Regulatory Focus™ > News Articles > Researchers Call for New Regulatory Framework for Transgenic Plant-Derived Products

Researchers Call for New Regulatory Framework for Transgenic Plant-Derived Products

Posted 21 February 2013 | By

Drug manufacturing-the regulator-approved pharmaceutical type, anyways-has traditionally been conducted at inspected facilities large and small. Everything from small compounding facilities and mid-sized laboratories to massive manufacturing plants have churned out medical products for the world. But how do you regulate a manufacturing plant that's quite literally a plant?

Call it pharming, if you will.

Around the world, manufacturers are already experimenting-and in some cases, obtaining approval for-plant-derived pharmaceutical products made from transgenic plants. These plants literally grow active pharmaceutical ingredients. That part isn't necessarily new, as most pharmaceutical ingredients have historically come from plants or plant byproducts.

The difference between historical methods and future ones, the authors of a study soon to be published in the journal Current Pharmaceutical Designexplained, are the possibilities afforded to them. Whereas in the past, researchers were in many ways limited to reproducing compounds already found in plants, they are now able to grow products not found in nature.

"This allows us to produce a wide variety of pharmaceuticals including vaccines, antibodies and enzymes in a plant species of our choice," explained Drs. Penny Sparrow, Joachim Schiemann, Julian Ma and Maurice Moloney in an interview with the group Sense About Science. "Essentially, we are using plants as cell factories to manufacture these pharmaceuticals."

Emerging Challenges for Regulators

The framework for regulating this method of development is still very much in its infancy, the authors noted.

The first plant-made pharmaceutical in the US, protein-based Elelyso (taliglucerase alfa) for Gaucher disease, was approved in 2012 by the US Food and Drug Administration. Several other plant-made pharmaceuticals (PMPs) have been approved or are under development in the EU as well, including an insulin product.

Derived from transgenic carrot cells, Elelyso avoids needing to be produced in bioreactors where it would be far more susceptible to contamination by viruses or other contaminants.

Difficulties of Scale

But producing these types of products at scale poses difficulties. Elelyso's patient population barely numbers 6,000 in the US. At that scale, a company might be able to raise the transgenic carrots inside a tightly controlled facility.

But what if the same technology was used for a more prevalent disease whose patients number in the millions?

"The decision on the plant production platform and the necessary containment (bioreactor, greenhouse, open field) depends on the nature of the product, its value and the amount to be produced," explained Schiemann. "This will be a case-by-case decision, mainly based on biosafety considerations."

The authors explained that insulin, one of the most commonly used proteins, is a perfect example of the larger manufacturing needs of some proteins. To produce the entire supply of insulin would take, in their estimation, around 16,000 acres of land-far beyond the capacities of a single greenhouse. Smaller protein products, such as EPI (erythropoietin), could be grown inside a 20,000-square foot greenhouse.

Security Considerations

But both examples raise a larger point: How do you secure these sorts of facilities and their products?

The researchers said security over the plant product is of the utmost importance, both for ensuring the safety of patients and the maintenance of current good manufacturing practices.

"The biggest perceived risk is 'What if these crops accidentally end up in the food chain?' Regulatory oversight would mean that a zero tolerance threshold would be in place to ensure the likelihood of such occurrence did not happen (as opposed to GM agricultural crops where there is a minimum threshold level for inadvertent mixing - as these crops have been evaluated as safe for the food/feed chain)," explained Sparrow.

"In the case of open field production (e.g. future production of human insulin in genetically modified safflower plants) the production chain has to be separated from other agricultural production chains," added Schiemann. "Of course, the safety requirements have to be different from insulin production in bioreactors or in the greenhouse. Irrespective of biosafety aspects, intermingling of food/feed products with pharmaceuticals has to be avoided."

Other Regulatory Aspects

Aside from manufacturing, however, the products are virtually identical to other products in terms of their regulatory considerations, said Moloney.

"It would be inconceivable at this time to suggest that a new plant-made pharmaceutical would not be subject to clinical trials. They are treated exactly like pharmaceuticals from any other source and follow the same regulatory path."

This includes showing that a plant-derived insulin product, for example, is bioequivalent to one derived from animal-based proteins.

This could be good news for the biopharmaceutical industry, as the researchers noted that "many types of medical conditions" could stand to benefit from this type of product development.

There will, however, be an overlap between various regulatory authorities, they said. In the EU, manufacturers will have to deal with both medical and agricultural regulators to ensure that a product does not enter the food supply. In the US, manufacturers may have to deal with the US Department of Agriculture as well as FDA for the same reason.

Need for New Regulations?

But even if the regulations can accommodate pharmaceutical-producing transgenic products, the authors said improvements are necessary.

"Openness and transparency are needed to develop new regulations that work for the public and for investors," said Sparrow. "Regulations need to be harmonized across the world, in order to keep advances and competition on a level playing field."

With a particular eye toward the EU, the researchers said EU Directive 2001/18 needs to be updated to allow for manufacturers to get a product approved without having to deal with agricultural regulators so long as they meet "clearly defined and enforced conditions" regarding their use and sale.

"Measures can include those adopted in the US, such as limited acreage, confinement, fallow zones and only supplying seed to farmers specifically contracted to grow PMPs."

"We need tight regulations enforced by continuous oversight to encourage investment, while maintaining trust," said Sparrow. "To make progress in this area we need to make sure [regulations] are applied sensibly to allow pharmaceuticals to be produced in plants."

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