Regulatory simulations at home and abroad: statutory and regulatory definitions for drugs, biological products, and biosimilars.

Information to support further reporting on regulation and non-regulation of biological product manufacturing, sample testing, lot-release, use.

Katherine Watt

Mar 13

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This overview is focused on the development of biological product definitions, statutes and regulations since July 1944, when Congress established the

Regulation of biological products program under the Public Health Service Act at Section 351, codified at 42 US Code 262.

Biological product manufacturing regulations may be found at 21 CFR Subchapter F, Parts 600 to 680 and related sections of the Code of Federal Regulations as they have developed, especially since 1973.

Key points:

Chemical drugs are produced by quantifiable, predictable, controllable chemical and physical manufacturing processes involving the breaking and forming of chemical bonds; they tend to have smaller molecular structures than biological products.

Biological products are produced by non-quantifiable, unpredictable, uncontrollable biological processes, such as replication and division within living cells and organisms, with widely variable effects on other living organisms when introduced into a recipient. Biological products tend to have larger molecular structures than chemical drugs.

Chemical drugs manufactured using predictable, measurable chemical reactions can be produced and assessed for compliance with purity, potency, activity, safety and efficacy standards.

Biological products manufactured using biological processes cannot.

November 2013 - Biosimilar Biological Products, Clinical Investigator Course, FDA

Statutory definitions of "drug"

June 30, 1906 - Pure Food and Drug Act, PL 59-384, 34 Stat. 768.

Through the Pure Food and Drug Act, Congress prohibited adulteration and misbranding of drugs, and established civil and criminal penalties for manufacturers producing and distributing adulterated and misbranded drugs.

Congress delegated authority to promulgate and enforce rules and regulations to the Secretary of the Treasury, Secretary of Agriculture, Secretary of Commerce and Labor, and US district attorneys, including "collection and examination of specimens."

Biological products, including "viruses, therapeutic serums, toxins, antitoxins, or analogous products" had been listed in a different Congressional act, signed in 1902 (see below) and were not covered by the Pure Food and Drug Act.

Congress defined "drug" to include

"...all medicines and preparations recognized in the United States Pharmacopoeia or National Formulary for internal or external use, and any substance or mixture of substances intended to be used for the cure, mitigation, or prevention of disease of either man or other animals."

June 25, 1938 - Federal Food Drug and Cosmetics Act, PL 75-717, 52 Stat. 1041.

Through the Food Drug and Cosmetics Act (FDCA), Congress repealed and replaced the 1906 Pure Food and Drug Act, and codified federal food and drug regulation at 21 USC Chapter 9, Sections 301 et seq.

Congress defined drug at 21 USC 321(g).

The term "drug" means
(1) 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
(2) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and
(3) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and
(4) articles intended for use as a component of any article specified in clause (1), (2), or (3) but does not include devices or their components, parts, or accessories.

Current FDCA Section 201/ 21 USC 321(g)(1)

The term "drug" means
(A) 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
(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and
(C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and
(D) articles intended for use as a component of any article specified in clause (A), (B), or (C).
A food or dietary supplement for which a claim, subject to sections 343(r)(1)(B) and 343(r)(3) of this title or sections 343(r)(1)(B) and 343(r)(5)(D) of this title, is made in accordance with the requirements of section 343(r) of this title is not a drug solely because the label or the labeling contains such a claim.
A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 343(r)(6) of this title is not a drug under clause (C) solely because the label or the labeling contains such a statement.

Drugs@FDA Glossary of Terms, last updated Nov. 14, 2017

A drug is defined as:
A substance recognized by an official pharmacopoeia or formulary.
A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.
A substance (other than food) intended to affect the structure or any function of the body.
A substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device.
Biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process versus biological process.)

Statutory and regulatory definitions of biologics, biological products and biosimilars

July 1, 1902 - Biologics Control Act or Virus-Toxin Act (32 Stat. 728).

Through the Biologics Control Act, Congress regulated "sale of and interstate traffic" in viruses, serums, toxins and analogous products, and delegated authority to promulgate and enforce rules and regulations to the Secretary of Treasury, in consultation with the Surgeon-Generals of the Army, Navy and Marine-Hospital Service.

"No person shall sell, barter, or exchange...any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention and cure of diseases of man...unless (a) such virus, serum, toxin, antitoxin, or product has been propagated and prepared at an establishment holding an unsuspended and unrevoked license, issued by the Secretary of the Treasury [and] ...that the Surgeon-General of the Army, the Surgeon-General of the Navy, and the supervising Surgeon-general of the Marine-Hospital Service, be...constituted a board with authority...to promulgate...such rules as may be necessary in the judgment of said board to govern the issue, suspension, and revocation of licenses for the maintenance of establishments for the propagation and preparation of viruses, serums, toxins, antitoxins, and analogous products...”

March 4, 1913 - Virus-Serum Toxin Act, 37 Stat. 832.

Through the Virus-Serum Toxin Act, Congress regulated preparation and sale of "virus, serum, toxin, or analogous product intended for use in the treatment of domestic animals," and delegated authority to promulgate and enforce rules and regulations to the Secretary of Agriculture.

"...It shall be unlawful for any person, firm or corporation to prepare, sell, barter, or exchange...or to ship or deliver...any worthless, contaminated, dangerous, or harmful virus, serum, toxin, or analogous product intended for use in the treatment of domestic animals, and no person, firm, or corporation shall prepare, sell, barter, exchange, or ship as aforesaid any virus, serum, toxin, or analogous product manufactured within the United States and intended for use in the treatment of domestic animals, unless and until the said virus, serum, toxin, or analogous product shall have been prepared, under and in compliance with regulations prescribed by the Secretary of Agriculture, at an establishment holding an unsuspended and unrevoked license issued by the Secretary of Agriculture..."

July 1, 1944 - Public Health Service Act (PHSA) Section 351, Regulation of biological products. PL 78-410, 58 Stat. 702.

Through the PHSA, Congress codified regulation and licensing of biological product manufacturing at 42 USC 262.

PHSA Section 351, Regulation of biological products (1944):

"Section 351(a) No person shall sell, barter, or exchange, or offer for sale, barter, or exchange...any virus, therapeutic serum, toxin, antitoxin, or analogous product, or arsphenamine or its derivatives (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of diseases or injuries of man unless (1) such...product has been propagated or manufactured and prepared at an establishment holding an unsuspended and unrevoked license..."

Notes

Congress did not place regulation of biological products under the Food Drug and Cosmetics Act, or under the Food and Drug Administration. Instead, Congress placed regulation of biological products under the control of the Public Health Service, which is a branch of the US military.

Congress provided a list of biological product categories to be regulated under 42 USC 262, but did not provide legal definitions of the specific products to be regulated, instead describing them generally as products "applicable to the prevention, treatment or cure of diseases or injuries of man."

Between 1937 and 1972, biological product regulation was housed in the National Institute of Health Division of Biologics Standards. In 1972, biological product regulation was moved to the FDA Bureau of Biologics, now called the Center for Biologics Evaluation and Research, or CBER.

Oct. 30, 1970 - Heart Disease, Cancer, Stroke, and Kidney Disease Amendments of 1970. PL 91-515, 84 Stat. 1297.

Congress added vaccine to the list of biological products subject to manufacturing regulation under the Public Health Service Act.

Section 351 of the Public Health Service Act [42 USC 262] is amended by inserting, after "antitoxin", each time such word appears, the following: "vaccine, blood, blood component or derivative, allergenic product."

As of 1970, biological products listed by Congress as subject to federal manufacturing regulation under 42 USC 262 included:

“Any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or its derivatives (or any other trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of diseases or injuries of man.”

Nov. 20, 1973 - Department of Health, Education and Welfare, Food and Drug Administration, Notice of Reorganization and Republication, 38 Federal Register 32048

Through this Federal Register notice, FDA Acting Associate Commissioner for Compliance William F. Randolph announced the consolidation and re-publication of federal regulations governing biological product manufacturing.

Sections included 21 CFR 600, Biological Products: General; 21 CFR 601, Licensing; 21 CFR 610, General Biological Products Standards; 21 CFR 620, Additional Standards for Bacterial Products; 21 CFR 630, Additional Standards for Viral Vaccines; 21 CFR 640, Additional Standards for Human Blood and Blood Products; and three other sections.

FDA defined several terms at 21 CFR 600.3, but did not define the term vaccine.

"21 CFR 600.3 (h) - Biological product means any virus, therapeutic serum, toxin, anti-toxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man."
21 CFR 600.3(h)(1) - A virus is interpreted to be a product containing a minute living cause of an infectious disease and includes but is not limited to filterable viruses, bacteria, rickettsia, fungi, and protozos.
21 CFR 600.3(h)(2) - A therapeutic serum is a product obtained from blood by removing the clot or clot components and the blood cells.
21 CFR 600.3(h)(3) - A toxin is a product containing a soluble substance poisonous to laboratory animals or to man in doses of 1 milliliter or less...and having the property, following the injection of non-fatal doses into an animal, of causing to be produced therein another soluble substance which specifically neutralizes the poisonous substances and which is demonstrable in the serum of the animal thus immunized.
21 CFR 600.3(h)(4) - An antitoxin is a product containing the soluble substance in serum or other body fluid of an immunized animal which specifically neutralizes the toxin against which the animal is immune.

Nov. 18, 1997 – National Defense Authorization Act FY1998, PL 105-85, 111 Stat. 1915. Congress amended 50 USC 1520a, Restrictions on the use of human subjects for testing of chemical or biological agents.

In the wake of the Gulf War (1990-1991), during which DoD forced soldiers to submit to batteries of vaccines and toxic exposures in theatre, including burn pits, Congress defined "biological agents."

50 USC 1520a(e) ...The term ‘‘biological agent’’ means any micro-organism (including bacteria, viruses, fungi, rickettsiac, or protozoa), pathogen, or infectious substance, and any naturally occurring, bioengineered, or synthesized component of any such micro-organism, pathogen, or infectious substance, whatever its origin or method of production, that is capable of causing—
(1) death, disease, or other biological malfunction in a human, an animal, a plant, or another living organism;
(2) deterioration of food, water, equipment, supplies, or materials of any kind; or
(3) deleterious alteration of the environment.

Note

The November 1997 NDAA section on biological agents is one of the main Congressional two-part maneuvers through which Congress appeared to be terminating illegal chemical and biological warfare programs, but actually just moved, renamed and expanded the same programs as public health emergency-medical countermeasures programs.

May 10, 2022 - Shell game. November 1997. Congress pretended to protect military servicemen and women from forced submission to biological and chemical weapons experiments. But really just transferred the program to FDA.
Sept. 28, 2022 - DOD chemical and biological warfare program: herd-culling plus stockpile disposal in one tidy package

March 23, 2010 - Biologics Price Competition Act, Title VII, Subtitle A of Patient Protection and Affordable Care Act, PL 111-148, 124 Stat. 814-815.

Through the BPCA, Congress added "protein (except any chemically synthesized polypeptide)" and added a new category of biosimilars to the list of biological products subject to regulation under 42 USC 262.

...Section 351(i) of the Public Health Service Act (42 U.S.C. 262(i)) is amended—
...by inserting "protein (except any chemically synthesized polypeptide)," after "allergenic product," and...by adding:
"(2) The term ‘biosimilar’ or ‘biosimilarity,’ in reference to a biological product that is the subject of an application under subsection (k) [Licensure of biological products as biosimilar or interchangeable], means—
(A) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
(B) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.
(3) The term ‘interchangeable’ or ‘interchangeability’...means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.
(4) The term ‘reference product’ means the single biological product licensed under subsection (a) [Biologics license] against which a biological product is evaluated in an application submitted under subsection (k).’’.

As of 2010, the list of biological products listed by Congress as subject to regulation under 42 USC 262 included:

"a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings" and "biosimilar" products.

Dec. 20, 2019 - Further Consolidated Appropriations Act, 2020, PL 116-94, 133 STAT. 3127

Congress removed "(except any chemically synthesized polypeptide)" — which had been added, with "protein" in 2010 — from the biological products definition.

Section 351(i)(1) of the Public Health Service Act (42 U.S.C. 262(i)(1)) is amended by striking "(except any chemically synthesized polypeptide)."

As of December 2019, biological products listed by Congress as subject to regulation under 42 USC 262 include:

“a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings” and “biosimilar” products.

FDA "What is a biological product?" (Undated, no author listed)

Biological products are regulated by the Food and Drug Administration (FDA) and are used to diagnose, prevent, treat, and cure diseases and medical conditions. Biological products are a diverse category of products and are generally large, complex molecules.
These products may be produced through biotechnology in a living system, such as a microorganism, plant cell, or animal cell, and are often more difficult to characterize than small molecule drugs.
There are many types of biological products approved for use in the United States, including therapeutic proteins (such as filgrastim), monoclonal antibodies (such as adalimumab), and vaccines (such as those for influenza and tetanus).
The nature of biological products, including the inherent variations that can result from the manufacturing process, can present challenges in characterizing and manufacturing these products that often do not exist in the development of small molecule drugs. Slight differences between manufactured lots of the same biological product (i.e., acceptable within-product variations) are normal and expected within the manufacturing process..."

Statutory and regulatory definitions of "vaccine"

Congress established the federal biological products licensing and regulation program in 1944.

Vaccines were added to the list of regulated, licensed biological products by Congressional statute in 1970, and regulatory, licensing functions were transferred from NIH to FDA in 1972; Congress did not define the term vaccine.

FDA regulations covering biological product manufacturing, including vaccines, were consolidated and re-published in 1973, and have been amended extensively since; FDA did not define the term vaccine.

In 1976, Congress authorized and funded a nationwide vaccination campaign including liability exemption for manufacturers, for swine flu, (National Swine Flu Immunization Act, PL 94-380, 90 Stat. 1113) without defining the term vaccine.

In 1986, Congress authorized and funded a nationwide child vaccination program, including liability exemption for manufacturers and establishment of the Vaccine Injury Compensation Program, (National Childhood Vaccine Injury Act, PL 99-660, 100 Stat 3755, codified at 42 USC 300aa-1 to 34), without defining the term vaccine.

Vaccine has not been defined by Congress through amendments to the Food Drug and Cosmetics Act (FDCA), or to the Public Health Service Act (PHSA), and the term has not been defined by the FDA through regulations published in the Federal Register.

In 1987, Congress provided a statutory definition of vaccine through in the Internal Revenue Code, 26 USC 4132.

The "Certain vaccines" provision authorized collection of excise tax by the Treasury Secretary, from manufacturers, per dose of vaccine sold. The list of taxable vaccines has been expanded since 1987.

26 USC 4132a(2) Vaccine.

The term “vaccine” means any substance designed to be administered to a human being for the prevention of 1 or more diseases.

26 USC 4132a(1) Taxable vaccine

The term “taxable vaccine” means any of the following vaccines which are manufactured or produced in the United States or entered into the United States for consumption, use, or warehousing:
(A) Any vaccine containing diphtheria toxoid.
(B) Any vaccine containing tetanus toxoid.
(C) Any vaccine containing pertussis bacteria, extracted or partial cell bacteria, or specific pertussis antigens.
(D) Any vaccine against measles.
(E) Any vaccine against mumps.
(F) Any vaccine against rubella.
(G) Any vaccine containing polio virus.
(H) Any HIB vaccine.
(I) Any vaccine against hepatitis A.
(J) Any vaccine against hepatitis B.
(K) Any vaccine against chicken pox.
(L) Any vaccine against rotavirus gastroenteritis.
(M) Any conjugate vaccine against streptococcus pneumoniae.
(N) Any trivalent vaccine against influenza or any other vaccine against seasonal influenza.
(O) Any meningococcal vaccine.
(P) Any vaccine against the human papillomavirus.

Federal public health officials have also published definitions of the term vaccine that have not been established by statute or regulation.

Some are dictionary definitions or medical and scientific definitions, including the revised definition promulgated by CDC in September 2021, replacing "a product that stimulates a person's immune system to produce immunity to a specific disease, protecting the person from that disease," to "a preparation that is used to stimulate the body's immune response against diseases."

CDC-Advisory Committee on Immunization Practices Glossary (ACIP) currently defines vaccine:

A suspension of live (usually attenuated) or inactivated microorganisms (e.g., bacteria or viruses) or fractions thereof administered to induce immunity and prevent infectious disease or its sequelae. Some vaccines contain highly defined antigens (e.g., the polysaccharide of Haemophilus influenzae type b or the surface antigen of hepatitis B); others have antigens that are complex or incompletely defined (e.g., Bordetella pertussis antigens or live, attenuated viruses).

CDC Vaccines and Immunizations Glossary defines vaccine:

A suspension of live (usually attenuated) or inactivated microorganisms (e.g., bacteria or viruses), fractions of the agent, or genetic material of the [sic] administered to induce immunity and prevent infectious diseases and their sequelae. Some vaccines contain highly defined antigens (e.g., the polysaccharide of Haemophilus influenzae type b or the surface antigen of hepatitis B); others have antigens that are complex or incompletely defined (e.g. Bordetella pertussis antigens or live attenuated viruses).

Brief Analysis

There are many terms for, and/or related to, biological products currently in use.

Statutes, regulations, FDA guidance documents, World Health Organization documents, Mutual Recognition Agreements, and other records include allergen; allergenic product; antitoxin; antigen; biopharmaceutical; biosimilar biological product; biotechnology product; biotechnology; blood, blood component, or derivative; cell therapies; emerging technology in the context of the pharmaceutical and related industries; first interchangeable biosimilar biological product; gene therapies; immunogen; intentionally altered genomic DNA; monoclonal antibody; plasma-derived pharmaceutical; plasma-derived product; plasmid; polypeptide; protein; recombinant protein; reference product; somatic cell therapy; synthetic biological product; therapeutic biotechnology-derived biological product; therapeutic recombinant DNA-derived product; therapeutic serum; vaccine; virus; toxin; and more.

Many of the documents acknowledge the extent to which biological product manufacturing cannot be standardized, such that product purity is an impossible regulatory standard for any biological product to achieve.

Manufacturing quality for a given package of biological material can, at best, contain a percentage of product assayed to be in conformity with contents as described on the label, at the moment of sample testing.

Even if products meet limited, fractional purity standards at the moment of sample testing, the contents of each package are subject to further changes over time due to metabolic processes and byproducts, sedimentation, mixing, temperature changes, degradation and other factors, because the contents are comprised of living, dynamic and therefore non-stable components.

After entering the body of each recipient, each biological product undergoes additional unpredictable, widely variant changes as the components interact with the living organism through billions of biological events.

Some documents