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

MACO Maximum Allowable Carryover,
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)
BW Body Weight of an average Adult
(i.e. 70 Kg)
UFc Composite Uncertainty Factor ,
Combination of factors which
reflects the inter-individual
variability, inter species differences , sub chronic to chronic
extrapolation
MF Modifying Factor, a factor to
address uncertainties not covered
by the other factors
PK Pharmacokinetics Adjustments
TDDnext Std. therapeutic daily dose for the
next product (mg/day)
MBSnext Minimum Batch size for the next
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

MACO Maximum Allowable Carryover,
Acceptable transferred amount
from the previous product into the next product
TDDprevious Std. therapeutic daily dose for the
investigated product (mg/day)
TDDnext Std. therapeutic daily dose for the
next product (mg/day)
MBSnext Minimum Batch size for the next
product (s) where MACO can end
up (mg)
SF Safety factor (Normally 1000 is
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

MACO Maximum Allowable Carryover,
Acceptable transferred amount
from the previous product into the next product
NOELprevious No Observed Effect Level (mg/day)
LD50 Lethal Dose 50 in mg/kg Animal.
Identification of animal (mouse,
Rat etc.) & Route of Administration  (IV, oral etc.) is important
BW Body Weight of an average Adult
(i.e. 70 Kg)
2000 Empirical Constant
TDDnext Std. therapeutic daily dose for the
next product (mg/day)
MBSnext Minimum Batch size for the next
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

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