When a pharmaceutical unit makes several products on the same equipment, a trace of product A can end up in the next batch of product B. Cleaning validation proves that the cleaning process removes the residue down to a level that cannot harm a patient. The maximum allowable carryover (MACO) is the number that defines that level. Every swab limit, rinse limit and sampling plan in a cleaning protocol comes from it, so an error in the MACO carries through the whole validation.
This guide explains the three common ways of calculating MACO, shows an example with every step, and explains how to turn the answer into limits that a laboratory can actually test.
What MACO means
MACO is the largest amount of a previous product’s active ingredient that may remain on shared equipment and still pass into the next product without a meaningful risk. It is expressed in mass, usually milligrams, for the whole next batch. The calculation is always made for a worst-case pair, the previous product that is the most potent or hardest to clean, and the next product with the smallest batch and the largest daily dose, because those are the conditions that give the lowest, strictest limit.
The three common approaches
1. Dose-based (therapeutic dose)
The carryover into one daily dose of the next product should not exceed a small fraction, traditionally 0.1%, of the smallest daily dose of the previous product.
All three quantities must be in the same units. The safety factor of 1,000 corresponds to the 0.1% rule. A stricter factor is used for some dosage forms, such as injectables, according to your own policy.
2. The 10 ppm criterion
No more than 10 parts per million of the previous product may be present in the next product. For a batch measured in kilograms this is simple:
3. Health-based exposure limit (PDE or ADE)
A toxicologist sets a permitted daily exposure (PDE) or acceptable daily exposure (ADE) for the previous product, the amount a person could take every day for life without harm. It replaces the therapeutic dose and the safety factor:
Regulators in the EU expect health-based limits for shared facilities, and the method is the most scientifically defensible. It needs a documented toxicological assessment for each product.
Worked example
Take following supposed values
| Input | Value (illustrative) |
|---|---|
| Product A (previous): smallest daily dose of active | 10 mg |
| Product B (next): smallest batch size | 200 kg (200,000,000 mg) |
| Product B (next): largest daily dose, by weight of product | 2,000 mg (4 tablets of 500 mg) |
| Safety factor | 1,000 |
| Shared equipment surface area | 50,000 cm² |
| Swab area | 25 cm² |
| Rinse volume for the equipment train | 100 L |
The three approaches give these results:
| Approach | Calculation | MACO |
|---|---|---|
| Dose-based (0.1% of a dose) | (10 × 200,000,000) ÷ (1,000 × 2,000) | 1,000 mg |
| 10 ppm | 10 mg/kg × 200 kg | 2,000 mg |
| Health-based (PDE of 1.5 mg/day, illustrative) | (1.5 × 200,000,000) ÷ 2,000 | 150,000 mg |
The dose-based result, 1,000 mg, is the lowest of the first two, so it governs unless your procedure says otherwise. Where a PDE exists, it should be assessed together with the others, and the final limit is chosen according to your approved cleaning validation policy. The lowest justified value is the one carried forward.
Turning MACO into limits you can test
A laboratory cannot test “1,000 mg per batch”. It tests a swab or a rinse sample, so the MACO is divided across the equipment surface or the rinse volume.
| Limit type | Calculation | Result |
|---|---|---|
| Surface limit | 1,000 mg ÷ 50,000 cm² | 0.02 mg/cm² = 20 µg/cm² |
| Swab limit (per 25 cm² swab) | 20 µg/cm² × 25 cm² | 500 µg per swab |
| Rinse limit | 1,000 mg ÷ 100 L | 10 mg/L (10 µg/mL) |
Two corrections are needed. First, swabbing never recovers everything, so the recovery of the method is measured during method validation, and each result is divided by it before comparing with the limit. For a recovery of 80%, a result of 400 µg on a swab corresponds to 500 µg on the surface. Second, the analytical method must be able to measure well below the limit, which means its limit of quantitation should be comfortably lower than 500 µg per swab in this example.
Step-by-step checklist
- List the products made on the shared equipment train, and the equipment surfaces that touch the product.
- Pick the worst-case previous product by potency, toxicity, solubility and difficulty of cleaning.
- Gather the smallest daily dose, and the PDE where available, for each possible previous product.
- Gather the smallest batch size and the largest daily dose for each possible next product.
- Calculate the MACO by each approach your policy uses, keeping the units consistent. A unit conversion check avoids slips between mg, g and kg.
- Choose the lowest justified value, and record why.
- Convert it into surface, swab and rinse limits using the total shared surface area.
- Confirm that the analytical method, its recovery and its limit of quantitation suit the limits.
- Write the limits, the calculation and the reasoning into the cleaning validation protocol.
Common mistakes
- Using the largest daily dose of the previous product instead of the smallest.
- Using the average or the largest batch of the next product, not the smallest.
- Mixing mg, g and kg between the three quantities, so the answer is out by a factor of a thousand.
- Using the surface area of a single machine when the limit must be spread over the whole shared equipment train.
- Forgetting to correct swab results for recovery.
- Choosing a limit that the analytical method cannot measure.
- Using the 10 ppm figure alone, without checking it against the dose-based and health-based results.
- Ignoring detergent residues, which also need a limit.
Frequently asked questions
Which MACO approach is best?
Many sites calculate more than one and use the lowest justified result. A health-based limit is the most defensible where a toxicological assessment is available.
Why use the smallest batch of the next product?
A smaller batch dilutes the carryover less, so the same residue gives a higher concentration. The smallest batch gives the strictest, safest limit.
Does MACO apply to cleaning agents too?
The same logic applies, but the limit is based on the toxicity of the cleaning agent, not on a therapeutic dose. Most protocols set a separate limit for detergent residues.
Is visual cleanliness enough?
No. Equipment must be visibly clean, but visual inspection cannot show the low levels that MACO limits cover, so measured limits are still required.