1. What methods are used in cleaning validation MACO Calculation?
There are a few different methods which have been used to calculate the maximum allowable carry over (MACO). If we look at the changes in the approach to calculating limits over time, we see the evolution of the MACO calculations from arbitrary limits to Science, health-based and risk-based limits.
Initially an arbitrary MACO calculation method was Part Per Million (PPM). Then dose-based criteria, using limited data like LD50 values was applied to derive allowable carry over into the next product. At present, the current regulatory thinking for MACO limits include the health-based limit calculations (HBELs) using acceptable or permitted daily exposure (ADE/ PDE). ADE and PDE values are calculated based on scientifically sound toxicological data and incorporate a risk-based approach to derive their values.
One should perform MACO for Active Pharmaceutical Ingredients, microbial residue, cleaning agent residue and disinfectants where applicable.
2. How do I calculate cleaning validation limits using spreadsheets?
Using spreadsheets are ubiquitous around the world and its intended use for businesses is to manage financial data and perform financial analysis.
Spreadsheet software was never intended to be used for cleaning validation data and advanced MACO calculations. These spreadsheets and spreadsheet tools have no built in compliancy, data integrity features, or formula validation features, and although some companies have used such spreadsheets for calculating cleaning validation limits, it is really a work around and can never replace a software system dedicated to the cleaning validation process.
It is better to use a dedicated cleaning validation software product that not only adheres to Data Integrity and 21 CFR Part 11 regulations but is flexible enough to calculate hundreds of risk factors simultaneously and provide the worst-case scenarios. Novatek International provides a pharmaceutical cleaning validation software.
3. How do I find the worst-case product?
The worst-case product is determined using the properties of both the product and the API in the product. The first measure of worst case is the toxicity based on daily exposure, the lower the PDE the more toxic the product is. Worst case also considers physical properties like solubility in water, solubility in other solvents, or the cleanability.
It is possible to use a simple calculation to obtain a risk score by assigning the toxicological data into ranges, the solubility, and other physical properties into risk ratings, and then assigning a weighting to each criterion.
Risk based worst case analysis takes into consideration the risk associate with every factor and choose the worst case among several options. Sometimes hard to reach equipment, hard to clean surface or a non-soluble API maybe worse than toxicity, so one needs to evaluate all types of risks and scientifically choose the worst-case scenario. Finally, the worst-case method should also consider the potent and non-potent products when determine the marker compound.
4. What are the MACO equations?
There are different approaches for calculating the MACO values on the batch level. These are equations used to calculate MACO. The last equation is the one which uses the toxicological data to calculate the MACO value. The industry is transitioning from MACO to MSC which represents the maximum safe carry over.
5. How do I calculate cleaning validation limits?
In the PIC/S PI 006-01 Guidelines, the following statements are made regarding the definition of limits.
Carry-over of product residues should meet defined criteria, for example the most stringent of the following three criteria:
a) No more than 0.1% (1/1000th) of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product.
b) No more than 10 ppm of any product will appear in another product.
c) No quantity of residue should be visible on the equipment after cleaning procedures are performed.
In the last 10 years the dose-based calculation (e.g., 1/1000th dose) has prevailed in the manufacture of pharmaceutical products. Where dose data are not available, an absolute value (e.g., 10 ppm) is prescribed.
For residues where dose data are not available but toxicological data are (e.g. tensides), it is normal to perform the calculation based on the NOEL/ADI (no effect level/acceptable daily intake) value along with a safety factor (SF).
Cleaning limits are calculated on the batch level, but they also need to be calculated at the sample point level so the results for samples collected for cleaning validation and interim monitoring events after cleaning operations can be compared to these limits to confirm that the cleaning process is effective. These equations use the shared and are and the sample point area, as well as the recovery factor of the sampling method to calculate the MAC limits per sample point.
6. What is the difference between MAC, MACO, and MSC?
MAC means the Maximum Allowable Carryover, and MACO means virtually the same thing, the difference being that the MACO acronym splits the C into two words which result in maximum Safe Carry Over. No matter which acronym, the meaning is the maximum allowable carry over of contamination of a previous product, cleaning agent, or any residue, into the next product being manufactured on the same equipment.
Over time, as the industry has evolved, subject matter experts have asked… Who is allowing this allowable carry over? Instead of what is allowed shouldn’t we use science to determine what is the Maximum Safe Carryover (MSC) level? The new science and risk-based approach to cleaning validation uses Health-Based Exposure Limits (HBELs), and the latest techniques, to provide companies with the means to effectively clean, to confirm the Maximum Safe Carryover is not exceeded, an to ensure product quality and patient safety.