FDA releases vaccine EUA guidance; distribution presents challenges

COVID-19 Treatments and Vaccines Update

On Oct. 19, 2020, Orgenesis, a biotechnology company specializing in cell and gene therapies, announced that it has completed its previously announced acquisition of Koligo Therapeutics, a regenerative medicine company, while also acquiring substantially all of the assets of Tissue Genesis, also a regenerative medicine company, and gaining Tissue Genesis’ Icellator technology for cell isolation.

Under the agreement, Orgenesis acquired all of the outstanding Koligo stock from Koligo shareholders for approximately $14.5 million in shares of Orgenesis common stock, which is valued at $7.00 per share, and an assumption of $1.9 million in liabilities (estimated to be substantially all of Koligo’s liabilities). Orgenesis acquired the assets of Tissue Genesis for an additional consideration of $500,000 in closing cash and future royalties.

With the Tissue Genesis acquisition, Orgenesis will now own the entire inventory of Icellator devices, related kits and reagents, a broad patent portfolio to protect the technology, registered trademarks, clinical data, and existing business relationships for commercial and development-stage use of the Icellator technology. The Icellator device is a point-of-care (POC) cell isolation technology. It rapidly recovers high yields of stromal and vascular cells (SVF) from adipose tissue, which has been recognized as a superior source of adult stem cells, to be used therapeutically.

The Icellator device is commercially available in Korea and the Bahamas where Orgenesis plans to continue commercial distribution. Clearance is expected in Japan for Icellator X in the first quarter of 2021, pending completion of manufacturing tests requested by the Japanese Pharmaceutics and Medical Devices Agency. In addition, Tissue Genesis has initiated several Phase I pilot trials of the Icellator system in the United States under FDA investigational device exemptions for use in erectile dysfunction, critical limb ischemia, tissue repair, and other therapeutic indications.

Orgenesis intends to potentially develop a broad range of POC autologous cell therapies with significantly reduced costs using the Icellator technology. The company plans to deploy these therapies across a growing POCare Network that includes leading hospitals and healthcare institutions.

“With the Koligo acquisition closed, we believe that we are making rapid progress on a number of fronts,” said Vered Caplan, CEO of Orgenesis, in a company press release. “Specifically, we plan to leverage the therapies and technologies from Koligo and Tissue Genesis across our POCare Platform. One of our first goals is to accelerate the commercial scaleup of KYSLECEL throughout the United States and, subject to regulatory and logistical considerations, in international markets as well. Subject to FDA review and clearance of our IND [investigational new drug] application, we also look forward to commencing patient recruitment for a [Phase II] randomized clinical trial of KT-PC-301, an autologous clinical-development-stage cell therapy candidate for COVID-19-related Acute Respiratory Distress Syndrome, or ARDS.We plan to use the Icellator device to support scalable, cost-effective production of KT-PC-301. Additionally, Koligo’s development stage 3D-V bioprinting technology for the vascularization of autologous cells to create biodegradable and shelf-stable three-dimensional cell and tissue implants will be explored for diabetes and pancreatitis applications, with longer term applications for neural, liver, and other cell/tissue transplants also potentially explored.”

“The Icellator system is highly complementary to our POCare technology systems, as well as Koligo’s 3D-V bioprinting technology. Technologies such as these support our mission of improving the efficacy and lowering the costs of cell and gene therapies by delivering autologous cell therapies at the point of care through our global network of hospitals and healthcare institutions,” Caplan added in the press release.

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Orgenesis has completed its previously announced acquisition of Koligo Therapeutics with the additional acquisition of Tissue Genesis’ cell isolation technology, Icellator.  

Orgenesis Completes Koligo Acquisition and Gains Icellator Technology in Related Transaction

Thermo Fisher Scientific has launched Gibco CTS Rotea Counterflow Centrifugation System, a modular, closed cell therapy processing system that enables scalable, cost-effective cell therapy development and manufacturing. The system is the first Gibco instrument for cell therapy processing applications, the company announced in an Oct. 15, 2020 press release. The CTS Rotea system facilitates workflows from research through to good manufacturing practice (GMP) clinical development and commercial manufacturing.

A modular, closed cell processing system enables time-consuming processes to be decoupled from rapid processes, which improves the utilization of both equipment and the manufacturing facility, thus reducing the capital investment required for cell therapy manufacturing operations, according to the company. Furthermore, use of the same system from research through to process development and commercial manufacturing lowers the risk of process delays associated with changing systems. Sterile, closed, single-use kits enable cell processing in grade C clean rooms, which can lead to cost-effective transfer and scale-out of processes.

With 675 clinical trials underway globally for cell therapy and cell-based immune-oncology as of mid-2020, according to the Alliance for Regenerative Medicine, there are yet few cell therapies in development that become commercially available. This is due to several factors: safety and efficacy requirements, difficulties in transferring research protocols to manufacturing processes, lack of scalability of these therapies, high cost of facilities, labor and equipment, and complexity of the processes involved, Thermo Fisher stated in the press release.

The CTS Rotea system, which is multifunctional and highly flexible, can easily integrate into existing workflows, process low- to mid-range input volumes, and deliver low output volumes. The system consists of an instrument, closed sterile single use kit, and user programmable software. It provides processing flexibility to support a broad range of protocols for cell separation, washing, and concentration. Cell recovery yield is greater than 95% and cell viability is maintained.

"It is notoriously difficult for cell therapies to advance from the research stage into the marketplace," said Amy Butler, president of the biosciences business at Thermo Fisher Scientific, in the press release. "Our goal is to help advance the development of cell therapies, including exciting new CAR T [chimeric antigen receptor T-cell] cell therapies and even potential cell therapies to repair lung damage caused by COVID-19. The CTS Rotea system will help researchers overcome manufacturing hurdles and bring the vast potential of cell therapies to more patients."

The company’s new closed cell therapy processing system enables scalable, cost-effective development and manufacturing of cell therapies.

Thermo Fisher Scientific Launches Closed System for Cell Therapy Manufacturing

Catalent announced on Oct. 19, 2020 that it is launching OptiGel DR technology for the formulation and manufacture of delayed/enteric release softgels.

OptiGel DR technology forms softgel capsules by combining pectin, a naturally derived polysaccharide, and gelatin, which eliminates the need for a separate capsule coating step, a company press release said. The capsules can also reduce gastric reflux effects.

“[T]his latest evolution of the technology allows innovators to design the most efficient products and bring superior pharmaceutical and nutraceutical products to the marketplace,” said Dr. Aris Gennadios, president, Softgel and Oral Technologies, Catalent, in the press release. “The technology we have developed allows the delayed release profile to be incorporated into the softgel capsule shell, broadening the applications, and making a separate capsule coating step unnecessary. This reduces time and yield loss and eliminates potential quality issues associated with coated softgels.”

Catalent’s St. Petersburg, FL, site will be the first to offer the new technology before it expands to the company’s other softgel manufacturing facilities in Brazil, Canada, Germany, Italy, and Japan.

OptiGel DR softgel capsules are formed by the combination of pectin, a naturally derived polysaccharide, and gelatin, which eliminates the need for a separate capsule coating step.

Catalent Introduces New Softgel Technology 

MilliporeSigma announced on Oct. 19, 2020 that it has selected Combined Therapeutics, a pre-clinical-stage biotechnology company located in Cambridge, MA, as the North American winner of its 2020 Advance Biotech Grant Program.

The company was selected because of its nucleic acid platform which, when combined with virotherapy, has the potential to treat liver cancer by using a lipid nanoparticle delivery system, a MilliporeSigma press release said. Through the program, Combined Therapeutics will receive MilliporeSigma products and consultation in downstream processing, formulation excipients, and sterile filtration.

“We help pioneering biotech companies bring lifesaving drugs to market faster,” said Andrew Bulpin, head of Process Solutions at MilliporeSigma, in the press release. “Combined Therapeutics’ platform shows promise to treat liver cancer, which affects thousands of people across the world each year.”

“MilliporeSigma’s expertise in large biomolecule filtration, scale-up and extensive range of excipients will play a pivotal role in moving this project forward to GMP and clinical trials,” added Romain Micol, CEO, Combined Therapeutics, in the press release. “We are honored to have been selected as the winner of MilliporeSigma’s Advance Biotech Grant, and we look forward to the collaboration.”

The company was selected because of its nucleic acid platform which, when combined with virotherapy, has the potential to treat liver cancer by using a lipid nanoparticle delivery system.

MilliporeSigma Awards Combined Therapeutics with Advance Biotech Grant

Rigaku, a Japanese analytical and industrial instrumentation technology company, announced on Oct. 19, 2020 that it will be showcasing its latest developments, modern analytical instrumentation, and techniques at the virtual 27th International Trade Fair for Laboratory Technology, Analysis, and Biotechnology conference from Oct. 19–23, 2020.

According to a company press release, Rigaku will feature its latest x-ray instrumentation at three virtual booths. The showcased products will include:

Rigaku MiniFlex—a benchtop X-ray diffraction diffractometer with the ability to determine crystalline phase identification and phase quantification while performing qualitative and quantitative analysis of polycrystalline materials.

Rigaku SmartLab—a high-resolution X-ray diffractometer that features guidance software for powder diffraction, thin film metrology, small angle X-ray scattering, in-plane scattering, and operando measurements.

Rigaku Supermini200—a high-power benchtop sequential wavelength dispersive X-ray fluorescence spectrometer for the elemental analysis of oxygen through uranium in solids, liquids, and powders.

Rigaku ZSX Primus IV𝒾—a high-power spectrometer for the analysis of liquids, alloys, and plated metals.

Rigaku NEX DE VS—a variable spot size spectrometer.

Rigaku Progeny – a handheld analyzer for raw material identification and finished product authentication.

Progeny ResQ—a Raman analyzer for rapid chemical threat identification.

Rigaku ResQ CQL—an analyzer for the identification and detection of chemical threats and narcotics.

Rigaku KT-100S—a handheld analyzer that uses laser-induced breakdown spectroscopy to identify alloy grades.

Rigaku is featuring its latest x-ray instrumentation at three virtual booths at the virtual 27th International Trade Fair for Laboratory Technology, Analysis, and Biotechnology conference.

Rigaku Corporation Showcases Analytical Devices at Lab Conference

Agnes Shanley is senior editor of Pharmaceutical Technology.

Machine Learning is being applied in a growing number of areas within pharma, including pre-clinical research, to focus efforts and speed up time to results. Leveraging this tool is Riffyn, whose cloud-based Process Data System, Riffyn Nexus was designed to incorporate principles from Six Sigma (specifically its define, measure, analyze, improve and control [DMAIC] rubric), as well as pharmaceutical quality by design (QbD) and measurement systems analysis.

Results have already been seen in industrial biotechnology companies such as the industrial enzyme developer, Novozymes. Established in 2014, Riffyn has recently been moving into more pharma applications. During the first quarter of 2020, before the COVID-19 pandemic began, CEO Tim Gardner, a specialist in synthetic biology, discussed the company’s origins and goals with 

 What made you develop the Process Data System and start the company?

: Riffyn was born out of an industrial biotech environment, and knowledge gained from the large-scale process development and manufacturing of chemicals produced by genetically engineered species. I had spent years in industrial microbiology and biotech, as vice-president of R&D for a company called Amyris, which focused on large-scale bio-manufacturing of renewable chemicals. We edited and genetically engineered yeast to make products that ranged from detergents to makeup oil.

In industrial biotech, speed to market and low costs of production are key to success. Ideally, you want to minimize capital investment costs while developing core technologies, so you compete not only on performance but on price. Being able to do this required harnessing data in ways that few companies were capable of doing 10 years ago.

At that time, pharma hadn’t yet made the transition to data-driven process development and manufacturing because they weren’t under the same performance pressures with their processes.

Of course, they were under pressure from regulators and had to have the right regulatory mindset, but, in general, the focus was not on whether the process worked well but on whether it would be approved. In fact, the worst process in the world would still be OK if it received regulatory approval. This type of mindset does not drive innovation.

With Riffyn, we figured that we could take data-driven process improvement and combine it with the principles behind the ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) guidelines from FDA and EMEA (the European Medicines Agency) and the QbD initiative. Those are fundamentally brilliant, some of the best technical directions for pharma that I’ve ever seen, and a recipe for data-driven process development.

Initially, few in the industry were really harnessing these concepts. There were too many difficulties entailed with practical issues (e.g., designing processes; integrating different teams of people; working on those processes and evolving them over time; capturing specifications; collecting data; and synthesizing data and specs of various forms of processes and versions). The goal was to put all of that together, to provide a holistic understanding of how manufacturing processes are working, but when QbD was introduced in 2004, it was too difficult to do.

However, it had already been done in other industries. Experiences that I had in industrial biotech showed it was not only possible to do, but that it could have a profound effect on R&D. In industrial biotech, utilizing QbD principles and data science practices led to four-to-five-fold increases in speed to market, cutting the average time from tech transfer to manufacturing down from more than a year, to three months.

We wanted to incorporate these principles into a software system that made it easy to harness them, not only for users in industrial biotech, but for pharma and biopharma development, to help usher in a transformation in speed-to-market and continuous improvement in the development and delivery of those products.

: Since those early days, before you set up the company, have you seen a significant change in the industry’s acceptance of the fundamentals of QbD?

: We have definitely seen a shift of mindset and culture within the industry, and some change in practice. Today, the concepts of digitization and speed to market are much more commonly discussed as key transformations needed to bring biopharmaceutical organizations to the next level of progress.

These ideas are getting embedded more into practice. Recent surveys have shown that more than half of all pharma companies are using ICH guidelines around process validation in their daily work. That’s encouraging. But many of them are still using outdated technologies.

: How would you describe the Process Data System? How does it work?

: It’s really a digitized Process Lifecycle Management environment, built around capturing production and analytical process designs and specifications and then accelerating improvement cycles for those processes until they are ready to transfer to manufacturing. The principles of DMAIC and QbD are embedded into its world view.

We had used these same principles at Amyris, to double the rate of catalyst and strain development without increasing headcount. 

Measurement system analysis is another important principle we used. All those principles aim to define R&D processes explicitly, instead of leaving that as an afterthought. This process of definition begins with the process that generates data, then the next step is measuring performance, analyzing performance, and improving processes to reduce variability.

Reducing variability is so important. It’s an almost unspoken but understood objective in manufacturing, but not in the research and development space.

That is why there is a lot of churn in pharma R&D. As a result, people can end up making bad decisions, chasing phantoms, and going down the wrong road because they respond to noise in the system rather than to significant developments. 

Once we took QbD into R&D, we achieved such fidelity in experimental answers that predictability, speed, and efficiency all improved. As a result, the number of experiments could be reduced, along with the level of overall churn, because we could understand what the critical process parameters were and take them right to the manufacturing floor.

At Novozymes, one of our first customers, we saw dramatic gains in R&D and tech transfer efficiencies (

. The company has been using the Riffyn Nexus for two years, during which it has increased capacity by an order of magnitude, and cut time to market by a factor of two, all with half the original number of staff members, Gardner says. Riffyn is currently working with a number of pharmaceutical and biopharmaceutical companies on pre-clinical and other development programs including bioassays, as well as formulation and bioprocess development. 

We don’t support manufacturing like a manufacturing execution system (MES) or batch-control software system. Instead, we support the development of processes and their transfer to manufacturing (e.g., catalyst and enzyme development, formulation development, analytical methods and assays used to collect data). We can transfer those designs into a manufacturing context. Right now, this is accomplished mainly by sharing documentation. It’s like transferring blueprints.

In the future, though, we hope to incorporate digital transfers so that users can transfer a design file directly from process development to manufacturing, sending the information right to the process control system (much like a CAD/CAM [computer-aided design/manufacturing] system would do in discrete manufacturing).

: When will this capability be introduced? 

: We’re prototyping and developing with pharma partners and biopharma process equipment companies. It’s probably one to two years away.

: What results are you seeing among customers in the biopharma space?

: We helped one pharma company, which had a team of four doing bioassay development, so that they could cut 2400 hours of labor each year from their processes using the improved data system, a 50% reduction in effort to achieve better outcomes from bioassays.

: How has the technology helped reduce false leads?

: There are a few examples that come to mind, although we cannot give client names. In one case, a group was struggling with cell-line development. They would pick what seemed to be the best cell lines, but these would continue to fail at the next developmental stage.

We collected data from 14 of their past experiments, assessed the resulting data in aggregate, and saw that seven of the 14 experiments they had performed had used the same cell lines, so these seven points became internal controls for their assay system’s performance.

Normally you just look at the controls week by week, but we also tested and followed a number of other variables in the data set (e.g., feed lot of culture media and temperature) from week to week. We found variations in these values across the experiments. As it turned out, this variation was driving aggregate decreases in cell line performance, and not just in the cell lines that the teams had selected as the best options.

The team was really chasing artifacts rather than real factors, so they were reacting to higher temperatures or better media rather than better cell lines, so some cell lines were failing downstream.

When we statistically corrected the data to remove all the temperature and lot effects and then renormalized the data across the experiments, the team could see that not one single cell line had been improved. If they had performed this analysis first, they could have prevented significant waste and loss. However, when they took the lessons learned from this work, they were able to improve processes and got real hits almost immediately.

: Why is there such a problem with reproducibility in pharma R&D, especially at the pre-clinical stage?

: One problem is that people are not transparently articulating what they’re doing. The first step in establishing this transparency is defining what you did, unambiguously.

Riffyn’s platform is designed to help with clear process definition, to get organizations to articulate their processes clearly, rather than fragments of the process, the bits and pieces that they may see on data boards. This can lead to huge boosts in reproducibility.

In addition, reproducibility requires a clear understanding of CPPs. In fact, in many ways, the concept of reproducing a process in the lab is exactly like scaling up a process. You need to understand CPPs, and, if you control them, the entire process can be much more efficient.

: Today a growing number of biopharma companies are doing their own work in machine language and artificial intelligence, using open source code and developing inhouse processes. Amgen is one example. Will it be more difficult to penetrate if everyone is doing this type of work independently? Will this make the market more competitive in the future?

: It's actually making it easier. We take an open ecosystem approach, and one that is vendor neutral in terms of access to data and process design. We adhere to, or provide interchangeability with S88 and S95, with the goal of Riffyn becoming part of a modular ecosystem that can be plugged or unplugged. In general, the more open, the better.

At this point, most of our work in tech transfer is partnered.

: How does the software work and what does the IT connect into at a customer facility?

: It’s cloud-based and can be accessed via web browser, but we can integrate it within customer networks so that it is embedded. All that is required is a web browser. As in VIZIO where you can have flowcharts, Riffyn starts by creating a flow diagram that represents the assay, manufacturing, or formulation process to describe ingoing process.

This can be replicated in the lab so that users can collect all data from instruments, from manual entry. What might have taken 40 hours of data integration in the past can be done in 1 to 2 hours.

: Does this data go into a Laboratory Information Management System (LIMS)?

: In fact, many customers are replacing LIMS with our system because it can integrate LIMS type data in the context of data from many other sources.

: Are contract research and development companies a part of your client base now?

 We expect to see that part of the business grow. Because our system is cloud-based, it can provide a means for contract development and manufacturing organizations to gain real-time access to unfolding experiments. 

Branching out from roots in industrial biotechnology, Riffyn Data Systems (and its CEO Tim Gardner) is taking the message of data-driven process improvement to biopharma. 

Bringing Six Sigma to Preclinical Pharma R&D 

Thermo Fisher Scientific announced on Oct. 14, 2020 that it is developing two new sterile filling lines in Singapore for the development and manufacturing of therapies and vaccines for the Asia-Pacific region.

The new $130 million facility will be operated by Thermo Fisher who will ensure the site has the ability to manufacture pharmaceutical products to meet demand and respond to health emergencies, a company press release said. The facility will include a high-speed sterile line for live virus filling, a line for standard fill/finish, cleanroom capacity, labs, warehousing, and offices to support production.

The site will be operational in 2022 and will have the potential to manufacture up to 30 million sterile doses per month and house more than 300 employees, the press release said.

"The COVID-19 pandemic has shown us the importance of government and industry collaboration to protect citizens by ensuring the availability of critical diagnostic tests, therapies, and vaccines," said Marc N. Casper, chairman, CEO, and president of Thermo Fisher Scientific, in the press release. "This partnership enables us to expand our sterile fill finish network in the region while strengthening the Singapore government's ability to respond quickly to future health crises."

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The facility will include a high-speed sterile line for live virus filling, a line for standard fill/finish, cleanroom capacity, labs, warehousing, and offices to support production.

Thermo Fisher Scientific to Develop Two Sterile Filling Lines at New Facility in Singapore

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

The much-anticipated meeting of FDA’s vaccine advisory committee this week is slated to address a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection. Although the Vaccines and Related Biological Products Advisory Committee (VRBPAC) will not review an application for any particular product, this panel of virologists and scientists 

will discuss policies and data requirements

 for determining that a pandemic vaccine can be considered safe and effective, particularly when based on more limited, early clinical trial data

Shaping the discussion is the current halt in two major vaccine trials due to unspecified safety issues. US investigators continue to seek more information on patient illness in the AstraZeneca vaccine study announced in early September, although enrollment has restarted for AZ trials in the United Kingdom and other countries. Johnson & Johnson more recently paused its massive COVID-19 vaccine trial due to an “unexplained illness” in a patient. The safety committee for the study has stated by examining whether the ill individual received the vaccine or was in the placebo arm. The sponsors emphasize that these research halts demonstrate their excessive caution and importance of calling on outside monitoring boards to fully investigate such cases.

FDA standards for documenting vaccine safety is an important topic for VRBPAC review, particularly as it relates to granting Emergency Use Authorization (EUA) to an experimental vaccine, an approach that agency officials consider likely and appropriate given the high costs of the pandemic in terms of public health risks and economic hardship. The Center for Biologics Evaluation and Research (CBER) specified in its recent 

 that it expects an EUA application to provide two months or more of safety data for at least half of the participants in a trial following completion of the full vaccination regimen

 . As most serious side effects appear within six weeks of individual vaccination, this timeframe is designed to provide a sufficient period for detecting events such as vaccine-induced enhanced respiratory disease and to distinguish such conditions from coronavirus disease.

A particularly challenging issue for the advisors is the how granting EUA status to an initial product could interfere with further assessment of the vaccine’s safety and with ongoing trials for other preventives. FDA says that the sponsor of an authorized vaccine should continue blinded follow-up assessments for months following an initial distribution, but there some authorities believe that an EUA sponsor should shift all participants in the placebo arm to receive treatment. While that might appear a more ethical decision, it could block efforts to gain further information on vaccine efficacy and side effects, including rare adverse events and fuller comparisons among patient groups with differences in age, sex, comorbidities, and ethnic characteristics. And because of limited information about how long immunity will last from initial vaccines, both manufacturers and regulators look for additional guidance on determining what data need to be collected further to indicate when boosters or additional vaccination would be advisable.

Most analysts expect that some vaccines likely to gain approval in subsequent months may be more effective or provide stronger protection than the early products. However, continued development of alternative vaccines may be hindered by difficulties in enrolling new subjects in randomized trials when a vaccine is on the market. Scientists and vaccine developers emphasize that it’s vital for research to continue on multiple preventives, as certain products may affect certain populations differently, and varying formulations may be more suitable for distribution in certain regions.

These issues raise important ethical considerations for the research community and health authorities. While randomized, placebo-controlled clinical trials are necessary to understand the true effects of a medical product on larger populations, individual participants may gain limited benefit and added risk. And in the face of a lethal pandemic, the risks are even more stark. An alternative research approach may be to use a newly authorized vaccine as a control in testing subsequent preventives, a form of noninferiority trial. Such studies may take much longer and cost more to produce results but could reduce the need for large placebo control arms that deny treatment for thousands.

The much-anticipated meeting of FDA’s vaccine advisory committee this week is slated to address a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection.

Early Vaccine Authorization Raises Ethical and Logistical Challenges for Trial Sponsors

MilliporeSigma has launched its VirusExpress lentiviral production platform, bolstering its viral vector manufacturing capabilities. This new platform helps overcome lentiviral production challenges and can additionally reduce process development time by approximately 40%, the company announced in an Oct. 13, 2020 press release.

The platform uses a suspension cell line rather than an adherent-based production system and is coupled with a chemically defined cell culture media and a process that has built-in scalability. Using a suspension cell culture format can accelerate process development. It also allows for higher yields from each batch of virus, resulting in more patient doses. The suspension culture format is also easier to scale up while being less labor-intensive. Furthermore, the chemically defined medium eliminates the safety, regulatory, and supply chain concerns related to animal- and human-derived materials.

The platform offers a simplified upstream workflow by making processes easier to manage, adjust, and scale. In addition, flexible licensing allows companies to manufacture vectors by using either MilliporeSigma’s contract manufacturing capabilities, a third-party contract development and manufacturing organization, or in-house development.

“Cell and gene therapies offer the potential for curative treatments and are being developed and commercialized in half the time it has taken traditional therapies,” said Angela Myers, head of Gene Editing & Novel Modalities at MilliporeSigma, in a company press release. “We are committed to accelerating manufacturing of cell and gene therapies with the ultimate goal of getting these lifesaving treatments to patients faster. By increasing dose yields and dramatically reducing process development time, this new platform will help us reach this goal.”

The new VirusExpress lentiviral production platform increases dose yields and reduces process development time for cell and gene therapies.

MilliporeSigma Launches Lentiviral Production Platform for Cell and Gene Therapies

Abzena has invested $60 million into a new, approximately 50,000-ft2 facility at its site in San Diego, CA, for late phase and commercial current good manufacturing practice (CGMP) manufacturing. The new facility houses a process development laboratory and two new CGMP manufacturing cleanrooms for 500-L and 2000-L scale single use bioreactors (Sartorius), the company announced in an Oct. 8, 2020 press release.

The facility also houses a GMP warehouse and analytical development and quality control (QC) laboratories and will enable Abzena to deliver Phase I to commercial manufacturing services for biologic projects. New 7400 ft2 of process development laboratory space uses single-use technology bioreactors ranging from 250-mL to 2-L (Ambr, Sartorius) and from 50 L to 200 L (STR, Sartorius) to screen important process parameters to develop robust scalable processes and ensure seamless manufacturability.

“Until now our other San Diego site has been focused primarily on development and manufacture of Phase I and II clinical trial materials. This expansion will allow us to provide seamless project integration for our customers as they move into Phase III and ultimately commercial manufacture,” said Matt LeClair, senior-vice president and site head of Abzena’s San Diego Operations, in a company press release. “This latest investment is testament to our commitment to developing our offering in line with the needs of our current customers and the rest of the market.”

The new facility at the company’s San Diego, CA, site will be for late phase and commercial CGMP manufacturing.

Abzena Invests in New $60-Million CGMP Manufacturing Facility

Recent data, published by the BioIndustry Association (BIA) and Clarivate, has revealed that investment in biotech companies in the United Kingdom continues to be strong with companies raising more than £1 billion (US $1.3 billion) in equity finance between June and August 2020.

A notable investment highlighted from the report includes the raising of £119 million (US $154 million) by Freeline Therapeutics—a clinical-stage gene therapy company—on the initial public offering on NASDAQ. Additionally, venture capital funding has returned to pre-COVID-19 levels, reaching £283 million (US $364 million) in the second quarter of 2020.

“In a year where COVID-19 has caused major disruptions to the global economy it is fantastic to see the strong investment picture for UK biotech continue to gather pace,” said Steve Bates OBE, CEO of the BIA, in an Oct. 12, 2020 press release. “During the pandemic, UK biotech has shown its strategic value and received great interest from UK based investors, with many investing in the sector for the first time. This could be transformative for patients and the economy, and for shareholders, when combined with the global money we already attract—large pharma, US, and Chinese venture capitalists are already aware of the vast opportunities UK biotech presents.”

Recent data, from BIA and Clarivate, has revealed that investment in UK biotech continues to be strong.

UK Biotech Investment Continues to be Strong, According to Data

The medicines and healthcare products regulatory agency (MHRA) of the United Kingdom has joined the Australia-Canada-Singapore-Switzerland (ACSS) Consortium of regulators, it was announced in an Oct. 14, 2020 press release. To accommodate the addition of the UK’s regulatory body, the ACSS Consortium will change its name to the Access Consortium.

According to the press release, Access Consortium partners will work together with the primary aim of providing patients across the five countries with timely access to high quality, safe, and effective therapeutic products. Through the addition of the UK, the new combined population to be covered by the consortium is approximately 145 million people.

Any pharmaceutical companies submitting applications to some, or all, of the consortium member countries will benefit from having products evaluated for marketing in Access countries simultaneously with reduced evaluation times. Additionally, the Access Consortium will update the guidance for industry on how product applications may be considered for marketing authorization across the five countries, Australia, Canada, Singapore, Switzerland, and the UK.

The UK will become a full member of Access from Jan. 1, 2021. New guidance will be available to industry from that date also.

The UK's MHRA has joined the Australia-Canada-Singapore-Switzerland (ACSS) Consortium of regulators.

MHRA Joins the Australia-Canada-Singapore-Switzerland Consortium

Francesca Speroni is project leader at PTM Consulting and is a member of the AFI process validation working group.

Ilaria Franceschini is in Pharmaceutical Technology at Italfarmaco and is a member of the AFI process validation working group.

Maurizio Valleri is in Pharmaceutical Technology at Menarini and is a member of the AFI process validation working group.

Mauro Silvestri is in Manufacturing Technology at Angelini and is a member of the AFI process validation working group.

Matteo De Nigris is part of Manufacturing Science and Technology at LEO Pharma Manufacturing and is a member of the AFI process validation working group.

in R&D CMC at Chiesi and is a member of the AFI process validation working group.

Alessia Garavaglia is in Good Engineering Practices at Grünenthal and is a member of the AFI process validation working group.

 at Mipharm and is a member of the AFI process validation working group.

Rosa Terribile is in QA at Mipharm and she is a member of the AFI process validation working group.

Stefano Pompilio is in Clinical Trial Manufacturing at Thermo Fisher Scientific and is a member of the AFI process validation working group.

Enrico Modena is in R&D at PolyCrystalLine and is a member of the AFI process validation working group.

Stefano Selva is in Pharmaceutical Technology at Recordati and is a member of the AFI process validation working group.

Lorenza Broccardo is project manager at S-IN Soluzioni Informatiche and is a member of the AFI process validation working group.

Cesare Armetti is an AFI member and participates in the AFI process validation working group.

 is an AFI member and participates in the AFI process validation working group.

The AFI (Industrial Pharmacist Association) is an Italian professional association aiming to promote cultural initiatives and practical/professional updating for its members within the pharmaceutical industry. This article contains a set of indications elaborated by the AFI working group on process validation (PV) according to current thinking and indications given in guidelines issued by regulatory authorities both in Europe and the United States.

The new approaches for PV suggest a roadmap from process design up to the validation and maintenance of the state of control. According to these concepts, drug product quality is generated starting from the initial development phases, is defined in the manufacturing process intended to be validated, and continues throughout the lifecycle according to quality-by-design (QbD) and quality risk management (QRM) principles. This article illustrates the concepts, the approaches, and the tools available to implement this modern vision of PV for pharmaceutical products, specifically in reference to sterile dosage forms (in particular liquid and freeze-dried products).

Francesca Speroni is project leader at PTM Consulting; Ilaria Franceschini is in Pharmaceutical Technology at Italfarmaco; Maurizio Valleri is in Pharmaceutical Technology at Menarini; Mauro Silvestri is in Manufacturing Technology at Angelini; Matteo De Nigris is part of Manufacturing Science and Technology at LEO Pharma Manufacturing; Simona Bertolini and Luca Rizzo are both in R&D CMC at Chiesi; Alessia Garavaglia is in Good Engineering Practices at Grünenthal; Camillo Bologna is QP and Rosa Terribile is in QA, both at Mipharm; Stefano Pompilio is in Clinical Trial Manufacturing at Thermo Fisher Scientific; Enrico Modena is in R&D at PolyCrystalLine; Stefano Selva is in Pharmaceutical Technology at Recordati; Lorenza Broccardo is project manager at S-IN Soluzioni Informatiche; Cesare Armetti and Marco Adami* are AFI members.
All authors are members of the AFI process validation working group.
*To whom all correspondence should be addressed.

BioPharm International Regulatory Sourcebook


eBook: Regulatory Sourcebook, October 2020
October 2020
Pages: 31–41

When referring to this article, please cite it as F. Speroni, 

, "Enhancing Process Validation for Sterile Liquid and Freeze-Dried Forms," 

BioPharm International Regulatory Sourcebook eBook

AFI representatives of the process validation working group explore and define key elements for an enhanced approach to process validation for sterile liquid and freeze-dried forms.

Enhancing Process Validation for Sterile Liquid and Freeze-Dried Forms

Cytiva will provide its FlexFactory, a flexible, single-use platform, to enable Akron Biotech to manufacture plasmid DNA (pDNA), which is used in many innovative therapies and vaccines, Cytiva said in an Oct. 15, 2020 press release. Cytiva and Akron will also work together on process design for pDNA production. Akron’s pDNA FlexFactory will be fully operational by the third quarter of 2021, the press release said.

“With this partnership, Akron demonstrates its continued commitment to supporting the advancement of cell and gene therapies with cGMP [current good manufacturing practice]-compliant solutions at industrial scale,” said Claudia Zylberberg, CEO, Akron Biotech, in the press release.

Materials for cell and gene therapy manufacturing, such as pDNA, have been experiencing capacity constraints, and the platform will enable rapid scale-up to address supply chain bottlenecks.

“With the accelerated growth of the biotechnology industry, companies must choose technologies and solutions that can quickly scale to meet future needs. Cytiva’s FlexFactory provides the speed and flexibility combined with the automation platform needed to meet the needs of such a dynamic market,” said Olivier Loeillot, senior vice-president, Bioprocess, Cytiva, in the press release. 

This is Cytiva’s first FlexFactory installation for the manufacture of pDNA. More than 70 FlexFactory installations around the world are already in use for clinical trials and commercial production of advanced and novel therapeutics and vaccines. The FlexFactory, designed for cGMP manufacturing, provides traceability and optimization by combining control, connectivity, automation, and supporting services that accelerate manufacturing, according to the press release.

Cytiva will provide the first FlexFactory to be used in the manufacture of pDNA to Akron Bio.

Akron Bio Will Install a Cytiva FlexFactory to Manufacture Plasmid DNA

Connect with pharmaceutical and healthcare regulatory authorities around the world via this directory.

BioPharm International's October 2020 Regulatory Sourcebook. ​ 

Regulatory and Standard Setting Organizations

Merck, known as MSD outside the United States and Canada, announced on Oct. 15, 2020 that FDA has approved an expanded label for its anti programmed death-1 (PD-1) therapy, Keytruda (pembrolizumab), as monotherapy for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

According to a company press release, the approval comes after a Phase III trial showed Keytruda reduced the risk of disease progression or death by 35%. An updated pediatric indication for Keytruda for the treatment of pediatric patients with refractory cHL was also approved by FDA.

“An estimated 8500 patients in the [United States], many of them 40 years of age or younger, will be diagnosed with cHL this year. Now patients with cHL who progress after frontline therapy have a new option in Keytruda, which has demonstrated a clinically meaningful improvement in progression-free survival compared to brentuximab vedotin,” said Dr. Vicki Goodman, vice-president, clinical research, Merck Research Laboratories, in the press release. “At Merck, we are committed to improving outcomes for patients with cancer. Today’s FDA approval builds upon our growing range of options for people with blood cancers.”

The approval comes after a Phase III trial that showed Keytruda reduced the risk of disease progression or death by 35%.

Merck’s Keytruda Approved for Expanded Indication in Classical Hodgkin Lymphoma

Regeneron Pharmaceuticals announced on Oct. 14, 2020 that FDA has approved Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn) for the treatment of infection caused by 

 (Ebola) in adult and pediatric patients.

Under the terms of the approval, Regeneron will distribute Inmazeb treatment doses over the course of six years to the Biomedical Advanced Research and Development Authority (BARDA), part of the US Department of Health and Human Services, a company press release said.

“We are incredibly proud that [FDA] has approved Inmazeb, which is also known as REGN-EB3. This is the first time [FDA] has approved a treatment specifically for Ebola, which has caused a number of deadly outbreaks,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer of Regeneron, in the press release. “Decades of investment in our VelociSuite rapid response technologies, the dedication of world-class scientists, and the courageous contributions of healthcare providers and patients, together with remarkable cooperation between leading international health organizations and governments, have led to this important moment. As we apply the same sophisticated technologies and manufacturing capabilities against COVID-19, we hope this will be one of many demonstrations of how the power of science can be successfully deployed against dangerous infectious diseases.”

“Since 2015, BARDA has partnered with Regeneron to develop a life-saving treatment for Ebola Zaire. The [FDA]’s approval of Inmazeb shows the power of public private partnerships to bring forward these critical treatments and improve global public health,” said Gary Disbrow, the acting director of BARDA, in the press release. “BARDA is continuing our collaboration with Regeneron on other life-threatening diseases such as MERS and COVID-19, and we look forward to continued success.”

Regeneron will distribute Inmazeb treatment doses over the course of six years to BARDA.

FDA Approves Regeneron’s Inmazeb as the First Treatment for Ebola

Bora Pharmaceuticals, a contract development and manufacturing organization, announced on Oct. 15, 2020 that its chairman and CEO, Bobby Sheng, was named ‘CEO of the Year’ at the CPhI Pharma Awards 2020.

The award is presented to a C-suite executive who demonstrates leadership skills to drive forward their organization, increase performance, and engage staff and customers, while remaining committed to the development of the pharma industry, a company press release said. The judges chose Sheng from a shortlist of seven candidates and highlighted his work in the Taiwanese and global markets while guiding the company through “pivotal changes” that demonstrated his abilities as a “top CEO.”

Throughout 2020, Sheng headed the expansion of Bora Pharmaceuticals from Asia into the United States and helped the company meet its international growth goals despite the ongoing COVID-19 pandemic, the press release said.

“Winning such a prestigious award is an incredible acknowledgement not just of me, but of the work, values, and expertise of the whole team at Bora Pharmaceuticals,” Sheng said in the press release. “I am incredibly proud of the growth we have achieved thanks to the excellent customer service, technical agility, and niche capabilities that the team at Bora provide to our customers across North America, Asia, and Europe.”

The judges chose Sheng from a shortlist of seven candidates and highlighted his work in the Taiwanese and global markets while guiding the company through “pivotal changes” that demonstrated his abilities as a “top CEO.”

Bora Pharmaceuticals’ Bobby Sheng Wins ‘CEO of the Year’ at the CPhI Pharma Awards

Robert Brokamp is director Automation Services, Jacobs.

Adi Karisik is global technology leader for Operational Technology at Jacobs.

As bio/pharma manufacturers make their operations and networks increasingly streamlined and interconnected, there is a need to connect older facilities to the supply chain. In turn, this means that operational technology (OT) cybersecurity measures must be introduced to legacy systems to support archaic equipment, older operating systems, and decades-old protocols as well as networks where it is not possible to fully monitor the operational network or to detect and control intrusions.

BioPharm International Regulatory Sourcebook 


eBook: Regulatory Sourcebook, October 2020
October 2020
Pages: 28–30

When referring to this article, please cite it as R. Brokamp and A. Karisik, “Tackling Cybersecurity Challenges in Legacy Systems,"

 BioPharm International Regulatory Sourcebook 

Ongoing and emerging cyber-risks to legacy operational technology systems in bio/pharmaceutical manufacturing must be addressed.

Tackling Cybersecurity Challenges in Legacy Systems

Christopher Burgess is with Burgess Consultancy, "Rose Rae," The Lendings, Starforth Barnard Castle, Co. Durham, DL12 9AB UK.

The title of this article is deliberatively provocative. Pharmacopoeias contain the legal standards for the quality of medicines with monographs for active ingredients, excipients, and finished products. Analysts should understand how a monograph, together with the associated general notices and general chapters, relates to their responsibilities under good manufacturing practices for ensuring data integrity. However, many pharmacopeial tests therein involve classical chemical analysis (e.g., color, appearance, titration) and rely on an analyst’s observation with little, if any, documented evidence for review. Hence, do pharmacopoeias inadvertently facilitate data integrity violations? 

Analysts should understand how a monograph, together with the associated general notices and general chapters, relate to their responsibilities under good manufacturing practices.

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