pqri/usp workshop on implementation status & progress...
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Elemental Impurities:
PQRI/USP Workshop on Implementation Status & Progress Report on Collaborative Studies
Donna Seibert Perrigo
23 March, 2017
Elemental Impurities Timeline
2014 2015 2016 2017 2018
ICH Q3D Final
Guideline
Ongoing harmonization…
Ongoing stakeholder engagement…
New Filings Require EI
Content
Existing Products
Require EI Compliance
Elemental Impurities Timeline
2014 2015 2016 2017 2018
ICH Q3D Final
Guideline
Ongoing harmonization…
PQRI/USP EI Workshop
Ongoing stakeholder engagement…
New Filings Require EI
Content
Existing Products
Require EI Compliance
Elemental Impurities Timeline
2014 2015 2016 2017 2018
ICH Q3D Final
Guideline
Ongoing harmonization…
PQRI/USP EI Workshop
Ongoing stakeholder engagement…
PQRI/USP EI Workshop
New Filings Require EI
Content
Existing Products
Require EI Compliance
Elemental Impurities Timeline
2014 2015 2016 2017 2018
ICH Q3D Final
Guideline
Ongoing harmonization…
PQRI/USP EI Workshop
Ongoing stakeholder engagement…
PQRI/USP EI Workshop
PQRI/USP EI Workshop
New Filings Require EI
Content
Existing Products
Require EI Compliance
2016 Elemental Impurities Workshop
Nov 9-10, 2016
Presentations posted on website at: http://pqri.org/httppqri-
orgpqriusp_workshop_2016-presentations/
PQRI/USP Workshop on Implementation Status of ICH Q3D Elemental Impurity Requirements—
Analytical and Risk Assessment Challenges
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
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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
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Session IV: Preparing for Existing Drug Product Implementation in January 2018
• Case Studies: – Oral solid, liquid, topical, parenteral, biologic – Most products are generally below ICH Q3D 30% control
threshold
• Breakout Session:
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Country/Region New Products Existing Products USA & EU – ICH Members New Submissions
Jun 1, 2016 Marketed Products Dec 31, 2017/Jan 1, 2018
Canada – ICH Member New submissions of ANDS or DIN. Or new supplemental (A)NDS or post DIN change for a major change to an existing Drug Product as a result of the risk assessment per Q3D December 31, 2016
Marketed Products January 1, 2018
Japan – ICH Member New submissions April 1, 2017
Marketed Products January 1, 2018
Swissmedic - ICH Member New submissions July 1, 2016
Marketed Products January 1, 2018
Taiwan New submissions July 1, 2016
No published implementation date
Australia TGA --Q3D applies to registration applications for prescription medicines --No official statement for current marketed product
-New products containing new drug substances June 2016
-New products containing existing drug substances December 2017
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
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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
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
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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 ([email protected])
• Collaborative Studies (more later)
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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
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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
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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
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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
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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
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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
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Evaluation Samples and Analysis
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Second Round Improvements— Evaluation
Samples
• Liquid sample to assess instrumental variation
• Evaluation samples with higher EI levels overall
• Multiple powdered or tableted evaluation samples targeting different levels
• EI source from pharma materials wherever possible
Powdered or tableted material at three concentrations and liquid sample are aliquoted and shipped to each participating laboratory.
Samples extracted in triplicate using the uniform method. Alternate extraction methods may be used if available in
addition to the uniform method.
Uniform method sample extracts/liquid
sample must be analyzed by ICP-MS.
Optional alternate method sample
extracts are analyzed by ICP-MS.
Replicate results and average/SD reported by extraction method and analysis method. Total samples for ICP-MS analysis are 12, alternative
digestion and analysis techniques will be in addition to basic results.Minimum samples: 12, maximum: 36.
Uniform method sample extracts, liquid may be analyzed by ICP-OES or other
instrument.
Samples extracted in triplicate using the uniform
acid leaching method.
Samples extracted by acid leaching method must be analyzed by
ICP-MS.
Results for replicates and average/SD are reported. Total samples for acid leach analysis
are 12.
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
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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
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1 lab
11 labs
17 labs
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
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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
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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
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