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 use systems. Although single-use plastic elements such as those now widely used in the biologics sector are not suitable, there is a trend to dispose of some of the relatively inexpensive kit, such as piping, rather than undertake the time-consuming and costly process of thorough, validated cleaning routines.
Protecting the environment is only half the story. When it comes to protecting people, containment and the proper PPE are vital, but the most important factor is ensuring that the workforce has the right level of training and skills in place to handle highly potent materials, as well as a proper understanding of the reasons behind the systems and protocols. Inexperienced workers, or those who are not up to date technologically, can engage in risky behaviors and practices that could potentially lead to the risk of exposure.
Everyone who works in pharmaceutical development or manufacturing needs training in the facility's SOPs, but those going on to work with HPAPIs require additional training so that they can work with optimum efficiency. Essentially, they have to be able to perform routine chemical processes but in a contained environment with all the additional complexities that entails. To put it simply, when handling HPAPIs you have to 'think before you do' rather than reacting afterwards.
But to be able to put appropriate containment measures in place and ensure that staff training is up to the levels required, a CMO must first know what hazards it is dealing with to be able to assess the risks accurately. Each highly potent molecule carries its own set of risks: the effects of exposure may range from moderate to severe or even fatal, and the effects may or may not be reversible. In the case of controlled substances, inhalation, absorption through the skin and/or ingestion are of particular concern.
For existing molecules, an Occupation Exposure Limit (OEL) may already have been established, but products in development will be, literally, an unknown quantity. It is then down to the CMO to assess what it believes will be a safe limit and position the molecule in an appropriate Exposure Control Band (ECB). This assessment can be carried out through in-house systems, or through programs such as those provided by SafeBridge Consultants.
To determine an ECB, the company's toxicologists will gather together and collate all the information that is known about a given molecule, including any prior experience with similar chemical entities, the mode and mechanism of action, any toxicology data, any existing animal, cell or human data, and whether the substance is carcinogenic, reprotoxic or mutagenic.
They will also research the core chemical structure and search the literature for similar molecules to find out what is known about them. The dosage form will also be taken into account - whether a drug is topical, parenteral or inhaled can affect the mode of action, and how rapidly a biological response would occur – as would the dosage range.
Once all this information has been acquired, an OEL or ECB can be established on the basis of sound scientific reasoning. The ECBs are generally divided into four categories, I – IV, each covering a specific OEL range. For example, products with an OEL of >1000µg/m³ would generally sit in Category I and those with an OEL of >10µg/m³ in Category II. Categories III and IV are for substances that would be classified as high potency with OELs of 10-1 andOnly once a molecule has been given an OEL or ECB is it possible to tailor the measures needed to protect the environment and the workforce. These measures will include SOPs, designing the kind of unit within the facility needed to handle this product, what documentation will be required, how the workforce should be trained and the type of personal protection equipment (PPE) that will be needed. Environmental controls and monitoring systems would also need to be set up.
For companies that manufacture controlled substances, there are some similarities between protocols carried out for the handling of HPAPIs, such as additional training, dedicated facilities and rigorous cleaning protocols. However, there is the possibility that controlled substances may also be highly potent and highly toxic molecules, and where there is overlap between both controlled and highly potent molecules, the procedures that need to be established put added responsibilities and accountability on contract manufacturers.
Process research, development, manufacturing, importation and purchase of controlled substances are highly regulated, and in the US cannot be undertaken without a license from the Drug Enforcement Agency (DEA). Handling of controlled substances demands exactly that: control at every stage. Access to the development and production suites is restricted to only those with authority and training to enter, and dedicated equipment and storage, including restricted, name only, access to General Services Administration (GSA) Class V rated vaults is used.
Every aspect of material handling is controlled - inventory management, control and disposal - while specialized handling procedures are put in place to deal with receiving, transferring, packaging and shipping of the substances. Accountability of the material is carried out by a detailed material balance down to grams. In both the manufacturing and storage facilities, security cameras operate to ensure all operations are observed and recorded.
Once projects are completed, final products are either stored or tested in stability chambers, again these must be undertaken in segregated facilities. Documentation must be undertaken and maintained to record the exact location and quantity of all controlled substances at all times. Facilities in the US handling controlled substances are audited by both the DEA and the FDA regularly, every one or two years, with regard to systems, SOPs, training, access and monitoring. Although each company is allowed to determine its own control and monitoring systems, the DEA demands that its controlled substance license holders meet its exacting standards.
Personnel are required to have experience in handling controlled substances and in the cases where they are also highly potent, that experience has to extend to handling hazardous materials, and highly regimented safety protocols and PPE requirements are put in place. In particular, they would be required to undertake specific training in legislative and regulatory requirements, in addition to which, a company will have a substance control officer on site.
Handling hazardous materials such as HPAPIs and controlled substances is obviously a risky business, but by working with an experienced outsourcing partner with the right containment - PPE, barriers and isolators – and most importantly the appropriate education and training of the workforce, they can be handled safely without danger to the product, the environment or people.
John Michnick has over 25 years’ experience within the pharmaceutical industry. He joined Cambrex in 2010 as Sales Manager, and is now Director of Sales and Business Development. Prior to Cambrex he held roles with SAFC Pharma and Cell Therapeutics (now CTI BioPharma Corporation). He gained a PhD in synthetic organic chemistry from Washington State University.