GMP & GUIDELINES , 

PHARMA INDUSTRY GUIDELINES , VALIDATION

MACO Calculation
Date: 07/03/2019Author: PharmaState Blog0 Comments

Maximum Allowable Carryover (MACO) shall be calculated based upon theses three
criteria.

Using Health Based Data

Based on Therapeutic Daily Dose (TDD)

Based on LD50

Acceptance Criteria using Health Based Data

CalculateADE (Acceptable Daily Exposure) according to following equation & use the
result for the calculation of MACO.

             NOAEL  × BW

ADE   =    ———————————

                UFc  × MF × PK

From ADE value, MACO can be calculated according to;

                      ADEprevious × MBSnext

MACO   =      ———————————–

                 TDDnext
TDDnext

Maximum Allowable Carryover, 

MACO Acceptable transferred amount 
from the previous product into the next product

ADE Acceptable daily Exposure (mg/day)

NOAEL No observed Adverse Effect Level (mg/kg/day)

Body Weight of an average Adult

BW
(i.e. 70 Kg)

Composite Uncertainty Factor ,

Combination of factors which 
UFc reflects the inter-individual 
variability, inter species differences , sub chronic to chronic 
extrapolation

Modifying Factor, a factor to 

MF address uncertainties not covered 
by the other factors

PK Pharmacokinetics Adjustments

Std. therapeutic daily dose for the 

TDDnext
next product (mg/day)

Minimum Batch size for the next 

MBSnext product (s) where MACO can end 
up (mg)

Acceptance Criteria Based On Therapeutic Daily Dose

When limited toxicity data is available & therapeutic daily dose is also known, then this
method may be used for final product changeover API process.

                       TDDprevious × MBS next

MACO   =     —————————————–

                     SF × TDD next

Maximum Allowable Carryover, 

MACO Acceptable transferred amount 
from the previous product into the next product

Std. therapeutic daily dose for the

TDDprevious
investigated product (mg/day)

Std. therapeutic daily dose for the 

TDDnext
next product (mg/day)

Minimum Batch size for the next

MBSnext product (s) where MACO can end
up (mg)

Safety factor (Normally 1000 is 

SF
used in calculation based on TDD)

Acceptance Criteria Based on LD50

In case where no other data is available (e.g. ADE, OEL, TDD etc.) & only LD50 data is
available, then MACO can be based upon LD50 Data.

Calculation of NOEL Number (No Observed Effect Level) & this result is used for the
MACO calculation.

                        LD50 × BW

NOEL   =     ——————————-

                         2000

MACO can be calculated according to:

                      NOELprevious × MBSnext

MACO   =    ——————————————

                     SFnext × TDDnext

Maximum Allowable Carryover, 

MACO Acceptable transferred amount 
from the previous product into the next product

NOELprevious No Observed Effect Level (mg/day)

Lethal Dose 50 in mg/kg Animal. 

LD50 Identification of animal (mouse, 
Rat etc.) & Route of Administration  (IV, oral etc.) is important

Body Weight of an average Adult 

BW
(i.e. 70 Kg)

2000 Empirical Constant

Std. therapeutic daily dose for the 

TDDnext
next product (mg/day)

Minimum Batch size for the next 

MBSnext product (s) where MACO can end 
up (mg)

SFnext Safety factor

Safety Factor (SF) varies depending on the ROA (Route of Administration)

Generally a factor of 200is employed when manufacturing APIs to be administered in

Oral Dosage Forms.

Topical 10-100
Oral Products 100-1000

Parenterals 1000-10000