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MACO Calculation prashant singh

The document outlines the calculation methods for Maximum Allowable Carryover (MACO) based on three criteria: Health Based Data, Therapeutic Daily Dose (TDD), and LD50. It provides formulas for calculating Acceptable Daily Exposure (ADE) and MACO using various parameters such as NOAEL, body weight, and safety factors. Additionally, it specifies acceptance criteria for different scenarios depending on the available toxicity data.

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prashant
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7 views

MACO Calculation prashant singh

The document outlines the calculation methods for Maximum Allowable Carryover (MACO) based on three criteria: Health Based Data, Therapeutic Daily Dose (TDD), and LD50. It provides formulas for calculating Acceptable Daily Exposure (ADE) and MACO using various parameters such as NOAEL, body weight, and safety factors. Additionally, it specifies acceptance criteria for different scenarios depending on the available toxicity data.

Uploaded by

prashant
Copyright
© © All Rights Reserved
Available Formats
Download as DOCX, PDF, TXT or read online on Scribd
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MACO Calculation

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)

BW Body Weight of an average Adult


(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

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