The Maximum Allowable Carryover (MACO) is the acceptable transferred amount of a previous substance into the next batch of a product during manufacturing. It represents the maximum amount of residue from a prior product that can remain on manufacturing equipment after cleaning and still be considered safe for the next product manufactured using the same equipment.
Understanding MACO
MACO calculations are critical in pharmaceutical manufacturing, biotech, and other industries where product purity and patient safety are paramount. It helps determine the effectiveness of cleaning procedures and sets limits to prevent cross-contamination. A general limit often applied is 10 ppm, which can be translated to 0.001% of the minimum batch size (MBS).
Key Considerations for Determining MACO
Several factors are considered when calculating and defining the MACO value:
- Minimum Batch Size (MBS): The size of the smallest batch manufactured using the equipment.
- Toxicity of the Previous Product: The inherent toxicity of the substance being carried over is a critical factor. Highly potent compounds will have much lower MACO limits.
- Therapeutic Dose of the Next Product: The typical therapeutic dose of the product being manufactured after cleaning.
- Safety Factors: Applying safety factors to account for uncertainties and ensure patient safety.
- Cleaning Validation Data: Data from cleaning validation studies that demonstrate the effectiveness of the cleaning process.
- Regulatory Guidelines: Compliance with regulatory guidelines from agencies like the FDA (Food and Drug Administration) or EMA (European Medicines Agency).
MACO Calculation
While specific formulas may vary depending on the industry and regulatory requirements, a common calculation approach is as follows:
MACO = (Acceptable Daily Intake (ADI) x Batch Size of Next Product) / (Dose of Previous Product)Where:
- ADI is often calculated based on animal toxicity data divided by a safety factor.
- Batch Size of Next Product refers to the minimum batch size.
- Dose of Previous Product is the maximum daily dose of the previous product.
Another general guideline is:
MACO = 0.001% of the minimum batch size (MBS) if using the 10 ppm guideline.
It's important to note that the calculated MACO must then be compared to visually clean limits and swab/rinse sampling results to ensure compliance.
Rationale and Documentation
It is crucial that the MACO value is scientifically justified and documented. This rationale should include:
- The basis for the acceptable daily intake (ADI).
- The rationale for the safety factors applied.
- The data from cleaning validation studies.
Acceptable Levels
Qualified levels, based on a scientific and documented rationale, are acceptable. This means that companies can justify their MACO limits based on a thorough risk assessment and scientific data, as long as it ensures product safety and patient health.
