API Testing Requirements to Support the EI Risk Assessment

Elisabeth CorbettAssociate Director, GRS-CMC, Bristol-Myers Squibb

November 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 Closure

Implementation across a Portfolio Driving consistency and Documenting Strategy

2

BackgroundReview of ICH Q3D Risk Assessment Principles

What 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? 3. What are the consequences (severity)?

3

BackgroundReview of ICH Q3D Risk Assessment Principles

Components 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 risk

4

Starting Materials and Reagents

Equipment Exposure

Container Closure

BackgroundChallenges Associated with Implementation

Implementation: If the risk assessment is:

– “A systematic process of organizing information to support a risk decision to be made within a risk management process.”

If the assessment starts with API:

5

What kind and how muchinformation is considered

adequate?

Starting Materials and Reagents

Equipment Exposure

Container Closure

How much and what kind of information is neededto assess these factors?

6

When? Preparation should begin prior to definition of acceptance

criteria for drug substance intended for clinical studies

How?1- Analysis of the Synthetic Route:Assess route for intentionally added EIs and EIs known to be introduced by starting materials

2- Outline of Testing Strategy for Development Lots:Route of Administration

Class 1

Class 2A

Class2B

Class3

Intentionally Added

Oral x x xParenteral x x x x

The API Risk AssessmentConstructing the Initial Risk Assessment

7

Conducting Testing Collection of general (non-intentional metal) data to

support the risk assessment should begin in development with qualified methods

– “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 metals to acceptable levels (e.g. < 30% of PDE remaining) should begin in development using specific method

– Specification may be needed for clinical supplies

The API Risk AssessmentConducting Testing and Collating Data

1 Elemental Impurities in Drug Products, DRAFT Guidance for Industry, FDA, June 2016.

8

Assessing 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 appropriate

The API Risk AssessmentConducting Testing and Assessing 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 on intended route of administration”

1 Implementation of ICH Q3D in the Certification Procedure, EDQM, August 2016.

9

Starting Materials 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 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 route

The API Risk AssessmentConsidering the Additional RA Factors

10

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?

– Qualified suppliers should be assessed as having adequate GMPs and cleaning procedures in place

1. 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 container

The API Risk AssessmentConsidering the Additional RA Factors

Implementation Across a PortfolioDriving Consistency and Documenting Strategy

12

Ideal State Harmonized approach to implementation across teams Risk assessments developed early in program Consistent approach with suppliers

Getting to the Ideal State… Centralized committee charged with:

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 questions

13