Comparability of Biotechnological Products - New Guidance Documents from FDA and EMEA

GMP News No. 573

GMP News
4 July 2005

Comparability of Biotechnological Products –
New Guidance Documents from FDA and EMEA

Within the last months FDA and EMEA have put their regulatory focus on comparability and similarity of biotechnological/biological medicinal products.

Last week alone three new guidances – two draft, one final – were published by FDA and EMEA.

It is very important to clarify that these documents cover two completely different topics. Although the technical terms used within these documents might be identical.

One topic is the comparability of biotechnological products that are subject to process changes – before and after the change. The other one is the comparability of a reference biological medicinal product with a similar biological medicinal product.

Concerning the first issue, FDA has published the final Guidance for Industry "Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process". This ICH document came into operation in the European Union (EMEA) in June as well.

The aim of the proposed comparability studies is to show that pre- and post-change products have similar attributes concerning quality, safety and efficacy.

Some important statements of this comprehensive document should be pointed out:

  • Most of the subchapters end with the phrase "… it might be necessary to conduct nonclinical or clinical studies …". This is the worst-case scenario for process changes - a fact one has to keep in mind at the very beginning of considering a process change. Therefore, the first question you have to ask yourself is: What is the impact of the process change on quality findings, the nature and the level of knowledge about the product and the existing nonclinical and clinical data.
  • The guidance distinguishes clearly between marketed products and products in development. Process changes are expected in a much wider range during development. For early phases of nonclinical and clinical studies less extensive comparability studies are required.
  • Words that are used frequently in this guidance document are: justified, consideration, evaluation. Due to continuous brainwashing all people working in a GMP environment are aware of the importance of traceable documentation. But for the scientifically sound assessment of the change in the manufacturing process you will be glad if you get comprehensive documentation from your colleagues in R&D. So you better tell them in advance!

You can download the pdf version of the document here:

The draft guidelines that were released by EMEA last week deal with the issue of biosimilarity. Both documents "Guidance On Biosimilar Medicinal Products Containing Recombinant Granulocyte-Colony Simulating Factor" and a "Guidance On Biosimilar Medicinal Products Containing Recombinant Erythropoietins" are Annexes to the "Guideline On Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical And Clinical Issues". The deadline for comments is October 2005.

Due to the impressive number of papers that have been released by EMEA on biosimilarity it is important to understand their structure.

The core "Guideline on Similar Biological Medicinal Products" (CHMP/437/04) was released for consultation in November 2004. The phase for comments ended in February 2005. A final version has not been published yet.

Based on this document two further guidelines were brought out dealing with quality issues (EMEA/CHMP/BWP/49348/2005) and non-clinical and clinical issues (EMEA/CHMP/42832/2005). For the first one the deadline for comments was June 2005; for the second one it will be October 2005.

In addition EMEA has edited four annexes to the guideline on non-clinical and clinical issues focussing on certain biological medicinal products: Somatropin (EMEA/CHMP/94528/2005), Recombinant Human Insulin (EMEA/CHMP/32775/2005), Recombinant Erythropoietins (EMEA7CHMP/94526/2005) and the Recombinant Granulocyte-Colony Stimulating Factor (EMEA/CHMP/31329/2005).

All draft documents can be downloaded from the EMEA homepage at

It is crucial to know that there are extra guidelines on APIs. These documents cover both aspects of comparability exercises: due to process changes and for "similar" products. The Doc Refs are EMEA/CPMP/3097/02/Final and EMEA/CPMP/BWP/3207/00/Rev 1. Life could be so simple!

The new FDA and EMEA guidelines emphasise the importance of considering the influence of a change on all process steps.

As an example the FDA document states:

" … in some cases, divalent ions leached from the container closure system might change the stability profile because of the activation of trace proteases not detected in stability studies of the prechange product."

If you need a deeper insight into these complex matters we recommend you to attend ECA's European Conference "Fill and Finish for Biopharmaceuticals" in Schaffhausen/Zurich, Switzerland on 14-15 September 2005.

At this event all fundamental aspects of the late steps in biopharmaceutical production will be discussed in detail. Industry experts will introduce you to state-of-the-art solutions that have stood the test in leading pharmaceutical companies.

Author: Dr. Ulrich Herber, CONCEPT HEIDELBERG

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