Steps to Calculate MACO for Cleaning Validation in Pharmaceuticals

Cleaning validation is one of the most studied and analyzed processes during the pharmaceutical inspections since it demonstrates that the cleaning of production equipment can be performed with high quality and with full assurance that there would be no cross-contamination. While visual inspection of surface cleanliness is crucial, authorities also require companies to define the maximum allowable residue levels to ensure that effective cleaning will take place.

The maximum allowable carryover or MACO is the highest limit of the residue of the previously manufactured product that can be transferred to the product that is currently manufactured while ensuring that the safety for patients will not be compromised. MACO is the basis for defining analytical acceptance criteria and determining whether the cleaning validation results are considered acceptable.

Despite the commonness of MACO calculations, they are not properly understood. I reviewed various validation protocols where these calculations were taken from earlier projects without check the assumptions or toxicological information. The MACO figure is not credible unless the information used in the calculations is credible. Therefore, any calculation should be supported by relevant scientific evidence.

Importance of MACO in Cleaning Validation

All cleanliness validation tests are conducted in accordance with pre-established criteria for acceptable levels of contamination. Without scientifically supported residue based contamination limits, the evaluation of the success of cleaning treatment cannot be performed.

The significance of well calculated MACO lies in the following:

1. Protection of patients from cross-contamination,
2. Establishment of criteria for acceptable levels of residues,
3. Support of cleanliness validation protocols,
4. Proof of compliance with good manufacturing practice (GMP),
5. Provision of consistent basis for analytical testing,
6. Support of decisions regarding risk-based validation.

Instead of applying arbitrary limits such as "10 ppm" or "visibly clean," the standards set by regulatory organizations currently prescribe the application of health based exposure limits (HBELs) to the greatest possible extent.

Understanding the Concept of Carryover

Let's assume Product A is produced today and Product B is produced tomorrow using one and the same equipment. Even after cleaning, there might still be traces of Product A left on the surfaces of the equipment.

The purpose of cleaning validation is not to show that no residues are present. Rather it is to show that any residue present is below an acceptable scientific value and doesn't pose a risk for a patient who is going to get Product B.

Information Required Before Calculating MACO

It is essential to acquire product and process information before computation can begin. Pertaining to the method used, this information includes:

• The therapeutic dose of the prior product
• The daily minimum dose of the succeeding product
• The HBEL or ADE or PDE
• The batch size of the next product
• The total surface area of the shared equipment
• The area of swab sampling
• The recovery factor from the swabs used
• The toxicological data unique to the product

If the information is incomplete, it could lead to invalid limits.

MACO Calculation Methods

There have been a few approaches to calculate MACO historically. Currently, health-oriented exposure limits are favored by groups that regulate the industry although the old methods might still be present in validation programs that have been used for a long time.

There are the three main methods available today:

• The therapeutic dose method
• The 10 ppm method
• Health-Based Exposure Limit (HBEL/PDE/ADE) method

Among the technique mentioned above, the HBEL method is the scientific standard now.

Step 1: Find out Health-Based Exposure Limit

One starts with finding a maximum level of Permitted Daily Exposure (PDE), Acceptable Daily Exposure (ADE) or any other established health-based limit for the former product. Such figures are formed on the results of toxicological studies and rely on the following factors:

• The pharmacological action
• Toxicity
• Genotoxicity
• Carcinogenicity
• Reproductive toxicity
• Safety factors

In case there is no official PDE, its value has to be derived by the appropriate expert in toxicology.

Step 2: Identify the Batch Size of the Next Product

The amount of residue that is safely transferable is contingent on the batch size of the upcoming product.
For instance,

• Previous Product: API A
• Next Product Batch Size: 500 kg

Larger batch sizes dilute any existing residue effectively allowing more carryover. Only the smallest commercial batch size of the next product should be used unless otherwise specified in company policy. This minimizes waste dilution and hence, it is considered the worst-case scenario.

Step 3: Apply the MACO Formula

When we use the health-based method for the MACO system, we have simply the equation:

MACO = (PDE × Batch Size of Next Product) ÷ Maximum Daily Dose of Next Product

Where:
PDE = Permitted Daily Exposure of last product
Batch Size = Smallest batch size of the next product
Maximum Daily Dose = Maximum dose of the next product in a day

Thus, the obtained number tells us the maximum allowable carryover in the manufacturing batch.

Step 4: Convert MACO to Surface Residue Limits

The MACO value which we have just calculated can be applied to the entire equipment train but has to be converted into a limit that we can use to verify via swab sampling. The procedure is very simple. The MACO value has to be divided by the equipment contact surface area.

Here is a sample calculation:
Total surface area of the equipment = 40,000 cm²
MACO = 200 mg
Surface limit 200 mg ÷ 40,000 cm² = 0.005 mg/cm²
The result gives the acceptance criterion for the surface sampling.

Step 5: Adjust for Swab Recovery

When we have our surface limit, we can start the process of adjusting it for swab recovery. It is known that swab sampling cannot recover 100% of residues on the surface, so we need to carry out some recovery studies.

In other words, swab recovery studies will help us assess the efficacy of our swab technique in residue removal.

In our example, surface limit = 5 µg/cm²
and swab recovery = 80%

Thus we will be able to calculate the analytical acceptance limit, based on the recovery factor.

A Practical Example

Let's take into consideration the example we will create:
Potency of Product A = 2 mg per day
The smallest batch size of Product B = 200,000 g.
The highest daily dose of Product B = 2 g per day.

By using the formula:
MACO = (2 mg × 200,000 g) ÷ 2 g
= (2 x 200,000 x 1000) ÷ (2 x 1000)
= 200,000 mg = 200 g

As a result of converting the units, the obtained MACO is the amount of Product A which can be found in the complete batch of Product B safely.

Then, the number is transformed into surface value based on total amount of areas of the equipment in contact as well as altered based on validated recovery of swabs.

The presented example points out that MACO interpretation cannot be produced just in one way, it requires several steps to calculate in order to obtain the relevant cleaning limit.

Importance of Worst Case Product Selection

MACO calculations should never be done separately. They are always related to worst case product selection.
A product with following things is very often selected as the worst case product for cleaning validation.

• Very low PDE
• High pharmacological effectiveness
• Poor cleaning recovery
• Low solubility
• Very high adhesion to the surface of manufacturing equipment

Wrong product choice can lead to either too strict or insufficient residue limits.

Common Errors in MACO Calculations

While auditing cleaning validation documentation, we notice several common errors.
This includes:

• Using the old PDE or ADE values.
• Using the largest instead of the smallest batch size.
• Ignoring recoveries from swabbing.
• Confounding the units (mg, g, µg) and not performing the actual conversion.
• Using the same MACO value for different pieces of equipment without assessing them.
• Using always the historical limits without providing any scientific rationale to do so.
• Not reassessing MACO after the product formulation or toxicological change has been made.

A mere unit conversion error is enough to change the acceptance limit significantly and make the cleaning validation study invalid.

Good Documentation Practices

Every MACO calculation must be completely traceable and subject to independent verification. Validation documentation must contain:

• Source of toxicological information
• PDE or ADE justification
• Calculation sheet
• Unit conversions
• Reasons for batch size
• Calculation of the area of equipment
• Test results of the wipe
• Final criteria for approval of results
• Signature of reviewer and approver

Properly documented calculations enable smooth passage through regulatory inspections and make it less likely that questions will arise regarding the scientific justification for the established residue limits.

MACO is much more than a formula in mathematics. It is actually an important scientific connection between toxicological risk assessment and current cleaning validation. Once health limits are set, it can be said with an evidence that cleaning processes really work in avoiding cross-contamination and ensuring patients’ safety.

In my opinion, the most successful MACO calculations are those conducted with the active involvement of specialists from validation, toxicology, quality control and analytical scientific domains. Therefore, it can be stated that such an integrated approach allowed to make calculations credible from the scientific standpoint, executable for verifying and completely compliant with the newest regulations. In the light of the transition of the pharmaceutical production to the risk-based quality systems, it is very important to know how to perform MACO calculations.

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