There is a increased focus from the regulators on manufacturing firms to ensure robust cleaning process are in place to control contamination and is supported by scientific rationale.
Typical approaches to establish cleaning validation acceptance criteria:
- Product Specific approaches: 0.1% (1/1000th reduction)
- Health Based Limits: LD50, NOAEL, ADE/PDE, TTC & Minimum therapeutic dose
A common approach to determine the cleaning validation acceptance criteria has been the Maximum Allowable Carryover (MACO).
MACO = (PDE a x Volume b) ÷ (Dosage b x SSA e)
Where,
- PDE a = Permitted Daily Exposure for Product A
- Volume b = Volume of first B batch (or minimum Batch Size of Product B)
- Dosage b = Maximum dose of Product B
- SSA e = Surface area of shared equipment
Read also: PDE Value Calculation
10 ppm Cleaning Validation Calculation
The value of 10 ppm comes from an article written by Gary Fourman and Dr. Michael Mullen more than 20 years ago, which suggested a combination of the following for setting acceptance limits for cleaning:
- No more than 0.001 dose of any product will appear in the maximum daily dose of another product
- No more than 10 ppm of a product will appear in another product
- No quantity of residue will be visible on the equipment after cleaning procedures are performed.
10 ppm criteria means 10 ppm API allow in to the subsequent product. Where, shared surface area of all the equipments shall be considered in the calculation.
FDA and EMA Process Validation Guidance expects a CPV (Continuous Process Verification) program for all production processes. Because the CPV programs provide significantly more information for able to review trends and to quickly make adjustments.
Example of a CPV Program
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