Abbreviated New Drug Application (ANDA)

Abbreviated New Drug Application An abbreviated new drug application (ANDA) is submitted to the FDA for review and potential approval of a generic drug, allowing the applicant to manufacture and market a cost-effective alternative to the brand-name drug. Generic drugs must be comparable to innovator drugs in dosage form, strength, administration route, quality, performance, and intended use. Approved products, whether brand-name or generic, are listed in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).

ANDAs are termed “abbreviated” because they typically do not require preclinical (animal) and clinical (human) data to establish safety and efficacy. Instead, generic applicants must scientifically demonstrate that their product performs similarly to the innovator drug. One method of demonstrating this similarity is through bioequivalence studies, which measure the rate and extent to which a generic drug reaches the bloodstream compared to the innovator drug. The FDA requires that generic versions deliver the same amount of active ingredients into the bloodstream in the same timeframe as the innovator drug to be approved.

The Hatch-Waxman Amendments of 1984 established bioequivalence as the basis for approving generic drugs, allowing FDA approval without repeating costly clinical trials. These amendments also granted patent term extensions for innovator drugs undergoing FDA review and periods of marketing exclusivity. Additionally, generic companies gained the ability to challenge patents in court and a 180-day exclusivity period before other generics can enter the market.

Through the ANDA process, generic drug applicants can gain FDA approval without conducting clinical trials if their drug is proven bioequivalent to the branded (innovator) drug. All FDA-approved generic drugs ensure the same high quality, strength, purity, and stability as their brand-name counterparts.

Types of ANDA filings include: Abbreviated New Drug Application

1. Paragraph I (Para I): This filing occurs when the innovator drug’s information is not listed in the FDA’s Orange Book.
2. Paragraph II (Para II): A Para II filing is made when the drug’s patent has expired, allowing for the generic version to enter the market.
3. Paragraph III (Para III): This filing is made when the applicant intends to market the generic drug only after the original drug’s patent has expired.
4. Paragraph IV (Para IV): A Para IV filing is made when the applicant believes their product does not infringe on the innovator’s patents, or that these patents are invalid or unenforceable. This type of filing typically triggers patent litigation between the generic and brand-name companies.

• Paragraph I and II (Para I and II): If an ANDA is certified under Para I or Para II, it can be approved immediately upon meeting all regulatory and scientific requirements (efficacy, safety, and bioequivalence). This means the generic drug manufacturer can start producing generic versions of the branded drug if either the branded drug’s patent information is not filed or if the patent has expired.
• Paragraph III (Para III): A Para III filing is made when the applicant plans to sell the generic drug only after the original drug’s patent expires. Approval of an ANDA under Para III certification depends on the patent’s expiration date, and the approval becomes effective from that date.
• Paragraph IV (Para IV): When filing under Para IV, the ANDA applicant must notify the patent holder. The patent holder has 45 days to bring a patent infringement suit. If such a suit is filed, the FDA suspends the ANDA approval until:
  • The court decides the patent is invalid or not infringed,
  • The patent expires, if found infringed, or
  • 30 months from the date the patent holder received notice of the Para IV filing (subject to court modifications).

During these 30 months, no ANDA can be approved unless the court finds the patent invalid or not infringed before that time. If the court rules the patent is invalid or not infringed before 30 months, the FDA can approve the ANDA. If the court upholds the patent’s validity and infringement, the FDA delays approval until the patent expires.

The FDA’s review process for drugs intended for human use involves evaluation by the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research for biological products. Here’s a summary:

1. The FDA sends the applicant’s application to the appropriate review team within CDER or another relevant center for evaluation and approval.
2. If the application is incomplete or deficiencies are identified, the FDA issues a “refuse to file letter” to the applicant.
3. Complete applications without deficiencies undergo internal review for bio-equivalence, chemistry/microbiology, plant inspection, and labeling issues.
4. If there are pending results or bio-equivalence deficiencies, the FDA issues corresponding deficiency letters and awaits satisfactory results from the applicant.
5. Upon completion of the ANDA submission and resolution of all queries, the applicant receives an FDA approval letter.

ANDA applicants can access a variety of resources to aid in their submissions. These resources include:

1. Statutory and Regulatory Requirements: Detailed guidelines outlining the legal and regulatory criteria for ANDA applications.
2. CDER Assistance: Support from the Center for Drug Evaluation and Research (CDER) to help applicants understand and fulfill these requirements.
3. Internal Review Principles, Policies, and Procedures: Guidelines and procedures followed by CDER during the internal review of ANDA submissions.
4. Summary Tables, Application Forms, and Other Resources: Accessible through the ANDA Forms & Submission Requirements, providing structured information and necessary forms for preparing and submitting an ANDA.

These resources are essential for ensuring that ANDA submissions meet all necessary standards for FDA approval.

For ANDA submissions, several key guidance documents and regulatory resources are critical:

1. Guidance Documents:
   • Generic Drugs Guidance: Provides comprehensive guidelines on various aspects of generic drug development and submission.
   • Biopharmaceutics Guidance: Focuses on the biopharmaceutical aspects relevant to generic drug approval.
   • Product-Specific Guidance: Offers specific requirements and considerations for the development of individual generic drug products.
2. Laws, Regulations, Policies, and Procedures:
   • Federal Food, Drug, and Cosmetic Act (FD&C Act): Establishes the foundational laws ensuring the safety and effectiveness of drugs, devices, and cosmetics in the United States.
   • Code of Federal Regulations (CFR):
     • 21 CFR Part 314: Outlines the requirements for submitting applications for FDA approval to market new drugs, including ANDAs.
     • 21 CFR Part 320: Sets forth the standards and requirements for demonstrating bioavailability and bioequivalence, crucial for ANDA approval.
3. Manual of Policies and Procedures (MAPPs):
   • CDER’s MAPPs: Internal documents that detail the policies and procedures followed by CDER staff during the drug review process.
   • Chapter 5200: Specifically covers processes and activities related to generic drugs within CDER, ensuring consistency and standardization in review procedures.

These resources are essential for ANDA applicants, FDA review staff, and holders to understand the requirements, procedures, and standards for generic drug approval in the United States.

Changes to an approved NDA / Abbreviated New Drug Application

This guidance offers recommendations for holders of NDAs and ANDAs planning post-approval changes under section 506A of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.70. It replaces the previous guidance issued in November 1999. The recommendations cover changes in:

1. Components and composition
2. Manufacturing sites
3. Manufacturing process
4. Specifications
5. Container closure system
6. Labeling
7. Miscellaneous changes
8. Multiple related changes

The guidance was developed under the oversight of the Chemistry, Manufacturing and Controls Coordinating Committee within the FDA’s Center for Drug Evaluation and Research (CDER).

The FDA Modernization Act of 1997, signed on November 21, 1997, amended the Act by introducing section 506A, outlining requirements for initiating and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes.

The FDA has updated its regulations concerning supplements and other modifications to approved applications under 21 CFR 314.70 to align with section 506A of the Act. These changes aim to evaluate their impact on the drug product’s identity, strength (e.g., assay, content uniformity), quality (e.g., physical, chemical, and biological properties), purity (e.g., impurities, degradation products), or potency (e.g., biological activity, bioavailability, bioequivalence) concerning the drug product’s safety or effectiveness.

CDER has issued guidance, including the SUPAC (Scale-Up and Post Approval Changes) guidance, which provides recommendations on reporting categories:

• Reporting Categories: This guidance excludes components and composition changes. Section 506A of the Act and 21 CFR 314.70(c) outline two types of changes:
  • A. Major Change: A substantial change with potential adverse effects on the drug product’s identity, strength, quality, purity, or potency concerning its safety or effectiveness. Applicants may request expedited review for public health reasons, such as drug shortages, through a Prior Approval Supplement.
  • B. Moderate Change: Changes with moderate potential adverse effects on the drug product’s identity, strength, quality, purity, or potency. Two types exist:
    • 30-Day Supplement: Requires submission to the FDA at least 30 days before distributing the modified drug product.
    • Changes Being Effected (CBE): Allows distribution upon FDA receipt.
  • C. Minor Change: Changes with minimal potential adverse effects. Applicants must list these changes in their next Annual Report, including:
    • Editorial changes (e.g., spelling corrections).
    • Submission requirements for supplements or annual reports.

Applicants making changes under section 506A of the Act must also comply with other relevant laws and regulations, including current Good Manufacturing Practice (cGMP) requirements (21 U.S.C. 351(a)(2)(B)) and the Code of Federal Regulations (e.g., 21 CFR parts 210, 211, 314). Labeling changes under 21 CFR 314.70(c)(6)(iii) necessitate submission of 12 copies of the final printed labeling, as specified under 21 CFR 314.70(c)(1). Any labeling changes made under 21 CFR 314.70(b) or (c) must adhere to 21 CFR 314.70(a)(4).

Assessment of the Impact of Manufacturing Changes

1. Adherence to Specifications: Specifications refer to quality standards outlined in an approved application, including tests, analytical procedures, and criteria for acceptance. Compliance with specifications means that the material, when tested according to the specified analytical methods, meets the defined acceptance criteria.
2. Additional Testing: In cases where manufacturing changes may affect the identity, strength, quality, purity, or potency of a drug product, the applicant should conduct additional testing as necessary. This evaluation includes assessing changes in chemical, physical, microbiological, biological, bioavailability, or stability profiles. For instance: a. Assessment of impurities: Toxicology testing may be necessary to qualify new impurities. b. Assessment of physical characteristics such as hardness or friability of tablets. Equivalence testing should determine the extent of impact on the drug product’s identity, strength, quality, purity, and potency. Equivalence does not imply identical performance but may include maintaining key quality attributes like stability. c. Identification of adverse effects: Certain manufacturing changes can negatively impact the drug product. In such cases, the FDA recommends submission of a prior approval supplement, regardless of the reporting category. d. Changes in formulation, including inactive ingredients, typically require a prior approval supplement unless exempted by regulation (314.70(b)(2)(i)). e. Removal or reduction of ingredients intended solely for color alteration may be reported in an annual report (314.70(d)(2)(ii)).
3. Guidance on Changes: Detailed guidance on changes affecting components and composition, suitable for submission via a changes-being-effected supplement or annual report, is not included here due to its complexity but can be found in post-approval change guidance documents (e.g., SUPAC documents).

General Considerations: CDER must be informed if a manufacturer changes to a different manufacturing site than those specified in the approved application (314.70(a)). Sites encompass facilities used by an applicant:

1. Manufacturing or processing of drug products, including in-process materials, drug substances, or drug substance intermediates.
2. Packaging of drug products.
3. Labeling of drug products.
4. Testing of components, drug product containers, closures, packaging materials, in-process materials, or drug products. a. Testing sites encompass facilities conducting physical, chemical, biological, and microbiological tests to monitor, accept, or reject materials, including those conducting stability testing. b. FDA recommends that a change to a different manufacturing site, especially if the site type is routinely inspected by FDA and lacks a satisfactory Current Good Manufacturing Practice (CGMP) inspection for the operation type being relocated, be submitted as a prior approval supplement.

 Major Changes: Here are examples of significant changes:

1. Changes that could impact controlled (or modified) release formulations.
2. Changes affecting drug product sterility assurance, including: a. Alterations in sterilization methods, such as transitioning from sterile filtration or aseptic processing to terminal sterilization. b. Addition of new equipment made from different materials to an aseptic processing line. c. Replacement of a Class 100 aseptic fill area with a barrier system or isolator for aseptic filling. d. Shift from bioburden-based terminal sterilization to an overkill process. e. Changes in materials or pore size ratings of filters used in aseptic processing.

1. Changes in Manufacturing Process or Technology:
   • Drug Product:
     • Transition from dry to wet granulation.
   • Drug Substance:
     • Shift from filtration to centrifugation.
     • Change in the synthesis route of a drug substance.
   • Addition of an ink code imprint or change in ink used for an existing imprint, where the new ink is not currently used in CDER-approved drug products.

Specifications refer to quality standards such as tests, analytical procedures, and acceptance criteria outlined in an approved application. These standards confirm the quality of drug substances, drug products, intermediates, raw materials, reagents, components, in-process materials, and container closure systems used in drug substance or drug product production. These specifications also apply to standards related to sterility assurance.

When making changes to or within the container closure system, the potential adverse effects on the drug product’s identity, strength, quality, purity, or potency, and thus its safety or effectiveness, depend on factors like the drug product’s route of administration, the performance of the container closure system, and the likelihood of interaction between packaging components and the dosage form. In some cases, there may be a significant risk of adverse effects, regardless of direct testing of the drug product against approved specifications.

A change to or within a packaging component often necessitates a new or revised specification for that component. This change does not typically trigger consideration as a multiple related change; only the reporting category for the packaging change needs to be addressed.

Changes in drug labeling encompass modifications to package inserts, package labeling, and container labels. All promotional labeling and advertising must promptly align with any implemented labeling changes. For ANDA drug products, all labeling changes must comply with section 505(j) of the Act.

Multiple related changes involve various combinations of individual changes. If an applicant has multiple related changes falling under different recommended reporting categories, CDER advises submission in accordance with the reporting category for each individual change.

This summary touches on general considerations provided in the guidance document. The FDA offers numerous examples of major, moderate, and minor changes.

For an overview of regulatory authorities such as those in India, United States, European Union, Australia, Japan, and Canada, including their organizational structure and types, additional specific details are available.