Risk assessment, evaluation and mitigation

Q. PharmTech: On an operational basis, what are key best practices to achieve the desired level of containment? What are key considerations for making the appropriate risk assessment, risk evaluation and risk mitigation? What types of metrics are used to monitor risk during operation?

Cascone (Metrics): Conducting a thorough risk assessment is the best practice to achieve a desired level of containment. It is important to note that 'more' containment may not be a 'desired level' of containment. Rather, the desired level of containment is derived from the need to protect employees and mitigate cross-contamination of drug products. The level of containment required in any instance should be technical and quantifiable. It is not speculative or derived from interpretation or opinion.

Bormett (SAFC): Utilisation of properly designed engineering controls is the primary means for achieving the desired level of containment. It is important to understand the OELs or potential OELs of developmental compounds, for the product to be handled in the facility, and then design and test to meet 50% of the lowest OEL. Planning for containment at 50% of the OEL allows for variability that may occur due to different operators, process scales, material densities and/or equipment use. Proper containment should be confirmed by obtaining industrial hygiene air/surface samples and conducting testing for the specific compound being handled, or using a representative surrogate product. Data generated during industrial hygiene testing should be used to assess areas of greatest potential risk for exposure to allow for improvements and changes to be implemented to minimise the risk. Testing must be repeated over time to evaluate containment systems and processes and to ensure that equipment continues to operate at expected levels.

Another key area for consideration is equipment cleaning following use with potent compounds. An effective and verified cleaning programme is critical to prevent potential cross-contamination, especially in a multiuse facility. Equipment cleaning also can be an activity for potential employee exposure. Therefore, CIP systems should be employed when possible, and monitoring should be performed during cleaning activities to verify that the OEL requirements are being met.

Facilities handling highly potent compounds should have a compound evaluation and categorisation system in place in order to conduct appropriate risk assessments and communicate hazards. This is especially critical when working on developmental compounds that may not have an established OEL. The categorisation can be used to determine proper handling and containment requirements for the compound based on the systems in place within the facility.

Iliopoulos (Euticals): A proper facility to handle HPAPIs should be designed considering technologies such as isolators, laminar flow hoods and local exhaust ventilation systems with air filtered before released to the ambient air. The air supplied to the rooms should be single-pass with proper air-pressure differentials to keep product-exposed areas negative to all adjacent areas or airlocks. Appropriately validated cleaning procedures should secure no cross-contamination with the next compound to be produced using same equipment or piping. ISPE launched the Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) Baseline Guide, which provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross- contamination (2, 3). EMA followed with a concept paper, published in Oct. 2011, and suggests using "a more scientific approach...to establish threshold values" (4).

In instances when the toxicity of a compound is not known, it must be treated as Band IV compound. Obviously, the best would be to determine the toxicity of a given compound prior to embarking in high-cost production set-ups. To minimise the risk and for extra safety purposes even if engineering controls are in place, personnel working with highly potent compounds should wear suitable personal protective equipment, including respiration equipment.

Best practices in dealing with HAPIs are the availability and checking of material safety data sheet (MSDS) data for any compound used in the process, process hazard analysis, start-up, safety review, training, change control, emergency planning and response. Measurement of the dust during operation in the production areas is a key parameter in defining and checking the safety level at the operational level.