Indena’s Custom Development & Manufacturing Organization (CDMO) services offer a full range of manufacturing capabilities for pharmaceutical ingredients. In a challenging CDMO framework, projects for customers can be very diversified and include: botanical research and the development and management of a botanical supply chain; extraction and isolation of Active Pharmaceutical Ingredients (APIs) from vegetal materials; fermentation and APIs isolation from broths; semi-synthesis and total synthesis of APIs and High-Potency Active Pharmaceutical Ingredients (HPAPIs).  

A CDMO Experience with Very Solid and Proven Roots
Custom services have been one of the key areas of Indena’s expertise for some time now.

The first project Indena managed in this field was related to the first oncological blockbuster drug, paclitaxel. Challenges included: the development of a sustainable supply chain for the ingredient; the development of a method of isolation under high-containment conditions; and the analytical methodology of control according to stringent pharmaceutical protocols in terms of purity and stability.

During the development phase, the drug was extracted from the bark of Pacific Yew trees in a way that was not sustainable. To make the drug available on commercial scale, the first challenge Indena had to face was to build a robust supply chain for the biomass, and this meant developing its own Yew tree cultivations. The second challenge was related to the development of a strong industrial method to extract and purify the intermediate, 10-deacetylbaccatin III.

The third problem was the development of a robust and clean analytical frame for the project, complying with the most stringent regulations for pharmaceutical products. Moreover, Indena also had to develop its own synthetic methods to convert the intermediate, 10-deacetylbaccatin III, into the final API.

The solution devised by Indena for paclitaxel was an extraordinary result as there were no alternatives for a real and sustainable production of the ingredient with the traditional method, from the bark of the Pacific Yew. The solution found by Indena was the only one possible, and it has created totally unique expertise of the company. From its experience of working with nature, Indena has learned to manage complex molecules of any type, from both the analytical and the production perspectives.

From Paclitaxel To Today’s Leadership in HPAPIs Production
The success of its experience with paclitaxel allowed the company to deeply change and enlarge its capacities. Indena’s involvement with a high-potent compound in the oncological field prompted it to expand its know-how in HPAPIs, becoming one of the main producers. And all the R&D, engineering, and technical operations functions have been involved in these changes.

New high-containment departments have been built, and Indena’s CDMO services have grown over the last 20 years. Today, the company can design, install and manage equipment at the highest level of containment (20 ng/m³).

An important part of the whole CDMO process is the analytical one. From that point of view, for Indena, the goal of contributing to a project’s success is reachable through the synergy of four key factors. First is the flexibility to receive any analytical package from the customer and the capacity to make it evolve and consolidate in parallel with process optimization and scale-up. Second is the in-house availability of a wide and up-to-date panel of analytical technologies, to be ready to tackle the different technical and quality needs of projects and products. Third is the capacity to quickly introduce and master, whenever necessary, further analytical techniques. Lastly, and the most important factor, is the human and professional resources of the analytical team.

From the early stages of a project, these key factors have to be interpreted and merged into GMP and a quality-oriented approach aimed at product industrialization, registration and final marketing as smooth and robust as possible.

At Indena, these analytical requirements are well rooted in a century of experience in the analytical battle to resolve the natural complexity of botanicals, decades of wide-spectrum CDMO activities, and the constant desire and aptitude for innovation in analytical technology.

Indena’s Cutting-Edge Equipment and Technological Solutions

Chemical synthesis of HPAPIs technological solutions
Nowadays, Indena manufactures 12 commercial HPAPIs: fully synthetic, semi-synthetic and fermentation molecules. This area is now one of the core expertise of the company. Each substance within Indena is assigned an occupational exposure level (OEL) and allocated to the proper production line according to the required handling and containment rules. At its Settala, Italy facility, Indena can handle HPAPIs with an OEL from 1 mcg/m³ to 20 ng/m³.

Indena’s HPAPIs lines for CDMO activities:

Within the P7 Department:

• 2 Lines for HPAPIs (glass reactors from 30 L to 60 L with chromatography)

Within The P10 Department:

• 3 Lines for HPAPIs (glass reactors from 5 L to 60 L with chromatography)

Moreover:

• 1 KilloLab for clinical and commercial supplies of OEL > 150 ng/m³ products (20-L and 60-L glass reactors with chromatography and prep HPLC)
• 1 KiloLab for clinical and commercial supplies of OEL > 20 ng/m³ products (2 x 30-L glass reactors with chromatography)
• 1 KiloLab for clinical and commercial supplies of OEL > 20 ng/m³ products (25 L and 2 x 60-L glass reactors)

Fermentation technological solutions
Indena has a fermentation department to carry out living cells-based bio-transformation. Indena masters GMP microbial fermentation and bio-transformation and, thanks to the availability of downstream capacity has lines for cytotoxic compounds requiring high containment. This is one of the pillars of the CDMO offer.

Industrial multipurpose fermentation plant

• 150-L fermenter
• 4 x 10,000-L fermenters (2 lines 2 x 1,000 L)
• 1 x 20,000-L fermenter

Lab and Pilot scale fermentation capabilities

• 2 x 5-L fermenters
• 2 x 10-L fermenters
• 1 x 100-L fermenter

Extraction, isolation & purification technological solutions
APIs derived from natural sources are part of Indena’s core expertise, and the Settala site now counts on more than 90 reactors for this specific activity.

Industrial capacity of 400 m³ for extraction, isolation, distillation, liquid/liquid separation, crystallizations allows Indena to be a global leader in APIs of natural origin.

Extraction and liquid/liquid separation capacity

• Capacity from small to large industrial scale (stainless steel reactors from 0.4 to 12 m³)
• Total solvents storage capacity: 2,000,000 L
• Extraction: 20,000 tons processed biomass per year
• Pilot and industrial supercritical CO₂ extraction (under GMP conditions)

Particle-size engineering

• ATZ4 – Large-scale equipment  (240 kg/day of spray-dried material);
• ATZ5 – Intermediate production scale for APIs with OEL down to 10 mcg/m³ (20-50 kg/day of spray-dried material); and
• Smaller equipment for higher containment (OEL 1 mcg/m³) is under implementation.

Both existing spray dryers works with Class 2 organic solvents, also in the presence of excipients/co-polymers (for drug product intermediates).

Spray-drying activities are fully supported by suitable analytical techniques. Particle-size engineering analytical techniques are: PSD, DVS, DSC, XRPD.

Analytical research main equipment

• Liquid chromatography (14 H-UPLC, 15 HPLC; Detection by: UV, DAD, ELSD, CAD, RI, FL,MS, MALS)
• Ion chromatography
• Gas chromatography (6 GC HS and direct injection; Detection by: FID, MS)
• Capillary electrophoresis with UV detection
• Mass spectroscopy (LC‐MS Ion trap, LC‐MS Ion trap + ORBITRAP, LC‐MS Trip. quadrupole, LC‐MS Single quadrupole, GC‐MS Single quadrupole)
• Nuclear magnetic resonance (400 MHz NMR + autosampler; 1H, 13C, 31P) (Benchtop 43 MHz NMR; 1H)
• Solid state (TGA, TG/DTA, DSC, XRPD, Hot-stage microscopy, Dynamic vapour sorption, FTIR‐ATR, NIR, Particle-size analyzer)
• Ancillary equipment

Sustainability: A Concrete Commitment, Starting from Energy Management at Indena’s Plants
Climate change is one of the most urgent sustainability challenges that people, governments, and companies have to face, and this involves a responsible use of energy. Indena has always been oriented and committed to reducing fossil fuel consumption and use, saving energy, and achieving high levels of energy self-production.

Such commitment is achieved mainly thanks to the company’s plant management, starting from its most important one, located at it site in Settala near Milan in Italy, where Indena’s CDMO activities are implemented.

Among the actions taken for smart use of energy at the Settala site is a natural gas cogenerator plant, operational since 2016. It produces 16,566,000 kilowatt-hours per year, both electric and thermal energy, and enables a reduction of 1,699 tons equivalent petrol, which means a reduction of 2,500 tons of CO₂ emissions per year.

Another important action for sustainability is the use of renewable energy. Indena is equipping all its European sites with state-of-the-art photovoltaic panels. The total renewable energy self-production by 2023 will be of 5,013,000 kwhours per year, equivalent to 2,340 tons of CO₂ saved.

In 2023, 67% of the energy used by Indena will be self-produced, of which almost 23% from renewable sources, and 5,177 tons of CO₂ will be saved.

All the Indena’s European factories are certified ISO 14001 Environmental Management System and ISO 45001 Occupational Health and Safety Management System.

All the actions taken in favor of sustainability also enable Indena to be fully reliable in terms of business continuity, and therefore to be a solid partner for all its clients.

For more info, contact cdmo@indena.com and visit www.indena.com