ICH Q3D - Elemental impurities in pharmaceutical products

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Elemental impurities in pharmaceutical products
ICH Q3D guideline

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Elemental impurities are traces of metals present in finished drug products
àThey do not provide any therapeutic benefit
àThey may possibly cause harm
The ICH developed guidelines to measure and control their presence within acceptable limits
à FDA and EMA encourage the ICH Q3D guideline implementation
àRelevant USP and Ph Eur chapters are adapted/introduced
àFDA: apply USP limit when different from ICH Q3D PDE values
All companies will have to be compliant for already authorised and marketed products as of
December 2017.
Context

• Safety assessment
• Classification of elemental impurities
• Risk assessment
• Control of elemental impurities in drug products
• Dossier expectations & assessment strategy
Index

Two steps:
1. Review of publicly available data
e.g.: scientific journals, government research reports, regulatory standards and reports, etc
2. Determination of Permitted Daily Exposure (PDE) values
àValues account for all patient populations
àValues apply to the finished drug product
Safety assessment must not be repeated by individual companies
à comply to PDE values identified by ICH
Safety assessment

à oral route, parenteral route & inhalation
ICH determined Permitted Daily Exposure (PDE) values
Factors considered in determination of the PDE values:
• Likely oxidation state of the element in the drug product
• Human exposure and safety data
• Most relevant animal study
• Route of administration (Oral, parenteral, inhalation)
• Relevant endpoint(s) / Local effects
Safety assessment

à additional exposure routes
Determine PDE value according to ICH Q3D concepts:
• Select most appropriate administration route as starting point
• Will administration have local effects?
• YES: need to adjust PDE?
à based on doses when adverse event is expected
• NO: no adjustment necessary
• Correct the PDE value based on bioavailability via administration route (if available)
• In case of increased PDE value: are quality attributes affected?
Safety assessment

Impurity levels > PDE value may be acceptable, when justified, in case of:
• Intermittent dosing
• Short term dosing: ≤ 30 days
• Specific indications: e.g. life-threatening, rare diseases
Lower levels may be warranted in case of
• High PDE values (ICH Q3A guideline)
• Impact on drug product quality attributes
Companies are not expected to tighten the limits based on process capability, provided that the
elemental impurities in drug products do not exceed PDEs.
Safety assessment

• Risk assessment
Content

Elements Toxicity Likelihood of
occurrence in DP
Risk Assessment
Class 1 As, Cd, Hg and Pb Human toxicants Limited or no use Obligatory
Class 2A Co, Ni and V
Route-dependent
human toxicants
High probability Required
Class 2B
Ag, Au, Ir, Os, Pd, Pt,
Rh, Ru, Se and Ti
Route-dependent
human toxicants
Reduced probability
Can be excluded
Mandatory when intentionally added
Class 3
Ba, Cr, Cu, Li, Mo, Sb
and Sn
Relatively low
toxicities
Reduced probability
Inhalation or parenteral: mandatory
Oral: can be excluded
mandatory when intentionally added
Other
Al, B, Ca, Fe, K, Mg, Mn,
Na, W and Zn
Low inherent
toxicity
Probable Addressed by other guidelines.
Classification of elemental impurities
Based on:
- Toxicity (PDE value)
- Likelihood of occurrence in the drug product (DP)
Determines the need for risk assessment

• Risk assessment
Content

Drug product manufacturers must carry out a risk assessment to identify and control elemental
impurities, considering all potential information sources:
• Information supplied by drug substance and/or excipient manufacturers
• Data available in published literature
• Link to patient safety considerations
• Understanding of the product and its manufacturing process
Three steps:
• Identify known and potential sources of elemental impurities
• Evaluate the presence of a particular impurity and compare with the PDE value
• Summarize and document
Risk assessment

• Residuals from elements added intentionally during formulation
• Impurities present in the drug substance, water or excipient
• Impurities introduced from the manufacturing equipment
• Impurities leached from the container closing system
Risk assessment: potential sources of
elemental impurities

Analysis of:
• drug product batches for the
presence of elemental impurities
• the Container Closure System
Risk assessment: evaluation approaches
Contribution from each component is
identified, evaluated and summarized
In-house manufacturing of drug substance
• Assessment of all potential sources of
elemental impurities and implementation
in overall assessment
Out-sourced manufacturing of drug
substance
• Information from the manufacturer (e.g.
CEP)
Drug Product Approach versus Component Approach (Preferred method)

Data obtained from 3 commercial or 6
pilot scale batches.
Observed elemental impurities need to be
calculated as a total daily amount.
Daily amount of elemental impurity =
(impurity concentration) x (mass of drug)
[µg/g]x[g/day]
Risk assessment: evaluation approaches
Compile data for components of the drug
product.
Drug Product Approach versus Component Approach (Preferred method)

Any element added during manufacturing must be included in the description of the drug substance
manufacturing process.
Impurities introduced or created early in the manufacturing process have more opportunities to
be removed in purification operations than impurities generated late in the manufacturing
process.
• Details about the API manufacturing process have to be consistently described and documented.
• If routine testing of an elemental impurity is needed, establish a specification.
• The absence of a specification must be justified that in spite of the late introduction, levels are
consistently below the control threshold (< 30% of the PDE).
Risk assessment: intentionally added
elements

Compare the total daily amount with the PDE value:
• Elemental impurities consistently <30% PDE: no additional controls required
• Elemental impurities >30% PDE but < PDE: define additional controls
• Elemental impurities >PDE: evaluate if higher level is justified (safety assessment & rational)
à YES: outline specific indications for which high PDE is justified
à NO: introduce additional up-stream controls
Risk assessment: summary

• Risk assessment
Content

• Introduce (non-)specific purification steps into the manufacturing process
• Implement in-process/upstream controls
• Establish specification limits for:
• Materials
• Excipients
• Drug substance
• Drug products
Control of elemental impurities

• Risk assessment
Content

Requirements and the standards of assessment for an ASMF dossier are the same as for a CEP
dossier.
Must contain:
• Route of synthesis of the drug substance, including transparent information on all intentionally
added catalysts and reagents.
• Summary of the DS risk assessment including impurity control or mitigation steps.
• Risk assessment covering all other potential elemental impurities, including any mitigation steps,
is recommended.
Routine testing of elemental impurities is not expected, unless risk assessment indicates this is
needed.
Dossier expectations & assessment strategy

Two possible scenarios:
• The API manufacturer submits a summary of a risk assessment for elemental impurities.
Information flow in the overall risk assessment of the manufacturer.
Data should be available for a GMP inspection.
• The API manufacturer does not perform risk assessment
Detailed description of the API synthesis including data on all metal catalysts used.
Final conclusion with regard to compliance with ICH Q3D will be done within the MAH of the
medicinal product.

According to the outcome of a risk assessment, no variation procedure is required when:
• There is no need for a control on elemental impurities to materials for the API, the API and its
intermediates and the excipients.
• No change is required in the production equipment or in the source of supply of the starting
materials, APIs and excipients.
• No change is needed in the manufacturing process.
Variation applications

Guideline for elemental impurities Q3D - ICH
Quality Guidelines - ICH
Implementation strategy of ICH Q3D guideline – EMA
Q3D Elemental Impurities Guidance for Industry – FDA
Implementation of ICH Q3D in the Certification Procedure - EDQM
Sources

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