Elemental impurities: ICH Q3D has reached step 4 (final guideline)

As already pointed out in the GxP Audit News 5/13, elemental impurities (=heavy metals) play a key role in the update of the ICH Q3X series of regulations. ICH Q3D, which is aiming to control the level of metal impurities in medicinal products, has now reached step 4 (final guideline) after step 2b was entered in July 2013. The guideline consists of three parts:

  • evaluation of the toxicity data for potential elemental impurities,
  • establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern, and
  • application of a risk-based approach to control elemental impurities in drug products

and is going to be implemented subsequently, first for new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances.

According to the scope of the guideline, it applies to drug products containing
purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or non-recombinant origins),
their derivatives,
products of which they are components (e.g., conjugates)
synthetically produced polypeptides, polynucleotides, and oligosaccharides

The 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,
  • 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) (sometimes referred to as: advanced therapy medicinal products)
  • drug products used during clinical research stages of development

Compared to the step 2b version, quite some elemental impurity limits (PDEs) have been changed and this means mostly tightened. Since the related elements are used as e.g. catalysts in the synthesis of active pharmaceutical ingredients (APIs), it is strongly recommended to further evaluate the step 4 guideline limits in more detail on a case by case basis.

The application of the guideline to existing drug products “is not expected prior to 36 months after publication of the guideline by ICH” as per the scope of the guideline.
The adoption into regional regulations and pharmacopoeias, such as the European Pharmacopoeia (Pharm. Eur.) and United States Pharmacopoeia (USP), which had been deferred in Mid 2013, is now also expected to take place accordingly.

Revised EU GMP part I chapter 5 Production comes into operation 1st March 2015

The revised chapter 5 “Production” of EU GMP part I, published mid of August 2014, will come into operation 1st of March 2015. Besides changes to sections 17 to 21 (prevention of cross-contamination, reference to toxicological assessment), changes to sections 27 to 30 have been made in order to ensure that active substances are produced in accordance with GMP and to strengthen supply chain traceability. With regard to this, the role of GMP & GDP audits has been further underlined and confirmed: “Audits should be carried out at the manufacturers and distributors of active substances to confirm that they comply with the relevant good manufacturing practice and good distribution practice requirements” . . . . “Audits should be of an appropriate duration and scope to ensure that a full and clear assessment of GMP is made.” At the same time detailed knowledge about the full supply chain is expected: “Supply chain traceability should be established and the associated risks, from active substance starting materials to the finished medicinal product, should be formally assessed and periodically verified.”

Major GxP Events I & II/2015