Cleaning Validation – Calculations of Residue Limits for Drug Product Therapeutic and Non-therapeutic Materials for Equipment Cleaning
Introduction
This guideline provides equations and examples for calculating the Maximum Allowable Residue (MAR), and Residue Acceptability Limits (RAL) for Drug Products and Non-Therapeutics.
Examples are provided for determining the acceptable equipment cleaning residue limits for therapeutic drug products (MART and RALT) and for non-therapeutic ingredients (MARN and RALN). For the therapeutic drug products both single product combination (Product A to B) and multiple products combination examples are given.
Recommendations & Rationale
The attached Appendices give equations and example calculations for therapeutic drug product cleaning limits for a solid oral dosage form (tablet), creams/ointment and ophthalmic product. In Case-1 therapeutic example it is included the calculation of Maximum Allowable Residue (MAR) limits using two formulas; dose MART and toxicity MAR. It also includes an example for determining the worst case limit for shared equipment using multiple products. Example for residue limits calculation of CIP® 100 detergent, a non-therapeutic ingredient is also given.
Background Information and Equations
The Maximum Allowable Residue for Therapeutics (MART) and Residue Acceptability Limit for Therapeutic Dose (RALT) should be calculated based on each product that is to be processed in a specific equipment train and determined by the formulas and equations provided in Appendix A. A common default MART is not more than ten (10) pm.
The calculated MART and the default MART should be compared and the lower of the two (2) used. A Toxicity limit may also be calculated and compared to the default MART and the NMT 10 ppm, and the lower of the three limits chosen.
The Maximum Allowable Residue for Non-Therapeutics (MARN) and Residue Acceptability Limit for Non-Therapeutic Materials (RALN), such as materials used for equipment cleaning, is a function of toxicity, and should be determined by use of the formulas and equations provided in Appendix B. A default MARN is not more than one hundred (100) ppm. The calculated MARN and the default MARN should be compared and the lower of the two (2) used. Residue
Acceptability Limits (RAL) should be calculated using the sum of product contact surface areas of common equipment items/units between product A and B. Where there are more than one equipment train configurations, the largest total surface area should be used in the RAL calculation. The manufacturing and packaging area may be considered as separate equipment trains for RAL calculations. In the case of stand-alone operations (operations that are not part of the routine manufacturing process and are used only when necessary, e.g., sorting), the RAL should be calculated using the equipment item surface area.
Appendices: (Product names used in the examples are common from the market)
- Contents: Product A to Product B Cleaning Limits Calculations Equations and Examples
- Appendix A: Equation for maximum allowable residue for therapeutics (MARt) and residue acceptability limit for therapeutic dose (RALt) equation.
- Appendix B: Equation for maximum allowable residue for Non-therapeutics (MARn) and residue acceptability limit for Non-therapeutic dose (RALt) equation.
- Appendix C: Example therapeutic drug products calculations.
- Case 1: Dose and toxicity calculation for single product combination (Tablets)
- Case 2: Dose calculation for worst case limit for multiple products (Tablets)
- Case 3: Dose calculation for single product calculation (Creams and Ointments)
- Case 4: Dose calculation for single product calculation (Opthalmic liquid product)
- Appendix D: Examples Non-therapeutic ingredients (detergent) for DP
- Case 1: Toxicity calculation for Non-therapeutic ingredient (detergent) for DP
- Appendix E: Cleaning from the specified compound type