New EMA Reflection Paper on Heparin and further Biological Starting Materials

With our GMP News from 29 February 2012 about FDA's Draft Guidance on the qualification of Heparin manufacturers, we've informed you about the latest FDA requirements. The link given in the FDA Draft Guidance to the analytical method is no longer valid. Instead, the analytical procedure for the testing of the quality of Heparin is available via the document Laboratory Procedure - Analysis of Crude Heparin by HPLC/SAX for Oversulfated Chondroitin Sulfate.

The Europeans also published a document on 16 February 2012 entitled "Reflection Paper on the use of starting materials and intermediates collected from different sources in the manufacturing of biological medicinal products".

This reflection paper essentially concerns the following three categories of biological products:

  • Heparin
  • Urine derived products
  • Plasma derived products.

For certain products such as Heparin, the difficulty in finding starting materials suppliers in the EU is increasing. Besides, manufacturers inevitably need to have several suppliers to ensure product supply through flexibility of sourcing in the biological substances.

The reflection paper addresses to what extent any variability may be acceptable in the early manufacturing steps. This can also be applied to other products like insulin and pancreatin from porcine pancreas.

Porcine mucosa is defined as the starting material for any Heparin. Different intermediates may result from various manufacturing processes. Nevertheless, these process intermediates cannot be considered as starting materials. Module 3 of the marketing authorization dossier should cover the whole manufacturing process starting from the sourcing of the mucosa. This includes species and country of origin, traceability from slaughterhouses/abattoirs and confirmation that the animals used are fit for human consumption.

Paragraph 4.2. of the document specifies that a so-called "early intermediate" can be defined composed of starting materials from different manufacturers. This procedure should however be well defined and its quality control and qualification a key step in the manufacturing process of the medicinal product.

The consequences of the heparin scandal will be dealt with at the 3rd Anti-Counterfeit Conference of the University of Würzburg. Read more about this conference featuring speakers of the FDA, the EDQM and from the pharmaceutical industry (Merck, Bayer, Novartis) at:

Please also see the EMA Reflection paper on the use of starting materials and intermediates collected from different sources in the manufacturing of biological medicinal products for further information.

Günter Brendelberger
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)

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