API Testing Requirements to Support the EI Risk Assessment - - PowerPoint PPT Presentation
API Testing Requirements to Support the EI Risk Assessment Elisabeth Corbett Associate Director, GRS-CMC, Bristol-Myers Squibb November 9, 2016 Agenda Background Review of ICH Q3D Risk Assessment Principles Challenges associated with
Review of ICH Q3D Risk Assessment Principles Challenges associated with API implementation
Constructing the initial assessment Conducting testing and assessing data Considering the additional RA factors
– Starting materials – Equipment and Container Closure
Driving consistency and Documenting Strategy
2
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:
3
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 risk
4
Starting Materials and Reagents Equipment Exposure Container Closure
If the risk assessment is:
– “A systematic process of
support a risk decision to be made within a risk management process.”
If the assessment starts
5
What kind and how much information is considered adequate?
Starting Materials and Reagents Equipment Exposure Container Closure
How much and what kind
to assess these factors?
6
Preparation should begin prior to definition of acceptance
Assess route for intentionally added EIs and EIs known to be introduced by starting materials
Route of Administration Class 1 Class 2A Class 2B Class 3 Intentionally Added Oral x x x Parenteral x x x x
7
Collection of general (non-intentional metal) data to
– “Should possess characteristics… such the manufacturer can be reasonably certain… the measurements can be relied upon to decided whether to include routine testing… in the control strategy”1
Collection of data to support removal of intentionally added
– Specification may be needed for clinical supplies
1 Elemental Impurities in Drug Products, DRAFT Guidance for Industry, FDA, June 2016.
8
Determine Control Strategy from LTSS to the Marketing
– Continue monitoring as per the development plan – Assess development and pilot data
Minimum 3 commercial batches OR 6 pilot batches
Demonstrate the absence of EI: “Show with convincing evidence that it is purged to a level which is consistently below 30% of the calculated concentration limit based
1 Implementation of ICH Q3D in the Certification Procedure, EDQM, August 2016.
9
Are EIs introduced via SM synthetic route?
– No: Screen 3 lots of vendor material to demonstrate absence of EI
Is there a supplier specification already in place for
– 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
– Yes: Screen lots for these EIs in addition to that of current route
10
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
– Qualified suppliers should be assessed as having adequate GMPs and cleaning procedures in place
it will go wrong?
consequences?
11
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 container
12
Harmonized approach to implementation across teams Risk assessments developed early in program Consistent approach with suppliers
Centralized committee charged with:
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 questions
13