Query for Calculation of MACO

Dear All,
This is query for calculating MACO value for a Formulated cleaning agent.
As per MSDS, the above said Formulated cleaning agent has 6 components[A,B,C,D,E,and F] in diffrent proportions. As per cleaning agent manufacturer, Toxicological studies have been performed only on component B, since it is considerable more toxic than the rest. Hence, LD50 value is only available to component B. Remaining component has no LD50 information.
MACO value is calculated as per formula provided by Fourmann & Mullen (ie) = NOEL /SF x K/J x U/L, Where NOEL is the No observed effect level = LD50 x Avg.Adult weight(Kg)/ Emprical constant
SF-Safety factor
K-Minimum Batch size manufactured in same equipment (Kg).
J- Maximum number of dosage units taken/day
L-Shared equipment surface area [in sq.inch]
U-Swabbed surface.[in sq.inch]

If we go ahead with the above mentioned formula, considering worst case approaches, the derived MAR value will be of which option
1.Amount of component_B/ Swab ? [or]
2.Amount of Formulated cleaning agent/Swab ?

NB: On analytical part, we are unable to find a suitable method for component B. But we have very good method for component E. If answer to the above query is [2], by quantitating amount of component E, Whether we can correlate Amount of Formulated cleaning agent/Swab. [Since proportion of each component is well known by MSDS data]

I think it is a good option to corelate the concentration of component E to component B as it is good to have something than having nothing.

But, I do not think that this is a good practice to corelate E to B. There may be different characteristics of components A, B, C, D & E and the result shown by E may not be corelated to B. Component B may be more reluctant to cleaning than E or may be easily washable by water or cleaning agents than E. In this scenario how can you corelate that the residue of component B is within the limit by considering the result of E?

For corelating you should prove that component B can be corelated to component E. Simply, you can not corelate B & E.

With regards,

Prawan Dahal

Dear Mr. Arun,

To begin with, kindly be informed that the formula stated in your query isn’t by Fourman & Mullen. The above-mentioned formula commonly used for the calculation of MACO for cleaning agents (and active ingredients also) is from W.E. Hall which was published in the article entitled “Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes”, Cleaning Validation - An Exclusive Publication, Institute of Validation Technology, 1997. The formula is also included in “Guidance on aspects of cleaning validation in active pharmaceutical ingredient plants” (CEFIC, Active Pharmaceutical Ingredients Committee, December 2000, available at
http://apic.cefic.org/pub/pub-cleaning-validation.pdf
) for the calculation of MACO.

Coming back to your query concerning determination of MACO for formulated cleaning agents. MACO for cleaning agents is usually determined using these methods: (A) Based on toxicity data (as mentioned in your query), (B) Based on 10 ppm method © Based on Visually clean criterion. Please bear in mind that the establishment of acceptance limit based on toxicity data is not a regulatory requirement but its use is common in pharmaceutical industry (hence, becomes important from regulatory point of view). In order to apply the formula based on toxicity data you need to know either the LD50 value for the formulated cleaning agent (as a whole) or the LD50 for individual components (in case if the earlier is not available). Using LD50 value of formulated cleaning agent as a whole is the most preferable way of calculating MACO. In cases where LD50 value of formulated cleaning agent (as whole) is not available but the LD50 values for individual components is obtainable then the lowest LD50 value is usually selected as worst-case (for example, component B in your case) assuming that the LD50 for whole formulation shall be equal to (or less than) the LD50 of component B. The established MACO value would then be amount of formulated cleaning agent (as whole)/swab (i.e. Option 2). However, this MACO would be applicable to all the individual components also, irrespective of the fact the LD50 value of the component being tested is more than the one used for calculation of MACO i.e. this value will be the MACO for all the individual components also (meaning same MACO for component A, B, C . . .F).

For using the toxicity data for the calculation of MACO, you need to consider few aspects/issues: (1) identification of the animal (mouse, rat etc.) (2) route of administration (IV, oral etc.) should be same as that of “subsequently manufactured product” (3) composition of the formulated cleaning agent should be known (4) toxicity data for individual components should be available (in order to justify the claim that the LD50 value selected is the lowest). If the LD50 values for components is not provided by the manufacturer try referring to some other sources (such as “Handbook of excipients”, MSDS of other products, some websites etc.).

Coming to your next concern regarding the analytical test method, it is not advisable to correlate individual components with the whole formulation (merely based on proportion). You can do that provided proper justification is given for selecting a particular component (not necessarily component E). This could be done by studying solubility data of individual component (to know which of the component is easily washable as compared to others) and conducting simulation studies (to prove that the component selected is the most difficult to clean as compared to rest).

The availability of analytical test method for individual components (or whole formulation if possible) is very important from regulatory/compliance aspect. PIC/S guideline says (in section 7.9 Detergents) “The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures” and “the composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. . . . . . the manufacturer should ensure that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.” Without appropriate analytical test method, it is difficult to justify that “no residue” level is achievable for cleaning agent residue, there is “no breakdown” of cleaning agent ingredients and that the cleaning agent is “compatible” with the drug product. Apart from this analytical test method is also needed for quality control and assurance of cleaning agent i.e. to determine lot to lot variability of the cleaning agent.

Ask your cleaning agent supplier to provide with the analytical test method for the formulation (I hope you must have received a certificate of analysis). If it is not available, look for alternate cleaning agent or supplier.

Dear all,

I agree fully with ovais. Specifically, it is not defendable to use the detection of one component of the cleaner as tracer only because the analytical method is available for that component only. The big providers of cleaning systems in the pharmaceutical industry (Alconox, Ecolab et al) include a “last to rinse component” study in the analytical documentation, thus justifying the choice of that component as tracer.

I would like to add a comment, regarding the conversion of the LD50 into the ADI: Usually, for the weight of the individual a figure of 70 kg is used, which corresponds to an average male adult. If there are pediatric formulations among the product portfolio, it is advisable to use a weight according to the WHO Child Growth Standards to convert the LD50 into the ADI.

Best regards

Alfred