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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