HIGH POTENCY APIS
Once sufficient preclinical data are available , including repeatdose toxicity studies in animals , mutagenicity , the predicted dose for first-in-human studies and further insights into its pharmacology , more accurate calculations of OELs can be made . 1 The reliability of both OEL and PDE values will increase as the compound moves through the development process , particularly when data from human clinical trials become available . The safety factors included in the calculations as an extra layer of caution can often be decreased as additional information comes in . A careful balance must be made . If the OEL is over-conservative , the project may become unviable because of its impact on costs and timeline . If it is not set high enough , operator safety may be put at risk . As larger amounts of material are required for Phase II and III clinical trials , more data are generated , creating the need for re-evaluation . Indeed , in some instances compounds that had been treated very cautiously have no longer been classified as highly potent in light of new clinical data . It is also important for the toxicology experts at the CDMO to provide updated OEL and PDE values , and to align those with the client ’ s expectations . The occupational toxicology team at a big pharmaceutical company is likely to be able to supply this data and it will only need to be checked for updates . Start-ups that rely on consultants will require full occupational toxicological support from a CDMO , based on all available data . However , problems can be magnified if a different CDMO is engaged later in the clinical development process , for example , if a pharmaceutical company is seeking help with a difficult manufacturing process . A company that had been treating a compound as a standard API might be surprised to find that the CDMO considers it highly potent . This will affect the way the manufacturing is conducted and may have a knock-on effect specific to the filing process . It could even lead to questions from the regulators about the accuracy of other details in the filing .
Intermediate investigations
It is important to remember that the HPAPI itself is not the only potential risk in the development process . Looking at the starting materials is only the beginning . It is essential to assess all the isolated intermediates and starting materials involved in a synthesis route , and any side or by-products to ensure that they do not pose significant risks , in order to set appropriate limits for cleaning or equipment needs . These are particularly important for multipurpose vessels where carry-over must be kept below strict thresholds . For example , the intermediate after step three of a six-step synthetic route , may be highly potent , whereas the intermediates made in the other steps might not be as potent . This will need to be accounted for during process implementation in the plant
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