6.2 Risk Analysis and Regulations
As any pharmaceutical molecules, plant-based biologics may be associated with
some risks. In the particular case of plant-based pharmaceuticals, some specific
features have to be considered.
It is obvious that these products should be free of classic impurities described
in other recombinant product manufacturing and in the case of a biosimilar or
biobetter requires demonstration of substantial equivalence to any legally marketed
product. This means that the new product is at least as safe and effective as the
predicate. In the area of plant-derived biopharmaceuticals, the main safety issues to
be addressed could be the different post-translational modifications of the plant cell,
such as the N-glycosylation that may induce allergic responses (mainly superable
by glycoengineering of plant expression; see below).
The potential risk of impact on the environment is limited, since plant-based
pharma production is strictly regulated and mainly envisaged under GAP (Good
Agricultural Practices) and GMP indoor manufacturing. Transient expression
systems seem to pose some risks in that, while enabling the rapid and robust
production of target proteins, they require the large-scale use of A. tumefaciens or
viral vectors, which are the only real GMO involved in the process. Therefore, agroinfiltration is covered by the existing legislation and risk assessment as GM microorganisms in plants and therefore might not fall under the scope of the genetically
modified plant legislation (Sparrow et al. 2013).
The use of CRISPR-Cas9 systems may alleviate regulatory concerns related to
genetically modified plants. Beside CRISPR, also other new plant breeding techniques (NPBT) differ substantially from the transgenic techniques that have been
used in the last two to three decades. For some of them, the regulatory framework in
the EU may no longer be feasible. In fact, the nuclease techniques used for only point
mutations or a few nucleotide changes might be considered not to determine GMO
as no foreign DNA is integrated in the plant cell. NPBTs used, instead, for gene
integration are covered by the existing guidance for risk assessment and GMO
legislation as they do not differ from the integration of genes by transgenesis, even
though greatly enhancing the accuracy of gene integration at the target locus and
minimizing unattended side effects which might result in an easier risk assessment.
In the United States, the FDA ensures the safety of manufacturing (including
approval of GMP facilities for plant production) and clinical use of plantbased biopharmaceuticals before licensing. The US Department of Agriculture
(USDA) also plays a role in the introduction of plant-made pharmaceuticals, being
responsible of the control and approval of veterinary biologics through the control of
the genetic background of plants, the probability of cross-pollination and evaluating
risk-management strategies.
In the European Union, the European Food Safety Authority (EFSA) and the
European Medicines Agency (EMA) are in charge of the regulation concerning food
safety, hence transgenic plants cultivation, and concerning medicines, respectively.
Engineering Plants for the Future: Farming with Value-Added Harvest
93
As any pharmaceutical molecules, plant-based biologics may be associated with
some risks. In the particular case of plant-based pharmaceuticals, some specific
features have to be considered.
It is obvious that these products should be free of classic impurities described
in other recombinant product manufacturing and in the case of a biosimilar or
biobetter requires demonstration of substantial equivalence to any legally marketed
product. This means that the new product is at least as safe and effective as the
predicate. In the area of plant-derived biopharmaceuticals, the main safety issues to
be addressed could be the different post-translational modifications of the plant cell,
such as the N-glycosylation that may induce allergic responses (mainly superable
by glycoengineering of plant expression; see below).
The potential risk of impact on the environment is limited, since plant-based
pharma production is strictly regulated and mainly envisaged under GAP (Good
Agricultural Practices) and GMP indoor manufacturing. Transient expression
systems seem to pose some risks in that, while enabling the rapid and robust
production of target proteins, they require the large-scale use of A. tumefaciens or
viral vectors, which are the only real GMO involved in the process. Therefore, agroinfiltration is covered by the existing legislation and risk assessment as GM microorganisms in plants and therefore might not fall under the scope of the genetically
modified plant legislation (Sparrow et al. 2013).
The use of CRISPR-Cas9 systems may alleviate regulatory concerns related to
genetically modified plants. Beside CRISPR, also other new plant breeding techniques (NPBT) differ substantially from the transgenic techniques that have been
used in the last two to three decades. For some of them, the regulatory framework in
the EU may no longer be feasible. In fact, the nuclease techniques used for only point
mutations or a few nucleotide changes might be considered not to determine GMO
as no foreign DNA is integrated in the plant cell. NPBTs used, instead, for gene
integration are covered by the existing guidance for risk assessment and GMO
legislation as they do not differ from the integration of genes by transgenesis, even
though greatly enhancing the accuracy of gene integration at the target locus and
minimizing unattended side effects which might result in an easier risk assessment.
In the United States, the FDA ensures the safety of manufacturing (including
approval of GMP facilities for plant production) and clinical use of plantbased biopharmaceuticals before licensing. The US Department of Agriculture
(USDA) also plays a role in the introduction of plant-made pharmaceuticals, being
responsible of the control and approval of veterinary biologics through the control of
the genetic background of plants, the probability of cross-pollination and evaluating
risk-management strategies.
In the European Union, the European Food Safety Authority (EFSA) and the
European Medicines Agency (EMA) are in charge of the regulation concerning food
safety, hence transgenic plants cultivation, and concerning medicines, respectively.
Engineering Plants for the Future: Farming with Value-Added Harvest
93