15 August 2019

Preeyaporn Natehin
Bureau of Drug Control
Thailand Food and Drug
Administration 1
Outline
 Introduction
 Background
 ICH Guideline for Elemental impurities (ICH
Q3D)
 USP General Chapter <232> and <233>
 Ph.Eur. 5.20 and BP SC IV Q Elemental
impurities
 Example

2
Introduction
Type of
Impurities

Organic Inorganic
Residual solvent
impurities impurities

- Reagent / Ligands / Catalysts

- Heavy metals or other
residual metals
- Inorganic salts

3
Introduction
 Elemental impurities in drug products may arise from several
sources and those impurities don’t provide any therapeutic
benefit to the patients.

 The levels of elemental impurity in Drug Product should be

controlled within acceptable limits.

 Implementation of ICH Q3D and USP General Chapters <232>

and <233>
 Non-compendial drug products should control elemental
impurities as described in ICH Q3D.
 Compendial drug products can comply with USP General
Chapters <232> and <233>

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Background
 USP General Chapter <231> was deleted and replaced by General
Chapters <232> and <233>. Effective date on January 1, 2018

 The revised version of <232> that aligns with ICH Q3D became
official on August 1, 2017.

 USP 40-NF 35 / Ph.Eur. 9th / BP 2018

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ICH Guideline for Elemental
impurities (ICH Q3D)
 ICH Q3D recommend drug product manufacturers applied a
risk-based approach to control elemental impurities.

 Manufacturers should evaluate each elemental impurity likely to

be present in the drug product by determining observed level
compared to the established PDE.

 Manufacturers should consider all potential sources of elemental

impurities.

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Exclusion
 Radiopharmaceuticals
 Vaccines
 Cell metabolites / DNA products / Cells
 Allergenic extracts
 Whole blood / Cellular blood components / Blood derivatives
 Plasma / Plasma derivatives
 Elements that are intentionally included in the drug product for
therapeutic benefit
 Gene Therapy / Cell Therapy / Tissue Engineering

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Exclusion

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Risk based approach
 The first step is performing a Risk Assessment.

 The results from the risk assessment is used to determine which

elemental impurities are likely to be present in the drug products
and whether current controls for those elemental impurities are
adequate.

 If additional controls should be put in place, the results of the

risk assessment can also help determine which types of controls
should be used.

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Risk Assessment
 The product risk assessment would be focused on assessing the
levels of elemental impurities in a drug product in relation to the
PDEs.

 PDEs = Permitted Daily Exposure

 3 steps of elemental impurities risk assessment

Summary and
Identification Evaluation
Documentation

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Identification
 Identify known and potential sources of elemental impurities.

 Potential sources of elemental impurities

 Residual impurities resulting from elements intentionally
added.
 Elemental impurities that are not intentionally added and are
potentially present in the drug substance, water or excipients.
 Manufacturing equipment
 Container closure systems

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Identification

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Elements classification
Class Toxicity (PDE) Likelihood of Elements
occurrence in
the drug product
Class 1 Human Toxicants Limited / No use As, Cd, Hg, Pb
Class 2A High probability Co, Ni, V
of occurrence in
drug product
Class 2B Route-dependent Reduced Ag, Au, Ir, Os,
human toxicants probability of Pd, Pt, Rh, Ru,
occurrence in Se, Tl
drug product
Class 3 Relatively low Probable use Ba, Cr, Cu, Li,
toxicities by the oral Mo, Sb, Sn
route of
administration

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Elements to be considered

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Evaluation
 Evaluate the presence of a particular elemental impurities in the
drug product.

 Possible outcome from the 1st step

 The risk assessment process does not identify any potential
elemental impurities.
 The risk assessment process identifies one or more potential
elemental impurities.

 Manufacturers should evaluate each elemental impurity likely to

be present in the drug product by determining the observed or
predicted level compared to the established PDE.

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Evaluation
 The data that support the risk assessment can come from a
number of sources:
 Prior knowledge / Published literature
 Data generated from similar processes
 Supplier information or data
 Testing of the components of the drug product
 Testing of the drug product

 The risk assessment can be facilitated with information provided

by suppliers of drug substances, excipients, container closure
systems, and manufacturing equipment.

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Evaluation
 Providing the data from three representative production scale
lots or six representative pilot scale lots of the components or
drug product.

 The PDE reflects only total exposure from the drug product, so it
is useful to convert the PDE into concentrations as a tool in
evaluating elemental impurities in drug product or components.

 There are the options to describe some acceptable approaches to

establishing concentrations of elemental impurities in drug
product or components that would assure that the drug product
does not exceed the PDEs.

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Options to convert between
PDEs (µg/day) and
concentration limits (µg/g)
ICH Option USP Option Evaluation Limit
Option 1 Individual Each component Concentration
component (Dose ≤ 10 g/day)
option
Option 2a Each component Concentration
(Actual product
dose)
Option 2b Summation Total element PDE
option (per day)
(Calculate from
component)
Option 3 Drug product Total element PDE
analysis option (per day)
(Calculate from
DP) 18
19
Option 1
 This option assumes the daily intake (amount) of the drug
product is 10 grams or less.

 The elemental impurities identified in the risk assessment are

present in all components of the drug product.

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Concentration of Cd (µg/day) = 5 µg/day / 10 g
= 0.5 µg/g

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22
Option 2a
 This option is similar to option 1 but the common permitted
concentration of each element is determined using Equation 1
and the actual maximum daily intake.

 The elemental impurities identified in the risk assessment are

present in all components of the drug product.

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Concentration of Pb (µg/day) = 5 µg/day / 2.5 g
= 2 µg/g
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Option 2b
 This option requires additional information that the applicant
may assemble regarding the potential for specific elemental
impurities to be present in specific drug product components.

 The applicant may set permitted concentrations based on the

distribution of elements in the components.

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Option 3
 Finished Product Analysis

 The concentration of each element may be measured in the final

drug product and equation 1 may be used with the maximum
total daily dose of the drug product to calculate a maximum
permitted concentration of the elemental impurity.

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Summary and Documentation
 As a measure of the significance of the observed elemental
impurity level, a control threshold is defined as a level that is
30% of the established PDE in the drug product.

 If the risk assessment fails to demonstrate that an elemental

impurity level is consistently less than the control threshold,
additional controls should be established to ensure that the
elemental impurity level does not exceed the PDE in the drug
product.

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Summary and Documentation
 Additional controls:
 Modification of the steps in the manufacturing process that result in
the reduction of elemental impurities
 Implementation of in-process or upstream controls
 Establishment of specification limits for excipients or materials
 Establishment of specification limits for the drug substance
 Establishment of specification limits for the drug product

 Acceptable approaches to summarizing and documenting the risk

assessment may be in:
 Tables
 Written summaries of considerations and conclusions of the
assessment
 The summary should identify the elemental impurities, their sources,
and the controls and acceptance criteria as needed.
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USP General Chapter <232>
and <233>
 USP General Chapters <232> Elemental Impurities—Limits

 USP <233> Elemental Impurities—Procedures

 The primary goals are to:

 set limits for acceptable levels of elemental impurities in finished
drug products
 update the methodology used to test for elemental impurities in
drug products to include modern analytical procedures.

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USP General Chapter <232>
 The chapter specifies limits for the amounts of elemental
impurities in drug products.

 General Chapter <232> endorses a risk-based approach to the

control of elemental impurities as described in ICH Q3D.

 Not apply to excipients and drug substances, except where

specified in an individual monograph.

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USP General Chapter <232>
 General Chapter <232> is applicable to all drug products with
USP monographs except for those drug products specifically
excluded in <232>.
 When specific limits are included in an individual monograph, or in
a general chapter referenced by a monograph, those limits are the
official limits which manufacturers must comply.

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USP General Chapter <232>
 A risk based control strategy may be appropriate when analysts
determine how to assure compliance with this standard.

 Due to the ubiquitous nature of arsenic, cadmium, lead, and

mercury, they (at the minimum) must be considered in the risk
assessment.

 Drug product manufacturers can use elemental impurity test

data on components from tests performed by drug substance
manufacturers or excipient manufacturers or, if applicable, risk
assessments.

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USP General Chapter <233>
 Analytical Procedure – Compendial method and alternative
procedures

 ICH Q3D complies this chapter for analytical procedures

 Two analytical procedures

 Procedure 1- ICP-OES
 Procedure 2 – ICP-MS

 Alternative procedures

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Compendial method
 Procedure 1- ICP-OES
 Procedure 1 can be used for elemental impurities generally
amenable to detection by ICP–AES or ICP–OES.

 Procedure 2 – ICP-MS
 Procedure 2 can be used for elemental impurities generally
amenable to detection by ICP–MS.

 Both of them must be verified according to mentioned in the general

chapter.
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Alternative method
 Alternative procedures must be validated and shown to be
acceptable, in accordance with the validation requirements for
alternative procedures.

 Any alternative procedure that has been validated and meets the
acceptance criteria that follow is considered to be suitable for
use.

 Validation of Compendial Procedures in USP General Chapter

<1225>

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Alternative method
 Atomic spectroscopic technique - flame or graphite furnace
atomic absorption (AA)
 Meets all requirement <1225>

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Ph.Eur. 5.20 and BP SC IV Q
 Ph.Eur. 5.20 and BP Supplementary Chapter IV Q

 Applies ICH Q3D to medicinal products.

 An applicant should provide that the elemental impurities in

drug products do not exceed the PDEs.
 Drug products
 Components

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Example
 A solid oral drug product with a maximum daily intake of 2.5
grams, containing 9 components (1 drug substance and 8
excipients)
 The drug substance synthesis uses Pd and Ni catalysts.

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Example
 Step 1 : Identification

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Example
 Step 1 : Identification

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Example
 Step 1 : Identification

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Example
 Step 2 : Evaluation
 Option 2b is selected to convert between PDE (µg/day) and
concentration (µg/g)

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Example
 Step 2 : Evaluation

Total daily mass of Pb = (0.2*0) + (1.1*0.1) + (0.45*0.1) + (0.35*1) +

(0.265*1) + (0.035*0.5) + (0.06*0.1) +
(0.025*20) + (0.015* 10)
= 1.205 µg
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Example
 Step 3 : Summary and Documentation

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