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

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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.

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.

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.

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.

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