ISPE issued the document, “Risk-Based Manufacture of Pharmaceutical Products,” (Risk-MaPP Guide) in September 2010. The goal of the Risk-MaPP is to address issues relating to regulatory bodies tending to require dedicated equipment and/or facilities for certain highly hazardous drug actives, such as genotoxic, mutagenic, teratogenic and cytotoxic compounds. The Guide addresses this issue by recommending an analysis of safety/toxicity data of these “highly hazardous” drug actives to determine a level that might be a negligible — but acceptable — risk in other drug products. The Guide proposes a “health-based” limit, called an ADE (Acceptable Daily Exposure), which is determined in a manner similar — but not identical — to a PDE (Permissible Daily Exposure) for solvents in ICH Q3C(R5).
This effort to set limits for cleaning purposes for these highly hazardous actives is to be applauded. It is consistent with the December 2009 EMA document, “Update on revision of Chapters 3 and 5 of the GMP Guide: Dedicated facilities.” That EMA document states, “Manufacturers introducing a product into shared facilities should carry out an assessment of all relevant product and process characteristics to evaluate whether it is suitable for production in shared facilities. This assessment should include input from a toxicologist.”
Unfortunately, the Risk-MaPP Guide goes beyond that basic focus to discuss cleaning validation in general for all products including those that are not highly hazardous. The Guide states that current methods of setting limits, such as “1/1,000th of the lowest clinical dose or 10 ppm in a batch” are “arbitrary limits.” Furthermore, it states, “The use of arbitrary non-health-based limits is not scientifically justified,” if data exists to calculate a health-based limit. Additionally it states, “Another non-science-based approach for setting cleaning limits is the use of the ‘10 ppm’ specification [. . . and] if default values such as 10 [ppm] are used arbitrarily to set allowable residue limits, they may be lower than they need to be from a health perspective.”
Essentially what the Guide is implying — or a reasonable inference one can make from the Guide — is that current methods of setting limits for cleaning validation purposes for all actives are arbitrary and not science-based. These statements may be the opinions of the authors of the Guide, but I do not find those assertions to be factually correct, nor is there anything in the Guide to support those assertions.
It is clear, and has been clear for a long time, that methods such as 0.001 of a dose are not appropriate for actives that that are mutagenic or genotoxic. The industry has realized this, and that is one reason regulators recommend dedicated facilities for such cases. For example, the PIC/S cleaning validation recommendations (PI 006-03) contains the statement, “For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.”
One would think that the RiskMaPP Guide would object to statements such as this, and then present the “health-based” limits as a better approach. But that is not the case. The primary objection in the Guide is to conventional methods of setting limits (0.001 of a dose, 10 ppm in the next product, and visually clean), and the main objection to this conventional method of setting limits appears to be that, for non-highly hazardous actives, it is “overprotective” of patient safety (at least as compared to the health-based limit). Really! What manufacturing procedure in pharmaceutical manufacturing is not overprotective of patient safety? So the Risk-MaPP approach is that we could be less rigorous in cleaning (at least for actives that are not highly hazardous).
Furthermore, the examples given in the Risk-MaPP Guide include cases of non-highly hazardous actives where the health-based limit is only 1/20 of the therapeutic dose. For example, an ADE of an unspecified NSAID active is given as 40 mg/day. A daily dose of this NSAID is given as 800 mg. The implication here is that 1/20th of the daily dose is a safe level to have in a daily dose of a subsequent product. If this ADE were present in a subsequently manufactured drug product involving 300 mg tablets given six tablets per day, the acceptable concentration of that active in that next product would be over 20,000 ppm (over 2%). Would anyone really consider allowing any drug active to be in a subsequent drug product at that level? It just wouldn’t be cGMP! This might be safe from a toxicologist’s viewpoint, but I doubt if most companies would — or should — allow such levels.
Can the Risk-MaPP document be fixed? Of course! It would be a relatively easy task to strip out from the Guide all the references to limits for non-highly hazardous actives. It would not change at all the basic thrust of setting limits for highly hazardous actives based on a toxicological evaluation. The danger of leaving statements in the Guide that these conventional methods for non-highly hazardous actives are non-scientific and arbitrary is that regulatory inspectors may challenge the appropriateness of current cleaning validation programs based on these statements.
In addition, there are opportunities for setting limits based on the principles in the Risk-MaPP Guide that should be further explored. For example, in biotechnology manufacture, where the active is generally degraded in the cleaning process, would it be possible to set limits not on the active itself (either based on its dose or its toxicity), but rather on the toxicity of degradants, since it is likely that any residues left after cleaning will be degradants, not intact active? This is one issue that could have been explored by the Risk-MaPP authors, rather than making unsupported statements about current methods of setting limits for non-highly hazardous actives.