Risk assessment, evaluation, and mitigation
PharmTech: What are key considerations in risk assessment, revaluation, and mitigation in high-potency manufacturing, including the metrics
used to monitor risk?
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.
A comprehensive risk assessment will determine what engineering, facility, and administrative controls are required. A risk
matrix may be developed for each step of the process. Each matrix will identify associated potential adverse events. Each
potential adverse event should be quantified by calculating the product of its probability of occurrence by its severity.
Risks cannot be monitored during a process, but actual events and exposures can. Proper feedback tools are essential to ensure
the 'desired level' is appropriate and effective.
Bormett (SAFC): Utilization 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 OEL of development 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 minimize 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
program is critical to prevent potential cross-contamination, especially in a multi-use 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 categorization 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 categorization 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
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 minimize 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.