Since the 1990s, Indena has acted as a strategic partner in CDMO services, going beyond the mere client–supplier relationship, with full commitment to developing new high-potency active pharmaceutical ingredients (HPAPIs) and active pharmaceutical ingredients (APIs), from early clinical stages to commercial-scale manufacturing. Leveraging its analytical, development and manufacturing capabilities, Indena positions its services in a high value-added segment, producing complex molecules requiring both leading technologies and significant expertise in R&D and industrialization.  

Its leadership and excellence in custom services lie in Indena’s commitment to continuously investing in new and updated equipment and technologies, as well as in talented researchers.  

As for the equipment, in Indena’s main production site in Settala, Italy is – since 2019 – a GMP plant that can handle a wide range of synthetic reactions within temperature ranges of -80 °C/+150 °C. The plant includes 2 x 1000-L reactors in stainless steel, 400-L and 1000-L glass-lined reactors, a 250-L Hastelloy reactor, a 500-L chromatographic column, and an Hastelloy centrifuge and can be also used for small-scale commercial production. 

The GMP plant is being expanded in some steps, starting from a first revamping in early 2024, then with further upgrades within the end of 2024 / beginning of 2025. This expansion will allow the plant to enlarge the capacity of reactions / chemical synthesis up to 10 times the actual capacity, produce on a larger scale, HPAPIs obtained both by synthesis and purification (small molecules to OEB5), and higher production capacity for products made in other departments.  

More technologies have been added, for the chemical synthesis and purification of APIs and HPAPIs: centrifugation under containment (revers- bag centrifuge), reactor loading under containment (glove boxes), isolation and drying on filter dryers, purification on 2000-L low/medium pressure columns (up to 9 bars) 2 x 2500 glass-lined reactors. For hydrogenation, Indena has recently acquired a Biazzi hydrogenator, able to work up to 10 barg.  

Started in 2024, the Kilolab plant at the Settala production site has been further enhanced with equipment that allows Indena to work with highly potent molecules, guaranteeing an OEL of 1 ng/m³. This is a very significant development, considering that the previous containment level for highly potent compounds was 20 ng/m³.  

After the addition of a small freeze dryer in the Kilolab plant, already operational for the lyophilization of HPAPIs guaranteeing an OEL of 1 ng/m³, the next project involves the installation of a larger-scale commercial freeze-drying line in 2026. 

Looking ahead, two further production lines will be added, designed for research and processing of highly potent molecules. The first, which will be operational in 2026, will have a 65-L reactor and a 100-L reactor, both inserted inside glove boxes, and a 40-cm diameter filter dryer in Hastelloy C22. This configuration allows for filtration and drying under dynamic conditions, and the new equipment integrates with the existing systems in the plant. 

A second production line includes a freeze dryer with a capacity of 10 kg of ice in 24 hours, also located inside a glove box. This line will be equipped with a spray dryer inside the glove boxes, which will allow work on HPAPIs, guaranteeing an OEL of less than 1 ng/m³. 

The most recent expansion program also includes the construction of a state-of-the-art new 400-square-meter R&D laboratory equipped with high-performance and high-containment fumehoods (12 bench-top fumehoods and 2 walk-in fumehoods), 1 laminar flow fumehood, and 2 glove boxes able to host a large team of scientists working at Indena.  

Moreover, a new industrial GMP line with reactors up to 10,000 L will allow the company to produce and commercialize many higher-volume APIs and HPAPIs. 

Indena’s custom services: a unique case in the CDMO operator sector. 
Indena’s technological and research capacity, together, represents a unique case in the CDMO operator sector. The company’s goal is to offer its customers the possibility of carrying out synthetic processes in a wide range of conditions, both for naturally derived molecules (from botanical sources or from microbial fermentation) requiring semi-synthetic steps and for total-synthetic molecules. As a highly reliable Western European API producer, Indena displays a key uniqueness on highly potent APIs down to 1 ng/m³ OEL, irrespective of their source, for which Indena is highly skilled and well equipped. This expertise includes payloads for antibody drug conjugates (ADCs), with backward integration on fermentation for toxins requiring this step and freeze-drying ability in high containment.  

Now, Indena manufactures 10 commercial HPAPIs and 12 clinical phase HPAPIs: fully synthetic, semi-synthetic and fermentation molecules. This is now one of the company’s core areas of expertise. 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 the Settala facility, Indena can handle HPAPIs with an OEL starting from 1 ng/m³. 

Moreover, Indena has a fermentation department for carrying out living cells-based bio-transformation or secondary metabolite production, which can be exploited for the in-house production of toxins used in ADCs payloads, guaranteeing an integrated and independent supply chain. Indena masters GMP microbial fermentation and bio-transformation, and thanks to the availability of high-containment lines for the downstream phase, it is the ideal partner for precision fermentation HPAPI development. 

The challenges of a growing market and the importance of ADCs 
The market for HPAPIs is growing due to the increasing prevalence of complex diseases and the development of targeted therapies. It has been estimated that HPAPIs may now account for more than 30% of the drug-development pipeline. Some of the conditions that use HPAPIs include: cancers, autoimmune disorders, infectious diseases and rare diseases.  

And Indena is at the forefront in addressing the lastest market challenges, as its capability in HPAPIs production comes from the experience gained more than 30 years ago with the first oncological blockbuster drug, paclitaxel.  

The production of paclitaxel involved some challenges: 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. The solution devised by Indena for paclitaxel was an extraordinary result and created a 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. 

Today, Indena’s ambition is to extend its expertise also to ADCs, which represent a significant advancement in targeted therapies, holding immense promise for the pharmaceutical industry. These engineered molecules combine the specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs, offering a more precise and potentially less toxic approach. 

Indena is now able to manufacture linker-payloads, which means specifically: 

• Development & Clinical Supply batches: payload-linker process development, scale-up, and analytical development.   
  Scale: from 10 mg to 100 g. 

• GMP Manufacturing: payload-linker clinical manufacturing and commercial manufacturing. Scale: from 50 g to 5 kg. 

• Outstanding analytical development capability. 

Indena is already present on the market with some payloads, as:  

• Maytansinoids – DM1 & DM4 entirely manufactured in Europe at the Indena plant (including fermentation and synthesis steps). 

• CDMO Payload-Linker: Manufacturing of a GMP Payload-Linker in Phase 1. 

New laboratories: the highest efficiency for research and production 
Indena has also invested in infrastructure designed to handle an increasing number of HPAPI projects, ensuring maximum efficiency and complete safety for both analytical research and production. The focus is once again on the possibility of studying and producing highly potent molecules, starting from research and tests on small quantities for industrial scale-up to large-scale production, in places where the necessary segregation between GMP manufacturing areas and those dedicated to R&D activities is guaranteed.  

The new laboratories will host numerous highly talented researchers, often young, dedicated to very different projects, who will work in complete safety thanks to equipment that guarantees high containment, up to 1 ng/m³. The equipment includes high-containment hoods and large glove boxes where solid product processing is carried out. Inside the new laboratories, process and crystallization development and analytical activities are performed, and chromatography and spray drying. The new research and development laboratories confirm the excellence of Indena’s CDMO services, which, thanks to continuous investments in facilities and people, stand out on the market for quality, reliability, and completeness. 

The importance of People 
One of the most important factors for the quality of the CDMO services delivered by Indena is its people. It means the human and professional resources of the whole team working on CDMO activities, where lifelong professional experiences are fused with the enthusiasm and fresh skills of many young scientists. At Indena, it is well-known that highly qualified, motivated and trained technical staff, supported by a corporate culture, strongly oriented toward quality and rigorous HSE policies, is essential to ensure that operations run safely, seamlessly and efficiently. 

Indena is also well-supported by a strong regulatory department that continuously interacts globally with the most important national health authorities, such as FDA, EMA, AIFA, ANSN, PDMA. The strengths of Indena’s CDMO offer are then supported by manufacturing excellence programs, the highest equipment standards and qualified human resources. 

Sustainability: a concrete commitment, also for business continuity  
Climate change is one of the most urgent sustainability challenges that people, governments and companies have to face. 

Among the actions companies should take, a responsible use of energy is a must. Indena has always been oriented and committed to reducing fossil fuel consumption and use, saving energy, achieving high levels of energy self-production and implementing the use of renewable energy. That’s why Indena is equipping all its European sites with state-of-the-art photovoltaic panels: considering the actual equipment and the upcoming projects, the Indena Group will be equipped with over 4 MW of photovoltaic systems with a total estimated producibility of 4 million kWh per year.   

In addition, all of the Indena’s European factories are ISO 14001 Environmental Management System and ISO 45001 Occupational Health and Safety Management System certified. 

All the actions taken in favor of sustainability also enable Indena to be fully reliable in terms of business continuity. More specifically, Indena has the commitment to pursue the adaptation of the production system to EU policies regarding the fight against climate change.  

The first goals of its commitment, and of the related investments, are the achievement of greater energy efficiency in the execution of business activities and an efficient use of resources. To pursue these ambitious goals, Indena set a medium-term program that includes the following implementations: 

• -2°C high-efficiency chiller, efficient nitrogen production system and high-efficiency heat pumps to reduce overall energy consumption. 

• 7-12°C high-efficiency chiller to reduce natural resources consumption (water). 

• Additional 1.5-MW solar photovoltaic power plant to increase the contribution of renewables on our electricity consumption. 

The attention paid by Indena to the goals of business continuity, working on risk mitigation, the development of a dedicated plan, the capability to resume operations in a timely manner, the protection of critical assets (including data, personnel, and technology infrastructure) makes Indena a total reliable partner for all its clients. 

Moreover, Indena has been awarded the ECOVADIS certification, achieving the Bronze Medal. ECOVADIS recognizes the company’s commitment to managing ESG risk and compliance, achieving corporate sustainability goals, and driving large-scale impact by fostering improved sustainability performance for the company and its value chain.  

A new challenge: producing squalene and other APIs from a vegetal and sustainable supply chain 
Squalene is a natural triterpene, an intermediate for the biosynthesis of phytosterol or cholesterol in plants, animals and humans, widespread in the animal and vegetal kingdom. It was identified for the first time in 1916 by Matsumaru Tsujimoto from the liver of sharks, but it is also found in the human body, secreted by sebaceous glands for skin protection, and forms part of 10–15% of lipids on the skin surface. 

It has several health benefits in nutritional, medicinal and pharmaceutical fields. According to promising results from recent studies, squalene is considered an important substance in practical and clinical uses with a huge potential in the nutraceutical and pharmaceutical industries. It acts as an antioxidant, anticancer agent, skin-care agent, drug-delivery agent, detoxifier, and anti-infection agent. 

Due to its different properties, squalene demand is fast growing, and by 2028, growth is estimated at 6.3% each year, with Europe as the main squalene consumer, followed by Asia and North America. Specifically, Indena utilizes this ingredient pharmaceutically, in particular in the production of vaccine adjuvants.  

Traditional extraction from sharks’ liver is getting more and more unsustainable, as around 3000 animals are required to produce 1 ton of squalene, and this is endangering some species to extinction. Luckily, since the last decade, squalene is also extracted from vegetables such as olive oil, walnut, rice bran, cashews and amaranth oil.  

Among them, a pseudograin Amaranthus sp., more recently introduced in Europe, is known to be the plant with the highest concentration of squalene in the vegetal world. The oil content in Amaranthus seed is only about 4–8%, but oil from amaranth seeds contains 6–8% of squalene (ca. 0.4% of the total seed mass). Indena is producing squalene from the Amaranthus seeds to be used as vaccine adjuvant and can also guarantee the entire GMP supply chain, from plant to finished product: the company will be able to carry out CO₂ extraction of the oil under GMP conditions as well. 

Two other APIs developed by Indena from natural ingredients are: 

• Resiniferatoxin from Euphorbia resinifera, used as a painkiller, for which large, dedicated plant cultivations have been set up and innovative harvesting methods employed by Indena to protect species and support propagation, helping to ensure long-term sustainability. 

• Cytisine, used as antismoking agent, and made by Indena using plants of Laburnum anagyroides with a defined origin, a controlled and fully traced biomass supply chain.