API Testing Requirements to Support the EI Risk …

1 API Testing Requirements to Support the EI Risk AssessmentElisabeth CorbettAssociate Director, GRS-CMC, Bristol-Myers SquibbNovember 9, 2016 AgendaBackground Review of ich q3d Risk Assessment Principles Challenges associated with API implementation The API Risk Assessment (RA) for EI Constructing the initial assessment Conducting Testing and assessing data Considering the additional RA factors Starting materials Equipment and Container ClosureImplementation across a Portfolio Driving consistency and Documenting Strategy2 BackgroundReview of ich q3d Risk Assessment PrinciplesWhat is a Risk Assessment? Per ICH Q3D: A systematic process of organizing information to Support a risk decision to be made within a risk management process. Per ICH Q9: Three fundamental questions are often helpful: 1. What might go wrong? 2. What is the likelihood (probability) it will go wrong?

2 3. What are the consequences (severity)? 3 BackgroundReview of ich q3d Risk Assessment PrinciplesComponents of the ICH Q3D Risk Assessment: The Fishbone Diagram: API and Excipients considered most likely sources for EI contamination for most dosage forms Diagram starts with API, but there are components that need to be assessed for contribution to overall risk4 Starting Materials and ReagentsEquipment ExposureContainer ClosureBackgroundChallenges Associated with ImplementationImplementation: If the risk assessment is: A systematic process of organizing information to Support a risk decisionto be made within a risk management process. If the assessment starts with API:5 What kind and how muchinformationis considered adequate?Starting Materials and ReagentsEquipment ExposureContainer ClosureHow much and what kind of information isneededto assess these factors?

3 6 When? Preparation should begin prior to definition of acceptance criteria for drug substance intended for clinical studiesHow?1- Analysis of the Synthetic Route:Assess route for intentionally added EIs and EIs known to be introduced by starting materials2- Outline of Testing Strategy for Development Lots:Route of AdministrationClass 1 Class 2 AClass2 BClass3 Intentionally AddedOralxxxParenteralxxxxThe API Risk AssessmentConstructing the Initial Risk Assessment7 Conducting Testing Collection of general (non-intentional metal) data to Support the risk assessment should begin in development with qualified methods Should possess such the manufacturer can be reasonably the measurements can be relied upon to decided whether to include routine in the control strategy 1 Collection of data to Support removal of intentionally added metals to acceptable levels ( < 30% of PDE remaining)

4 Should begin in development using specific method Specification may be needed for clinical suppliesThe API Risk AssessmentConducting Testing and Collating Data1 Elemental Impurities in Drug Products, DRAFT Guidance for Industry, FDA, June Data Determine Control Strategy from LTSS to the Marketing Application Continue monitoring as per the development plan Assess development and pilot data Determine whether process control or routine Testing is appropriateThe API Risk AssessmentConducting Testing and Assessing DataMinimum 3 commercial batches OR 6 pilot batchesDemonstrate the absence of EI: Show with convincing evidence that it is purged to a level which is consistentlybelow 30% of the calculated concentration limit based on intended route of administration 1 implementation of ich q3d in the Certification Procedure, EDQM, August Materials Are EIs introduced via SM synthetic route?

5 No: Screen 3 lots of vendor material to demonstrate absence of EI Is there a supplier specification already in place for intentional EIs? No: Calculate max allowable to remain below threshold in API and determine whether a spec is needed based on screening of 3 vendor lots Yes: Calculate max contribution in API at spec and determine if adequate or if an internal or lower vendor spec is needed Could other metals serve as alternative to the intentional EI? Yes: Screen lots for these EIs in addition to that of current routeThe API Risk AssessmentConsidering the Additional RA Factors10 The API Risk AssessmentConsidering the Additional RA FactorsStarting Materials (cont. ) What if the vendor makes changes? Quality agreements and change control address-not necessarily more Testing ! What if the vendor introduces new EIs into facility in other syntheses?

6 Qualified suppliers should be assessed as having adequate GMPs and cleaning procedures in place1. What might go wrong? 2. What is the likelihood it will go wrong? 3. What are the consequences?11 Equipment and Container Closure Equipment-Low Risk Screening for class 1 elements and additional known EIs from stainless (Ni, V and Co) throughout development (see ICH Q3D Case Study 1A) Combination of screening information and quality system procedures in place (see ICH Q3D Case Study 2) Biologics may need to consider possible EI contribution more thoroughly Container Closure- No Risk Solid API offers no mechanism for transfer of EI from storage containerThe API Risk AssessmentConsidering the Additional RA FactorsImplementation Across a PortfolioDriving Consistency and Documenting Strategy12 Ideal State Harmonized approach to implementation across teams Risk assessments developed early in program Consistent approach with suppliersGetting to the Ideal Centralized committee charged with.

7 Providing training and background on the guideline Working with individual development program teams to : Construct initial EI strategy/approach for API Assess the EI risk associated with raw materials and intermediates Implement the appropriate Testing strategy with suppliers Provide guidance/responses in the event of regulatory questions13