CMO
Handling Highly Potent Actives and Controlled Substances Safely and Securely
John Michnick, PhD
Director, Sales & Business Development Cambrex
Abstract
Growth in demand for new anti-cancer drugs has seen more and more pharmaceutical companies researching highly potent molecules, but these companies may not have the specialist resources and infrastructure needed to take these developments beyond the R&D scale. Meanwhile, for projects that involve DEA Schedule II-III controlled substances, there is also a need for knowledgeable, experienced, and licensed partners to work with these compounds safely and within legislative constraints. John Michnick, Ph.D., Director, Sales & Business Development at Cambrex, discusses how and why specialist contract manufacturers are in a good position to take on these challenges.
Overcoming the Fear
Handling a highly potent active pharmaceutical ingredient (HPAPI) can, quite rightly, involve a significant fear factor. Exposure to these molecules can have serious consequences – the effects may be moderate to severe, they may not be reversible and, in some extreme instances, could be life-threatening or even lethal.
It is no surprise, therefore, that many of the innovator companies who start to research these substances do not feel equipped to continue their development beyond the early phases of discovery and look for an outsourcing partner with the expertise and facilities to take the molecule from preclinical, all the way up to commercialization.
This is reflected in the rapid growth of high potency projects within the outsourcing market, particularly in the last 10 years, and the sector is seeing continual, significant investment by existing contract manufacturing organizations (CMOs), as well as by those entering this area for the first time.
The rise in demand for outsourcing of highly potent development and manufacturing is driven largely by the expansion of the oncology sector, which is among the fastest growing in the entire pharmaceutical industry. As well as cytostatic and cytotoxic drugs, there is also an increase in kinase inhibitors as the movement towards specialized medicines advances, and in antibody-drug conjugates, which require highly potent chemical 'warheads' to target specific tumor cells.
A CMO facility looking to develop or manufacture HPAPIs must have systems in place to offer three-fold protection: it has to protect the
product, the environment and the people working with the HPAPI. These requirements can be met only if the company has the appropriate containment capabilities and a thorough understanding of how to use them, an experienced and highly trained workforce, and a system for assessing the risks posed by the substances it is handling and knowing how these risks should be addressed.
The time and cost of putting all these elements in place is something that an innovator company, with perhaps only one highly potent molecule in its portfolio, would see as a less attractive option than outsourcing the project to a specialist CMO that already has the systems in place. With a partner, the appropriate facilities, expertise and capacity are available, so it would make sense to use them.
To protect the integrity of the drug product, as well as the safety of the environment and workforce, areas handling highly potent projects within facilities are segregated to avoid cross-contamination. And this separation not only applies to the manufacturing side, but also to the development labs, the stability chambers, the analytical labs and the personnel engaged in all these areas.
It goes without saying that containment in the HPAPI facilities should be state-of-the-art, and manufacturers will often work with the isolator manufacturers to ensure that their equipment is best-in-class and suitable for the projects in which they are engaged.
An understanding of the type of personal protection equipment (PPE) required is also crucial. This goes beyond simply making sure that the workforce has the correct garments and breathing apparatus to protect them from the HPAPI – it also means ensuring that the gloves used in the isolators are compatible with the chemicals used in the processes being carried out. For example, if there was not an adequate compatibility check in place, a particular type of glove might be affected by contact with one of the solvents used within the isolator. This then puts not only the operator but potentially also the environment at risk of exposure.
Another important factor in protecting the environment is to be able to prove that the equipment is thoroughly clean between batches. For every high potency molecule it is necessary to have a validated decontamination process that is proven to remove or destroy it.
Proving that something is clean is quite a challenge, especially when the validation figure for some substances can be as low as 25 nanograms per sample. For this reason, CMOs handling high potency small molecules are looking to increase the use of disposable or single
Pharmaceutical Outsourcing | 24 | November/December 2016
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