Basics of US FDA - Things You Must Know

US FDA is one of the most important regulatory agencies in the world. It works based on the Food, Drug and Cosmetic Act (FD&C Act). Its structure and administrative procedures made it unique in the world. The high-quality standards and the style of regulatory inspections, making the FDA special among its peers. Its role in preventing the entry of adulterated drugs into the US market is profound. FDA is now collaborating with the other countries' regulatory agencies, to bring high quality and safe medicines into the market.

The USA - A Destination of Pharmaceutical Companies

The USA (United States of America) is a destination of every company in the pharmaceutical industry.US market is attracting the medical companies with its enormous opportunities and providing scope for the expansion of the business.

Good awareness of the public on the health issues and the government's responsibility to get high-quality medicines into the US market, creating a plenty of opportunities for the multinational companies. Thus, the USA stands as an ultimate business place for the pharmaceutical companies.

Protection of public health is a major responsibility of the US Government. Hence, it is inevitable to control the medicinal drugs and prevent unwanted incidents.

As the lucrative market created a lot of competition between the companies, for the entry in the US, healthy developments, as well as unhealthy practices, took place simultaneously in pharmaceutical manufacturing.

This situation is leading to the entry of adulterated drugs into the market. So, to stop the flow of this low-quality medicines into the country, the government formed an agency, which is very well known to the world as Food and Drug Administration (FDA).

Why Was FDA Formed?

Consumer protection gained a prime importance, in the USA, since a long time. It was started with the control of agricultural products by the Department of Agriculture in 1862. In those days, syrups and tonics were used to prepare using alcohol, opium, or morphine. People who used these medicinal drugs, as part of the treatment, addicted to them. But, at that time, there were no sufficient government controls on the manufacturing of medicines.

After a lot of scientific discussions on controlling the side effects of drugs, in 1906, Pure Food and Drugs Act came into effect with the aim to prevent misbranded and adulterated food and drugs. As per this act, manufacturers had to label the ingredients on all drugs. The law was enforced by the Bureau of Chemistry which was part of Department of Agriculture.

But due to the limited scope and some gaps in the law, many hazardous products entered into the market legally. Many people's health was damaged due to the poisonous products; deaths also happened with the consumption of adulterated drugs.

As per this 1906 Pure Food and Drugs Act, manufacturers do not need any approval from the government before releasing their products into the market. They just needed to comply with some labelling requirements and U. S. Pharmacopoeia or the National Formulary. Federal statute was not in effect which can control commercialization of medicinal products. Due to this, the situation was becoming worse and worse day by day.

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The 1937 Elixir Sulfanilamide Incident

The intense bad effect of the uncontrolled drug market resulted in a shocking disaster of Elixir Sulfanilamide in 1937. More than 100 patients were died because of this medicine.

Sulfanilamide was used for the treatment of streptococcal infections. Initially, the Sulfanilamide was distributed into the market in a tablet form; it was a safe dosage form. But later on, it was released in the liquid dosage form which led to the above-said fatal incident.

Sulfanilamide is soluble in diethylene glycol. Diethylene glycol is a highly toxic liquid. The company prepared the Sulfanilamide in a liquid form by dissolving it in diethylene glycol; then released it into the market without testing the toxicity of this new dosage form. This has happened because the law had no requirement of the safety studies before releasing a new formulation into the market. The result is 100 deaths and more.

Refer Taste of Raspberries, Taste of Death The 1937 Elixir Sulfanilamide Incident

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Formation of Food, Drug and Cosmetic Act

The Sulfanilamide incident raised many questions about the commercialization of medicinal drugs and patient safety.

Immediately federal government responded and identified the need of a new law. As a result, the Food, Drug and Cosmetic Act (FD&C Act) came into effect in 1938.

During this period, the Food and Drug Administration (FDA) was formed, to enforce the law, replacing the Bureau of Chemistry.

FDA is an administrative agency. It is part of the Department of Health and Human Services (HHS). The FD&C Act empowered the FDA and gave full authority to regulate the food and drug industry.

What Is The Legal Basis Of FDA?

The legality of FDA is unquestionable. It was formed on the foundation of Food, Drug and Cosmetic Act (FD&C Act).

In 1938, Congress passed the law Food, Drug and Cosmetic Act (FD&C Act) and was recorded in the United States Code (USC) under Title 21 Food and Drugs.

Chapter 9 describes the Federal Food, Drug, and Cosmetic Act. It contains sections from 301 to 399d.

It is the responsibility of the Department of Health and Human Services (HHS) to implement this law.

The HHS prepares the regulations to enforce the law. To enforce the law and to create regulations, it needs a well defined regulatory system.

So HHS formed an agency, which is very well known to us as Food and Drugs Administration (FDA), to supervise and regulate the areas of food, drugs and cosmetics.

FDA is an administrative agency and an inherent part of the Department of Health and Human Services (HHS). In that way, it has the legal sanctity.

How FDA Works?

FDA operates under a certain legal framework which originates from federal laws. Statutory Laws passed by Congress cannot be enforced directly until the regulations are issued.

It is the responsibility of FDA to issue the regulations following the procedures mentioned in the Administrative Procedure Act (APA). FDA prepares regulations as per statutory requirements set forth in the law of Food, Drug and Cosmetic Act (FD&C Act).

As soon as the regulations are ready for the implementation, they will be codified into the Code of Federal Regulations (CFR). FDA regulations are composed in Title 21 of the Code of Federal Regulations (CFR). These regulations come under federal law but they are not part of the FD&C Act.

FDA also issues guidance documents which reflect the agency's current thinking on a regulatory issue. These documents are for the FDA staff, public and applicants. FDA may release its guidance documents on, but not limited to, the statutory requirements of manufacturing, labelling, testing of regulated products, inspection and enforcement policies.

The guidance document will not bind legally the public or FDA. It is just the agency's latest thinking on the particular regulatory issue. You can deviate from the proposals made in the document. But the chosen alternative approach must comply with the regulations and statutory requirements.

50 United States, the District of Columbia, Puerto Rico, Guam, the Virgin Islands, American Samoa, and other U.S. territories and possessions come under the scope of FDA's responsibilities.

Source of information: What does FDA do?

What Is The Regulatory Jurisdiction Of The FDA?

The Food, Drug and Cosmetic Act has provided unquestionable authority to the FDA and empowered it to regulate the food and drug industry.

FDA's scope is very broad and it works together with other government agencies.

Here are some categories, for illustration, that come under FDA regulatory jurisdiction.

Juridiction of FDA

Sr,No.	Category	Areas included
1	Foods	Dietary supplements Bottled water Food additives Infant formulas Other food products
2	Drugs	Prescription drugs (both brand-name and generic) Non-prescription (over-the-counter) drugs
3	Biologics	Vaccines Blood and blood products Cellular and gene therapy products Tissue and tissue products Allergenics
4	Medical devices	Simple items like tongue depressors and bedpans Complex technologies such as heart pacemakers Dental devices Surgical implants and prosthetics
5	Electronic products that give off radiation	Microwave ovens X-ray equipment Laser products Ultrasonic therapy equipment Mercury vapor lamps Sunlamps
6	Cosmetics	Color additives found in makeup and other personal care products Skin moisturizers and cleansers Nail polish and perfume
7	Veterinary products	Livestock feeds Pet foods Veterinary drugs and devices
8	Tobacco products	Cigarettes Cigarette tobacco Roll-your-own tobacco Smokeless tobacco

Source of information: What does FDA regulate?

What Is The Structure of FDA?

FDA reports to the Department of Health and Human Services (HHS).

It has one commissioner office and four directorates.

These wings help the agency in overseeing the main functions of food and drugs.

Structure of FDA

Sr,No.	Office/Directorate	Activities
1	Office of the Commissioner	Scientific activities, communication, legislative liaison, policy and planning, woman's and minority health initiatives, agency operations, toxicological research.
2	Office of Foods and Veterinary Medicine	Leads FDA Foods Program to achieve public health goals.
3	Office of Global Regulatory Operations and Policy	Provides leadership for the FDA's domestic and international product quality and safety efforts.
4	Office of Medical Products and Tobacco	Provides advice and counsel to the commissioner on all medical product and tobacco-related programs and issues.
5	Office of Operations	Provides agency-wide services including information technology, financial management, procurement, library services, freedom of information, FDA history and facilities.

Source of information: FDA Organization

Apart from the above Office of the Commissioner and directorates, advisory committees provide independent advice to FDA. The members of the advisory committee may be from consumers, industry, patients and experts of drugs, biological products, medical devices and food. The committee provides only a piece of advice, but the call for the final decision belongs to FDA itself.

FDA has 17468 employees (Fy 2018 Estimate) to assist in its critical activities and responsibilities. They are a mix of 16344 civilian employees and 1124 military employees.

The budgeted amount set aside for FDA is $9.11 per year, per American.

How FDA Regulates The Pharmaceutical Industry?

FDA regulates the pharmaceutical industry based on the authority provided by FD&C Act and other statutory laws.

FD&C Act very clearly defines what to regulate by the FDA along with the regulatory actions in case of violation of the law.

Let us go through some important clauses related to drugs in the FD&C Act.

CHAPTER 9—FEDERAL FOOD, DRUG, AND COSMETIC ACT

SUBCHAPTER III—PROHIBITED ACTS AND PENALTIES

Sr,No.	Section	Regulatory Entity
1	331	Prohibited acts.
2	332	Injunction proceedings.
3	333	Penalties.
4	333 a	Repealed.
5	334	Seizure.
6	335	Hearing before report of criminal violation.
7	335 a	Debarment, temporary denial of approval,and suspension
8	335 b	Civil penalties.
9	335 c	Authority to withdraw approval of abbreviated drug applications.
10	336	Report of minor violations.
11	337	Proceedings in name of United States; provision as to subpoenas.

SUBCHAPTER V—DRUGS AND DEVICES; PART A — DRUGS AND DEVICES

Sr,No.	Section	Regulatory Entity
1	351	Adulterated drugs and devices.
2	352	Misbranded drugs and devices.
3	353	Exemptions and consideration for certain drugs, devices, and biological products.
4	353 a	Pharmacy compounding.
5	353 b	Prereview of television advertisements.
6	354	Veterinary feed directive drugs.
7	355	New drugs.
8	355-1	Risk evaluation and mitigation strategies.
9	355 a	Pediatric studies of drugs.
10	355 b	Adverse-event reporting.
11	355 c	Research into pediatric uses for drugs and biological products.
12	355 d	Internal committee for review of pediatric plans, assessments, deferrals, and waivers.
13	355 e	Pharmaceutical security.
14	356	Fast track products.
15	356-1	Accelerated approval of priority countermeasures.
16	356 a	Manufacturing changes.
17	356 b	Reports of post marketing studies.
18	356 c	Discontinuance of life saving product.
19	357	Repealed.
20	358	Authority to designate official names.
21	359	Non applicability of subchapter to cosmetics.
22	360	Registration of producers of drugs or devices.
23	360 a	Clinical trial guidance for antibiotic drugs.
24	360 b	New animal drugs.
25	360 c	Classification of devices intended for human use.
26	360 d	Performance standards.
27	360 e	Premarket approval.
28	360 e-1	Pediatric uses of devices.
29	360 f	Banned devices.
30	360 g	Judicial review.
31	360 h	Notification and other remedies.
32	360 i	Records and reports on devices.
33	360 j	General provisions respecting control of devices intended for human use.
34	360 k	State and local requirements respecting devices.
35	360 l	Post market surveillance.
36	360 m	Accredited persons.
37	360 n	Priority review to encourage treatments for tropical diseases.

SUBCHAPTER V—DRUGS AND DEVICES; PART B — DRUGS FOR RARE DISEASES OR CONDITIONS

Sr,No.	Section	Regulatory Entity
1	360 aa	Recommendations for investigations of drugs for rare diseases or conditions.
2	360 bb	Designation of drugs for rare diseases or conditions.
3	360 cc	Protection for drugs for rare diseases or conditions.
4	360 dd	Open protocols for investigations of drugs for rare diseases or conditions.
5	360 ee	Grants and contracts for development of drugs for rare diseases and conditions.

SUBCHAPTER V—DRUGS AND DEVICES; PART E — GENERAL PROVISIONS RELATING TO DRUGS AND DEVICES

Sr,No.	Section	Regulatory Entity
1	360 bbb	Expanded access to unapproved therapies and diagnostics.
2	360 bbb-1	Dispute resolution.
3	360 bbb-2	Classification of products.
4	360 bbb-3	Authorization for medical products for use in emergencies.
5	360 bbb-4	Technical assistance.
6	360 bbb-5	Critical Path Public-Private Partnerships.
7	360 bbb-6	Risk communication.

SUBCHAPTER V—DRUGS AND DEVICES; PART F — NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES

Sr,No.	Section	Regulatory Entity
1	360 ccc	Conditional approval of new animal drugs for minor use and minor species.
2	360 ccc-1	Index of legally marketed unapproved new animal drugs for minor species.
3	360 ccc-2	Designated new animal drugs for minor use or minor species.

No individual is allowed to import drugs into the USA for personal use. This kind of action is illegal. Even though the drug is approved by the other regulated agencies in other countries, it is not allowed into the country until unless that is approved by the FDA.

Why FDA Conducts Inspection in Manufacturing Facilities?

FDA inspects all the facilities and laboratories that come under its jurisdiction to prevent the entry of adulterated drugs into the USA market.

This inspection applies to local firms as well as foreign firms.

FDA verifies, during the inspection, whether the manufacturers or processors are complying with the regulations or not.

FDA inspects the firms based on six quality systems. The quality systems are :

         1. Quality system
         2. Production system
         3. Facilities and equipment system
         4. Laboratory controls system
         5. Materials system
         6. Packing and labelling system

FDA inspects the facilities to ensure the safety, quality and efficacy of the medicinal products and to protect the public health.

There are five types of FDA inspections.

1	Pre-approval inspection: This inspection is conducted before providing the approval for an NDA or an ANDA to ensure the identity, strength, quality, and purity of the product.

2	Post-approval inspection: This inspection is conducted soon after the approval of an NDA or an ANDA. This inspection is product specific.

3	Surveillance or Routine inspection: Dosage formulation, APIs, biologics, contract packagers, contract sterilizers and contract laboratories are inspected periodically by FDA as it is mandated by law. The inspectors may visit the facility without announcement.

4	Compliance follow-up inspection: This inspection is for the review of corrective and preventive actions after the issuance of a 483 form or warning letter. FDA thoroughly checks the adequacy of the actions taken for the violations identified in the previous inspection.

5	For-cause inspection: This inspection is conducted to investigate specific problems, such as severe cGMP violations and a recall of the product, came to the notice of FDA.

Failure to comply with the regulations may lead to serious regulatory actions.

Why FDA Is Asking For Quality Metrics?

Quality Metrics is an important initiative taken by the FDA to understand the health of manufacturing sites in terms of quality.

A set of measurements are brought forth to evaluate the quality of the facilities.

The companies which are manufacturing FDA-regulated drugs and biologics has to submit the Quality metrics to help the agency in the evaluation of the quality of the products.

FDA believes that Quality metrics will help the agency in ensuring the safety and efficacy of the FDA-regulated drugs and biologics.

Quality metrics ensure whether the products are manufactured continually under strict quality standards or not.

FDA can identify the facilities, which have high-risk quality problems, with the help of quality metrics data. These metrics really help the manufacturers also, in understanding their products' and processes' quality status on a real-time basis.

For more information refer: QUALITY METRICS TECHNICAL CONFORMANCE GUIDE

Summary

FDA is an administrative agency and part of the Department of Health and Human Services (HHS).

FD&C Act granted full authority to FDA to regulate food and drugs.

Office of the commissioner and four directorates help the agency in implementing the statutory requirement.

FDA releases guidance for the industry on regulatory issues. This guidance reflects the agency's current thinking on the issues.

FDA regulates the pharmaceutical industry using the statutory requirements set forth in the Food, Drugs and Cosmetic Act.

FDA conducts various types of inspections to ensure the safety, quality, purity and efficacy of the medicinal products.

Quality metrics are useful for the agency to ensure whether the products are manufactured under strict quality standards or not.

Protection of public health and control of adulterated drugs are the primary responsibilities of the US FDA.

It is the responsibility of the agency to ensure the safest drug products are available in the market for the public.

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Author Profile

Ram Kumar Reddy

Ram Kumar Reddy is the founder of Pharma Times Now. Helping Pharmacy and Chemistry students, along with the pharma employees, in learning pharmaceutical science. He has 24 years of rich experience in the Pharmaceutical industry and well versed in quality systems. He worked with Dr.Reddys and Sai Life Sciences. He lives in Hyderabad, India.