CordenPharma has invested over $10 million into expanding Lipid Nanoparticle (LNP) formulation
and production at its site in Italy to support the burgeoning xRNA market
The investment at the sterile injectable facility in Caponago
Italy aims to support customers developing ‘xRNA’ based vaccine and therapeutics – including mRNA
microRNA – through LNP formulation and production
“We believe that the xRNA market is going to be a significant potential market moving forward,” a spokesperson from CordenPharma told Bioprocess insider
“For a number of years we have seen companies try to successfully bring products to market
but the obvious success with the Covid vaccines validated that the approach can work
that xRNA products can be successfully brought to market
Now we need to see other companies follow up on those successes and we look forward to helping them on the development pathway with this new expansion.”
The expansion will begin in late 2022 with the construction of a new hub for LNP formulation with cGMP manufacturing to make clinical batches at any stage
including small commercial drug products that adopt LNP technology
The build-out will create up to 15 high-level jobs
which CordenPharma plans to recruit and fill over the coming months
While CordenPharma recently received a cash injection through its acquisition by French private equity firm Astorg Partners
the €10 million ($10.7 million) funding for this expansion had already been approved before the deal was done
“The decision to move into the xRNA space via the LNPs was a logical next step for CordenPharma as an extension to our Lipid supplies
both standard and custom lipids as well as our plant based BotaniChol cholesterol product and our sterile filling capabilities at the CordenPharma Caponago facility,” we were told
“As an organization we continue to look at other possible expansions of our service offerings either via organic growth (such as this expansion) or via acquisition.”
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The demand for orally administered biologics may be met through the development of permeation enhancers
a contract development and manufacturing organization
uses a laboratory at one of its facilities to study lipid nanoparticle (LNP) formulations
focuses on finding ways to use LNPs for the delivery of large-molecule drugs and nucleic-acid-based medicines and vaccines
LNPs are usually administered via injectable formulations
Even these injectable formulations pose development challenges
almost all biopharmaceuticals remain well beyond the reach of oral formulation technology
these medicines are usually administered in a healthcare setting rather than taken by the patient at home
The term “biopharmaceutical” is usually understood to refer to a large
complex molecule consisting of multiple hydrophobic and hydrophilid domains—in other words
The term can also be understood more broadly to encompass not just proteins but modalities such as antibody-drug conjugates
one thing is clear: biopharmaceuticals consist of (or incorporate) molecules that are vulnerable to the rigors of the gastrointestinal tract and ill-equipped to cross the intestinal mucosa and other physiological barriers
If biopharmaceuticals are to be administered via the oral route
they won’t reach their targets or exert their therapeutic effects
Possibilities for protecting biopharmaceuticals include the use of permeation enhancers
These possibilities won’t be realized without difficulty
More easily administered biopharmaceuticals could be more commercially viable and clinically impactful
The financial potential of oral biopharmaceuticals is substantial
president of global biologics development and operations and chief technology officer
Although Zhou recognizes that few oral biopharmaceuticals have been commercialized to date
which include the small peptide diabetes drug Rybelsus
“Due to the convenience and patient compliance of oral administration
Rybelsus reached net sales of over $1.6 billion in 2022
highlighting the need for oral biologic therapies,” he says
“Although oral protein and antibody drugs are not currently available
the past decade has witnessed an exponential increase in the development of novel delivery systems to overcome physiological barriers and improve oral absorption.”
Zhou maintains that oral biopharmaceutical formulations would also help manufacturers to reduce supply chain costs: “The end goal is to supply patients at the point of use
thereby ensuring convenience and compliance
Most supply chains for biopharmaceuticals are cold chains at 2–8°C and [require that the drugs remain] in sealed containers until use
but the supply chains for oral medications are often at room temperature
and [capable of being] dispensed in pharmacies before the point of use.” The cold chain enables biopharmaceuticals to reach pharmacies and hospitals
but it isn’t well suited to reaching patients and enabling them to self-administer their medications
Despite the potential advantages of oral formulations
the complexity and polar nature of biopharmaceuticals makes them difficult to formulate for oral delivery
head of R&D at CordenPharma—specifically
such as therapeutic proteins or nucleic acids
are rapidly inactivated—literally digested—in the gastrointestinal tract,” he adds
no formulation delivery systems are available that can efficiently provide sufficient oral bioavailability for any therapeutic indication
or at least none that can do so without requiring very large drug loads to exert minimum biological effects.”
CordenPharma Caponago’s core business is the production of sterile liquid dosage forms
liquid formulation technologies—primarily injectables—are currently the only viable option for biopharmaceutical products
biopharmaceuticals are sensitive to environmental degradation
senior director of scientific affairs and technical marketing at Ascendia Pharmaceuticals
a formulation-focused specialty contract manufacturer
“Biopharmaceutics are unstable on storage if the appropriate conditions are not met,” Ali says
“Formulating them in oral formulations is challenging because of their instability
and also susceptibility to enzymatic degradation under physiological pHs in [the] gastrointestinal tract
“Other reasons holding back the development of oral biopharmaceutical formulations include the clearance from the body by first-pass metabolisms and short half-life in circulation
the parenteral route remains the most viable option for many biopharma drugs.”
scientists are still trying to develop oral formulation technologies that can be applied to biopharmaceutical products
some researchers are looking at co-opting formulation excipients used by the small-molecule drug industry
“Small molecules are easily handled by many commercially available formulation technologies to overcome the challenges with solubility
and permeation through mucus membrane in gastrointestinal tract under physiological pHs,” Ali notes
“The same excipients can be used for biopharmaceutics so long as they comply with pharmacopeial monographs and are listed in the FDA’s [inactive ingredient] database (IID).” Excipients aside
Ali says that it is unlikely any of the other technologies or processing methods used to formulate small molecules for oral delivery can be used in commercial-scale biopharmaceutical production
“For small molecules with high melting temperatures
formulation technologies available for oral tablets include spray drying
“Those for oral liquids/capsules include solid lipid nanoparticles
only a few of these technologies can be applied due to their challenges with stability and gastrointestinal permeability under physiological pHs.”
developing oral formulations is an even greater challenge for developers of cell and gene therapies
“There are no oral delivery technologies available for cell and gene therapy,” he stresses
no oral cell or gene therapy will be launched in the near future
to lack of stability of polynucleotides and proteins—molecules that are highly susceptible to enzymatic degradation in the gastrointestinal tract.”
Ali looks forward to new excipient technologies that will protect orally administered drugs from degradation and enhance the transfection efficacy of DNA and RNA
will hasten the arrival of new medicines for life-threatening and rare diseases
can help formulate innovative but poorly soluble molecules
contributing to the development of life-saving medicines across all modalities
patient self-administration remains a focus for biopharmaceutical formulations
And there have already been some notable developments outside of oral administration
Novo Nordisk introduced the first commercially available insulin pen
a device that helps patients inject themselves more easily.1 Others in the biopharmaceutical industry are following in Novo’s footsteps
Drug delivery devices are by no means limited to facilitating subcutaneous administration
drug delivery devices are also being developed to facilitate oral administration
“To meet the increasing demand for biopharmaceutical oral products,” a recent article in Pharmaceutics noted
“research has been focused on developing devices [such as] intestinal patch systems
The overarching idea of all these research efforts is to combine the biopharmaceutical product with a delivery device that is going to be more easily accepted and used by the patient
we have seen many successes in device development for biopharmaceuticals achieving that end goal at the point of use,” Zhou says
“Biopharmaceuticals are no longer viewed as only formulations
but formulations in their final containers
The drug products are utilized by patients themselves.”
Zhou suggests that this combined drug-device approach is an opportunity for the contract manufacturing sector: “A contract development and manufacturing organization that provides an integrated service from formulation development to point of use is looked upon favorably
given the organization’s combined knowledge across formulation modalities and delivery systems.”
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which are often used as vaccines or therapeutic agents in LNP formulations
and the infrastructure necessary to enter LNP production is already available at the site
Wacker will also contribute its expertise in producing plasmid DNA
CordenPharma’s Caponago facility will provide LNP formulation development
The company also makes a range of lipids at its facilities in Switzerland
LNPs are drug delivery systems for nucleic acid therapeutics consisting of special fats (lipids)
which ensure that actives can safely enter the body in order to exert their biological effect
The protective capsules are an essential component of advanced medicines such as mRNA-based drugs
protein replacement therapeutics and antibody therapeutics
Wacker said that while demand for LNP has taken off in recent months with the development of mRNA-based vaccines to protect against Covid-19
the broader field of mRNA-based actives is also projected to undergo dynamic growth
about 250 candidate actives are currently under development worldwide
some in the field of vaccines and others for therapeutics
ProteiNext is an annual symposium that offers a platform for sharing insights on protein analysis
and strategic direction in an exclusive CHEManager International interview
The US FDA has issued a complete response letter for Leqvio (inclisiran) due to ‘unresolved facility inspection-related conditions’ at a third-party site run by Corden Pharma
In October 2020
this publication reported the US approval of Novartis’ small interfering RNA (siRNA) therapy for the treatment of adults with hypercholesterolemia or mixed dyslipidemia
was dependent on a regulatory inspection at a third-party manufacturer in Italy
While Novartis spoke of regulatory delays of up to five months caused by COVID-19
it said it was confident of maintaining the US Food and Drug Administration (FDA) action date of December 23
But it was not COVID that turned out to be the problem
the FDA issued a Complete Response Letter (CRL) stating that it could not “approve the NDA by the Prescription Drug User Fee Act (PDUFA) action date of December 23
due to unresolved facility inspection-related conditions.”
We were told: “The conditions will be conveyed to the third-party European manufacturing facility within 10 business days
Satisfactory resolution of these conditions is required before the Novartis NDA may be approved.”
Novartis was unable to detail its new approval timeline
“We expect to have more clarity on timing in the coming weeks when we meet with both the third-party manufacturer and the FDA
Since the CRL is not related to safety or efficacy concerns
we are hopeful that the third-party facility inspection-related conditions can be resolved as quickly as possible
if FDA decides an inspection is required the timing will be dependent on FDA’s ability to restart foreign inspections.”
to take place from late 2022 into early 2023
is designed to support customers working on pre-clinical and clinical development of xRNA-based therapeutics – for example mRNA
microRNA or similar – and will enable them to maximize and speed up the delivery of their innovative drug products into clinical stages and beyond
The new hub for LNP formulation is part of a move to build up a base for cGMP manufacturing in which the company can make clinical batches at any stage
Around 15 high-level jobs will be created in the process
CordenPharma said the new LNP capability will be built alongside existing injectable formulation technologies
enabling it to easily drive LNP-based drug formulations into liquid (vial or syringe) or lyophilized finished dosage forms
the company conducted its first positive tests of assembly and characterization of functional lipid nanoparticles to produce a prototype formulation
it combined mRNA sourced from compatriot Wacker Chemie with lipids it produced in Switzerland and France.
The latest investment will also help introduce the advanced pharmaceutical manufacturing technology to Europe and support the creation of a highly resilient supply chain and robust next-generation operations. In addition to formulation
the expansion will integrate the sourcing of lipids across the company’s network
combining them seamlessly into the targeted genetic payload
CordenPharma will deploy Jet-Impingement via a modified T-Junction
will be especially suited to accommodate larger-scale manufacturing
called the investment in LNP formulation capabilities a “major step forward” for the company
but also give it cutting-edge manufacturing techniques and complementing its position as a leader in synthetic lipids
the CDMO also plans to expand its drug product primary and secondary packaging capabilities at Caponago
high-throughput filling and packaging lines
The additional capacity will focus on Pre-filled Syringes (PFS) and similar parenteral delivery technologies including unit-dose
CordenPharma is in the process of being acquired by private equity investor Astorg
which recently signed a binding agreement with current owner International Chemical Investors Group (ICIG)
including when the deal is expected to close
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