What are the pros and cons of different MACO calculation methods, such as 10 ppm, 1/1000th, and health-based?

It is applicable for general API or for other potent API like onco and peptide? Please clarify . Also need information about critical cleaning methods

First of all there should not be any scope of discussion except HBELs. Next point is all are retired and expired so no point in talking about these or drawing comparison too.

10ppm approach was utilized generally in cleaning validation in earlier days. the concentration of 10 ppm of dose is allowed from one product to other product post to the established cleaning. This approach was used where the calculated MACO limit is found to be more than 10 ppm concentration..Nowadays this approach is utilized for some of the non product contact parts where the MACO calculation is difficult to determine.

-10 PPM criteria is useful in case of high MACO value (More than 10 PPM) for safe products , but definitely , the health based approach is suitable for potent and highly active products.

10 ppm Method has been obsoleted. MACO should be based on the Scientific data from Expert Toxicologist on the basis of ADE/PDE Value . Some organization uses 10 ppm approach due to high MACO value obtained from ADE/PDE value. But it's not scientific , if the PDE value is scientifically justified MACO should be accepted

Dose criteria (1/100h or 1/1000th) was also used along with 10 ppm concept for establishing the limit for cleaning validation evaluation in past days before the evolution of health based approach in pharma industry.. basically the LTD is used for limit calculation and calculated residue is allowed between product A to product B..this dose criteria is more stringent method than 10 ppm criteria..ADE/PDE based criteria is replaced this dose and 10 ppm criteria's..

1/1000th method: Pros: This method is less stringent than 10 ppm, potentially reducing cleaning costs. It takes into account the dilution factor during product processing. Cons: Lack of scientific basis which is crucial, also might not be conservative enough for highly potent drugs.

Health-based exposure limits (HBELs) are required by various regulatory agencies: European Medicines Agency (EMA), Pharmaceutical Inspection Co-operation Scheme PIC/S, ANVISA, the World Health Organization (WHO), and others. These limits need to be determined by qualified toxicologists (such as a DABT or an ERT) and thoroughly documented. As indicated in the EMA Q&A, HBELs need to be determined for all medicinal and veterinary products, not just the highly potent products. The use of HBELs replaces the outdated 10 ppm or 1/1000th methods. In the case of early stage compounds with limited data, methods such as the threshold of toxicological concern (TTC), read-across, or in silico methods may be used to determine the appropriate HBEL value.

Pros: By considering the toxicity of the residue, a scientific evaluation is done. Two approaches exist: Therapeutic approach: Uses the minimum therapeutic dose and maximum daily dose of the next product. Toxicological approach: Uses the acceptable daily intake (ADI) and lethal dose 50 (LD50) of the residue. Allows for a more targeted cleaning validation strategy. Cons: This method is more complex and requires more data such as ADI and LD50. It might require justification for chosen safety factors.

This is an area where many companies incorrectly choose the lowest of the 3 methods (i.e. 10 ppm, 1/1000th, or HBEL). This creates a problem for low potency APIs in that the value will be artificially lower than necessary thus causing unnecessary elaborate cleaning processes and the potential for cleaning failures. The HBEL method should always be used.

MACO methods set limits for leftover drug residue in equipment. Here's a quick guide: 10 ppm: Simple, safe, but might be overly cautious. 1/1000th: Less strict, but lacks scientific basis. Health-Based: Most accurate (considers drug toxicity), but requires more data. Choose based on regulations, drug potency, and cost. Start with 10 ppm, consider health-based for strong drugs or cost concerns. Always ensure achievable cleaning and consult experts if needed.