ANDA Process: Legal Requirements for Generic Drug Approval in the U.S.

The ANDA process is the legal pathway in the United States that lets generic drug companies get approval to sell cheaper versions of brand-name medications. It’s not a shortcut-it’s a carefully designed system that balances patient safety, innovation, and affordability. Since the Hatch-Waxman Act became law in 1984, this process has been responsible for bringing 90% of all prescriptions in the U.S. to generic drugs, saving consumers over $2.2 trillion in the last decade alone.

What Is the ANDA Process?

The Abbreviated New Drug Application (ANDA) is the formal submission a company must make to the U.S. Food and Drug Administration (FDA) to get approval for a generic drug. Unlike the full New Drug Application (NDA) used by brand-name companies-which requires years of clinical trials to prove safety and effectiveness-the ANDA skips those studies. Instead, it relies on the FDA’s previous approval of the original drug, called the Reference Listed Drug (RLD).

The goal is simple: prove your generic version is the same as the brand drug in every way that matters. That means the same active ingredient, the same strength, the same way it’s taken (pill, injection, inhaler), and the same effect on the body. The FDA doesn’t need to retest whether it works-it already knows from the brand drug. All you have to show is that your version behaves the same way in the body.

The Legal Foundation: The Hatch-Waxman Act

The ANDA process exists because of the Drug Price Competition and Patent Term Restoration Act of 1984, better known as the Hatch-Waxman Act. Named after its sponsors, Senator Orrin Hatch and Representative Henry Waxman, this law was a compromise. Brand-name companies got extended patent protection to make up for time lost during FDA review. Generic companies got a clear, faster path to market.

Before Hatch-Waxman, generic manufacturers had to repeat expensive clinical trials just to prove a drug worked. That made generics too costly to produce. After the law passed, the number of generic drugs available jumped. Today, nearly all prescriptions in the U.S. are filled with generics. The law didn’t just lower prices-it reshaped the entire pharmaceutical market.

Core Legal Requirements for ANDA Approval

To get an ANDA approved, a company must meet five non-negotiable legal and scientific standards set by the FDA:

1. Identical Active Ingredient: The generic must contain the exact same active pharmaceutical ingredient as the brand drug. No substitutions. No changes. Even a tiny difference can trigger rejection.
2. Same Dosage Form, Strength, and Route: If the brand drug is a 10mg tablet taken by mouth, the generic must be the same. No liquid versions, no higher doses, no patches unless you file a special petition.
3. Bioequivalence: This is the most critical part. The generic must deliver the same amount of drug into the bloodstream at the same rate as the brand drug. The FDA requires pharmacokinetic studies showing that the 90% confidence interval for peak concentration (Cmax) and total exposure (AUC) falls between 80% and 125% of the brand drug’s values. This range is based on decades of clinical data and is considered scientifically equivalent.
4. Identical Labeling: The prescribing information must match the brand drug’s label, except for minor differences like the generic manufacturer’s name or patent information. You can’t add new warnings or remove existing ones without FDA approval.
5. Manufacturing Compliance: The facility where the drug is made must follow Current Good Manufacturing Practices (cGMP). The FDA inspects these sites-often without notice-and rejects applications if there are violations. In 2022, 68% of FDA Form 483 observations (notices of violations) came from overseas facilities.

What You Must Submit: The ANDA Package

An ANDA isn’t just a form. It’s a massive technical dossier with 15 modules, submitted electronically in eCTD format. Here’s what’s required:

• Form FDA-356h: The official application form.
• Form FDA-3674: The user fee cover sheet.
• Chemistry, Manufacturing, and Controls (CMC): Detailed documentation on how the drug is made, including raw materials, equipment, process controls, and quality testing. This section causes the most rejections-23% of applications are refused because of incomplete CMC data.
• Bioequivalence Study Report: Must follow FDA guidance, use validated methods, and include data from at least 24 healthy volunteers.
• Stability Data: Shows the drug won’t break down over time under normal storage conditions. Exhibit batches must be made at commercial scale-either 10% of the planned commercial batch size or 100,000 dosage units, whichever is larger.
• Patent and Exclusivity Certifications: You must certify whether the brand drug’s patents are expired, will expire soon, or if you’re challenging them. This triggers legal consequences.

There’s also a $129,500 user fee for a new ANDA submission under the Generic Drug User Fee Amendments (GDUFA) for fiscal year 2024. That fee funds faster FDA reviews. Without it, your application won’t even be accepted.

Patent Certifications and Legal Hurdles

One of the most complex parts of the ANDA process is navigating patents. Under Hatch-Waxman, you must file one of four certifications:

• Paragraph I: No patent listed for the drug.
• Paragraph II: The patent has expired.
• Paragraph III: The patent will expire on a certain date-you’ll wait until then.
• Paragraph IV: The patent is invalid or won’t be infringed.

Paragraph IV is the most aggressive-and the most risky. If you file it, the brand-name company has 45 days to sue you for patent infringement. If they do, the FDA can’t approve your drug for 30 months, even if your product is perfect. This is called a “30-month stay.”

Some brand companies abuse this system by filing dozens of weak patents on minor changes-like coating color or packaging-to delay generics. This is called “evergreening.” In 2023, Harvard’s Dr. Aaron Kesselheim found that brand manufacturers filed 1,450 new patents on existing drugs between 2015 and 2020. These tactics have stretched approval times for some generics from 30 months to over 4 years.

Complex Generics: The New Challenge

Not all drugs are easy to copy. Inhalers, nasal sprays, topical creams, and injectables are considered “complex generics.” Their effectiveness depends not just on the chemical, but on the delivery system. A generic inhaler might have the same drug-but if the aerosol spray doesn’t reach the lungs the same way, it won’t work.

The FDA’s approval rate for complex generics is only 42% on first review, compared to 78% for simple pills. Companies often spend millions more and wait years longer to get approval. Teva’s generic version of Advair Diskus took 42 months and $28 million in extra costs because the FDA kept asking for better device testing.

The FDA is trying to fix this. In 2023, they launched a $15 million initiative to develop better scientific tools for testing complex products. They’re also increasing pre-ANDA meetings-where companies can get feedback before submitting-to 1,842 in 2022 alone.

How Long Does It Take?

Under GDUFA III (2023-2027), the FDA aims to review standard ANDAs in 10 months and priority ones in 8 months. But reality is slower. The average review time is now 36 months, up from 30 months in 2015. Why? Because more applications are incomplete. The FDA refuses to review 147 specific issues-from missing stability data to poorly written bioequivalence protocols.

Some companies get lucky. Lupin Limited got approval for a generic version of Jardiance in just 9.5 months because they submitted a “clean application” with flawless CMC and bioequivalence data. Others get stuck in cycles of deficiency letters, which can add years.

Who’s Winning the Market?

Generic drug sales hit $127.3 billion in 2022. Teva leads with 18.7% of the market, followed by Sandoz and Amneal. But the real winners are patients. Generic competition drives prices down 80-85% in the first year after launch. After multiple generics enter, prices drop by 90%.

For chronic conditions like hypertension or diabetes, generic use is over 93%. That’s not just savings-it’s access. A diabetes patient who can’t afford $500 a month for the brand can now pay $10 for the generic.

What Happens After Approval?

Getting approval isn’t the end. The FDA can inspect your facility at any time. If they find violations, they can pull your drug from the market. You must report any changes to your manufacturing process, supplier, or formula. Even a new packaging supplier requires a prior approval supplement-and another $5,000 fee.

There’s also post-market surveillance. If patients report unexpected side effects, the FDA can require new studies or label changes. You’re legally responsible for the safety of your product, even if it’s a generic copy.

How to Get Started

If you’re a company looking to enter the generic market:

1. Find the right Reference Listed Drug (RLD) in the FDA’s Orange Book.
2. Check all patents and exclusivity periods-don’t assume they’re expired.
3. Build a GMP-compliant facility or partner with one that is.
4. Hire a regulatory affairs team with real ANDA experience. The average professional needs 2-3 years to master this.
5. Consider a pre-ANDA meeting with the FDA. It costs nothing but can save you millions.
6. Prepare your CMC section like your life depends on it-because it does.

Most failures happen before submission. Companies rush the CMC section, skip stability testing, or misunderstand bioequivalence requirements. The FDA doesn’t give second chances on paperwork. If your application is refused to receive, you lose your place in line-and your fee.

Future of the ANDA Process

The FDA is investing in AI tools to speed up document review and real-time communication with applicants. The goal: cut approval times for simple generics to 24 months by 2027. But complex products will still take longer.

Legislation like the Affordable Prescriptions for Patients Act of 2023 aims to limit patent thickets and stop brand companies from blocking access to samples needed for testing. That could remove one of the biggest barriers for generics.

For now, the ANDA process remains the backbone of affordable medicine in the U.S. It’s not perfect. It’s not fast. But it works. Millions of people rely on it every day. And if you’re trying to build a generic drug company, understanding its legal and technical requirements isn’t optional-it’s survival.