1

ICH Guidelines Elemental Impurities:

Strategies for Implementation for APIs

Frankfurt, October 2017

Dr. Landry Le Chevanton

2

ICH Guidelines Elemental Impurities:

Strategies for Implementation for APIs

• Introduction

• ICH Q3D: short history

• What has changed

• Increased complexity

• Practical implications

• Conclusions

3

Introduction

What / who is APIC?

• A Technical European Industry Association, based in Brussels

• Focused on APIs from a quality and regulatory

perspective

4

Introduction

APIC‘s Mission

• To promote the use of compliant APIs in medicinal

products to ensure patient safety

• To represent the interests of pharmaceutical and

chemical companies producing APIs and

intermediates in Europe by being recognized

experts who advance and influence the global

GMP and Regulatory environment

5

Introduction

What / who is Landry Le Chevanton

• Working for DSM Nutritional Products Ltd. in Switzerland as

Head of Global Regulatory Affairs and Quality Management

Operations

• Over 10 years of experience in the regulatory field

• Excom member of APIC, Chair of APIC TaskForce on ICH Q3D.

6

Short History of ICH Q3D (1/2)

• The story started in 1995 with USP publishing a stimuli article

identifying issues with the ‘Heavy Metals Limit Test’

• 1998 EMA drafted a guideline on Specification Limits for

Residues of Metal Catalysts

• 2008 EMA issued the Guideline on Residual Catalysts and

Reagents

• 2010, ICH convened Q3D to develop harmonized limits for

elemental impurities in pharmaceuticals

7

Short History of ICH Q3D (2/2)

• June 2013 ICH Q3D reached step 2

• 16 December 2014, ICH Q3D (at step 4) was published on the

ICH Website

8

What are the changes introduced by ICH

Q3D

Before (EMA Guideline) ICH Q3D

Apply to Drug Products Apply to Drug Products

14 elements considered 24 elements considered

PDE defined Certain PDE revised

Focused on metals intentionally

added during syntheses

Takes into account all possible

sources of EI

Control strategy defined in

guideline

Risk Assessment is basis for

control strategy

9

Consequences of the Change: Complexity

Increased

10

Where to start ?

ICH Q3DGuidelines

ICH Q3DModules 1-9

EMA

Implementation strategy of ICH Q3D guideline (Mar

2017)

EDQM

Implementation of ICH Q3D in the Certification Procedure (Aug 2016)

The essentials

11

And also…

Trade Associations(ask APIC!)

Webinars

Conferences Scientific Literature

FurtherSupport

12

API

MetalCatalysts

Manufact. Equip.

Processingaids

Inorganicreagents

Organicmaterials

Water

Solvents

Packaging

Primary sources of elemental impurities in API

13

Frequently encountered issues

Issue APIC position

Request for confirmation that API

complies with ICH Q3D.

ICH Q3D does not apply to APIs.

This confirmation cannot be

provided.

Request for providing batch data on

API for all 24 elements listed in ICH

Q3D.

Availability of such data is not

required by ICH Q3D.

ICH Q3D is not a testing guideline

14

Not all API are the same

Contribution of the API to the total mass of the drug products varies

a lot.

Some APIs works at a really low dose.

Levothyroxine 25 – 300 µg/tablets

Vitamin D3 20 µg/tablets

In those case the contribution to potential contamination of

elemental impurities are really negligible

15

The reality. (1/2)

The reality is that to date there is simply no evidence of a substantive risk

to patients regarding elemental impurities in pharmaceuticals.

Assessments of both development compounds and marketed products

across the industry have shown there to be virtually no risk, and

specifically for established products, there has proven to be virtually no

incidence where it has been necessary to replace the outdated heavy

metals limit test with specific testing.(Teasdale A., Org. Process Res. Dev. 2016, 20, 1850−1854)

16

The reality. (2/2)

This is confirmed also at the API level, where EDQM communicated in

June 2017 that approximatively 150 Risk Management Summary were

submitted during CEP revisions to the agency, none of them indicated

higher level of risks than before, on the contrary, in several cases, the

control strategy could be ‘relaxed’.