The cleaning validation acceptance criteria preferably should be based on the Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE) calculations whenever this data is available. The APIC Guidance refers primarily to ADE in the examples of calculations included in this chapter, in line with the ISPE recommended calculations.
Acceptance Criteria Using Health-based Data
The Maximum Allowable Carryover (MACO) should be based upon the Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE) when this data is available. The principle of MACO calculation is that you calculate your acceptable carry-over of your previous product, based upon the ADE / PDE, into your next product.
Procedure
Calculate the ADE (Acceptable Daily Exposure) or PDE (Permitted Daily Exposure) according to the following equations and use either result for the calculation of the MACO.
Instead of calculating each potential product change situation, the worst case scenario can be chosen. Then a case with most active API (lowest ADE or PDE) is chosen to end up in the following API with the smallest ratio of batch size divided with TDD (MBS/TDD ratio). If OEL data is available, the ADE or PDE can be derived from the OEL.
Acceptance Criteria based on Therapeutic Daily Dose
When limited toxicity data is available and the Therapeutic Daily Dose (TDD) is known, this calculation may be used. It is used for final product changeover API Process —A to API Process —B.
Procedure
Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.
Acceptance criteria based on LD50
In cases where no other data is available (e.g. ADE, OEL, TDD,…) and only LD50 data is available (e.g. chemicals, intermediates, detergents, …), the MACO can be based upon LD50 data.
Procedure
Calculate the so called NOEL number (No Observable Effect Level) according to the following equation.
The safety factor (SF) varies depending on the route of administration (see below). Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms.
Safety factors
- Topical products: 10 – 100
- Oral products: 100 – 1000
- Parenteral products: 1000 – 10 000
General Limit as Acceptance Criteria
If MACO calculations result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a general limit may be suitable.
- For a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS), and
- For a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS).
Related: Bracketing and Worst Case Rating in Cleaning Validation
Examples of MACO Calculation
1. Acceptance criteria based on Acceptable Daily Exposure
Product A will be cleaned out. The product has an ADE of 5 µg and the batch size is 200 kg. The next product B has a standard daily dose of 250 mg and the batch size is 50 kg. Calculate the MACO for A in B.
MACO = (0.005 mg × 50000000 mg)/ 250 mg = 1000 mg = 1.0 g
Result: MACO is 1.0 g or 1000 mg
2. Acceptance criteria based on Therapeutic Daily Dose
Product A will be cleaned out. The product has a standard daily dose of 10 mg and the batch size is 200 kg. The next product B has a standard daily dose of 250 mg and the batch size is 50 kg. Both A and B are administrated orally and SF is set to 1000. Calculate the MACO for A in B.
MACO = (10 mg × 50000000 mg)/ (1000 × 250 mg) = 2000 mg = 2.0 g
Result: MACO is 2.0 g or 2000 mg
Read details: Cleaning Validation in Pharmaceutical Industry