Drug Regulators, Manufacturing, EMEA publish concept paper on using transgenic animals for biological manufacturing.

Following rapid changes in the area and products making it to the market (related article) The EMEA has published the following “CONCEPT PAPER ON THE NEED TO REVISE THE GUIDELINE ON THE USE OF TRANSGENIC ANIMALS IN THE MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (3AB7A OF JULY 1995)”

Introduction to Regulations

Recombinant proteins for medicinal use are routinely produced in bacterial or mammalian cell lines. The regulatory requirements to make and test the production lines and cell banks, and the subsequent manufacture and testing of the medicinal product are well established. Many relevant Guidelines are available for production in cell lines. An alternative production platform for recombinant proteins is transgenic animals, where a foreign gene, which codes for a therapeutically useful protein, is inserted into the genome of the chosen
species and is expressed under the close control of a promoter. The recombinant protein is generally expressed in some easily harvested body component such as milk or eggs and does not harm the animal.

The Problem to Tackle

A guideline was prepared by CPMP and entered into force in July 1995 (3AB7A). Although it contains advice which was useful for a technology platform which was in its infancy, since it came into force, this production method has progressed significantly and the guidance has not been revised to take account of these advances. The current guideline was prepared at a time when the scientific possibilities for transgenic animals were being investigated and no product had been generated for commercial or clinical trial purposes. In addition, many relevant guidelines, such as the ICH Q5 series had not been prepared.

Discussion on the Problem

It is proposed that the scope of the guidance covers the quality issues regarding biological active substances produced by the expression of one or more transgenes stably located in the genome of animals. Production using cloned animals falls outside the scope.

The following improvements to the published guideline have been identified:

• The current document contains too many references to the benefits of transgenic technology but is not sufficiently detailed technically. A complete re-write to bring the structure of the document in line with the current format of CHMP guidance documents is needed.
• The lay-out of the document is not logical or easy to follow. It is not broken down into logical sections which follow CTD headings and concepts.
• There is no specific section on pathogen safety.
• There is no discussion of specific Quality systems, particularly for generation of transgenic lines, breeding and maintenance of production animals.
• A discussion on product characterisation is omitted.
• Breeding strategy is not mentioned, nor the concept of master and working cell/transgenic banks.
• Control of active substance or raw material is not adequately covered.
• Advice on residual Host Cell Proteins and DNA is incomplete.
• Since products from transgenic animals are (to date) the product of sexual reproduction, and not of cloned animals, the potential inherent variability of transgenic proteins needs to be explicitly discussed and the regulatory requirements to map this variability should be updated.
• Advice on the information which is required regarding development genetics is confusing and should be clarified.
• Advice is given that material from different genetic lines should not be mixed when producing product for a single license. This advice needs to be reviewed in light of more recent regulatory considerations.

The Biologics Working Party recommends developing a guideline on the use of transgenic animals in the manufacture of biological medicinal products for human use to replace the existing guideline.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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