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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
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
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7 8 9 10 >10
Num
ber o
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.
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?
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?
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.
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
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