FDA Perspective and Expectations for

Control of Elemental Impurities in

Drug Products
PQRI/USP Workshop on Implementation Status of ICH Q3D
Rockville, MD
November 9-10, 2016

Danae Christodoulou, Ph.D.

CDER/OPQ Office of New Drug Products

This presentation reflects the views of the author and should not be
construed to represent FDA’s views or policies.
 Prospective Challenges
• Expectations for method validation: risk assessment vs.
routine testing
• Pharmacopeial Challenges (In U.S., concern over differences
between Q3D and <232>)
– Harmonization between Q3D and <232> have minimized
this concern.
• Application of the “control threshold”
– A new concept in Q3D, intended as a tool for risk
assessment
• Regulatory expectations
– Where should risk assessment appear in CTD?
– What is expected in the risk assessment summary?
– Will expectations be consistent over time and across
regions?
– How will risk assessments for existing products be
conveyed to regulatory authorities?
– What information should suppliers provide to their
customers?
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 El Implementation Working Group at FDA
• Members: Review Divisions, OPQ-ONDP and
OLDP, OPPQ, OTR and OND-PT, CBER
• Develop a Guidance for the regulated industry for
implementation of ICH Q3D and <232>/<233>.
– FDA Draft Guidance: Elemental Impurities in Drug
Products*
– recommendations for filing requirements and
implementation timelines for new and existing drug
products.
• Review and adopt training material developed by
the ICH Q3D WG.
*See http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm509432.pdf or search FDA Guidance Elemental Impurities
Note: Harmonization of Q3D and <232> was published after this guidance was written.
Appropriate corrections will be made in revision to reflect the harmonization.
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 Timeline considerations

• NDAs and ANDAs with USP Monographs

– Follow recommendations of Q3D if submitted after 1
June 2016
– Comply with USP <232>/<233> after 1 January 2018
• NDAs and ANDAs without USP Monographs
– Follow recommendations of Q3D if submitted after 1
June 2016
• Compendial products not marketed under an
approved ANDA or NDA (e.g., OTC)
– Comply with USP <232>/<233> after 1 January 2018

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 Timeline considerations
• Non-compendial products not marketed under an
approved ANDA or NDA (e.g., OTC)
– Follow recommendations of Q3D after 1 January 2018
• Changes to conditions established in approved
ANDAs and NDA needed to meet PDE
recommendations of Q3D or comply with <232>
PDEs
– Report according to applicable regulations and
guidance
– See FDA Draft Guidance: Elemental Impurities in Drug
Products, Section III.E for more details.

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 Timeline considerations
• FDA anticipates that 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.
– See FDA Draft Guidance: Elemental Impurities in Drug
Products, Section III.E for more details.

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 Documentation and
Risk Assessment
• 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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 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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 Q3D Table 5-1:
Elements considered in the risk assessment

Reference this table in the summary of the risk assessment.

 Documentation
(In Q3D Module 5)
Documentation to be maintained in Company Documentation to be included in regulatory dossiers
Pharmaceutical Quality System (new or updates)
Complete risk assessment document describing process, Summary of product risk assessment process used
data used, data references and information needed to
support dossier summary
GMP related processes to limit the inclusion of Summary of identified elemental impurities and
elemental impurities observed or projected levels

Change management processes Data from representative commercial or pilot scale

(defining triggers for product assessment or control batches (component or drug product as appropriate)
strategy updates)

Periodic review processes Conclusion of the product risk assessment

Original data used in the product risk assessments,

quality agreements, supplier qualification, etc.

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 Life-cycle approach to
Control Strategy (In Module 6)

Review Revise
Risk Risk
Assessment Assessment
New Information

Review
Update Control
Control
Strategy
Strategy

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 GMP expectations for EI
• If risk assessment results in setting specifications
in the drug substance and/or product, then
– Testing Laboratories are subject to GMPs
– Validation of analytical methods at the site and in the
application
• If risk assessment confirms “minimal level” of EI,
then
– Risk assessment and any testing method(s) used
during the risk assessment and results should be
available during inspection and review.
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 Method Validation
• “Data must be available to establish that the
analytical procedures used in testing meet proper
standards of accuracy, sensitivity, specificity, and
reproducibility and are suitable for their intended
purpose.” [FDA Guidance: Analytical Procedures
and Methods Validation for Drugs and Biologics,
July, 2015]
• Analytical procedures for both risk assessments
and routine testing should be validated, but the
validation criteria (e.g., accuracy, precision,
detection limits) can depend on the analytical
procedure’s intended purpose.

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 Method Validation for
Risk Assessments
• Manufacturers should establish that the analytical procedures used during
risk assessments possess characteristics (e.g., accuracy, precision,
specificity) such that the manufacturers can be reasonably certain (e.g., at
the 95-percent confidence level) that the measurements can be relied
upon to decide whether to include routine testing of materials in the
control strategy.
– This decision depends on whether the amounts of
the elemental impurities in the materials are
consistently below control thresholds.
– The analytical procedures should be validated with
this goal in mind.

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 Early Adoption
• FDA supports and encourages the early adoption of ICH Q3D
and USP <232>/<233> before the implementation date.
• In the case of compendial products, upon early adoption of
General Chapters <232> and <233>, products and any
components are not expected to demonstrate compliance
with General Chapter <231>.

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 Drug Development
• Challenges with PDEs or “Acceptable exposure
levels”?
• Analytical Methods limitations?
• Product specific considerations?
• We encourage you to contact the appropriate
review divisions for guidance as needed during
interdisciplinary or CMC-only meetings, EOP2
or pre- NDA meetings.

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Proposed EI limit does not meet ICH

How does it link to the patient?

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 Examples
• Drug substance sourced from an ore
• EI-X is a theoretical impurity based on morphology of
the naturally occurring raw material. EI-X confirmed by
analytical method A but detection limit was high
• Levels in the drug product may exceed oral EI-X
permissible exposure
• Drug product is a diagnostic with no chronic or
intermittent use
• Resolution: EI-X and additional EI controls in the drug
substance
• Firm proposed the development and validation of
method B, with analytical test results from several
pilot scale and production batches submitted for
review
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 Examples (contd.)
• FDA was asked whether a proposed EI-X was
acceptable for an OTC product
• The sponsor requested a waiver of EI-X levels
specified in <232> as use was intermittent and
not considered a safety issue; no other
information provided
• FDA analysis
– EI-X was of concern to patients in a sensitive subpopulation
– EI-X exceeded oral PDE by several multiples
– Label did not indicate intermittent use only
– Level of EI-X was at ~ 50% a level not known to be adverse
– Conclusion: sponsor assessment was not adequate

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 Examples (contd.)
• Still unresolved, but based on usual approach for impurities:
– Likely ask the sponsor to provide a rational as to why EI
cannot be reduced to PDE
• Reducing EI level to PDE – additional assessment toward revision of
manufacturing and formulation processes
• Future control plans?
– If the EI cannot be reduced, provide a scientific
justification to exceed the PDE; consider
• Bioavailability in formulation
• Provide information about risk in sensitive subpopulations
• Risk mitigation (restrict use in sensitive subpopulations to medical need)
• Provide data to support intermittent use claim
• Label changes
• Other

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THANK YOU FOR YOUR ATTENTION!
EI WG Members
Danae Christodoulou, John Kauffman, John
Leighton, Frank Holcombe, Matthew Vera, Pallavi
Nithyanandan, Yana Mille, Rogelio Ruvalcaba,
John Bishop (CBER)

OPPQ Ashley Boam and John Smith (retired)

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