Pharmaceutical Calculation Suite
The largest quantity of residual active from the previous product that may be carried into the next product made on shared equipment — computed by four methods, with the lowest candidate governing.
Maximum Allowable Carryover (MACO) is the largest quantity of a residual active from a previously manufactured product (Product A) that may be carried over into the next product (Product B) made on shared equipment, before the residue is judged unsafe or non-compliant. MACO is a total quantity (mg) spread over the batch of Product B; it is later converted to a surface limit (µg/cm²) or an analytical limit (e.g. a TOC or HPLC acceptance value) for the cleaning method to test against.
Four methods are in common use. Each produces a candidate MACO; the lowest (most conservative) candidate governs unless a documented rationale excludes a method — for example, the dose-based methods do not apply to compounds without an established therapeutic dose, and the 10 ppm method is a default only.
Where this is used:
Define units once and carry them through every step. Keep all masses in the same unit — the most common error is entering a batch size in grams while treating it as milligrams, which understates the MACO by 1000×.
Units: (mg/day × mg) / (— × mg/day) = mg. Permits at most 1/SF of Product A's minimum therapeutic daily dose in a full daily dose of Product B; SF = 1000 is the common 1/1000-dose convention.
Units: mg × (mg/mg) = mg. A generic default; use only when no dose- or health-based value applies.
Units: (mg/day × mg) / (mg/day) = mg. When a toxicologically derived ADE (equivalently HBEL/PDE) exists for Product A, this is the health-based limit the EMA HBEL guideline expects to drive the decision.
Units: (mg/kg/day × kg) / — = mg/day. The calculator estimates the NOEL from an entered LD50 (with species and route recorded) using the empirical ÷2000 conversion of APIC (2021) §4.2.1.2 (the factor traces to Layton et al. 1987), then derives the acceptable daily intake with your body weight and safety factor. If you have a measured NOEL, prefer a toxicologist-derived ADE/HBEL (Method 3).
Units: (mg/day × mg) / (mg/day) = mg. Exactly as Method 3, with ADI in place of ADE. Body weight appears once, in Step 4a, to turn a per-kg NOEL into a per-person daily intake — it must not appear a second time in the denominator.
Governing MACO: the lowest of the calculated candidates governs. A method is only a valid candidate if its inputs exist and apply — exclude a method with a written rationale rather than silently dropping it. Method 2 (10 ppm) is a floor/default, not a health-based limit; where an ADE/HBEL exists, Methods 1 and 3 (and 4) should drive the decision. In the calculator, three methods are selectable — dose-based (Method 1), health-based ADE/HBEL (Method 3), and the LD50-based toxicological route (Method 4), which computes the 10 ppm default of Method 2 as a built-in sub-criterion and takes the lower of the two; deselecting Method 4 therefore also drops the 10 ppm floor from the comparison.
| Symbol | Variable | Units | Description |
|---|---|---|---|
| MinTDDA | Minimum therapeutic daily dose of Product A | mg/day | The lowest therapeutic dose of Product A prescribed to patients, from the approved product label or clinical literature. |
| MaxDDB | Maximum daily dose of Product B | mg/day | The highest therapeutic daily dose of Product B — the exposure route for any carried-over residue. |
| MBSB | Minimum batch size of Product B | kg (input) / mg (in formulas) | The smallest batch quantity of Product B manufactured on the shared equipment. The calculator input is kilograms (100,000 g = 100 kg) and is converted to mg internally for the formulas above — entering a value already converted to mg would overstate the batch a million-fold. |
| SF | Safety factor | dimensionless | 1000 for the 1/1000-dose convention (Method 1) and for scaling a NOEL to an acceptable daily intake (Method 4, Step 4a). APIC (2021) suggests tiers by the next product’s route: topical 10–100, oral 100–1,000, parenteral/inhalation 1,000–10,000 — the calculator warns when your SF sits outside the tier. |
| ADEA | Acceptable Daily Exposure (= HBEL/PDE) of Product A | mg/day | Toxicologically derived daily exposure limit for Product A, equivalent to the PDE of the EMA HBEL guideline. From qualified toxicological assessment. |
| NOELA | No-observed-effect level of Product A | mg/kg/day | The highest dose in animal studies producing no observed effect. In the calculator it is estimated from an entered LD50 (÷2000, APIC 2021) when no ADE is available (Method 4). |
| BW | Human reference body weight | kg | Converts a per-kg NOEL to a per-person daily intake in Step 4a. Enters the calculation exactly once. See Assumptions below for the choice of value. |
Scenario: A facility produces Lisinopril tablets (Product A) and Metformin tablets (Product B) on shared equipment. Lisinopril: MinTDD = 5 mg/day, ADE = 0.15 mg/day, NOEL = 25 mg/kg/day. Metformin: minimum batch size 100,000 g = 100 kg (the calculator input), which the calculator converts to 100,000,000 mg for the formulas; maximum daily dose 4,000 mg/day. SF = 1000; BW = 70 kg.
PharmaCalc returns your MACO by up to four candidate limits, with the governing limit identified. It is computed server-side against the published method and written into a GMP PDF report with the inputs, formula chain, references, document control and signature pages — traceable to the software release that produced it.
Open the MACO calculator — free demo