Jun 02, 2021
The biotechnology company Angany recently announced the successful production of neutralizing monoclonal antibodies (NAbs) derived from the plasma of COVID-19 patients using its plant-based system. Angany has now joined forces with global technology company Phylloceuticals to leverage its PhAASTTM (Pharmaceuticals as a Service Technology), plant-made commercial production system, to rapidly scale up commercial manufacturing.
Technology Networks spoke with Phylloceuticals’ chief science officer Dr Barry Holtz and Angany’s senior vice president Guy Tropper to learn more about key considerations when scaling up manufacturing, the benefits of a plant-based production system and how this approach is helping to accelerate the development of NAbs against SARS-CoV-2 and its variants.
Q: Could you comment on some of the key challenges encountered when scaling up the production of biopharmaceuticals, particularly considering the exceptional need for preventives and treatments to combat COVID-19?
A: Time to construct and commission, capital expenditures (CapEx) and personnel training are all key challenges to bringing on a new production facility. To frame any of these issues in the need to address epidemic and pandemic disease presupposes that there is a constant and vigilant effort to identify new viruses and other microbial threats. It also presupposes that preemptive vaccine and antiviral product development efforts are proactive and not reactive. Regional facilities will have to be created proactively and commissioned to make vaccines and antibodies for current needs. These facilities will need to be designed to pivot quickly to produce vaccines, antivirals and other products to address an outbreak. These facilities need to be in constant use so that personnel are trained and ready to pivot to a new product. Technologies that can address rapid product development and innovative scale-up and purification should replace or augment hardware heavy systems that require a long scale-up cycle to produce a consistent product. Response time is paramount. The trillions that COVID-19 has cost the global economy could have been greatly diminished by even a 6-month faster response to a vaccine and useful antiviral monoclonal antibodies (mAbs).
Plant-made pharmaceutical (PMP) manufacture can cut capital expense by 75% and operating expenses (OpEx) by 66%. PMPs have been around for a long time, but most new biopharmaceuticals are developed out of culture-based systems, likely due to familiarity with the approach. Adopting a “know how it’s done", established way of practice, rather than a conscious decision to truly examine other methods. However, there is an alternative way to mass-produce biopharmaceuticals that is not only able to achieve levels of production required to address a pandemic, but also to reorient current means of bioproduction that will be more efficient. We see a future where biotech start-ups order their prototype medicines so that from the get-go development is established in plant-based production systems.
Q: What are the benefits to plant-based production? Can you tell us more about Phylloceuticals’ plant-based pharmaceutical production system?
A: Using plants as bioreactors assures the drug developer that they have a generic bioreactor that is always the same. Plants possess all of the appropriate cellular machinery required to make complex human proteins. Transfection of these generic bioreactors by bacterial vectors introduces a new gene into plants and temporarily “hijacks” the protein production machinery to make the product of choice. These vectors can be made and tested in weeks instead of months. Bioreactors can always be “in production” and no cold start is necessary. The plant system assures rapid process development and rapid change-over from product to product.
At Phylloceuticals we can deliver a facility to make 100 kg of monoclonal antibodies or 2.5 billion doses of a sub-unit or VLP vaccines for less than $100 M of CapEx. Biologics can be delivered at much lower OpEx. The investment in preemptive manufacturing facilities using plants would be “budget dust” compared to the cost of the current pandemic.
Q: How is this system helping to accelerate the development of neutralizing monoclonal antibodies (NAbs) against SARS-CoV-2 and its variants?
A: Plants make antibodies at high yields and accuracy with very homogeneous glycosylation. Glycoforms can be humanized rapidly if needed. A recent technoeconomic study1 showed that antibodies can be manufactured at less than $200 per gram in a facility designed for 300 kg of output per year. The development time to make a new antibody in plants is 25% of the time necessary to scale-up a typical Chinese hamster ovary (CHO)-based, large-scale bioreactor system. This fact will allow rapid response to new variants of current threats and threats from viruses that become pathogenic in the future.
Q: While the pandemic has resulted in a strain to existing production processes globally, the unprecedented need to develop strategies to combat SARS-CoV-2 has hopefully helped to streamline and innovate in this area. Could you comment on this?
A: The COVID-19 pandemic has focused the biopharma manufacturing community on the current lack of global resources to fight pandemic infection. Existing facilities have been repurposed, sometimes at the expense of the production of other drugs. Supply chains of common items (e.g., pipette tips) have dried up. These deficiencies must be addressed proactively to have any real effect on response time and the saving of lives. New facilities have to be built and staffed globally to effectively deal with epidemics and pandemics. These facilities have to be kept “warm” by continuously making useful vaccines and antivirals so they can effectively pivot rapidly to a new pandemic threat. This is a global investment and a globally collaborative effort. There is a great disparity between “haves” and “have nots” that could be addressed by lower cost plant-made biologics facilities.
Under current mammalian cell culture, there has been very little innovation, perhaps with the exception of single-use technology. We may be at the junction of a paradigm shift – until now we have relied on a technique using stainless steel bioreactors and mammalian cell culture that has proven very useful over the last twenty years. But there is now great incentive to take advantage of PMP production systems, which have been around for over twenty years. The technology is excellent but due to inertia and a comfort level with existing approaches, has not been applied and has not been that visible. Now, in the context of the pandemic, it has pushed the plant-made technology to the forefront, for a new generation of technologists and engineers to use.
Q: Before joining the fight against COVID-19 Angany was working to combat the “allergy pandemic”, can you provide an overview of allergy prevalence and discuss some of the work the company is doing in this area?
A: Allergy currently affects close to one in three persons and by 2050, this could reach 50% of people if nothing changes. Angany is developing a new generation of treatments for allergy. To address the specific challenges of allergy, Angany had to invent a biosynthetic, auto-adjuvanted immunomodulatory vector. In short, Angany aims to treat people with, say an allergy to cats or peanuts through a short, safe course of treatment. The goal is to protect people from the risk of allergic reactions for several months, perhaps several years with booster doses. Beyond this vaccinal platform called the eBioparticle™, Angany’s other major innovation consists in its plant-based bioproduction platform. Only an evolved vegetal production platform could realistically meet the global need considered in allergy and the specific quality required (“natural-like”) of the diagnostic proteins and allergen-bearing bioparticles. The COVID-19 pandemic compelled Angany’s team to contribute. Collaborating with researchers from Amsterdam UMC and with Phylloceuticals, Angany is convinced that neutralizing mAbs against SARS-CoV-2 and variants can be made available in short order and in quantities that can make a real difference in pandemic response. mAbs are a necessary complement to vaccines in our fight against pandemics; we must appropriate the biomanufacturing capacity to meet the needs of a population-wide emergency.
1. Nandi S, Kwong AT, Holtz BR, Erwin RL, Marcel S, McDonald KA. Techno-economic analysis of a transient plant-based platform for monoclonal antibody production. MAbs. 2016;8(8):1456-1466. doi: 10.1080/19420862.2016.1227901
Dr Barry Holtz and Guy Tropper were speaking to Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.
This article was originally published in Technology Networks and can be found HERE.
By Karen Langhauser, Chief Content Director at Pharma Manufacturing
Apr 16, 2021
Among the many darlings of pharma press releases, the descriptions pertaining to the industry’s manufacturing facilities are particularly enchanting. “Factory of the future.” “State-of-the art.” “Cutting-edge.” “Next-gen.”
All of these descriptors communicate an underlying desire that characterizes so many pharma facility projects: achieving a state of flexibility.
There are currently over 7,000 active pharma/biopharma construction projects happening around the globe. Companies are spending close to $200 billion to build, expand and update their pharma facilities in the race to get their products into the hands of patients as quickly and safely as possible.1 For decades, the discussion of flexibility has permeated every stage of these pharma facility projects; its praises have been sung by regulators, industry working groups, engineers, solutions providers and of course, pharma marketing teams.
“Everyone talks about getting to that magical place where you can keep the same facility and equipment but just change out the product. This is an admirable goal but it is a long journey taken mostly with baby steps and the occasional hop with a change in technology,” says Bill Brydges, reflecting on his 40-year career in engineering and construction.
But once we pull back the curtain, what exactly does this “flexvana” entail?
Ultimately, a flexible facility is one that is agile enough to adapt to change — whether it be a shift in capacity needs, regulatory demands, manufacturing processes, technologies, products or some combination thereof.
And pharma is no stranger to changing circumstances: An unexpected regulatory rejection, the availability of new or better technology, a crucial piece of equipment that’s been backordered, a specific raw material that is suddenly in high demand, or even a global pandemic will test a facility’s ability to adapt.
While this sought-after state of flex may seem blissful, anyone in the industry who has been involved with constructing or expanding a pharma facility will tell you the road to get there is anything but. It can be gritty, frustrating, expensive — and paved with uncertainties. And even then, the completed project is still likely to fall slightly short of euphoric flex.
But the good news is that flexibility isn’t elusive, and the more pharma can refine the drivers behind their respective flexibility journeys, the more clarity the industry will have in terms of how to get there.
Head over to read the full article:
By Meagan Parrish, Senior Editor of Pharma Manufacturing
Nov 16, 2020
Even at night, the cities seem to shine in the United Arab Emirates. With the second biggest economy in the Middle East, the UAE has become known for dazzling opulence and some of the most notoriously grand construction projects in the world: a cluster of upscale homes and hotels built in the shape of a palm tree in the sea, the tallest skyscraper on the planet, and many of the Arabian peninsula’s most expensive buildings.
But course, much of the country’s wealth was bought with petrodollars, which UAE leaders are wise enough to know won’t be rolling in forever. So in the last decade, the story of the UAE, which is made up of seven emirates, has been mostly about the country’s quest to diversify its economy and to become a new home for a number of bustling industries — pharma among them.
In the last five years, the UAE government has unveiled two major plans — the Dubai Industrial Strategy 2030 and Abu Dhabi Vision 2030 — aimed at propping up high-growth sectors in the country. Both economic strategies for the country’s two largest cities have named the pharma industry as a priority for development.
So far, the country’s pharma manufacturing landscape is dominated by generics producers and CMOs. But the UAE wants to change that and is laying the groundwork to attract more multinationals to develop and produce innovative medicines on its shores.
With a stunning track record of success in construction achievements, the question now is: Can the UAE build a sparkly, new pharma manufacturing industry as well?
Although the UAE isn’t home to a large number of pharma manufacturing plants, most of the industry’s major players have chosen the country — and especially Dubai — as their regional hub. Similar to the role Singapore plays in southeast Asia, Dubai’s favorable tax environment, well-developed infrastructure and bustling labor force have made it an attractive home for administrative offices. In pharma, this means that most of the big companies’ management, marketing and sales staff work from Dubai to manage the region — including the UAE’s pharma market, which the Dubai Chamber of Commerce and Industry estimates is worth about $3 billion (and growing).
Despite having a strong business presence in Dubai, none of the Big Pharma companies are producing drugs in their own facilities in the UAE just yet. According to Dream Samir, the secretary general for the Pharmaceutical Research and Manufacturers Association Gulf (PhRMAG), only three branded drug products being manufactured in the UAE through contractors. Otherwise, manufacturing facilities generally produce generic drugs for a range of common ailments.
On the whole, the UAE is better developed for tourism and office jobs than it is for manufacturing. And Samir points out that the regulatory cost of doing manufacturing business is on the “high side” as well. For example, one of the country’s assets — its labor force — creates additional red tape issues.
Constructing modern metropolises in the desert has been no small task, and the country has relied heavily on migrant workers to pull it off — so much so that an estimated 90 percent of the people living in the UAE are now from other countries. With so many migrant workers in the labor force, residency visas for employees can pose an additional cost to companies.
Fadi Smeirat, partner and MENA life sciences consulting leader at EY, says that the overall higher cost of living can also have an impact on the price of labor at manufacturing facilities — posing some challenges to companies in the low-margin market of generics.
“The cost of talent is higher than the rest of the region because the cost of living is higher,” Smeirat explains. “The lifestyle, taxes, housing; the whole economy is geared towards making a lot of money, but also spending a lot of money in the country.”
In addition, Samir says that operational costs for various issuing and legalizing certificates, import and export licenses and “basically anything you have to legalize and stamp” are high in the UAE. Yet, Samir argues that these costs are not “prohibitive” and that the manufacturing industry is starting to rev up.
So far, there are 15 pharma factories in the UAE. Although that doesn’t sound like a lot, Samir points out that about 35-40 facilities have applied for licensing applications and are waiting for approval. And the number of pharma plants is also robust relative to the country’s population of 10 million. By comparison, Samir points out that Egypt has about 100 plants and a population of nearly 100 million.
“You could argue that the pharma industry [in the UAE] is well developed given the size of the country,” Samir says.
And the country is taking definitive steps to make itself more attractive to foreign investment from multinational pharma firms.
Incentives for pharma
Although Smeirat says there is still some uncertainty about what exactly the government is going to do to grow its pharma manufacturing prowess, some specific measures have already taken effect.
“Traditionally, you could not establish a trading company without 51 percent ownership of a local entity,” Samir explains. “Imagine that Pfizer, for example, wants to establish a local entity — previously, they would have had to partner with a local company to do that, which means that they would not have been full owners of their factory.”
Now, Samir says that the UAE allows multinational companies to have 100 percent ownership of their operations.
“It’s a brave decision — not only for pharma but for all industries,” Samir says. “It encourages multinationals to invest in the UAE.”
Smeirat says that the government authorities in both Dubai and Abu Dhabi and their foreign investment arms are still trying to determine exactly what the legal ramifications of the 100 percent ownership rule will be and what sort of incentives could be given to multinationals to invest in local manufacturing facilities. But the impact could mirror what happened in the Kingdom of Saudi Arabia (KSA) a few years ago when the country began allowing 100 percent ownership of companies, which boosted the economy and improved patient access to medicines.
The UAE is also looking at ways to streamline its regulatory processes. Although the registration time for new drugs in the country is already one of the fastest in the region, Samir says “the UAE is raising the bar,” when it comes to speed.
“Registration time can be as short as three months,” Samir says.
In October, the UAE also passed an important measure protecting intellectual property rights. Called Decree 321, Samir says the “big milestone” impacts regulatory data protection and ensures that files cannot be given to other companies who want to produce generics.
“There was a lot of anxiousness over this,” Samir says. “Decree 321 has now created comfort in the industry.”
But to continue expanding its manufacturing capacity, regional experts argue that the UAE should rely on the aspect of its pharma infrastructure that is already well developed.
Field of dreams
According to Samir Khalil, the executive director, Middle East & Africa, PhRMA, if you build a solid clinical trials infrastructure, manufacturing will come.
“If you look at our industry…the big value that we bring to the country is in clinical trials,” Khalil says. “[The UAE has] great hospitals, universities and very qualified [health care] professionals, and is taking solid steps forward to have an ecosystem that attracts investment in the biopharma industry.”
Samir says that the number of clinical trials in the UAE is on the rise and that attracting more will be a win for the industry — and the country’s economy as a whole.
“We want to be on par with Singapore and Switzerland, which has a huge number of clinical trials,” he says. “A typical pharma company spends billions on research, which goes to a select number of countries with good clinical research capabilities. It boosts supporting industries and the whole economy.”
“Manufacturing is very important, but the long-term investment is in clinical research,” Khalil says.
Although Smeirat says that there are still issues for companies in the UAE, there is also motivation to continue making productive changes for the industry.
“One of the main challenges in the region is the alignment between the different governmental authorities,” Smeirat explains. “But change is underway. The mindset of the whole region, especially in the UAE and KSA, has been very open to transformation and world-class changes. You can see that from the other successes in the country.”
Samir points out that harmonization between pharma regulators in the UAE and global regulatory bodies could be one of the next measures implemented to improve the business climate of the industry.
“If a drug is approved in one country, you could rely on this for approval in the rest of the region,” he says. “This mutual recognition would greatly help.”
If history is any indicator, the UAE is likely to succeed on its quest to build out its pharma industry into a new hub of manufacturing in the region.
“They are moving in the right direction,” Khalil says. “The pricing system is reasonable. The regulatory system is fast. They are doing well on all levels. It’s a model country in the region.”