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Sample Submission


Sample Proposal Submission


Title of Session:  
Non-genotoxic Impurities in Pharmaceuticals—Is It Time to Review Acceptance Levels, Specifications, and Toxicology Qualification?


What is the specific scientific issue that you seek to address? Please limit your answer to 1-2 sentences:

• Revising Qualification Thresholds for early phase clinical trials, short-term indications for non-cancer drug candidates, and for anticancer compounds that fall under ICH S9
• Harmonization the study design for impurity qualification studies to ensure the 3Rs principles for animal testing
• Harmonizing calculations for new qualification thresholds when applying animal toxicity or metabolite data
• Defining how human data can be used to qualification impurities or degradation products
• Defining non-mutagenic structural features which can be used to determine if a compound is unusually potent or toxic


Please provide a summary statement/abstract for your session. Please describe the rationale for this session—including information on which regulatory agencies might be affected by this issue, the goals of this session, what information will be presented and how it will promote substantive and constructive dialogue among all participants.

Management of non-mutagenic impurity levels in pharmaceutical drug substance and drug product is guided by ICH Q3A and Q3B. If the level of an impurity(s) is higher than the acceptance level in these guidances and was present in appropriate GLP toxicology studies, it is considered qualified for clinical use. If new impurities, or higher levels of a previously present impurity are present in subsequent manufacturing batches, qualification in additional animal studies is required prior to release for clinical use. Initially published in 2006, the application and scientific understanding around impurity qualification has continued to evolve. This has led to challenges for process chemistry as the expectations for impurity control can change or be inconsistently applied. One example of this evolution is for early phase clinical trials. There is a regulatory expectation that pharmaceutical sponsors ensure impurity control and qualification of impurities in these early trials. While early phase clinical trials are outside the scope of ICH Q3A / B, no other guidelines exist for control of ordinary impurities at this stage. Qualification thresholds listed in ICH Q3A and Q3B are too restrictive at this stage of development since the process chemistry is still being developed and limited batches are available. A recent publication by Harvey et al, (2017) following from an EFPIA workshop in 2012, put forward a scientific approach for using a modified Haber’s law approach (similar to what was used for ICH M7) to support the acceptance of higher qualification thresholds for impurities and degradation products in early clinical trials of durations less than 6 months. Other harmonization efforts are needed to facilitate consistent and safe manufacturing of active pharmaceuticals while instituting the 3Rs principles for animal testing such as study harmonization for impurity toxicity qualification studies, using human data to qualify impurities, qualification thresholds for anticancer compounds that fall under ICH S9 or short-term indications and calculating new qualified levels of impurities based on animal toxicity data. It is hoped that the discussion will facilitate consistency in the application of ICH Q3A and Q3B.

Reference: James Harvey, Andrew Fleetwood, Ron Ogilvie, Andrew Teasdale, Phil Wilcox, Steven Spanhaak. Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development. Regulatory Toxicology and Pharmacology. 2017; 84:116-123.


Who are the proposed speakers:

Dr. Timothy Hart, GlaxoSmithKline
Session Organizer and Past Chair of IQ DruSafe Leadership Group

Dr. Andy Teasdale, AstraZeneca
The challenges with existing impurities guidelines and why recrystallisation isn’t a cure all approach

Dr. James Harvey, GlaxoSmithKline 
Scientific justification for (higher) impurity levels in early clinical trials

Dr. Joel Bercu, Gilead
Initiatives of the Drug Impurities Working Group to Clarify Aspects of Impurity Qualification

Dr. Timothy McGovern, US FDA
Regulatory perspective of impurity levels in drug substance/drug products.

Participants in Round Table Discussion: Dr. John Nicolette, Abbvie; Aisar Atrakchia, US FDA; Dr. Krista Dobo, Pfizer; Dr Mark Powley, Merck.