Glossary

MACO (Maximum Allowable Carryover)

What is MACO?

MACO stands for Maximum Allowable Carryover. In the pharmaceutical industry, MACO is a cleaning validation limit defining the highest amount of residue from one product that may be permitted to remain on shared manufacturing equipment before the next product is manufactured.

The purpose of setting a MACO value is to prevent cross-contamination and ensure patient safety, product quality, and regulatory compliance. Regulatory authorities such as the FDA, EMA, and WHO require scientifically justified MACO limits as an integral part of Good Manufacturing Practices (GMP).

Why is MACO Important?

Maximum Allowable Carryover (MACO) is relevant in pharma for ensuring:

  • Prevents Cross-Contamination: MACO ensures that remnants of previously manufactured products, especially active pharmaceutical ingredients (APIs), do not contaminate subsequent products, which could otherwise result in safety risks.
  • Supports Product Quality: By keeping residues below defined thresholds, MACO maintains product purity, potency, and efficacy.

  • Satisfies Regulatory Expectations: Setting and defending a scientifically justified MACO is a core expectation in cleaning validation protocols reviewed during audits and inspections. Inadequate cleaning limits are a frequent finding in regulatory observations.

  • Limiting Risk of Adverse Reactions: By limiting the amount of carryover, MACO reduces the risk of adverse reactions in patients due to contamination or residue from previous products.

How is MACO Calculated?

The Maximum Allowable Carryover (MACO) value is determined using risk-based and scientifically sound approaches. The two most common methods are:

Dose-Based Calculation
This relies on the therapeutic daily dose of both the previous and next product, along with a safety factor. The dose-based MACO formula typically uses:

  • Minimum therapeutic dose (MTD) of the previous product
  • Maximum daily dose (MDD) of the next product
  • Safety factor (usually 1/1000 for oral drugs)
  • Batch size of the next product

Formula:
MACO = (MTD_previous × MBS_next) / (SF × MDD_next)
Where:

  • MTDprevious = Minimum therapeutic dose of the previous product
  • MBSnext = Minimum batch size of the next product
  • SF = Safety factor (typically 1,000 for oral medicines)
  • MDDnext = Maximum daily dose of the next product

2. Health-Based (Toxicological) Approach
This uses Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE) values derived from toxicological data, especially for highly potent or toxic actives.

Formula:
MACO = (ADE_previous × MBS_next) / MDD_next
Where:

 

  • ADEprevious = Acceptable daily exposure of the previous product
  • MBSnext = Minimum batch size of the next product
  • MDDnext = Maximum daily dose of the next product

When neither therapeutic dose nor ADE/PDE data are available, calculations may fall back on toxicological values such as LD50 or regulatory default limits (e.g., 10 ppm).

MACO in Cleaning Validation

During cleaning validation, MACO is used as the residue limit; cleaning procedures must be able to reduce residues on equipment surfaces below the MACO for each product changeover. Modern validation typically includes:

  • Health risk assessment for all residues (APIs, solvents, detergents)

  • Analytical method validation to confirm the detection of MACO levels
  • Swab or rinse sampling to verify cleaning effectiveness

Regulatory and Industry Practice

Setting MACO limits is a requirement across all regions. The MACO calculations and analytical results must be documented and justified in cleaning validation protocols and reports. Failing to establish or exceed MACO limits is a recurring reason for regulatory citations and product recalls internationally.

Best Practices for MACO Calculation

Some of the best practices in MACO calculation for cleaning Validation are –

  1. Use Health-Based Limits First
    When possible, base MACO (Maximum Allowable Carryover) calculations on toxicological data, such as Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE). This method reflects actual patient safety considerations instead of relying solely on traditional generic thresholds.
  2. Always Choose the Lowest Scientifically Supported Limit
    If multiple calculation methods (dose-based, health-based, 10 ppm rule) are available, use the strictest, most protective value. This reduces the risk of cross-contamination and meets global regulatory expectations.
  3. Justify All Inputs and Assumptions
    Clearly document product data, batch sizes, safety factors, and calculation choices. Provide rationales, especially when default values or surrogate data must be used. Regulators expect full transparency for every MACO determined.
  4. Validate All Analytical and Sampling Methods
    Confirm that swab and rinse techniques recover a high percentage of residues, preferably above 70%. Analytical methods should detect residue levels at or below the MACO without interference. Validation must be recorded and repeatable.
  5. Prioritize “Worst-Case” Assessment
    Focus on the most difficult-to-clean equipment areas and the most potent or toxic residues in your product range. Base MACO on these challenging scenarios to ensure robust cleaning validation.
  6. Review and Update Calculations Regularly
    MACO values must be reassessed when new data or products are introduced, equipment changes, or when process modifications impact cleaning. A structured change control process is key.

Common Mistakes in MACO Calculation

  • Using Only Generic Safety Margins
    Applying a blanket safety factor (like 1,000) or relying solely on the 10 ppm threshold, regardless of actual product risk, often results in non-compliant or insufficiently protective limits.
  • Outdated Methods and Assumptions
    Continuing to use old criteria when new ADE/PDE data is available, or not switching to updated toxicological limits for potent products, creates regulatory gaps.
  • Inadequate Sampling
    Only sampling easy-to-reach or visibly clean areas can miss hidden residues. Ignore worst-case locations, and your validation may fail under scrutiny.
  • Lack of Method Validation
    Using unproven analytical or sampling methods undermines the reliability of cleaning validation data.
  • Inconsistent Documentatio
    Failure to document calculation steps, justification, and input values weakens audit readiness and can result in findings.

Setting MACO correctly depends on accurate science, good record keeping, and careful application. Regular reviews, solid validation, and transparent documentation are critical to maintaining compliance and protecting patients during pharmaceutical production.

Summary

MACO (Maximum Allowable Carryover) is a core pharmaceutical concept that determines how much residue from one batch is acceptable to remain on shared equipment before producing the next product. Its accurate calculation and application are critical for patient safety, product quality, and GMP compliance. Properly set MACO values form the foundation for robust cleaning validation, support audit readiness, and reduce the risk of cross-contamination in pharmaceutical manufacturing.