The Health-Based Exposure Limits (HBEL) approach is a method used to calculate cleaning limits in pharmaceutical manufacturing facilities. Cleaning limits are the maximum allowable levels of residual drug product and cleaning agents that can remain on equipment surfaces after cleaning. The HBEL approach uses scientific data and risk assessments to determine safe cleaning limits that protect patients from harmful exposure to residual drug products. The HBEL approach consists of three primary steps: setting a permitted daily exposure (PDE), calculating a safety factor (SF), and determining a cleaning limit based on the PDE and SF.
Setting the Permitted Daily Exposure (PDE) The PDE is the maximum amount of a drug substance that a patient can be exposed to on a daily basis without experiencing harmful effects. To determine the PDE, toxicologists conduct a thorough risk assessment that considers the toxicity of the drug, its intended use, and the patient population. The PDE is expressed in milligrams per day.
Calculating the Safety Factor (SF) The SF is a multiplier applied to the NOAEL (No Observed Adverse Effect Level) to account for uncertainties in the risk assessment and to provide an additional margin of safety. The SF is typically calculated based on factors such as the quality of the toxicology data, the severity of the drug’s toxicity, and the variability of patient response. A typical SF is 10, meaning that the cleaning limit should be set at one-tenth of the PDE.
Determining the Cleaning Limit The cleaning limit is calculated by multiplying the PDE by the number of therapeutic doses (the worst-case scenario) in the next product. For example, if the PDE is 50 mg/day and the number of therapeutic doses is 100, the cleaning limit would be 5 g per equipment surface area. This means that after cleaning, no more than 5 g of residual drug product or cleaning agent can remain on any given equipment surface. To calculate the number of therapeutic doses, the minimum batch size of the next product should be divided by the maximum daily dose of this product. The cleaning limit is typically expressed in micrograms per square centimeter (µg/cm2) or parts per million (ppm). The limit may vary depending on the equipment and the cleaning process. In general, equipment surfaces that come into direct contact with the drug product will have lower cleaning limits than those that do not. The cleaning limit calculation must take into account the surface area of the equipment being cleaned. For example, a large mixing tank may have a higher cleaning limit than a small piece of equipment that is used to dispense the drug product. However, usually drug products are manufactured on a train of equipment so the sum of surface areas of all product-contact equipment is used to calculated the swab limit (remember: carryover is cumulative).
Verification of Cleaning Limits Once the cleaning limit has been calculated, it is important to verify that it can be achieved using the cleaning process that is used in the facility. This may involve conducting cleaning validation studies to demonstrate that the cleaning process can consistently achieve the desired cleaning limit. If the cleaning limit cannot be achieved using the current cleaning process, changes to the process may be necessary. This may involve using different cleaning agents or adjusting the cleaning parameters such as the temperature, time, or pressure.
Conclusion
The HBEL approach is an effective method for determining cleaning limits in pharmaceutical manufacturing facilities. It is based on scientific data and risk assessments and provides a margin of safety to protect patients from harmful exposure to residual drug products.
It is important for pharmaceutical manufacturers to use the HBEL approach when setting cleaning limits to ensure that their products are safe for patients. The cleaning limit calculation must take into account the surface area of the equipment being cleaned, and the cleaning process must be validated to ensure that it can consistently achieve the desired cleaning limit.
By following the HBEL approach, pharmaceutical manufacturers can ensure that their products meet regulatory requirements and are safe for patients to use.
References:
- EMA Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. - EMA Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ - ASTM E3219-20 Guide For Derivation Of Health-Based Exposure Limits (HBELs).
コメント