ICH Q3D: Elemental Impurities Frequently Asked Questions






Purpose: To provide answers to questions that have been frequently asked of members of the
ICH Q3D Expert Working Group.

General FAQs

1. Why is Q3D necessary?

Q3D is the culmination of several initiatives intended to modernize the control of elemental
impurities in pharmaceutical products. The U.S. Pharmacopeia had been discussing the
modernization of its heavy metals monograph for several years prior to the initiation of the Q3D
Expert Working Group. The European Medicines Agency, after many years of discussion, had
implemented a safety and risk-based approach to control of residual catalysts in pharmaceutical
products approved to be marketed in the EU. Q3D arose out of a need to develop a globally
harmonized guideline, which built upon these efforts as well as the efforts of other
pharmacopeias and regulatory authorities.

Q3D comprises safety-based permitted daily exposures for 24 elementals and recommendations
for a risk-based and science-based approach to control of those elements in pharmaceutical

2. How can Q3D be implemented?

The Q3D Implementation Working Group has provided 10 training modules to assist with
implementation. When appropriate, the modules include examples of the application of certain
principles recommended in Q3D. The modules are available on the ICH website. See Module 0
for a summary of the module content.(http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html)

3. Why are herbal products excluded from Q3D?

Herbal products are subject to regulations that differ between ICH regions. Regional regulations
take precedence over harmonized guidances. Application of Q3D to herbal products will be
addressed by regional regulatory authorities.

4. Are sunscreens within the scope of Q3D?

Sunscreens are treated differently by regulatory authorities in different ICH regions. Application
of Q3D to sunscreens will be addressed by regional regulatory authorities.
FAQs Related to Pharmacopeial Considerations

5. What is the relationship between ICH Q3D and pharmacopoeia specifications?

Q3D applies to new finished drug products and new drug products containing existing drug
substances. Application to existing products is not expected prior to 36 months after publication
on the ICH website.

Pharmacopoeias establish and maintain legally binding quality standards. Pharmacopoeial
standards include not only specifications but also general texts and general methods, for existing
substances for pharmaceutical use (i.e. drug substances, excipients and other components of drug
products), dosage forms and drug products.

Q3D has been developed as a harmonised guideline under the aegis of ICH. Q3D does not deal
with testing methods, however it stipulates in chapter 9 that “pharmacopoeial procedures or
suitable alternative procedures for determining levels of elemental impurities should be used”.
The pharmacopoeias of the three ICH regions (JP, Ph. Eur. and USP) participated in the
development of Q3D as observers to help ensure prospective alignment according to respective
legislations. A concrete example of this alignment is the Ph. Eur., which will reproduce
verbatim the content of the Guideline in its chapter 5.20. and cross-reference to the general
monograph on Pharmaceutical preparations, thereby making it legally binding in Europe.
The three pharmacopoeias are in the process of elaborating texts on elemental impurities testing.
See the respective websites for more information.

FAQs Related to Safety

6. What elements were included in the guideline? What elements were excluded?

Elements included in the guideline were based on evaluation of toxicity, previous regional
guidelines, and industry survey. After safety evaluation, some elements were dropped from
inclusion due to lack of safety concern in the Step 4 guideline (e.g., B).

Elements of low risk (Fe, B, W, Zn, K, Ca, Na, Zr, Mn, and Mg) were not considered by the
EWG to require route specific PDEs. Individual safety monographs were not prepared for these
elements. These elements do not need to be included in a risk assessment, unless required by
regional regulations. The rationale for not providing a PDE is discussed in Section 4 of Q3D
under “Other elements”.

For Al, the EWG recognized there are regional regulations regarding the acceptable levels in
parenteral drug products that take precedence over ICH guidance. This is discussed under
“Other elements” in Section 4 of Q3D.

7. Why is Cr (III) used in the chromium monograph rather than Cr (VI)?

Because Cr (VI) is reactive, the EWG did not consider it likely that this form would appear in
pharmaceuticals. As noted in the monograph, if this form is used as a catalyst, than the
assessment should incorporate this form.

8. Please provide a scientific explanation why the inhalation PDE for mercury shall be lower than
the parenteral PDE.

The rationale for derivation of PDEs is discussed in Section 3.1 of Q3D and in the individual
monograph. The parenteral and inhalation PDEs for mercury are in the same order of magnitude
(3 and 1 µg/day). There is little data for inorganic mercury by the parenteral route and the
inhalation PDE is based on occupational data.

What about other routes of administration that are not covered in the Guideline or the training
material? What starting point should I use?

In brief, Q3D recommends using the PDE developed for the oral route as the starting point for a
risk assessment. Details for developing a PDE for a risk assessment for routes other than oral,
parenteral and inhalation are discussed in Section 3.2 of Q3D and Module 1of the IWG training

FAQs Related to CMC

10. What information regarding the risk assessment should be held at the manufacturing site?

The detailed risk assessment should be documented in the manufacturer’s pharmaceutical quality
system. Regional regulatory authorities may provide additional guidance on how these
recommendations may be satisfied.

11. What information on the risk assessment should be presented in a regulatory submission?

Training Modules 5, 6 and 8 (case studies) provide some suggestions regarding the content of the
risk assessment and the summary that should be included in the new drug application dossier.
However, currently there is no universal agreement on where a risk assessment should be located
in the CTD. Regulatory authorities may provide additional guidance as experience with Q3D

12. Until recently, the control of residual catalysts and heavy metal impurities has been addressed
separately through the EMA residual catalyst guideline and compendial heavy metals
monographs, respectively. Why was it considered necessary to address a wider range of
elemental impurities in a single guideline?

It has been recognized for several years that certain metals can be introduced into a drug product
from impurities in raw materials or from processing equipment, which are not satisfactorily
controlled by a test for heavy metals. From a scientific point of view, the characteristic that is
relevant to patient safety is the total daily mass of an elemental impurity delivered to the patient
because the toxicological risk depends only on the total exposure. Thus a science-based
approach should consider all elemental impurities in the same way, regardless of their source.

Q3D emphasizes a holistic, risk-based approach to control of elemental impurities, and provides
a rational assessment mechanism that is appropriate for all elemental impurities. The risk
assessment provides an opportunity to identify those elemental impurities that have the potential
to pose a safety risk to the patient, whether or not they are intentionally added. Within the risk
assessment, it is prudent to consider the most toxic elements that may be introduced as impurities
in raw materials, including the Class 1 and Class 2A elements. These elements would only
require routine testing in drug products or components of drug products if the risk assessment
provides evidence that there is a risk that these elements could exceed the permitted daily

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