Cleanroom monitoring is an industry that some reports estimate will be valued at as much as $7.1 billion by 2028 (1). In spite of that massive projected value proposition, however, many questions remain regarding the current (and future) state of the industry. How are recent advances affecting the field? What upcoming changes should we be aware of? Is the industry stable or in flux?

To learn more about the current state of cleanroom monitoring, recent advances in the field, and potential upcoming changes that might impact the industry, 

 spoke with the Alex McDaniel, Environmental Monitoring Program manager, Element; Joe Mundell, chief research officer, Sonicu; and Stephen Tierney, president, XiltriX North America.

When taken together their perspectives provide insight not only into the current state of cleanroom monitoring, but also into changes that may be cresting over the horizon. Topics of discussion include the current state of cleanroom monitoring, recent advances in the industry, upcoming changes, and more.

: Broadly speaking, can you share your thoughts on the current state of cleanroom monitoring? Would you say it is in flux, or a relative state of stability?

: Over the course of the past six years, it has been apparent the current state of cleanroom monitoring is always seemingly in flux. As the industry works to align the methodology, frequency, and validation of a formal environmental monitoring (EM) program, many applicable guidance documents and standards are undergoing revision. This includes 

] General Chapter <797> (2), which is (hopefully) nearing the finish line of its long overdue revision. An increased frequency of surface sampling within the cleanroom suite is anticipated in the 

 <797> revision, in addition to changing the organism identification requirements to be more pragmatic to delivering patient care.

In the current good manufacturing practices sector, the EU Annex 1 revision will emphasize the increasing need for a contamination control strategy, whereas the current version lacks specificity on this. A more consistent and patient-focused approach to EM will be embraced by the industry, as the Annex 1 revisions will impact cleanroom monitoring, especially as it relates to an enhanced focus on conducting a risk assessment of the activities within the facility.

: Cleanroom technology is rapidly evolving as more healthcare and life science customers migrate to the cloud and demand mobile-first solutions that are always on and can be accessed from anywhere. Moreover, clients are looking for monitoring solutions that both integrate with and serve as a multiplier for their BMS/BAS [building management system/building automation system] systems.

: Can you discuss some of the most recent advances in cleanroom monitoring? What makes these technologies fundamentally different from those that came before?

: Some of the recent advances in cleanroom monitoring would be continuous particle counting and measurements, such as volatile organic compounds (VOCs), becoming more and more ‘the norm’. Technologies never fundamentally change because it’s evolution, not revolution. Legislation and regulation would not be able to keep up if it were the latter.

[Increasingly] sensors [are being seen] in a single system. For example, analog magnehelic differential pressure sensors can now be digitally integrated into an [environmental monitoring system] alongside a room’s conditions and particle counters, as well as the equipment stored inside.

: Rapid microbiology has garnered a great deal of interest, yet it remains an unknown quantity and certainly does not look to unseat conventional microbiological testing methods in the near future. The turnaround time for traditional incubation of viable media is its primary pain point, as it takes a minimum of (roughly) a week to 10 days, depending on duration of media dual incubation conditions. This does not include the time microbial identification and reporting takes. Rapid test methods allow for quicker batch release and insight into the state of microbial control, as firms can receive insight into potential growth of bioburden much sooner (some within minutes or hours).

Fundamentally, the validation process for this is not necessarily as straightforward as traditional methods. Guidance documents like 

 <1223> Alternative Microbiological Methods (3) are a good starting point to consult when considering validation of this system. The data comparison is not ‘apples to apples’, as the rapid method employs the use of technologies like ATP [adenosine triphosphate] bioluminescence and viability staining to detect the presence of viable organisms. Rapid forms can cover a wide range of assays, from bioburden of raw materials to sterility confirmation, water monitoring, and active air sampling. However, it is important to ensure that rapid methods are of equal or better quality than traditional testing.

: Has there been any recent changes in what customers want in their environmental monitoring systems? If so, how has the industry changed to accommodate it?

: Data security is continuously becoming more stringent every year. Since the pandemic, life science facilities have been in greater need of remote accessibility; to have full insight into everything going on in a facility, no matter where the staff are located. [Facilities’ operators] want their electronic management systems more integrated with other critical systems like LIMS [laboratory information management system], building management systems, electronic lab notebooks, batch records, asset management, [and so on].

: Along with automation, clients are asking for trended data from their monitoring projects. While trending is a wide-ranging regulatory requirement, it is currently performed via a very manual process. To produce better reports that feature trended data as a standard inclusion, [Element implements and uses] LIMS.

Compressed gas testing is also more frequently requested in the industry. Including secondary points, such line drops within the building that are not routinely monitored, can provide a holistic diagnosis of how the entire system is performing versus a fragmented approach of selecting only certain locations. [It is expected that there will be a] significant increase in this [request] moving forward, especially in terms of validating a previously installed system.

Within the next several years, the momentum will likely swing towards systems that can provide continuous and automated sample collection during a production run. Some processes are still performed in a very manual way and require a great deal of human intervention, from differential pressure monitoring, temperature, and humidity data, or non-viables. Some manufacturers of monitoring devices are also developing viable particle counting units to provide real-time data of colony forming unit (cfu) counts with the use of laser technology similarly used for non-viable particle count testing.

: As the EU GMP Annex 1 revisions edge closer to publication, what changes, if any, will this make to environmental monitoring specifically? If we’re anticipating significant change, what future-proofing (if any) are you seeing in customer orders?

: There is an increased onus on manufacturers to implement and document a contamination control strategy and a vigorous risk assessment within the pharmaceutical quality system. Manufacturers may need to completely overhaul their program to include additional sampling locations if a formal monitoring program was not previously established, or the original program was not updated to reflect current processes or was based upon previous facility designs. An increase in EM performance qualifications conducted on existing cleanroom areas to align with an updated and more modern approach to the documented risk assessment [is expected].

Given the push to take a comprehensive look at processes to identify failure points and consequences of those failures in the upcoming Annex 1, using the failure mode and effects analysis (FMEA) tool has worked out well for clients looking to future-proof their risk assessments.

: Do you have any final thoughts on the topic that you can share with our readers?

: [A] greater attention from larger healthcare systems to include air pressure differential and humidity as well as O2, CO2, and VOCs [is being witnessed]. Infection control experts are driving the conversation as part of their risk management focus while construction firms are being consulted on both new build and retrofit projects to work collaboratively on these projects. [Additionally, a] significant demand relative to pre-COVID [is being seen] and [this is] expected to continue accelerating.

: [From personal experience, it is apparent that] critical gaps within an operation may not be identified until it is too late. Downtime can be eliminated, back-end costs reduced, and production lines will stay in operation if those within the industry tasked with maintaining compliance to these standards establish documented protocols in partnership with a subject matter expert (SME) and team of microbiologists.

As professionals, [there is] a responsibility to seek out continual education, as well as educate others in the industry. Establishing a partnership with a collaborative organization with a consultative team invested in teaching others is vital to staying on top of these dynamic requirements—and that is only the beginning. Selecting a firm that has a robust scope of service offerings and quality procedures that can look at processes, provide a gap analysis, establish methods to help mitigate contamination control before it becomes problematic, and even assist in validating a cleaning and disinfection program is a gamechanger when the FDA walks through the door.

USP, General Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” 

USP, General Chapter <1223>, “Alternative Microbiological Methods,” 

Grant Playter is the Assistant Editor at Pharmaceutical Technology.

Articles

Features

Recent technological advancements may have put cleanroom monitoring into a state of flux.

Environmental Monitoring Advances

Viral vectors must be free of contaminants, such as adventitious viruses introduced via raw materials and helper viruses introduced purposefully to stimulate expression of the desired viral product. Viral clearance used with incoming raw materials and, where possible, viral-vector products combined with testing is essential. Because conventional viral clearance methods used for protein biologics may degrade or destroy viral vectors, assessment of the potential risk for contamination and the implementation of prevention and control strategies are essential.

The most common source of viral contamination is usually traced back to animal-derived raw materials, such as certain cell-culture media (e.g., serum) and trypsin, according to Artur Padzik, adeno-associated virus (AAV) production manager at Biovian, a contract development and manufacturing organization (CDMO). Non-animal-derived raw materials can be an issue as well, particularly glucose if a chemically defined medium is used. A risk-based approach to process development combined with extensive testing of raw materials (and often the application of virus removal steps at raw material entry points), in-process materials, and final products is essential to ensuring the safety of viral vectors.

Similar to other biologics but challenging

The requirements for adventitious agent testing for viral vectors overall are consistent with those performed for other biological therapeutic products. As with other biologics, too, selection of appropriate testing methods is guided by the need to mitigate the risk of viral contamination taking into account the materials and processes used.

“Viral vectors are biologics, and as with all biologics, the concern around adventitious agents must be addressed with a thorough risk assessment that [considers] control and probability of contamination. The principals from the three-pronged complementary core strategy (material selection, testing, and clearance assessment) to prevent and minimize adventitious agents can and should be applied to viral vector manufacturing processes and products,” says Audrey Chang, executive director, Rightsource and Biologics at Charles River.

Direct adoption of strategies used for recombinant proteins and monoclonal antibodies may not be possible, however, Chang adds, due to biological differences between viral vectors and large protein molecules. Indeed, it may be necessary to modify standard assays or use alternative methods because viral vectors are viruses themselves and could interfere with virus detection methods, notes Leyla Diaz, a technical consultant in the Technical and Scientific Solutions unit of MilliporeSigma.

Specifically, adventitious agent detection can be challenging if cell-based assays are being used in combination with live-virus vaccines, replication-competent gene therapy vectors, or vectors exhibiting the cytopathic effect (CPE), Padzik observes. This issue arises largely because human cell lines are used for cell-based assays, and human cells are susceptible to human viruses. Lytic viruses such as adenoviral products, for example, will infect human and primate-based cells and can cause invalid assays. Robert Schrock, director of bioassay services at Lonza Houston, adds that even if adenovirus is only conditionally replicating and does not replicate, cellular toxicity may occur.

In these cases, neutralization of interfering and abundant product viruses is required, says Padzik. There are three approaches that can be taken, according to Schrock. One is to block antibodies specific to the virus product to “soak up” the product as much as possible without interfering with the detection of other adventitious viruses. Alternatively, the sample can be diluted so as to avoid overwhelming the detection cells. Often these two approaches are used in combination. The third option is to pull the test sample from an uninfected parallel satellite culture that is split off the bioreactor just prior to transduction with the virus bank. “For oncolytic vectors, FDA guidance mentions the use of #3 as acceptable. The first two have limitations, such as with test #2, where the value of the test can rapidly decline due to sample dilution,” Schrock comments.

In general, the key is to select the appropriate test method for a given product. For example, Sophia Nguyen, director and head of quality control at Lonza Houston, points to the selection of cell lines for infectivity assays as being important. “Viruses differ in their ability to infect host cell types.” For the endpoint assay used to determine whether a host cell is infected with a virus, a monolayer culture is preferable to a semi-adherent or suspension culture. With the former, CPE and hemadsorption (HAd) can be visualized by microscopy, making the analysis relevant both to viral detection and subsequent viral identification.

The plethora of potentially contaminating sources arising from the complexity of the viral-vector production process favors a holistic scheme for adventitious agent testing, according to Padzik. In this approach, both general and species-specific assays are used.

Adventitious virus detection assays, explains Nguyen, mostly fall into three testing categories: cell-culture-based infectivity assays, targeted nucleic acid-based amplification, and antibody production tests. Both in vitro cell-culture detection methods and in vivo assays are employed. No universal method is available to detect all adventitious agents, and therefore various complementary methods must be used. “There is a clear tendency, however, to move away from assays that require animal models toward assays with higher sensitivity, specificity, and rapid turnover, such as polymerase chain reaction (PCR),” Padzik remarks.

In vitro cell-based detection methods are typically broad-spectrum and intended to detect viruses that are able to replicate in cell lines—a human diploid cell line, a non-human primate cell line, and a cell line of the same species as the one used to produce the vector, Diaz observes. In vivo, animal-based detection methods are also broad-spectrum and intended to detect viruses that replicate in animal models—typically mice and embryonated eggs, but also other animal species based on specific risks associated with the product being tested.

With these non-specific 14- and 28-day adventitious agent tests, CPE or haemagglutination and HAd values serve as the readouts. The obvious limitation, notes Padzik, is the difficulty in detecting adventitious viruses that do not cause CPE. The limits of detection for these assays can also be an issue. Padzik says a partial remedy, but with limited sensitivity, is the use of transmission electron microscopy (TEM) to detect, for example, retroviruses. XC plaque, S+L focus assays, co-cultivation assays, or fluorescent product enhanced reverse transcriptase (FPERT) testing are also commonly used to detect retroviruses.

Molecular methods such as PCR tests are used to detect specific viruses that are either not detectable by other methods or that are emerging as particular biosafety concerns, according to Diaz. Known contaminating entities, including porcine and bovine viruses, minute virus of mice, vesivirus, rhabdovirus, polyomavirus SV40, and arboviruses for various animal and insect cells are addressed with PCR-based specific assays, Padzik says. PCR-based methods that can detect virus families rather than specific viruses are also being employed. They are also used to detect mycoplasma, spiroplasma, mycobacterium species, and mice DNA sequences, according to Nguyen.

Nguyen stresses that each method exhibits a different level of sensitivity, and the testing requirements and sample preparation protocols differ as well. It is imperative, therefore, to select the appropriate test for each vector product.

Adventitious agent testing of raw materials should be proportional to the risk posed by the raw materials, and the testing methods chosen based on such an assessment, states Horst Ruppach, executive director, scientific and portfolio global biologics for Charles River.

The most common methods of adventitious agent testing for raw materials are cell-culture-based assays using specific indicator cell lines, with Vero cells preferable because they can detect viruses from all sources, according to Nguyen. The added risk for introducing animal viruses posed by animal-derived components requires the use of sensitive cell-based assays that can detect replicating infectious viruses, Ruppach adds.

PCR-based methods are also used depending on the raw material and turnaround requirements. It is important to recognize, though, Ruppach stresses, that while using molecular methods can be advantageous due to their speed, they do not discern between a nucleic acid positive signal and an actively replicating virus.

Viral vectors produced to modify cells for the production of ex vivo cell therapies have some additional raw material concerns with respect to adventitious agents. Human serum albumin (HSA), a commonly used excipient for cell therapies, is a high-risk material with respect to virus and prion transmission, but there is no practical assay for direct prion testing, according to Ruppach. “Here, special emphasis must be placed on HSA donor screening and the manufacturing process in order to mitigate the risk of virus and prion transmission,” he says.

In addition, Ruppach notes that for gene-modified cell therapies, the viral vector is considered a critical raw material, and the same three-pronged complementary core strategy involving material selection, testing, and clearance assessment should be applied to mitigate the introduction of adventitious agents into the final cell therapy product.

Allogeneic, off-the-shelf cell therapies in which the cells used to produce ex vivo-modified cell products are derived from multiple human donors are worth a special mention, according to Diaz. They require a carefully derived risk-mitigation strategy, because each donor contributes a separate, individual virus risk to the product. “Upfront donor screening plays a large role in the development of a strategy that can mitigate the risk of virus contamination of these cell-based therapeutic products,” she states. In addition to normally performed adventitious agent product testing, it may be necessary to also perform additional virus testing to address potential risks associated with a specific set of donors or even a specific geography.

While traditional in vivo and in vitro methods for adventitious agent testing of viral vectors are sufficient to ensure the production of safe and effective products, they do suffer from some limitations, including sensitivity, the time required to perform the assays, throughput, and the detection of unknown contaminants, according to Padzik.

“Delivery times of adventitious virus test results have always been a serious challenge regardless of the method used, with some of them taking four to five weeks, and up to a few months with full analysis and documentation,” Padzik observes. For some gene therapy products that have a short shelf life, Diaz notes that these lengthy periods can be prohibitive. This concern is particularly relevant for autologous gene-modified cell therapies that must be administered to patients shortly after production. Molecular methods are being used to fill this gap, in particular PCR-based methods are being fine-tuned or developed to fill this need.

“The growing scope of required assays is creating continuous pressure, especially on early-stage clinical projects where results from the first human clinical studies are pivotal in securing the funding for full clinical medicine development,” Padzik adds.

“A partial solution could be a new pan-microbial microarray comprising 29,455 sixty-mer oligonucleotide probes for screening on a single chip vertebrate viruses, bacteria, fungi, and parasites,” Padzik comments. He cautions, though, that PCR-based methods are not able to help with the recognition of undefined adventitious agents and they suffer from noticeable instances of false positive cases.

Sample volume is another concern, particularly for viral vectors used in gene-therapy products. “Depending on the scale of vector production, adventitious virus testing can take up a significant amount of volume that could be otherwise used for patient dosing,” Diaz explains. This issue is of particular concern in early stages of product development before a production scale-up strategy has been implemented.

Nguyen reiterates that the different methods used for adventitious agent testing have different sensitivities for the detection of different contaminants and limitations. “These methods are intended to complement each other to provide a greater understanding of the detection of adventitious agents. In addition, the methods also have specific pharmacopeial and regulatory requirements/guidelines, such as sampling size. As always, these requirements must be considered when establishing a testing strategy,” she contends.

Tried-and-true test methods such as in vivo and in vitro virus assays and mycoplasma culture and microbiology culture assays have been used to demonstrate the biosafety of biologics for decades and can be applied in viral-vector manufacturing for certain steps such as cell-line and viral-seed-stock characterization, Ruppach emphasizes. During the past few years, adds Nguyen, understanding and methodologies have evolved significantly for adventitious agent testing, and Lonza believes this trend will continue to accelerate.

Given the limitations of existing methods and the advances being made in molecular-based methods, Ruppach expects the eventually the industry will switch to molecular test methods and rapid alternatives such mycoplasma PCR and rapid microbiological testing.

NGS-based assays are attractive for a number of reasons. The biopharma industry is focusing on using the full potential of NGS for adventitious testing requirements due to its low turnaround time in particular, according to Nguyen. The other main reason NGS is attractive is its ability to detect unknown contaminants, says Padzik. NGS can also be used to detect low-level known virus DNA/RNA sequences, according to Schrock. Identification will, of course, still require a comprehensive library of known and potential viral genomic sequences, and verification will be necessary by comparing results to those obtained using established methods.

In addition to these technical benefits, rapid NGS development has the potential to reduce costs and increase accessibility. “These advantages are driving significant interest and the urgency within the industry to validate this technique so that it can be swiftly implemented and applied for routine use,” Padzik remarks. The Advanced Virus Detection Technology Interest Group (AVDTIG) is an industry-based organization facilitating the exchange of experiences with the development of NGS-based assays to accelerate the introduction of practical solutions.

For Ruppach, one of the main challenges to effective viral-vector adventitious agent testing today is the resistance to new analytical methods. “There are several barriers to the adoption of new techniques such as NGS, including fear of regulatory delays, the risk associated with changing platforms, the resources (financial, personnel, time) needed, the tendency within the biopharma industry to be more focused on the short-term and less on the long-term, and the hesitancy to share information and desire to protect company trade secrets,” he explains.

“While all are valid reasons, it is essential to develop and share data that will support progress in the NGS field,” Ruppach says. He points specifically to the need for reference standards that will allow sharing of data obtained during development, comparability studies, validation and re-validation, technical transfer and assay trending, and ultimately the design of appropriate bridging studies that will enable translation to commercial application.

“Switching to rapid methods for adventitious agent testing must be done carefully, taking into consideration the fact that viral-vector manufacturing processes offer limited viral clearance steps,” states Ruppach. “Certainly, new alternatives such as NGS have applicability for viral assessment,” he adds. Padzik is hopeful as well. “The requests for using unbiased NGS are significantly increasing, especially in vaccine development. The current COVID-19 pandemic accelerated this transition even further,” he comments.

Ruppach also observes that a revision to International Council for Harmonisation (ICH) Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin is currently in the works and expected to include updated guidance to reflect updated scientific knowledge and advances in analytical technologies for new modalities, including viral vectors. For Padzik, the changing regulatory landscape and pressure to reduce animal testing are important drivers for NGS adoption, along with the apparent increasing acceptance of NGS-based assays in vaccines and other products where contaminating virus detection by the classical test is difficult and vaccine release is time-sensitive. “It is possible to envision gradual supplementation and, ultimately, the replacement of in vivo and other nucleic-acid technologies by NGS,” he concludes.

Taking a holistic view is the best strategy

“For most virus-based vaccines and viral vectors, the removal of contaminating viruses is not feasible, so the prevention and detection of virus contamination become more critical in a virus risk mitigation strategy,” emphasizes Diaz.

Although the principles used for adventitious agent testing of monoclonal antibodies (mAbs) apply to viral vectors, it is certainly not a “plug-and-play situation”, according to Chang. She stresses that a holistic view of the product, manufacturing, and ultimate use of the viral vector must be taken into account when performing risk assessments and establishing risk-control strategies.

For instance, the batch size for viral vectors is different from that for mAbs, with only a small number of doses produced per batch. In addition, some aspects of viral-vector manufacturing, such as the level of empty capsid production and consequent impact to the patient, are not fully understood. “Furthermore,” says Chang, “it is not possible to introduce robust viral removal/inactivation steps that exist with antibody manufacturing. Therefore, closer characterization of the starting raw materials, including biological characterization that assesses adventitious agents thoroughly, is prudent.”

Diaz agrees that an effective adventitious agent testing strategy starts with an appropriate risk assessment that evaluates all possible sources of virus contamination, including cell banks, virus seeds, plasmids, media, and other substances used in production. The risk assessment should also include identification of any steps in the manufacturing process (upstream and downstream) where virus contamination could be introduced.

“Evaluating the manufacturing components and processes for their contribution to the virus contamination risk allows for a multi-pronged approach that includes appropriate sourcing of materials, the selection of relevant virus detection methods for the risks identified, and the potential removal of contaminants associated with specific viruses in downstream processes,” Diaz summarizes.

There are several key aspects of any strategy for adventitious agent testing, according to Nguyen. Appropriate testing regimens must be included that monitor the possible introduction of adventitious agents. These methods must be suitably sensitive or use indicator cell lines or animal models in which a specific viral entity is known to replicate. The potential for matrix interference must be avoided; spiking of the test sample matrix with a positive control virus enables assessment of potential interference and the limit of detection of the method. “As a general rule of thumb,” she says, “the assays should be sufficiently developed with the appropriate set of predetermined system suitability and acceptance criteria, including relevant positive and negative controls, and fully established before validation.”

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

Production of viral vectors requires a holistic view of the product, including its manufacturing process and its ultimate end use.

Testing for Adventitious Agents in Viral Vector Production

Citius Pharmaceuticals, a late-state biopharmaceutical company, recently announced a collaboration with Haider Madhi, MD, an assistant professor at the University of Pittsburgh. The collaboration will focus on an investigator-initiated trial evaluating I/ONTAK (denileukin diftitox), a recombinant fusion protein that combines the interleukin-2 (IL-2) receptor binding domain with diphtheria toxin fragments, in combination with pembrolizumab, for the treatment of recurrent or metastatic solid tumors.

According to a company press release, the trial is an open label, Phase I/Ib study designed to evaluate regulatory T-cell (T-regs) cell depletion through the denileukin diftitox and pembrolizumab combination; it consists of two parts. Part I is a dose escalation study of four cohorts (3, 6, 9, 12 mcg of denileukin diftitox) that is expected to enroll 18–30 patients. Part II is a dose expansion study enrolling approximately 40 patients to evaluate the safety and tolerability of the recommended dose. Additionally, the study will investigate the alteration of the immune microenvironment within tumors and peripheral blood.

"This study will expand the body of knowledge about [denileukin diftitox] unique mechanism-of-action targeting the CD25 component of the IL2-receptor, which is present on both malignant T-cells (T-cell leukemias and lymphomas) and immunosuppressive T-regs," said Myron Czuczman, chief medical officer, Citius Pharmaceuticals, in the release. "Preclinical research in a syngeneic solid tumor mouse model shows that [denileukin diftitox] enhances anti-tumor activity and significantly extends [the] survival benefit of anti-PD-1 [programmed cell death 1] therapy. This data provides a positive signal of denileukin diftitox's potential in the immuno-oncology space.”

"Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T-cell responses against cancer result in a significant survival benefit in patients with advanced malignancies,” said Mahdi in the release. “Overexpression of PD-L1 [programmed cell death ligand 1] on tumor cells has been reported to impede anti-tumor immunity, resulting in immune evasion. The interruption of the PD-1:PD-L1 pathway combined with diminishing the suppressive effect by T-regs may represent an attractive strategy for restoring tumor-specific T-cell immunity.”

In addition to this study withUniversity of Pittsburgh, Citius is collaborating with an investigator-initiated study at the University of Minnesota. This Phase I dose-finding study is to evaluate denileukin diftitox prior to tisagenlecleucel chimeric antigen receptor-T cell therapy in patients with diffuse large B-cell lymphoma; the study enrolled its first patient in May 2021.

News

Citius and the University of Pittsburgh will investigate I/ONTAK in combination with pembrolizumab for treatment of recurrent or metastatic solid tumors.

Citius Pharmaceuticals Announces Clinical Collaboration with the University of Pittsburgh

The National Institute of Health (NIH) recently unveiled a new process for revealing key details of choroideremia, a rare genetic disorder that leads to blindness. Found through a study by the National Eye Institute (NEI), the approach combines traditional eye imaging techniques with adaptive optics, a type of technology that enhances imaging resolution.

According to an agency press release from Sept. 13, 2022, this approach was developed by Johnny Tam, head of the Clinical and Translational Imaging Unit at NEI. By combining adaptive optics with indocyanine green dye, the team was able to view live cells in the retina, including light-sensing photoreceptors, retinal pigment epithelium (RPE), and choroidal blood vessels. This allowed the researchers to see the extent to which choroideremia disrupts these tissues, information which can be used to design effective treatments for the condition.

The major findings of the study concerned the retinal pigment epithelium (RPE), a layer of pigmented cells needed for the nourishment and survival of photoreceptors. Patients with choroideremia had RPE cells that were significantly enlarged, with some enlarged as much as five-fold; by contrast, photoreceptor and blood vessel layers had less disruptions. According to the release, this suggested to the researchers that RPE disruptions may play a significant role in the disease.

“It’s not obvious at first, but using an existing tool in the clinic, we can monitor and track the cellular status of the RPE layer,” said Tam in the release. “This could prove valuable in identifying which patients would benefit the most from therapeutic interventions.”

New Technology

A combination of eye imaging techniques and adaptive optics has revealed key details of choroideremia.

Novel Imaging Approach Reveals Key Details About Rare Eye Disease

FDA and the National Institutes of Health (NIH) announced the launch of the Critical Path for Rare Neurodegenerative Diseases (CP-RND), a public-private partnership, on Sept. 14, 2022. The goal of this partnership is to advance the understanding and develop treatments for amyotrophic lateral sclerosis (ALS) and other rare degenerative diseases.

The Critical Path Institute (C-Path) will convene the partnership, bringing together rare neurodegenerative disease experts, including patient communities, advocacy organizations, private entities, and more. According to an agency press release, areas of focus will include patient-focused drug development, characterization of neurodegenerative diseases and their natural history, the identification of molecular targets for neurodegenerative disease, and increased efficiency, predictability, and productivity of clinical development of therapies.

“There is a crucial need to develop new treatments that can improve and extend the lives of people diagnosed with rare neurodegenerative diseases, including ALS. Collaboration across public and private sectors can accelerate the progress to address this urgent need,” said Hilary Marston, chief medical officer, FDA, in the release. “The partnership we are announcing today will leverage the shared expertise of all participants to create a path towards new breakthroughs in treating these diseases. We look forward to working with NIH, C-Path, and other public and private partners to carry out this important effort.”

“This public-private partnership will convene the entire ALS community to develop novel strategies and approaches to therapy development and clinical testing with the goal to finally produce a treatment that stops the tragic progression of ALS,” said Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, part of the NIH, in the release.

The Public-Private Partnership for Rare Neurodegenerative Diseases will work to enhance understanding and develop treatments for rare neurodegenerative diseases.

FDA and NIH Enter Rare Neurodegenerative Diseases Partnership

Glenn Youngkin, governor of Virginia, announced on Sept. 8, 2022 that Civica, a non-profit generic drug company, will invest $27.8 million to establish a new laboratory testing facility at Meadowville Technology Park in Chesterfield County, VA.

 facility will support Civica’s Petersburg pharmaceutical manufacturing operation through quality testing and development of new products. According to a press release, the project will create 51 jobs, as well as additional employment through the hosting of a scale-up manufacturing facility operated by Virginia Commonwealth University’s Medicines for All Institute.

“Civica’s investment is another transformational step forward in strengthening the advanced pharmaceutical manufacturing hub in the Richmond-Petersburg region and positioning Virginia as a key player in domestic drug manufacturing in America,” said Youngkin in the release. “Civica is a critical partner in the Commonwealth’s emerging pharmaceutical ecosystem that will ensure access to affordable, lifesaving medications while providing high-quality jobs and an incredible boost to our economy.”

“Civica’s new laboratory testing facility in Chesterfield County extends the footprint of the rapidly growing pharmaceutical manufacturing cluster in the region and will support the coalition’s long-term vision to serve as the world’s central access point for advanced pharmaceutical manufacturing and R&D,” said Caren Merrick, Viriginia Secretary of Commerce and Trade, in the release. “Today we celebrate Virginia’s vital role in addressing the shortage of affordable essential medicines in our nation and the investment in a new facility that will create high-paying jobs and accelerate research and innovation in the industry.”

Source: 

Civica is expanding in the greater Richmond-Petersburg region and investing $27.8 million in a new testing facility. 

Civica to Invest $27.8 Million in New Testing Facility

Novo Nordisk announced on Sept. 12, 2022 that it has entered a strategic collaboration with Microsoft to accelerate drug discovery and development. The collaboration will combine Microsoft’s computational services, cloud, and artificial intelligence (AI) with Novo Nordisk’s drug discovery, development, and data science capabilities.

According to a company press release, AI models arising from the collaboration will be applied to a range of use cases, two of which are currently in execution. One of the uses will be automated summarization and analysis of information from sources such as literature, patents, scientific reports, and discussion forums. The AI will be used to gain novel scientific insight. The second use aims to develop models that predict a person’s risk of developing atherosclerosis, a cardiovascular disease caused by fat build-up, cholesterol, and other substances on the artery walls. The AI will also be used to establish biomarkers of the disease.

“We are very excited about this new partnership that allows us to work closely together with key experts from Microsoft as we look to expand our digital science and AI capabilities,” said Lars Fogh Iversen, senior vice-president, digital science & innovation at Novo Nordisk, in the release. “Together, we are on a path to enable faster and scaled use of AI in drug discovery, ultimately leading to more breakthrough innovations and efficiency gain to better serve the needs of patients.”

Novo Nordisk and Microsoft are collaborating to accelerate drug discovery and development using big data and artificial intelligence. 

Novo Nordisk and Microsoft Collaborate to Accelerate Drug Discovery and Development

Salipro Biotech, a Swedish biotech company focused on the stabilization of membrane proteins for drug development, announced on Sept. 7, 2022 that its patent entitled “Saposin Lipoprotein Particles and Libraries from Crude Membranes” has been issued by both the US Patent and Trademark Office and by the China National Intellectual Property Administration.

The patents cover the company’s novel method of direct extraction of membrane proteins from cells or crude membranes to enable drug development for challenging drug targets. The patents also protect the generation of Salipro libraries representing the membrane proteome, the particles themselves, and their use in drug discovery and membrane protein research, amongst others.

According to a company press release, the Salipro technology enables the development of novel therapeutics against targets that previously could not be investigated.

“We are excited to announce the granting of these patents in the [United States] and in China. This news represents an important corporate achievement that fosters our position to accelerate drug discovery programs with pharma companies on challenging drug targets,” said Jens Frauenfeld, CEO of Salipro, in the press release.

Salipro has been granted patents in the United States and China for its proprietary technology to enable the development of therapeutics against challenging drug targets.

Salipro Biotech Obtains Patents in US and China for Direct Extraction of Membrane Proteins and Library Generation

Avance Clinical, an Australia-based contract research organization (CRO) for biotechs, announced on Sept. 6, 2022 that it has expanded its services into North America with the acquisition of C3 Research Associates, a US-based CRO partner company. The acquisition will enable Avance to offer biotech clients an easier transition from early phase to later phase studies.

With the acquisition, Avance will have the capability to progress early phase studies in Australia and New Zealand into the United States, allowing biotech clients to continue their clinical development programs while retaining the same CRO services. This efficiency would reduce time and cost and allow for biotech companies to deliver quality data that will be acceptable to FDA.

The company intends to make significant investments in its US operations, including growing its team to more than 120 people and leveraging deep industry experience across a broad range of therapeutic areas, specifically oncology, according to a company press release.

“Avance Clinical has been working with C3 Research Associates in recent years, and they share a similar culture and focus on customer service and clinical excellence. This strong relationship made C3 Research Associates a natural acquisition choice for Avance Clinical’s expansion plans into North America. The due diligence process has taken more than [six] months, and we are excited to now welcome our US team and offer the GlobalReady model for our clients,” said

Yvonne Lungershausen, CEO of Avance Clinical, in the press release.

Avance Clinical’s acquisition of C3 Research Associates expands its CRO services to North America.

Avance Clinical Acquires C3 Research Associates

ElevateBio, a biotechnology company specializing in cell and gene therapies, recently announced a long-term strategic partnership with the University of Pittsburgh to accelerate the development of innovative cell and gene therapies. Under the agreement, ElevateBio will locate one of its next BaseCamp process development and good manufacturing practice manufacturing facilities, the Pitt BioForge at Hazelwood Green, in Pittsburgh.

According to an Aug. 25, 2022 company press release, the new facility will be equipped with gene editing, induced pluripotent stem cell, cell, vector, and protein engineering capabilities. The university was awarded a $100 million grant by the Richard King Mellon Foundation in November 2021 to support creation of the facility. The facility is expected to generate 170 full-time jobs, 900 construction jobs, and 360 off-site support jobs.

“This announcement supports the region's rise as a leader in cell and gene therapy and advances our vision of bringing an entirely new commercial manufacturing sector to the area," said Patrick Gallagher, chancellor, University of Pittsburgh, in the press release. "The University of Pittsburgh is proud to partner with ElevateBio in this work, which will see us leveraging lessons from the lab—in new and exciting ways—for the benefit of human health.”

“To realize our vision of transforming the cell and gene therapy field for decades to come, broadening our footprint across metropolitan areas is a key priority for us, and we are thrilled that the University of Pittsburgh will be home to one of our BaseCamp facilities,” said David Hallal, chairman and CEO, ElevateBio, in the press release. “We’ve identified Pittsburgh as an ideal location to extend our BaseCamp presence as it sits at the intersection of science, technology, and talent. We are grateful for the support of the Governor and County Executive as we bring the first-of-its-kind offering we have built at ElevateBio BaseCamp to advance the work of the entire biopharmaceutical industry.”

In partnership with the University of Pittsburgh, ElevateBio will open its next manufacturing center in the city.

Pharmaceutical Technology's In the Lab eNewsletter, October 2022