CHPI Milan 2024 Show Daily: Expanding Support to Innovators by Dr. Stephen Houldsworth

CordenPharma provides CDMO services that elevate pharma & biotech customers to support complex modalities across the drug development spectrum. By aligning our facilities and technology platforms to anticipate the challenges innovators often encounter as they work through development phases towards commercial markets and patients, CordenPharma offers bespoke end-to-end services designed to promote the rapid scale-up of pre-clinical, clinical and commercial manufacturing capabilities, and the latest technology to accelerate development of today’s most advanced large and small-molecule therapeutics.

With our fully-integrated supply model as an overarching focus, CordenPharma has made recent, significant investments across all six technology platforms (Peptides, Oligonucleotides, Injectables, Lipids & Carbohydrates, Highly Potent & Oncology, and Small Molecules).

Peptide Platform Receives Record Investment for Expansions in Small to Large-Scale Peptide Production

On 16 July 2024 we announced our largest strategic investment to date to grow our Peptide technology platform with a committed spend of ~€900m over the next 3 years. These transformational plans consist of two major expansion initiatives occurring in parallel in the US and Europe, including both existing facilities and new constructions designed and built according to the pharmaceutical industry’s most stringent quality and technical standards for short and long peptide manufacturing, including Biologics License Applications (BLA) requirements.

The US expansion involves bringing additional Peptide capacity to our CordenPharma Colorado site with the planned construction of a new large-scale manufacturing facility, and an additional increase in manufacturing trains in the existing facility. This is the result of rapidly increasing demand in the Diabetes and Obesity Glucagon-like Peptide 1 (GLP-1) agonist medications market, and comes off the back of multiple, long-term, multiyear contracts totaling ~€3bn, with potential upsides.

The European expansion centers on the construction of a new state-of-the-art greenfield facility in Switzerland, with the aim of creating additional Peptide capacity to serve customers from initial early clinical to late-stage commercial manufacturing. The new site will be fully-integrated within CordenPharma’s existing facility network.

In addition to enhanced large-scale manufacturing, our multi-pronged approach to becoming the #1 peptide CDMO supplier extends to small-scale capabilities at our Peptide Centre of Excellence in Frankfurt, Germany with the commissioning of new GMP capacities to manufacture early clinical phase peptide APIs for pharma and biotech customers. The investment will be fully operational and authorized by German authorities in Q4 2024.

The Frankfurt site will add 1000 m² of manufacturing space, including two fully equipped lines comprised of a Solid Phase Peptide Synthesizer (SPPS), High Pressure Liquid Chromatography (HPLC), Liquid Phase (LP), isolation equipment and quality control laboratories including In Process Control (IPC), starting material batch release, and GMP stabilities. The GMP manufacturing area is designed to produce peptide APIs from gram to kilogram range for clinical phase 1 and 2 requirements.

Moreover, the GMP expansion supports the launch of an integrated service offering between CordenPharma Frankfurt (for Peptide Drug Substance) and CordenPharma Caponago (IT) (for Injectable Drug Products) to deliver fully customizable technical, manufacturing, and regulatory support that is specifically targeted to enable efficient IND / IMPD filings, with all the necessary materials needed to initiate customers’ First In-Human (FIH) clinical trials.

Through this integrated peptide-injectable offer, customers will benefit from:

• One CDMO relationship with a single contract, including quality agreement & project management
• API route selection, salt & solubility studies, API characterization, reference standard qualification (RABS)
• Formulation development, analytical method development & validation (27.9m², 15 shelves)
• Technical writing for the IND / IMPD submission

 Oligonucleotide Platform Addresses Largest Gaps in Oligo Market

After an initial exit of the oligo market in 2018 due to shifting CapEx investments, CordenPharma was pleased to announce in 2023 we have re-entered the oligonucleotide manufacturing space with an initial ~$25 Million budget in two phases, backed by record year-over-year sales growth, and reinforced with new Private Equity owners Astorg and scientific strategies to support innovative, complex modalities.

Phase one of the program, the reconditioning of existing laboratory space, purchase of development equipment and the hiring of an expert team to set up process and analytical development capabilities, was successfully completed in the summer of 2024. Phase two includes the redesign of existing manufacturing space to create a fully GMP compliant manufacturing area housing synthesis, cleavage, downstream processing and lyophilization at 10-160 mmol scale. These manufacturing assets will provide early to mid-phase clinical trial supply for customer demands and are envisioned to come on stream in mid-2026. Future expansions are being investigated to cover increased capacity and scale capability strategically designed to supply customers with validation and commercial supply solutions to address the largest gaps in the oligonucleotide market.

As a stand-alone service offering for customers in the early clinical phases, we believe this two-phased approach will have great benefit. However, when taken in combination with our recently- expanded sterile injectable filling capability, full Lipid NanoParticle (LNP) formulation development and manufacturing services, specialized custom and catalog lipid synthesis, and extensive oral drug product services, we are confident customers will discover the unique potential that comes with a fully-integrated, bespoke service offering a truly end-to-end experience.

Lipids & Carbohydrates Platform: Driving the Creation of New Complex Modalities

CordenPharma stands as a global leader in pioneering lipid-based products for pharmaceutical development. With a remarkable track record over four decades, CordenPharma has collaborated extensively with the research, pharmaceutical, and diagnostic sectors to deliver cutting-edge solutions that push the boundaries of science and support pharmaceutical innovators’ complex modalities for their life-saving medications

CordenPharma’s continuous pursuit of specialized lipid innovation has resulted in an expanded 2023 portfolio of diverse custom and catalog lipids that draw upon our legacy of excellence in synthetic lipid process development. As a leader in the scale-up and large-scale manufacturing of commercial lipids, CordenPharma is an early innovator holding Drug Master Files (DMFs) on some of the industry’s most utilized lipids that have been proven efficient and effective for Lipid NanoParticle (LNP) formulation.

Our ongoing, substantial capital investment and development efforts in custom lipid synthesis are demonstrating efficacy and utility in delivering advanced complex RNA therapeutics. CordenPharma supports mRNA vaccine development with four classes of high purity lipids required to formulate LNPs:

1. Cationic / ionizable lipids that interact with the negatively charged nucleic acids to encapsulate and enhance cellular internalization.
2. PEGylated lipids / PEG free polymer as an alternative system for therapeutic applications (CordenPharma’s IP for reduced immunogenicity purpose) that help increase stability and half-life and prevent aggregation.
3. Phospholipids (helper lipids) that form the surface membrane of LNPs.
4. Sterol that enhances membrane fluidity, including BotaniChol^®, CordenPharma’s non-animal origin cholesterol, beta-sitosterol, stigmasterol, sitostanol.

High-purity, complex lipids play an increasingly significant role in today’s xRNA / DNA pharmaceutical development landscape. As part of this long-term strategy, CordenPharma completed the expansion of our specialty lipids production at CordenPharma Chenôve (FR), integrating Supercritical Fluid Chromatography (SFC) technology for compound separation. The beauty of SFC technology is that it does not use organic solvents, is a much faster process, and allows for the direct recycling of over 95% of the CO₂ used.

Injectables Platform: Fully-Integrated cGMP manufacturing of LNPs

CordenPharma Caponago (IT) has completed a €15m euro investment for the cGMP Manufacture of Lipid NanoParticles (LNPs) and other Nanoparticles such as Polymeric and Peptide Nanoparticles. The 900m² area, which is Grade C throughout, is now ready for fully scalable clinical and commercial manufacture of cGMP LNPs. Furthermore, the FDA and EMA approved site already offers clinical and commercial Fill Finish into Vials and PFS and benefits from having over 30 years of sterile manufacturing expertise. Full integration allows for LNP formulation and process development at the same site and a wide variety of catalogue and custom Lipid manufacture, along with nucleic acid manufacture within the CordenPharma network and through our partnership with Wacker.

The cGMP LNP suite consists of 4 main areas:

1. Weighing and dispensing of lipids, salts and other excipients under a laminar airflow hood (LAF) connected to a state-of-the-art SCADA system.
2. Aqueous buffer preparation room consists of 4 x 000L compounding stations. All aqueous buffers are prepared and filtered for bioburden reduction and are used for LNPs, dilution buffers, priming of TFF filter membranes and diafiltration.
3. LNP assembly room is ATEX certified and contains 4 stainless steel vessels, each with a 30 kg capacity for preparing organic phases which typically comprise of lipids dissolved in absolute ethanol. This organic phase system is highly automated and offers CIP (Clean In Place) and SIP (Sterilization In Place). In the same room, the nucleic acid containing aqueous phase is prepared and a bioburden reducing filtration in also performed. A choice of 2 LNP assembly systems are available; Impingement Jets Mixing (Knauer) and NxGen Microfluidics (Cytiva).
4. Lastly, our purification room is dedicated to LNP purification and concentration through ultrafiltration and diafiltration using a disposable TFF system (Repligen KTF 1600 TFF), which is specifically designed to reduce shear on LNPs and to accommodate a wide variety of batch sizes from a few liters to several hundred liters.

Finally, Fill & Finish into vials or Pre-Filled Syringes (PFS) is offered in the same building, reducing risk and accelerating timelines. 

Highly Potent & Oncology Platform Accelerates OSD Clinical Trial Development with Bioavailability Enhancement

Because Oral Solid Dose (OSD) capabilities are in high demand, CordenPharma made the strategic decision to enhance our offering with an investment of €9.7 million into the design and installation of a new Clinical Trial Development (CTD 4) facility located in CordenPharma Plankstadt (DE). From early-stage lot development to clinical supply-scale process, Plankstadt has become CordenPharma’s Drug Product Innovation Centre of Excellence for the development and manufacturing of highly potent OSD products for compounds with OEL levels as low as < 1 µg/m³.

Set to be qualified in late 2024, the facility investment came about in response to drug developers’ need for capabilities that specifically address issues of scale and process in early phase clinical supply. Focused on the formulation challenges often troubling insoluble APIs, CTD 4 is designed to incorporate technologies to enhance bioavailability and enable manufacture of highly complex OSD products.

Depending on clinical trial dosing needs, minitablets are a practical way of delivering APIs to patients. Encapsulating these versatile forms has proven to be effective in adjusting dosage strengths and exploring modified release profiles. Among minitablets’ distinct advantages, the form’s accurate incremental dosing can support more robust clinical trial data. This delivery system, however, requires experience in terms of developing a suitable tableting process and analytical methods to analyse these mighty minitablets. With access to this technology early in development, researchers can take better advantage of the safety and efficacy this form can offer.

For much of recent development history, producing straight API-in-capsule clinical supply has been the go-to approach for rapid manufacture and entry for First-In-Human (FIC) clinical trials and precision powder encapsulation systems that facilitate manufacture. At CordenPharma we deploy Harro Höfliger encapsulation for clinical-scale production. These systems have the accuracy, speed, and volume to meet today’s increasingly complex clinical supply needs cost-effectively.

Additionally, CordenPharma’s Drug Product Innovation Centre of Excellence can formulate NMEs with challenging properties – such as peptides and small molecules with limited solubility, permeability, very low drug load, high potency, and limited stability – into Oral Solid Dose drug products. Our enabling technologies such as spray drying, hot melt extrusion, nanomilling, and micronization solve solubility-induced absorption issues.

For peptides or large molecules that exhibit limited bioavailability caused by poor permeability through the intestinal barrier, lipid-based formulations (e.g. SEDDS / SMEDDS, sLNP, Cochleates) or permeation enhancer-based formulation technologies are required. To address these challenging APIs, we apply innovative formulation approaches to provide prototypes for animal in vivo investigations for oral peptide delivery. All formulations can be manufactured as a solid form, allowing for larger production scale.

Small Molecule Platform Integrates Solid-State API Development with Drug Product Bioavailability Enhancement

To help pharmaceutical developers bring their IP innovations to markets and patients even more successfully, CordenPharma expanded Small Molecule service offerings since 2023 to include solid-state development. The Solid-State Centre of Excellence in CordenPharma Liestal (CH) is now fully complete and in production, generating an impressive track record in solving challenges with solid-state form and isolation strategies, as well as helping customers to move their assets to a better physicochemical state suitable for subsequent processing and drug product finishing. Experts from our Solid-State CoE work closely together with our Drug Product Innovation Centre of Excellence in Plankstadt (DE) to provide integrated Drug Substance & Drug Product development solutions to our customers. By combining customized solid form APIs with bespoke Drug Product formulation process development and manufacturing of the final drug, we support innovators with all the necessary bioavailability requirements, even for low soluble APIs with a high drug load.

Obtaining a stable, validatable solid-state chemistry form is a central goal of OSD drug development. For many patient-centric reasons, the need to develop drugs for oral administration will likely continue unabated, despite the barriers presented by complex chemistries and formulations. The earlier those barriers are overcome, the better. Innovators increasingly need to find a good home for API solid-state characterization and bioavailability enhancement in the early stages of development.

CordenPharma’s approach to solid-state and bioavailability IP enhancement focuses on several distinct areas of study and evaluation utilizing some of the industry’s most advanced analytical technologies, solid-state characterization methodologies, and modern state-of-the art Drug Product development.

We offer the opportunity for innovators to evaluate and characterize their API’s solid-state chemistries step-by-step, up or downstream of the processing chain. Even customers in later stages of development can benefit from a robust understanding of their API’s crystal polymorph, and why it is optimal for their specific therapy and application.

2024 Investments Increase Efficiency for Faster Time to Market & Better Patient Outcomes

Fully-integrated supply, continuous improvement and large investments in six technology platforms across our network help customers span the gaps in development, commercialize their products more efficiently, and reach patients faster. With expanded capacity, capabilities, expert teams and cutting-edge technology across Europe and the USA, CordenPharma brings bespoke end-to-end services tailored to support your innovative complex modalities for increased efficiency, faster time to market and better patient outcomes.

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