More complex and challenging compounds require a tailored formulation approach.

Unique Molecules Push Formulation Boundaries

UK approves emergency use for Pfizer/BioNTech vaccine; industry ups manufacturing, awaits FDA EUA decisions.

Bio/Pharma Science Drives Pandemic Solutions

Honeywell announced on Dec. 3, 2020 that it successfully completed a remote control system migration for Richter Gedeon, a pharmaceutical and biotechnology company headquartered in Budapest, Hungary. The project was the first of its kind to enable plant operators to deploy advanced remote solutions to eliminate control technology obsolescence, enhance operations and improve business results, Honeywell stated in a company press release.

The migration project, which was deployed at Richter’s production facility in Dorog, northwest of Budapest, involved updating a Honeywell Experion PKS R431.5 control system to the latest R511.3 release. During the COVID-19 pandemic, the Honeywell service team executed the migration tasks using limited resources allowed on site and completed the work during strict schedule constraints associated with a plant shutdown.

Because of the pandemic, industrial companies are seeking ways to minimize their on-site presence while keeping equipment up-to-date and with minimum downtime. A failure to address outdated plant automation systems could lead to crucial assets being rendered inoperable. Organizations with a solid roadmap for ongoing technology upgrades can mitigate risks and drive plant operations seamlessly without unnecessary disruptions, Honeywell stated in its press release.

With the Remote Migration Services, Honeywell experts can perform control and safety system upgrades on a 24/7 schedule. This type of migration is performed in-house on Honeywell’s Virtual Data Center, which can be accessed remotely by technical support specialists along with local Honeywell staff and Richter’s on-site personnel. This access enables the fastest migration possible. The service includes migration readiness, software migration, offsite or remote acceptance testing, and production system upgrading. Honeywell specialists perform the software migration and then invite the end user to test the new Experion software release prior to introducing it into their production system.

Honeywell’s remote migration solution can improve project execution cycle time by as much as 50% and increase migration productivity by at least 60%, the company reported in its press release. Honeywell also offers enhanced industrial cybersecurity capabilities and control technology improvements to achieve optimum results.

“As a manufacturer of innovation-driven specialty pharmaceutical products, we believe there are significant benefits in proactively addressing the risks and issues of control technology obsolescence,” said Csaba Ódor, deputy head of the investment department for Richter Gedeon, in the press release. “Honeywell’s Remote Migration Services will help us reduce total cost of ownership, increase production rates, extend the life and performance of their systems, and improve response to changing business demands.”

“Honeywell’s strategy for remote control system migration is well-suited to the current business situation. By executing migration projects remotely, plant operators can reduce potential risk, minimize operational downtime, and make migration an advantageous experience rather than a burdensome requirement,” said Pramesh Maheshwari, vice-president and general manager, Lifecycle Services and Solutions, Honeywell Process Solutions, in the press release. “Beyond traditional on-process migration, the latest technology advancements allow system modernization to be performed on the cloud—just like a simple update. Industrial facilities can leverage value-added support on a remote basis with limited risks to their personnel or other assets.”

Articles

Honeywell’s project team has remotely and efficiently migrated Richter Gedeon’s process control system with limited onsite staffing and resources.

Honeywell Completes Remote Control System Migration for Hungarian Pharma Manufacturer

On Dec. 1, 2020, BioSkryb, a developer of genomic amplification technologies, reported the release of foundational data demonstrating that primary template-directed amplification (PTA) has a superior ability to accurately and uniformly amplify the genomes of single cells. The data was released on bioRxiv, the preprint server, prior to publication.

Whole genome amplification (WGA) is required for low-input DNA and single-cell analysis, and single-cell approaches are critical for tackling difficult biological questions involving genomic heterogeneity. Current WGA technologies and methods for single-cell or low-input DNA analysis, however, only cover a fraction of the genome, have a limited capacity to detect genetic variation in each cell, and suffer from significant biases, experimental artifacts, and poor reproducibility. The new data show that PTA can overcome these limitations as well as provide high-quality, scalable analysis of single-cell genomic heterogeneity. Having access to this analysis can enable new insights into human disease at the cellular level and empower high-resolution diagnostics for cancer, gene-editing, and other applications, BioSkryb stated in a company press release.

Furthermore, the PTA technology accurately calls genomic variants within tissues, one cell at a time, and reproducibly captures more than 95% of the genomes of those cells in a more controlled and accurate manner than existing approaches. According to the data released, PTA can be reliably used to call copy number variation in primary cancer cells and genome-wide variant detection in gene-edited cells. The technology can enable the feasibility of performing single-cell evaluations of biopsies from cancer and gene-edited tissues.

The PTA technology has been made a part of BioSkryb’s ResolveDNA kits, which contain all the enzymes and reagents needed for whole genome amplification from single cells or ultra-low DNA inputs. The kits employ a unique set of nucleotides to prevent recopying of the amplification products, which results in less errors and higher, more uniform coverage of the genome. The PTA technology also enables the attachment of cell barcodes to the resultant products for pooling and downstream analysis.

“We developed PTA to accurately and efficiently decipher genetic diversity at the cellular level so that we can better detect, understand, and treat disease,” said Charles Gawad, MD, PhD, inventor of the PTA technology, cofounder of BioSkryb, and associate professor at Stanford University, in the press release. “These data show that PTA amplifies the genomes of single cells with high coverage breadth and uniformity in a reproducible manner to significantly improve variant calling of all types. The ability of PTA to enable highly accurate genetic information at single-cell resolution could uncover new drug targets for cancer and neurological diseases as well as identify CRISPR off-target activity to monitor the safety and fidelity of gene editing.”

“Chuck and I cofounded BioSkryb to ensure researchers had access to the most advanced DNA analysis technologies, so it’s especially exciting to see the superior performance of PTA over current methods and to be able to make it commercially available through our ResolveDNA kits,” said Jay West, PhD, CEO, and cofounder of BioSkryb, in the press release. “Existing whole genome amplification methods uncover a fraction of the genomic information, but now with ResolveDNA, researchers can explore new places in the genome and be confident in the quality of the sequencing data at those sites.”

A novel PTA technology captures more than 95% of the genomes of single cells, providing more uniform, accurate, and reproducible single-cell analysis data.

BioSkryb Discusses First Data Demonstrating Improved Accuracy in Single Cell Analyses

On Dec. 3, 2020, Cytiva and 4Tune Engineering, a manufacturing-sciences and technology company, announced that they have entered into an agreement to include 4Tune Engineering’s iRISK platform in Cytiva’s cell therapy product offering.

Cytiva customers in the early stages of cell therapy product development will gain access to these tools, which can identify risks and evaluate and implement structured risk management plans. Cytiva research has shown that 75% of global respondents are actively developing or have a risk management program in place. With early stage development programs approaching commercial launch, some organizations are currently relying on manual processes or reactive mitigation strategies.

The iRISK platform is a fully integrated automated solution that identifies, quantifies, and prioritizes risks. The platform can also formulate risk mitigation strategies for new or existing processes throughout the manufacturing lifecycle. The platform can be customized to meet specific customer needs.

“The manufacture of cell therapies is inherently more risky than traditional biotherapeutics. As we look to improve the manufacturing process, working with 4Tune Engineering to provide our customers with an automated and structured risk management platform is a clear choice. Our customers will have peace of mind knowing they have a strong risk mitigation process in place,” said Catarina Flyborg, vice-president, Cell and Gene Therapy, Cytiva, in a company press release.

“Our collaboration with Cytiva will provide their customers with an automated, systematic, and user-friendly approach to risk management that will improve lifecycle management of cell and gene therapies and business performance of companies involved in that space,” added Marcos Domingues, CEO, 4Tune Engineering, in the press release.

The collaboration addresses the need for risk mitigation plans in cell therapies.

Cytiva and 4Tune Engineering Collaborate on Cell Therapy Quality Risk Management

Johnson & Johnson announced on Dec. 1, 2020, that the company has initiated rolling submissions with Health Canada and the European Medicines Agency for Janssen’s investigational single-dose vaccine candidate for the prevention of COVID-19.

The reviews are based on positive non-clinical data showing that the vaccine candidate elicited a robust immune response, as demonstrated by neutralizing antibodies, in an ongoing Phase I/IIa clinical trial that is studying the safety profile and immunogenicity of a single-dose and two-dose vaccination. Immune responses were similar across the age groups studied, including older adults, the company reported in a press statement. The Janssen COVID-19 vaccine candidate is being evaluated in Phase III clinical trials.

The investigational COVID-19 vaccine candidate uses Janssen’s AdVac vaccine platform, which was also used to develop and manufacture the company’s European Commission-approved Ebola vaccine regimen and construct its Zika, RSV, and HIV investigational vaccine candidates, the company reported.

Janssen reported in the statement that the company “is committed to bringing an affordable COVID-19 vaccine to the public on a not-for-profit basis for emergency pandemic use.”

Janssen announces rolling submissions for its COVID-19 vaccine with Health Canada and EMA.

J&J Initiates COVID-19 Vaccine Approvals in Canada and Europe

Janssen Pharmaceuticals, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, announced on Dec. 2, 2020 that it has acquired US-based biotechnology company Hemera Biosciences’ investigational gene therapy, HMR59, for the preservation of vision in patients with geographic atrophy, a form of age-related macular degeneration (AMD).

According to a Janssen press release, the gene therapy works to increase the ability of retina cells to make a soluble form of CD59, a protein that shields the retina from damage, to prevent additional damage to the retina and to preserve vision.

“Geographic atrophy is a devastating form of AMD that impacts the ability to accomplish everyday tasks, such as reading, driving, cooking, or even seeing faces,” said James F. List, MD, PhD, global therapeutic area head, Cardiovascular and Metabolism, Janssen Research & Development, in the press release. “Our aim with this novel, single-administration gene therapy is to use our development expertise and deep heritage in vision care to help improve patient outcomes by intervening early, halting the progression to blindness, and preserving more years of sight.”

The gene therapy increases the ability of retina cells to make a soluble form of CD59, a protein that shields the retina from damage, to prevent additional damage and to preserve vision. 

Janssen Pharmaceuticals Announces Acquisition of Vision Care Gene Therapy

KBI Biopharma, a JSR Life Sciences company, announced on Dec. 1, 2020 that it has opened a new $150 million commercial manufacturing facility in Research Triangle Park, NC.

Set to be operational by the first quarter of 2022, the 140,000-ft

 facility will feature up to six 2000-L, single-use bioreactor systems along with additional harvest and purification equipment to produce up to 100 commercial batches annually, a company press release said. The new site will also be equipped to provide accommodations for mammalian-based biologics manufacturing processes for KBI’s future and existing collaborators.

“Expansion of our US-based cell culture operations is a key investment to support our client’s commercialization strategies,” said KBI president and CEO Dirk Lange in the press release. “This state-of-the-art facility will leverage the latest innovation in automation and digitalization to best meet the needs for our clients.”

Set to be operational by the first quarter of 2022, the 140,000-ft2 facility will feature up to six 2000-L, single-use bioreactor systems along with additional harvest and purification equipment to produce up to 100 commercial batches annually. 

KBI Biopharma to Open $150 Million Commercial Manufacturing Facility in North Carolina

Colorcon announced on Dec. 3, 2020 that it is entering into a research collaboration with i2O Therapeutics, a US-based biotechnology company, to aid in the development of i2O’s liquid technology for the oral delivery of challenging drugs.

Under the terms of the partnership, Colorcon will work to accelerate the company’s research and development efforts, a Colorcon press release said.

“We are excited to collaborate with Colorcon to help advance our ionic liquid technology given their rich history of innovation and expertise in pharmaceutical development,” said Samir Mitragotri, PhD, co-founder of i2O Therapeutics, in the press release.

“Colorcon Ventures’ strategic focus on technologies that transform conventional delivery pathways aligns well with i2O,” added Martti Hedman, Colorcon’s CEO, in the press release. “The ability to deliver injectable therapies orally has the potential to significantly improve patient adherence and outcomes.”

Under the terms of the partnership, Colorcon will work to accelerate i2O’s research and development efforts.

Colorcon and i2O Therapeutics Partner for Liquid Technology Development 

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Highly potent compounds present numerous challenges with respect to process development, formulation, and delivery. “The key features at the interface of drug delivery and highly potent APIs (HPAPIs) are the ability to maintain operator safety through containment of the API during processing and to deliver a drug product in which the HPAPI is evenly dispersed, even when doses are as low as micrograms,” asserts David Lyon, a senior research fellow with Lonza.

Doing so is becoming more challenging as the molecular complexity of HPAPIs
continues to increase significantly. “These molecules are much more specific in how they interact with the body and different cellular targets,” says Brian Haney, director of technical operations for AMRI. “As a result, it makes them much more difficult to manufacture, more difficult to test, and more unstable,” he observes.

In fact, HPAPIs have largely been too fragile for traditional oral solid-dose formulation, and the majority are delivered parenterally via infusion or intravenous injection, according to Haney.

Historically, HPAPIs have been almost exclusively associated with oncology therapeutics. “Highly potent molecules for such acute indications could be delivered by intravenous infusion even if an oral drug product could not be developed,” Lyon explains.

Currently, however, HPAPIs include a growing number of classes of molecules and new chemical entities for a broader range of indications, thus covering a much wider swath of the developmental pipeline. “For many of these indications,” Lyon comments, “oral delivery is required due to the chronic or frequent dosing needed for the molecule and indication. The need for oral solutions has thus led to adaptation of existing pharmaceutical processes to enable the handling [of] HPAPIs in a safe and efficient manner,” he adds.

Examples include microdosing, liquid-filling of capsules, and wet granulation, which help balance therapeutic benefit versus risk. These processes address safety concerns for operators by properly containing the HPAPI, according to Lyon.

“Liquid-fill and wet granulation processes remove much of the concern with operator exposure because the powder risk is removed once the HPAPI is dissolved in a lipid or solvent for either filling into a capsule of spraying onto a solid support dispersible,” explains Lyon. Once the HPAPI powder is dissolved or emulsified, further processing of the liquid becomes simpler and less costly, requiring less strict containment. Lyon also notes that these processes allow for highly accurate dosing down to low API levels, helping ensure content uniformity and reproducible dosing for caregivers and patients.

Managing poor solubility/bioavailability challenges

Handling a highly potent compound across the oral drug development process becomes even more complex when the compound is also bioavailability-challenged. The simplest approach, according to Lyon, is to fill the micronized active ingredient into an empty capsule shell using equipment that can be deployed in a contained space (microdosing).

Many HPAPIs, however, have material properties (sticky, semisolid, liquid, too light, too fluffy) that preclude the use of conventional microdosing. The powder may also have poor flow properties or the size and shape of the HPAPI particles may be inconsistent. In some cases, Lyon observes, HPAPI compounds may be so potent that a safe containment level cannot be easily achieved or the dosage itself may simply be below the weighable range of microdosing.

In these cases, liquid-filled hard capsules (LFHCs) can effectively minimize operator exposure to the solid HPAPIs. “The liquid-filling process is straightforward, involving only four steps: dispense, mix, fill, and seal. LFHCs contain either room-temperature liquids or thermo-softening materials manufactured as molten liquids at temperatures of up to 65 °C.
Typically, sticky semisolid and liquid HPAPIs are miscible in liquid excipients, forming a homogeneous mixture, no matter how low the dosage is,” says Lyon.

In addition, the use of solubility-enhancing excipients and liquid lipid-based options such as self-emulsifying drug delivery systems (SEDDS) and self-micro emulsifying drug delivery systems (SMEDDS) is also possible. Milling and micronization of HPAPIs to produce nanoparticles is also safer when performed in an oily solvent.

Size reduction, in fact, through “top down” approaches such as micronization and “bottom up” techniques such as crystallization, expands the surface area-to-mass ratio, thereby increasing the dissolution rate of the HPAPI, according to Ilan Avni, vice president of business development with Wavelength Pharmaceuticals. Other techniques for increasing bioavailability of HPAPIs, he remarks, include spray drying and hot-melt extrusion to generate amorphous solid dispersions in polymeric matrices and the formation of cocrystals with appropriate conformers to improve physicochemical properties.

One of the challenges to formulating highly potent APIs is the fact that often only small quantities of the drug substance are required in each unit dose. Only formulation approaches that can ensure homogenous distribution throughout the product, even at extremely low doses, are therefore appropriate. These constraints also require accurate analytical methods; again, preparing liquid solutions or emulsions for further processing (encapsulation, wet granulation, then tableting) is effective.

The melt-spray-congeal (MSC) process is also now being successfully applied to advance potent oncology compounds in lipid multiparticulate (LMP) formulations, according to Lyon. “This technology is increasingly used to address controlled release, taste-masking, and/or low solubility challenges,” he says.

In the MSC process, the API is suspended or dissolved in a molten lipid formulation at elevated temperatures (70–90 °C) and then pumped to a spinning disk where the solution/suspension is atomized and then congealed, forming a multiparticle of 100–300 microns. Notably, Lyon says, these lipid multiparticles can contain from as little as a few percent API to 50% API, making them an effective vehicle for diluting HPAPIs.

Particularly for targeted oncology therapies, it takes time to deliver the HPAPI to the specific cancer cells of interest. “Sustained- or modified-release formulation makes it possible for the active substance to stay in the body longer as it travels to where it needs to go,” says Haney.

To achieve this goal, newer delivery approaches include conjugation of the HPAPI via a chemical linkage to another inert molecule that has an affinity toward the target cells. “Antibody-drug conjugates (ADCs) are an ever-growing class of drugs in this category. The HPAPI is conjugated to a monoclonal antibody that carries it to the target cells, where it is released for targeted action,” Haney explains.

AMRI, Haney adds, has been seeing other conjugation approaches as well, such as linkage of HPAPIs to polyethylene glycol (PEG) resins. “These PEG polymers, often 5000–20,000 Daltons in size, are slowly degraded by the body. The conjugated system consequently remains intact for much longer than the inherently unstable HPAPI would by itself, providing sustained release,” he comments.

Similarly, extended-release parenteral formulations based on bioabsorbable poly(lactide-co-glycolide) (PLG) microparticles can improve therapeutic efficacy and increase patient compliance. In some cases, HPAPIs can be delivered from PLG microparticles for weeks and months following a single administration.

Other approaches can also be used. For instance, if a simple modified release profile—such as delivery of the API to the duodenum—is required, a simple fill of either the solid or dissolved API into an enteric capsule may provide the desired release profile with minimal handling, according to Lyon.

Other release profiles, however, such as a zero-order release profile, will likely require a wet granulation step to obtain a homogeneous drug product intermediate prior to the final tableting step, Lyon notes. “Of course, each of these unit operations must be appropriately contained and validated for the required occupational exposure levels for the operators,” he adds.

Because many highly potent drug products are low-dose, small-volume drugs, it is important to understand and manage development of the formulation process, according to Iain MacGilp, director of GMP manufacturing at AMRI. During final formulation, for instance, aseptic filtration can potentially lead to loss of costly drug product via adsorption, which is not acceptable for complex HPAPIs.

With respect to delivery techniques for parenteral HPAPIs, MacGilp adds that it is important to understand and minimize interactions between the drug product and the delivery device while also keeping in mind the volume requirements during different phases of drug development.

There is also significant effort focused on further removing operators from the process to minimize risk, both for operator protection and product assurance, according to MacGilp. That has translated, for example, into the development of robotic systems for product filling. “While these systems can be costly, highly potent drugs often address unmet therapeutic needs and there is a drive to implement advanced formulation filling and delivery technologies to enhance specific safety requirements,” MacGilp observes.

Lyon adds that the biggest recent advances are, in fact, largely around containment. “As HPAPIs become increasingly potent, the need for containment during processing becomes increasingly rigorous,” he states. It is important to remember, he points out, that contained processing is required across HPAPI development and manufacturing, including any particle engineering and other processing required to generate a finished dosage form. “Each of the technologies used is able to be contained to different levels based on its footprint and the need for powder handling,” Lyon adds.

One of the ways to reduce risk during the manufacture and formulation of HPAPIs, at least for liquid HPAPI solutions, is to employ single-use containment systems. “Disposable solutions can be designed to be much more specific for a particular process and are just as safe in terms of band 5 containment, but significantly less expensive than traditional barrier isolation systems,” Haney explains. In particular, disposable solutions are ideal for early-phase products for which it is undesirable to dedicate manufacturing capacity and suites.

At its multiproduct sites, AMRI has implemented a single-use philosophy because it reduces risk of cross-contamination, which is a key issue for HPAPIs. “Anything that is used for our formulation process or the pathway for delivery into the vial is one-use and then disposed of,” MacGilp says. In fact, the company has moved the upstream formulation process to a single-use isolator that can contain any compound below 0.1 µg/m³. The system has been fully qualified by SafeBridge and is used as a single-use system on a routine basis.

“We are excited to blend the manufacturing controls of traditional barrier isolators and hard-sided containment with new opportunities that are more flexible and single use,” concludes Haney.

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


Vol. 44, No. 12
December 2020
Pages: 20–22, 46

When referring to this article, please cite it as C. Challener, “HPAPI Complexity Prompts New Delivery Mechanisms,” 

Operator, caregiver, and patient safety are at the forefront when selecting the best options and dosage forms.

HPAPI Complexity Prompts New Delivery Mechanisms

Susan Haigney is managing editor of BioPharm International, susan.haigney@ubm.com.

The race for the development and approval of treatments and vaccines for COVID-19 is well under way, and regulators and other organizations are working with the bio/pharmaceutical industry to get these products into the hands of the public. As ever, pharmacopoeias play a role in providing a standards framework for the development, manufacture, and quality of these life-saving medicines.

With the current challenges facing industry and regulators, how has the US Pharmacopeia (USP), which publishes the 

United States Pharmacopeia–National Formulary

), been assisting in the development of COVID-19 treatments and how has the pandemic affected the organization’s operations?

USP, like many other organizations, has been ensuring the safety of its staff and shifted the majority of its staff to working remotely in March 2020, according to Jaap Venema, PhD, chief science officer at USP.“Critical lab functions continued in a way that minimizes the risk to on-site staff,” says Venema. “Similar measures were taken for USP’s expert volunteers, who now regularly meet virtually to advance their standard-setting work.”

For USP, building trust in the effectiveness of COVID-19 vaccines and treatments, ensuring global access to these treatments, and combating falsified and substandard medicines are the focus, according to Fouad Atouf, PhD, vice president, USP Global Biologics. USP has been offering free resources and technical expertise to developers of COVID-19 vaccines and treatments since early 2020, says Atouf, including free and discounted education, limited-time free access to the

, and free samples of USP monoclonal antibody reference standards.

“Scientists and manufacturers working on developing new vaccines and treatments, increasing the production of approved drugs, and advancing other projects to tackle COVID-19 can access the 

 Online free for six months. Also, we have extended implementation dates and comment periods for our compendia, recognizing the challenges that the pandemic has brought to drug developers and manufacturers,” says Atouf.

“USP’s role in the wake of COVID-19 is multi-pronged: we are helping to accelerate the work of scientists and manufacturers in developing vaccines and treatments; supporting front line workers who will administer COVID-19 vaccines and treatments and who have been affected by shortages of critical drugs and personal protective equipment; and working on developing insights on current supply chain vulnerabilities and ways to strengthen it,” says Atouf. “Our expert volunteers and scientific staff can advise on novel vaccines, monoclonal antibody therapies, antiviral and cell therapies, and immunoglobulins or convalescent plasma treatments. And for existing and new therapies, 

 compendial tests and methods address common issues shared by all drug manufacturers, such as suitability, validation, contamination control, stability testing, and qualification of raw materials,” he adds.

One of the key topics USP is planning to address in 2021, according to Edwin Gump, PhD, vice president, USP Small Molecules, is the detection and control of nitrosamine impurities, which are known carcinogens that have been found in some medications. USP has proposed General Chapter <1469> Nitrosamine Impurities that identifies sources of nitrosamines and risks associated with each source. The proposed chapter, says Gump, will give recommendations on a nitrosamine risk assessment and control strategies. It will also provide different test methods for controlling nitrosamines at levels below acceptable intake limits in angiotensin II receptor blockers.

According to Horacio Pappa, PhD, director of USP General Chapters, USP is also developing a chapter on supplier qualification that will provide a quality risk-based approach to the selection, assessment, approval, and monitoring of suppliers. “Suppliers for pharmaceutical ingredients, medical devices, as well as dietary supplement manufacturing companies and compounding pharmacies will be within the scope of the chapter,” says Pappa. “The current thinking is to develop the chapter around the supplier qualification lifecycle—a five-step process that includes identification/selection, evaluation/acceptance, performance, monitoring, and disqualification—along with discussions about expectations and a rationale for each step,” he says.

 General Chapter <1220> Analytical Procedures Life Cycle offers “an alternate framework for analytical procedures that holistically incorporates the events that take place over the procedure life cycle,” says Pappa. “It is designed to demonstrate that a procedure is, and remains, fit for the intended purpose.”

The proposed chapter also seeks to build the connections between validation, verification, and transfer through the life cycle approach, says Pappa. At the same time, the International Council for Harmonization (ICH) has started the revision of the

 Q2 Validation of Analytical Procedures: Text and Methodology

 guideline on validation and proposed the creation of a complementary guide (

) on the development of analytical procedures. “These guidelines will incorporate some of the concepts presented in <1220>,” says Pappa.

In 2021, USP also will propose procedures based on inductively coupled plasma spectroscopy (ICP) to element-specific general chapters, which impact 

 General Chapters <206> Aluminum, <211> Arsenic, <241> Iron, <251> Lead, <291> Selenium, and <261> Mercury, according to Pappa. “This will give our stakeholders the option to continue using the classical wet chemistry tests as currently included in these chapters, or to adopt the use of an ICP-based procedure for analysis of the element in question, as similarly outlined in 

 <233> Elemental Impurities—Procedures. This ensures the same approach is used throughout 

 regarding the analysis of individual metals with elemental impurities. This revision will provide stakeholders with an option for a single analysis to meet both monograph and chapter requirements, rather than multiple procedures,” says Pappa.

USP also is planning a chapter on batch release testing. “USP is aware that many of our tests are commonly used for batch release, but the procedures and acceptance criteria in General Chapter <905> Uniformity of Dosage Units refer only to the units tested, so any passing results should not be extrapolated to larger populations. The approach to release the batch (with respect to content uniformity) based on passing the <905> requirement is neither appropriate nor acceptably rigorous,” says Pappa.

When it comes to large molecules, USP added additional performance standards for monoclonal antibodies, according to Atouf. “These reference standards can be used as independent control materials for method development, training, method transfer, and internal assay control support, standardization of physicochemical testing, such as intact mass, charge heterogeneity, size variants, purity, and glycan analyses. These types of standards will have a positive impact on access to these critical drugs,” says Atouf.

In addition, a Plasmid DNA Expert Panel has been formed under USP’s Advanced Therapies Expert Committee to develop a new general chapter on the use of plasmid DNA in cell and gene therapies, according to Atouf. USP will also be developing a lentiviral vector copy number standard to “standardize the quantitation of viral vectors in cellular genomes. This is important because the number and persistence of inserted genes in patients may lead to health complications, and quantifying vectors efficiently in preclinical studies for gene therapies and vaccine development may prevent adverse events in patients,” says Atouf.


Vol. 44, No. 12
December 2020
Pages: 42–46

When referring to this article, please cite it as S. Haigney, "USP, COVID-19, and Plans for the Future," 

USP is preparing for 2021 while also supporting the development of vaccines and treatments for COVID-19.

USP, COVID-19, and Plans for the Future

On Dec. 1, 2020, PlantForm, a privately held Canadian biopharmaceutical company, announced that the Natural Sciences and Engineering Council of Canada (NSERC) awarded it and its research partner, University of Alberta (UAlberta) scientist Dr. Warren Wakarchuk, an Alliance Grant to conduct research that will enable the commercial-scale production of effective, low-cost, plant-made protein therapeutics, including an antidote to chemical nerve agents.

The Wakarchuk lab pioneered the use of enzymes to make or remodel glycans, which play a key role in regulating immune cell signaling and function, and PlantForm’s plant-based manufacturing system for large-molecule protein drugs (biologics) requires glycan remodeling. Glycan remodeling on proteins effectively mimics human glycan structures, which reduces the risk of rejection and improves the circulation lifetime of the protein, according to PlantForm in a company press release.

The two-year project, which will be supported by $184,000 from NSERC plus a $92,000 cash and in-kind investment by PlantForm, will focus on using 

 glycan remodeling to improve the efficacy and serum half-life of butyrylcholinesterase (BuChE), a countermeasure for chemical nerve agents, such as soman and sarin. The BuChE is produced using PlantForm’s proprietary plant-based vivoXPRESS platform. The researchers will use enzymes engineered by the Wakarchuk team to remodel glycans on target proteins for improved stability and drug efficacy, with a focus on commercial-scale production.

“This Alliance Grant expands and strengthens our research collaboration with Dr. Wakarchuk and his team to continue to advance our novel glycosylation technology for our pipeline of innovative protein-based drugs,” said Dr. Don Stewart, PlantForm’s president and CEO, in the press release.

“Plants are an excellent alternative to mammalian cell cultures for the low-cost production of protein-based drugs. But the production of the authentic human glycan structures is difficult to control in both mammalian- and plant-based expression systems,” said Wakarchuk, a professor in the Department of Biological Sciences at the Faculty of Science as well as scientific director of GlycoNet, a pan-Canadian Network of Centers of Excellence consisting of more than 140 researchers centered in UAlberta, in the press release.

The grant will support the advancement of glycoengineering technology for plant-derived proteins developed by a University of Alberta scientist partnered with PlantForm.

Featured Content

Unique Molecules Push Formulation Boundaries

Bio/Pharma Science Drives Pandemic Solutions