APEC - Safeguarding patients from Impurities in the drug supply chain - Nitrosamines

Today is day 2 of the APEC Medical Product Supply Chain Dialogue co-sponsored by FDA and hosted by USP in Rockville MD.

16 APEC economies and 35 government agencies are siting in the round table discussions. Of course, Nitrosamines had to be at the center stage of the discussion.

Jason Bunting from FDA and Gary Condran from Health Canada presented some progress and ongoing activities around Nitrosamines Impurities. I did my best to summarize some of the key messages:

  • Assessing mutagenicity - FDA’s National Center for Toxicological Research (NCTE) has been testing different conditions to develop an enhanced Ames Test
  • Computational Toxicology - a) Q(SAR) can predict, with acceptable confidence, the outcome of an Ames test and to classify an impurity. b) Can be done more rapidly than in citro or in vivo testing and can be an efficient means to assess nitrosamine toxicity in the absence of experimental data
  • Collaboration - FDA is collaborating with the Health and Environmental Sciences Institute (HESI): a) Multi-lab projects, optimizing Ames tests. b) Identifying research gaps
  • CDER recognizes the need for a center-level framework for strategic, cross-cutting management of novel or complex impurities and contaminants
  • The CDER Emerging Impurities and Contaminants Committee (EICC) has been established to oversee: operations, policy, and applied regulatory research for these novel or complex impurities.

Dr. Condran dedicated a good time in his presentation on the topic of Risk Assessment. It’s clear that gaps have been identified during the review

  • ‘Checklist style’ summary of RA: missing discussion on the rationale, scientific basis, or justification for the overall risk determination
  • A ‘silo approach’ to the RA: absence of a holistic approach is observed with separate, unlinked drug substance and drug product RSs
  • RA Approach is unstated or unclear: Delegation of RA activities to third parties, manufacturers are responsible that personnel involved have acceptable expertise, training, knowledge
  • RA is NOT robust: potential risk factors which have been noted by regulators or in literature are not addressed adequately
  • Data/scientific justification to support the conclusions of the RA is missing (e.g. purge factors, solubility data, nitrite data in excipients)
  • The potential for increases in nitrosamines levels over the rest period or shelf-life is not considered in the assessment
  • Tertiary amines, API-related compounds are not adequately addressed as risk factors
  • Proposed Acceptable intakes (AI) limits were not satisfactorily qualified

Are you considering all those gaps in your risk assessment?