Medical Device Link.

Originally Published IVD Technology September 2003

Commentary

Lon Crosby, PhD, is the director of research and development at Numedloc Inc. (Webster City, IA), a technology consulting firm. He can be reached via e-mail at lon.crosby@ starband.net.

Imagine gaining access to a market of 2400 new tests during the next decade. Would IVD manufacturers ignore it or embrace it? Presumably, they would welcome it with open arms. But what if this new market involved a number of special issues? Would manufacturers still be willing to cooperate with other companies to create standards and establish systems for this new market? 

The production of agricultural transgenic pharmaceuticals is rapidly emerging. The fact that agricultural crops have been genetically engineered to produce pharmaceuticals is not surprising since about half of the pharmaceuticals were originally derived from biological sources. Hence, all drugs could be produced from agricultural crops by transferring the appropriate genes. 

With the completion of human, animal, plant, microbial, and other genomes, the development of biological-based drugs is expected to mushroom. It has been predicted that 400 pharmaceuticals will be directly produced from agricultural crops within a decade. To produce these 400 drugs, at least 2400, and more likely 4000, compounds will have to go through the entire drug development process, including field production.¹

The rapid growth of this market is also not surprising when considering simple economics. Producing a transgenic pharmaceutical from agricultural crops reduces production costs by 75–95%, compared with existing production approaches of transgenic fermentation and transgenic cell culture.² In addition, using the transgenic agricultural approach offers technical advantages related to drug safety.

Recognizing this emerging trend, the Center for Biologics Evaluation and Research at FDA released draft good guidance practices (GGP) regulations for transgenic agricultural pharmaceuticals last September.³ While the public comment period ended in January, FDA indicated at a public forum last November that it would try to publish final GGP regulations soon enough so that those companies that are prepared could begin commercial production in 2004. The U.S. Department of Agriculture (USDA) has also solicited public comment on this issue.

What is interesting to note in this draft GGP is that the second paragraph in section II.C.1 states: “We strongly recommend that [manufacturers] have tests available that can detect the presence of the target gene and the protein product in the raw agricultural commodity.” 

While this statement refers only to proteins since all of the first-generation drugs being developed using transgenic technology are proteins, there are many drugs also being developed in 100 other different classes including complex molecules such as antibodies, vaccines, steroids, and lipid-soluble chemicals.

FDA has made it clear that the availability of rapid field tests that are used while these drugs are being developed is a vital requirement to ensure worker safety, process safety, and environmental safety. Moreover, these tests will improve production efficiencies and improve profitability.

The Need for Tests

The gene expression rates, as defined by the amount of the target drug in the crop component of interest, are currently 0.2% (or two parts per thousand). At these rates, all personnel in production, field management, and regulatory affairs may be exposed to potentially therapeutic doses of a drug during the various operations and inspection stages. This is especially true considering the amount of a drug required to elicit an acute reaction in sensitized individuals can be astonishingly small. Plant effects are well known. For example, when farm workers walk through a wet tobacco field, their clothes, and consequently their skin, absorb the surface moisture which is in chemical equilibrium with the tobacco plant’s intracellular nicotine. This leaves them susceptible to green tobacco disease (i.e., nicotine toxicity). 

During the various production operations, plant residues can end up on the exterior surfaces of the machinery. Plant residues can also end up on the inside and outside of harvesting machines during harvest. Field tests are needed to document cleaning and chemical decontamination procedures in both of these situations.

Moreover, manufacturers should consider the implications of developing an agronomic production scheme that could increase the gene expression rate in a crop, and how that would affect drug extraction costs. Simple, rapid tests for each drug provide the tools needed to enable such developments.

Crop producers also have special testing needs. The pharmaceutical crops being grown have substantial value. However, genetic engineering invariably creates management problems such as reduced crop vigor or increased disease susceptibility. Hence, crop producers need tests that can identify these problems and define appropriate interventions. There is also a need for field-deployed tests of plant health and for specific plant diseases.

The inclusion of field tests within the draft GGP is significant. These tests are going to become an integral part of the current good manufacturing practices (CGMPs) for agricultural transgenic drugs.⁴ Presumably, the results of these tests will also become part of an electronic database and subject to requirements for electronic records, according to the Code of Federal Regulations.⁵ A level of sophistication will evolve, including quality assurance and quality control requirements for both the tests and the devices used to read them. This sophistication also extends to the creation of databases and data warehouses.

A Multidepartmental Effort

At a public forum held last November, FDA stated that it will regulate the agricultural transgenic pharmaceutical industry as an extension of the transgenic fermentation industry, as opposed to an extension of the food/feed industry. In the agency’s words, that means zero tolerance, zero cross-contamination, verification of all activities, and more.

While FDA has the lead regulatory responsibility in this industry, USDA and Environmental Protection Agency (EPA) will also be playing roles. USDA in particular has already been extensively involved in this area. In 2002, the department released guidelines on the production of seed planted for transgenic crops, which provides some background information.⁶ USDA also maintains a database that lists all of the permits issued for the outdoor production of transgenic crops.⁷ At a recent public forum, USDA indicated that there were at least 20 active permits for producing pharmaceuticals in corn. At the same time, an industry report pegs the actual number of drugs currently in late-stage development at 100.⁸

USDA’s and EPA’s history of involvement in agricultural and environmental issues is also going to come into play in the agricultural transgenic pharmaceutical industry. While some are seeking more-stringent requirements, it is safe to assume that basic concepts such as soil testing for nutrients (e.g., nitrogen, potassium, phosphates, etc.) and monitoring agricultural chemicals in the run-off from fields for both nutrients and chemicals used in production (e.g., herbicides, insecticides, etc.) will be integral components of the pharmaceutical crop production process. Even though some of these field tests are already commercially available, meeting GMP requirements will require a significant upgrade.

A Common Reader

Skipping ahead a few years, imagine a government official being in charge of inspecting agricultural fields used to produce drugs that are currently in commercial production and in the medical marketplace. This official might have oversight responsibility for 150 drugs produced by 50 different pharmaceutical companies, covering 450,000 production acres and 10,000 individual fields. These fields could range in size from 10 to 500 acres, and could be scattered over many states because of the need to control environmental risk. Therefore, each field official may well have to inspect fields producing 100 different drugs during the course of a month. USDA has in fact said that its inspectors will visit each production field five times during the 2003 crop production year, and two times the following year to check for gene escapes. Rather than 150 unique instruments each with a separate test, what is preferable is a common reader that could handle all of the tests in one device. 

A production manager in charge of pharmaceuticals in the development phase faces even greater challenges with 10 times the number of drugs that need to be tested. A common system would make life easier for everyone involved. 

The single system that would make the most sense for field use is a reader for chemical and immunochemical test strips. A properly designed reader would allow the generation of quantitative data from relatively simple chemical and immunochemical strip tests. The technology for such a reader is already mature and powerful.⁹

The trick is designing a robust system that meets GMP requirements for accuracy, repeatability, quality assurance, and traceability. Such a system requires a number of elements, including the strip, the reader, temporary databases, long-term data warehouses, and test traceability capabilities. While designing such a system is not that difficult, it is a different approach than has been used historically within the IVD industry. 

References

1. L Crosby, “Commercial Production of Transgenic Crops Genetically Engineered to Produce Pharmaceuticals,” BioPharm Magazine 16, no. 4 (2003) 60–67.

2. D Mison, J Curling, “The Industrial Production Costs of Recombinant Therapeutic Proteins Expressed in Transgenic Corn,” BioPharm Magazine 13, no. 5 (2000) 48–54.

3. Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals, [on-line] (Rockville, MD: Food and Drug Administration, 2002 [cited 8 August 2003]); available from Internet: www.fda.gov/cber/gdlns/bioplant.htm.

4. Code of Federal Regulations, 21 CFR 210–211, [on- line] (Rockville, MD: Food and Drug Administration, 1996 [cited 11 August 2003]); available from Internet: www.fda.gov/cder/ dmpq/cgmpregs.htm.

5. Title 21 Code of Federal Regulations (21 CFR Part 11) Electronic Records; Electronic Signatures, [on-line] (Rockville, MD: Food and Drug Administration, 2000 [cited 11 August 2003]); available from Internet: www.fda.gov/ora/ compliance_ref/part11/.

6. Summary of Confinement Measures for Organisms Producing Potential Pharmaceuticals, [on-line] (Washington, DC: U.S. Department of Agriculture, 2002 [cited 11 August 2003]); available from Internet: www.aphis.usda.gov/ ppq/biotech/pdf/pharm-2002.pdf. 

7. Field Test Releases in the U.S., [on-line] (Blacksburg, VA: Virginia Polytechnic Institute and State University, 2003 [cited 11 August 2003]); available from Internet: http:// www.nbiap.vt.edu/cfdocs/fieldtests1.cfm. 

8. D Hairston, “Sowing New Rules for Genetically Engineered Crops,” Chemical Engineering 110, no. 4 (2003) 29–31.

9. L Crosby, “Taking IVD Test Technology Beyond Human Clinical Diagnostics,” IVD Technology 7, no. 5 (2001) 35–44. 

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