Risk-MaPP and ADEs

Now that Risk-MaPP has been out for 6 months and industry is beginning to incorporate the principles into their systems for managing the risk of cross contamination, companies are trying to understand the importance of developing ADEs (acceptable daily exposure) for their products.  ADEs are the cornerstone of this risk-based approach because the ADEs bring scientific justification into the process.  ADEs are developed by toxicologists based on data from clinical studies, package inserts, etc.  Some companies look to use the OEL (operator exposure limit) or a derivative of the OEL in place of the ADE.  Caution needs to be taken as OELs are based on workers which are assumed to be healthy working age adults most likely with inhalation as the primary mode of exposure whereas ADEs are set to be protective of all sub-populations by any route.

What issues have you found?  Please share.

Please visit the FAQ document on the Risk-MaPP resource page for more information on the use of ADEs.

About stephaniew

Task team co-chair for the development of the ISPE Risk-MaPP Baseline Guide.
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15 Responses to Risk-MaPP and ADEs

  1. Kit Erlebach says:

    The other issue we have encountered is the limited data available for manufacturing clinical trial material and thus generating ADEs for these compounds.
    We have seen differences between ADE and OEL levels but in the majority of cases there is a relationship between the two.

    • Jan Glazemakers says:

      I completely agree with Stephany’s comment on the fundamental differences between ADE’s used for occupational health purposes (OEL – operators’ health) on the one side and ADE’s used for patient safety (MACO) on the other. All to often I encounter the view that one ADE fits all purposes.

      Wonder how we should come up with a ADE for potent sensitisers (say LLNA EC3 less than 0,01 %) ?
      Stephany, any idea here ?

      regards to all

      • stephaniew says:

        Jan, the regulators are not convinced there is a safe level for potent sensitizers. This is certainly an area where toxicologists should be providing some data/studies to prove or disprove the perceptions. This is a bit out of my area of expertise. Jan can you suggest a group that might want to take this on?

    • stephaniew says:

      Kit, Risk-MaPP suggests using the Threshold of Toxicological Concern for products with limited data. As for the relationship between ADE and OEL you are correct that the majority of cases have a relationship, but we need to understand when the relationship does not apply so as to use the correct limits.

  2. Destin LeBlanc says:

    I have expressed concerns about the RiskMaPP document as it refers to cleaning validation for actives that are not “highly hazardous”. The RiskMaPP document calls conventional ways of setting limits (0.001 of dose, 10 ppm in the next product, visually clean) as non-scientific and arbitrary. Certainly 0.001 of a dose is not the approach for a cytotoxic or mutagenic active, but why does the RsikMaPp document insist that ADEs be used for all actives?
    I have emailed various RsikMaPP leaders, and basically they will not reply to my concerns. The ISPE supposedly had an “independent” review of my concerns, and found the RiskMaPP to be a accurate document. However, ISPE will not tell me who was on the review panel, nor will they share the results of the review. I have posted my concerns on my website (www.cleaningvalidation.com); they are in my November 2010 Cleaning Memo and my February 2011 Cleaning Memo. Can anyone tell me why (or in what way) the conventional ways of setting limits for non-highly-hazardous actives are “non-scientific” and “arbitary”. The only point made in RiskMaPP is that the calculated limits using 0.001 0f a dose are lower than limits set using the ADE calculation. Will the RiskMaPP authors defend their position? Why is there no transparency in the process?

    • stephaniew says:

      The document does not insist on using ADEs for cleaning limits for all actives, what it states is that you do not know if the limits derived from “conventional ways of setting limits” are protective of patient health until you assess them against the ADE. For example in section 5.4 states “While an appropriate safety margin should be incorporated when establishing limits, these current approaches to limits have ignored toxicological data and can either be too restrictive or not sufficiently restrictive. The addition of extra safety factors to the calculation of limits may be appealing by appearing conservative, but in many cases result in overly restrictive limits that can severely limit the handling of products in multi-use facilities or result in partial or totally dedicated facilities.” Further in the same section it states “As will be discussed below, the current standards of 1/1000th of the Low Clinical Dose (LCD) and 10 ppm for setting cleaning validation limits do not always provide adequate protection, especially for compounds within the classes of hazardous drugs such as hormones and antineoplastic agents. However, for many compounds , this method may result in allowable residue limits that are health protective. For example, compounds with a low clinical dose >10 mg/day that do not trigger any of the criteria listed above for identifying hazardous drugs…” Setting excessively conservative cleaning standards may potentially result in unnecessary expense/waste in cleaning activities through the use of more aggressive cleaning procedures.

      As a matter of fact the document supports and certainly during the launch sessions encourages the use of visually clean.

      I would also like to highlight that the EMA has stated that the ADE method is an improvement over the 1/1000th of the Low Clinical Dose.

      I would like to turn your question on why the conventional ways of setting limits for non-highly-hazardous actives are “non-scientific” and “arbitrary” around, please provide the scientific data that supports that the conventional ways of setting limits are protective of patient health.

      I am not sure of the point of your statement beginning with “The only point made in …”. Again when the limits are lower with the 0.001 of a dose than with the ADE calculation, this is indeed protective of patient health and a company certainly can use these as limits, but when they do they are spending more effort (i.e. more money) on cleaning then is necessary for patient health and they also could be driving themselves into failure of the cleaning process with artificially low limits.

      In the end I am not sure your concerns have been addressed as you have not adequately described them.

  3. Kit Erlebach says:

    Just before RiskMaPP was launched the PDA published a guide on cleaning for biologics (no 49) in which they included some statements on degradation studies. Given that if the molecule you are making is degraded by the cleaning solutions has anyone combined the degradation form the PDA and the risk assessment from RiskMaPP. If so how has this been received? Would be interested to hear of any progress on this area.

  4. Destin LeBlanc says:


    You don’t really answer why question as to why the conventional way of setting limits is arbitrary and non-scientific. However, you end with a question to me about providing the “scientific data that supports that the conventional way of setting limits are protective of patient health”. First of all I assume you are talking in the context of non-highly-hazardous actives. I could point to the fact that methods such as the 0.001 dose criteria are in many regulatory guides. I could also point to fact that industry has used this criterion for 18 years. However, the best evidence is the quotes from the document you assisted in writing and are trying to defend.

    For example, on page 44 of RiskMaPP is the statement “For example, compounds with a low clinical dose >10 mg/day that do not trigger any of the criteria listed above for identifying hazardous drugs, would yield an allowable residue level of 0.1 mg (100 mcg) if a 1000-fold safety factor was applied. As will be shown below in the section on the application of the threshold for toxicological concern concept, this level of exposure is unlikely to represent a health-concern for compounds with no evidence of unusual toxicity or potency.” (Emphasis added). Note that an active would have to have a dose of 100 mg/day for the conventional criteria of 0.001 of a dose to bring the safe level down to 0.1 mg.

    Furthermore, on page 45 are the statements “An example is when the allowable residue level is calculated by dividing the low clinical dose by 1000, as recommended by Fourman and Mullen, 1993 (Reference 22, Section 15.1). For many APIs, this approach yields a value that is overprotective compared to the science-based ADE.” If the ADE is protective, then it is a reasonable conclusion for that statement that the 0.001 dose criterion is also protective. Here again, I am talking in the context of active that are not highly hazardous.

    One can also look at Table 14.1 in Appendix 1. In that table are the ADEs and doses of three actives: an antacid, an antihypertensive, and an NSAID. Now the RiskMaPP doesn’t calculate the safe level of active based on the dose criteria, but if one did, here would be the results:
    Antacid ADE = 50 mg/day 0.001 dose = 2 mg/day
    Antihypertensive ADE = 0.5 mg/day 0.001 dose = 0.01 mg/day
    NSAID ADE = 40 mg/day 0.001 does = 0.8 mg/day
    What this data suggests is that in these three cases cited by RiskMaPP, the dose criterion was protective of the patient if the ADE value was also protective of the patient.

    There is also a statement on page 39, referring to ADE methods that automatically require use of factors of 10 when the toxicologist could possibly choose a lower factor. That statement is “The fact that they are overprotective compared to science-based limits is not a problem from a health standpoint if the overall goal is to provide protection.” In other words, you don’t call the technique of automatically using 10 for the toxicological evaluation “arbitrary” and “non-scientific”. What’s different about the 0.001 dose criteria that the RiskMaPP seems to go out of the way to call it “arbitrary” and nonscientific?”

    I believe I have answered your question. However, I am still waiting for a reply on why conventional ways of setting limits are “non-scientific” and arbitrary” for non-highly-hazardous actives. I don’t know how to be more specific than that. I certainly agree that they are overprotective as compared to the ADE calculation. But being overprotective does not make it “arbitrary” and “non-scientific”.

    Destin LeBlanc

  5. Destin LeBlanc says:


    Is the stateemnt in 5.4 the only support for your comment that “what it states is that you do not know if the limits derived from the “conventional ways of setting limits” are protective of patient health until you assesss then against the ADE.”? It seems that the context of that section is that 0.001 dose is inadequately-protective for highly hazardous actives and overprotective for non-highly hazardous actives. That is the reason that regulatory agencies have specified dedicated facilities or non-detectable limits for these highly hazrdous actives. RiskMaPP is a step in the right driection for these highly hazardous actives. However, I believe calling the 0.001 dose criterion for non-highly-hazrdous actives “arbitrary’ and “non-scientific’ is not appropriate. In fact I would call the statement “Setting limits by 0.001 dose criterion is non-scientific and arbitrary” to be itself a non-scientific and arbitrary statement. There is nothing in RiskMaPP to support that statment; just saying it is “overprotective” is not cause to call the 0.001 dose criterion “arbitrary” and “non-scientific”.


  6. ovclean says:

    Dear Mr. Destin LeBlanc,

    Finally! I am glad to find you here.

    Before I answer to the query, I would like to clarify few things.

    1. How do you define highly hazardous actives? or simply how do you distinguish between highly hazardous and non-highly hazardous actives? In your opinion ciprofloxacin, ranitidine or omeprazole are hazardous or non-hazardous?

    2. Why a safety factor of 1000 is used to derive the dose criterion? I think the safety factor is less stringent. I am recommending to use 10000 as safety factor for cleaning validation studies. Let me tell you, I have the logic for doing so. Do you agree with the proposal?


  7. Nick Haycocks says:

    There has been a lot of discussion regarding the cleaning limits used – the article in this months PE helps by explaining the history behind some of the limits used.
    Readers can make their own judgement as to the science behind the limits.

  8. G Sundar says:

    Dear Sir/Madam,
    I wrote to regulators about adopting ADE based cleaning validation limits and got replied that they never use ADE based limits. One concept paper published in EMA, but still none of the cleaning validation guideline uses ADE based Limits. There are many ways of calculating ADE, formulas like one uses with PK data, another uses without PK data, another approach of 10 x OEL =ADE. I hereby request ISPE kindly help Which ADE formula is adequate and what is acceptance of ADE values with Regulators like USFDA, EMA, PIC(S) and WHO.

    Some regulators are thinking ADI (Acceptable daily exposure limits), PDE (permissible daily exposure instead of ADE) kindly clarify which is adequate, because ADI, PDE alraedy established by regulators.


    • Stephanie Wilkins says:

      Dear Mr. Sundar,

      Please refer to the ISPE Risk-MaPP Guide, chapter 5 on Risk Identification as this provides an excellent discussion on how to set ADEs.

      As this is a relatively new approach some inspectors may not be familiar with using ADE values in setting cleaning limits, but as you mention, once the EMA publishes their toxicological tool document using values such as ADEs will become the norm.


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