International Pharmaceutical Excipients Council Collaborative solutions for excipient industry stakeholders Multiple stakeholders; one objective. ICH Q3D Elemental Impurities - Implementation Considerations ExcipientFest 2017 Phyllis Walsh: Vice Chair for Harmonization and Compendial Monographs Dave Schoneker: Vice Chair for Science & Regulatory Policy Copyright 2017, All Rights Reserved, IPEC-Americas 2 Elemental Impurities Workshop Agenda Back Ground Information on Elemental Impurities Scope of ICH Q3D Guideline Compendial Requirements Specific Metals Tests in Monograph EMA Guideline Draft FDA Guideline ICH Q3D Developments for Topicals Pb As Hg Cd Co V Ni ???
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International Pharmaceutical Excipients Council
Collaborative solutions for excipient industry stakeholders
Multiple
stakeholders;
one objective.
ICH Q3D Elemental
Impurities -
Implementation
Considerations
ExcipientFest 2017
Phyllis Walsh: Vice Chair for
Harmonization and Compendial
Monographs
Dave Schoneker: Vice Chair for
Science & Regulatory Policy
Copyright 2017, All Rights Reserved, IPEC-Americas 2
Elemental Impurities Workshop Agenda
Back Ground Information on Elemental
Impurities
Scope of ICH Q3D Guideline
Compendial Requirements
Specific Metals Tests in Monograph
EMA Guideline
Draft FDA Guideline
ICH Q3D Developments for Topicals
Pb As Hg
Cd Co V
Ni ???
Copyright 2017, All Rights Reserved, IPEC-Americas 3
Elemental Impurities Workshop Agenda
Implementation by Region
Implementation Timelines & ICH regions - Regulatory Filings
Developments in other countries
Life Cycle Management
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Elemental Impurities Workshop Agenda
Analytical and Risk Assessment Challenges
Methodologies concerns
Collaborative study performed
PQRI Phase 2 testing initiated
Lhasa database
Supplier information (API and Excipient)
Risk Assessment Approaches
Q&A
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Elemental Impurities Workshop Agenda
Case studies – ICH Modules
Solid Oral Dosage
Working Example
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Back Ground Information on Elemental Impurities
6
Scope of ICH Q3D Guideline
Compendial Requirements
Specific Metals Tests in Monograph
EMA Guideline
Draft FDA Guideline
ICH Q3D Developments for Topicals
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ICH Q3D Approach to Risk Assessment
ICH Q3D defines a science and risk based assessment process to identify, evaluate, and define controls to limit elemental impurities in drug products.
Identify known and potential sources of elemental
impurities that may find their way into the drug product.
Evaluate the presence of a particular elemental impurity in the drug product by determining the observed or predicted level of the impurity and comparing with the established PDE.
Summarize and document the risk assessment. Identify if controls built into the process are sufficient or identify additional controls to be considered to limit elemental impurities in the drug product.
Scope of ICH Q3D Guideline
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Risk Process – General Principles
ICH Q3D advocates a 3 step process:
Identify
Evaluate
Summarize Control
Different approaches to each stage are examined through a series of actual risk assessments.
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Risk Assessments
ICH allows you to use the Component Approach or Finish Product Analysis.
The Component Approach is ICH Q3D option 1,
2A or 2B.
The Finish Product Analysis is option 3.
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Risk Assessments
Finish Product Analysis
The Finish Product Analysis is option 3.
Assessment of potential elemental impurities from
each component of the drug product (API,
excipients, container closure system).
Need to know what potential elemental impurities
are present.
May need to test finished product.
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Risk Assessments
Component Approach
The component approach is ICH Q3D option 1, 2A or 2B.
Assessment of potential elemental impurities from each component of the drug product (API, excipients,
container closure system).
Assess each component for potential sources of elemental impurities.
Identify known or likely elemental impurities.
Determine the contribution of each component or source of elemental impurity to the levels in the final drug product.
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Compendial Requirements
USP
General Chapters <232> & <233> are
official but not yet implemented.
<232> revisions proposed in PF to align with ICH Q3D
General Notices 5.60.30 Elemental Impurities official
01-Jan-2018.
General Notices 5.60.30 Elemental Impurities official on
January 1, 2018 is the date on which General Chapter
<232> will become broadly applicable to drug products.
Heavy Metals General Chapter <231>
Chapter will be deleted from USP-NF on 01-Jan-2018.
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Compendial Requirements
European Pharmacopoeia (Ph. Eur.)
Prior to 2008 No guideline for safety limits
only Heavy Metals General Chapter.
2008 EMA guideline on specification limits for
residues of metal catalysts or metal reagents
(known metals).
General Chapter 5.20
2014 ICH Q3D development and implementation
(Official 01-Jan-2018 Ph. Eur. 9.3)
Replace General Chapter 5.20 - Only parts of the
introduction and the scope of ICH Q3D together with
information specific to Q3D in the Ph. Eur.
Will not republish entire ICH Q3D into Ph. Eur.
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Compendial Requirements
European Pharmacopoeia (Ph. Eur.) (cont.)
General method 2.4.20 Determination of elemental
impurities.
Editorial revision to align the wording with the ICH Q3D
guideline will be published in Ph. Eur. 9.3.
“metal catalyst and metal reagent residues” to “elemental
impurities.
General Method 2.4.8 Heavy Metals
Will not be deleted since needed for Veterinary use.
All references in monographs for Human products is
deleted.
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Compendial Requirements
European Pharmacopoeia (Ph. Eur.)
(cont.)
General monograph on Substances for
Pharmaceutical use (2034):
Introduce requirements for the control of elemental
impurities intentionally added during production and
explains the absence of a test for elemental impurities from
individual monographs except for special cases.
The identity of the elemental impurities derived from
intentionally added catalysts and reagents is known and
strategies for controlling them should be established by
using the principles of risk management.
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Compendial Requirements
European Pharmacopoeia (Ph. Eur.) (cont.)
General monograph on Pharmaceutical Preparations (2619)
Refers to chapter 5.20, rendering it and by extension the ICH Q3D guideline legally binding.
Clarification for medicinal products outside of the scope of ICH Q3D guideline manufacturers of these products remain responsible for controlling the levels of elemental impurities using the principles of risk management.
■ If appropriate, testing is performed using suitable analytical procedures according to general chapter 2.4.20 Determination of elemental impurities.
■ Elemental Impurities should at least be considered in risk management strategy
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Specific Metals Tests in Monographs - USP
USP published a Stimuli Article Future of
Element - Specific Chapters in the USP–NF
with questions on specific metal tests in monographs.
What will be the future of USP chapters that provide specific
information regarding the analysis of individual elements, such as arsenic (As) Arsenic ⟨211⟩, lead (Pb) Lead ⟨251⟩, selenium
(Se) Selenium ⟨291⟩, mercury (Hg) Mercury ⟨261⟩, and others?
What about USP monographs that may have limit tests for
specific elements and refer to their respective element-
specific chapters for methodology?
What about USP monographs that include limits for specific elements that differ from the limits established in ⟨232⟩?
Limit tests and references to element specific chapters are
included in about 1000 monographs
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Specific Metals Tests in Monographs Industry Concerns
Industry response to USP Pharmacopeias should not change an existing monograph
specific element requirement (methods/limits) unless evaluated as part of an individual monograph modernization activity designed to include specific metal requirement.
Existing element limit requirements and test methods should stay in the monographs and not be removed – to allow for comparisons with historical methods/data.
History supports limits/test methods which can be used in risk assessments as worst case examples AND provide useful information to users since actual detailed information is limited.
No changes should be made to the limits and no new elements should be added based on a limited amount of batch testing, since excursions won’t show up except over long-term history.
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Specific Metals Tests in Monographs Industry Concerns
Industry response to USP (cont.) Current monograph limits and test methods are linked,
USP should not change the monographs to use the approaches for methodology and analysis in <233> or the existing limits unless validation work conducted demonstrates that the current methods in the monograph and any alternative methods give equivalent results
API suppliers: Elemental Impurities is for the finished drug product not the Drug Substances.
Removing specific metal tests from USP would impact API supplier, FDA would not allow deletion without justification.
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Specific Metals Tests in Monographs Industry Assistance
IPEC-Americas is assisting USP in developing a priority list of monographs containing specific metals.
IPEC-Americas is requesting Industry to supply historical data to USP directly on specific metals in the monographs.
USP will evaluate the historical data and determine if any changes are needed in the monographs.
If changes are needed they will proceed through the normal PF process.
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Specific Metals Tests in Monographs Ph. Eur.
In Ph. Eur. approx. 300 monographs describe more than 450 specific metal tests
Concerns - Specific Elemental Impurities in
individual monographs
Historical reason for the presence of the test in the
monograph
No change control for updating production pathways
(intentionally added metals)
Substances of natural origin (e.g. mined excipients) =>
Elemental Impurities potentially present but not intentionally
added
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Specific Metals Tests in Monographs Ph. Eur.
EDQM announced actions:
Test for heavy metals (method 2.4.8) will be deleted from all individual monographs except from monographs of substances for veterinary use only (9th edition).
Other tests for specific Elemental Impurities in individual monographs will be reviewed by groups of experts on a case by case basis. Secretariat provided lists of monographs concerned to the groups.
Specific tests in individual monographs for elements not covered by ICH Q3D will remain untouched but may be considered upon discussion of a monograph in the group.
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Specific Metals Tests in Monographs Ph. Eur.
EDQM decided to keep the published specific
elemental impurities tests in monographs on
substances of Natural Origin only.
Given the intrinsic nature of elemental impurities in Natural Origin
substances, they are amongst the major potential sources of elemental
contamination in medicinal products.
Recommended keeping the different tests for elements for which no
Permitted Daily Exposure limits have been established, i.e. those
identified as “other elements” in the ICH Q3D guideline (such as
aluminum and iron), in individual monographs.
Specific elemental impurities tests will be deleted from monographs on
other substances (i.e. not from natural origin), unless otherwise justified.
Specific tests for elemental contaminants originating from the
production process will be deleted.
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Specific Metals Tests in Monographs Ph. Eur.
EDQM Focus: Substances of Natural
Origin (mainly mined excipients)
Obtain batch data and revise tests / or add new
ones, if necessary based on batch data
Need for more expertise and support (especially
from manufacturers) to revise / maintain the tests
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EMA - Implementation Strategy of ICH Q3D Guideline
EMA Implementation strategy of ICH Q3D guideline published as final on 08-Mar-2017
Same Risk Assessment Approaches as ICH Q3D for Drug Product or Component
Particulars for Intentionally Added Element(s) Any element intentionally added during manufacturing
must be included in the description of the drug substance manufacturing process in the marketing authorization dossier, an ASMF or a CEP application, as well as its fate and the need for any controls (for instance the use of a metal catalyst in the last step of the synthesis).
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FDA Draft Guidance FDA draft Guidance for Industry published June 2016
Scope
How applicants submitting new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for non-compendial drug products should control elemental impurities as described in ICH Q3D. ICH Q3D contains recommendations on applying a risk-based approach to control elemental impurities and permitted daily exposure (PDE).
How manufacturers of compendial drug products that are not marketed under an approved NDA or ANDA can comply with USP General Chapters Elemental Impurities—Limits and Elemental Impurities—Procedures and the Federal Food, Drug, and Cosmetic (FD&C) Act.
How holders of NDAs or ANDAs for compendial drug products should report changes in chemistry, manufacturing, and controls specifications to FDA to comply with General Chapters and 21 CFR 314.70.
How manufacturers of non-compendial drug products that are marketed without an approved NDA or ANDA should control elemental impurities.
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FDA Draft Guidance
FDA Final Guidance is expected soon
Expected clarity on Biologics.
Expected clarity on OTC products documentation.
Expected filings by Annual Reports.
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FDA Advice to Industry
Risk Assessment: Potential considerations during review
Intentionally added elements.
Contributions from raw materials derived from plant or marine origins.
Contributions from raw materials that are mined, e.g., Inorganic drug substances and excipients.
Contributions from manufacturing, e.g., high shear micronization using metal discs.
Leachable elemental impurities from container/closure.
Extractables information from container/closure components typically included in a supplier Type III DMF.
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ICH Q3D Developments for Topicals
Currently topicals fall under ICH
“Other Routes of Administration”.
ICH Q3D announced the start of Q3D(R1) - Revised PDEs for the cutaneous and transdermal Route of Administration on September 15, 2016.
Develop PDEs for EIs for products administered on skin and its appendages (e.g., hair, nails); these products remain the largest area where PDEs for EIs have not been established.
Cutaneous and transdermal PDEs were not developed at that time due to the late request for inclusion (post Step 2). These products include both prescription and over-the-counter products.
Since the intact skin serves as a barrier to absorption, it is possible that not all EIs in Q3D will require cutaneous and transdermal PDEs, streamlining the risk assessment process for these products.
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Implementation by Region
31
Implementation Timelines & ICH regions -
Regulatory Filings.
Developments in other Countries.
Life cycle management.
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Implementation Timelines for US
FDA Draft Guidance Recommendations and Timelines for risk assessment and documentation of risk assessment:
New NDA and ANDA applications submitted after June 1, 2016 should follow the recommendations of Q3D.
Consistent with the EMA implementation timeline
For existing marketed products, manufactures should follow the recommendations of Q3D and/or comply with USP <232> by January 1, 2018. Consistent with USP implementation timeline for <232>
and <233>.
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ICH Regions - Regulatory Filings - FDA
Anticipates most approved drug products marketed in the United States do not contain any elemental impurities that exceed the Q3D/ <232>PDEs.
Products that meet PDE recommendations of Q3D or comply with <232>PDEs.
Perform risk assessment to determine if additional controls (e.g. upstream controls, specifications) are needed by 1 January 2018.
Document changes in the next Annual Report.
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ICH Regions - Regulatory Filings - FDA
New NDAs or ANDAs. Include a summary of the risk assessment application. Cite
supporting material (e.g., controls) as warranted.
The P.2 section (Pharmaceutical Development) is an appropriate location for the risk assessment summary.
Approved NDAs or ANDAs. Include a summary in the next Annual Report following the
completion of the risk assessment. Document changes to controls.
See FDA Draft Guidance for details if drug products exceed PDEs and changes are implemented to reduce EI levels
For drug products not approved under an NDA or ANDA. Include risk assessment in the documentation maintained at
the manufacturing site for Agency review during an inspection.
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Implementation Timelines for EU
CHMP recommendations and timelines:
New MA for new product (new active substance).
Implementation date June 2016
New MA for product with existing active substance.
Implementation date June 2016
Marketed products including new MR applications of already approved products.
Implementation date December 2017
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ICH Regions - Regulatory Filings - EU
New Marketing Authorizations:
Compliance with the Q3D PDEs.
Should document the risk assessment and the
control approaches.
The documentation of the risk assessment should be
kept available for inspection on site.
A summary of the Risk Assessment and any
measures taken to ascertain compliance is needed
in the regulatory filing.
The overall Control Strategy for elemental impurities
including any specifications included in the
regulatory filing.
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ICH Regions - Regulatory Filings - EU
Existing Marketed Products
Risk Assessment should be performed, documented
and be kept available.
No variation is necessary if the Risk Assessment shows
compliance: No further controls on elemental impurities to materials such as
the designated active substance starting material, synthesis
intermediates, active substance, excipients or the finished
product are needed.
No replacement or change of quality of materials such as the
designated active substance starting material, synthesis
intermediates, active substance, excipients or of the
manufacturing equipment is needed.
No change of the manufacturing process is needed.
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ICH Regions - Regulatory Filings - EU
Existing marketed products
In other cases a variation is needed:
Categorized according the Variation Guidelines
(Official Journal 2013/C 223/01)
Accompanied with the documentation required in
the Variation Guideline.
In addition contain a summary of the Risk
Assessment and the conclusions drawn.
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ICH Regions - Regulatory Filings - EU
Submission expectation
A Summary of the Risk Assessment to be submitted.
Full documentation of Risk Assessment available at site.
What should the Summary look like?
Should follow the principles lined out in ICH Q3D
Contain what is needed to evaluate the appropriateness and
completeness of the elemental impurities Risk Assessment.
Tell a story to the assessor on what has been considered,
done and concluded.
Raw data not expected, but summary of findings may be
necessary.
The justification for the Control Strategy (what to control and
not to control).
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ICH Regions - Regulatory Filings - EU
Where to be put in the dossier?
It is suggested: Summary of the Risk Assessment
3.2.P.5.5 Characterization of impurities (DP) (rather
than 3.2.P.2 Pharmaceutical development)
Depending on the outcome, data may also go into e.g.:
3.2.S.3.2 Impurities (DS)
3.2.S.4.5 Justification of specification (DS)
3.2.P.4 Control of Excipients
3.2.P.5.6 Justification of specification
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Implementation Timelines for Japan
Japan MHLW recommendations and timelines:
For New Drugs – Implementation date: April 1, 2017.
For Marketed Products – Application of Q3D to
existing products approved before April 1, 2017 will
not be expected to 36 months (January 1, 2018) after
publication of the ICH guideline.
Official date on application to existing Marketed
products have not been announced.
The sponsor should study the feasibility of Q3D.
MHLW will evaluate applicability of Q3D to existing
products.
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Developments in other Countries Australia TGA Q3D applies to registration
applications for prescription medicines.
The date for coming into effect aligns with implementation in the EU. New products containing new drug substance/s:
from June 2016.
New products containing existing drug substance/s: from December 2017.
No official statement for current marketed product.
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Developments in other Countries Health Canada
Document for new
application/supplement Implementation date
Submission of a new abbreviated new
drug submission (ANDS) or drug
identification number (DIN) application
for a drug product should include the
content requirements as per Q3D.
Submissions received after
December 31, 2016.
Submission of a 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.
Submissions received after
December 31, 2016.
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Developments in other Countries Health Canada
Document for marketed drugs Implementation date
Completion of the risk assessment for
elemental impurities. January 1, 2018.
Implementation of any manufacturing
changes to control the levels of elemental
impurities.
January 1, 2018.
Updated drug product specifications with a
statement confirming compliance with ICH
Q3D.
January 1, 2018.
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Developments in other Countries Health Canada
OTC should comply with Q3D; natural health products
excluded
The risk assessment should be documented and
available for inspection
The locations where the elemental impurities-related
information can be placed for new submissions
Summarized in Module 2.3.P.5: Control of Drug Product of the
Quality Overall Summary, QOS.
Module 3.2.P.5.6 Justification of Specifications.
Risk assessment for the container closure system may be cross-
referenced to a master file.
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Developments in other Countries Health Canada
The locations where the elemental impurities-related information can be placed for currently marketed products.
Quality Overall Summary Module 2.3.P.5: Control of Drug Product: a summary of the Module 3 locations where the elemental impurities-related information can be found.
Module 3.2.P.5.6 Justification of Specifications includes the overall risk assessment summary for elemental impurities.
Appropriate data to support any changes made to comply with Q3D or Canadian changes guidance.
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Developments in other Countries Swissmedic
For New Drugs or Existing drugs.
Both new drug substances and existing drug
substances apply Implementation date: July 1, 2016.
For Marketed products
Implementation date: January 1, 2018.
Complied with Ph. Eur. Supplement 9.3.
During the transition period companies should
perform a risk assessment covering all potential
sources of elemental impurities.
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Developments in other Countries Taiwan FDA
For New Drugs
Both new drug substances and existing drug
substances apply.
Implementation date: July 1, 2016.
For Marketed Products
Implementation date is not published.
Guiding principle would be:
Perform risk-based assessment according to Q3D Guideline.
Reduce regulatory reviewing burden without oversight.
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Developments in other Countries
China, India, or South American Countries have not indicated the implementation of
ICH Q3D or any timelines for implementation at this time.
China may start discussions on ICH Q3D in 2020.
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Summary on Implementation of ICH Q3D
New drugs (new drug substances and existing
drug substances).
The Health Authorities in US, EU, Japan, Canada,
Switzerland, Australia and Taiwan announced the
Q3D implementation schedule.
Currently marketed products.
The Health Authorities in US, EU, Canada and
Switzerland announced the Q3D implementation
schedule.
Risk assessment is a must
Australia, Japan and Taiwan are still in the planning
stage.
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Lifecycle Management
The Lifecycle approach is to ensure ongoing compliance to Elemental Impurity requirements.
It is defined as an understanding of the product and/or process changes which have the potential to change the Elemental Impurity content of the final product and therefore may require a re-evaluation of the overall risk assessment and control strategy to ensure ongoing compliance to Elemental Impurity requirements.
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Lifecycle Management Essential to Lifecycle management is an
understanding of how changes in the product/process and/or components may impact the Elemental Impurity risk assessment and the need for a control strategy on the drug product.
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Lifecycle Management
Lifecycle Approach
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Lifecycle Management
Possible Changes to a Drug Product
Examples of changes which may lead to reviews of
the original risk assessment and control strategy are:
Synthetic routes
Excipient suppliers / changes to the source or
manufacturing process of the excipient
API suppliers
Materials
Processing equipment
Container closure
Water supply
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Lifecycle Management
55
Initial
Elemental
Impurities
Risk
Assessment
completed
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Lifecycle Management Summary
Elemental Impurity Lifecycle Management ensures that a change to the product and/or process have been properly evaluated for the potential to change the elemental impurity content of the final product.
Changes made to any of the 5 components of the Drug Product (Manufacturing Equipment, Water Systems, Container closure, API and Excipient) require review and potentially revision of the risk assessment and control strategy.
Risk Management principles and Global Change Management processes are key to ensuring ongoing compliance to Elemental Impurities.
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Analytical and Risk Assessment Challenges
57
Methodology Concerns
Collaborative study performed
PQRI Phase 2 testing initiated
Lhasa database
Supplier information (API and Excipient)
Risk assessment approaches
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Methodology Concerns
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 complimentary technique to ICP-MS.
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Methodology Concerns
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 – now working with PQRI.
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
Appropriate Use of Published Data – Data will be blinded so it will be important to establish a scientifically sound bridge from this data to the grades and suppliers actually used in the drug product – cannot simply use the data in your risk assessment!
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Supplier Information (API and Excipient)
There is NO regulatory requirement for API or Excipient suppliers to perform or supply elemental impurity information to pharmaceutical users.
Some suppliers will want to provide some useful information to support their customers but this will depend on the amount of business done in the pharmaceutical market.
The level of information provided will typically vary quite a bit from supplier to supplier.
Users should not try to pressure suppliers for EI data that may not exist, otherwise supplier may leave the market and availability will then be a problem.
Requests should be for whatever information the supplier is willing to share about their products and processes but not focus on the development of specifications since many suppliers will not agree to specifications on EI.
IPEC-Americas developed an information sharing mechanism which is well used throughout the industry.
Sharing Information between Makers & Users IPEC Template Information Exchange Request
IDEAL WORLD….
Pro-actively completed by suppliers and sent to
users
download THE TEMPLATE
URGENT industry need for BASE-LINE DATA!
REAL WORLD…
Few suppliers have data or will complete and
return the form to users
download THE LETTER
PDE Calculator also available on IPEC-Americas website
to assist in Risk Assessment
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Risk Assessment Approaches
ICH Q3D is a global policy for limiting elemental impurities in drug products.
Harmonised, safety-based limits for elemental impurities, especially those of highest toxicological concern.
Selection of elements to control.
Methodology for establishing safety-based limits.
Permitted daily exposure for specific elements.
Appropriate risk-based approach to ensure control for elements likely to be present in drug products and ingredients.