Elemental Impurities Database for ExcipientsECA Impurities ForumPost-Conference Workshop

Senior Data Scientist

grace.kocks@lhasalimited.org

Grace Kocks

Overview

• Introduction to Lhasa Limited Who we are and what we do

• Elemental impurities excipient database Introduction to the data sharing initiative How to use the database

• Demonstration of the database

• What does the database consortium do?

• Using the database in ICH Q3D risk assessments Regulators and pharmacopeial bodies Case studies

• Getting involved

Introduction to Lhasa Limited

Not-for-profit & educational charity

Facilitate collaborative data sharing initiatives in the chemical and life science industries

Controlled by our members

Currently more than 160 employeesHQ in Leeds, UKAccount Managers in the USAdditional offices in Newcastle, UK and Poznan, Poland

Lhasa Limited – Product Suite

Purge Factor

calculation tool

Statistical/machine learning

DatabaseExpert system

Derek NexusToxicity

Meteor NexusXenobiotic metabolism

ZenethChemical degradation

ViticData sharing

SetariaToxicity

Sarah NexusMutagenicity

Elemental Impurities Data Sharing Initiative

Section 5.5 - According to ICH Q3D, evidence collected in the risk

assessment can be derived from numerous sources:

• Prior knowledge;• Published literature;• Data generated from similar processes;• Supplier information or data;• Testing of the components of the drug product;• Testing of the drug product.

However, in the case of excipients, supplier information relatingto elemental impurities can be limited and published literature isalso sparse.

http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

Elemental Impurities Data Sharing Initiative

As an experienced honest broker for various data sharing initiatives,

Lhasa Limited worked closely with industry to establish how it could

support its members and other with the ICH Q3D regulatory guideline.

shared knowledge shared progress

Elemental Impurities Data Sharing Initiative

A proactive action from the pharma industry

Facilitate more scientifically driven elemental impurities risk

assessments under ICH Q3D and reduce unnecessary testing

as part of elemental impurities risk assessment efforts.

Elemental Impurities Data Sharing Initiative

The initiative• The data shared is analytical data generated to establish the levels of

elementals within batches of excipients.

• Lhasa acts as the ‘honest broker’ and facilitates the data sharing.

• A database of shared excipient elemental impurity determinationswith equivalent provenance to published literature, can be used asan additional source of information.

• This aims to save time and reduce the amount of testing requiredfor ICH Q3D risk assessments.

The vision

• Data is accessible to industry and regulators and can be used to

make it clear why specific excipients are regarded as low

(negligible) or higher risk in a particular formulation at a given

daily intake.

What is the Strategic Intent of the Database?

Elemental Impurities Excipient Database

• A consortium was established in 2015 and the first release ofthe Elemental impurities excipient database was in 2016.

• The database contains the results of 2304 analytical studies,34,239 elemental determinations, for 264 excipients.

• The next database update will be released in July 2019.

Elemental Impurities Excipient Database

Currently the largest known collection of this type of data

Database updates

Num

ber o

f ana

lytic

al st

udie

s

0

500

1000

1500

2000

2500

3000

2016 2017 2018 2019

Elemental Impurities Excipient Database

Data quality is critical

• Validation and data entry guidelines were developed and are

regularly evaluated to aid consistency and quality of the data.

Data on excipients NOT suppliers

• The supplier and batch information is blinded.

• The data is for scientific purposes not for business interest.

Elemental Impurities Excipient Database

49 novel drugs approved in 2018.

A list of the excipients used in formulation was compiled

41 excipients were used > once

87% (36 of these 41) have ≥ 3 studies in the database

92% (38 of these 41) ≥ 1 study in the database

The relevance of the excipients within the

database was confirmed by a review of novel

drugs approved by the US FDA in 2018.

Elemental Impurities Excipient Database

• Use of an Excel template for data donation.• Data is collected on all 24 elements in the ICH Q3D guidelines (plus

B, Al, Mn, Fe, Zn, W).

Elemental Impurities Excipient Database -Validation Approach

Elemental Impurities Excipient Database

Members in-house analytical

study data

Complete the donation template using the guideline and validation

protocols provided

The data is anonymised and entered into the

Vitic database

The supplier and batch information

are blinded by Lhasa Limited

Full access to standardised excipient names and their corresponding elemental

impurity profiles is provided

The data is actively managed by Lhasa Limited

Submit the data to Lhasa Limited where it is stored confidentially

Elemental Impurities Excipient DatabaseMost excipients in the database have been tested in more than one analytical

study:

• multiple batch testing

• multiple suppliers and/or testing organisations

0

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30

40

50

60

70

80

1 2 3 4 5 6 7 8 9 10 >10

Num

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f exc

ipie

nts

Number of analytical studiesExcipients for which samples are from more then one supplier

Excipients for which samples are from one supplier

72 excipients have been tested 3 times; in only 4 cases were the samples from different suppliers.

50 excipients have been tested > 10 times; in only 4 cases were the samples all from the same supplier.

38 excipients have been tested once and from one supplier

Elemental Impurities Excipient Database

Members of the consortium are able to query, review and exportdata. They cannot modify the contents of the database in anyway.

Vitic is the platform used to host the data sharing initiative.

How to Use the Database

1. Identify all excipients in the drug product of interest2. Search the database for each excipient3. Review and export relevant elemental impurity results

How to Use the Database

SearchThe database can be searched in a number of ways including;excipient name, class, element.

How to Use the Database

ReviewThis shows the data in the Summary table.Summary statistical parameters such as mean and range valuescan be viewed.

How to Use the Database

ExportThe data from queries andreviews can be exported in asuitable format for incorporationinto risk assessments.

These can be downloaded andsaved.

Are there any questions?

Demonstration of the Database

The demonstration will run through:

• Building a query• Displaying the results• Exporting the results to Excel

What does the Consortium do?

What does the Consortium do?

Discuss and agree upon the scientific direction of the project.

Contribute and share expertise and knowledge.

Monitor the data provided by the member organisations andensure it meets predefined quality standards.

Identify data gaps and recommend priorities for work on theproject.

What does the Consortium do?

Face to face meetings are held twice a year.

What does the Consortium do?

The consortium aims for the data to be accessible to industry,regulators and pharmacopeial bodies.

Lhasa Limited is working with the database consortium topromote and share information on the initiative.

The Elemental Impurities Excipient Database is beingreferenced and used in the same way as information from thepublished literature to support the ICH Q3D risk assessment ofexcipient components.

ICH Q3D risk assessments

- Regulators and pharmacopeial bodies

- Case Studies

Regulators and Pharmacopeial Bodies

The consortium and Lhasa Limited have introduced two

regulatory bodies to the initiative and they will receive access

and will be trained on the database.

Two pharmacopeial bodies have access to the database and

have received training. The data is used to review and update

the monographs.

European Pharmacopeia Commission Feedback

April 2019

“Specific elemental impurity tests are dealt with individually. Experts

concerned examine these monographs individually and decisions are

taken on a case-by-case basis. For this reason, your database has been

very useful because it provides batch data of several batches of

different excipients which we could use for the revision of a number of

monographs.”

United States Pharmacopeia Feedback

April 2019

“I think this database is great and has a lot of information. I see USP

using it again and again while working on the topic of Element

Specific Chapters”.

Oral Formulation Case Study

The risk assessment process identified that the API and 5 excipients were the

only potential sources of elemental impurities.• Data for all 5 excipients were sourced from database.

Assessment of all data using ICH Q3D option 2B concluded that there was no

significant risk from any component.

This conclusion was confirmed by drug product testing.

The risk assessment was accepted by the regulatory authorities.

Excipient Number of records Number of suppliers1 80 82 107 53 13 34 56 45 60 4

IV Formulation Case Study

New formulation of existing IV drug submission.

Elemental impurity data were collected:• Generated for the API.• Retrieved from the database for excipients.

The risk assessment using ICH Q3D option 2B concluded there was

no significant risk.

No drug product testing was considered necessary in part because

as an IV drug it had a simple formulation.

The risk assessment was accepted by the regulatory authority.

Conclusions

The feasibility of sharing excipient elemental impurity data has beensuccessfully demonstrated.

The shared data has the same provenance as published literature and can beused as a source of information to support ICH Q3D risk assessments.

Pooling and publishing data;

• Can improve the ease with which risk assessments can be completed and

reduce the amount of testing required.

• Will give a better picture of which materials represent a more significant

risk than others (indicate where the risk is real & where it is negligible).

Risk assessments using the database have been accepted by multiple regulatory

authorities including in the absence of drug product testing.

Getting Involved!

New consortium members (pharmaceutical organisations and

excipient suppliers) are actively being sought to expand the database.

Member organisations participating in the data sharing initiative will

join with the intent of regularly (e.g. annually) providing elemental

impurity data on non-proprietary excipients.

Getting Involved!

Companies interested in joining the initiative can directly contact

Crina Heghes at Lhasa Limited at Crina.Heghes@lhasalimited.org

Acknowledgements

The Elemental Impurities Database Consortium steering group in 2019 is chaired by Laurence Harris (Pfizer), and consists of the following representatives:

Helmut Rockstroh (Hoffmann-La Roche), Christopher Day (AstraZeneca), Andrew Teasdale (AstraZeneca), Fiona King (GlaxoSmithKline), Laura Rutter (GlaxoSmithKline), Wilfried Keurentjes (MSD), Frans Maris (MSD), Peter Jacobs (MSD), Nancy Lewen (Bristol Myers-Squibb), Mark Schweitzer (Novartis), Radu Horga (Apotex), Lance Smallshaw (UCB), Juan Gil (B.Braun), Elaine Shannon (Takeda), Philip Lienbacher (Takeda), Agnieszka Ceszlak (ZF Polpharma), Valerie Chiva (Sanofi), and Enid Gatimu (Abbvie). Grace Kocks (Lhasa Limited), Carol Marchant (Lhasa Limited), Crina Heghes (Lhasa Limited).

Lhasa Limited

Granary Wharf House, 2 Canal Wharf

Leeds, LS11 5PS

Registered Charity (290866)

Company Registration Number 01765239

+44(0)113 394 6020

info@lhasalimited.org

www.lhasalimited.org

Thank you for listening.

Are there any questions?

Further information

• Boetzel R et al.. An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug

Product Risk Assessment. Journal of Pharmaceutical Sciences 107 2335-2340 (2018).

https://doi.org/10.1016/j.xphs.2018.04.009

• Kocks G & the Elemental Impurities Database Consortium. Sharing elemental impurity data

for excipients aids ICH Q3D risk assessments. Poster presented at Joint Pharmaceutical

Analysis Group meeting, London, 6th December 2018.

https://www.lhasalimited.org/publications/sharing-elemental-impurity-data-for-excipients-

aids-ich-q3d-risk-assessments/4874

• Lhasa Limited. Elemental Impurities. https://www.lhasalimited.org/Initiatives/Elemental-

Impurities.htm

• Vitic Products https://www.lhasalimited.org/products/vitic.htm

• ICH Q3D Training Package Modules 0-9.

https://www.ich.org/products/guidelines/quality/article/quality-guidelines.html