PP10-75: Application of ICH S9 and Haber’s Law for Impurities Specifications in a High Dose Early Development Oncology Program
Poster Presenter
Brian Dow
Scientist, Dossier Development and Operations
Janssen Research & Development, LLC United States
Objectives
The objective of this study is to examine global health authorities’ responses to the application of ICH S9 and a modified Haber’s Law for short-term exposure to justify expanded acceptance criteria limits on impurities in a small molecule, early development program for advanced cancer indications.
Method
We compared the use of ICH Q3A, ICH S9, and Haber’s Law to justify limits for specified and unspecified impurities in a high dose small molecule program by calculating the maximum qualified specified impurities limits and percent total daily intake and total amount (mg) of unspecified impurities all
Results
Specified Impurities
In toxicology studies, the NOAEL (20 mg/kg/day) from monkeys was 3x below the proposed highest clinical dose (HCD) (3g/day), and the HNSTD (40 mg/kg/day) was 1.5x below the HCD. Applying ICH S9, the HNSTD was used to qualify specified impurities for clinical doses >2g/day. Overall this strategy was accepted, but Country A demanded that the limit for 2 degradants be reduced from 0.50% to 0.15%. These degradants grew on stability, so a 0.25% limit was proposed for clinical doses <1.8g, where the TDI for individual impurities equaled that proposed by Country A. For clinical doses >1.8g, impurities would be controlled at a lower limit or qualified in toxicology studies. This proposal was accepted by Country A and demonstrates a leniency on product-related impurities as opposed to process-related impurities.
Unspecified Impurities
A limit of 0.25% (5mg TDI) was proposed to Countries A and B, and a limit of 0.50% (10mg TDI) was proposed to Country C. These limits correspond to 5x and 10x the qualification limits described in ICH Q3A and 1.5x and 2x the 5 mg TDI limit described by a version of Haber’s Law modified for short-term exposure. ICH S9 supports this by stating 1) exceeding ICH Q3A limits could be appropriate for anticancer pharmaceuticals, 2) limits based on lifetime risk are not appropriate, and 3) justifications described in ICH S9 should be considered to set higher limits. Countries B and C approved the 0.25% and 0.50% limits, respectively.
Country A demanded an unspecified impurity limit of 0.15% (4.5mg TDI or 3x the ICH Q3A qualification limit) for the HCD. This equals 90% of the Modified Haber’s Law 5 mg TDI limit. We responded to Country A’s demand by proposing to keep the unspecified impurity limit (0.25%) for doses <1.8g. For doses >1.8g, an unspecified impurity limit of 0.15% will be implemented unless qualified. This allowed for a 4.5mg unspecified impurity TDI limit up to the HCD. This proposal was accepted by Country A.
Conclusion
Global health authorities and industry are placing a major focus on rapid development of pharmaceuticals for advanced cancer indications. However, this typically leads to placing the Quality module of the IND/IMPD on the critical path for regulatory approval. This can create several CMC challenges, including supplying the clinic with multiple drug substance batches manufactured with fit-for-purpose syntheses and minimal stability. These challenges are compounded by unnecessarily tight acceptance criteria for impurities and by the variation in regulatory requirements by global health authorities. This case study highlights the successful application of ICH S9 guidance and Haber’s Law to set limits on specified and unspecified impurities much higher than those described in ICH Q3A. The HNSTD from toxicology studies can be used to qualify specified impurities and set limits for specified impurities. For unspecified impurities, there is a relatively wide range of TDI that are acceptable for high dose early development oncology programs by different health authorities. At least in the case of Country A, the 5 mg limit described by Harvey et al. appears to be more clinically relevant as determined by the health authority. These expanded limits appear to be mostly accepted by various global health authorities. However, the harmonization of drug substance control strategy expectations by global health authorities for early development oncology programs remains challenging. As both applicants and global health authorities continue to gain experience developing and evaluating the quality module for clinical trial applications under accelerated development timelines, emphasis should be placed on developing clinically relevant specifications based on ICH S9 justifications rather than a more conservative ICH Q3A in order to allow advanced cancer patients to enter clinical studies, while assuring patient safety and product quality.
