The Maximum Allowable Carryover (MACO) for an Active Pharmaceutical Ingredient
(API) is determined based on the safety of the next product to be manufactured and the
acceptable residue limits for that product. The MACO ensures that any carryover of the
previous product does not exceed a level that would have a negative impact on the next
product's safety, efficacy, or quality.
General Approach to Calculate MACO:
The MACO is typically calculated using the formula:
MACO=(Minimum daily dose of the next product×Batch size of the next product)Safety Fact
or×Maximum daily dose of the previous product\text{MACO} = \frac{(\text{Minimum daily
dose of the next product} \times \text{Batch size of the next product})}{\text{Safety
Factor} \times \text{Maximum daily dose of the previous
product}}MACO=Safety Factor×Maximum daily dose of the previous product(Minimum dai
ly dose of the next product×Batch size of the next product)
Where:
Minimum Daily Dose of Next Product: The smallest dose required for therapeutic
effect of the next product.
Batch Size of Next Product: The total amount of the next product that will be
manufactured in a batch.
Safety Factor: Typically ranges between 100 to 1000, depending on the risk
associated with the carryover of residues.
Maximum Daily Dose of Previous Product: The maximum dose of the previous
product (whose residue may remain) that could be administered to a patient safely.
Regulatory Guidance:
FDA, EMA, and WHO-GMP guidelines recommend that the MACO calculation
considers the safety of the subsequent product. For example, a highly potent API (like
Methylprednisolone Hemi Succinate) will have a low MACO limit to avoid any
potential contamination, while for less potent APIs, the MACO limit could be higher.
The MACO should not exceed a certain threshold (usually calculated as a fraction of
the maximum allowable dose of the next product) in order to avoid any potential
harmful effects on patients.
CLEANING VALIDATION: MACO CALCULATION REPORT
Manufacturing Line: Shared Line for Two Products are Involved:
Previous Product: Hydrocortisone Hemi Succinate
Next Product: Methylprednisolone Hemi Succinate (MHS)
Total Equipment Surface Area: 500,477.89 cm²Batch Size of MHS (Next Product): 84
kg = 84,000 g = 84,000,000 mg Maximum Daily Dose (MDD) of MHS: 60 mg
1. MACO Calculation Based on 10 ppm Criterion
Formula:
MACO = (10 ppm) × (Batch size of next product in g) / 1,000,000
Calculation:
MACO = (10 × 84,000) / 1,000,000 = 840 mg
2. MACO Calculation Based on Maximum Daily Dose (Therapeutic Dose Method)
Formula:
MACO = (MDD of next product / MDD of previous product) × Minimum batch size
of next product
Assumptions:
MDD of Hydrocortisone Hemi Succinate (Previous Product): 800 mg/day
MDD of MHS (Next Product): 60 mg/day
Batch Size of MHS: 84,000,000 mg
Calculation:
MACO = (60 / 800) × 84,000,000 = 0.075 × 84,000,000 = 6,300,000 mg = 6300 g
3. MACO Calculation Based on LD₅₀ (Toxicological Method)
Formula:
MACO = [(LD₅₀ × Body Weight) / Safety Factor] × (Batch size of next product /
MDD of next product)
Assumptions:
LD₅₀ of Hydrocortisone Hemi Succinate: 2500 mg/kg (rat, oral)
Body Weight: 70 kg
Safety Factor: 1000
Batch Size of MHS: 84,000,000 mg
MDD of MHS: 60 mg
Calculation:
MACO = [(2500 × 70) / 1000] × (84,000,000 / 60) = 175 × 1,400,000 = 245,000,000
mg = 245,000 g
Final Decision:
Lowest of the three calculated MACO values should be used.
✔ Final MACO Limit = 840 mg (based on 10 ppm criterion)
This limit will be used to establish cleaning validation acceptance criteria for the
equipment train used in the manufacture of the above-mentioned products.
Conclusion:
In the worst-case scenario, considering a 10 ppm residue acceptance criterion and a
batch size of 84 kg of Hydrocortisone Hemi Succinate, the calculated Maximum
Allowable Carryover (MACO) for Methylprednisolone Hemi Succinate is 8.5716 mg.
This value is based on a total equipment surface area of 500,477.89 cm² (equivalent to
50.047789 m²).
Therefore, after cleaning, the residual amount of Methylprednisolone Hemi Succinate
on the equipment must not exceed 8.5716 mg to comply with the 10 ppm limit.
Product Information
Previous Product (Residue): Methylprednisolone Hemi Succinate
Next Product: Hydrocortisone Hemi Succinate
Batch Size of Next Product: 84 kg (84,000,000 mg)
Total Equipment Surface Area: 500,477.89 cm² (or 50.047789 m²)
Maximum Daily Dose of Next Product (Hydrocortisone Hemi Succinate): 60 mg
A) 10 ppm-Based MACO
Formula:
MACO= 10 mg residue
---------------------- X Batch size of next product
1,000,000 mg product
MACO= 10
------------- X 84,000,000 = 840 mg
1,000,000
MACO (10 ppm criterion) = 840 mg
B) MDD-Based MACO
Assumptions:
MDD of previous product (Methylprednisolone Hemi Succinate) =
MDD of next product (Hydrocortisone Hemi Succinate) = 60 mg
Surface area of equipment: 50.047789 m²
Formula:
MACO= MDD of next product
---------------------------- x Minimum batch size of next product
MDD of previous product
Alternatively, for residue per surface area:
MACO =MDD next
---------------------- X Batch size next / Surface area
MDD previous
MDD of Methylprednisolone Hemi Succinate = 500 mg
MACO = 60
---------- X 84,000,000 = 10,080,000 total dose basis
500
×
84
,
000
,
000
=
10
,
080
,
000
mg total dose basis
MACO=
500
60
×84,000,000=10,080,000mg total dose basis
But to convert to residue over surface area:
MACO (mg)
=
10
,
080
,
000
84
,
000
,
000
×
50.047789
=
8.5716
mg
MACO (mg)=
84,000,000
10,080,000
×50.047789=8.5716mg
MACO (MDD-based) = 8.5716 mg
Summary Table
Criterion MACO (mg) Comment
10 ppm 840.00 mg Less stringent, commonly used for API cleaning.
MDD-based 8.5716 mg More stringent, patient safety-focused.
Conclusion:
In this case, the MDD-based MACO (8.5716 mg) is much more stringent than the 10
ppm-based MACO (840 mg), and should be adopted as the acceptance limit in
cleaning validation to ensure patient safety.
Product Information
Previous Product (Residue): Methylprednisolone Hemi Succinate
Next Product: Hydrocortisone Hemi Succinate
Batch Size of Next Product: 84 kg (84,000,000 mg)
Total Equipment Surface Area: 500,477.89 cm² (or 50.047789 m²)
Maximum Daily Dose of Next Product (Hydrocortisone Hemi Succinate): 60 mg
1. 10 ppm-Based MACO
Formula:
MACO=10 mg residue1,000,000 mg product×Batch size of next product\
text{MACO} = \frac{10 \, \text{mg residue}}{1,000,000 \, \text{mg product}} \times
\text{Batch size of next product}MACO=1,000,000mg product10mg residue
×Batch size of next product MACO=101,000,000×84,000,000=840 mg\text{MACO}
= \frac{10}{1,000,000} \times 84,000,000 = 840 \, \text{mg}MACO=1,000,00010
×84,000,000=840mg
MACO (10 ppm criterion) = 840 mg
2. MDD-Based MACO
Assumptions:
MDD of previous product (Methylprednisolone Hemi Succinate) = 500 mg (assumed
for example — please confirm the actual value)
MDD of next product (Hydrocortisone Hemi Succinate) = 60 mg
Surface area of equipment: 50.047789 m²
Formula:
MACO=MDD of next productMDD of previous product×Minimum batch size of next
product\text{MACO} = \frac{\text{MDD of next product}}{\text{MDD of previous
product}} \times \text{Minimum batch size of next
product}MACO=MDD of previous productMDD of next product×Minimum batch siz
e of next product
Alternatively, for residue per surface area:
MACO=MDDnextMDDprevious×Batch sizenext÷Surface Area\text{MACO} = \
frac{\text{MDD}_{\text{next}}}{\text{MDD}_{\text{previous}}} \times \
text{Batch size}_{\text{next}} \div \text{Surface Area}MACO=MDDprevious
MDDnext×Batch sizenext÷Surface Area
Assuming:
MDD of Methylprednisolone Hemi Succinate = 500 mg
MACO=60500×84,000,000=10,080,000 mg total dose basis\text{MACO} = \
frac{60}{500} \times 84,000,000 = 10,080,000 \, \text{mg total dose
basis}MACO=50060×84,000,000=10,080,000mg total dose basis
But to convert to residue over surface area:
MACO (mg)=10,080,00084,000,000×50.047789=8.5716 mg\text{MACO (mg)} = \
frac{10,080,000}{84,000,000} \times 50.047789 = 8.5716 \, \
text{mg}MACO (mg)=84,000,00010,080,000×50.047789=8.5716mg
MACO (MDD-based) = 8.5716 mg
Summary Table
MACO
Criterion Comment
(mg)
Less stringent, commonly used for API
10 ppm 840.00 mg
cleaning.
MDD-based 8.5716 mg More stringent, patient safety-focused.
Conclusion:
In this case, the MDD-based MACO (8.5716 mg) is much more stringent than the
10 ppm-based MACO (840 mg), and should be adopted as the acceptance limit in
cleaning validation to ensure patient safety.
