Stakeholder input needed to achieve consensus on concomitant components.

Understanding Excipient Composition

Can shortened clinical trial timelines be sustained post-pandemic?

Putting the Pedal to the Metal

CDMOs tackle technology challenges technology to fill-finish COVID-19 vaccines.

Filling Vaccine Capacity and Process Demands

The technology awaits but challenges remain

Reshoring Pharmaceutical Manufacturing?

Third vaccine promises easier administration; Expediting vaccine production

US Greenlights J&J Vaccine

Editor of Pharmaceutical Technology Europe

Elemental impurities present in a drug product are associated with potential safety and toxicological risks, and, therefore, appropriate analysis of elemental impurities is imperative to minimize patient exposure. “Elemental impurities are any elements that are not meant to be present in the final formulation of drug product,” asserts John Ferencz, manager, Trace Element and Contaminant Analysis at Avomeen. “These [impurities] can be introduced through numerous steps in the drug manufacturing process … Since most medications are taken on a daily or weekly basis, routine exposure to toxic elements and chronic health conditions could occur without proper impurities testing.”

According to regulatory guidance, there are two sources of elemental impurities, explains Paul Kippax, Pharmaceutical Sector director at Malvern Panalytical, which are either intentionally added impurities or non-intentionally added ones. For the former, impurities could enter the drug product via the use of catalysts in the synthesis of APIs, for example. Non-intentionally added impurities can include contaminants from naturally sourced materials or from manufacturing equipment, dose container systems, or water used in drug manufacturing or formulation.

“Several potentially toxic metals, such as palladium and rhodium, are used as catalysts or reagents in the synthesis of APIs and must be removed to limit patient exposure,” notes Daniel Ingles, technical leader for trace elements, Metrics. “Other metals, such as lead and cadmium, are not commonly encountered in pharmaceutical products but are controlled because they accumulate in patients over time.”

Taking cadmium as an example, which is known to be toxic, Ingles iterates the necessity of the analysis and removal of trace metals in pharmaceuticals. “Cadmium toxicity is associated with liver and kidney injury, osteoporosis, skeletal deformations, neurological deficits, and it’s classified as a category 1 carcinogen,” he says. “The biologic half-life of cadmium in the kidney is estimated to be between six to 38 years, and between four and 19 years in the liver (1). These half-lives reflect the fact that humans do not have effective elimination pathways for a number of toxic metals which have no known biologic function in humans. Excessive bioaccumulation is therefore regarded as potentially toxic and every effort must be made to analyse and limit patient exposure.”

“Raw materials used for chemical synthesis can contain traces of elemental impurities based on their production or origin source,” adds Johannes Hesper, product manager, Spectroscopy, Shimadzu Europe. “Catalysts and filters may release inorganic ions, and surfaces of tube reactors may react to a very low extent with the synthesis products. Additional risks are changes in ion strength and pH of synthesis media as often occurs during the process. Last but not least, formulation and packing can introduce impurities into the final pharmaceutical products.”

For biopharmaceuticals in particular, any materials that potentially come into contact with the final product should be inert, Hesper confirms. “Metal ions may interact with or covalently bond to the molecular structure [of the drug], replacing standard counter ions,” he says. “In the worst case, [the metals] are transferred into the human body where they can negatively influence the normal metabolism pathways.”

In recent years, regulatory requirements for elemental impurity testing have been adapted and harmonized (2,3), and manufacturers are expected to demonstrate compliance via validated instrumental methods. “The most significant change in recent years is the withdrawal of the wet chemistry method for determination of heavy metals from all regulatory guidance,” states Ferencz. “Elemental impurities testing must now be performed using validated instrumental methods to ensure proper exposure limits are met.”

“For nearly a century, heavy metals were controlled using a benchtop wet chemistry procedure, of which the 

) had similar versions,” Ingles reveals. “The assumption was that any metals that formed an insoluble sulfide would respond to it. Unfortunately, in practice, it was not effective in detecting heavy metals at concentrations of interest to modern industry and was gradually phased out and replaced by more technologically advanced methodologies.”

Currently, drug manufacturers are required to demonstrate compliance with the International Council for Harmonization’s guidance—ICH Q3D (4)—and USP’s guidance—

 <232> (5), Kippax highlights. Additionally, 

 <233> outlines which analytical procedures may be used for the detection of elemental impurities (6), he adds.

“ICH Q3D sets out the harmonized requirements for detection of 24 elemental impurities, depending on whether these are intentionally or unintentionally added to a product. These limits are based on an understanding of the bioavailability of each element,” Kippax says. “

 <232> sets the maximum permissible daily exposure (PDE) for elements, again based on an assessment of their bioavailability. In general, the guidance provided is harmonized with ICH Q3D, except for total parenteral nutrition (TPN) products.”

Hesper stresses that regulations around the detection of elemental impurities are updated frequently. “Thanks to modern detection technologies and methods, the limits of detection are getting lower and lower,” he notes. “New studies on the effects of such impurities trigger reconsiderations of risks and limits.”

“While the elemental impurities themselves are well defined, the exposure limits are under constant review by various governing and regulatory bodies,” concurs Ferencz. “There have been efforts to harmonize these limits internationally, but several regulatory agencies still choose to set their own levels based on alternative guidance.”

In terms of potential future updates, Ferencz reports that there have been several pushes to introduce separate limits for additional exposure pathways. “While drug introduction techniques have been expanding, the guidance has not, and parenteral now covers a large range of introduction techniques that do not necessarily have the same exposure risks for the various elemental impurities,” he says. “As more research is done on organ specific effects of different elements, the pressure for this [regulatory update] will increase.”

“Based on the actual push in terms of biopharmaceuticals, especially due to vaccine development, regulations on limits for metal contamination could again be under discussion to avoid influences on final products by metal ions,” adds Hesper. “As processes for release and approval of new pharmaceuticals and vaccines are getting shorter and faster, it becomes more important to reduce possible risks to a minimum.”

The most commonly used techniques to analyze elemental impurities are inductively coupled plasma–mass spectrometry (ICP–MS) or inductively coupled plasma–optical emission spectroscopy (ICP–OES). “Both techniques use a high energy plasma to ionize any elements present in the sample preparation and detect them using elemental masses or elemental emission bands,” Ferencz states.

“The advantage of using ICP is that it can detect a wide range of elemental impurities at very low concentrations,” confirms Kippax. “This [capability] enables the product safety requirements for the main product types (oral solid dose, inhaled, and injectable products) to be assessed.”

Hesper concurs that ICP–MS is a robust and highly sensitive method used for trace analysis of heavy metals and adds that ICP–atomic emission spectroscopy (ICP-AES) has the ability to quickly analyze multiple elements in a large concentration range. “Of some use regarding elemental impurities is atomic absorption spectroscopy (AAS) for quantitative and qualitative analysis of many elements mostly in aqueous solutions and solids,” he says. “Rarely applied to the detection of elemental impurities is energy dispersive X-ray fluorescence spectroscopy (ED–XRF), which can analyze toxic elements in solid and liquid samples with high sensitivity.”

Even though ICP–MS is required to reach the desired levels of sensitivity, there are some limitations to the technique, according to Ingles. “The instrumentation is expensive and requires a trained analyst to operate it,” he says. “Additionally, there are technical complications in the analysis of arsenic and the digestion of nearly insoluble oxides of silicon and titanium.”

Although, it is possible to mitigate the complications with ICP–MS or ICP–OES through the use of appropriate sample preparation and background correction techniques, the cost and operation remains a barrier to businesses and leads to outsourcing, Ingles continues.

Another issue with ICP is that the sample preparation can be a lengthy process, asserts Kippax. “In addition, the preparation route, which involves sample digestion and dilution, requires a high degree of training,” he says. “As a result, although the method is routinely used in batch release, it is more difficult to apply during process development, where more rapid feedback and the application of quality-by-design (QbD) aids with process optimization and the development of a realistic process design space.”

There is also the possibility of gaining false positive results when using ICP–MS, as some elements have different isotopes with the same mass to charge relation, Hesper highlights. “But, basically, all 24 elements of the ICH classes can be analyzed using the ICP–MS technique,” he notes. “Gold, mercury, and osmium can sometimes be challenging. If the focus [of the analysis] is only on the seven most toxic elements, AAS can be the method of choice.”

A major limitation, as is the case with any instrumentation, can be sensitivity, stresses Ferencz. “Methods must balance matrix effects with detection limits to properly monitor for the elemental impurities at the required levels,” he says. “The other major limitation of these techniques is speciation. Because ICP requires the atomization and ionization of elements for analysis, it cannot provide the information about the valence states and molecular forms of the elements.”

Ferencz explains that even though speciation can be relatively more commonplace for certain elements, such as arsenic and mercury, for other elements it is still a niche technique. “As pharmaceutical companies experiment with the use of different elements, especially transition metals, in novel molecules and biologic therapies, there is a growing need to quickly and accurately assess whether the element exists free in the toxic elemental form or properly bound in the clinically proven novel product,” he asserts.

“In the future, species analysis may become more important,” reveals Hesper. For example, if an analyst was seeking to differentiate chromium III/VI rather than simply measuring total chromium, then liquid chromatography (LC) coupled with ICP–MS is more interesting, he states.

The use of chromatography was also key for the future for Ferencz, who believes that the next shift in elemental impurities analysis will be the use of high-performance liquid chromatography (HPLC) coupled with ICP–MS. “The ability to separate and speciate all elements in a drug product allows for a more thorough risk assessment, especially as studies continue to prove the marked difference in toxicity between free elements and various bound states,” he notes. “This technique is still only used for very specific novel drug products, but as the market grows, it will move to be the technique of choice.”

When considering the practical issues that are associated with ICP-based methods, Kippax asserts that XRF, which offers a faster turnaround of samples, cost efficiencies, and simpler measurement workflows, is starting to be more widely adopted. He explains that there are two main areas in which XRF provides the greatest advantages—in-process development and quality control (QC) screening.

“XRF is applied to guide process development scientists toward effective elemental scavenging processes, providing rapid feedback on the capabilities of the process,” Kippax says. “This [application] can speed the time to release of candidate batches. In this mode of use, ICP may be used as validation that a realistic endpoint is achieved, ensuring that the concentration of impurities within the final dosage will be within specification.”

In QC screening, XRF can be applied in the manufacturing process to track the elemental concentration, Kippax continues. “For some pharmaceutical products, this may be sufficient to meet ICH Q3D or 

 <232> requirements, depending on the product dosing regimen,” he says. “Where XRF is unable to meet the requirements for detection, it can provide information on the general concentration of elements within a sample—this can then guide sample preparation for ICP, avoiding measurement failures caused by the elemental concentration within the sample being too low or too high.”

However, Ingles states that, despite the technique being useful in the detection of a variety of metals, there are significant cost and operation barriers to the implementation of XRF in the pharmaceutical industry. “Alternative techniques more commonly adopted in the agriculture and food sectors may at some point be considered for pharma, they include AAS, atomic emission fluorescence spectrometry (AES/AFS), neutron activation analysis (NAA), and anodic striping voltammetry (AVS),” he says. “As mentioned earlier, the techniques will need to meet ICH and USP reference requirements. There will also need to be a good use case to move away from the current, widely accepted approach.”

1. Agency for Toxic Substances & Disease Registry, “Cadmium Toxicity: What is the Biological Fate of Cadmium in the Body?” 

 [Accessed Jan. 11, 2021].
2. USP, “Elemental Impurities Updates,” 

 [Accessed Jan. 11, 2021].
3. ICH, “The ICH Q3D(R1) Guideline Reaches Step 4 of the ICH Process,” Press Release, March 21, 2019.
4. ICH, 

Q3D (R1) Guideline for Elemental Impurities

, Final Version (March 22, 2019).
5. USP, General Chapter <232>, “Elemental Impurities—Limits” 

 (Rockville, MD, 2017).
6. USP, General Chapter <233>, “Elemental Impurities—Procedures” 

Felicity Thomas is the European editor for Pharmaceutical Technology Group.


Vol. 45, No. 2
February 2021
Pages: 46–48

When referring to this article, please cite it as F. Thomas, “Approaching Elemental Impurity Analysis,” 

Articles

Common approaches to analyze elemental impurities for compliance with regulatory requirements are robust but still have some limitations.

Oncoming Elemental Impurity Analysis

As labs continue to advance and expand, many are choosing to divert from the many valves and pumps that come with traditional lab equipment and are instead opting for more compact, space-saving lab equipment and systems. The following are a sampling of these devices.

The Spectrum Compact CE System from Promega is a benchtop capillary electrophoresis (CE) instrument that allows users to perform sequencing and fragment analysis at the bench in laboratories of all sizes (1). It features run scheduling, an easy-to-use interface, convenient benchtop size, separate plug-and-play consumables, and on-site installation and operational training.

Additionally, the system supports microsatellite instability analysis, mixed sample analysis, forensic short tandem repeat analysis, and cell line authentication while processing up to 32 samples in a single run. Users can access the instrument via an integrated touchscreen or through added software that provides access to any computer on the same network. Guided software can also enable capillary electrophoresis capabilities to users regardless of skill level.

“The Spectrum Compact CE is personal and that’s one of the huge advantages that scientists will see with this instrument,” said Promega’s head of research, Doug Storts in a company press release. “An individual can walk into the laboratory and with minimal training, be able to change all the consumables, select which chemistries they want to use for both DNA sequencing as well as for fragment analysis, and perform the experiment. Literally everybody has access. It democratizes the use of the instrument in the laboratory.”

Thermo Fisher Scientific’s Tundra Cryo Transmission Electron Microscope (Cryo-TEM) uses artificial intelligence (AI), guided automation, and loader technology to simplify the overall usage of the microscope for researchers of any experience level (2).

The compact device features a cryo-loading station for sample loading and transfer to the microscope for assessment and structure determination, resolutions of 3.5 angstrom, and throughput within 24 to 72 hours.

"Cryo-EM is speeding the path to disease understanding and treatment. However, many institutions find these instruments to be out of reach because of cost and because they are too complex for new researchers," said Trisha Rice, vice-president and general manager of life sciences at Thermo Fisher Scientific, in a press release. "We worked with cryo-EM luminaries to develop an instrument that not only delivers results, but, more importantly, brings cryo-EM to more users."

Computrac Vapor Pro XL Autosampler from AMETEK Brookfield, part of AMETEK's Instrumentation and Specialty Controls Division, aims to increase the efficiency of the Vapor Pro’s moisture-specific analysis technology by analyzing up to 16 samples automatically with individual test profiles (3).

The compact device is suited for applications that require test automation and increased throughput and provides a chemical-free substitute for Karl Fischer titration. Additionally, it provides testing for applications in the pharmaceuticals industry as well as in other industries (food, lubricants, paints and coatings, plastics, and batteries).

"Busy quality managers will enjoy peace-of-mind and boosted productivity with an automated moisture analysis of up to 16 product samples," said Kai Johnstad, AMETEK Brookfield's global product manager, in a company press release. "Product stakeholders will also benefit from time and cost savings by ensuring the perfect moisture content without using Karl Fischer titration."

Enzo Biochem launched a portable microplate reader for users looking to perform simplified lab work outside of traditional research facilities (4). The instrument, which is one-tenth the size of the average benchtop plate reader, can be used in conjunction with Enzo’s enzyme-linked immunosorbent assay and assay kits to deliver results regarding metabolites, hormones, proteins, and protein characterization.

The MiniSlide MSA series is a compact linear actuator that is highly configurable and easy to integrate (5). Available in a 2-mm, size 8 and a 20-mm, size? [as in “size 19000”?] 19000 with nine different lead screw options ranging from ~0.3 mm to 8 mm, the series is best suited for sample handling, spectrometers and chromatographers, molecular analyzers, optical microscopes, and other inspection equipment. Additionally, the series provides resolution down to 0.001524 mm (0.00006 inches) per step, axial forces up to 45 N, stroke lengths of up to 150 mm, and four different lubrication options, a rotary encoder feedback option, and English- or metric-mounting hardware standards.

1. Promega, “Personal Capillary Electrophoresis System Performs Sanger Sequencing and Fragment Analysis,” Press Release, Sept. 1, 2020.
2. Thermo Fisher Scientific, “Thermo Scientific Tundra Cryo-TEM Democratizes Cryo-Electron Microscopy, Extends to Users of Any Experience Level,” Press Release, Nov. 18, 2020.
3. AMETEK Brookfield, “AMETEK Brookfield Launches the Vapor Pro XL Autosampler, Offering Chemical-Free Moisture Analysis,” Press Release, Nov. 25, 2020.
4. Enzo Biochem, “Enzo Launches Portable Microplate Reader for Use With its Elisa and Assay Kits to Simplify Laboratory Workflow,” Press Release, Nov. 5, 2020.
5. AMETEK, “Haydon Kerk Pittman Launches the MiniSlide MSA Series of Linear Actuators,” Press Release, Oct. 7, 2020.

The latest advances in compact lab equipment include a benchtop CE instrument, a cryo transmission electron microscope, a Vapor Pro XL Autosampler, a portable microplate reader, and a compact linear actuator.

What’s New in Compact Lab Equipment

Jennifer Markarian is manufacturing editor of BioPharm International.

Traceability of the raw materials used in pharmaceutical and biopharmaceutical manufacturing is a crucial part of quality management. Digital tools offer time savings, better compliance, and greater efficiency for all aspects of raw materials qualification and handling.

Raw material quality begins with raw material suppliers, and supplier and material qualification are crucial steps for any drug manufacturing process. Quality management systems (QMS) can be useful here, says Patrick Nieuwenhuizen, senior manager and consultant at PharmaLex.

PharmaLex introduced a digital tool in November 2020 to help companies perform risk assessments of excipient interactions in the final drug product, which are required by Europe’s 

 Volume 4, Part III guidelines (1). “The SmartRisk tool prompts the user with a series of questions to help organize the assessment,” explains Nieuwenhuizen. He notes that the commercially available, cloud-based system complies with US 

 Annex 11 (3), including data integrity protection.

“Having a robust quality management system with procedures and processes for raw material traceability and management supports consistency and reliability throughout the supply chain,” adds Jessica Cansler, senior quality management specialist for Nutrition & Health, North America, at BASF. “Adhering to appropriate quality standards, as well as establishing a program based on risk and application will help ensure the appropriate level of review of raw materials.”

BASF’s Virtual Pharma Assistants, introduced in 2019, are digital tools for pharmaceutical development. “ZoomLab allows formulators to predict their next starting formulation for a pharmaceutical product; RegXcellence untangles the complexity of the compliance process via instant access to regulatory and quality documentation; and MyProductWorld helps customers find the optimal excipient or API solution for their next formulation challenge,” says Valerie Van Hulle, global strategic marketing manager, Pharma Solutions, at BASF. The company continues to update the online tools, she reports.

Quality systems should not be separated in “silos” from other operations, suggests Matt Lowe, chief product officer at MasterControl, which released a new version of its life sciences QMS software on Feb. 3, 2020. “Gaining greater visibility is the first step toward ensuring traceability. Connecting your QMS with other systems and stakeholders helps provide the necessary visibility and transparency to extend a culture of quality not only across your organization, but also your supplier network. With the technology that we have today, any company should be considering a digital QMS and connecting systems in a paperless environment.”

Digitalization for raw materials handling can take many forms—from online certificates of analysis (CoAs) to electronic batch records (EBR). While the trend is toward digitalization, companies in the pharma industry are at various stages in the process, with some completely manual, others completely automated and paperless, and others in between.

Automated systems for raw materials records remove the double verification required in manual paperwork. “The system virtually does the verification for you as it can act as a ‘pass or fail’ whereby the system is working for you instead of you working for the system, which is a time savings and results in better compliance,” adds Nieuwenhuizen.

“It does take effort and time to implement digital systems,” Nieuwenhuizen cautions. He notes one example in which a company implemented a complex vendor management system that required a dedicated project team. The result, however, was the ability to link materials management and ordering with EBR, which also helped manage stock levels. Nieuwenhuizen notes that when implementing digital systems, it can be challenging and potentially counterproductive to translate manual workflows directly into digital workflows. “It may be better to embrace a new way of working and look first at how the digital tools are designed to be used,” he suggests. “The software suppliers have the knowledge about the benefits of the tool, and they can be a resource.”

Integrating digitalized systems within a company eliminates data silos, in which data are stored in separate, unconnected digital systems. An integrated platform makes all the data in an organization accessible so that data can be analyzed to identify trends and make data-based business decisions, notes Lowe. For example, he says, if raw materials supplier data were integrated with other quality and manufacturing data, a manufacturer would have another tool to help better identify the root cause of a deviation.

Integrating QMS and laboratory inventory management systems (LIMS) is beneficial, adds Nieuwenhuizen. “Inventory control systems help with QMS. Quality control of materials can be linked to LIMS for intake, quarantine of problem batches, and release or rejection of material. An important aspect is that it gives you full traceability by batch number,” says Nieuwenhuizen. LIMS can then be interfaced to inventory control systems and to vendor management.

Inventory management and supply-chain visibility software can help with managing complex supply chains. “There are more platforms seen in the industry to alert when there is a possible supply disruption in an area due to natural disasters and other issues in the region or sourcing company,” notes Cansler.

Although data interfaces between raw materials suppliers and drug manufacturers are not yet widespread, there is a move toward sharing information so that parties can make informed decisions more quickly. Data security and confidentiality, however, are important. “Use of password protection and user vetting helps maintain confidentiality,” says Cansler. “Confidentiality can be further addressed by allowing visibility only one level up and down; [users would need to] request authorization to further review the transparency beyond their one level capability.”

Connecting supply chain management systems and QMS also improves efficiency of the supplier audit process, adds Lowe. “Manufacturing organizations need to be able to securely track and store supplier audit information, reports, deviations, supplier corrective action requests (SCARs), and more while making it easy to find suppliers that meet audit requirements.” He notes that digital audit tools within quality systems connected to supplier information allowed remote audits to take place during the COVID-19 pandemic’s travel restrictions. “A digital system can even allow you to invite suppliers to participate in tasks relevant to them, providing a secure, online collaboration space and restricted access to suppliers for collaboration and concurrent engineering efforts. For many companies, having this technology has impacted their business continuity. If there is something good that comes from COVID-19, it’s that it has illustrated the need for digitization to maintain business operations and has spurred companies to make the digital transition.”

While more companies are now embracing these well-established digital tools and systems, new data analysis tools are also being increasingly used. “Machine learning (ML) and artificial intelligence (AI) are tools that some companies are already taking advantage of, and I would expect this will be the big trend in the coming years,” suggests Lowe. “Integrating [supplier, quality, and manufacturing] systems to share information and using AI/ML and natural language processing to analyze that data will be a game-changer for companies.”

 “Guidelines of 19 March 2015 on the Formalised Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use,” (Brussels, 2015). 

 “Computerised Systems,” (Brussels, 2011).

Jennifer Markarian is manufacturing editor for 

Volume 45, No. 3
March 2021
Pages: 42–43

When referring to this article, please cite it as J. Markarian, “Digital Tools Enhance Raw Material Traceability," 

Integrated, paperless data systems can improve efficiency and quality.

Digital Tools Enhance Raw Material Traceability

Regis Technologies, a US-based contract development and manufacturing organization, announced on Feb. 17, 2021 that it has completed the expansion of its laboratory facilities in Morton Grove, IL to accommodate the development of APIs.

The 9000-ft.2 expansion features additional process chemistry and analytical laboratories, an Inductively coupled plasma mass spectrometry suite, added climate-controlled storage,14 new fume hoods, new kilo-scale reactors, and process safety equipment for reaction calorimetry measurements for secure control and scale-up, the company said in a press release. Additionally, the laboratories come equipped with an advanced variable air volume air system for clean energy-efficient operations.

“Our investment in this new capacity broadens Regis’ capabilities and our flexibility to support the growing need for US-based custom pharma services,” said Joe Miller, PhD, chief technology officer at Regis Technologies, in the press release. “The desire to reduce supply chain risk, ensure quality, and maintain intellectual property is driving a surging interest in domestic on-boarding of API development and manufacturing. This timely expansion allows us to meet this demand, enabling our scientists to support additional API projects as our customers advance their novel drugs to market.”

The company has completed the expansion of its laboratory facilities to accommodate the development of APIs. 

Regis Technologies Completes Expansion of its Illinois Lab Facilities 

In a recently formed collaboration with Roche, Cambridge Quantum Computing (CQC) will design and implement noisy-intermediate-scale-quantum (NISQ) algorithms for early stage drug discovery and development. The multi-year collaboration will combine the industry expertise of both companies to significantly advance the application of quantum computing to pharmaceutical-relevant problems, with the aim of accelerating the industry closer towards quantum advantage.

The collaboration, formed in late January 2021, will employ CQC’s quantum chemistry platform EUMEN, to augment Roche’s Alzheimer’s Disease research efforts and will be considered a substantive research effort in the field of quantum computing. The collaboration will strive to enable the development of next-generation, quantum-inspired therapeutics.

“For many years quantum computing has held out great promise for discovering new therapeutics that aid humanity in fighting some of the most devastating and damaging diseases. We are pleased that due to the careful and pioneering efforts of our research teams, some of this promise is starting to come to fruition. We are excited to collaborate with Roche and their quantum computing taskforce. It is a true privilege to collaborate in pursuit of quantum advantage,” said Ilyas Khan, CEO of CQC, in a company press release.

The companies intend to design and implement algorithms for the early stages of research for drug discovery and development of drug candidates to treat Alzheimer’s disease.

Roche and Cambridge Quantum Computing Use Algorithms for Early Alzheimer's Drug Research

SPT Labtech, a company that designs and develops automated instrumentation and consumables for life science applications, has expanded its sample management capabilities for the life sciences industry with the recent acquisition of BioMicroLab, a US-based robotics automation provider for life science laboratories. SPT Labtech made the acquisition in February 2021.

BioMicroLab designs and manufactures laboratory automation equipment for biotechnology and scientific research, and its offerings include an extensive range of sample handling and tracking solutions, which complements SPT Labtech's capabilities in modular, automated sample storage systems as well as expands SPT Labtech's product portfolio in the sample management market, SPT Labtech said in a Feb. 15, 2021 press release.

"Over the last 25 years, BioMicroLab has established a well-deserved reputation as a dependable partner for intuitive and reliable benchtop automation. This important investment delivers significant benefits to customers by creating a powerful end-to-end solution to streamline sample management workflows. We are delighted to welcome BioMicroLab to SPT Labtech," said Patrick Bennett, group CEO at SPT Labtech, in the press release.

"SPT Labtech has an impressive track record of harnessing innovation to overcome tough research challenges and deep expertise across a range of life sciences applications. We are confident that customers will benefit from our combined capabilities and look forward to continuing to enable their research success as part of the SPT Labtech team," added David Miller, president of BioMicroLab, in the press release.

The acquisition strategically expands SPT Labtech’s offering in sample management for life sciences.

SPT Labtech Strengthens Automation Services with BioMicroLab Acquisition

The BioChromato Smart Evaporator C10 from BioChromato, launched in February 2021, uses Vacuum Vortex Concentration technology to evaporate up to 10 samples in vials in parallel, thus improving lab productivity. Available in four colors, the benchtop device provides a sample preparation tool for labs in need of solvent removal directly from liquid chromatography vials or concentration of multiple samples from extraction or fractionation processes.

Additionally, the Smart Evaporator C10 features safe drying of temperature sensitive compounds, drying of solvent volumes as low as 0.1ml, and drying of samples without solvent bumping or splashing, removing the risk of sample loss and contamination, the company said in a Feb. 10, 2021 press release.

The benchtop device provides a sample preparation tool for labs in need of solvent removal directly from liquid chromatography vials or concentration of multiple samples from extraction or fractionation processes. 

Smart Evaporator from BioChromato Improves Lab Productivity 

The Waters Acquity Premier Solution from Waters Corporation is a liquid chromatograph featuring Waters’ MaxPeak High Performance Surface technology, which works to improve analytical data quality and eliminate the need for passivation.

Used in combination with Acquity Premier Columns, the solution is formulated to ease the problem of analyte/metal surface interactions when analyzing organic acids, organophosphates, oligonucleotides, phosphopeptides, acidic glycans, and phospholipids by reversed phase and hydrophilic interaction chromatography. Additionally, the solution:

Increases analyte recovery with 10–100X improvement in detection sensitivity for low-level phosphorylated and carboxylated analytes, reducing the risk of unseen analytes going undetected

Produces sharper peak shapes and greater peak capacity for precise analyte identification and data interpretation

Provides greater reproducibility for separations prone to adsorptive losses

Simplifies the relocation of methods from site-to-site and from company-to-company

Offers ultra-performance liquid chromatography (UPLC) performance for the analysis of metal-sensitive and non-metal-sensitive analytes.

“The Acquity Premier Solution represents our biggest innovation in separation science since UPLC,” said Ian King, senior vice-president, Global Products, Waters Corporation, in a Feb. 10, 2021 press release. “Chromatography has an immeasurable impact on the development of novel therapeutics and treatments for innumerable diseases. The result of decades of separations science know-how along with the combined efforts of our materials scientists, chemists, and engineers, Acquity Premier addresses a long-standing problem that has held back scientific progress long enough. We firmly believe it will redefine the value that separations science brings to scientific achievement.”

The solution eases the problem of analyte/metal surface interactions when analyzing organic acids, organophosphates, oligonucleotides, phosphopeptides, acidic glycans, and phospholipids by reverse-phase and hydrophilic interaction chromatography.

Waters Launches Liquid Chromatograph Featuring High-Performance Surface Technology

Researchers of Karl Mechtler’s Group at the Research Institute for Molecular Pathology (IMP) in Vienna have achieved integration of their ultra-sensitive second-generation µPAC micro-Chip technology into their advanced single cell proteomics workflow, according to PharmaFluidics, a provider of life sciences instruments.

In a newly published joint study (available on bioRxiv), results showed a 10-fold increase in detection sensitivity, which was achieved using PharmaFluidics’ second-generation µPAC technology in an optimized workflow, as compared to previous reports, the company stated in a Feb. 17, 2021 press release. Key results in the study include untargeted and unbiased analysis achieving identification depth of over 2000 protein groups from as little as 500 picogram of HeLa protein tryptic digest.

“The microstructured and extremely reproducible µPAC microfluidic devices are conducive to the generation of high-quality data. With the further downscaling of the critical dimensions in our second-generation technology from 2.5 µm to 1.25 µm, we are now definitely opening a new league in proteomics LC [liquid chromatography], as indicated by the order of magnitude improvement in sensitivity for limited sample workflows,” said Paul Jacobs, co-founder and chief operating officer at PharmaFluidics, in the press release.

“We are grateful to IMP researchers for bringing PharmaFluidics’ technology to the forefront of protein biology, and to our own staff for relentless support to their fellow-scientists,” added Johan Devenyns, CEO of PharmaFluidics, in the press release.

The new ultra-sensitive second-generation micro-chip technology is a key enabler in advanced single-cell proteomics workflow.

PharmaFluidics Offers Second-Gen µPAC Technology for Single Cell Proteomics

Inoculations with the first one-dose vaccine to combat COVID-19 are slated to begin in the United States in the first week of March 2021, after FDA issued an Emergency Use Authorization (EUA) for Janssen’s adenovirus type 26 (Ad26) vaccine on Feb. 27, 2021.

FDA announced the EUA following the unanimous recommendation of the vaccine by FDA's Vaccines and Related Biological Products Advisory Committee on Feb. 26. Two days later, on Feb. 28, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention endorsed safety and effectiveness of the vaccine for individuals age 18 and older.

"This milestone follows a year of incredible work by our dedicated teams and unprecedented collaboration with health leaders around the world—all of whom shared a goal of bringing a single-shot vaccine to the public," said Alex Gorsky, chairman and chief executive officer at Johnson & Johnson in a press statement. "We will do everything we can to help bring this pandemic to an end, in the United States and throughout the world."

The EUA for the vaccine was issued to Janssen Biotech Inc., a Janssen Pharmaceutical Company of Johnson & Johnson. The company reported in a press statement that it plans to file for a biologics license application with FDA later in 2021. The company “is committed to making its COVID-19 vaccine available on a not-for-profit basis for emergency pandemic use,” according to the press statement.

The vaccine, developed on the company’s AdVac vaccine platform, uses Ad26 to deliver a piece of the DNA that is used to make the spike protein of the SARS-CoV-2 virus; the vaccine triggers the human immune system to produce an immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Effectiveness data from an ongoing randomized, placebo-controlled study of nearly 40,000 participants found the vaccine was approximately 67% effective in preventing moderate to severe/critical COVID-19 occurring at least 14 days after vaccination and 66% effective in preventing moderate to severe/critical COVID-19 occurring at least 28 days after vaccination.

Additionally, the vaccine was approximately 77% effective in preventing severe/critical COVID-19 occurring at least 14 days after vaccination and 85% effective in preventing severe/critical COVID-19 occurring at least 28 days after vaccination, FDA reported.

Clinical trial participants reported mild to moderate side effects including pain at the injection site, headache, fatigue, muscle aches, and nausea following vaccination, which lasted 1–2 days. Data are not available to demonstrate how long the vaccine will provide protection, or if it prevents transmission of SARS-CoV-2 from person to person.

“The authorization of this vaccine expands the availability of vaccines, the best medical prevention method for COVID-19, to help us in the fight against this pandemic, which has claimed over half a million lives in the United States,” said Acting FDA Commissioner Janet Woodcock, in an FDA press statement. “The FDA, through our open and transparent scientific review process, has now authorized three COVID-19 vaccines with the urgency called for during this pandemic, using the agency’s rigorous standards for safety, effectiveness, and manufacturing quality needed to support emergency use authorization.”

Johnson & Johnson estimates the vaccine will remain stable for two years at -4 °F (-20 °C), and up to three months at routine refrigeration at temperatures of 36–46 °F (2 to 8 °C).

The vaccine will be distributed by the US government with several million doses in the initial shipment. Johnson & Johnson expects to deliver 20 million doses by the end of March 2021 and 100 million single-shot vaccines during the first half of 2021.

Johnson & Johnson has applied for emergency approval with the European Medicines Agency, the World Health Organization, and in several countries worldwide.

anssen Pharmaceutical Companies of Johnson & Johnson

Distribution of the first one-dose vaccine for COVID-19 to start in early March.

J&J Vaccine Approved for Emergency Use

Seven Bridges, a bioinformatics ecosystem provider, announced on Feb. 24, 2021 that it is supporting Pfizer’s development of a data management and collaboration solution for its single-cell ribonucleic acid sequencing (scRNASeq) data.

Under the terms of the partnership, Seven Bridges will centralize and manage terabytes of raw and processed scRNASeq data using its cloud-based bioinformatic analysis platform while working to expand Pfizer’s cloud platforms and capabilities, Seven Bridges said in a company press release.

"Interpreting large-scale, complex transcriptomics data is critically important for understanding the molecular and cellular basis of disease," said Enoch Huang, vice-president, Medicinal Sciences, Pfizer, in the press release. "We are confident that by working with the unique multi-cloud technology developed by Seven Bridges and by benefiting from the depth and breadth of their expertise in bioinformatics and cloud computing, their solution will assist us in maximizing the value of the data we generate."

"Seven Bridges believes that genomics—and single-cell RNA sequencing in particular—will continue to play an increasingly vital role in the discovery of novel drugs and vaccines," said Bill Moss, CEO, Seven Bridges, in the press release. "We are thrilled that Pfizer has chosen our platform to help the company address these unique data management needs. And we look forward to supporting the development of a scRNASeq data storage solution that meets Pfizer's research and development requirements."

Through the partnership, Seven Bridges will centralize and manage terabytes of raw and processed scRNASeq data using its cloud-based bioinformatic analysis platform while working to expand Pfizer’s cloud platforms and capabilities.

Seven Bridges to Support Pfizer’s Data Management Solution for Single-Cell RNA Sequencing

Novo Nordisk announced on Feb. 25, 2021 that it is investing DKK 500 million (US$80 million) into the expansion of its facilities at its production site in Måløv, Denmark.

Currently, the facility manufactures products for oral diabetes treatment and will be expanded to increase capacity for these products, Novo Nordisk said in a company press release. The expansion is set to be completed in 2022.

“This investment in our production facilities in Måløv is an important step in building and ensuring future capacity for production of Rybelsus (oral semaglutide). Måløv is currently our cornerstone in the production of oral semaglutide, and it is critical that we invest timely in capacity expansion to meet the future demands,” said Henrik Steen Jensen, corporate vice-president for Novo Nordisk oral semaglutide production, in the press release.

Currently, the facility manufactures products for oral diabetes treatment and will be expanded to increase capacity for these products.

Novo Nordisk to Invest $80 million into the Expansion of its Denmark Production Site

Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

Despite shortages in critical components and experienced staff, vaccine manufacturers anticipate significant boosts in output in the coming weeks for these innovative products. The companies with the first Emergency Use Authorizations (EUAs) for vaccines to combat the pandemic produced only 63.7 million doses as of Jan. 31, 2021, far less than the initial goal of 300 million doses, raising skepticism of even meeting the 200 million-dose goal for the end of March 2021. But in recent weeks, the prospects for greater vaccine output have brightened, and the entry of Johnson & Johnson into the market should help. To prevent future production delays of critical products, the Biden administration is examining supply chain vulnerabilities for pharmaceutical ingredients as part of a longer-range consideration of products important to public health.

Efforts to expand production of vaccines to combat COVID-19 have had to overcome a wide range of shortages in materials, qualified facilities, and experienced workers such as engineers and quality control managers. A particular problem is scarce supplies of the ionized lipid nanoparticles needed for the Pfizer-BioNTech and Moderna mRNA vaccines. Only a handful of companies previously produced very small amounts of lipids, most for clinical trials involving rare disease treatments. More contract manufacturers now are licensing the lipid technology, but production scale-up has been a slow process. In addition, finish/fill operations have emerged as serious bottlenecks due to shortages affecting key components for new and revised operating lines plus requirements for high levels of sterility.

 recent hearing before the House Energy & Commerce subcommittee on Oversight & Investigations,

 leading vaccine makers outlined efforts to enhance production and packaging processes. Pfizer Chief Business Officer John Young summarized company plans for boosting vaccine shipments from 5 million to 13 million doses per week by the middle of March. Similarly, Moderna President Stephen Hoge outlined efforts to deliver millions of doses by the end of March and other increases leading to a total of 700 million doses this year.

Johnson & Johnson now expects to provide 100 million doses of its single-dose adenovirus vaccine by the end of June 2021, starting with 20 million doses by late March, following FDA granting Emergency Use Authorization (EUA) for the product. Janssen Vice President Richard Nettles described for the House committee how the company had to assess nearly 100 potential production sites to find eight able to support its accelerated development timeline. Drug substance production takes about two months and is being done at Emergent BioSolutions in Maryland and at Janssen’s Netherlands plant and another facility in India, Nettles explained. And another five to six weeks are needed to produce, test and release the drug product, which is occurring at U. sites in Indiana, Michigan, and Pennsylvania, plus operations in Spain, Italy, India, and Africa.

Pfizer-BioNTech now projects 2021 global production to reach 2 billion doses, almost double early estimates. Some of that increase is due to FDA approval for extracting six doses per vial, as opposed to five doses originally approved. Pfizer CEO Albert Bourla provided further details on company production scale-up in conjunction with

 President Joe Biden’s visit to Pfizer’s Kalamazoo, MI manufacturing facility on Feb. 19, 2021

. Bourla cited plans to add new formulation suites and lipid production in Kalamazoo and at its research site in Groton, CT. Additional finish/fill lines have been established at its McPherson, KS site. This expansion, together with contracts with two additional US contract manufacturers and improved processes, will enable Pfizer to reduce the time needed to produce vial-ready product from 110 days to 60 days. Innovations involve doubling batch size to increase yield and utilizing more efficient lab test methods to reduce release times.

In addition, Pfizer’s vaccine will be easier to ship and store with FDA approval of higher temperatures – that is sub-zero (-15 to -25 oC), as opposed to the ultra-cold level initially authorized. That change is based on stability studies conducted over the past nine months and should facilitate distribution to pharmacies and smaller health facilities.

Moderna’s production gains arise from added efficiencies in creating batches of the drug substance at its facility in Norwood, MA and at the Portsmouth, NH plant operated by contract manufacturing partner, Lonza, Ltd. Moderna also is expanding its fill/finish process agreement with Catalent and looking to contract with another partner. And the company expects to speed up manufacturing runs with FDA approval of providing 15 doses per vial, filling up the empty space in vials that currently hold 10 doses.

The difficulties for manufacturers in securing critical ingredients for vaccine production, packaging, and delivery has prompted the Biden administration to assess the situation as part of a larger review of shortages related to components of critical industrial products. In an Executive Order issued Feb. 24, 2021, 

President Biden initiated a comprehensive review 

of supply chain risks for APIs, critical minerals, semi-conductors, and large-capacity batteries. The aim is to identify factors underlying shortages and supply interruptions of these products and steps the government can take to address relevant problems in the short term. Pharmaceutical products are considered particularly vulnerable in a pandemic or other global crisis due to the high proportion of offshore production of APIs.

To reduce such problems in the future, the White House plans to examine more broadly US supply chain issues related to products important for public health and biological preparedness, as well as for national defense, communications technology, food production, and the industrial base for energy, transportation, and communications sectors. Federal agencies will review goods and materials vulnerable to supply chain disruptions, locations of key manufacturing and production assets, the availability of alternative sources for critical goods, and issues arising from a failure to develop needed domestic capabilities. This initial review of supply chain vulnerabilities leaves off the more strident “Buy American” rhetoric of the Trump administration, but it opens the door to further initiatives to support more “on-shoring” of biopharmaceutical production.

To prevent future production delays of critical products, the Biden administration is examining supply chain vulnerabilities for pharmaceutical ingredients as part of a longer-range consideration of products important to public health. 

COVID-19 Vaccine Makers Overcome Challenges to Ramp Up Production

Merck, known as MSD outside of the United States and Canada, announced on Feb. 25, 2021 that it has acquired Pandion Therapeutics, a US-based clinical-stage biotechnology company, for $1.85 billion.

Through the acquisition, Merck will have access to Pandion’s pipeline of precision immune modulators targeting critical immune control nodes, including its lead candidate, PT101, an engineered interleukin (IL)-2 mutein fused to a protein backbone designed to activate and expand regulatory T cells (Tregs) for the treatment of ulcerative colitis and other autoimmune diseases, Merck said in a company press release.

“This acquisition builds upon Merck’s strategy to identify and secure candidates with differentiated and potentially foundational characteristics,” said Dr. Dean Y. Li, president, Merck Research Laboratories, in the press release. “Pandion has applied its TALON technology to develop a robust pipeline of candidates designed to re-balance the immune response with potential applications across a wide array of autoimmune diseases.”

“Pandion grew out of our founders’ personal and scientific mission to change the way patients living with autoimmune diseases are treated. In just a few years, we have taken that mission from idea to clinical proof of mechanism with PT101, our lead IL-2 mutein. We are proud that Merck has recognized our team’s innovation and drive in creating a pipeline of diverse candidates that activate natural immune regulatory mechanisms and thereby have the potential to achieve better clinical responses for patients,” added Dr. Rahul Kakkar, CEO, Pandion Therapeutics, in the press release. “We believe Merck is well positioned to bring our novel approach to the millions of those living with autoimmune diseases, and we look forward to seeing these molecules progress in the clinic.”

Through the acquisition, Merck will have access to Pandion’s pipeline of precision immune modulators targeting critical immune control nodes, including its lead candidate, PT101.

Merck to Acquire Pandion Therapeutics for $1.85 Billion

Starlab International, a group of companies specializing in liquid handling technology and laboratory products, released their findings from a December 2020 survey evaluating current laboratory situations and the supplies of liquid handling materials in Europe. Starlab concluded that labs can expect a rise in demand for materials in the liquid handling field in 2021 due to 2020’s increased materials consumption and limited availability of liquid handling materials because of COVID-19.

According to a Feb. 4, 2021 company press release, Starlab surveyed 226 laboratory workers in Germany, Austria, Great Britain, Italy, and France. Of the 226 participants, 44% said their material supplies are currently arriving late or not at all; 42% are aiming to build their material inventories with a view to future peaks; 50% felt that liquid handling materials are currently harder to obtain because supplies to medical laboratories are being prioritized; and 56% said their greatest challenge has been the shortage of specialist staff.

All in all, the majority of survey participants expect 2021 to be another year of tension, with 26% saying the increase in demand for liquid handling materials will be around 25%; 8% predicting a rise to over 50%; and a total of 56% expecting it to remain at its current level, Starlab said in the press release.

“We are currently seeing a tense situation in all laboratories. The shortages are not only impacting hospitals and diagnostic laboratories responsible for combatting the coronavirus crisis,” said Klaus Ambos, managing director of Starlab International, in the press release. “This has been confirmed by another up-to-date survey among our European sales managers.”

Ambos continued, “Many laboratory equipment suppliers are in a dilemma. Just because public and societal pressure is being driven higher by COVID-19, this does not mean that other areas of medicine should be allowed to suffer. So, we are endeavoring to balance the availability of material supplies.”

Starlab concluded that labs can expect a rise in demand for materials in the liquid handling field in 2021 due to 2020’s increased materials consumption and limited availability of liquid handling materials because of COVID-19. 

Starlab Survey Shows Predicted Rise in Demand for Liquid Handling Materials in Europe in 2021

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has started a rolling review of regdanvimab (CT-P59), which is a monoclonal antibody being developed by Celltrion for the treatment of COVID-19.

EMA revealed in a Feb. 24, 2021 press release, that the decision to start the rolling review of regdanvimab has been based on preliminary results from an ongoing study assessing the therapy’s ability to treat COVID-19. However, the full data set has not yet been evaluated and the regulatory agency stressed that it is too early to draw any conclusions regarding the benefit-risk balance of the medicine.

The first batch of data, which has been obtained via animal studies and clinical trials, are currently being evaluated by EMA along with any data relating to the quality of the medicine. All data will be evaluated by EMA as they become available, with the rolling review continuing until sufficient evidence is available to support a formal marketing authorization application.

EMA's CHMP has started a rolling review of regdanvimab (CT-P59), which is a monoclonal antibody being developed by Celltrion for the treatment of COVID-19.

EMA Commences Rolling Review of Regdanvimab

The National Institute for Health and Care Excellence has issued guidance recommending the use of TheraSphere Y-90 Glass Microspheres, from Boston Scientific, as a treatment for patients with hepatocellular carcinoma (HCC).

According to a Feb 26, 2021 press release from Boston Scientific, based on the results of more than 100 clinical studies, the effectiveness of TheraSphere to improve tumor response in all stages of liver cancer has been proven. The targeted treatment, which is commonly known as selective internal radiation therapy (SIRT), can be used as an outpatient procedure.

“Outpatient treatment options are important for patients diagnosed with liver cancer as they are especially vulnerable to complications from COVID-19 and the use of TheraSphere can help avoid risk of exposure to infection in the healthcare setting,” said Jane Healy, vice-president Peripheral Interventions, EMEA at Boston Scientific, in the press release. “We look forward to bringing this proven treatment option to a greater number of patients with HCC, to improve their chance of survival against this disease in today’s challenging healthcare landscape and for many years to come.”

NICE has issued guidance recommending the use of TheraSphere Y-90 Glass Microspheres, from Boston Scientific, as a treatment for patients with HCC.

NICE Recommends TheraSphere as Treatment for HCC

Eli Lilly and Company announced on Feb. 25, 2021 that it has entered into a collaboration and licensing agreement with Welldoc to integrate its digital insulin management solution, BlueStar, into Lilly’s connected insulin solutions. 

Under the terms of the agreement, the companies will create a new version of the management solution that will feature insulin dosing data for Eli Lilly insulins. In the first version of the platform, a data transfer module will attach to the top of a prefilled, disposable insulin pen, Eli Lilly said in a company press release. Eli Lilly also plans to develop a fully disposable connected insulin pen for future versions. The app will allow healthcare providers to provide insight regarding diabetes care.

The companies will integrate Welldoc’s digital insulin management solution, BlueStar, into Eli Lilly’s connected insulin solutions.

Featured Content

Understanding Excipient Composition

Putting the Pedal to the Metal

Filling Vaccine Capacity and Process Demands

Reshoring Pharmaceutical Manufacturing?

US Greenlights J&J Vaccine