Elemental Impurities:

PQRI/USP Workshop on Implementation Status &

Progress Report on Collaborative Studies

Donna Seibert
Perrigo
23 March, 2017
Elemental Impurities Timeline
Existing
ICH Q3D New Filings Products
Final Require EI Require EI
Guideline Content Compliance

2014 2015 2016 2017 2018

Ongoing harmonization…

Ongoing stakeholder engagement…

Elemental Impurities Timeline
Existing
ICH Q3D New Filings Products
Final Require EI Require EI
Guideline Content Compliance

2014 2015 2016 2017 2018

PQRI/USP EI
Workshop

Ongoing harmonization…

Ongoing stakeholder engagement…

Elemental Impurities Timeline
Existing
ICH Q3D New Filings Products
Final Require EI Require EI
Guideline Content Compliance

2014 2015 2016 2017 2018

PQRI/USP EI PQRI/USP
Workshop EI Workshop

Ongoing harmonization…

Ongoing stakeholder engagement…

Elemental Impurities Timeline
Existing
ICH Q3D New Filings Products
Final Require EI Require EI
Guideline Content Compliance

2014 2015 2016 2017 2018

PQRI/USP EI PQRI/USP PQRI/USP EI

Workshop EI Workshop Workshop

Ongoing harmonization…

Ongoing stakeholder engagement…

2016 Elemental Impurities Workshop

PQRI/USP Workshop on Implementation Status

of ICH Q3D Elemental Impurity Requirements—
Analytical and Risk Assessment Challenges

Nov 9-10, 2016

Presentations posted on website at:

http://pqri.org/httppqri-
orgpqriusp_workshop_2016-presentations/
Session I: Regulatory Filing Observations for New Drugs—
Industry and Regulator Perspectives
• Industry Perspective:
– Significant infrastructure and cross-functional work to address EI
– Up to 10 filings using multiple options for risk assessment across
multiple dosage forms (e.g., oral, parenteral, transdermal)
– Multiple strategies/workflows in use for existing products vs. new
products based on timelines, availability of samples, and availability
of data
– Available information continued to evolve during 2016
– Generally not seeing products exceeding 30% PDE control threshold;
bigger challenge may be producing an acceptable risk assessment
– Limited feedback to date from regulators
– (Breakout Discussion) Need additional clarification for addressing
products that exceed PDEs

7
Session I: Regulatory Filing Observations for New Drugs—
Industry and Regulator Perspectives
• Regulator Perspective:
– Seeing risk assessments, both acceptable and not acceptable
– ICH training materials including case studies and FDA Guidance available
– European and Canadian authorities have some key differences from US in
filing expectations/timing
– Documentation to include in filings vs. available on site
– Control threshold—build on minimum expectations…give more attention
the higher the potential risk
– Lifecycle—relevant changes need to be considered
– When products exceed PDEs, consider impact on patient

8
Session IV: Preparing for Existing Drug Product
Implementation in January 2018
Country/Region New Products Existing Products
USA & EU – ICH Members New Submissions Marketed Products
• Case Studies: Jun 1, 2016 Dec 31, 2017/Jan 1, 2018

– Oral solid, liquid,

Canada – ICH Member
topical, parenteral,
New submissions of ANDS or DIN. Or
biologic
Marketed Products
new supplemental (A)NDS or post DIN January 1, 2018
– Most productschangeare
for a generally
major change to below
an ICH Q3D 30% control
existing Drug Product as a result of the
threshold risk assessment per Q3D
December 31, 2016
Japan – ICH Member New submissions Marketed Products
April 1, 2017 January 1, 2018
Swissmedic - ICH Member New submissions Marketed Products
July 1, 2016 January 1, 2018
• Breakout Session:
Taiwan New submissions No published implementation date
July 1, 2016
Australia TGA -New products containing new drug -New products containing existing drug
--Q3D applies to substances substances December 2017
registration applications for June 2016
prescription medicines
--No official statement
for current marketed
product 9
Session IV: Preparing for Existing Drug Product
Implementation in January 2018
• Implementation:
– Significant harmonization between USP <232> and ICH Q3D
– Element specific chapters and limits in individual monographs may
still be a point of diversion
• USP solicited input through Stimuli Article in PF 42(4)
• (Post PQRI) Ph. Eur. to retain tests and limits for materials of natural origin
– Filing location
• Summary of the risk assessment should be included and referenced/hyperlinked
• (Breakout Discussion): Harmonize if possible
Country Potential Filing Locations
USA Module 3.2.S.3.2 - Impurities
Module 3.2.P.2 - Product Development Report
Module 3.2.P.5.5 - Characterization of impurities
Module 3.2.S.4.5 - Justification of specification
Module 3.2.P.2 - Pharmaceutical Development
Module 3.2.P.4 - Control of Excipients
Canada QOS Module 2.3.P.5 - Control of Drug Product
Module 3.2.P.5.6 - Justification of Specifications

10
Session III: Risk Assessment Approaches that Work

• Case Studies:
– Presented for a variety of dosage forms (e.g., oral solid, liquid, topical,
parenteral, biologic)
– Stepwise approaches (decision trees) and successive reduction of risk
through solid understanding & focus where risk actually may exist
– Approaches reflect variety of options—most cases below ICH Q3D
30% control threshold
– (Breakout Discussion): Need further clarification of amount of data
needed for adequate risk assessment

11
Session II: Data Sharing, Collaborative Studies, and
Analytical Testing Considerations
• Database Development:
– Database created by EI Pharma Consortium to gather a critical mass of
data for excipients
– Aid in risk assessment and overall understanding of excipient risks
– Intent to publish key findings to de-risk common excipients
– Current membership mainly from big pharma in partnership with Lhasa
– Contact: Crina Heghes (crina.heghes@lhasalimited.org)
• Collaborative Studies (more later)

12
Session II: Data Sharing, Collaborative Studies, and
Analytical Testing Considerations
• Analytical Testing Considerations:
– Difficult sample matrices—implications for sample preparation and
subsequent analysis
– Fundamentals of ICP-MS with respect to solving problems for
pharmaceutical samples
– Contract lab perspective on common misconceptions and practical
aspects of sample analysis and validation
– API and excipient supplier perspectives demonstrating risk assessment
principles
– Alternative methods—WD-XRF as a complementary technique to ICP-MS

13
2017 EI Workshop—Save the Dates!

November 2-3, 2017

USP Headquarters, Rockville
• Update on Recent US/EU/JP Regulatory Guidance, Compendial Chapters and
further ICH EI Initiatives
• Company and regulator experience for new drug applications since June 2016
• Implementation of Q3D requirements for OTC and existing Prescription Drugs
in January 2018 – Challenges and Expectations
• Acceptable risk assessment strategies
• Global Developments for EI Requirements
• PQRI Phase 2 Collaborative study outcomes and recommendations
• Outstanding Analytical Challenges
• Breakout Sessions on each major topic

14
 Elemental Impurities:

PQRI/USP Workshop on Implementation Status &

Progress Report on Collaborative Studies

Donna Seibert
Perrigo
23 March, 2017
Background
• Risk assessment requires some basis in data
• Key question for industry and the regulatory community
– How reliably can we measure elemental impurities in drug products,
APIs and excipients at the levels outlined in ICH Q3D and USP
<232>/<233>?
• Variety and complexity of pharmaceutical samples
• Many labs expanding capabilities
– Pharmaceutical labs adapting to ICP-MS analysis
– Existing spectroscopy labs adapting to the requirements of <233>

• Technical/Analytical Challenges Project Team formed in 2013

as a sub-team of the Coalition for Rational Implementation

16
TECHNICAL/ANALYTICAL CHALLENGES PROJECT TEAM

Team Chartered June 2013

Membership (42+ colleagues)
• Comprised of scientists from
– Coalition companies
• 5 pharmaceutical companies
• 7 raw material suppliers (API/excipient)
– 8 Contract laboratories
– 1 Government laboratory
– 1 University laboratory
 Examples of Key Challenges
• Sample Preparation
– Ensure appropriate and effective solution preparation
– Total metal extraction implies clear solutions
• Instrumental Analysis
– System suitability/data integrity
– Options for sample introduction and interference reduction
• Sample introduction accessories, reaction gasses & collision cells, correction equations, etc.
– Calibration & LOQs
• LOQ can be a concern for large dose products and for raw material analysis
• Data review & interpretation
– Recognition of issues
• Drift, carryover/memory, interferences or element-specific pitfalls, non-ideal recoveries
– Reportable data
• Multiple modes of analysis possible
• No pharmaceutically relevant reference materials available

18
Inter-laboratory Study Objectives
• Address some of the key technical challenges faced by industry in
preparation for compliance to ICH Q3D and USP <232>/<233>
• Provide a data-driven way to discuss technical aspects and expected
variation of ICP-MS analysis of elemental impurities
• More specific objectives:
– Inter-laboratory data comparison for standardized samples
– Inter-laboratory evaluation of effectiveness of microwave digestion
– Comparison of acid leach/extraction techniques to total metal extraction
– Examination of the correlation (good or bad) between the analysis of individual
components (summation) vs. the formulated tablet analysis
– Comparison of ICP-MS and alternative techniques (ICP-OES and XRF)

• First round study reported preliminary results at PQRI 2015, final results at
AAPS 2015, and XRF arm at PQRI 2016
• Second round benefits from PQRI Sponsorship—allows wider participation
& Study Administrator—RTI International
19
Second Round Design Improvements & Best Practices
General
• Consistency among alternative techniques and digestion methods to ensure
adequate data for comparison
• ICP-OES (14) and XRF (6) analysis considered proactively
• Raw materials to be distributed widely for summation approach comparison

Uniform Sample Preparation

• Specify parameters such as sample size, sampling technique, acid mixtures,
and digestion temperature/pressure
• Document type of digestion vessels and microwave model used

Uniform Analysis
• Define procedures around LOQs, calibration, and data reporting
• Document interference management (reaction/collision gases, correction
equations, etc.) and internal standards

20
 Evaluation Samples and Analysis

Powdered or tableted material at three concentrations and liquid

sample are aliquoted and shipped to each participating laboratory.
Second Round
Improvements— Evaluation
Samples
Samples extracted in triplicate using the
uniform method. Alternate extraction
Samples extracted in • Liquid sample to assess
instrumental variation
triplicate using the uniform
methods may be used if available in
acid leaching method.
addition to the uniform method.

• Evaluation samples with

Uniform method
Uniform method
Optional alternate Samples extracted by
higher EI levels overall
sample extracts, liquid
sample extracts/liquid method sample acid leaching method
may be analyzed by
sample must be
analyzed by ICP-MS.
ICP-OES or other
instrument.
extracts are analyzed
by ICP-MS.
must be analyzed by
ICP-MS. • Multiple powdered or
tableted evaluation
samples targeting different
levels
Replicate results and average/SD reported by extraction method and Results for replicates and
analysis method. Total samples for ICP-MS analysis are 12, alternative
digestion and analysis techniques will be in addition to basic results.
average/SD are reported. Total
samples for acid leach analysis • EI source from pharma
materials wherever
Minimum samples: 12, maximum: 36. are 12.

possible

21
Formulation Challenges

• Ideal solid formulation is tableted

– To preserve homogeneity
• Pharmaceutical materials that contain significant, known
levels have been elusive
– Few materials contain significant As & Hg
• Combination of materials must have
– Favorable mixing & flow properties
– Compressibility
• Current path for solid formulations
– Tablets similar to the first round tablets
– Include small amounts of matrix XRF standards
– Three levels of elemental impurities

22
Recruiting

• Distributed participant questionnaire for analytical laboratories in early

August 2016.
• 29 laboratories enrolled
• Pharma manufacturers: 16 laboratories
• Contract/CRO: 9 laboratories
• Instrument manufacturers: 2 laboratories
• Government: 2 laboratories
11 labs

17
labs 1 lab

23
Next Steps

• Tablet and liquid sample production

– Partnering with Liverpool John Moore’s University
• Uniform method and acid leach method development—critical step
– To be developed with finalized tablets prior to distribution
• Package assembly & shipment
• Sample analysis during summer months
• Results readout at PQRI in November

24
Acknowledgements

• James Harrington, RTI

• Frank Weber, RTI
• Phil Riby, Liverpool John Moore’s University
• Dave Schoneker, Colorcon
• Josh Foote, Perrigo
• PQRI
• TAC Team members
• All participating labs

25
2017 EI Workshop—Save the Dates!

November 2-3, 2017

USP Headquarters, Rockville
• Update on Recent US/EU/JP Regulatory Guidance, Compendial Chapters and
further ICH EI Initiatives
• Company and regulator experience for new drug applications since June 2016
• Implementation of Q3D requirements for OTC and existing Prescription Drugs
in January 2018 – Challenges and Expectations
• Acceptable risk assessment strategies
• Global Developments for EI Requirements
• PQRI Phase 2 Collaborative study outcomes and recommendations
• Outstanding Analytical Challenges
• Breakout Sessions on each major topic

26