The statute-conformance review procedures practiced by the regulatory agencies require considerable time because the laws were established to focus on patient safety, product quality, verification of efficacy, and truth in labeling. The median times required by the FDA, EMA, and Health Canada for full review of NDA applications were reported to be 322, 366, and 352 days, respectively . Collectively, typical interactions with regulatory agencies will add more than 1 year to a drug development program. Although these regulatory timelines are the status quo during normal times, they are clearly incongruous with the needs for rapid review, approval, and deployment of new products in emergency use scenarios, such as emerging pandemics.Plant-made intermediates, including reagents for diagnostics, antigens for vaccines, and bio-active proteins for prophylactic and therapeutic medical interventions, as well as the final products containing them, are subject to the same regulatory oversight and marketing approval pathways as other pharmaceutical products. However, the manufacturing environment as well as the peculiarities of the plant-made active pharmaceutical ingredient can affect the nature and extent of requirements for compliance with various statutes, which in turn will influence the speed of development and approval. In general, the more contained the manufacturing process and the higher the quality and safety of the API, the easier it has been to move products along the development pipeline. Guidance documents on quality requirements for plant-made biomedical products exist and have provided a framework for development and marketing approval . Upstream processes that use whole plants grown indoors under controlled conditions,drainage pot including plant cell culture methods, followed by controlled and contained downstream purification, have fared best under regulatory scrutiny. This is especially true for processes that use non-food plants such as Nicotiana species as expression hosts.

The backlash over the Prodigene incident of 2002 in the United States has refocused subsequent development efforts on contained environments . In the United States, field-based production is possible and even practiced, but such processes require additional permits and scrutiny by the United States Department of Agriculture . In May 2020, to encourage innovation and reduce the regulatory burden on the industry, the USDA’s Agricultural Plant Health Inspection Service revised legislation covering the interstate movement or release of genetically modified organisms into the environment in an effort to regulate such practices with higher precision [SECURE Rule revision of 7 Code of Federal Regulations 340].4 The revision will be implemented in steps and could facilitate the field based production of PMPs. In contrast, the production of PMPs using GMOs or transient expression in the field comes under heavy regulatory scrutiny in the EU, and several statutes have been developed to minimize environmental, food, and public risk. Many of these regulations focus on the use of food species as hosts. The major perceived risks of open-field cultivation are the contamination of the food/feed chain, and gene transfer between GM and non-GM plants. This is true today even though containment and mitigation technologies have evolved substantially since those statutes were first conceived, with the advent and implementation of transient and selective expression methods; new plant breeding technologies; use of non-food species; and physical, spatial, and temporal confinement . In the United States, regulatory scrutiny is at the product level, with less focus on how the product is manufactured. In the EU, much more focus is placed on assessing how well a manufacturing process conforms to existing statutes. Therefore, in the United States, PMP products and reagents are regulated under pre-existing sections of the United States CFR, principally under various parts of Title 21 , which also apply to conventionally sourced products. These include current good manufacturing practice covered by 21 CFR Parts 210 and 211, good laboratory practice toxicology , and a collection of good clinical practice requirements specified by the ICH and accepted by the FDA .

In the United States, upstream plant cultivation in containment can be practiced using qualified methods to ensure consistency of vector, raw materials, and cultivation procedures and/or, depending on the product, under good agricultural and collection practices . For PMP products, cGMP requirements do not come into play until the biomass is disrupted in a fluid vehicle to create a process stream. All process operations from that point forward, from crude hydrolysate to bulk drug substance and final drug product, are guided by 21 CFR 210/211 . In Europe, bio-pharmaceuticals regardless of manufacturing platform are regulated by the EMA, and the Medicines and Healthcare products Regulatory Agency in the United Kingdom. Pharmaceuticals from GM plants must adhere to the same regulations as all other biotechnology-derived drugs. These guidelines are largely specified by the European Commission in Directive 2001/83/EC and Regulation No 726/2004. However, upstream production in plants must also comply with additional statutes. Cultivation of GM plants in the field constitutes an environmental release and has been regulated by the EC under Directive 2001/18/EC and 1829/2003/EC if the crop can be used as food/feed . The production of PMPs using whole plants in greenhouses or cell cultures in bioreactors is regulated by the “Contained Use” Directive 2009/41/EC, which are far less stringent than an environmental release and do not necessitate a fully-fledged environmental risk assessment. Essentially, the manufacturing site is licensed for contained use and production proceeds in a similar manner as a conventional facility using microbial or mammalian cells as the production platform. With respect to GMP compliance, the major differentiator between the regulation of PMP products and the same or similar products manufactured using other platforms is the upstream production process. This is because many of the DSP techniques are product-dependent and, therefore, similar regardless of the platform, including most of the DSP equipment, with which regulatory agencies are already familiar. Of course, the APIs themselves must be fully characterized and shown to meet designated criteria in their specification, but this applies to all products regardless of source.During a health emergency, such as the COVID-19 pandemic, regulatory agencies worldwide have re-assessed guidelines and restructured their requirements to enable the accelerated review of clinical study proposals, to facilitate clinical studies of safety and efficacy, and to expedite the manufacturing and deployment of re-purposed approved drugs as well as novel products .

These revised regulatory procedures could be implemented again in future emergency situations. It is also possible that some of the streamlined procedures that can expedite product development and regulatory review and approval will remain in place even in the absence of a health emergency, permanently eliminating certain redundancies and bureaucratic requirements. Changes in the United States and European regulatory processes are highlighted, with a cautionary note that these modified procedures are subject to constant review and revision to reflect an evolving public health situation.In the spring of 2020, the FDA established a special emergency program for candidate diagnostics, vaccines, and therapies for SARS-CoV-2 and COVID-19. The Coronavirus Treatment Acceleration Program 5 aims to utilize every available method to move new treatments to patients in need as quickly as possible, while simultaneously assessing the safety and efficacy of new modes of intervention. As of September 2020, CTAP was overseeing more than 300 active clinical trials for new treatments and was reviewing nearly 600 preclinical-stage programs for new medical interventions. Responding to pressure for procedural streamlining and rapid response, the FDA refocused staff priorities,drainage planter pot modified its guidelines to fit emergency situations, and achieved a remarkable set of benchmarks . In comparison to the review and response timelines described in the previous section, the FDA’s emergency response structure within CTAP is exemplary and, as noted, these changes have successfully enabled the rapid evaluation of hundreds of new diagnostics and candidate vaccine and therapeutic products.The European Medicines Agency has established initiatives for the provision of accelerated development support and evaluation procedures for COVID-19 treatments and vaccines. These initiatives generally follow the EMA Emergent Health Threats Plan published at the end of 2018 . Similar to FDA’s CTAP, EMA’s COVID-19 Pandemic Emergency Task Force aims to coordinate and enable fast regulatory action during the development, authorization, and safety monitoring of products or procedures intended for the treatment and prevention of COVID-19 . Collectively, this task force and its accessory committees are empowered to rapidly address emergency use requests . Although perhaps not as dramatic as the aspirational time reductions established by the FDA’s CTAP, the EMA’s refocusing of resources and shorter response times to accelerate the development and approval of emergency use products are nevertheless laudable. In the United Kingdom, the MHRA6 has also revised customary regulatory procedures to conform with COVID-19 emergency requirements by creating 6 MHRA regulatory flexibilities resulting from coronavirus .During a public health emergency, one can envision the preferential utilization of existing indoor manufacturing capacity, at least in the near term. Processes making use of indoor cultivation and conventional purification can be scrutinized more quickly by regulatory agencies due to their familiarity, resulting in shorter time-to-clinic and time-to-deployment periods. Although many, perhaps most, process operations will be familiar to regulators, there are some peculiarities of plant-based systems that differentiate them from conventional processes and, hence, require the satisfaction of additional criteria. Meeting these criteria is in no way insurmountable, as evidenced by the rapid planning and implementation of PMP programs for SARS-CoV-2/COVID-19 by PMP companies such as Medicago, iBio, and Kentucky Bio-processing.

During emergency situations when speed is critical, transient expression systems are more likely to be used than stable transgenic hosts, unless GM lines were developed in advance and can be activated on the basis of demand . The vectors used for transient expression in plants are non-pathogenic in mammalian hosts and environmentally containable if applied indoors, and by now they are well known to the regulatory agencies. Accordingly, transient expression systems have been deployed rapidly for the development of COVID-19 interventions. The vaccine space has shown great innovation and the World Health Organization has maintained a database of COVID-19 vaccines in development,8 including current efforts involving PMPs. For example, Medicago announced the development of its VLP-based vaccine against COVID-19 in March 2020, within 20 days of receiving the virus genome sequence, and initiated a Phase I safety and immunogenicity study in July.9 If successful, the company expects to commence Phase II/III pivotal trials by late 2020. Medicago is also developing therapeutic antibodies for patients infected with SARS-CoV-2, and this program is currently in preclinical development. Furthermore, iBio has announced the preclinical development of two SARS-CoV-2 vaccine candidates, one VLP and one subunit vaccine.10 Kentucky Bio-processing has announced the production and preclinical evaluation of a conjugate TMV-based vaccine and has requested regulatory authorization for a first in-human clinical study.These efforts required only a few months to reach these stages of development and are a testament to the rapid expression, prototyping, and production advantages offered by transient expression.The PMP vaccine candidates described above are all being developed by companies in North America. The rapid translation of PMPs from bench to clinic reflects the conformance of chemistry, manufacturing, and control procedures on one hand, and environmental safety and containment practices on the other, with existing regulatory statutes. This legislative system has distinct advantages over the European model, by offering a more flexible platform for discovery, optimization, and manufacturing. New products are not evaluated for compliance with GM legislation as they are in the EU and the United States but are judged on their own merits. In contrast, development programs in the EU face additional hurdles even when using well-known techniques and even additional scrutiny if new plant breeding technologies are used, such as the CRISPR/Cas9 system or zinc finger nucleases .Process validation in manufacturing is a necessary but resource intensive measure required for marketing authorization. Following the publication of the Guidance for Industry “Process Validation: General Principles and Practices,” and the EU’s revision of Annex 15 to Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use, validation became a life-cycle process with three principal stages: process design, process qualification, and continuous process verification . During emergency situations, the regulatory agencies have authorized the concurrent validation of manufacturing processes, including design qualification , installation qualification , operational qualification , and performance qualification .