Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) FAQs

Question: For decades, common industry practice has been to use 1/1000th of the lowest clinical dose or 10 ppm to derive cleaning limits.  Why is Risk-MaPP proposing a different approach?

Answer: Risk-MaPP recommends deriving an Acceptable Daily Exposure (ADE) for all compounds to guide cleaning validation and facility risk assessments.  Use of 1/1000th of the low clinical dose and/or the 10 ppm specification provides a large margin of safety for most compounds.  Unfortunately, there is a subset of potent, toxic, or genotoxic compounds where the traditional approaches do not provide sufficient protection, i.e., the ADE leads to a lower cleaning limit.

Question: Are ADEs derived only for pharmaceutical products or do they also apply to biotech products?

Answer: ADEs should be derived for all compounds, whether small molecules used in traditional pharmaceuticals or large molecules used in biotechnology products. Some biotechnology products are extremely potent. Biological materials (e.g., proteins, lipids, high molecular weight polysaccharides) are large molecular weight substances (≥ 2 kd) used to conduct research or produce drugs and vaccines. Biological materials may include fragments and fractions from killed biological organisms. They also may include therapeutic proteins, recombinant peptides, antigens, antibodies (e.g., monoclonal antibodies, mAb) and synthetic siRNA molecules (small interfering RNA that interfere with the production of proteins). They should all have an ADE value to support proper cleaning and handling.

Question: The ADE provides a more precise estimate of the dose of a compound that is considered safe. Are there other advantages to using this approach?

Answer: Use of the traditional methods results in cleaning limits that may be more stringent than they need to be to ensure patient safety, often at greater expense for the company. Deriving an ADE for compounds of lower toxicity provides a means to demonstrate how large a margin of safety there is between potential carryover residues and safe doses using reasonable cleaning procedures. More rapid turn-around times represents opportunities for cost savings.

Related Links:

  • Baseline® Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP)
  • Participate in the Risk-MaPP Blog