate oversight of products with limited chemistry, manufacturing, and controls information due to expedited development treatment; and wider use of smaller, mobile drug production methods, such as distributed and point-of-care manufacturing.

FDA recognized the challenges in overseeing these developments as it moved to revive field inspection operations for manufacturing facilities and bioresearch operations. The agency indicated its intent to continue utilizing alternative remote inspection methods adopted during the pandemic based on the experience of inspection personnel in gaining needed information remotely on the status and compliance of sites, especially those with strong histories of meeting regulatory requirements (2). This shift to a dual inspection mode that incorporates document reviews and online “site visits” with real-time inspections is likely to become a permanent part of the agency’s oversight operations for manufacturers and clinical research operations in the United States and overseas.

This past year was a difficult one for FDA Commissioner Robert Califf, who faced critical questioning and a long delay in gaining Senate confirmation to head the agency again after a brief time as commissioner in 2016. Califf came back to FDA with long experience in advancing the development and oversight of critical new therapies to further combat global pandemics and lethal diseases. However, the commissioner had to spend much time and energy on a host of health crises, including a serious shortage in infant formula, rising death rates from opioid overdoses, and pressure to curb marketing of vaping products and e-cigarettes.

A serious challenge for Califf and health authorities is the continued rise in misinformation about coronavirus medical treatments and vaccines. FDA and other public health agencies struggled to boost COVID-19 vaccination rates and counter anti-vaccine voices, while also combatting the promotion of untested and dangerous “treatments” for COVID and other serious health conditions. This anti-science rhetoric was a major frustration for all involved and will continue to shape public health initiatives and FDA leadership and operations in the months ahead.

340B: The Unintentional Hospital and Pharmacy Profit Stream That Was Supposed to Help Patients

FDA Details Optimized Approach for Regulatory Oversight Tools to Better Protect Public Health


Vol. 35, No. 12
December 2022
Pages: 8–9

When referring to this article, please cite it as J. Wechsler, “Managing mRNA Instability During Formulation, Manufacturing, and Shipment,” 

Regulatory Beat

Health crises, political tension, and budget concerns were major challenges.

Pandemic and Politics Shaped Pharma and FDA in 2022

The combined market capitalization of the five companies focusing on messenger RNA (mRNA) platform development was approximately US$15 billion at the end of 2019 and more than US$300 billion as of August 2021, according to Xie 

(1). While that’s staggering, in many ways its entirely understandable. In October 2022, I helped organize and run a high caliber event in San Diego, CA for “mRNA day” with TriLink BioTechnologies, to discuss common manufacturing, supply, and regulatory challenges relating to mRNA as a platform. Interspersed between the high cost of required enzymes, the need to be serious about how to manage DNA as a starting medium, and cut off points for potency assays, we devoted significant time and energy to discussing what benefits might accrue from establishing a supplier-developer consortium.

Standards and regulatory streamlining came quickly. But during a hour-and-a-half panel, we added the idea of a central railway station system for supply shortage oversight, easy access to best new publications, and centralized advocacy for staff recruitment though university and technical college classes, alongside staff training best practices generally. Because of the tricky intellectual property landscape and competitive commercial aspects involved, we all thought “consortia” might have unhelpful exclusionary connotations. “Alliance” or “organization” was accepted as reducing hesitancy instead. It was a genuine pleasure and delight to be part of this wonderful event. We said heartfelt goodbyes, I took a deep breath, then headed off to the high-octane capaciousness of CPHI Frankfurt, and thence a deserved week’s holiday in Germany.

Tuning out work for a week was delightful, refreshing, and against expectation. Arriving at each new city, getting our bearings required tuning into WiFi at the train station (Hauptbanhof). Each and every time, a new message also turned up from one of the San Diego attendees. They had “been thinking” and wanted to share a “new suggestion” for a secondary role the mRNA alliance might play. When an idea follows you around the globe, when you feel tracked down at a train station, you know something special is happening. This feels like the field of proteomics 20 years ago. There is a real need for both consolidation and standardization of resources. It’s not a train we necessarily all need to get onboard immediately, but we should know where the central train station is located, and what it connects us to.

1. W. Xie, B. Chen, and J. Wong, “Evolution of the Market for mRNA Technology,” Nature Reviews Drug Discovery, 

Chris Spivey is the editorial director of 


Volume 46, Volume 12
Dcember 2022
Page: 10

When referring to this article, please cite it as C. Spivey, "mRNA Hauptbahnhof," 

From the Editor

mRNA may not be a train we necessarily all need to get onboard immediately, but we should know where the central train station is located, and what it connects us to.

mRNA Hauptbahnhof

No matter how busy or complicated life becomes, science news can occasionally stop us in our tracks. Science news can be just so weird, or weirdly useful, that everything else recedes as we ponder whether it is true and what consequences it might bring.

For example, the armadillo is the only known host for the leprosy bacterium other than humans. Unimpressed? What if I told you this bacterium has the power to convert one type of bodily tissue into another? Results from a recent study show that the liver nearly doubles in size in armadillos infected with the leprosy bacterium (1). This kind of growth on the surface looks destined to be defective or even cancerous (inherent to some cell and gene therapy approaches) but the livers in the infected animals were found to be both healthy and functional, including the full complement of blood vessels, enzymes, and bile ducts that would be found in a normal liver. Professor Anura Rambukkana, who led the study, heads a group in regenerative medicine at the University of Edinburgh, that for the last decade has been pioneering an approach around cellular reprogramming. The leprosy causing bacterium hijacks the plasticity of adult tissue niche Schwann cells, reprograming them to modified stem cells, weirdly, to simply have more tissue to feed off.

There may be several practical outcomes from elucidating this mechanism. The leprosy bacterium practices this biomolecular “alchemy” at a relatively slow and natural pace, largely outflanking paths typically understood to also promote cancer growth. Because the bacterium is doing this for reasons of prosecuting its plans to “infect” its host, understanding details here may well lead to new avenues to treat or inhibit infectious disease and related pathologies such as inflammation. On his university webpage, Rambukkana states, “We are also studying how these reprogrammed progenitor/stem cells can be combined with endogenous innate immune cells with natural regenerative properties to promote repair processes in demyelinating neurodegenerative, neuromuscular, and liver diseases in varying model systems” (2).

It feels odd to say it, but I am now genuinely looking forward to hearing more about what leprosy can do for us in the future. Science, or knowledge of how the natural world works, is full of unexpected twists and turns, heroes and villains, saints and sinners. If we can turn the tables and make a villain a hero—how wonderful will that be!

Mike Hennessy Jr. is the President and CEO of 

When referring to this article, please cite it as M. Hennessy, “Of Mice and Men and Armadillos,” 

From the CEO

Science news can be just so weird, or weirdly useful, that everything else recedes as we ponder whether it is true and what consequences it might bring.

BioPharm International, December 2022

Controlling Quality in Aging Facilities

Viral Clearance Studies: Challenges and Beyond

Digitalization of Biomanufacturing: A Status Update

Pandemic and Politics Shaped Pharma and FDA in 2022

mRNA Hauptbahnhof

Of Mice and Men and Armadillos