03.05.2017 |

LOGFILE No. 17/2017 – Chemical Active Substances - Special Risks

Chemical Active Substances – Special Risks

An excerpt from the GMP Series Practice Guide for Conducting Audits of Chemical Active Substance Manufacturers

4 min. reading time

by Stefan Kettelhoit, PhD

In 2012 the ICH published Guideline Q 11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities), which focuses more on the development of active substances, for which reason it engages much earlier in the life cycle of an active substance.

The primary emphasis of this guideline is on identifying the critical product features of active substances. Impurities are considered to be one of these critical product features. According to the Guide: “Impurities are an important class of potential drug substance CQAs because of their potential impact on drug product safety. For chemical entities, impurities can include organic impurities (including potentially mutagenic impurities), inorganic impurities e.g., metal residues, and residual solvents (see ICH Q3A and Q3C).”

Accordingly, the ICH fundamentally subdivides impurities for chemical active substances into the following categories:

  • Organic impurities
  • Inorganic impurities
  • Residual solvents

The ICH guidelines of the Q3X series (i.e. currently ICH Q3A, ICH Q3B, ICH Q3C and draft ICH Q3D) deal with these possible impurities.

How these impurities occur and what control strategies must be developed as a result will be explained below.

Figure 10 shows that impurities can result from the manufacturing process itself or from degradation processes, and they can be organic or inorganic.


The inherent properties of chemical synthesis steps pose special risks: This type of synthesis typically involves several steps in organic solvents, with metallic catalysts being used under increased or reduced pressure and/or at higher or lower temperatures.

There are very few instances in which the reaction can be carried out with a 100% yield of (C) in a clear, stereoselective reaction equation such as the one given below:

reactant (A) + reactant (B) = product (C)

Chemical reactions often result in complex mixtures of reactants (including any impurities) formed during or after the reaction takes place, such as (A), (B), (C) in the solvent or the solvent mixture with additional auxiliary processing agents if applicable and/or catalysts and reaction by-products (E) - (X). Many active substance operations are run as multipurpose sites/plants, with the consequence that parts or all of entire process equipment streams/trains are used in a vast range of synthesis steps for intermediates or finished products. As a result, additional potential impurities (undesired, of course) and/or degradation products that appear after the preliminary products have been purified have to be taken into account.

A wide variety of actions can be taken to deal with these special risks. Certain categories of active substances, such as

  • Sensitising/allergenic antibiotics (such as those of the beta-lactam type)
  • Hormones (e.g. highly effective oestrogens, gestagens or androgens)
  • Cytotoxic substances (e.g. alkylating agents, platinum analogues, intercalate substances, antimitotics, taxanes, topoisomerase inhibitors or antimetabolites) and
  • Other highly effective substances

must be manufactured in specially dedicated or segregated self-contained facilities, in order to rule out any cross-contamination with these substances. Special attention should also be paid to cleaning validation in multipurpose plants: To avoid cross-contamination the effectiveness of the cleaning procedure must be substantiated here, not only for undesirable microbial impurities or reaction by-products and degradation products, but also for impurities from the preliminary product.

Taking these general quality-assurance actions ensures that the quality of a monographed active substance can be adequately monitored in keeping with the state of the art for a known chemical synthesis scheme by maintaining an appropriate, GMP-compliant quality assurance system and following the general and special testing procedures stipulated in the current version of the European Pharmacopoeia.

The general monographs are applicable in addition to the specific substance monographs of the European Pharmacopoeia. Particularly Monograph 2034, Substances for Pharmaceutical Use, with its general requirements and references to specific tests, should be taken into account in this connection. Experience has shown that this monograph is often not given adequate consideration, especially in third countries. It applies primarily to “any organic or inorganic substances that are used as active substances or excipients for the production of medicinal products for human or veterinary use […] obtained from natural sources or produced by extraction from raw materials, fermentation or synthesis”. In addition to general explanations, references to specific pharmacopoeial methods are also found here (see the numbering given below).

Limit values for the following tests are also given in individual cases:

  • Polymorphism, 5.9
  • Related substances, 5.10 (in active substances and/or peptide active substances)
  • Residual solvents, 5.4 / 2.4.24
  • Microbiological quality, 5.1.4
  • Sterility, 2.6.1
  • Bacterial endotoxins, 2.6.14
  • Pyrogens, 2.6.8
  • Additional properties such as e.g. assay, labelling etc.

As illustrated above, impurities resulting from synthesis pose special risks for chemical active substances. Such impurities include:

  • Genotoxic or potentially genotoxic substances (impurities or synthesis by-products)
  • Residual solvents
  • Heavy metals or residues from metal catalysts



The PDF-Download Practice Guide for Conducting Audits of Chemical Active Substance Manufacturersleads you step-by-step through the following key issues:

Auditing active substance manufacturers

  • Regulatory requirements and professional prerequisites
  • Active substances from Europe and/or third countries (such as China or India)
  • Audits
  • Third-party audits
  • Audit checklists

Chemical active substances

  • What are chemical active substances
  • Definition of terms
  • Scope of GMP regulations
  • Basic GMP requirements
  • Special Risks
  • Typical GMP deficiencies in chemical active substance manufacturing


Dr. Stefan Kettelhoit
Hermann Bock GmbH, Verl