The European Medicines Agency (EMEA) published a set of five final guidelines on similar biological medicinal products. They are intended to give guidance to industry in the development of this new type of applications for marketing authorisation.

They give guidance on quality, non-clinical and clinical issues. The product class specific annexes to the guideline on non-clinical and clinical issues give guidance for certain classes of medicines: those containing insulin, containing somatropin and those containing recombinant granulocyte-colony stimulating factor (an annex for medicines containing epoetin will also be available soon). The guidelines come into effect from June 1, 2006.

EMEA has also published two new concept papers. The first is a concept paper on comparability of biotechnology-derived medicinal products after a change in the manufacturing process (non-clinical and clinical issues). The second is a concept paper on immunogenicity assessment of therapeutic proteins.

The guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance addresses (a) when a change is introduced in the manufacturing process of a given product (either before the granting of a marketing authorization or after the granting of a marketing authorization) and (b) when a product is claimed to be similar to another one already authorized in the EU after the expiry of the data protection period.

The guideline addresses the requirements regarding manufacturing processes, the comparability exercise for quality, considering the choice of reference product, analytical methods, physicochemical characterization, biological activity, purity and specifications of the similar biological medicinal product. A company may choose to develop a new biological medicinal product claimed to be similar (Similar Biological Medicinal Product) in terms of quality, safety and efficacy to an original, reference medicinal product, which has been granted a marketing authorization in the EC.

Similar biological medicinal products are manufactured and controlled according to their own development, taking into account relevant and up-to-date information. Comparison can be made against the official data, e.g. pharmacopoeial monographs or against other published scientific data. However, such comparisons at the level of both active substance and finished product are limited and not sufficient to establish all aspects pertinent to the evaluation. Consequently, an extensive comparability exercise will be required to demonstrate that the similar biological medicinal product has a similar profile in terms of quality, safety and efficacy to the reference medicinal product.

The manufacturer developing similar biological medicinal products would normally not have access to all necessary information that could allow an exhaustive comparison with the reference medicinal product. Nevertheless the level of detail must be such that firm conclusions can be made. Based on the comparability approach and when supported by sufficiently sensitive analytical systems, the comparability exercise at the quality level may allow a reduction of the non-clinical and clinical data requirements compared to a full dossier.

The similar biological medicinal product may refer to the non-clinical and clinical data previously generated with the reference product; however, non-clinical and clinical data will normally be required as identified in related non-clinical and clinical guidelines on similar biological medicinal products.

The guideline addresses quality issues during demonstration of comparability for Similar Biological Medicinal Products containing recombinant DNA-derived proteins. As a consequence, the principles adopted and explained in this document apply to proteins and peptides, their derivatives and products of which they are components (e.g. conjugates).

The similar biological medicinal product, as for any other biological medicinal product is in part defined by its own specific manufacturing process for both active substance and medicinal product. These processes should be developed and optimized taking into account state-of-the-art information on manufacturing processes (i.e. expression system / cell substrate, culture, purification, viral safety, excipients, formulation, primary packaging interactions, etc.) and consequences on product characteristics.

In addition, each medicinal product is defined by the molecular composition of the active substance resulting from its process, which may introduce its own process related impurities. Consequently, the similar biological medicinal product is defined by the following two sets of characteristics: i) related to the characteristics of the molecule (including product related substances/impurities), and ii) related to its process (which may affect molecular characteristics and includes process related impurities).

The Applicant must demonstrate the consistency and robustness of his own process according to existing guidelines. Formulation studies should be considered in the course of the development of a suitable dosage form, even if excipients are qualitatively and quantitatively the same as the reference product. These studies should demonstrate the suitability of the proposed formulation with regards to stability, compatibility (i.e. with excipients, diluents and packaging materials), and integrity of the active substance (both biologically and physico-chemically) for its intended medicinal use.

As is the case for any biotechnology-derived medicinal product, a comparability exercise should be considered when a change is introduced into the manufacturing process (active substance and finished product) during development. For the purposes of clarity, any comparability exercise(s) for process changes introduced during development should be clearly identified and addressed separately from the comparability exercise versus the reference product. It is not expected that the quality attributes in the similar biological and reference medicinal products will be identical.

Adopted Guidelines

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