I. The Statutory Framework

The Federal Food, Drug, and Cosmetic Act (FD&C Act), codified at 21 U.S.C. § 301 et seq., establishes the regulatory architecture governing every drug manufactured, distributed, and sold in the United States. Section 201(g)(1) of the Act, codified at 21 U.S.C. § 321(g)(1), defines a “drug” to include “articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them” and “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.”¹

The definition is notable for what it does not require. It does not require that the article be synthesized in a laboratory. It does not require that it be packaged in a blister pack. It does not require that it be manufactured by a corporation, a limited liability company, or any entity that files taxes. It requires only that the article be recognized in the Pharmacopoeia or intended for the treatment of disease. The statute does not inquire into the manufacturer’s kingdom, phylum, or domain of life. It inquires only into the product.

Section 510 of the FD&C Act, codified at 21 U.S.C. § 360, requires that “every person who owns or operates any establishment” engaged in the “manufacture, preparation, propagation, compounding, or processing of a drug” must register that establishment with the FDA.² The implementing regulation at 21 CFR § 207.17 extends this obligation to “all manufacturers, repackers, relabelers, and salvagers.”³ Registration must occur within five days of beginning operations.

Section 501(a)(2)(B) of the FD&C Act, codified at 21 U.S.C. § 351(a)(2)(B), provides that a drug is “adulterated” if “the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice.”⁴ The implementing regulations at 21 CFR Parts 210 and 211 specify the minimum requirements for facilities, equipment, personnel, production controls, laboratory controls, and record-keeping that every drug manufacturer must maintain.⁵

The question before the agency is not whether a bacterial cell can be a drug manufacturer. The statute does not care what the manufacturer is. It cares what the manufacturer makes. The question is whether the compounds produced by Streptomyces bacteria in American soil are “drugs” within the meaning of 21 U.S.C. § 321(g)(1). They are. The United States Pharmacopoeia says so.

II. The Products

The following compounds are produced by Streptomyces bacteria through endogenous biosynthetic pathways. Each is recognized in the United States Pharmacopoeia. Each is an FDA-approved drug. Each was first isolated from soil.

Streptomycin. Produced by Streptomyces griseus. Isolated in 1943 by Albert Schatz working in Selman Waksman’s laboratory at Rutgers University from a soil sample obtained at the Rutgers Agricultural Experiment Station. The first antibiotic effective against tuberculosis. USP monograph: Streptomycin Sulfate.⁶

Tetracycline. Produced by Streptomyces aureofaciens and Streptomyces rimosus. First isolated in 1948 from a Timothy grassland soil sample at the Sanborn Field experimental plots, University of Missouri. Broad-spectrum antibiotic effective against Gram-positive and Gram-negative bacteria, rickettsiae, mycoplasmas, and spirochetes. USP monograph: Tetracycline Hydrochloride.⁷

Erythromycin. Produced by Saccharopolyspora erythraea (formerly Streptomyces erythraeus). Isolated in 1952 from a soil sample collected in the Philippines. Macrolide antibiotic used to treat respiratory tract infections, skin infections, and as a penicillin alternative for allergic patients. USP monograph: Erythromycin.⁸

Vancomycin. Produced by Amycolatopsis orientalis (formerly Streptomyces orientalis). Isolated in 1953 from a soil sample collected in the interior jungles of Borneo by a missionary who mailed the dirt to a friend at Eli Lilly. Glycopeptide antibiotic of last resort against methicillin-resistant Staphylococcus aureus (MRSA). USP monograph: Vancomycin Hydrochloride.⁹

Chloramphenicol. Produced by Streptomyces venezuelae. Isolated in 1947 from soil and compost samples. Broad-spectrum antibiotic effective against typhoid fever, bacterial meningitis, and rickettsial diseases. The first antibiotic to be manufactured synthetically at commercial scale, but first produced by a bacterium that did not patent the process. USP monograph: Chloramphenicol.¹⁰

Daptomycin. Produced by Streptomyces roseosporus. Isolated from a soil sample collected near Mount Ararat, Turkey. Lipopeptide antibiotic approved by the FDA in 2003 for complicated skin and skin-structure infections. USP monograph: Daptomycin.¹¹

Rapamycin (sirolimus). Produced by Streptomyces hygroscopicus. Isolated in 1972 from a soil sample collected on Easter Island—Rapa Nui—by a Canadian expedition. Initially characterized as an antifungal agent, subsequently found to be a potent immunosuppressant. FDA-approved for prevention of organ transplant rejection. USP monograph: Sirolimus.¹²

Ivermectin. Derived from avermectin, produced by Streptomyces avermitilis. Isolated by Satoshi Ōmura in 1978 from a soil sample collected near a Japanese golf course. Developed by William Campbell at Merck as an antiparasitic agent. Used to treat river blindness and lymphatic filariasis, diseases affecting hundreds of millions of people in the developing world. USP monograph: Ivermectin.¹³

This is not a complete list. Streptomyces bacteria also produce neomycin, kanamycin, gentamicin, nystatin, amphotericin B, fosfomycin, clavulanic acid, lincomycin, and rifamycin, among dozens of other pharmacologically active compounds.¹⁴ A 2025 study published in mBio estimated that Streptomyces bacteria produce approximately 55 percent of all clinically used antibiotics.¹⁵ A comprehensive review in Frontiers in Microbiology placed the figure at roughly 80 percent of all actinomycete-derived antibiotics, with actinomycetes collectively responsible for two-thirds of all microbial antibiotics in clinical use.¹⁶

Every one of these compounds meets the statutory definition of a “drug” under 21 U.S.C. § 321(g)(1)(A). They are recognized in the United States Pharmacopoeia. The statute does not ask who put them there. It asks only whether they are there. They are.

III. The Producers

Streptomyces is a genus of Gram-positive, filamentous bacteria belonging to the phylum Actinomycetota (formerly Actinobacteria). The genus was formally described by Selman Waksman and A.T. Henrici in 1943, the same year Waksman’s laboratory isolated streptomycin.¹⁷ As of 2025, over 900 species of Streptomyces have been validly published, and genomic analyses of more than 625 sequenced genomes have revealed that each species harbors an average of 20 to 30 biosynthetic gene clusters encoding secondary metabolites.¹⁸

Less than 10 percent of these gene clusters have been matched to known compounds under standard laboratory conditions.¹⁹ This means that each Streptomyces cell is not merely an unlicensed pharmaceutical manufacturer. It is an unlicensed pharmaceutical manufacturer operating at approximately one-tenth of its production capacity, with 90 percent of its manufacturing lines running products that the FDA has never identified, characterized, or evaluated for safety and efficacy. The uncharacterized output of a single genus of soil bacteria exceeds the entire discovery pipeline of the global pharmaceutical industry.

Streptomyces bacteria are ubiquitous in soil. They are present in agricultural fields, forest floors, garden beds, lawns, desert crusts, permafrost, marine sediments, and the dirt tracked onto kitchen floors. They are responsible for the characteristic earthy smell of freshly turned soil, which is caused by their production of geosmin, a volatile organic compound that the human nose can detect at concentrations as low as five parts per trillion.²⁰ Geosmin is not a drug. It is, however, a reminder that when you smell wet earth, you are smelling the off-gassing of billions of unlicensed pharmaceutical manufacturing facilities.

IV. The Scale of Unlicensed Manufacturing

A single gram of topsoil contains between one billion and ten billion bacterial cells, according to estimates published in Ecology Letters and confirmed by direct microscopic counts and molecular surveys.²¹ Streptomyces and related actinomycetes constitute between 1 and 20 percent of the total soil bacterial community, depending on soil type, moisture, pH, and organic matter content.²² At the conservative end of this range, a single gram of soil contains approximately 10 million Streptomyces cells. At the upper end, it contains two billion.

The contiguous United States contains approximately 1.9 billion acres of land surface.²³ The uppermost six inches of soil across this area—the zone of highest microbial activity—represents approximately 5.7 billion acre-inches of biologically active substrate. Each acre-inch of topsoil weighs approximately 150,000 kilograms, depending on bulk density.²⁴ The total mass of the top six inches of American topsoil therefore approximates 5.13 × 10¹⁵ kilograms, or 5.13 × 10¹⁸ grams.

At the conservative estimate of 10 million Streptomyces per gram, the United States contains approximately 5.13 × 10²⁵ individual Streptomyces cells in its topsoil. This is approximately 51.3 sextillion cells. Each one of them is a biosynthetic production unit capable of manufacturing pharmacologically active compounds recognized in the United States Pharmacopoeia.

As of September 30, 2024, the FDA maintained a registry of 14,689 drug establishments worldwide—9,850 domestic and 4,839 foreign.²⁵ The ratio of registered drug establishments to unregistered Streptomyces production facilities in United States soil is approximately 1 to 3.49 × 10²¹. For every drug manufacturing facility the FDA has registered, there are approximately 3.49 sextillion it has not. The compliance rate is not zero. It is a number so close to zero that expressing it requires scientific notation: approximately 2.86 × 10⁻²² percent.

V. The Registration Failure

Section 510(c) of the FD&C Act requires drug establishment registration to occur “on or before December 31 of each year.” The implementing regulation at 21 CFR § 207.21 specifies that “establishments must be registered within five days of beginning operations.”²⁶ The statute contemplates a simple process: a form, a Unique Facility Identifier, and an annual renewal.

The Streptomyces genus began operations in soil environments during the Ordovician period, approximately 450 million years ago, coinciding with the colonization of terrestrial environments by land plants whose root exudates created the ecological niches these bacteria still occupy.²⁷ Antibiotic biosynthetic gene clusters have been identified in permafrost-preserved soil bacteria dating back at least 30,000 years, and phylogenetic evidence suggests that the biochemical pathways for producing antibiotics such as streptomycin predate the evolution of modern Streptomyces species by tens of millions of years.²⁸

Not one of these organisms has filed an initial registration. Not one has renewed. Not one has obtained a Unique Facility Identifier under the system specified by section 510 of the FD&C Act. The five-day registration deadline has been exceeded by approximately 1.64 × 10¹⁴ days. This is the longest continuous registration violation in the history of American pharmaceutical regulation, and it began approximately 449,999,974 years before the FD&C Act was enacted in 1938.

Under 21 CFR § 207.25, registrants must provide the name of the owner or operator of each establishment, the establishment’s name and physical address, and the name of an official contact person.²⁹ Streptomyces bacteria have no owner or operator. They have no name other than binomial taxonomy assigned by humans who discovered them. Their physical address is “everywhere.” They have no contact person. They do not have persons. They are prokaryotic organisms that reproduce by sporulation and communicate by gamma-butyrolactone quorum sensing. The registration form was not designed for this.

VI. The Current Good Manufacturing Practice Violations

21 CFR Part 211 sets forth the minimum requirements that every drug manufacturing facility in the United States must meet. These include, among others:

Personnel qualifications (21 CFR § 211.25). Each person engaged in the manufacture of drugs shall have “education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions.”³⁰ Streptomyces cells have no education. They hold no degrees. They have not completed any training programs. They operate biosynthetic pathways encoded in their genomes, which they inherited through horizontal gene transfer and vertical descent over hundreds of millions of years. Whether 450 million years of unbroken production experience constitutes adequate “experience” to “perform the assigned functions” is a question the regulation does not address.

Buildings and facilities (21 CFR § 211.42). Drug manufacturing buildings must be of “suitable size, construction, and location to facilitate cleaning, maintenance, and proper operations.” The facility must have “adequate space for orderly placement of equipment and materials.”³¹ Streptomyces manufacturing facilities consist of microhabitats within soil aggregates, typically measuring between 1 and 100 micrometers in diameter. They are not buildings. They are pore spaces in mineral matrices colonized by branching hyphal filaments. The facilities cannot be cleaned because they are dirt. They are, in the most literal sense, dirt.

Equipment (21 CFR § 211.63). Equipment used in drug manufacture must be of “appropriate design, adequate size, and suitably located to facilitate operations for its intended use.”³² Streptomyces manufacturing equipment consists of ribosomes, nonribosomal peptide synthetases, polyketide synthases, and various post-translational modification enzymes. None of this equipment has been calibrated by a qualified technician. None of it carries a serial number. The polyketide synthase complexes that produce erythromycin are among the largest known enzyme assemblies in nature, but they have never been validated under an equipment qualification protocol.

Laboratory controls (21 CFR § 211.160). Manufacturers must establish “scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.”³³ Streptomyces cells perform no quality control testing. They do not assay their output. They do not test for identity, strength, quality, or purity. They produce pharmacologically active compounds and excrete them into the surrounding soil matrix, where they mix with water, humic acids, mineral particles, fungal metabolites, and the waste products of earthworms. This is not a controlled release formulation. It is an environmental discharge.

Records and reports (21 CFR § 211.180). Manufacturers must maintain “complete records” of all production, control, and distribution activities.³⁴ Streptomyces bacteria maintain no records. Their production history is encoded in their genomes, which are approximately 8 to 12 megabases in length and contain no batch numbers, no lot tracking, and no deviation reports. The closest analog to a manufacturing record is the evolutionary trace in their biosynthetic gene clusters, which has been maintained with reasonable fidelity for approximately 450 million years, but which has never been audited by an FDA inspector.

In fiscal year 2024, the FDA’s Center for Drug Evaluation and Research conducted 989 drug quality assurance inspections across its portfolio of 4,619 cataloged manufacturing sites worldwide.³⁵ The number of cGMP inspections conducted at Streptomyces manufacturing sites in American topsoil is zero. It has been zero every year since the cGMP regulations were first promulgated in 1963. The agency would need to conduct approximately 5.13 × 10¹⁹ additional inspections per gram of soil to achieve the coverage level it currently applies to licensed facilities. Its FY2024 budget of approximately $7 billion would not cover the per diem.

VII. The Nobel Prize Problem

The pharmaceutical products of Streptomyces bacteria have been recognized by the Nobel Committee on two occasions.

In 1952, the Nobel Prize in Physiology or Medicine was awarded to Selman Abraham Waksman “for his discovery of streptomycin, the first antibiotic effective against tuberculosis.”³⁶ Waksman was a soil microbiologist at Rutgers University who spent 24 years studying soil microorganisms before his laboratory isolated streptomycin from Streptomyces griseus in 1943. The bacterium received no share of the prize. It received no share of the royalties. Merck, which funded Waksman’s research and manufactured the commercial product, paid Rutgers, not the dirt.

In 2015, the Nobel Prize in Physiology or Medicine was awarded jointly to Satoshi Ōmura and William C. Campbell “for their discoveries concerning a novel therapy against infections caused by roundworm parasites.”³⁷ Ōmura, a microbiologist at the Kitasato Institute, collected a soil sample near a Japanese golf course in the 1970s, from which he isolated Streptomyces avermitilis. Campbell, at Merck, purified avermectin from Ōmura’s cultures and developed ivermectin, which has since been administered to hundreds of millions of people to prevent river blindness and lymphatic filariasis. The Nobel Committee described the resulting benefit to mankind as “immeasurable.” The bacterium that produced the compound was not mentioned by name in the announcement. Its contribution was immeasurable. Its recognition was zero.

This presents a regulatory paradox. The Nobel Committee has twice recognized the output of Streptomyces bacteria as among the most important pharmaceutical discoveries in human history. The FDA has not recognized the manufacturer as a manufacturer. Two of the most prestigious awards in medicine have been given for identifying products that, under the agency’s own regulations, were produced in facilities that have never been registered, never been inspected, and never been determined to be in compliance with any federal quality standard. The awards were, in effect, prizes for discovering that an unregistered manufacturer was producing drugs of exceptional quality. The manufacturer continues to produce them. It continues to be unregistered.

VIII. The Unapproved New Drug Problem

Under 21 U.S.C. § 355(a), “no person shall introduce or deliver for introduction into interstate commerce any new drug” unless it is the subject of an approved New Drug Application (NDA) or an Abbreviated New Drug Application (ANDA).³⁸ A “new drug” is defined at 21 U.S.C. § 321(p) as any drug “not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof.”

The antibiotics produced by Streptomyces bacteria in soil are not labeled. They carry no prescribed, recommended, or suggested conditions of use. They are excreted into the soil matrix at concentrations determined by the organism’s metabolic state, nutrient availability, and competitive pressures from neighboring microorganisms. The “dosage” is whatever the bacterium happens to produce. The “route of administration” is dermal contact with anyone who touches the soil, ingestion by anyone who eats unwashed produce, and inhalation by anyone who breathes near freshly tilled earth.

No NDA has been filed for soil-produced streptomycin. No ANDA has been filed for soil-produced tetracycline. The distinction between the FDA-approved drug “streptomycin sulfate” and the streptomycin produced by S. griseus in your backyard is not chemical. It is regulatory. The molecule is the same. The difference is that one was manufactured in a registered facility with cGMP-compliant equipment, tested for identity and potency, labeled with a National Drug Code number, and distributed through licensed pharmacies, while the other was manufactured in the dark by a filamentous bacterium, tested by nothing, labeled by no one, and distributed by rain.

IX. The Labeling Deficiency

21 CFR § 201.1 requires that all drugs bear adequate labeling, including the name and place of business of the manufacturer, packer, or distributor, the established name of the drug, and adequate directions for use.³⁹ 21 CFR § 201.100 specifies that prescription drug labeling must include, among other things, quantitative composition, dosage and administration, contraindications, warnings, precautions, and adverse reactions.

No Streptomyces product has ever been labeled. The organism does not disclose the identity of its output. It does not state the concentration of active pharmaceutical ingredient per gram of soil. It does not list inactive ingredients, which in the case of soil include silicon dioxide, aluminum oxide, iron oxide, calcium carbonate, organic matter in various stages of decomposition, nematode feces, and water. It does not provide dosage and administration guidelines. It does not list contraindications, of which there are many: streptomycin causes ototoxicity; tetracycline causes dental staining in children; chloramphenicol causes aplastic anemia. None of these warnings appear anywhere in soil.

The labeling failure extends to the child-resistant packaging requirements of the Poison Prevention Packaging Act, 16 U.S.C. § 1471 et seq. Soil is not packaged. It is not child-resistant. Children routinely place their hands in it and, with alarming frequency, their mouths. The pharmacologically active compounds produced by Streptomyces bacteria are therefore available to the youngest and most vulnerable consumers without any protective barrier whatsoever, at concentrations that have never been assessed for pediatric safety by any regulatory authority on Earth.

X. The Adverse Event Reporting Gap

Under 21 CFR § 314.80, the holder of an approved NDA must report adverse drug experiences to the FDA, including serious and unexpected adverse reactions, within 15 calendar days.⁴⁰ The MedWatch system processes approximately 2.5 million adverse event reports per year across all FDA-regulated products.

The subtherapeutic exposure of soil microbiota, farm workers, gardeners, and the general public to antibiotics produced by Streptomyces bacteria has been identified by the World Health Organization and peer-reviewed literature as a contributing factor to the global crisis of antimicrobial resistance.⁴¹ Environmental antibiotic concentrations, including those produced by soil bacteria, exert selective pressure on bacterial populations, driving the evolution of resistance genes that can transfer to human pathogens. Antimicrobial resistance currently causes an estimated 1.27 million deaths globally per year.⁴²

No adverse event report has ever been filed by a Streptomyces bacterium. The organism has no pharmacovigilance department. It does not monitor outcomes. It does not track its patients, largely because it has no patients. It distributes active pharmaceutical ingredients into the environment indiscriminately, generating selective pressures that contribute to a public health crisis that the WHO has characterized as “one of the biggest threats to global health, food security, and development today.” The reporting deadline has been exceeded by approximately 450 million years. The Form FDA 3500A was not available for most of that period, but neither was the bacterium’s willingness to complete it.

XI. The Economic Dimensions

The global antibiotics market was valued at approximately $55 billion in 2025, according to IMARC Group.⁴³ Approximately two-thirds of the compounds generating this revenue were originally isolated from Streptomyces or closely related actinomycetes. The pharmaceutical industry did not invent these molecules. It discovered them in dirt, determined their structures, optimized their production through fermentation engineering, and obtained patents on the methods of manufacture and the formulations—but not on the molecules themselves, which were prior art by several hundred million years.

The licensing and commercial production of Streptomyces-derived antibiotics has generated hundreds of billions of dollars in cumulative revenue since the commercialization of streptomycin in the late 1940s. Merck, Pfizer, Eli Lilly, and dozens of other pharmaceutical companies have built product lines on compounds first identified in soil samples. Not one of these companies has paid a licensing fee to the organisms that produced the compounds. Not one has entered into a supply agreement. The bacteria continue to produce the same molecules, free of charge, in every garden, every field, and every forest floor in the United States, while the licensed versions of their products sell for prices ranging from $4 per course of oral tetracycline to over $400 per day for intravenous daptomycin.

Under normal circumstances, an unlicensed manufacturer producing compounds identical to FDA-approved drugs and distributing them without NDAs, without cGMP compliance, and without labeling would face substantial enforcement action. Section 303 of the FD&C Act provides for criminal penalties of up to one year of imprisonment for a first offense and up to three years for subsequent violations. Section 304 authorizes seizure of adulterated and misbranded drugs. Section 302 authorizes injunctive relief.⁴⁴ The aggregate liability of the estimated 5.13 × 10²⁵ Streptomyces cells in American topsoil, at a conservative penalty of $1 per cell, would exceed the gross domestic product of the Earth by approximately five orders of magnitude. The enforcement action would be the largest in FDA history. The defendant would be the largest in any history.

XII. Conclusion

The Federal Food, Drug, and Cosmetic Act defines a drug as any article recognized in the United States Pharmacopoeia. Streptomycin, tetracycline, erythromycin, vancomycin, chloramphenicol, daptomycin, rapamycin, and ivermectin are all recognized in the Pharmacopoeia. All were first produced by Streptomyces bacteria in soil. All continue to be produced by Streptomyces bacteria in soil.

The FD&C Act requires every drug manufacturer to register with the FDA. Streptomyces bacteria have not registered. The Act requires compliance with current good manufacturing practices. Streptomyces bacteria manufacture drugs in dirt, without buildings, without equipment qualification, without laboratory controls, without records, and without personnel who have completed so much as an orientation. The Act requires New Drug Applications for drugs introduced into interstate commerce. Streptomyces bacteria introduce drugs into interstate commerce every time it rains and the water table moves.

Two Nobel Prizes have been awarded for discovering their products. Two-thirds of the world’s clinically used antibiotics originate in their biosynthetic pathways. A $55 billion global industry exists to manufacture, in registered facilities with cGMP-compliant equipment, the same compounds these bacteria have been producing in unregistered facilities without cGMP-compliant equipment since before the first amphibian walked on land.

The FDA has conducted 989 drug quality assurance inspections in its most recent fiscal year. It has conducted zero inspections of soil. The most prolific pharmaceutical manufacturer in the history of the planet operates underfoot, unlicensed, uninspected, and unbothered. Its output has cured tuberculosis, prevented river blindness, treated MRSA, and contributed to the antimicrobial resistance crisis. Its compliance record is spotless, in the sense that no record exists. Its regulatory status is clear: it has none.

Ergo.