Meeting large-scale HPAPI production needs


A recent expansion at Olon’s Rodano site will enable the company to produce highly potent APIs in large-scale product batches ranging from 30-150 kg

Meeting large-scale HPAPI production needs

New generation molecules are the focus of much of the research and development efforts of the global pharmaceutical market. The general industry trend has been to steer the development of therapies towards increasingly selective, and therefore increasingly potent, molecules, with the possibility of extending to additional therapeutic areas (oncology in particular).

Olon Group, a CDMO which has more than doubled its growth in strategic investments during the last five years, is building capabilities to provide support for pharmaceutical partners throughout all stages of the development process.

Reactors are supervised through a distributed control system with a local human machine interface

Target therapies - drugs that are selective and therefore better tolerated by the patient - have an action that targets only the mechanism underlying development of the disease. They are finding increasingly broad application in treating the world's most widespread oncological diseases (primarily breast cancer), but also rheumatic and respiratory diseases and other major therapeutic categories with unmet needs.

Improvements in treatment selectivity result in demand for increasingly potent active pharmaceutical ingredients. These ingredients require highly specific technologies, systems and skills to meet the appropriate standard of containment and guarantee there has been no contamination of operators and products.

"We have built large-volume containment facilities," says Giorgio Bertolini, VP R&D Olon Group, "to support the production of new drug classes, in particular oncology drugs. Despite containing a very small quantity of highly potent active ingredient, these have to be made available to a large number of patients worldwide. This requires large batch sizes of product, so as to allow pharmaceutical companies to guarantee access to therapies for all patients who need it."

A complete platform

Following recent investments in its integrated manufacturing network, Olon offers the capacity to develop and produce highly potent APIs, from very small to commercial scale, along the entire development chain. The company operates all types of reactors, regardless of required size, with extensive experience in high containment production processes.

Meeting large-scale HPAPI production needs

Olon has now completed an extremely high containment OEB5 production line, with reactors enabling the production of highly potent APIs in large-scale product batches ranging from 30-150 kg. This expansion was planned to allow the company to assist customers across all stages of scale up, across multiple sites. The €10m ($10.9m) project is part of a long-term growth initiative which will see the company invest €110m ($116.8m) in 2022.

In this regard, the company offers partners investing in these drug classes a flexible and solid platform for the development and production for third parties of highly potent APIs and highly toxic intermediates.

Starting with a few grams in the GMP laboratory, the company progresses to batches of 1 or 2kg, then several tens of kilograms, followed by the 30 to 150 kg range - which the new line will facilitate - before reaching commercial quantities. With the addition of the OEB5 line, the company offers the full range of specific integrated capabilities necessary to support customers from the first clinical phase up to industrialisation, regardless of the quantity of product or batch size required and regardless of the ongoing molecule development phase.

Production line 5

Production line 5 is installed in building F1 and has been designed for OEB5 containment, processing APIs with an occupational exposure limit of 1 μg/m3. It is equipped with two glass-lined reactors (with a further reactor planned to be available by the end of 2022) and a hastelloy filter dryer. To maintain safety on this production line, specialised equipment and training is required.

Meeting large-scale HPAPI production needs

The production line is distributed across four levels. The third floor encompasses utilities, condensers, vacuum pumps and solvent distribution. A reactor charging glovebox is housed inside process rooms on the second level, while the reactor bottom valve for solvent recovery and fluid transfer is located on the first floor. A filter dryer for solid separation and a discharging glove box have been installed on the ground floor.

All reactors are equipped with utilities for heating, cooling, pressure and vacuum control. The rooms are certified to ISO Class 8 according to ISO 14644-1:2015, with airlocks controlling the entry and exit of personnel and material. Reactors are supervised through a distributed control system with a local human machine interface.

The line has been designed to integrate with existing production, as well as future lines at the same level of containment. This interoperability is important for the company to reach maximum process flexibility in terms of available equipment and batch size. The equipment on the line is suitable for acid synthesis and all components are maintained under inert ambient conditions with nitrogen. Additionally, flammable solvents are handled in strict compliance with ATEX regulations for vapours and solids.

The OEB5 line completes a manufacturing platform for every stage of drug development into commercialisation, meeting API production needs from a few kg to hundreds of kg per year, depending on the disease.

Long-term lessons

Just as important as the equipment used to produce APIs, however, is the expertise and in-house know-how required to effectively operate it. For Olon, recent decades have seen the company develop expertise in the management of processes at the plant, including operator protection and training, policies and procedure, waste disposal and management of related issues.

In the 1970s, the company's plants in Rodano and Settimo were employed for the production of cytotoxic anticancer products, and since that time, Olon has continued to invest in its high containment facilities.

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"The ability to offer highly potent products translates into sustainability for the entire pharmaceutical industry," Bertolini continues. "We are sustainable partners, contributing to the global access to therapies, producing pharmaceutical ingredients that are more active and decreasing the quantity produced. Through this, we can significantly reduce the use of natural resources - raw materials, solvents, and energy - and the overall impact on the environment. The result is a more sustainable drug supply chain. The future of our sector is to have increasingly small facilities with increasingly high activity - we are moving into this future."