Regulatory Acceptance of Risk-Based Control Strategies for ICH Q3D: Using Shared Elemental Impurities Data for Risk Assessments Craig Havenhand, Investigator Grace Kocks, Senior Scientist craig.x.havenhand@gsk.com grace.kocks@lhasalimited.org
Overview Elemental Impurities Excipient Database Introduction to the data sharing initiative Demonstration of the database What does the consortium do? Regulators and pharmacopeial bodies Using the database in ICH Q3D risk assessments Introduction to ICH Q3D guidelines Primary sources of elemental impurities Risk assessment case studies Conclusions Getting involved in the data sharing initiative
Elemental Impurities Data Sharing Initiative
Elemental Impurities Data Sharing Initiative Section 5.5 - According to ICH Q3D, evidence collected in the risk assessment can be derived from numerous sources: • Prior knowledge; • Published literature; • Data generated from similar processes; • Supplier information or data; • Testing of the components of the drug product; • Testing of the drug product. However, in the case of excipients, supplier information relating to elemental impurities can be limited and published literature is also sparse. http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html ICH Q3D Training Package Modules 0-9. https://www.ich.org/products/guidelines/quality/article/quality-guidelines.html
Elemental Impurities Data Sharing Initiative As an experienced honest broker for various data sharing initiatives, Lhasa Limited worked closely with industry to establish how it could support its members and others with the ICH Q3D regulatory guideline. shared knowledge shared progress
Elemental Impurities Data Sharing Initiative The initiative • The data shared is analytical data generated to establish the levels of elementals within batches of excipients. • Lhasa acts as the ‘honest broker’ and facilitates the data sharing. • A database of shared excipient elemental impurity determinations with equivalent provenance to published literature, can be used as an additional source of information. • This aims to save time and reduce the amount of testing required for ICH Q3D risk assessments.
What is the Strategic Intent of the Database? The vision Data is accessible to industry and regulators and can be used to make it clear why specific excipients are regarded as low (negligible) or higher risk in a particular formulation at a given daily intake.
Elemental Impurities Excipient Database • A consortium was established in 2015 and the first release of the Elemental Impurities Excipient Database was in 2016. • The database contains the results of 2,633 analytical studies and 39,517 elemental determinations for 295 excipients. • The last database released was in July 2019.
Elemental Impurities Excipient Database 3000 Number of analytical studies 2500 2000 1500 1000 500 0 2016 2017 2018 2019 Database updates Currently the largest known collection of this type of data.
Elemental Impurities Excipient Database Data quality is critical • Validation and data entry guidelines were developed and are regularly evaluated to aid consistency and quality of the data. Data on excipients NOT suppliers • The supplier and batch information is blinded. • The data is for scientific purposes not for business interest.
Elemental Impurities Excipient Database How to use the database 1. Identify all excipients in the drug product of interest 2. Search the database for each excipient 3. Review and export relevant elemental impurity results Vitic Products https://www.lhasalimited.org/products/vitic.htm Kocks G & the Elemental Impurities Database Consortium. Sharing elemental impurity data for excipients aids ICH Q3D risk assessments https://www.lhasalimited.org/publications/sharing-elemental-impurity-data-for-excipients-aids-ich-q3d-risk-assessments/4874
Demonstration of the Database
What does the Consortium do? Regulators and Pharmacopeial Bodies
What does the Consortium do? Discuss and agree upon the scientific direction of the project. Contribute and share expertise and knowledge. Monitor the data provided by the member organisations and ensure it meets predefined quality standards. Identify data gaps and recommend priorities for work on the project.
What does the Consortium do?
What does the Consortium do? The consortium aims for the data to be accessible to industry, regulators and pharmacopeial bodies. Lhasa Limited is working with the database consortium to promote and share information on the initiative. The Elemental Impurities Excipient Database is referenced and used to support the ICH Q3D risk assessment of excipient components. Boetzel R et al.. An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug Product Risk Assessment. Journal of Pharmaceutical Sciences 107 2335-2340 (2018). https://doi.org/10.1016/j.xphs.2018.04.009
Regulators and Pharmacopeial Bodies The consortium and Lhasa Limited have introduced five regulatory bodies to the initiative and two are in the process of receiving access and training on the database. Two pharmacopeial bodies have access to the database and have received training. The data is used to review and update the monographs. Positive feedback has been received from both on the initiative and the data in the database.
Using the database in ICH Q3D risk assessments Craig Havenhand
ICH Q3D Guideline for Elemental Impurities The International Conference on Harmonisation (ICH) brings together the Regulatory Authorities and Pharmaceutical Industry of Europe, Japan and the United States ICH Guidelines • ICH Q1A – Q1F Stability • ICH Q2 Analytical Validation • ICH Q3A – Q3D Impurities • Q3A Impurities in Drug Substances • Q3B Impurities in New Drug Products ICH Q3D Guideline for Elemental Impurities: • Q3C Impurities: Guideline for Residual Solvents • Q3D Impurities: Guideline for Elemental Impurities • Presents a process to assess and control elemental impurities in • ICH Q4 – Q4B Pharmacopoeias Drug Products • ICH Q5A – Q5E Quality of Biotechnological Products • ICH Q6A – Q6B Specifications • Contains limits for the Permitted Daily Exposure (PDE) to • ICH Q7 Good Manufacturing Practice patients for a range of elements which could be in Drug • ICH Q8 Pharmaceutical Development Products • ICH Q9 Quality Risk Management • ICH Q10 Pharmaceutical Quality System • Provides a platform to develop a risk based control strategy • ICH Q11 Development and Manufacture of Drug Substances • ICH Q12 Lifecycle Management
Potential Sources of Elemental Impurities • ICH Q3D Guideline on Elemental Impurities strongly advocates the use of risk assessments in order to define a final control strategy More Likely Sources Drug Excipients substance Elemental impurities in the drug product Lower Risk Manufacturing Container Closure Processing equipment System aids e.g. water • Excipient data is collated from different sources to feed into risk assessments • Data sourced from the Elemental Impurities Database • Prior knowledge • Data generated internally • Supplier information or data
Which Elements to Consider? Refer to Table 5.1 in Q3D for guidance on the elements to consider Route Q3D Class Elements Oral 1 Cd, Pb, As, Hg 2A Co, V, Ni Parenteral 1 Cd, Pb, As, Hg 2A Co, V, Ni 3 Li, Sb, Cu Inhalation 1 Cd, Pb, As, Hg 2A Co, V, Ni 3 Li, Sb, Ba, Mo, Cu, Sn, Cr Any 2B Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt Only if intentionally added All Elements intentionally added for therapeutic benefit do not need to comply with the PDE limits in Q3D
Primary Sources of Elemental Impurities Highest Risk Metal Catalysts Considerations for excipients. Highest Risk Mined (e.g., Talc) • Mined? • Natural? Manufacturing Equipment • Synthetic? Synthesized with Metal Catalyst Processing Aids (e.g. mannitol) Increasing Risk of Inorganic Reagents Elemental Contributing Elemental Plant Origin Impurities in (e.g. cellulose Impurities in Excipients derivatives) Elemental API s Organic Materials Impurities Animal Origin Water (e.g., lactose & gelatin) Solvents Synthesized without Metal Catalyst (e.g. colloidal SiO2) Primary Container Closure
Risk Assessment - Calculations • Q3D offers several options for evaluating the potential amounts of elements in a product • Identifies the contribution to the PDE from each component • Approach selected may be product dependant Option Elemental Concentration Daily Dose 1 Same for all components 10 g/day 2A Same for all components Actual Daily Dose for Product 2B Different for each component Actual Daily Dose for Product 3 Use test data Actual Daily Dose for Product • By first intent, GSK perform product assessments using Option 2B (Summation Option) • By first intent, if API is to be tested use Option 1 (if sensitivity allows) • Results below the control threshold, < 30% of PDE, may allow no specification testing (should consider variability in data)
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