Overview
One limit, distributed backwards and verified forwards
The finished-product limit (K/M) is the only fixed number. Upstream limits are derived from it with the reverse approach and verified by summing every contribution at its specification limit with the cumulative approach.
Calculators
Settings
Calculated values are always shown unrounded; rounding only applies to the proposed specification. Inputs accept a comma or a dot as decimal separator. Work is saved automatically in this browser.
Finished product
Endotoxin limit = K / M
K is the threshold pyrogenic dose set by the route. M is the maximum recommended dose per kg of body weight; for products infused or injected at frequent intervals, the maximum total dose administered in a 1-hour period. Use the paediatric dose when it is higher per kg/h.
Inputs
Raw materials and excipients
Summing the contributions of a compounded solution
Each component is taken at its applied limit — the worst case, not the routine result. Assuming endotoxin does not change during processing, the total must comply with the solution specification. A component with no limit leaves a hole in the budget: assign one.
Components
| Component | Conc.g/L (= mg/mL); v/v fraction for liquids | Limit unit | Product owner spec | Monograph | Supplier CoA | Internal spec | Applied limitsource | ContributionEU/mL | |
|---|---|---|---|---|---|---|---|---|---|
| Total contribution | — | ||||||||
Applied limit, decided in four steps: 1 · the product owner's specification always prevails · 2 · pharmacopoeial monograph, parenteral grade, as written · 3 · supplier CoA vs internal specification: the stricter one · 4 · no limit anywhere: derive it so the excipient cannot consume more than its share of the budget.
Contribution = concentration (g/mL) × applied limit (EU/g); for liquids (EU/mL) = v/v fraction × limit. Enter WFI q.s. as fraction 1 at its compendial limit.
Raw materials and excipients
Deriving a limit when none is given
When no manufacturer specification, monograph or acceptable supplier limit exists, the limit is calculated by subtraction: start from the solution limit and remove the contributions of all the other components.
Inputs
In-process controls · cumulative approach
Sum of contributions
Start from the API or mAb and add each solution introduced at the step. Multiply every volume by its limit, sum the endotoxin units and divide by the total volume. Best when the upstream limits are known and the question is: what is the worst case entering this step?
Inputs to the step
| # | Process step | VolumeL | LimitEU/mL | ContentEU | |
|---|---|---|---|---|---|
| Total | — | — |
Content (EU) = volume (mL) × limit (EU/mL). Each input is taken at its own specification limit.
In-process controls · reverse approach
Distribution of the limit
Start from the finished-product (or formulated bulk) specification, calculate the total endotoxin allowed, subtract what the known intermediates may already contribute and divide by the volume at the step. Best when the process is fixed by the product and the question is: how much may this step contribute?
Final step
Known intermediates
| Intermediate | VolumeL | LimitEU/mL | ContentEU | |
|---|---|---|---|---|
| Σ known | — | |||
Method suitability
Maximum Valid Dilution
Interference is overcome by dilution, never beyond the MVD. When dilution up to the MVD does not remove the interference, a suitable treatment (filtration, neutralisation, dialysis, heating) may be used, provided it is shown to eliminate interference without loss of endotoxin.
Inputs
Documentation
Printable report
Inputs, formulas, intermediate steps and results of the selected calculations, ready to attach to the risk assessment. Use “Print / Save as PDF” and choose “Save as PDF” as the printer.