Q3D training module 5

Risk Assessment

Module 5
Product Risk Assessment General
Approaches
ICH Q3D Elemental Impurities

Disclaimer:
This presentation includes the authors’ views on Elemental Impurities theory and practice.
The presentation does not represent official guidance or policy of authorities or industry.

International Council for Harmonisation of Technical Requirements for

Pharmaceuticals for Human Use

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Purpose
• To provide an overview of an elemental impurities risk
assessment for a product consistent with ICH Q3D.
• To provide illustrative examples for developing product risk
assessments
o Other approaches may also be acceptable
• The information presented here does not provide new
guidance, rather, it elaborates on how the recommendations
in the guidance may be implemented

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Overview
• Potential sources of elemental impurities
• Risk assessment approaches
• Output of elemental risk assessment
• Product risk assessment Process
o Drug product based
o Drug product component based
• Evaluation

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Elemental impurity risk assessment process

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.

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Potential sources of elemental impurities

Excipients Drug Substance

Elemental
impurities in
Drug Product

Manufacturing Container
Utilities*
Equipment Closure System

* Water is the primary utility of potential concern

The product assessment should consider the potential of each of
these categories to contribute elemental impurities to the drug product
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Risk assessment approaches

• Examples of general approaches that may be considered during elemental
impurities risk assessment are:
o These approaches or others may change as information becomes available or additional experience
is gained.

• Assessment of potential elemental impurities in the drug product

o Determine or assess the levels of elemental impurities in the final drug product
o Depending on the formulation type, an evaluation from the container closure system may also be
required

• Assessment of potential elemental impurities from each component of the

drug product (API, excipients, container closure system)
o Assess each component for potential sources of elemental impurities
o Identify known or likely elemental impurities
o Determine the contribution of each component or source of elemental impurity to the levels in the
final drug product

• Irrespective of the approach chosen – consider the elemental impurity

classification and recommendations in Table 5-1 (see following slide)

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Q3D Table 5-1: Elements to be considered in the

risk assessment

Reference this table in the summary of the risk assessment.

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Generalized risk assessment process flow

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Risk Assessment Output

Elemental impurities excluded from the risk

assessment (see Q3D: Table 5.1)

Elemental impurities that may be

present below the control threshold in
the drug product
Product risk Control Threshold:
30% of PDE
assessment Elemental impurities that may exceed
the control threshold but do not Input to Control
exceed the PDE in the drug product Strategy
PDE
Elemental impurities that may exceed the
PDE in the drug product

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Examples of potential outputs of the risk

assessment

• Class 2B elements that are not intentionally added

• Elements in Table 5.1 that may be excluded based on the route of
administration
Example:
• For a solid oral drug product, the following class 3 elemental impurities were not
intentionally added and therefore were not considered in the risk assessment: Li,
Sb, Ba, Mo, Cu, Sn, and Cr.

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Examples of potential outputs of the risk

assessment

Elemental impurities in this category would be those that have the potential
to be found, but if present would be found at low levels They are often
associated as low level impurities in components that can be handled
through incoming material controls or with GMP Quality System elements
(e.g. vendor/supplier qualification processes and procedures).
Example:
• Pb is a potential impurity in TiO2. If the formulation contained 10 mg TiO2 in a 1 g
tablet (1% TiO2) and the observed Pb level in TiO2 was 1-10 µg/g; the total
amount of Pb contribution to the drug product would be (0.01-0.1 µg/day), less
than the control threshold of Pb (1.5 µg/g) in the drug product.

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Examples of potential outputs of the risk

assessment

Elemental impurities in this category would be those that have the potential
to be found in the drug product or in drug product components.
Example:
• Pb is a potential impurity in K2CO3. If the formulation contained 500 mg K2CO3 in
a 1 g tablet and the observed Pb level in K2CO3 was 1-8 µg/g, the total amount of
Pb contribution to the drug product would be 0.5-4 ppm. The range of observed
levels is above the control threshold but below the PDE (5 µg/g).

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Examples of potential outputs of the risk

assessment

Elemental impurities in this category would be those that exceed the PDE in
the drug product. (See Module 2 for justification)

Example:
• Cd is a potential impurity in CaHPO4. If the formulation contained 500 mg
CaHPO4 in a 750 mg tablet and the observed Cd level in Ca2HPO4 was 8-9 µg/g,
the total amount of Cd contribution to the drug product (5.3 - 6 µg) would exceed
the PDE for Cd 5 (µg/day).

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Information to consider in the risk assessment

• Assumptions, risks considered and identified, controls inherent in the
process and product evaluated
• Data where available and estimated levels when literature or published
data or calculations are used to justify exclusion of elemental impurities
from further consideration
• The rationale for elemental impurity clearance steps/reduction steps
included or inherent in the process design
• Consideration of using compendial quality components
• Consideration of GMP controls and
• Discussion of any additional controls to be considered when developing
the drug product control strategy

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Special considerations for biotechnologically

derived products
• It is recognized that the risks associated with the presence of
elemental impurities at levels of safety concerns for biotechnology-
derived products are low
o This is generally due to the absence of use of inorganic catalysts or
reagents and to the typical purification schemes used in the
manufacture of biotechnology-derived products

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Documentation
Documentation to be maintained in Company Documentation to be included in regulatory
Pharmaceutical Quality System dossiers (new or updates)
Complete risk assessment document describing Summary of product risk assessment process used
process, 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
strategy updates) appropriate)

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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Elemental Impurity risk assessment process –

general considerations

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Considerations in determining drug product

assessment approach
The decision of the risk assessment approach (component or drug product) is dependent
on many factors, including but not limited to the following;
 Knowledge of the elemental impurity levels of components of the drug product
 Situations where the drug substance (or drug product or both) is managed by a third party manufacturer
with potentially different internal quality systems and controls
 Demonstrated high variability of the elemental impurity levels in one or more components of the drug
product
 High formulation percentages of excipients known to have concomitant elemental impurities
 Knowledge of the levels of elemental impurities in the drug product components or excipients that have
been established as having limited potential to introduce elemental impurities
 Primary contribution of elemental impurities to the drug product can be traced to a limited number of
components
 Identification of one or more components that contribute the greatest to the elemental impurity ‘burden’
providing improved control options (material controls, periodic verification testing, etc.)
In many situations, the risk assessment may be a combination of both the component
approach and the drug product approach. Knowledge of components that have potential
elemental impurities can provide information to improve the drug product assessment
approach
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Product Assessment – Drug Product Approach

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Potential sources of elemental impurities

For an assessment focused on the drug product

Excipients Drug Substance

Elemental
impurities in
Drug Product

Manufacturing Container Focus of the

Utilities*
Equipment Closure System assessment

* Water is the primary utility of potential concern

• This risk assessment focuses on the measured levels of potential elemental impurities in the
drug product
• The assessment may require the evaluation of the impact of the container closure system on the
drug product and the potential to contribute elemental impurities to the drug product

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Drug product assessment approach

• Implicit in the drug product risk assessment approach is the availability of
data concerning elemental impurity levels in the drug product
• Justification of the elemental impurities included in the assessment
o Preliminary multiple element screening methods can establish the elemental
impurities of interest (if any)
o Table 5.1 in the guideline provides guidance on what elements should be
considered in the assessment
• In the absence of other justification, the level and variability of an elemental
impurity can be established by providing the data from three (3)
representative production scale lots or six (6) representative pilot scale lots
of the component or components or drug product.
o For some components that have inherent variability (e.g., mined excipients),
additional data may be needed

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Drug product assessment approach – container

closure systems
• Depending on the drug product type, additional evaluation for potential
elemental impurity introduction into the drug product may be needed
o Solid oral dosage forms
- The interaction of solid oral dosage forms with packaging components has essentially a
negligible risk of transferring elemental impurities from the container closure system (packaging)
to the drug product.
- No further evaluation is required
o Liquid, suspension and semi-solid dosage forms
- Depending on the packaging material and the formulation components, there may be a potential
for leaching of elemental impurities from the packaging components
- Data may be generated in leachable studies (evaluating the potential for inclusion of elemental
impurities using an appropriate methodology)
- Table 1 provides additional information on the level of risk associated with various drug products
and container closure systems.

• Questions for consideration

o Does the packaging inherently contain large quantities of metals which might leach?
o Is the drug product likely to leach metals from its packaging over the shelf-life?

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Relative potential of interaction of CCS with
drug product categories
Potential for inclusion of elemental Specific drug product classes Example considerations/potential
impurities introduced to the drug packaging components of concern
product from the container closure
system

Injections and Injectable Suspensions Glass containers – potential to leach As

Inhalation Aerosols and Solutions;
Parenteral solutions
Ophthalmic Solutions and Suspensions; Glass containers - potential to leach As
Relative potential

Transdermal patches Metal containers – potential to leach

Ointments and Creams elemental impurities (dependent upon
Nasal Aerosols and Sprays composition of CCS and
composition/pH of formulation
Topical Solutions and Suspensions; Plastic containers - potential to leach
Topical and Lingual Aerosols; elemental impurities from polymeric
Oral Solutions and Suspensions materials is low
Oral Tablets Solid – solid interaction provides little or
Oral (Hard and Soft) Capsules no opportunity to transfer elemental
Oral Powders impurities from CCS to drug product
Sterile Powders
Inhalation Powders
low Powders for Injection
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Evaluation
• Using the data from the drug product testing results, obtained from 3
commercial or 6 pilot scale batches, the observed elemental impurities
need to be calculated as a total daily amount based on the total daily
dose of the drug.
Daily amount of elemental impurity = (impurity conc.,(µg)/g)×(mass of drug g/day)

• Compare the total daily amount of each elemental impurity with the
established Permitted Daily Exposure value (PDE)1.
o Elemental impurities consistently below the control threshold do not require
additional controls
o Elemental impurities that exceed the control threshold require additional
evaluation during the development of the controls

1Or proposed Acceptable Levels (AL) for those routes of administration not included in ICH Q3D (see
Module 1 for AL determination)

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Comparison of Observed Levels with PDE

• The elemental impurity level is <30% of the PDE. If this is the case, then no
additional controls are deemed necessary.
• The elemental impurity level in the drug product is greater than the control
threshold but does not exceed the PDE; additional measures may be
implemented to insure that the level does not exceed the PDE
• The elemental impurity level exceeds the PDE ,
o Additional measures should be considered to ensure the levels do not exceed the PDE.
o When additional measures are either not feasible or unsuccessful, levels of elemental
impurities higher than the established PDE may be justified in certain circumstances.
- The safety impact of the elemental impurity level should be evaluated as described in Q3D and
Training Module 2.

It should be noted that if an acceptable level (AL) is the level forming the basis of the
comparison, the final acceptance of the proposed limit is dependent on approval by the
appropriate regulatory authority. Module 1 contains additional information on the
establishment of ALs.

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Product Assessment – Component Approach

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Potential sources of elemental impurities –

component approach

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Lower risk sources of elemental impurities –

assessment for utilities contributions
• In general GMP policies, processes and procedures ensure that the
contribution of elemental impurities to drug products is low.
o Facility & utility design and qualification
o Facility & utility maintenance procedures

• Water produced under GMP controls ensures that the contribution of

elemental impurities from water to the drug product is low
o Qualification and maintenance of water systems
o Specification for water quality
o Routine monitoring of the water quality

• Use of compendial grade water (e.g. PW, WFI) further reduces the potential
contribution of elemental impurities
o The source water used to prepare WFI or PW is first required to meet drinking water
standards which already include strict control on the levels of elemental impurities of
concern.
o The purification processes employed to produce WFI or PW provide a mechanism to
further reduce the elemental impurity content
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Lower risk sources of elemental impurities –
assessment for Manufacturing Equipment
Contributions
• In general GMP policies, processes and procedures ensure that the
contribution of elemental impurities to the drug products is low.
o Equipment design and qualification
o Equipment maintenance procedures
o Equipment cleaning/visual inspection procedures

• Knowledge of the elemental impurity profile of drug substance can

assist in the evaluation of potential contributions from
manufacturing equipment
o Drug substance processes often are more chemically aggressive than drug
product processes.
o Monitoring of drug substance for potential impurities from manufacturing
equipment (e.g. stainless steel – Cr, Mn, Mo, V, Ni) can provide insight into
potential impact to the drug product
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Lower risk sources of elemental impurities –

assessment for CCS contributions
• The potential of release of elemental impurities from CCS
components into the drug product depends on the dosage form
 Empirical results confirmed low potential of introduction of
elemental impurities to the drug product from the CCS
o Jenke, D. et.al., “A Compilation of Metals and Trace Elements Extracted from
Materials Relevant to Pharmaceutical Applications Such as Packaging
Systems and Devices”, PDA J. Pharm. Sci. Technol., 67(4):354-75, 2013
• Potential risk may be further explored by use of prior knowledge or
conducting an appropriate leachables study.

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Relative potential of interaction of CCS with
drug product categories
Potential for inclusion of elemental Specific drug product classes Example considerations/potential
impurities introduced to the drug packaging components of concern
product from the container closure
system

Injections and Injectable Suspensions Glass containers – potential to leach As

Inhalation Aerosols and Solutions;
Parenteral solutions
Ophthalmic Solutions and Suspensions; Glass containers - potential to leach As
Relative potential

Transdermal patches Metal containers – potential to leach

Ointments and Creams elemental impurities (dependent upon
Nasal Aerosols and Sprays composition of CCS and
composition/pH of formulation
Topical Solutions and Suspensions; Plastic containers - potential to leach
Topical and Lingual Aerosols; elemental impurities from polymeric
Oral Solutions and Suspensions materials is low
Oral Tablets Solid – solid interaction provides little or
Oral (Hard and Soft) Capsules no opportunity to transfer elemental
Oral Powders impurities from CCS to drug product
Sterile Powders
Inhalation Powders
low Powders for Injection
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Product risk assessment – Excipient contribution

• A limited number of excipients of mineral origin may include
elemental impurities that are embedded in or tightly bound to the
solid matrix preventing their release except with extreme extraction
procedures
o e.g. smectic (mineral) clays1,2
• Some mined excipients (e.g. Talc, Titanium dioxide) are known to
have low but variable levels of some elemental impurities of concern
(e.g. As and Pb)
o Due to the nature of the isolation of the excipients, it is often not possible to
reduce the level of elemental impurity
o Some demonstrate variation in the observed level based on mine location as
well as variation within the same mine
1 Morman SA, Plumlee GS, Smith DB (2009) Application of in vitro extraction studies to evaluate element bioaccessibility in soils from a transect across the United
States and Canada, Applied Geochemistry 24, 1454–1463

2 Oomen AG, Hack A, Minekus M, Zeijdner E, Cornelis C, Schoeters G, Verstraete W,Van de Wiele T, Wragg J, Rompelberg CJM, Sips A, Van Wijnen JH, (2002)

Comparison of five in vitro digestion models to study the bioaccessibility of soil contaminants. Environmental Science & Technology, 36, 3326-3334

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Product risk assessment – drug substance

contribution
• A significant potential source of elemental impurities arises
from the use of metal catalysts in the synthesis of drug
substances, especially if used in the latter stages of synthesis
o Knowledge of potential elemental impurities in synthetic steps prior to
the final drug substance may provide information that can assist in the
preparation of the risk assessment

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Evaluation
• Compile data for components of the drug product
o Published information
o Data generated by the applicant or suppliers
o Where data are not available, consider if surrogate information can be used to establish
a reasonable estimate of the elemental impurity potential for inclusion
• Calculate the observed elemental impurities for each component, in which elemental
impurities are identified, as a function of the percent composition of the formulation and the
total daily dose of the drug.
• The level of each elemental impurity should be determined by summing the contribution
from each component to determine the final amount in the drug product

= ×
=1
where, i = an index for each of N components in the drug product, Ci = permitted concentration of the elemental impurity in
component i (μg/g), and Mi = mass of component i in the maximum daily intake of the drug product (g)

• Compare the total daily amount of each elemental impurity with the established Permitted
Daily Exposure value (PDE).
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Comparison of Observed Levels with PDE

• Elemental impurities excluded from the risk assessment (see Table 5.1)
• The elemental impurity level is <30% of the PDE. If this is the case, then no additional
controls are deemed necessary.
• The elemental impurity level in the drug product is greater than the control threshold but
does not exceed the PDE; additional measures may be implemented to insure that the level
does not exceed the PDE
• The elemental impurity level exceeds the PDE,
o Additional measures should be considered so that the levels do not exceed the PDE.
o When additional measures are either not feasible or unsuccessful, levels of elemental
impurities higher than the established PDE may be justified in certain circumstances.
- The safety impact of the elemental impurity level should be evaluated as described in Q3D and
Training Module 2.

It should be noted that if an AL is the level forming the basis of the comparison, the final
acceptance of the proposed limit is dependent on approval by the appropriate
regulatory authority. Module 1 contains additional information on the establishment of
ALs.
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This portion of the training material was intended to provide an

overview of the processes that may be used to complete the
risk assessment.

Related topics are:

Module 6: Controls

Module 8: Case studies

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