MACO Calculation In Pharmaceuticals: Learn With 3+ Case Studies and 7+FAQs

The MACO calculation, or the Maximum Allowable Carryover calculation in pharmaceutical manufacturing, determines the maximum residue from a previous product that can remain on shared equipment without risking contamination or harm to the next product or patient. It is essential for cleaning validation to ensure effective cleaning and prevent cross-contamination.

FAQs on MACO Calculation

What is MACO in pharmaceuticals?

MACO stands for Maximum Allowable Carryover — it is the maximum amount of residual active pharmaceutical ingredient (API) or cleaning agent that can be carried over into the next product without causing harm or cross-contamination.

Why is the MACO calculation important?

It ensures patient safety by preventing harmful levels of contamination, supports regulatory compliance, and is a key part of cleaning validation in multiproduct facilities.

What are the main approaches used to calculate MACO?

The most commonly used approaches are:
1. Health-based limit (HBEL) method using ADE or PDE values.
2. 10 ppm method (parts per million).
3. 1/1000 dose criterion method (older, less preferred).

What is the formula for MACO using the HBEL (ADE/PDE) method?

Where:
ADE/PDE = Acceptable Daily Exposure or Permitted Daily Exposure
TDS = Maximum Daily Dose of the next product

What is the difference between ADE and PDE?

Both refer to safe exposure levels:
ADE: Acceptable Daily Exposure (used by EMA)
PDE: Permitted Daily Exposure (used by FDA)
They are essentially the same and based on toxicological data.

What are the acceptance limits based on?

MACO limits are based on:
Toxicological properties of the previous product
Daily dose of the next product
Batch size and equipment surface area
Swab/rinse recovery factors in some cases

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MACO Calculation In Pharmaceuticals: Overview

The MACO is used to determine the maximum amount of a contaminant (carryover) that can be present in the next batch of a drug or product, ensuring that the amount is well below any safety or regulatory threshold. It ensures that carryover does not exceed an acceptable level, which could lead to cross-contamination, misdosing, or unintentional therapeutic effects.

Formula for MACO Calculation

The MACO is typically calculated based on the Threshold of Toxicological Concern (TTC) or No-Observed-Adverse-Effect Level (NOAEL). Here’s a general formula:

Formula-1

Where:

• Toxicological Limit: The acceptable daily intake (ADI) or NOAEL of the compound.
• Batch Size: The amount of the subsequent product being manufactured or processed.

For practical applications, the Toxicological Limit can also be determined based on maximum allowable exposure levels, such as < 1 ppm or specific safety thresholds for drugs, depending on the active ingredient.

Step-by-Step MACO Calculation:

1. Determine the Threshold Value or Toxicological Limit:
   • The Toxicological Limit is usually determined based on the TTC or NOAEL for the active pharmaceutical ingredient (API). Regulatory agencies like the FDA or EMA provide guidelines for acceptable limits for contamination.
   • Example: If the maximum acceptable daily dose for a compound is 10 mg/day, this is your Toxicological Limit.
2. Identify the Size of the Subsequent Batch:
   • For a new batch of drug to be manufactured, this is the total quantity of the active pharmaceutical ingredient (API) in the batch.
   • Example: If the batch size is 1000 kg (1,000,000 g), this will be your Batch Size.
3. Use above the Formula -1
   

MACO = (Toxicological Limit/Batch Size) x10⁶

MACO Calculation Example 1:

If you have an active compound where the acceptable daily intake (TTC) is 10 mg/day, and the batch size is 1000 kg (1,000,000 g):

MACO = (10/1,000,000 ) x 10⁶ = 10μg

Explanation:

• The maximum allowable carryover for Product X from a previous batch is 10 micrograms (µg).
• This means that if there is 10 µg or more of residue from a previous product remaining in the equipment, it would exceed the acceptable limit for Product X.

Essential Considerations in MACO Calculation:

• Safety Factor: A safety factor may be applied to account for uncertainties or variations in contamination levels. This is common when the exact composition or exposure is not fully known.
• Cleaning Validation: To ensure that the MACO level is not exceeded, thorough cleaning validation of equipment is performed after every batch to prevent any residual contamination from affecting the next production cycle.
• Regulatory Guidelines: The calculation of MACO must adhere to guidelines provided by regulatory agencies like ICH, USP, and FDA. These agencies may define specific acceptable limits for different products.

MACO Calculation for Multiple Products)

If a production line is used for multiple products, the calculation must ensure that the carryover from one product to another does not exceed a permissible level. This is often calculated on the worst-case product scenario.

For example:

• Product A: Toxicological Limit = 10 mg/day
• Product B: Toxicological Limit = 20 mg/day
• Batch Size = 500 kg

If calculating for Product A, the MACO may be calculated for both the highest daily dose or the most toxic compound present, ensuring that carryover is below an acceptable threshold for both products.

MACO in Cleaning Validation

In the context of cleaning validation:

• MACO determines the acceptable level of residue from a previous product that can remain on equipment before contamination of the next batch.
• Cleaning protocols are designed to ensure that the residue does not exceed the MACO, which is established during the cleaning validation process.

MACO Calculation Steps:

1. Determine Toxicological Limit: Identify the maximum safe level of exposure or no-observed-adverse-effect level (NOAEL) for the contaminating substance.
2. Batch Size: Measure or estimate the size of the batch of the next product being produced.
3. Apply Formula: Use formula 1 to calculate the maximum allowable carryover:
4. Ensure Compliance: Check that cleaning processes can achieve residue levels below the calculated MACO to prevent cross-contamination.

MACO Calculation Example 2 (Multiple Products on Shared Equipment)

In pharmaceutical production, it is common to use shared equipment for multiple products. In this case, it’s important to calculate the MACO for each product to ensure no cross-contamination occurs between batches.

Given:

• Product A:
  • Toxicological Limit = 5 mg/day.
  • Batch Size = 500 kg (500,000 g).
• Product B:
  • Toxicological Limit = 2 mg/day.
  • Batch Size = 800 kg (800,000 g).

Formula for Each Product:

Explanation:

• Product A: The maximum allowable carryover for Product A from a previous batch is 10 µg.
• Product B: The maximum allowable carryover for Product B from a previous batch is 2.5 µg.
• When sharing equipment, the worst-case scenario is often the key concern. This would mean that the cleaning validation process must be able to remove at least 10 µg of residue from the equipment to ensure both products are not contaminated.

MACO Calculation Example 3 (Safety Factor)

Sometimes, a safety factor is added to the calculation to account for uncertainties, variations in the process, or more stringent contamination controls.

Given:

• Toxicological Limit (TTC) for a highly potent compound = 0.1 mg/day.
• Batch Size for the next production = 200 kg (200,000 g).
• Safety Factor = 10 (this is applied due to the high potency of the active ingredient, ensuring extra caution).

Formula with Safety Factor:

MACO = {(0.1mg x 10)/200000} x 10⁶ = 5μg

Interpretation:

• The maximum allowable carryover in this case is 5 µg (due to the safety factor), which is even more stringent than the initial calculation without the factor.
• This ensures that even trace amounts of the active ingredient will not compromise the quality or safety of the next batch.

MACO Calculation Example 4 (Cleaning Validation for MACO Compliance)

Suppose you’re manufacturing Product C (with a Toxicological Limit of 5 mg/day) in a facility that also produces Product D (with a Toxicological Limit of 2 mg/day). After manufacturing Product C, you need to ensure that carryover does not exceed the MACO before starting Product D.

Given:

• Product C (Toxicological Limit = 5 mg/day, Batch Size = 1000 kg).
• Product D (Toxicological Limit = 2 mg/day, Batch Size = 500 kg).

Step 1: Calculate MACO for Product C:

MACO for Product C = (5mg/100000) x 10⁶ = 5μg

Step 2: Calculate MACO for Product D:

MACO for Product D= (2mg/500000) x 10⁶ = 4μg

Step 3: Cleaning Validation

• After producing Product C, you must ensure that the equipment cleaning process removes at least 5 µg of the previous product’s residue.
• This ensures that no more than 5 µg of carryover remains in the equipment when starting Product D, which has an acceptable carryover limit of 4 µg.

Note: If your cleaning validation test shows a carryover of 7 µg, this exceeds the acceptable MACO for Product D. In this case, additional cleaning protocols (longer rinse cycles, stronger solvents, etc.) should be applied to meet the required MACO for both products.

Expert Tips:

1. MACO Calculation Formula: MACO= Refer Formula-1
2. Multiple Products: When multiple products are produced on shared equipment, the worst-case MACO should be considered for cleaning validation.
3. Cleaning Validation ensures that carryover levels from the previous batch are below the acceptable MACO for the next batch.

Further Reading:

• Automating MACO Calculations in Cleaning Validation