Compliance Management / QRM Process

Catalent's Holistic Approach to High Potency API Operations

How Catalent’s approach to containment mitigates cross-contamination risk and regulatory issues, ultimately safeguarding patients

By Karolina Narczykiewicz, Operations EHS Manager, Catalent


The more potent a drug substance is, the more stringent the handling requirements throughout the manufacturing process. Occupational health must be taken into account across the board, from the time any potent material enters (or is made in) the facility, to the time it leaves as a final dosage form. A careful consideration must be made of any environmental impact that might result if something goes wrong, such as air pollution or water contamination. The safe and proper handling of waste must be considered, too.

Regulatory compliance and quality also play an important role in ensuring safety within a facility that handles potent and highly potent compounds. These functions help to ensure there is no cross-contamination, and assist in the development of appropriately designed vessels that are easily cleaned. This is particularly important in a multipurpose plant where the vessels are not dedicated to one specific product.

COMPOUND CLASSIFICATION
Any company that works with highly potent compounds must have a rigorous system in place for classifying the potential hazards and risks of each individual product. Many different factors are taken into account, such as the lowest therapeutic dose, the compound’s bioavailability, mode of action, and an understanding of its overall pharmacological activity. Are there any known target organ toxicities? Is it a known mutagen, carcinogen or genotoxic agent? Is it a sensitizer? Does it exhibit any warning properties?

The occupational exposure limit, or OEL, may already have been determined for the compound, and this can be an important starting point for compound classification as it represents the maximum acceptable concentration in workplace air. 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.

The Catalent compound categorization code is laid out in Table 1. It was developed in partnership with experts at Safebridge Consultants Inc., and we use it across all our sites around the world. When we receive a new compound, we determine which of the four categories it fits into, which informs all handling requirements. Class 1 is the least potent, and corresponds to an OEL band of >100µg/m3. Typically, we do not consider those that fall into classes 1 and 2 to be potent. Those in class 3 are potent, and class 4, corresponding to the OEL band for solids of <1g/m3, are highly potent.

If data are lacking, which is often the case in the early stages of a product’s development, we will default to a conservative banding, and assume that it is potent. This does increase cost, and thus it is important to reassess its categorization in the light of new data as it becomes available.

RISK ASSESSMENT AND CLASSIFICATION
To determine whether a compound is compatible with a facility, a full risk assessment and classification must be carried out, taking into account hazard, exposure and risk. Hazard is the potential for a compound to produce harm. For exposure, we look at the potential for the compound to be absorbed via inhalation, ingestion or skin absorption; the compound’s physical state and how it is handled can affect how it behaves. Risk is the probability that the compound will produce harm under the specified exposure conditions. These factors all lead to 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.

The scope of manufacture also drives facility compatibility. For example, some sites cannot handle beta-lactams, antibiotics, hormones or cytotoxic molecules. Is it reactive or inflammable, or does it create an explosive dust? Are we able to develop suitable cleaning methods to prevent cross-contamination and carryover, and is the facility layout and available equipment in line with minimizing risk? We will also need to review quality agreements and site licences, to ensure the compound class is not precluded. If it is a controlled drug, additional requirements may add complexity to containment, and more operators may need to be involved.

This is all part of our formal onboarding process for compounds and projects. As we may handle many different products and projects in our multipurpose facilities, we need to mitigate the risk of cross-contamination, and the attendant risk to patient safety. Not only do we have to comply with both regulatory and licence requirements, but clients may have their own specific requirements that could preclude us working with certain other classes of compounds within the facility. Onboarding is very important from an Environmental, Health and Safety (EHS) point of view, too, when determining the containment strategy. It also helps reduce the risk to business and client relations by ensuring everything works as it should, and that we only work with appropriate material for the site’s capabilities.

FURTHER CONSIDERATIONS
The level of flexibility required must also be determined. Can (or must) the process be run from start to finish with no stoppages, or can it be broken down into different segments? If it can, we also need to identify the points of intervention, such as intermittent cleaning or pausing to take a sample, and how this fits into the overall containment and control strategy. Batch size is also important, as this determines the equipment scale. Cleaning requirements will vary depending on the containment that is used. A fixed containment system will have to be cleaned; disposable containment is thrown away, removing the need for this level of cleaning intervention.

Effective cleaning is essential, and at Catalent, we develop cleaning master plans for all our sites to ensure carryover and cross-contamination are prevented. For example, in our oral solids manufacturing facility in Somerset, NJ, the plan consists of two parallel pathways. In one, environmental, health and safety data are collated, and studies are carried out to determine the acceptable residue limit, or ARL, based on the maximum allowable carryover for the compound. In parallel, tests are run to identify the optimal cleaning agent. These two activities culminate in the development of an analytical method, and the validation of the cleaning process.

The starting point for exposure control is the facility infrastructure. Is the HVAC system single pass or recirculating air? The former is more appropriate when handling potent compounds. How many air changes an hour is the room designed for? Again, higher numbers are preferred for potent compounds. Are the rooms equipped with airlocks that allow for a unidirectional flow of personnel, and a separate flow of materials and equipment? This is important for reducing the potential for cross-contamination. And is clean-in-place possible? Manual cleaning adds an additional point of exposure potential for the workers.

The decision on containment approach is between containing hazardous compounds at source, and running 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. Transfer systems such as split butterfly valves can have containment advantages over flexible systems like continuous liners.

It may also be appropriate to use additional PPE even if containment is in place. We typically use powered air purifying respirators as a failsafe, and some specific processes might require items such as special gloves or suits.

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 give a picture of how well the containment is working, alongside the level of containment that can be achieved. If a surrogate has been used in a particular area before, it is advisable to run background samples to ensure there is no carryover that could skew the results. In environments with routine cleaning procedures this should not be an issue, but it is still worthwhile. Wipe tests may also be carried out.

Ongoing monitoring is carried out 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.

Table 2 shows an example of containment and control from Catalent’s softgels business. As we move from dispensing through mixing to encapsulation, drying and the final packaging of the softgels, containment requirements are much higher in the early stages, with isolators and disposable glove bags for dispensing, than at the final packaging stage, where there is little chance of airborne contamination so containment requirements are minimal.

THE IMPORTANCE OF ADAPTABILITY
It is important to recognize that there is no single approach that fits all applications when working with potent compounds. Risk assessment is essential, and must be done before manufacturing or onboarding compounds to ensure the best solution for that particular case is chosen. Tailoring the approach to the process is key, with hazard, exposure, controls and understanding of acceptable risk all important factors in making the correct decision. Flexibility may cost more, but for small batches it can be a more cost-effective solution.
Selecting the right approach to containment when working with potent and highly potent compounds carries with it many benefits in terms of safety and environmental protection. Containment reduces the risk of cross-contamination and, when matched with the correct cleaning methods, leads to a reduction in regulatory risk, and, further down the line, minimizes the risk to patients.