MACO calculation with HBEL(Health-Based Exposure Limits) in cleaning validation

Maximum allowable carry over[MACO] calculation is changed in APIC [ Active pharmaceutical ingredients comitte] and the same was accepted by almost all regulatory bodies. So we need to change from TDD based calculation to HBEL calculation.

The Maximum Allowable Carryover (MACO) should be based upon the Health-Based Exposure Limits (HBEL), which can be an Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE), calculated when sufficient data is available. The principle of MACO calculation is that you calculate your acceptable carry-over of your previous product, based upon the HBEL, into your next material

MACO =HBEL previous x MBSnext x PF / TDDnext x SF

MACO Maximum Allowable Carryover: acceptable transferred amount from the previous product into your next material (mg)

HBEL : Health-Based Exposure Limit (mg/day) of the previous compound

MBSnext : Minimum batch size for the next material(s) (where MACO can end up) (mg)

TDDnext : Maximum Therapeutic Daily Dose for the next material (mg/day)

PF : Purging Factor reflects the ability of a process to reduce the level of the previous product in the downstream synthetic route of the next material (in case the next material is not yet the final API). The default value is “1” unless R&D can provide case-specific purging ability evidence (e.g. in case of control LOD limitation.)

SF: Safety factor reflects the effects from the interaction between previous product and next material. This factor should be applied in case of a risk for patient safety. Possible risk are for example contra-indications, possible allergens, risk for children, previous products that should not be taken daily, next material which is only applied once, but with daily controlled release of the active product, etc (case-by-case specific). Assessed by a toxicologist. In case of no effects from the interaction between previous product and next material can be found the default value is “1”

Example 1:

Product A will be cleaned out. The product has an ADE of 2 μg and the batch size is 200 kg. The next product B has a standard daily dose of 250 mg and the batch size is 50 kg. Calculate the MACO for A in B.

MACO =HBEL previous x MBSnext x PF / TDDnext x SF

Product A details:

ADE= 2µg= 0.002mg

Batch Size: 200 kg

Product B Details:

TDD=250mg

Batch Size: 50Kg

Safety factor = 1

Purging Factor= 1

MACO = 0.002 (mg) x 50 000 000 (mg)x1 / 250 (mg)x1 =400 (mg)

Result: MACO is 0.4 g (400 mg)

Example 2:

Product A will be cleaned out. The product has an ADE of 20 μg and the batch size is 50 kg. The next product B has a standard daily dose of 250 mg and the batch size is 200 kg. Calculate the MACO for A in B.

Product A details:

ADE= 20µg= 0.020mg

Batch Size: 50 kg

Product B Details:

TDD=250mg

Batch Size: 200Kg

Safety factor = 1

Purging Factor= 1

MACO = 0.020 (mg) x 200 000 000 (mg)x1 / 250 (mg)x1 =400 (mg)

Result: MACO is 1600mg(1.6gm) this is too high

Then we will go for General limit

Companies may choose to have a MACO upper limit as an internal policy, if MACO calculations result are less stringent, or toxicological data for intermediates are not known, the approach of a general limit may be suitable. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch.

Establish MACO, based on a general limit, using the following equations.

MACO = MAXCONC x MBS

MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product (“previous”). Calculated from general ppm limit.

MAXCONC General limit for maximum allowed concentration (mg/kg or ppm) of “previous” substance in the next batch.

MBS Minimum batch size for the next product(s) (where MACO can end up)

For Drug products maxconc is 10 ppm and for drug products it is 100 ppm

Example:

MACO = MAXCONC x MBS

MBS =200Kg

MAXCONC = 10mg/kg x 200kg

=2000 mg

Note: calculation of ADE and PDE shall be in next article.