Q3D Guideline For Elemental Impurities

Q3D
Guideline For Elemental Impurities

Source of Elemental Impurities
• Environmental contaminants
• Catalysts
They may be:
• Naturally occurring – minerals , Hyflo
• Added intentionally - Catalyst
• Introduced inadvertently
–Through interactions with processing equipment
–Through non-GMP routes - Reagents , early stage material
• Elemental Impurities are
• known to be present,
• have been added, or
• have the potential for introduction,
• A risk-based control strategy may assure compliance.
• compliance with the limits is required for all drug products at all
times.

• There are three parts of this guideline:
• Evaluation of the toxicity data for potential elemental impurities.
• Establishment of a Permitted Daily Exposure (PDE) for each element of
toxicological concern.
• Application of a risk- based approach to control elemental impurities in drug
products.
• An applicant is not expected to tighten the limits based on process
capability, provided that the elemental impurities in drug products do
not exceed the PDEs.
• The PDEs established in this guideline are considered to be
protective of public health for all patient populations.

• In some cases, lower levels of elemental impurities may be warranted when
levels below toxicity thresholds have been shown to have an impact on other
quality attributes of the drug product (e.g., element catalyzed degradation
of drug substances).
• In addition, for elements with high PDEs, other limits may have to be
considered from a pharmaceutical quality perspective and other guidelines
should be consulted (e.g., ICH Q3A).
• This guideline presents a process to assess and control elemental impurities in the drug
product using the principles of risk management as described in ICH Q9.
• This process provides a platform for developing a risk-based control strategy to limit
elemental impurities in the drug product.

• The guideline applies to
• New finished drug products (as defined in ICH Q6A and Q6B) and new drug products
containing existing drug substances.
• The drug products containing purified proteins and polypeptides (including proteins
and polypeptides produced from recombinant or non-recombinant origins), their
derivatives, and products of which they are components (e.g., conjugates) are within
the scope of this guideline, as are drug products containing synthetically produced
polypeptides, polynucleotides, and oligosaccharides.

• This guideline does not apply to
• Herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products,
allergenic extracts, cells, whole blood, cellular blood components or blood derivatives
including plasma and plasma derivatives, dialysate solutions not intended for systemic
circulation, and elements that are intentionally included in the drug product for
therapeutic benefit.
• Products based on genes (gene therapy), cells (cell therapy) and tissue (tissue
engineering).
• In some regions, these products are known as advanced therapy medicinal products.
• Drug products used during clinical research stages of development.
• As the commercial process is developed, the principles contained in this
guideline can be useful in evaluating elemental impurities that may be
present in a new drug product.
• Application of Q3D to existing products is not expected prior to 36 months
after publication of the guideline by ICH. 7

Safety assessment of
potential Elemental
impurities
Oral, Parenteral and Inhalation Routes of Administration

• The method used for establishing the PDE for each elemental impurity is
discussed in detail in Appendix 1.
• Elements evaluated in this guideline were assessed by reviewing the publicly
available data contained in scientific journals, government research reports
and studies, international regulatory standards (applicable to drug products)
and guidance, and regulatory authority research and assessment reports.
• This process follows the principles described in ICH Q3C: Residual Solvents.
• The available information was reviewed to establish the oral, parenteral and
inhalation PDEs.
• For practical purposes, the PDEs to be applied to the drug product that are
presented in Appendix 2Table A.2.1 have been rounded to 1 or 2 significant
figures.

• A summary safety assessment identifying the critical study for setting a PDE
for each element is included in Appendix 3.
• There are insufficient data to set PDEs by any route of administration for
iridium, osmium, rhodium, and ruthenium.
• The PDEs for these elements were established on the basis of their
similarity to palladium.
• The factors considered in the safety assessment for establishing the PDE
are listed below in approximate order of relevance:
• The likely oxidation state of the element in the drug product;
• Human exposure and safety data when it provided applicable information;
• The most relevant animal study;
• Route of administration;
• The relevant endpoint(s).

• Standards for daily intake for some of the elemental impurities discussed in
this guideline exist for food, water, air, and occupational exposure. Where
appropriate, these standards were considered in the safety assessment and
establishment of the PDEs.
• The longest duration animal study was generally used to establish the PDE.
• When a shorter duration animal study was considered the most relevant,
the rationale was provided in the individual safety assessment.
• Inhalation studies using soluble salts (when available) were preferred over
studies using particulates for inhalation safety assessment and derivation of
inhalation PDEs.
• Depending on available data, inhalation PDEs were based on either local
(respiratory system) or systemic toxicity.
• For PDEs established for inhalation (and oral or parenteral routes as
applicable), doses were normalized to a 24-hour, 7- day exposure.

• In the absence of data and/or where data are available but not considered
sufficient for a safety assessment for the parenteral and or inhalation route
of administration, modifying factors based on oral bioavailability were used
to derive the PDE from the oral PDE:
• Oral bioavailability <1%: divide by a modifying factor of 100;
• Oral bioavailability ≥ 1% and <50%: divide by a modifying factor of 10;
• Oral bioavailability ≥50% and <90%: divide by a modifying factor of 2; and
• Oral bioavailability ≥ 90%: divide by a modifying factor of 1.
• Where oral bioavailability data or occupational inhalation exposure limits
were not available, a calculated PDE was used based on the oral PDE
divided by a modifying factor of 100 (Ref. 1).

potential Elemental
impurities
Other Routes of Administration

• PDEs were established for oral, parenteral and inhalation routes of
administration.
• When PDEs are necessary for other routes of administration, the concepts
described in this guideline may be used to derive PDEs.
• An assessment may either increase or decrease an established PDE.
• The process of derivation of the PDE for another route of administration
may include the following:
• Consider the oral PDE in Appendix 3 as a starting point in developing a route-specific
PDE. Based on a scientific evaluation, the parenteral and inhalation PDEs may be a
more appropriate starting point.
• Assess if the elemental impurity is expected to have local effects when administered by
the intended route of administration:
• If local effects are expected, assess whether a modification to an established PDE is
necessary.
• Consider the doses/exposures at which these effects can be expected relative to the
adverse effect that was used to set an established PDE.
• If local effects are not expected, no adjustment to an established PDE is necessary.

• If available, evaluate the bioavailability of the element via the
intended route of administration and compare this to the
bioavailability of the element by the route with an established
PDE:
• When a difference is observed, a correction factor may be applied to an
established PDE.
• For example, when no local effects are expected, if the oral
bioavailability of an element is 50% and the bioavailability of an element
by the intended route is 10%, a correction factor of 5 may be applied.
• If a PDE proposed for the new route is increased relative to an
established PDE, quality attributes may need to be considered.

potential Elemental
impurities
Justification for Elemental Impurity Levels Higher than an
Established PDE

• Levels of elemental impurities higher than an established PDE (seeTable
A.2.1) may be acceptable in certain cases.
• These cases could include, but are not limited to, the following situations:
• Intermittent dosing;
• Short term dosing (i.e., 30 days or less);
• Specific indications (e.g., life-threatening, unmet medical needs, rare diseases).
• Examples of justifying an increased level of an elemental impurity using a
subfactor approach of a modifying factor (Ref. 2,3) are provided below.
• Other approaches may also be used to justify an increased level.
• Any proposed level higher than an established PDE should be justified on a
case-by-case basis.

Guiding principles
• The PDEs derived under Q3D have been set to ensure that exposure to an
element, which is present as an impurity in a drug product, is safe based on
daily exposure over a lifetime.
• The calculations for the PDE were performed using the modifying factor
approach (for detail see Guideline appendix 1).
• Typical steps are:
1. Identify the most relevant study (animal or human)
2. Identify the most relevant starting point (SP) for the calculation (NOEL, LOAEL etc.)
3. Select appropriate modifying factors
4. Calculation:
PDE = SP x MassAdjustment / [F1 x F2 x F3 x F4 x F5]

Examples for Risk-Based approaches
A. The subfactor approach (WHO, 2009), subdivides F2 into a subfactor for
pharmacokinetics and a subfactor for pharmacodynamics
B. Modification of modifying factors used for the established PDE, which
improve the alignment with the intended use profile
C. Replacing the study used to define the PDE with a more relevant study
(based on exposure duration or route of administration)
Other approaches may be justified.
Note: all approaches will have to be supported by published references and/or
proprietary data

Example 1: element X is present in an oral drug product.
• From the element X monograph in Appendix 3, a No-Observed- Adverse-Effect
Level (NOAEL) of 1.1 mg/kg/day was identified.
• Modifying factors F1-F5 have been established as 5, 10, 5, 1 and 1, respectively.
• Using the standard approach for modifying factors as described in Appendix 1, the
PDE is calculated as follows:
• PDE = 1.1 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 220 μg/day
• Modifying factor F2 (default = 10) can be subdivided into two subfactors, one for
toxicokinetics (TK) and one for toxicodynamics, each with a range from 1 to 3.16.
• Using the plasma half-life of 5 days, theTK adjustment factor could be decreased
to 1.58 for once weekly administration (~1 half-life), and to 1 for administration
once a month (~5 half- lives).
• Using the subfactor approach for F2, the proposed level for element X
administered once weekly can be calculated as follows:
• Proposed level = 1.1 mg/kg/d x 50 kg / 5 x (1.6 x 3.16) x 5 x 1 x 1 = 440 μg/day
• For practical purposes, this value is rounded to 400 μg/day.

Example 2:
• TheTK adjustment factor approach may also be appropriate for elemental
impurities that were not developed using the modifying factor approach.
• For element Z, a Minimal Risk Level (MRL) of 0.02 mg/kg/day was used to
derive the oral PDE.
• From literature sources, the plasma half-life was reported to be 4 days.
• This element is an impurity in an oral drug product administered once every
3 weeks (~ 5 half-lives).
• Using first-order kinetics, the established PDE of 1000 μg/day is modified as
follows:
• Proposed level = 0.02 mg/kg/d x 50 kg / 1/3.16 = 3.16 mg/day
• For practical purposes, this value is rounded to 3000 μg/day

potential Elemental
impurities
Parenteral Products

• Parenteral drug products with maximum daily volumes up to 2 liters may
use the maximum daily volume to calculate permissible concentrations from
PDEs.
• For products whose daily volumes, as specified by labeling and/or
established by clinical practice, may exceed 2 liters (e.g., saline, dextrose,
total parenteral nutrition, solutions for irrigation), a 2-liter volume may be
used to calculate permissible concentrations from PDEs. (Ref. 4)

Classification as per ICH Q3D
• Class 1:The elements, As, Cd, Hg, & Pb, are human toxicants; testing
should only be applied when the risk assessment identifies
• Class 2: Elements in this class are generally considered as human toxicants
are route-dependent;
• Class 2A elements have relatively high probability of occurrence in the
drug product. Elements are: Co, Ni andV.
• Class 2B elements have a reduced probability of occurrence in the drug
product related to their low abundance and low potential
• they may be intentionally added during the manufacture. Elements :
Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se andTl.
• Class 3: The elements in this class have relatively low toxicities.The elements
in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn.
Asses if high PDEs, generally > 500 μg/day.

Other elements
• Some elemental impurities for which PDEs have not been established due
to their low inherent toxicity and/or differences in regional regulations are
not addressed in this guideline.
• If these elemental impurities are present or included in the drug product
they are addressed by other guidelines and/or regional regulations and
practices that may be applicable for particular elements (e.g., Al for
compromised renal function; Mn and Zn for patients with compromised
hepatic function), or quality considerations (e.g., presence ofW impurities in
therapeutic proteins) for the final drug product.
• Some of the elements considered include: Al, B, Ca, Fe, K, Mg, Mn, Na,W
and Zn.

Risk Assessment and
Controls on Elemental
Impurities

• In developing controls for elemental impurities in drug products, the principles of
quality risk management, described in ICH Q9, should be considered.
• The risk assessment should be based on scientific knowledge and principles.
• It should link to safety considerations for patients with an understanding of the
product and its manufacturing process (ICH Q8 and Q11).
• In the case of elemental impurities, the product risk assessment would therefore be
focused on assessing the levels of elemental impurities in a drug product in relation to
the PDEs presented in this guidance.
• Information for this risk assessment includes but is not limited to: data generated by
the applicant, information supplied by drug substance and/or excipient manufacturers
and/or data available in published literature.
• The applicant should document the risk assessment and control approaches in an
appropriate manner.
• The level of effort and formality of the risk assessment should be proportional to the
level of risk.

• It is neither always appropriate nor always necessary to use a
formal risk management process (using recognized tools and/or
formal procedures, e.g., standard operating procedures.)
• The use of informal risk management processes (using empirical
tools and/or internal procedures) may also be considered
acceptable.
• Tools to assist in the risk assessment are described in ICH Q8 and
Q9 and will not be presented in this guideline.

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.

Potential sources of elemental impurities
Excipients Drug Substance
Utilities*
Manufacturing
Equipment
Container
Closure System
Elemental
impurities in
Drug Product
The product assessment should consider the potential of each of these categories to
contribute elemental impurities to the drug product
*Water is the primary utility of potential concern

Risk assessment approaches
• • Examples of general approaches that may be considered during elemental
impurities risk assessment are:
• These approaches or others may change as information becomes available or additional
experience is gained.
• Assessment of potential elemental impurities in the drug product
• Determine or assess the levels of elemental impurities in the final drug product
• 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)
• 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
• Irrespective of the approach chosen – consider the elemental impurity
classification and recommendations

Elements to be considered in the risk assessment
Element Class
If
intentionally
added (all
routes)
Oral Parenteral Inhalation
Cd 1 yes yes yes yes
Pb 1 yes yes yes yes
As 1 yes yes yes yes
Hg 1 yes yes yes yes
Co 2A yes yes yes yes
V 2A yes yes yes yes
Ni 2A yes yes yes yes
Tl 2B yes no no no
Au 2B yes no no no
Pd 2B yes no no no
Ir 2B yes no no no
Os 2B yes no no no
Rh 2B yes no no no
Ru 2B yes no no no
Se 2B yes no no no
Ag 2B yes no no no
Pt 2B yes no no no
Li 3 yes no yes yes
Sb 3 yes no yes yes
Ba 3 yes no no yes
Mo 3 yes no no yes
Cu 3 yes no yes yes
Sn 3 yes no no yes
Cr 3 yes no no yes
If not intentionally added

Generalized risk assessment process flow

Risk Assessment Output
ControlThreshold:30% of PDE
Input to Control Strategy
PDE

Examples of potential outputs of the risk
assessment
• Class 2B elements that are not intentionally added
• Elements inTable 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.

Examples of potential outputs of the risk assessment
(2)
Elemental impurities in this category would be those that have the potential to be
found, but if present would be found at low levelsThey 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 inTiO2. If the formulation contained 10 mgTiO2 in a
1 g tablet (1%TiO2) and the observed Pb level inTiO2 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.

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).
(3)

• 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).
(4)

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

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
• This is generally due to the absence of use o inorganic catalysts or reagents and to the
typical purification schemes used in the manufacture of biotechnology-derived
products

Control of Elemental
Impurities
ICH Q3D Elemental Impurities

Control Strategy - Definition
• A planned set of controls, derived from current product and process
understanding, that assures process performance and product quality.
• The controls can include parameters and attributes related to drug
substance and drug product materials and components, facility and
equipment operating conditions, in-process controls, finished product
specifications, and the associated methods and frequency of monitoring
and control. (ICH Q10)

Control Strategy - Key Principles
• The control strategy is designed to ensure that a product of required quality
will be produced consistently in alignment with the QualityTarget Product
Profile (ICHQ8(R2))
• Reviewers will evaluate and approve the control strategy; and investigators
(inspectors) will verify the implementation of the control strategy at the
manufacturing site
• The control strategy needs to be maintained across the product life-cycle

Control of Elemental Impurities 1
• Control of elemental impurities is an important component of the overall
control strategy for a drug product that assures that elemental impurities
do not exceed the PDEs
• It is not expected to tighten the limits based on process capability, provided
that the elemental impurities in drug products do not exceed the PDEs
• Lower levels of elemental impurities may be warranted when levels below
toxicity thresholds have been shown to have a negative impact on quality
attributes of the drug product
• For example, element catalyzed degradation of drug substances

• Q3D does not apply to drug products used during clinical research stages of
development
• However, as the commercial process is developed, the principles contained in the
guideline may be used to develop the controls for elemental impurities
• The principles in this guideline can be applied to evaluate the controls for
elemental impurities in existing products

• If the risk assessment fails to demonstrate than an EI level is consistently
below the control threshold, then controls need to be established to
ensure the EI level does not exceed the PDE
• Routine testing of elemental impurities (including Class 1 elements i.e. Cd,
Pb, As and Hg) is not expected, unless the risk assessment indicates this is
needed
• Application of the principles outlined in Q3D provides a platform for
developing a risk-based control strategy to limit elemental impurities in the
drug product

From Risk Assessment to Controls on Elemental Impurities

From Risk Assessment to Controls on
Elemental Impurities
• The output of the risk assessment classifies elemental impurities to be
considered in the control strategy into one of the following categories:
• Elemental impurities that may be present, but are below the control threshold in the
drug product
• Elemental impurities that may exceed the control threshold, but are below the PDE in
the drug product
• Elemental impurities that may exceed the PDE in the drug product

May exceed the control threshold but below PDE
• When the level of an elemental impurity may exceed the control threshold,
additional measures may need to be implemented to ensure that the level
does not exceed the PDE.
• These additional measures include, but are not limited to:
• Reduction of elemental impurities to levels that do not exceed the control threshold
through purification steps or implementing in-process or upstream controls
• Selection of components of improved quality, if appropriate
• Establishment of specification limits for the drug substance, excipient or drug product,
if appropriate
• Selection of appropriate container closure system

Exceeding the PDE
• When the level of an elemental impurity exceeds the PDE additional
measures should be considered to bring the levels below the PDE
• When additional measures are either not technically feasible or have been
unsuccessful, levels of elemental impurities higher than the established PDE
may be justified in certain circumstances, for example:
• Intermittent dosing
• Short term dosing (i.e. 30 days or less)
• Specific indications (e.g. Life threatening, unmet medical needs, rare diseases)
(Refer to training module 2 for further details on safety considerations)
• Recommend early dialogue with Regulatory Authorities to discuss
appropriate control strategy in this situation

Periodic Testing
• Periodic testing may be applied to elemental impurities according to the
principles described in ICH Q6A.
• Application of periodic testing to drug products and components of drug products will
depend on regional regulations.
• Where the risk assessment indicates that routine testing is considered
unnecessary but some additional assurance is needed post approval,
periodic testing of the drug product or one or more individual components
may be proposed by the applicant and implemented upon acceptance by
the regional regulatory authority.

Application of Periodic Testing to Drug Substance –
an example
• An applicant has the developed a new tablet form medicine:
• The active substance is manufactured by a route where the last step is a catalytic
hydrogenation with platinum on carbon as catalyst.After filtration to remove the catalyst,
the substance is isolated by crystallisation.
• In the risk assessment the applicant concludes that the filtration and the crystallisation are
likely to reduce the levels of Pt.This is also confirmed on three production scale batches
where Pt where found in 24%, 19% and 22% of an amount corresponding to a PDE
calculated by Option 2b.
• For these three batches the levels of Pt is below 30% of the PDE. However, impurities
introduced late in the synthesis constitutes a higher risk of being carried through (ICH Q11)
and the control threshold could be exceeded.
• A specification for the drug substance was set that ensures compliance of the drug product
with the PDE.The applicant proposed to apply PeriodicTesting (ICH Q6A) after
confirmation on 10 batches.

Regulatory Submission
• The information on the control of elemental impurities that should be
provided in a regulatory submission includes a summary of the risk
assessment, appropriate data as necessary, and a description of the controls
established to limit elemental impurities (if needed).

Life-cycle approach to Control Strategy 1
• Product and/or process changes across the product lifecycle have the potential
to impact (positively or negatively) the elemental impurity content of the drug
product.
• Changes could include, but are not limited to:
• Changes in synthetic routes, excipient suppliers, materials, processes, equipment,
container closure systems or facilities
• The impact of such changes on the original risk assessment should be evaluated,
and implications for the control strategy should be considered
• The regulatory implications of modifications to the risk assessment and
control strategy should be considered, and appropriate variations submitted
according to specific regional requirements
• Consideration should be given for periodic review of the control strategy, as
part of ongoing continual improvement

Life-cycle Approach to Control Strategy 2
• Elemental impurity data for some components may be limited during drug
development, which may direct the applicant to a particular control strategy.
• For example, the applicant may choose to carry out end product testing as the initial
strategy.
• As additional experience and knowledge is gained with time, an applicant may determine
that a change in the calculation option, risk assessment and/or control strategy may be
warranted
• See next slide for pictorial representations

Life-cycle approach to Control Strategy 3

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
• This is generally due to the absence of use of elemental impurities as catalysts
or reagents and to the typical purification schemes used in the manufacture of
biotechnology-derived products
• In general, a specific control strategy for elemental impurities up to the
biotech drug substance is not needed. However, potential elemental impurity
sources (e.g., excipients, environmental sources, container/closure) in drug
product should be considered.

Converting between PDEs
and Concentration Limits
ICH Q3D Elemental Impurities

General Principles (1)
• PDEs provide safety based limits to patient exposure.
• Q3D Section 7 provides some options for converting PDEs to concentration
limits.
• Concentrations derived from PDEs may be used during the risk assessment
to evaluate the significance of predicted levels of elemental impurities.
• Concentrations derived from PDEs may be used to convey the suitability of
controls on elemental impurities.

• “The applicant may select any of these options as long as the resulting
permitted concentrations assure that the drug product does not exceed the
PDEs.”
• Permitted concentrations may be used:
• As a risk assessment tool to compare observed or predicted 183

• Sources to be considered when applying options
• Components of the drug product
• Drug substances & excipients
• Container/Closure systems (CCS)
• Manufacturing Equipment
• When it is determined thatCCS or manufacturing equipment do not contribute to the elemental
impurity level in the drug product, they are not included in the option calculations.
• WhenCCS or manufacturing equipment contribute to the elemental impurity levels in the drug
product, the estimated daily intake from these sources may be subtracted from the PDE before
calculation of the allowed concentrations in excipients and drug substances.

Examples
• Q3D Appendix 4 Example: solid oral product
• Parenteral product
• Inhalation product
• These examples are intended to illustrate the principles described in Section
7 of Q3D.

Q3D Appendix 4 Example: Solid Oral Dosage Form
• Maximum daily intake of drug product: 2.5 grams
• 9 components: 1 drug substance, 8 excipients
• See table on next slide for product formulation
• Drug substance: Pd and Ni catalysts
• Risk Assessment: Pb, As, Cd, Hg andV are potentially present in the drug
product

Q3D Appendix 4 Example: Solid Oral Dosage Form

Q3D Appendix 4 Example: Option 1
• Compute maximum concentration limits common to all components using a
maximum daily drug product dose of 10 grams.
• Q3D table A.2.2 provides these concentrations.
• Use theTable A.2.2 concentrations and the actual mass of components to
compute the maximum daily intake of elemental impurities in the drug
product.

Option 1 Concentrations and Daily Intakes

Q3D Appendix 4 Example: Option 2a
• Compute maximum concentration limits common to all components using
the maximum daily dose of the drug product.
• The Appendix 4 example considers a drug product with 2.5 gram maximum
daily dose.
• PDEs fromTable A.2.1 are divided by 2.5 grams to compute the maximum
permissible concentration of elemental impurities in the components.

Option 2a Concentrations and Daily Intakes

Q3D Appendix 4 Example: Option 2b
• The applicant proposes permissible concentrations in each component of the
drug product based on prior knowledge of expected concentrations of
elemental impurities in the components.
• Expected concentrations derived from:
• Published literature
• Elemental impurity limits in compendial grade materials when available
• Vendor-supplied information
• Data or information generated by the applicant

Option 2b Appendix 4 Example
Concentrations1

Option 2b Appendix 4 Example Estimated total
daily intake
1. Intake of component (MDI) in grams
2. Concentration of elemental impurity (C) in micrograms per gram.
3. EI intake from component (MDI*C) in micrograms.
4.Total Intake of EI in the drug product is the sum of EI intake from components.

Potential Concentrations in Components
** Maximum permitted concentrations are proposed by the applicant based on expected
concentrations. Other sets of concentrations may also be proposed.
*The risk assessment determined that Pd was not a potential elemental impurity; a
quantitative

Q3D Appendix 4 Example: Option 3
• Option 3 determines the permissible concentrations of elemental impurities
in the finished drug product.
• Based on the mass of the maximum daily dose

Implementation of
Elemental Impurities in
APIs

Content
• Introduction
• Guidelines on elemental impurities
• Background for new requirement
• Standard / Limit
• Procedure & instrument
• Method development & validation
• Implementation

General Notices USP 38—NF 33
• General chapters <232> was published June 1, 2012, in the
Second Supplement to USP 35 to effect from Feb 1, 2013 and
deferred.
• As per USP37 Sup-2, General Notices provision becomes
official from January 1, 2018.
• Elemental impurities has to be controlled in official drug products
according to the principles defined and requirements standard
specified in Elemental Impurities—Limits <232>, Also see <232>
for information related to drug substances and excipients.
• But It is expected for drug substances and excipients.

USP on Elemental Impurities
 USP General Chapter <231> Background and issues
 Toxicology considerations
 Chapter <232> - Elements and Limits
 Chapter <233> - Procedures
 Implementation Plans

Guidelines
1. Guideline OnThe Specification Limits For Residues Of
Metal Catalysts Or Metal Reagents ;
EMEA/CHMP/SWP/4446/2000; 21 February 2008
2. ICH Guideline- Q3D on Elemental Impurities (Step-4;
16 December 2014)
3. CDER adopted ICH: Q3D Elemental Impurities-Guidance
for Industry; September 2015
4. EMA adopted ICH :EMA/CHMP/ICH/353369/2013- 25
August 2015

Why this new requirement
Presently, there is a test for Heavy metals; then
why regulatory/ standard setting agencies are
insist for revision
Is this change required?
• As a professional in Industry
• As consumer

Disadvantages of Heavy metal test:
• Difficulties in reproducibility
• Colour of solution is subjective.
• standards change with time.
• recovery issues.
• Difficulties with reagents – safety issues
–All procedures generate H2S (including Thioacetamide) and H2S more toxic than
cyanide
–Thioacetamide is not allowed in several countries
• Non-discriminatory screening test
–Not element specific
–Sensitivity varies by element
–Only a few elements respond at required sensitivities

Disadvantage of Heavy Metals test

Key Elements under heavy metals
• As, Cd, Pb, Hg are clasifed as key /major
elements under heavy metals
• Heavy metals are classified based on toxicity
• ICH classified as class-1, 2 & 3

Toxicology
• Approach to elemental impurity control that is
both health based and risk based
• Control metals that are toxic
• Setting limits that are toxicologically relevant
• At all times during a drug product’s shelf life
• Risk-based approach -what is to be tested and
when to test

Dose Levels andToxicity
–NOEL: No-Observed Effect Level
–NOAEL: No-Observed-Adverse Effect Level
–LOAEL: Lowest-Observed-Adverse Effect Level
–MTD : MaximumTolerated Dose
–LD50: Lethal Dose to 50% of population
Increasingdose
Safe
Less safe

Reference Dose (RfD)
(toxic level)
• An estimate of the daily dose of a chemical that will avoid
toxic effects other than cancer
• NOAEL or LOAEL is adjusted by uncertainty factors (UF) to
allow for differences in sensitivity to chemicals
–Human data UF = 10
–Animal data UF: –100 (NOAEL)
–1000 (LOAEL)
–1000 (NOAEL, less data)

PDE Calculation
RfD = NOAEL/UF
eg. NOAEL is 10 μg/kg/day based on human data
UF=10:
RfD = 10μg/kg/day (NOAEL)/10 (UF) = 1μg /kg/day
RfD is used to calculate Permissible Daily Exposure (PDE)
(RfD X Weight) = PDE
PDE Example: 50 kg person and RfD = 1 μg/kg/day:
PDE = 1 μg/kg/day X 50 kg = 50 μg/day

PDE Calculation
What if only LOAEL or limited NOAEL is available
RfD = NOAEL/UF
eg.: NOAEL = 10 μg/kg/day based on animal data
UF=1000:
RfD = 10 μg/kg/day (NOAEL)/1000(UF) = 0.01 μg/kg/day
RfD is used to calculate Permissible Daily Exposure (PDE)
(RfD XWeight) = PDE
PDE Example: 50 kg person and RfD = 0.1 μg/kg/day:
PDE = 0.1 μg/kg/day X 50 kg = 0.5 μg/day

Elemental Impurities-Limits <232>
• Implementation of Chapters <232> and <223>
• Omission of Chapter <231> Heavy Metals
• Elemental Impurities:
• Scope and application
• Elemental Impurities
• Implementation :
• Drug Product Analysis Option
• Summation Option
• IndividualComponent Option

General Notices USP 37—NF 32 Suppl- 2
• “Elemental impurities to be controlled in official drug
products according to the principles defined and
requirements standard”.
Scope:
• This General Chapter specifies limits for the amounts of
elemental impurities in drug products.
• The limits presented in this chapter do not apply to excipients
and drug substances, except where specified in this chapter or
in the individual monographs. However, elemental impurity
levels present in drug substances and excipients must be
known and reported.

General Chapter <232> Basics
• Applies to drug products
• Drug substances
• Excipients
• Does not apply to dietary supplements
• Does not apply to veterinary products
• Does not apply to Dialysates andTotal Parenteral
Nutritions (TPN)
• Does not apply to vaccines
• Speciation is not addressed in this Chapter
• Procedures are specified in <233>

Elemental Impurities compliance
Options available for determination of drug product:
• Drug Product Analysis Option
• Summation Option
• Individual Component Approach for LVP
Drug Product Analysis Option is Generally Applicable / well acceptable
Determination & Calculation:
–The results obtained from the analysis of a typical dosage
unit scaled to a maximum daily dose.
–Daily Dose PDE > measured value (μg/g) x maximum daily
dose (g/day)

Default Concentration Limits for Drug Substances
Inorganic arsenic0.15 0.15 0.15
Inorganic mercury1.5 0.15 0.15
Iridium 10 1.0 0.15
Osmium 10 1.0 0.15
Palladium 10 1.0 0.15
Platinum 10 1.0 0.15
Rhodium 10 1.0 0.15
Ruthenium •10• (ERR 1-Oct-2012)•1.0• (ERR 1-Oct-2012)•0.15• (ERR 1-Oct-2012
Chromium —a —a 2.5
Molybdenum 10 1.0 •1.0• (ERR 1-Oct-2
Nickel 50 5.0 0.15
Vanadium •10• (ERR 1-Oct-2012)•1.0• (ERR 1-Oct-2012)•3.0• (ERR 1-Oct-2
Copper 100 10 •10• (ERR 1-Feb-2
a Not a safety concern. ã2013 The United States Pharmacopeial Convention All Rights Reserved.

Limits as per ICH
Element Class2 Oral PDE μg/day Parenteral PDE, μg/day Inhalation PDE,μg/day
Cd 1 5 2 2
Pb 1 5 5 5
As 1 15 15 2
Hg 1 30 3 1
Co 2A 50 5 3
V 2A 100 10 1
Ni 2A 200 20 5
Tl 2B 8 8 8
Au 2B 100 100 1
Pd 2B 100 10 1
Ir 2B 100 10 1
Os 2B 100 10 1
Rh 2B 100 10 1
Ru 2B 100 10 1
Se 2B 150 80 130
Ag 2B 150 10 7
Pt 2B 100 10 1
Li 3 550 250 25
Sb 3 1200 90 20
Ba 3 1400 700 300
Mo 3 3000 1500 10
Cu 3 3000 300 30
Sn 3 6000 600 60
Cr 3 11000 1100 3

Calculation
–The results obtained from the analysis shall be calculated to
maximum daily dose.
–Daily Dose PDE > measured value (μg/g) x max. daily dose
(g/day)
Example
1. 500 mgTablet used Once a day dosing . Measured content of arsenic of
0.75 μg/g of tablet contents
1.5 μg/day (PDE limit) > 0.75 μg/g x 0.5 g/day x 1 (0.375 μg/day)
2. 1gTablet used thrice a day dosing . Measured content of lead 2μg/g of
tablet contents
IsTablet meet the requirement or fails

Compendial Procedures
• Procedure 1: Can be used for elemental impurities generally
amendable to detection by ICP-AES/OES
• Procedure 2: Can be used for elemental impurities generally
amendable to detection by ICP-MS.
• Verification: Meets ProcedureValidation Requirements

Implementation of Elemental
Impurities
 Why <231> cannot be validated
 Choosing the appropriate instrument
 Qualifying the lab
 Determining which elements need to be validated
 Setting specifications
 Method development
 Method validation

Elemental Impurities - Procedures <233>
• Definitions
• Compendial Procedures
–Procedure 1: ICP-OES
–Procedure 2: ICP-MS
• Validation
–Limit Procedures
–Quantitative Procedures
• Calculations and Reporting

Analysis of Metal Residues as per EP 2.4.20
• Describes general approach for determination of metal
catalyst or metal reagent residues in substances for
pharmaceutical use.
• System suitability needs to be demonstrated
• Validation required for non-monograph procedures
• Sample preparation, detection limit technique,
instrument parameters is responsibility of the user
• Allows AAS, XRF, ICP-AES, ICP-MS

• Sample Preparation
• Aqueous of dilute nitric acid solutions
• Hydrogen peroxide, hydrochloric acid, sulfuric acid, perchloric acid, hydrofluoric acid
• Dilute bases
• Organic solvents
• Digestions
• Hot-plate
• Microwave-assisted digestions
• Can be open-vessel if supported by spiking studies
• Acceptance criterion for preparation of sample solution: a clear
solution is obtained.

Measurement
–Acceptance criteria for measurement system: measured concentration of
standard solution does not differ from actual concentration by NMT 20%
QuantitativeValidation
–Specificity
–Range
–Accuracy – Recovery
–Repeatability
–Intermediate Precision
–Limit of Quantification
–Limit of Detection (Limit test only)

Elemental Impurities – Procedure USP <233>
Sample Preparation:
• Neat or dilute as per analysis range
• Direct aqueous solution – Sample is soluble in dilute acids and bases
• Direct organic solution – Sample is soluble in an organic solvents
• Indirect solution/Closed vessel digestion – Digestion is required using
concentrated acids
• Incomplete digestion: should dissolve majority of sample
• Supported by spiking – if after filtration or centrifuge, recoveries are within
limits set in USP <233>
• Prepare appropriate ref (SRM) to matrix, values should be within COA
• Leachate extraction can be justified
• Total metal extraction is preferred

Instrument for Elemental analysis
• ICP-AES
• ICP-OES
• ICP-MS

ICP-OES and ICP-AES
Advantages
–Dynamic range: 10^6-10^8
–Ability to analyze multiple elements at one time
–Ability to perform a scan
–Able to analyze samples with high dissolved solids
without significant signal suppression
–Precision: RSD < 5%
Disadvantages
–Higher detection limits
–Spectral interferences
–Consumes 2 – 5 mL of sample preparation

Elemental Impurities – Procedure
Procedure I: ICP-AES, ICP-OES and Procedure II: ICP-MS
–Standardization solution 1: 1.5J of theTarget elements in a Matched matrix
–Standardization solution 2: 0.5J of theTarget elements in a Matched matrix
–Prepare a matrix matched blank
–Sample solution: Prepare/dilute the sample to obtain a final concentration of
Target elements at 1.5J.
J =The concentration (w/w) of the element t at theTarget limit,
appropriately diluted to the working range of the instrument.
Note: Dilutions will be required if sample concentration exceeds 1.5J.
Analyze in accordance with manufacturer’s suggestions
–System suitability requirements –Tuning the instrument
–Suggested wavelengths

Elemental Impurities – Procedure
Procedure I: ICP-AES, ICP-OES and Procedure II: ICP-MS
Analysis:
• Standardization standard solution 1, Standardization standard
solution 2, and Blank
• Evaluate system suitability (after tuning)
Note: Confirm the standards prepared correctly? & background of the instrument clean enough for use
• If system suitability has been met – Analyze the Sample solution(s)
• –Drift:Analyze standardization solution 1 (1.5J) after Sample solutions
• Suitability criteria: NMT 20% drift for eachTarget element

Method Development
Sample preparation used should yield a clear solution if at all possible
• If solubility of sample is known, dissolve & dilute to get desired level
• If solubility is unknown:
• –Dissolve in dilute acid solution (1 – 5%) / Dissolve in organic solvent
• Ensure solvent is not contaminated with elements of interest
• Digest the sample in an open-vessel / Hot block or microwave
• Needs to be supported by spiking studies to address possible loss of volatile elements
• Digest samples in a closed-vessel microwave
• Digestion tubes may need to be pre-screened prior to use
• Keep acid concentration low in sample prep, if possible.
• suggest <5% for nitric, hydrochloric and <2% for hydrofluoric
• Dissolve in dilute base solution (<10%)
• Stability of metals needs to be established
• Bases may not be appropriate for all elements

Method Development
Prepare sample at a dilution to the desired level
• Example: Specification is 0.5 μg/g for Pb – LimitTest
• Instrument detection limit is 0.1 μg/L
• Detection limit of 0.25 μg/g is needed
• A maximum dilution factor of 2500x will be required
• Example: Specification is 0.5 μg/g for Pb – Quantitative Method
Validation
• Instrument detection limit is 0.1 μg/L
• Detection limit of 0.125 μg/g is needed (based on 50% spike at 0.25 μg/g)
• A maximum dilution factor of 1250x will be required

Method Development
• Prepare a sample, replicates, spike, spiked replications; use individual sample
portions for each preparation
• Spike the matrix spike and matrix spiked replicates at the specifications prior to sample
preparation
• If spiking for a wide range of specifications (ex. 0.5 μg/g – 100 μg/g)
• Prepare sample to obtain detection limits low enough for 0.5 μg/g
• Dilute this sample preparation to bring the 100 μg/g spike within the linear range of the
standards
• Spike recoveries need to be:
• Limit test: 85 – 115% and RSD < 20% between sample and spike preparations
• Quantitative method validation: 70 – 150% and RSD < 20% between sample and spike
preparations
• LOQ satisfied by meeting the Accuracy requirements
• Internal standard responses should not be suppressed or enhanced
• Recoveries of 50 -125% are suggested, but may vary based on specific method
• May need to evaluate sample preparation and use an alternative prep or technique

Method Development
Decide on a limit test or a quantitative method validation, if
not specified in monograph
Limit test
• Applicable when the elements of interest are not detected or
trend at levels well below the specification
• Raw materials where catalysts are not used in manufacturing
Quantitative method validation
• Applicable when elements of interest trend above the limit of
quantitation, especially when they are close to the specification
• Data needs to be trended
• Draft a method validation protocol for review by all parties
involved

MethodValidation
• Limit Procedures
• Detectability
• Precision (Repeatability)
• Specificity
• Quantitative Procedures
• Accuracy
• Precision
• Repeatability
• Ruggedness (Intermediate Precision)
• Specificity
• Limit of Quantitation, Range, and Linearity—satisfied by meetingAccuracy
requirement

MethodValidation
Limit Procedures
Detectability
• Spiked sample solution 1: Prepare sample:
• Spike at the target concentration (100%) for each target element
• Spike prior to sample preparation
• Analyze in triplicate
• Spiked sample solution 2: Prepare sample:
• Spike at the 80% of target concentration for each target element
• Standard solution: Prepare working standard for the target element(s) at target
concentrations
• Analyze in triplicate
• Unspiked sample solution: Prepare an unspiked sample aliquot
Acceptance criteria: average of triplicate measurements of Spiked sample solution 1
is within ±15% of the average of triplicate measurements of Standard solution

MethodValidation
Limit Procedures
• Precision (Repeatability)
Sample solution (spiked) Prepare:
• Six independent sample preparations
• Spike each at the target concentration (100%) for each target
element
Acceptance criteria: RSD NMT 20% for eachTarget element
• Specificity:
• Unequivocally assess eachTarget element in the presence of
components that may be expected to be present, including other
Target elements, and matrix components

MethodValidation
• Limit Procedures
• Specificity (example ICP-OES, ICP-AES)
• Spectral interferences may be caused by background emission
from continuous or recombination phenomena, stray light or
overlap of spectral lines from another element or unresolved
overlap of molecular band spectra. "subarray" on the CID
detector.
• A metals screen/scan analysis performed on this material
demonstrated that the sample does/does not contain appreciable
concentrations of any element that are likely to cause
interferences on the analytes of interest. Discuss specific
elements with the potential to cause interference and how they
will be monitored or addressed.

MethodValidation
Quantitative Procedures
• Accuracy
• Standard solution: Prepare working standard for the elements of interest at
target concentrations ranging from 50% to 200% of J
• Test solution: Prepare sample:
• Use the method developed
• Spike at target concentrations of 50% to 200% of J for each target
element
• Prepare three replicates at each concentration
• Acceptance criteria: 70% - 150% for the mean of three replicate preparations
at each concentration

MethodValidation
Precision (Repeatability)
• Test solution: Prepare sample:
• Six independent sample preparations
• Spike at target concentrations (J) for each target element
• Acceptance criteria: RSD NMT 20% for eachTarget element
Precision (Ruggedness)
• Perform Repeatability analysis over three independent events using the following
events or combinations thereof:
• on different days, or
• with different instrumentation, or
• with different analysts
• Acceptance criteria: RSD NMT 25% (N=12) for eachTarget element

MethodValidation
• Specificity (refer to slide for limit test)
• Limit of Quantitation, Range, and Linearity
–Demonstrated by meeting the Accuracy requirements (at 0.5 J)

Establishing In-house Lab
Purchase appropriate instrumentation
Purchase apparatus to assist in sample digestion
• Hot block with polypropylene disposable digestion vessels : 50 mL / 15 mL
– limited sample size available
• Microwave system with digestion vessels : 50 mL /15 mL
• Quartz – most appropriate for screen
• Teflon – resistant to hydrofluoric acid
• Borosilicate – disposable, may not be clean enough for trace levels
Purchase
• High Purity Acids (nitric, hydrochloric, hydrofluoric, sulfuric, perchloric)
• Hydrofluoric, Perchloric
–Bases
• Ammonium hydroxide , Sodium hydroxide ., CFA-C,TMAH

Preparedness for implementation
• Standards (NIST traceable)
• Single element for spiking at varying specifications
• Multi-element
• Custom multi-element for specification levels
• Single element standards for internal standards
• Second source standards for verification
• Plastic bottles or vials for sample preparation
• Gases : Argon, hydrogen, helium gases
• Highest purity – Ultrapure grade , Low krypton content
• Use stainless steel gas lines, avoid aluminum and copper

Preparedness for Contract Lab
Audit the lab for cGMP compliance/FDA / appropriate approvals;
• Each material shall require its own validation
• System suitability can be established with daily tune for ICP-
OES,
• ICP-OES and ICP-MS have a wide dynamic range, single
standard analysis at 0.5J and 1.5J are sufficient, do not need to
analyze 5 standards
• Not all elements listed in the chapters will need to be validated
for every material
• As, Cd, Pb, Hg needs to be validated, at a minimum
• If catalysts are not used validation is not required
• Strongly suggest incorporating ICH Class 2A elements in minimum
evaluation, as well

Preparedness for Contract Lab
• Audit the contract lab for suitability of resources and compliance
• Provide all information related to product
• Solubility , handling & storage
• Set specifications, work appropriate dilution/ concentration
• Ensure to full metals scan at time of method development, so that
• Communicate which elements require method validation based on risk
assessment
• Submit samples in plastic bag/containers to avoid metal contaminant ion
• Ensure sufficient samples for development & method validation
• Prepare or review and approve method validation protocol and Review
and approve the report.

Summary
Heavy Metals <231> must be replaced
USP chapters <232> and <233>,
Elemental Impurities – Limits <232>
–Toxicological basis for limits
–Options to determine compliance
–Limits (aligned to ICH- Q3D)
Elemental Impurities – Procedures <233>
–Two compendial procedure
–LimitTest and Quantitative procedures
• Sample preparation
• Method development
• Method validation
Working with contract Lab

Q&A
1. What are the elements need to be shown in the analysis
1. Big Four
2. Catalysts used in the process
3. All the elements present in <232>
4. Elements present as per the process only
5. Elements present in the drug product as per the process

Q&A
2. In the manufacturing process, there are no catalysts used and
there is no possibility of any elemental impurity present.
What are the elements to be shown in the analysis?
1. Big Four
2. All the elements present in <232>
3. Elements present in the drug product as per the process
4. No element is required

Q&A
3. What is the preferred way to determine the elemental
impurities in the drug product.
1. Analysis of drug product
2. Individual components of product
3. Both
4. None

Answer
• Q-1
• Ans: (1), (2), (5)
• Q-2
• Ans: (1), (3)
• Q-3
• Ans: (1)

Q3D Guideline For Elemental Impurities

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Q3D Guideline For Elemental Impurities

Similar to Q3D Guideline For Elemental Impurities (20)

Recently uploaded

Recently uploaded (20)

Q3D Guideline For Elemental Impurities