05.11.2019 | LOGFILE Feature 41/2019

Organic and Mutagenic Impurities / Environmental Risk Assessments (ERAs)

New Toxicological Assessment Services of GMP Publishing

New Toxicological Assessment Services of GMP Publishing

10 minutes reading time | by Sabine Paris


Pharmaceutical manufacturers regularly have to implement new regulatory requirements. The EMA, for example, requires the setting of health based exposure limits (PDE values) for all medicinal products manufactured in shared facilities.

The ICH's demand for a safety assessment for potential elemental impurities in finished medicinal products also caused a lot of work.

However, it is not only the patient taking the medicinal product who should be protected from harmful influences, but also the employees who manufacture it. Therefore, it is also mandatory to define occupational exposure limit values (OEL values).

Every pharmaceutical company is obliged to perform calculations and prepare assessments - what an enormous effort!

GMP publishing supports you with its assessment service which we offer in cooperation with our Spanish business partner Atreiza. Toxicological reports for PDE values, elemental impurities and occupational exposure limits have been an integral part of our services for several years.

From now on we also offer

  • Assessments for organic impurities according to ICH Q3A/Q3B
  • Assessments for mutagenic impurities according to ICH M7
  • Assessments for analysis and evaluation of environmental risks (Environmental Risk Assessment, ERA)

What are the underlying requirements of these assessments? Our editor Sabine Paris explains the technical background and presents our new services.


Organic and mutagenic impurities

Any ingredient present in a medicinal product or in an active substance (API) which is not chemically equivalent to the active substance, excipient or other additive is an impurity.

In the vast majority of cases, impurities in medicinal products are not caused by GMP deficiencies during manufacturing. Primarily, impurities are the result of chemical processes taking place during synthesis of the API or storage of the medicinal product.

Causes of impurities in chemical agents (Source: GMP Compliance Adviser, Chapter 21.F.5)


If an impurity in a new finished medicinal product (containing a chemical API) or in a new chemical API reaches or exceeds the qualified limit, the manufacturer shall assess the toxicity of the impurity according to the ICH guidelines for organic impurities (ICH Q3A/Q3B) and mutagenic impurities (ICH M7).

Organic and mutagenic contaminants must be identified and analysed. Then the associated health risk for the patient must be assessed.


Organic impurities

The ICH Q3A guideline for impurities in new APIs distinguishes between:

Reporting threshold: Limit above which an impurity should be reported.
Identification threshold: Limit above which an impurity should be identified.
Qualification threshold: Limit above which an impurity should be qualified.

Thresholds for organic impurities in active substances according to ICH Q3A


Any impurity with a concentration greater than the identification threshold must be identified. If an impurity cannot be identified, a summary of the laboratory studies should be included in the marketing authorisation application.

Impurities with a concentration below the identification threshold do not need to  be identified. However, if they show toxic or pharmacological effects even at these low concentrations, analytical methods must be developed.

All impurities should be qualified. Qualification is the process of obtaining and evaluating data and determines the biological safety of an individual impurity or an impurity profile at a specified concentration.

The relationships are shown in the decision tree for identification and qualification of impurities.

Decision tree for the identification and qualification of impurities (Annex 3 of ICH Q3A)


Mutagenic impurities

The ICH M7 Guideline on DNA reactive (mutagenic) contaminants in pharmaceuticals applies to:

  • New chemical APIs and new medicinal products
  • New marketing authorisations for medicinal products with known APIs or amendments to existing marketing authorisations if
    • new impurities or higher acceptance criteria result from changes in the synthesis of the API,
    • changes in the composition or manufacture of the medicinal product  result in new degradation products or higher acceptance criteria,
    • the risk of cancer may be increased by changes in the indication or dosing regimen.

The guideline takes safety aspects and quality risk management into account when setting the limit value for mutagenic impurities, which is likely to be a negligible carcinogenic risk.

The mutagenicity of a substance is detected in a bacterial reverse mutation assay (Ames test). Structure-based assessments are useful for predicting toxicity and mutagenicity. Chemical compounds with similar structure and known toxicity profile provide indications. For this purpose, available literature can be evaluated and/or computer-aided toxicological tools (in-silico tools) can be used.

Classification of impurities with respect to mutagenic/carcinogenic potential and resulting control measures according to ICH M7:


How does GMP Publishing support you?

Together with our Spanish partner Atreiza, we prepare complete toxicological assessments that meet the requirements of ICH Q3A, Q3B and M7. You will receive a toxicological evaluation and an individual risk assessment for your medicinal product/API.


Our services:


Environmental Risk Assessment (ERA)

An evaluation of potential environmental risks, Environmental Risk Assessment (ERA), is mandatory for every application for a new marketing authorisation for a medicine for human use.

ERA refers to risks associated with the use, storage and disposal of pharmaceuticals and not to risks arising from the synthesis or manufacture of these products.

The requirements for the ERA are laid down in a guideline issued by the European Medicines Agency (EMA). The guide

  • describes the assessment strategy and the assessment scope
  • specifies the concrete data requirements for environmental exposure, fate and behaviour of the API in the environment as well as for its ecotoxicity

The examination shall take place in a two-stage procedure:

  • Phase I: Initial assessment of environmental impact
  • Phase II: In-depth environmental assessment (data on metabolism, excretion and degradability)

How does GMP publishing support you?

We can provide you with complete assessments on the analysis and evaluation of possible environmental risks of an API.

  • The ERA evaluations are carried out in accordance with the EMA guideline (EMEA/CHMP/SWP/4447/00 corr 2) in a two-stage procedure.
  • Risk assessment for each API using the latest version of the IQVIA database

The assessments are prepared by environmental toxicologists from our partner Atreiza with special expertise in the approval of new medicinal products. Over 50 assesments were prepared for European products last year.



Abbreviation Explanation
ADI Acceptable Daily Intake
IQVIA Service provider for information technology in healthcare (formerly Quintiles and IMS Health)
LTL Less than Lifetime (higher acceptance level for products with shorter duration of treatment)
PDE Permitted Daily Exposure
QSAR Quantitative Structure Activity Relationship
TTC Threshold of Toxicological Concern (limit value for an acceptable health risk for life-long exposure: 1.5µg/person/day)


You can find further information on our assessment service on our website under the heading "Toxicological assessments".

Your contact person for toxicological assessments is

Mrs. Cynthia Schulz
Phone: +49 7622 6668670
E-Mail: cynthia.schulz@gmp-publishing.com

Sabine Paris


Sabine Paris, PhD
Senior GMP Expert / Chief Editor of the GMP Compliance Adviser
E-Mail: sabine.paris@gmp-publishing.com