Choosing a partner to manufacture potent or highly potent materials requires more consideration than a normal CMO partnership, reports Karolina Narczykiewicz, Operations EHS Manager, Catalent
It is crucial for any company that manufactures or works with potent drug substances to have a rigorous and carefully designed plan as to how to handle the compounds safely. Considerations must be made to reduce not only the potential exposure of workers to the effects directly, but also any impact on the environment in case of problems, as well as guaranteeing the safe handling of any waste materials resulting from such processes.
It is vital that cleaning regimes in multi-use plants are appropriate to eliminate the risks of cross-contamination between processes, and steps can be taken in the design of facilities to make a plant that handles potent and highly potent materials as easy as possible to clean. To this end, company occupational health departments work side by side with their counterparts from regulatory compliance in drawing up plans to ensure that the safety and quality protocols minimise risks such as plant contamination and exposure to staff.
As with any new process in a facility, when a company is looking to manufacture or handle highly potent compounds a risk assessment is done well in advance of undertaking the work. Catalent utilises a four-tiered categorisation code, which is used in all its global locations, when evaluating the potential risks of potent compounds. It was developed in collaboration with safety experts Safebridge Consultants, and it allows rapid decisions to be made with respect to product handling and specific project needs.
This classification takes many different factors into account, such as the lowest therapeutic dose, its bioavailability, the mode of action and an understanding of its overall pharmacological activity. It is important to determine whether there are any known target organ toxicities, and if it is a known mutagen, carcinogen or genotoxic agent, or whether data in these areas are unavailable.
The occupational exposure limit (OEL) may already have been determined for the compound, and where this information is available, it can be a starting point for compound classification as it is a representation of the maximum acceptable concentration in workplace air. However, before deciding whether to use that OEL, it is important to know whether it is based on human data, and what studies were performed to determine it.Table I highlights the Catalent approach when a new compound is received at one of its facilities. The compound will be placed into one of the four categories, which then determines all handling requirements of that compound. Class 1 is the least potent, and corresponds to an OEL band of >100µg/m3 and typically, compounds that fall into classes 1 and 2 are not considered to be potent. Those in class 3 are potent, and class 4, corresponding to the OEL band for solids of <1g/m3, are regarded as highly potent.
It is not uncommon for products in the early stages of development to be lacking data in this area, and in these cases, Catalent will default to a conservative decision on categorisation and assume the compound to be toxic. This has an effect on the cost of such projects, and so when new data becomes available it is important to reassess the risks as early as possible, so that if the risks are lower, changes can be made to ensure that cost savings can be passed on.
Once the nature of a product is known and classified, it must be determined whether a facility is compatible and suitable to handle it. Here, the CMO should undertake an overview of the hazard, which is the potential for the compound to cause harm; exposure potential for the compound to be inhaled, ingested or absorbed during handling based on its physical state; and risk that the compound will produce harm under the specified exposure conditions. By evaluating these, it is possible to gain an understanding of the acceptable risk level, which is the probability of exposure occurring, and the harm that may result. This must be as low as is reasonably practical, but still tolerable.
As part of the formal ‘onboarding’ process implemented by Catalent, there are a host of practical aspects that must be looked at before a site can start processing materials, whether potent or not. For example, some sites are not compatible with beta-lactams, antibiotics, hormones or cytotoxic molecules. Physical characteristics need to be evaluated to ensure the risks of reactivity, flammability and explosion are known and can be minimised appropriately. The layout of the facility and the associated cleaning protocols must be practical and applicable to eliminate the risk of cross-contamination. Legal aspects, for example, where licences are needed for controlled drugs, will also be factored in at the start, as well as environmental, health and safety (EHS) implications, so that an appropriate containment strategy is developed.
The effectiveness of containment is verified by performing industrial hygiene studies
As well as regulatory and licence requirements, clients may have additional demands that preclude the handling of certain classes of compounds within a shared facility. Catalent’s network of facilities around the world handle many different products, and in many cases, are multipurpose in nature. The combination of these factors ensures that from the start of any project, everything is planned and considered to ensure a site’s capabilities match the needs and demands of a new project.
Once a site is selected to host a project, there are other practical and operational evaluations that must take place. The level of flexibility of a process is assessed to evaluate whether it can – or must – be fulfilled with no stoppages, or whether it can be undertaken in a number of stages, or falls within a restrictive batch size at a certain step for process or equipment scale reasons. Where stoppages are necessary – for example, for intermittent cleaning or inline sampling – the implications for the overall containment and control strategy must be assessed.
Cleaning requirements will vary depending on the containment method used; a fixed containment system will have to be cleaned, whereas if disposable containment is implemented, this can be thrown away, subject to satisfactory waste disposal techniques. Effective cleaning is essential, and cleaning master plans must be developed to ensure carryover and cross-contamination are prevented. This can be done in parallel, such as in Catalent’s oral solids manufacturing facility in Somerset (NJ, USA) where EHS data are collated to determine the acceptable residue limit alongside studies to determine optimal cleaning agents; this approach culminates in the development of both an analytical method, and the validation of the cleaning process.
Facility infrastructure and design is the starting point when assessing exposure control. Single-pass air handling systems are more appropriate for handling potent compounds, and systems with a greater number of air changes per hour are preferred. Ideally, a unidirectional flow of personnel, and a separate flow of materials and equipment would be in place, further reducing the potential for cross-contamination.
There is also a decision when designing facilities as to whether the containment approach adopted is to contain the hazardous compounds at source, or to run an open process with personal protective equipment (PPE) to safeguard the operators. The nature of the containment type that is selected – fixed hard-shell or disposable – will depend on the application, but it may also be appropriate to use additional PPE even if containment is in place.
The effectiveness of containment is verified by performing industrial hygiene studies. These will typically be carried out via surrogate monitoring, using compounds such as naproxen or lactose in place of the potent compound itself. Air monitoring samples for the personnel working within the operation will be taken, along with area samples to determine the efficiency of containment, against the level of containment that can be achieved. Ongoing monitoring is appropriate at set frequencies, according to an industrial hygiene plan. This is used to inform decisions on whether altered protocols, additional controls or different containment equipment are required.
When dealing with potent compounds, thorough risk assessment is essential before the commencement of any project, as there is no single approach that is applicable. Finding the best solution, and tailoring the approach to each project is important, so that risks can be minimised and safety is not compromised. Having a flexible approach is more suited to small batch handling, and although this may affect costs, making the correct decision for the process is paramount.
By adopting a multidisciplinary approach to hazard assessment, and ensuring compliance throughout the process, and afterwards with appropriate cleaning protocols, handling highly potent compounds does not mean high risk. Materials can be handled safely and appropriately, ultimately minimising the risk to patients.