Regulatory Acceptance of Risk-Based Control Strategies for ... · The Elemental Impurities...

[email protected] Kocks, Senior Scientist Craig Havenhand, Investigator

[email protected]

Regulatory Acceptance of Risk-Based Control Strategies for ICH Q3D: Using Shared Elemental Impurities Data for Risk Assessments

Overview

Elemental Impurities Excipient Database Introduction to the data sharing initiative Demonstration of the database What does the consortium do? Regulators and pharmacopeial bodies

Using the database in ICH Q3D risk assessments Introduction to ICH Q3D guidelines Primary sources of elemental impurities Risk assessment case studies

Conclusions

Getting involved in the data sharing initiative

Elemental Impurities Data Sharing Initiative


Section 5.5 - According to ICH Q3D, evidence collected in the risk assessment can bederived 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 relating to elemental impurities canbe limited and published literature is also sparse.

http://www.ich.org/products/guidelines/quality/article/quality-guidelines.htmlICH Q3D Training Package Modules 0-9. https://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

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

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


As an experienced honest broker for various data sharing initiatives, Lhasa Limitedworked closely with industry to establish how it could support its members and otherswith the ICH Q3D regulatory guideline.

shared knowledge shared progress


The initiative

• The data shared is analytical data generated to establish the levels of elementals withinbatches of excipients.

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

• A database of shared excipient elemental impurity determinations with equivalentprovenance to published literature, can be used as an additional source of information.

• This aims to save time and reduce the amount of testing required for ICH Q3D riskassessments.

The vision

Data is accessible to industry and regulators andcan be used to make it clear why specific excipientsare regarded as low (negligible) or higher risk in aparticular 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 of the Elemental

Impurities Excipient Database was in 2016.

• The database contains the results of 2,633 analytical studies and 39,517

elemental determinations for 295 excipients.

• The last database released was in July 2019.


Currently the largest known collection of this type of data.

Database updates

Num

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f ana

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al st

udie

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0

500

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1500

2000

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3000

2016 2017 2018 2019


Data quality is critical

• Validation and data entry guidelines were developed and are regularly evaluated toaid 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.


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

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

Kocks G & the Elemental Impurities Database Consortium. Sharing elemental impurity data for excipients aids ICH Q3D risk assessmentshttps://www.lhasalimited.org/publications/sharing-elemental-impurity-data-for-excipients-aids-ich-q3d-risk-assessments/4874

https://www.lhasalimited.org/products/vitic.htm

https://www.lhasalimited.org/publications/sharing-elemental-impurity-data-for-excipients-aids-ich-q3d-risk-assessments/4874

Demonstration of the Database

What does the Consortium do?

Regulators and Pharmacopeial Bodies


Discuss and agree upon the scientific direction of the project.

Contribute and share expertise and knowledge.

Monitor the data provided by the member organisations and ensure it meetspredefined quality standards.

Identify data gaps and recommend priorities for work on the project.


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

Lhasa Limited is working with the database consortium to promote and shareinformation on the initiative.

The Elemental Impurities Excipient Database is referenced and used to support theICH Q3D risk assessment of excipient components.

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

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

Regulators and Pharmacopeial Bodies

The consortium and Lhasa Limited have introduced five regulatory bodies tothe initiative and two are in the process of receiving access and training onthe database.

Two pharmacopeial bodies have access to the database and have receivedtraining. The data is used to review and update the monographs. Positivefeedback has been received from both on the initiative and the data in thedatabase.

Craig Havenhand

Using the database in ICH Q3D risk assessments

ICH Q3D Guideline for Elemental Impurities

The International Conference on Harmonisation (ICH) brings together the Regulatory Authorities and Pharmaceutical Industry of Europe, Japan and the United States

ICH Guidelines• ICH Q1A – Q1F Stability• ICH Q2 Analytical Validation• ICH Q3A – Q3D Impurities

• Q3A Impurities in Drug Substances• Q3B Impurities in New Drug Products• Q3C Impurities: Guideline for Residual Solvents• Q3D Impurities: Guideline for Elemental Impurities

• ICH Q4 – Q4B Pharmacopoeias• ICH Q5A – Q5E Quality of Biotechnological Products• ICH Q6A – Q6B Specifications• ICH Q7 Good Manufacturing Practice• ICH Q8 Pharmaceutical Development• ICH Q9 Quality Risk Management• ICH Q10 Pharmaceutical Quality System• ICH Q11 Development and Manufacture of Drug Substances• ICH Q12 Lifecycle Management

ICH Q3D Guideline for Elemental Impurities:

• Presents a process to assess and control elemental impurities in Drug Products

• Contains limits for the Permitted Daily Exposure (PDE) to patients for a range of elements which could be in Drug Products

• Provides a platform to develop a risk based control strategy

Potential Sources of Elemental Impurities

Elemental impurities in the drug product

ExcipientsDrug substance

Container Closure System

Processingaids e.g. water

Manufacturingequipment

More Likely Sources

Lower Risk

• Excipient data is collated from different sources to feed into risk assessments

• Data sourced from the Elemental Impurities Database• Prior knowledge• Data generated internally• Supplier information or data

• ICH Q3D Guideline on Elemental Impurities strongly advocates the use of risk assessments in order to define a final control strategy

Which Elements to Consider?

Route Q3D Class ElementsOral 1 Cd, Pb, As, Hg

2A Co, V, NiParenteral 1 Cd, Pb, As, Hg

2A Co, V, Ni3 Li, Sb, Cu

Inhalation 1 Cd, Pb, As, Hg2A Co, V, Ni3 Li, Sb, Ba, Mo, Cu, Sn, Cr

Any 2B Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, PtOnly if intentionally added

All Elements intentionally added for therapeutic benefit do not need to comply with the PDE limits in Q3D

Refer to Table 5.1 in Q3D for guidance on the elements to consider

Primary Sources of Elemental Impurities

Elemental Impurities in

APIs

Metal Catalysts

Manufacturing Equipment

Processing Aids

Inorganic Reagents

Organic Materials

Water

Solvents

Primary Container Closure

Elemental Impurities in Excipients

Mined (e.g., Talc)

Synthesized with Metal Catalyst

(e.g. mannitol)

Plant Origin(e.g. cellulose derivatives)

Animal Origin(e.g., lactose & gelatin)

Synthesized without Metal Catalyst

(e.g. colloidal SiO2)

Increasing Risk of

Contributing Elemental Impurities

Highest Risk Highest Risk Considerations for excipients.• Mined?• Natural?• Synthetic?

Risk Assessment - Calculations

• Q3D offers several options for evaluating the potential amounts of elements in a product• Identifies the contribution to the PDE from each component• Approach selected may be product dependant

Option Elemental Concentration Daily Dose1 Same for all components 10 g/day2A Same for all components Actual Daily Dose for Product2B Different for each component Actual Daily Dose for Product3 Use test data Actual Daily Dose for Product

• By first intent, GSK perform product assessments using Option 2B (Summation Option)• By first intent, if API is to be tested use Option 1 (if sensitivity allows)• Results below the control threshold, < 30% of PDE, may allow no specification testing (should consider variability in data)

Oral Formulation Case Study # 1Risk Assessment as per Option 2B

24

Oral Formulation Elemental ImpuritiesConcentration (mcg/g) Potential Exposure (mcg/day)

Component Cd Pb As Hg Co V Ni Cd Pb As Hg Co V Ni

Excipient 1* 0.0001 0.003 0.014 0.003 0.0006 0.005 0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01

Excipient 2* 0.1 0.1 1 0.1 0.1 1.02 1.26 <0.01 <0.01 0.03 <0.01 <0.01 0.03 0.03

Excipient 3 0.1 0.3 0.1 0.1 0.1 0.1 2 0.11 0.32 0.11 0.11 0.11 0.11 2.14

Excipient 4 0.05 2.5 0.35 0.05 20 150 20 <0.01 0.14 0.02 <0.01 1.08 8.10 1.08% Oral PDE 2.3 9.2 1.1 0.4 2.4 8.2 1.6

• Test data on 3 commercial scale drug product batches also generated and submitted in marketing application to underpin risk assessment

• All Class 1 and 2A elements below the control threshold• No regulatory questions received to date (Approved in United States, Australia and Brazil)

• Formulation consists of 4 excipients• Data for 2 excipients sourced from the Lhasa Elemental Impurities Excipient Database (2016)• ICP-MS data generated on commercial scale batches of API

* Data sourced from Lhasa Elemental Impurities Database


25



Excipient 1* 0.15 0.15 0.45 0.9 1.5 3 6 0.02 0.02 0.07 0.13 0.22 0.44 0.87

Excipient 2* 0.2 0.3 0.2 0.2 0.2 1 2 0.01 0.01 0.01 0.01 0.01 0.04 0.08

Excipient 3* 0.15 0.15 0.45 0.9 1.5 3 0.18 <0.01 <0.01 <0.01 0.01 0.01 0.02 <0.01

Excipient 4* 0.2 0.2 1 0.9 1.5 3 6 <0.01 <0.01 <0.01 <0.01 0.01 0.01 0.03

Excipient 5 0.1 0.3 0.1 0.1 0.1 0.1 2 0.01 0.02 0.01 0.01 0.01 0.01 0.12

Excipient 6 0.1 0.1 0.1 0.1 0.1 0.1 1 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.02

Excipient 7 0.05 2.5 0.25 0.05 0.59 2.3 2 <0.01 0.05 <0.01 <0.01 0.01 0.04 0.04

Excipient 8 0.1 0.3 0.1 0.1 0.1 0.1 2 0.03 0.08 0.03 0.03 0.03 0.03 0.56

% Oral PDE 1.4 3.7 0.8 0.6 0.6 0.6 0.9

• Formulation consists of 8 excipients• ICP-MS data generated on commercial scale batches of API• Data for 4 excipients sourced from Lhasa Elemental Impurities Excipients Database (Version 2017.1.0)• Remaining excipient data sourced from internal data or supplier information


• Maximum values for each Class 1 and 2A elements from the database were used

• All elements well below control threshold• No final drug product testing was performed• Marketing Application submitted via paper based risk assessment• Regulatory Question from EMA: Provide more context on the risk assessment process• Responded to request by including calculation for potential daily exposure• Product approved in EU, US, Canada and Australia

Oral Formulation Case Study # 2

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Excipient Number of Records Number of Suppliers

1 45 5

2 9 3

3 6 1

4 57 4




Excipient 1* 0.2 0.2 1 0.9 1.5 3 6 0.02 0.02 0.1 0.09 0.15 0.3 0.6

Excipient 2* 0.2 0.2 0.45 0.9 1.5 3 20 <0.01 <0.01 <0.01 <0.01 <0.01 0.01 0.06

Excipient 3* 0.05 3 0.61 0.05 6.8 11 20 <0.01 <0.01 <0.01 <0.01 0.07 0.11 0.19

Excipient 4* 0.2 0.2 0.2 0.2 0.2 0.8 2.1 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.01

Excipient 5* 0.06 0.15 0.45 0.3 1.5 1 2 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01

Excipient 6 0.03 0.07 0.2 0.04 0.07 0.15 0.3 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01

Excipient 7* 0.15 0.15 0.45 0.9 1.5 3 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01

Excipient 8* 0.15 0.15 0.45 0.9 1.5 3 6 0.04 0.04 0.11 0.22 0.36 0.72 1.44

Excipient 9* 0.2 0.2 1 0.9 1.5 3 6 0.01 0.01 0.07 0.06 0.11 0.22 0.43

Excipient 10* 0.2 1 0.45 0.9 1.5 3 6 <0.01 <0.01 <0.01 <0.01 <0.01 0.01 0.01

Excipient 11* 0.15 0.23 0.45 0.9 1.5 3 6 <0.01 <0.01 <0.01 <0.01 <0.01 0.01 0.01

Excipient 12* 0.2 0.2 0.2 0.2 0.2 0.2 1 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01

Excipient 13* 0.2 0.2 1 0.9 1.5 3 6 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01

% Oral PDE 1.5 2.1 2.0 1.3 1.4 1.4 1.4

Formulation contains 18 excipients and for 13 of them data was sourced from the elemental impurities database (Version 2018.1.0)


• The remaining excipient data was sourced from internal data or supplier information

Component Number of Records Number of SuppliersExcipient 1 87 5

Excipient 2 56 4

Excipient 3 9 2

Excipient 4 2 2

Excipient 5 6 2

Excipient 6 8 1

Excipient 7 10 2

Excipient 8 12 2

Excipient 9 87 5

Excipient 10 29 7

Excipient 11 13 2

Excipient12 3 1

Excipient13 60 4

Oral Formulation Case Study # 3

• All elements well below control threshold

• Data for 13 excipients sourced from Lhasa Elemental Impurities Excipients database (Version 2018.1.0)

• Maximum values for each Class 1 and 2A elements from the database were used

• Remaining excipient data sourced from internal data or supplier information

• Regulatory Question from PMDA: Provide risk assessment data to support the calculated PDE

• Response provided context to the calculated potential daily exposure

Parenteral Formulation Case Study # 4Risk Assessment as per Option 2B

ParenteralFormulation

Elemental ImpuritiesConcentration (mcg/g) Potential Exposure (mcg/day)

Component Cd Pb As Hg Co V Ni Li Sb Cu Cd Pb As Hg Co V Ni Li Sb Cu

Excipient 1 0.1 0.11 0.2 0.2 0.1 0.2 0.4 10 2 3 0.01 0.01 0.01 0.01 0.01 0.01 0.02 0.6 0.12 0.18

Excipient 2 0.1 0.1 0.13 0.11 0.1 0.1 0.4 0.25 0.22 0.26 0.01 0.01 0.01 0.01 0.01 0.01 0.02 0.02 0.01 0.02

Excipient 3 0.15 0.3 0.9 0.9 1.5 3 6 17 36 180 0.02 0.03 0.09 0.09 0.16 0.32 0.63 1.79 3.78 18.9

% Parenteral PDE 1.4 0.9 0.8 3.8 3.4 3.3 3.4 1.0 4.3 6.4

• Formulation consists of 3 excipients• ICP-MS data generated on commercial scale batches of API• Data for 3 excipients sourced from Lhasa Elemental Impurities Excipients database (Version 2018.1.0)


• Lhasa Elemental Impurities Excipients database (Version 2018.1.0)• Maximum values for each class 1 and 2A elements from the database were used

• All elements well below control threshold• No final drug product testing was performed• Marketing application submitted via paper based risk assessment• Regulatory question from FDA: Provide detailed assessment of excipients and provide the results of

elemental impurities testing for the extractables of container closure system• Response provided details of excipient data

Parenteral Formulation Case Study # 4

Excipient Number of Records Intended Use

1 10 Parenteral & Oral

2 10 Oral

3 55 Parenteral & Oral

Conclusion

Getting Involved

• Lhasa Elemental Impurities Excipient Database successfully used to assess the potential risk of elemental impurities in

oral and parenteral drug products.

• Lhasa database has rapidly grown with a wide variety of excipients available with many common excipients having

multiple data records from several suppliers providing greater confidence in ICH Q3D assessments.

• The case studies demonstrate elemental concentrations in excipients do not exceed Option 2B oral concentration limits

for Class 1 and Class 2A elements and Option 2B Parenteral concentration limits for Class 1, Class 2A and Class 3.

• Performing a comprehensive risk assessment utilising the Elemental Impurities Excipient Database has negated the

requirement to routinely test drug product.

• Marketing applications successfully approved using a risk-based approach sourcing data from the Lhasa Elemental

Impurities Database.

Conclusions

Getting Involved in the Data Sharing Initiative

The feasibility of sharing excipient elemental impurity data has been successfullydemonstrated.

New consortium members (pharmaceutical organisations and excipient suppliers) areactively being sought to expand the database.

Member organisations participating in the data sharing initiative will join with the intentof regularly (e.g. annually) providing elemental impurity data on non-proprietaryexcipients.

https://www.lhasalimited.org/Initiatives/Elemental-Impurities.htm

https://www.lhasalimited.org/Initiatives/Elemental-Impurities.htm

Acknowledgements

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

Fiona King (GlaxoSmithKline), Laura Rutter (GlaxoSmithKline), Craig Havenhand (GlaxoSmithKline), Tim Cartwright (GlaxoSmithKline), Harpreet Sangha (Genentech), Christopher Day (AstraZeneca), Andrew Teasdale (AstraZeneca), Wilfried Keurentjes (MSD), Frans Maris (MSD), Peter Jacobs(MSD), Juliano Kathleen (Bristol Myers-Squibb), Mark Schweitzer (Novartis), Lance Smallshaw(UCB), Juan Gil (B.Braun), Elaine Shannon (Takeda), Roman Lauchart (Takeda), Philip Lienbacher(Takeda), Agnieszka Ceszlak (ZF Polpharma), Valerie Chiva (Sanofi), Ruimin Xie (Celgene Corporation), David Liu (Celgene Corporation), Diego Zulkiewicz Gomes (Ache), Jessica Cunha (Ache), Enid Gatimu (Abbvie) and Crina Heghes (Lhasa Limited).

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Leeds, LS11 5PS

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