Andre Hermans – Merck & Co., Inc.

PQRI/USP Elemental Impurities Workshop

09 Nov 2016

ICH Q3D Risk Assessment Methodologies and Regulatory Strategies for New Filings

Outline

• Timing considerations – Initial hurdles and experiences for early ICH Q3D risk

assessments • Risk assessment approaches

– Drug product testing – Component based testing / risk assessment

• Separate assessment exercise • Inclusion in existing risk assessment processes

• Inclusion of information in filing • 2 staged approach for Elemental impurities risk

assessment during development 2

• Timing considerations: – Different implementation timelines for ICH Q3D implementation for

commercial product (January 2018) and new filings (June 2016): • Leading to separate internal work streams for developing strategies

for ICH Q3D implementation for new filings and commercial products while maintaining consistency across all products.

– Release of training material and additional guidances throughout the 2016 • ICH training material (Modules 0-7) (21 March 2016) • ICH case studies and FAQ (Module 8,9) (August 2016) • FDA Draft Guidance (Jun 2016) • EMA Draft Guidance “Implementation strategy of ICH Q3D

guideline” (Jul 2016) • Health Canada recommendations for implementation of the ICH

Q3D guideline for new and marketed products (Jul 2016)

Strategies to EI risk assessments evolved throughout the year

Initial hurdles for early ICH Q3D risk assessments for new filings

3

Initial hurdles for early ICH Q3D risk assessments for new filings

4

• Hurdles: – Short implementation timelines Speed

• Testing and risk assessment needed to be adapted to development and filing timelines

• Excipient EI information and testing efforts not aligned internally with implementation timelines for new filings

– Unfamiliar concept to many development teams • Not known how much time needed • Steep learning curve • Some information needed to be generated / retrieved for the first

time • No standard company procedures in place

• Work around: – “Individual “ approaches based on product needs and timelines – Strategy adaptation based on evolving leanings within company and

across industry

Risk Assessment approaches

5

Risk assessment approaches /

methodologies for new filings

Drug product testing along with component

based risk assessment

Component testing

Component testing and EI risk

assessment as separate exercise

Component testing and as part of

developmental risk assessment activities

Generally fastest

approach

Only fast approach if data on components is available or

can readily be retrieved

Timeline dictated by developmental

timelines / activities

Approach 1 : Drug Product testing for solid oral dosage form (Option 3)

6

Rationale for Selecting Option 3:

• Drug product testing enabled speed and certainty to evaluate risk for EI in drug product

• At least 3 commercial drug product batches were available for testing at the time of risk assessment

Elemental Impurities Risk Assessment was conducted along with Drug Product Testing • Extensive EI data was available for several developmental and

commercial drug substance lots • Appropriate risk evaluation on intentionally added impurities was

possible • Vendor information for Excipients available

Approach 2: EI Risk Assessment for injectable large molecule (Option 2b)

7

Rationale for Selecting Option 2b:

• Data on components available at the time of risk assessment • Possible to conduct worst case calculation for elemental impurities

based on available data

Elemental Impurities Risk Assessment was conducted based on: • Extractable profiling data of product contact materials used during

DS manufacturing • Specifications for elemental impurities of excipients and water • Extractable profiling data of product contact materials used during

DP manufacturing • Data of extraction studies on the primary packaging components

and supplier information of silicone oil. • Excipient testing data and/or vendor data for excipients was found

sufficient

Approach 3: Incorporation of Elemental impurities into developmental risk assessment

8

• Approach: – Incorporation of EI as Critical Quality Attribute (CQA) into existing developmental

product risk assessment – Use of existing risk assessment process for manufacturing and raw materials Example Inclusion of EI as CQA in raw materials risk assessment

Initial risk assessment Final risk assessment

Approach 3: Incorporation of Elemental Impurities into Manufacturing Risk Assessment

9

Pros Cons Streamlined procedure Time savings

Difficult to score Risk Priority Number (RPN) for Elemental Impurities

One workflow and methodology for all developmental quality risk assessments

Developmental risk assessment methodologies are not necessarily aligned across developmental areas

EI risk assessment fits into the developmental timeline as part of site transfer activities to supply site

EI risk does not evolve during development unless additional data becomes available or additional controls are needed

Experience demonstrated that Elemental impurities risk assessment can be handled more effectively as a separate

risk assessment exercise

Inclusion in submission

10

Location of ICH Q3D information in new filings:

• CTD locations in filing submissions: • 3.2.S. Drug Substance

• 3.2.S.3.2 - Provided risk assessment summary to demonstrate all elemental impurities levels are below PDE

• 3.2.P. Drug Product • 3.2.P.5.5 – Included risk assessment summary/testing results to

demonstrate all elemental impurities levels are below PDE

• Based on FDA draft guidance: Risk assessment summary should be located in 3.2.P.2 (Pharmaceutical Development)

• Health Canada Notice: “The locations where the elemental impurities-related information can be found in Module 3 should be clearly summarized in Module 2.3.P.5: Control of Drug Product of the Quality Overall Summary. The overall risk assessment summary for elemental impurities should be placed in Module 3.2.P.5.6 Justification of Specifications”

Result summary for ICH Q3D risk assessments

11

Elemental impurities risk assessments have been successfully conducted for 10 new filings.

Mostly solid oral dosage and parenteral formulations

No elemental impurities >30% PDE limit were identified in any of the risk assessments

In cases where drug product testing was performed, the EI levels found in drug product, were below the worst case calculation from individual components

Implementation of ICH Q3D during drug development of solid oral dosage forms : Two Stages

12

• Formulation development: – No formal risk assessment performed – Consider high risk excipients and drug substance

contributions during formulation selection •Calculate worst case levels of EI based component

contribution – Opportunity to adjust formulation if needed

• Scale-up / Site transfer: – Final Elemental Impurities Risk Assessment

• Based on final formulation, process, and manufacturing equipment

Note: Solid knowledge management is crucial for successful implementation

Summary

13

• Various approaches for Elemental Impurities risk assessments were used based on: – Project and testing timelines – Availability of samples – Existing data

• Elemental impurities considerations can be build into existing risk assessment processes or as a stand-alone exercise

• A 2-staged risk approach can be applied during drug development

• Location of EI information in registration dossier is not clearly aligned world wide

Acknowledgements

14

• Bill Stevens • Terri Hennessy • Max Li • Xiaoyi Gong • Phyllis Walsh • Frans Maris • David Goldfarb • Peter Colvin • Jenny Drake