As cell-based methods continue to evolve in support of gene therapies to assess product potency through gene or protein expression, the increased complexity and variation of assay readouts can bring questions on best-practice approaches for method development and analysis. According to FDA, the number of investigational new drug (IND) filings for cell and gene therapies (CGT) has undergone rapid growth in the past several years. There were approximately 50 related filings per year from 1995 to 2015, but that number increased to more than 300 filings between 2016 and 2020, indicating an industrywide trend toward the development and implementation of CGT products. In fact, FDA has approved multiple types of viral therapies for commercial use since 2015, including herpes simplex virus, adeno-associated virus (AAV), lentivirus, and retrovirus (1).

As the biotech industry moves further into gene therapies, we have to acknowledge the changes in production and clinical processes. Gene therapy development time is cut in half with potency and titer method development, further overlapping with process development. Autologous and allogenic cell therapies have different production processes resulting in varied cell-based testing panels that continue to evolve as we learn from the data. Considering that process changes commonly correlate with shifts in potency and titer methods, continuous data collection and review of trending data to confirm impact of process changes on these results are important to maintain acceptable method performance.

Mechanism of action of viral-mediated gene therapies is measured by multiple approaches, with a fundamental aspect being viral infectivity, which is core to its ability to deliver a therapy. Several assay types may be used to measure infectivity, such as plaque assays, focus-forming assays, and tissue culture infectious dose 50 (TCID

. For these assays to be used in a good manufacturing practice (GMP) environment, they must be objective in their measurements and statistically robust.

 method meets these considerations and is frequently performed in a 96-well-plate format, which lends itself to higher throughput. It measures viral infectivity by using a dilution scheme to back calculate the starting titer based on the dilution where the virus infects cells at a statistical frequency of 50%, often using approaches such as quantitative polymerase chain reaction (qPCR) or droplet digital polymerase chain reaction (ddPCR) to detect viral nucleic acids. Given the variety of TCID

 approaches, multiple choices must be made in assay development to create an assay that best suits the virus being titered and the end use.

First, a cell line must be chosen that is permissive for viral replication, and unique cell lines must be engineered in the case of replication-incompetent viruses. For example, titering a replication-incompetent AAV requires a cell line that expresses the Rep and Cap genes of AAV to induce productive infection. Second, a dilution scheme that suits the state of the drug product must be designed. The broader the dilution range, the greater the titer range of the assay, though this is at the cost of accuracy. The use of 10-fold dilutions in TCID

 is common and can produce assays with wide ranges, even up to 10% to 1000% of an expected value. However, due to the wide jumps between levels, the statistical data is limited and produces less accurate results. The TCID

 method works across dilution schemes with narrow dilution steps generating more accurate results. For drug products undergoing manufacturing optimization, the range should be kept wide while late-phase products could benefit from narrow dilution steps and more accurate results.

Perhaps the most common debate when developing TCID

 methods is what readout should be used. Any approach that can differentiate infected wells from uninfected wells could be chosen, pending several considerations. First, the detection technique must be able to identify wells with de novo viral replication. Defective viral particles may infect cells and even express protein. Therefore, the approach should rely on the generation of progeny virus. Second, the signal being measured should be as close to viral replication as possible. Relying on secondary effects of viral replication such as cell death may be misleading. Third, the measurement should be objective. Many traditional TCID

 approaches rely on microscopy and human identification of viral foci. This type of approach may produce different results depending on which analyst reads the assay, leading to uncertainty in the data.

Finally, the detection method need not be overly sensitive and care should be taken to avoid an overly restrictive system suitability to prevent false positives. Ideal methods of detection give repeatable thresholding for determining if a well was infected without detecting the inoculum or nonproductive infections. Exact genome copy number across replicates has no impact since the statistical modeling used to calculate the TCID

 value only relies on whether the well was positive or negative for infectious virus.

Assay requirements for cell and gene therapies

CGT products are intended to elicit a cellular response that is directly responsible for the therapeutic effect. This response is often in the form of protein expression or modification in the target cells and tissues. While an understanding of how the virus behaves is an important part of the process, how that behavior translates into the therapeutic effect is key to determining drug efficacy, dosing, and, ultimately, patient response.

Potency assays are a direct means of measuring the targeted result of the viral infection. Although potency assays have been used in drug development for decades, application in CGT products is a more recent development. CGT products present specific challenges due to complex mechanisms of action and manufacturing processes. Often CGT products have higher variability due to cell lines, donors, and errors in replicating virus. These products also may have limited stability and potential interference from multiple expressed genes.

FDA has issued recommendations for the development of potency assays to support the drug manufacturing process for cell and gene therapies. Because the potency assays are specific for each product, it is the responsibility of the drug developer or contract research organization (CRO) to ensure the assays are a true representation of the drug’s mechanism of action and that the best statistical and laboratory practices are followed.

Potency assays measure the strength or therapeutic activity of a product and are part of product conformance testing, comparability studies, and stability testing. Together, these tests measure product quality and manufacturing controls throughout all phases of the clinical study and determine if any manufacturing changes have a detrimental effect. While assays that are designed to characterize the virus are typically focused on nucleic acid analysis, such as qPCR, sequencing, or ddPCR, potency testing focuses on the outcomes of the viral transductions or infections. This often takes the form of gene expression by protein modification, activity, or production. For example, the virus may modify immune cells in such a way that they are now expressing novel receptors that can recognize cancer cells, resulting in customized immune response to a particular disorder. Potency assays designed to measure the outcomes of such modifications are recommended to be cell-based in later stages to better demonstrate biological activity.

Common potency readouts include the enzyme linked immunosorbent assay (ELISA) platform where antibodies recognizing specific proteins or protein modifications can be used to detect an analyte in cell lysates, fixed intact cells, or fixed permeabilized cells. ELISAs produce valuable quantifiable information about the production of a specific analyte but do not measure protein’s functionality and so are often combined with functional cell-based assays to tackle quantity and function.

Western blot is considered less powerful than ELISA due to its qualitative limitations but can still be used to determine protein production from cell lysates after viral transduction or infection. Semi-quantitative measurements can be made if a known amount of protein is loaded and its intensity derived using software to detect pixels. However, as with ELISA, protein functionality cannot be established from this test.

Ligand and receptor binding assays are used to evaluate the drug’s mechanism of action and interaction with cell receptors. CGT products evoke a response in signal transduction and undergo optimization comparable to antibodies with aspects regarding the reference standard preparation and layout, cell surface receptor, cell line, and specificity. Ligand and receptor assays and their subsequent readout can lead to a quantifiable, functional output. Receptors can elicit a response without binding and, alternatively, signal transduction may not occur upon binding, thus, rigorous examination at these levels is imperative.

Enzyme activity assays provide functional readouts after cell infection or transduction and highlight the intended biological activity from CGT products aimed at replacing misfolded enzymes or an overall replenishment of these proteins. Dose-response relationship needs to be demonstrated between the enzymatic capabilities of a CGT vector and its readout.

The potency test is required by FDA before releasing any lot of product from the manufacturer. Although mandated, FDA allows for considerable flexibility in determining the measurements for each product. However, all potency assays must meet minimum current good manufacturing practice (CGMP) regulations, such as indicating biological activity specific to the product, providing quantitative data, meeting pre-defined acceptance criteria, and including appropriate reference materials and controls.

FDA also includes requirements, such as establishing the accuracy, sensitivity, specificity, and reproducibility through method validations. Because of the complexity of CGT products, FDA recommends an incremental approach to implementing potency assays and recognizes that potency measurements may evolve as the product is developed.

The biological properties of CGT products must be well understood as part of the approval process. FDA recommends that a wide array of attributes be examined in addition to the routine tests for lot release. These attributes may be used to help develop robust potency assays that demonstrate a specific mechanism of action and which components of the product are contributing to any observed effect.

FDA also has recommendations on how refence material and controls should be used. A product-specific in-house reference material should be used when possible, such as well-characterized clinical lots. When applicable, commercially available material may be used, such as adenovirus type 5 retrovirus vectors and AAV type 2 vectors. All standards used for potency testing must be assigned data-driven expirations with appropriate retest dates.

In the past decade, the focus of pharmaceutical development has shifted from monoclonal antibody (mAb) therapy to gene therapy. While potency assays for cell and gene therapies have additional challenges compared to traditional products such as mAbs, there are many lessons to be learned from previous experiences. Due to the similarity in traditional potency assays between mAb therapy and gene therapy, the 

) bioassay chapters, specifically <1032> 

Design and Development of Biological Assays

, provide guidance that remains valuable in method development for evaluating gene therapy pharmaceuticals (2).

Similar bias and variation sources exist across CGT methods, and so should be similarly considered during optimization. New assay designs bring different ways to assess robustness and inherent variation, which may make it harder to see shifts in potency or infectious titer. Infectivity methods still have room to establish best practices for striking the appropriate balance between range and sensitivity. Since process and method development now overlap more than they had previously, closer attention also must be paid to which is driving method performance changes in order to optimize the method

Proper design of experiment should be performed when developing method qualifications and validations. Cell lines and the type of potency assays should be selected to demonstrate mechanism of action and biological activity. Assays should be linear, precise, and accurate, but assay criteria should be established based on sound statistical analysis while remaining phase appropriate for the study with more stringent criteria for later phase products.

Regulatory Expectations for Cell and Gene Therapies

, 4th PQRI/FDA Conference on Advancing Product Quality: Patient-Centric Product Design, Drug Development, and Manufacturing (Rockville, Md., April 9, 2019).
2. USP, General Chapter <1032>, “Design and Development of Bioassays,” 

Catherine Liloia*, Catherine.Liloia@ppd.com, is director; Benjamin Ziehr, PhD, is senior group leader; Derrick McVicker, PhD, is group leader; Yat Yee Wong, PhD, is group leader; Esteban Carrillo, PhD, is senior research scientist; and Alexander Rodriguez, PhD, is research scientist; all at PPD Laboratories’ GMP cell lab.

*To whom all correspondence should be addressed.

Articles

Features

Developing bioassay methods requires a new approach for cell and gene therapy drug development.

Analytical Strategies for Cell and Gene Therapy Development

Keeping pharmaceutical facilities clean and germ free seems an obvious prerequisite for any company that manufactures medicines. However, regulatory citations suggest that pharmaceutical manufacturers and contract manufacturing and
development organizations (CDMOs) may take cleaning and cleaning validation for granted.

An April 2021 Form 483 issued by FDA to the Maryland-based CDMO, Emergent Biosolutions, which is under contract to Johnson & Johnson (J&J) and AstraZeneca to manufacture their COVID-19 vaccines, showed how deeply rooted this problem may be (1). J&J and AstraZeneca use very different manufacturing processes, but both involve the use of viral vectors.

FDA inspectors found fundamental deviations from good manufacturing practices (GMPs) at the facility. Among the observations noted were failure to maintain clean and sanitary conditions; lack of written procedures for cleaning and decontamination of the vessels used to transport and store materials at the site; and no formal requirements to clean and sanitize these vessels after each use.

In addition, no tests were conducted to determine how long viruses used in a client’s production process remained viable on equipment surfaces in one area within the facility.

If these omissions seem basic, it might be helpful to remember that in pre-pandemic 2019, the last full year when FDA performed routine site inspections, roughly 60% of FDA 483 regulatory observations involved deficiencies in cleaning and sanitization and their validation.

This fact was presented by Matt Cokely, senior global technical consultant manager for Ecolab Life Sciences in a best-practices webinar presented by the International Society for Pharmaceutical Engineering (ISPE) on April 9, 2021 (2). The most often cited problems, he said, were the lack of procedures for preventing contamination, deficiencies in cleaning, failure to keep cleaning records, and inadequate standard operating procedures (SOPs).

Cleaning validation consultant Rich Forsyth agrees. “Problems often boil down to a failure to follow cleaning procedures. Either people are doing something that is not in the SOP or there’s something in the SOP that they aren’t doing,” he says. For example, Forsyth notes, many procedures fail to specify cleaning frequency, or the amount of time that should be spent to clean a piece of equipment using documented procedures and materials. This forces operators to take the unprovable position that ‘it’s not clean until it’s clean’, he says.

Cleaning and cleaning validation practices need to be reproducible, Cokely noted, and employees must be trained, not only in the basics of microbiology and hygiene pertaining to cleaning, but in cleanroom procedures and gowning and in understanding potential risks and safety hazards. “They need to understand not just how, but why they are performing a task, and to be trained to actually perform it,” he said, rather than simply being given a pile of SOPs to read and sign off on. Given the trend to outsource cleaning and sanitization activities, Cokely noted, this training must be given to contract cleaning workers as well.

Elaborating further, Cokely noted that written instructions in SOPs should specify who is responsible for the duties, and set a schedule of frequency for cleaning, describe the materials and techniques to be used in detail, and the preparation and storage of cleaning materials. In addition, documentation must include the names and signatures of staff performing the work, as well as the product batch number, cleaner expiry date, and disinfectants used. Cokely also noted that disinfectants with different modes of action should be rotated. Care must also be taken, he said, to avoid interactions between different cleaning chemistries that might inhibit microbe-killing mechanisms and promote the buildup of cleaning solution residues.

The basic problem, Cokely noted on the webcast, is that cleaning and disinfection are undervalued in the pharmaceutical industry, despite their importance to patient and overall safety. “At some companies, cleaning procedures have been used for years, or the facility may have inherited practices that have never been reviewed or scrutinized,” he said.

Regulations for cleaning and its validation abound, supplemented by best practices circulated by ISPE, the Parenteral Drug Association (PDA), and now the American Society for Testing and Materials (ASTM), which has set standards for pharmaceutical cleaning operations and validation. Risk-based standards for cleaning validation, set in 2018 (3) began to establish a more scientific basis for practices at individual facilities.

These standards have had a positive impact, notes Forsyth, getting pharmaceutical companies to go beyond thinking simply about products, equipment, and detergents in their cleaning operations. “Risk-based standards forced people to formalize their risk assessments. Many of them began to consider peripheral risks that they hadn’t factored in before, such as the air-handling system’s impact or the material and equipment traffic in the facility,” he says.

However, in the end, some companies may view having a formal cleaning validation program and strategy as involving too much work. “Companies pay a lot of attention to their cleaning and cleaning validation programs when they get cited by regulators for those programs’ failings,” Forsythe says. But establishing a program or updating one that hasn’t been reviewed in several years, takes commitment, he notes, and it generally requires a year to do because everyone has their regular jobs to do, too. “Often, shepherding a cleaning validation project through to its end becomes more problematic the longer the projects continue. At many companies the success or failure of a cleaning and cleaning validation program may rest on one champion supporting it,” Forsyth says.

Today, multiproduct facilities, and particularly biopharmaceutical facilities, pose several cleaning validation challenges, Forsyth notes. “You worry more about bioburden in a biological plant than in a small-molecule facility, but generally if you have an effective cleaning validation program, you’re fine,” he says.

However, setting cleaning limits can be tricky because traditional methods fail to consider some of the most significant differences between biopharma and small-molecule facilities. “The most notable difference between the two types of plants is that biopharmaceutical facilities start processes using equipment with large surface area but generate small batches, both of which require the use of lower cleaning limits, so if you use the entire equipment train, your limits may, at first, appear to make no sense,” Forsyth says. Single-use systems and equipment have eliminated some of those problems, but they persist for hybrid plants still using stainless steel equipment.

Another question is how batches are finished and whether pre-cleaning equipment preparation processes are consistent from one batch to another. If they are not, varying amounts of product may be left on equipment surfaces after each run. “Some types of equipment will empty completely, but others won’t,” Forsyth says.

He recalls one of his first experiences working on cleaning validation in a pharmaceutical development lab. “We were concerned about pouring active ingredients down the drain, so we wound up scraping equipment and then vacuuming it before cleaning. By the time we started cleaning that equipment, it was almost visually clean,” he says, noting that this type of approach reduces the risk of cleaning failures and compliance problems. At some companies, varying amounts of material may be left on the equipment when cleaning officially begins.

CDMOs that focus on clinical trial drug manufacturing face unique challenges in setting cleaning limits. “For clinical operations, you are not making a lot of batches of the same thing, so you don’t make enough batches of any single product to validate the cleaning methods using standard approaches,” says Forsyth. “In this case, it is usually best to work with a more general model, establish a worst case, and then evaluate each new product coming in. However, this approach increases the effort and justification required to maintain the model, and a lot of CDMOs don’t do this very well,” says Forsyth.

Specific approaches are needed to prevent cross-contamination in multiproduct facilities, Forsyth says. “Best practices call for calculating the amount of residue that can safely be carried over for every product. For a multiproduct facility that makes 10 products, that means calculating the limit of one product versus those of the other nine, taking the lowest number and then using that, and then following the same procedure for the rest of the products,” he says.

ASTM standards have been focusing on use of statistics, which are important after a cleaning program has been validated and needs to be maintained, says Forsyth. Maintenance requires trending data. “The basic statistics needed for trending are fairly straightforward, and more advanced statistics can also be applied, but it has been difficult to motivate some companies to do that in the current environment,” he says.

More work is also being done to use analytical methods to reduce the subjectivity of visual inspection, but Forsyth hasn’t seen any consistently effective methods coming into general use. The best way to remove subjectivity from inspections has been to qualify those who must perform those inspections, a step that most regulatory agencies now require.

“I advise clients to set visual limits for residues and have staffers who might be assigned to perform visual inspections go through specialized training to recognize clearly what various levels of residues look like on equipment, compared with images of surfaces with residues that meet safe carryover limits. It’s important to have exercises in place that will allow people to visually recognize cleanliness levels to avoid patient safety risks,” Forsyth says.

Cleaning is not a popular activity, Cokely noted in his presentation, but it is essential. Taking cleaning and sanitization validation programs for granted only puts facilities and people at risk and increases the likelihood of costly noncompliance.

1. FDA, Form 483, Emergent Biosolutions, 

, April 20, 2021.
2. ISPE, “Regulatory Requirements and Expectations for Cleaning and Disinfection of Controlled Manufacturing Areas,” Webcast, April 9, 2021.
3. ASTM, E3106-18e1, Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation (2018). 

Agnes Shanley is the former senior editor for 


Vol. 45, No. 6
June 2021
Pages: 44–46, 52

When referring to this article, please cite it as A. Shanley, “Prioritizing Cleaning Validation,” 

With COVID-19 vaccine facilities receiving recent citations, it is evident that failure to meet cleaning and sanitization requirements puts patients, facilities, and operators at risk. 

The Necessity of Prioritizing  Cleaning Validation

Corbus Pharmaceuticals Holdings has expanded its therapeutics pipeline with the addition of two new monoclonal antibodies (mAbs), CRB-601 and CRB-602, that target integrins to inhibit activation of transforming growth factor β (TGFβ). This new integrin program, acquired under two exclusive licensing agreements and added to the company’s existing endocannabinoid system program, expands Corbus’ immunology pipeline for inflammatory, fibrotic, and metabolic diseases as well as cancer. Corbus expects to have four compounds in addition to lenabasum in Phase I testing in 2022.

Under the combined terms of the licensing agreements, Corbus will pay $2 million upfront and will make potential development and sales milestone payments totaling up to $206 million as well as pay low single-digit royalties on sales, the company stated in a June 1, 2021 press release.

CRB-601 was rationally designed by Stephen Nishimura and his colleagues at the University of California San Francisco. It is potent at picomolar concentrations in inhibiting activation of TGFβ. The parent mAb of CRB-601, C6D4, has single agent activity as well as synergistic activity when combined with an anti-programmed death-1 (PD-1) mAb in syngeneic mouse tumor models. Corbus plans to develop CRB-601 for treatment of solid tumors in combination with existing therapies, including checkpoint inhibitors.

CRB-602 was developed by Panorama Research, a privately-owned biomedical research and development holding company, to specifically inhibit both avb6 and avb8, integrins that have been implicated in fibrotic diseases and in cancers of epithelial cell origin. Corbus believes that targeting both integrins at once is a rational approach to treating fibrotic diseases and carcinomas, the company stated the press release.

“We look forward to a strong partnership with Corbus and hope to see our mAb make a positive impact on the lives of cancer patients all over the world,” said Anthony Francis, executive director of Technology Management at UCSF Innovation Ventures, in the press release.

“Corbus is committed to developing new medicines to improve the lives of people who need them,” stated Yuval Cohen, PhD, CEO of Corbus, in the press release. “We believe these two new integrin-targeting mAbs offer a promising approach to inhibiting TGFβ, fit well with our expertise in immunology, and diversify and expand our pipeline. We plan to advance up to four new programs into the clinic next year and have the capital and resources to do so.”

News

Corbus Pharmaceuticals has licensed two integrin-targeting mAbs, expanding its therapeutics pipeline into inflammatory, fibrotic, and metabolic diseases as well as cancer.

Corbus Pharmaceuticals Expands Pipeline with Two New mAbs

Researchers at Chalmers University of Technology, Sweden, announced on June 30, 2021 that they have succeeded in developing a fluorescence method to label messenger RNA (mRNA) molecules, allowing them to track, in real time, the path of the mRNA molecules through cells with the use of a microscope while not affecting the molecules’ properties or subsequent activity. The breakthrough could be of great importance in facilitating the development of new RNA-based medicines, according to a university press release.

While RNA-based therapeutics offer a range of new opportunities to prevent, treat, and potentially cure diseases, the delivery of such therapeutics into the cell is currently inefficient. Therefore, for new therapeutics to fulfill their potential, the delivery methods need to be optimized.

The research behind the RNA tracking method developed by Chalmers researchers was conducted in collaboration with chemists and biologists at Chalmers and AstraZeneca via their joint research center, FoRmulaEx, as well as a research group at the Pasteur Institute, Paris, France. The method involves replacing one of the RNA building blocks with a fluorescent variant, which, apart from that feature, maintains the natural properties of the original base. The fluorescent units were developed with the help of a special chemistry technique (?), and the researchers have shown that it can be used to produce mRNA without affecting the mRNA’s ability to be translated into a protein at natural speed.

The method represents a breakthrough that has not been done successfully before, according to the press release. The fluorescence furthermore allows researchers to follow functional mRNA molecules in real time with a microscope and observe how they are taken up into cells.

mRNA molecules are challenging to work with because of their large size and the fact that they are charged and, at the same time, fragile. They cannot enter cells directly and must be packaged. The method for mRNA uptake that has proven most successful to date uses lipid nanoparticles to encapsulate the mRNA. However, there still exists the need to develop new and more efficient lipid nanoparticles, which the Chalmers researchers are also working on. The ability to monitor, in real time, how lipid nanoparticles and mRNA are distributed through the cell is an important tool.

"Since our method can help solve one of the biggest problems for drug discovery and development, we see that this research can facilitate a paradigm shift from traditional drugs to RNA-based therapeutics," said Marcus Wilhelmsson, professor at the Department of Chemistry and Chemical Engineering at Chalmers University of Technology, in the press release.

“The great benefit of this method is that we can now easily see where in the cell the delivered mRNA goes, and in which cells the protein is formed, without losing RNA's natural protein-translating ability,” said Elin Esbjörner, associate professor at the Department for Biology and Biotechnology, Chalmers University of Technology, in the press release.

Researchers working in the area of RNA studies can use this fluorescent tracking method to gain greater knowledge of how the uptake process works, which can accelerate and streamline (?) the discovery process for new therapeutics.

“Until now, it has not been possible to measure the natural rate and efficiency with which RNA acts in the cell. This means that you get the wrong answers to the questions you ask when trying to develop a new drug. For example, if you want an answer to what rate a process takes place at, and your method gives you an answer that is a fifth of the correct, drug discovery becomes difficult,” explained Wilhelmsson in the press release.

Chalmers University researchers have developed a method to label and track mRNA molecules.

Chalmers Researchers Develop Fluorescence Method to Track RNA

Thermo Fisher Scientific’s new and enhanced Quick to Clinic solution may help biopharma companies reach Phase I/first-in-human trials and file for investigational new drug (IND) review in as little as 13 months from transfection, the company announced in a June 14, 2021 press release. With this solution, emerging biopharma companies working on early development can now leverage a lab-to-clinic drug development solution designed to accelerate the journey from DNA to drug product.

Quick to Clinic leverages Gibco Freedom ExpiCHO, which is a royalty-free, high-yield expression system that can scale seamlessly from an R&D environment. The solution also includes critical activities, such as cell line development, process fit, analytical development, and qualification, resulting in a robust process platform for biopharma companies developing mammalian recombinant proteins. This capability allows companies to scale quickly from discovery phase, leveraging toxicology and good manufacturing practice (GMP) material. In addition, documentation provided by the Quick to Clinic program will allow companies to file for IND in an expedited manner and get to Phase I clinical trials quicker.

Furthermore, Quick to Clinic leverages Thermo Fisher's global network of facilities and scientific experts, combined with its track record and more than 30 years of development and manufacturing experience, to help biopharma companies target an accelerated pathway to IND without taking on significant risks that would disrupt their goals. Biopharma companies will also be able to create a strong foundation for future scale-up success.

"Emerging biopharma companies now make up a majority of the biologics development pipeline. Meeting critical milestones is paramount to the continued support of these programs, making speed to clinic more important than ever," said Paul Jorjorian, vice-president and general manager, biologics, at Thermo Fisher Scientific, in the company press release. "With our Quick to Clinic solution, we provide biopharma companies with the supply assurance and foundational platform they need to see their therapy through to the clinic that mitigates risk, accelerates timelines, and navigates the complex and changing regulatory environment. Ultimately, this will help to expedite the development of important medicines for patients."

New Technology

Thermo Fisher Scientific has introduced its new Quick to Clinic solution, which is designed to accelerate biologic drug development from discovery to the IND phase in a shortened period.

Thermo Fisher Scientific’s Clinic Solution Aims to Accelerate Biologic Drug Development

CatSci’s new analytical sciences laboratory in Dagenham, UK, is now open and will focus on combining analytical and synthetic chemistry expertise with the latest high-end equipment to solve current and future complex problems in the pharmaceutical industry. The new facility, launched in June 2021, will further cement the company’s position in the United Kingdom, making it a center for excellence in pharmaceutical research and development, the company stated in a June 8, 2021 press release.

The new facility is fully equipped with state-of-the-art analytical equipment, through a collaboration with Shimadzu, and provides high-quality analytical data and critical interpretation. The facility is a key early milestone in CatSci’s £3 million (US$4.15 million) investment plan and will better equip the company to meet the demand for solving multi-disciplinary analytical problems, which are growing because of the progress of new modalities and asset classes, such as oligonucleotides and cannabinoids. At the same time, new or modified regulatory requirements, such as nitrosamine determinations and trace impurity analysis, require the development of highly specific and sensitive methods.

“The opening of our analytical laboratory at LondonEast in Dagenham, UK, is an exciting step on our journey towards becoming a fully integrated CMC [chemistry, manufacturing, and controls] company that accelerates medicine development to deliver best-in-class therapeutics to those in need. Solving complex challenges that our customers face is at the core of what we do, and this new facility, filled with Shimadzu’s cutting-edge equipment, sets a new exemplary standard for measurement science in the industry,” said Ross Burn, CEO, CatSci in the company press release.

“The opening of this new facility deepens the level of support we can offer,” added Nigel Richardson, director of Analytical Technology & New Modalities, CatSci, in the press release. “We will also be upgrading the site with capacity for GMP [good manufacturing practice] analytical development and testing, which will further increase our ability to provide innovative, tailored solutions from early development pre-clinical data packages to late development Phase III impurity fate studies.”

CatSci has opened its new Dagenham, UK-based laboratory, which is dedicated to analytical excellence.

CatSci’s New UK Laboratory Now Open and Poised to be Analytical Center of Excellence

Sphere Fluidics, a provider of single cell analysis systems, and ClexBio, a provider of solutions for tissue engineering and single-cell techniques, now offer a biocompatible CYTRIX Microfluidic Hydrogel Kit, which they launched in June 2021.

The kit combines ClexBio’s novel CYTRIX Hydrogel with Sphere Fluidics’ specially designed Pico-Gen double aqueous biochip to allow the plug-and-play generation of defined, reproducible and tailorable hydrogel microstructures for three-dimensional (3D) cell culture, organoids, single-cell analysis, and other applications. These capabilities allow researchers to study valuable cells over many weeks rather than days in defined microenvironments that mimic the natural extracellular matrix, the companies stated in a June 7, 2021 press release.

The novel hydrogel overcomes the challenges of existing microfluidic hydrogel formation techniques, such as clogging, temperature control difficulties, or time-critical mixing procedures, and offers cytocompatibility and microfluidic-optimized gelation kinetics. These benefits provide researchers with a cell-friendly solution to reduce the effect of harmful temperatures, pH changes, and use of ultraviolet light required for existing hydrogel formation techniques. Paired with the Sphere Fluidics Pico-Gen double aqueous biochip and microfluidics, the CYTRIX Hydrogel enables efficient encapsulation of mammalian cells, bacteria, and other microorganisms in a homogeneous and defined extracellular matrix that supports cell viability.

“The CYTRIX Microfluidic Hydrogel Kit mimics the 3D microenvironment and helps researchers explore the potential of hydrogel-based microfluidics in tissue engineering, drug discovery and regenerative medicine over many weeks,” said Xin Li, associate director of Science at Sphere Fluidics, in the press release.

“This exciting collaboration with Sphere Fluidics has enabled us to deliver one of the first commercial solutions that allows simple and cell-friendly formation of cell-laden microgels, lengthening the time that researchers can study the contents of microspheres,” said Armend Håti, CEO and co-founder of ClexBio, in the press release.

The CYTRIX Microfluidic Hydrogel Kit is the first in Sphere Fluidics’ new range of 3D cell culture kits in partnership with ClexBio.

Sphere Fluidics and ClexBio Introduce CYTRIX Microfluidic Hydrogel Kit

Miele Professional, a provider of commercial and industrial appliances, including lab equipment, has earned the Accountability, Consistency, and Transparency (ACT) Label from My Green Lab, a non-profit organization that supports sustainability in science, for three Miele glassware washer machines—the PG 8583, the PG 8593, and the PG 8583 CD. The ACT Label represents the standard for lab sustainability, and this achievement makes Miele the only glassware washer manufacturer to have achieved the certification, Miele announced in a June 2, 2021 press release.

The ACT label shows how products “rate” in sustainability-related categories. The Environmental Impact Factor is a sum of verified information on a product's energy consumption, water use, and end-of-life. The three Miele glassware washers received the following Environmental Impact Factors:

Miele PG 8583 glassware washer—Environmental Impact Factor of 72.5

Miele PG 8593 glassware washer—Environmental Impact Factor of 76.6

Miele PG 8583 CD glassware washer—Environmental Impact Factor of 74.5.

Miele’s PG 8583 glassware washer already achieved ACT Label certification in 2019, and following My Green Lab’s rigorous testing process, the model was recertified, along with the first-time certification of the PG 8593 and PG 8583 CD. Certifications will be valid for one calendar year.

Miele PG 8583, PG 8593 and PG 8583 CD Laboratory Glassware Washers offer the following benefits:

Deionized water connection, liquid dispensing

Optimized cleaning performance and efficient use of resources—variable speed pump with integrated heating elements

Safety through monitoring—wash pressure and spray-arm monitoring

Convenient drying—EcoDry or DryPlus with high-efficiency particulate air filter.

“Sustainability is at the core of everything we do at Miele. We continuously strive to be a global leader in environmental protection within our industry and are committed to our promise to conserve valuable resources, save energy, and reduce emissions,” said Marion Anacker, head of Sales, Lab—Medical—Dental, Miele Professional USA, in the company press release. “We believe there is a great opportunity to continue to reduce the environmental impact of labs across the country through smarter equipment, and My Green Lab’s eco-nutrition label is making sustainable purchasing decisions easier every day. We applaud this initiative and are incredibly proud that three of our machines have earned ACT Label certification.”

“By certifying their glassware washers through our ACT Label program, Miele is helping set the standard for sustainable laboratory equipment. The label supports their customers to make more informed purchasing decisions, leveraging a trusted third-party system,” said James Connelly, My Green Lab’s CEO, in the press release. “Ultimately, this helps save water [and] energy and reduce[s] the environmental impact of a critical, but often resource intensive, industry.”

The three Miele washer machines have been officially certified with the “eco-nutrition” label by My Green Lab. 

Miele Earns ACT Label Certification for Three Glassware Washers

The new Waters SELECT SERIES multi reflecting time-of-flight (MRT) mass spectrometry platform, launched in June 2021, offers high-quality resolution at fast speeds. The instrument combines MRT technology with both enhanced desorption electrospray ionization (DESI) and new matrix-assisted laser desorption ionization (MALDI) imaging sources.

Together, these technologies enable scientists to more precisely explore molecular structure and function with a unique combination of speed, resolution, and mass accuracy. A scientist can research how an investigational oncology drug interacts with its intended target, such as a specific brain tumor receptor, for example, and can now do so at much faster speeds, up to 10 Hz, without compromising mass accuracy or resolution, Waters stated in a June 8, 2021 press release.

DESI is a direct-from-sample, soft ionization technique performed under ambient environmental conditions, requiring no prior sample preparation. This technology provides imaging information about the biochemical distribution of small-molecule drugs, lipids, and naturally occurring metabolites within a slice of tissue or on other sample surfaces after a single measurement. Scientists today are applying DESI to research breast and ovarian cancer, to study drug metabolism and pharmacokinetics (DMPK), to investigate the function of key metabolites in natural products in traditional medicines, and to get a closer look at the biotransformation of bacterial colonies after gene modifications.

The advanced DESI XS features a new high-performance sprayer and a heated transfer line source. It delivers new levels of usability, image clarity and sensitivity at high speed, bringing more accessible imaging to scientists through mass spectrometry data.

The SELECT SERIES MRT is available with a newly designed MALDI source, making it usefule for scientists interested in conducting MALDI imaging experiments, MALDI is an ideal complementary technique for the imaging of biological molecules, such as peptides, and can visualize tissue sections at spatial resolutions of less than 10 microns. Taken together, the combination of imaging sources gives researchers the means to generate fine spatial information and morphological detail for biological samples and even visualize brain vasculature.

The SELECT SERIES MRT platform forms the basis of next-generation Waters high-resolution mass spectrometers. This product is the first commercially available instrument of its kind that is capable of attaining 200,000 full width half maximum (FWHM) resolution and part-per-billion mass accuracy, independent of scan speed, according to Waters. The instrument allows scientists to get the highest quality mass spectrometry data and information at faster times than other commercial mass spectrometers on the market today, the company stated in its press release. The new MRT technology features an extended flight path of almost 50 meters to give scientists a clearer picture of structural information, including fine isotope structure.

“The Waters SELECT SERIES MRT opens the door to a greater understanding of molecules and their mechanisms of action in numerous scientific fields,” said Dr. Udit Batra, CEO and president, Waters. “The clarity of images produced by this instrument can yield profoundly important molecular information to scientists in research areas such as targeted therapeutics, to provide insights and enable deep biological discoveries.”

The new multi reflecting time-of-flight mass spectrometry platform from Waters delivers highest quality resolution at fast speeds.

Waters’ New SELECT SERIES MRT Mass Spec Platform Delivers Speedy High-Quality Resolution

SP Scientific Products (SP) launched its SP Hull LyoStar 4.0 R&D and process development freeze dryer is based on a full-scale production freeze dryer to support rapid lyophilization cycle development, optimization, and scale-up. The pilot-scale lyophilizer offers shelf mapping and rapid shelf freezing, as well as a suite of process analytical technology (PAT) tools. In addition, the equipment uses a more eco-friendly refrigerant gas that reduces the carbon footprint involved in lyophilization.

PAT tools used by the equipment include LyoFlux TDLAS sensors for vapor mass flow measurement; AutoM/SMART Freeze Dryer Technology, a primary drying cycle optimization tool; ControLyo Nucleation Technology, which gives pinpoint control of freezing point; a three-dimensional modeling package for computational fluid dynamics and process monitoring; and Tempris wireless sensors for real-time product temperature measurement.

The equipment was designed to both scale up to production and down to R&D as part of SP’s Line of Sight approach across all its products. The LyoStar 4.0 scales up to the SP Hull LyoConstellation line of production lyophilizers and uses the same efficient refrigeration technology. Line of Sight also enables continuous process monitoring and improvement, in line with Pharma 4.0.

SP Scientific Products’ SP Hull LyoStar 4.0 R&D freeze dryer supports rapid freeze-dry cycle development, optimization, and process scale-up.


Pharmaceutical Technology's In the Lab eNewsletter 07-07-2021