NDAINTRODUCTION: New Drug Application is a Critical component for drug approval process which required to submit to USFDA before drug commercialization. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA. The regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization. Goals of the NDA:To provide enough information to permit FDA reviewer to reach the following key decisions: Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks. Whether the drugs proposed labeling (package insert) is appropriate, and what it should contain. Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity. NDA Classifications: New Molecular Entity New Salt of Previously Approved Drug (not a new molecular entity) New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) New Combination of Two or More Drugs Already Marketed Drug Product - Duplication (i.e., new manufacturer) New Indication (claim) for Already Marketed Drug (includes switch in marketing status from prescription to OTC) Already Marketed Drug Product - No Previously Approved NDA.

Assembling Applications for Submission:

Assembling Applications for Submission the FDA requires drug sponsors to submit multiple copies of the NDA The archival copy, the review copy, the field copy. In 1997 the FDA Center for Drug Evaluation and Research (CDER) published guidelines that allow sponsors to submit NDAs electronically instead of on paper. The Archival Copy: The Archival Copy Contains all sections of the NDA, including the cover letter, Form FDA-356h (Application to Market a New Drug, Biologic, or an Antibiotic for Human Use), the administrative sections, Comprehensive NDA index, and All technical sections. It must contain four copies of the Labeling section. It must contain three additional copies of the CMC and Methods Validation Package in a separate binder. The archival copy is the only copy that contains the Case Report Tabulation and Case Report Forms.The Review Copy:The Review Copy Intended for reviewers in the corresponding technical disciplines. In addition to the appropriate technical section, each review copy also includes The cover letter, Form FDA-356h, The administrative sections, Comprehensive NDA index Individual table of contents, The Labeling section, and The Application Summary. The Field Copy:The Field Copy required since 1993 for use by FDA inspectors during pre approval facilities inspections. It includes the Cover letter and Form FDA-356h, the administrative sections, the

comprehensive NDA index Individual table of contents, The Labeling section, The Application Summary, and CMC and Methods Validation Package. NDA CONTENTS: The NDA may have as many as 20 different sections in addition to the Form FDA-356h itself. The specific contents of the NDA will depend on the Nature of the drug and the information available at the time of submission. The application Form FDA-356h serves as Checklist as well as Certification that the sponsor agrees to comply with a range of legal and regulatory requirements. Section 1: Index Section 2: Labeling Section 3: Application Summary Section 4: Chemistry, Manufacturing, and Controls (CMC) Section 5: Nonclinical Pharmacology and Toxicology Section 6: Human Pharmacokinetics and Bioavailability Section 7: Microbiology Section 8: Clinical Data Section 9: Safety Update Reports Section 10: Statistics Section 11: Case Report Form Tabulations Section 12: Case Report Forms (CRFs) Section 13: Patent Information Section 14: Patent Certification Section 15: Establishment Description Section 16: Debarment certificate Section 17: Field copy certification Section 18: User fee coversheet Section 19: Financial Disclosure Section 20: Other/ PediatricsSection 1: Index:The NDA index is a comprehensive table of contents that enables the reviewers to find specific information in this massive document quickly. The NDA index should follow immediately after the Form FDA-356h and the administrative items. It must show the location of every section in the archival NDA by volume and by page number. Index It should guide reviewers the data in the technical sections, the summary, and the supporting documents each separately bound technical section should also contain a copy of the overall NDA index in addition to its own table of contents based on the index.

Section 2: Labeling:The labeling section must include all draft labeling that is intended for use on the product container, Cartons or packages, the proposed package insert.Section 3: Application Summary:The application summary is an abbreviated version of the entire application. This overview is one of the few elements of the application that all reviewers receive, and it should give them a clear idea of the drug and its application. The summary usually comprises 50 to 200 pages. The draft product labeling include the following sections 1. Description2. Clinical Pharmacology 3. Indications and Usage4. Contraindications5. Warnings

6. Precautions7. Adverse Reactions8. Drug Abuse and Dependence9. over dosage 10. Dosage and Administration 11. How Supplied (primary and secondary packages)For each section of the labeling, include annotations referring to information in the summary and technical sections of the application that support the inclusion of each statement in the labeling with respect to Animal pharmacology and/or animal toxicology, Clinical studies, Integrated Summary of Safety (ISS) and Integrated Summary of Effectiveness (ISE) Safety (ISS) and Integrated Summary of Effectiveness (ISE) Pharmacologic class Scientific rationale Intended use Potential clinical benefits.Foreign marketing history: The summary must include a list of any countries in which the drug is or was marketed, along with the dates when it was marketed, if they are known. It must also include a list of any countries in which the drug has been withdrawn from marketing for any reason relating to safety or efficacy or in which an application has been rejected.

Section 4: Chemistry, Manufacturing, and Controls (CMC):The first technical section of the NDA.It includes information on the composition, Manufacturing, and Specifications of the drug substance and the drug product. The CMC information must include Description of the drug substance or active ingredient, Its stability, Physical and chemical characteristics, Provide the names/designations of the drug substance, including Generic/common name Chemical name (IUPAC/USAN/CAS) Code(s) (CAS/internal).It Provide a structural overview including Molecular structure, Empirical formula, Molecular weight, Elemental composition. The description of the drug substance physical and chemical characteristics should include: Appearance, including color, crystalline form, and odor Melting/boiling point Refractive index, viscosity, and specific gravity Polymorphs, including modifications (forms) and relative kinetic/ thermodynamic stabilities. The physical and chemical characteristics should also include Solubility, Ionization constants, and Partition coefficients at various pHs. Solubility in common organic solvents as well as in various aqueous mediaWater0.1 N HCl 0.02 N HCl SGF without pepsin Water buffered to various acidic/neutral/basic pHs. It Provide a reference standard (RS) to elucidate the drug substance chemical structure, including Preparation method, Test methods, Test results as shown by a certificate of analysis (C.O.A).Provide proof that the reference standard was adequately tested and characterize the spectra completely. Provide structural elucidation using a reference standard as applicable. Measures might include X-ray (in the case of absolute configuration or polymorphism) UV/visible spectrum, FTIR spectrum, 1H NMR/13C NMR spectrum, Low-resolution/high-resolution mass spectrum, Elemental analysis. The CMC information must also include theNames, addresses and functions of each site where the drug substance is manufactured or tested. The description of the drug substance manufacturing methods must include Synthesis scheme, Synthesis description, Typical executed manufacturing record Compilation of and analytical controls for starting materials, Reagents, Solvents Catalysts, and Intermediates Suppliers for starting materials. The discussion of drug substance analytical controls should include the following: Specifications Methods Rationale for methods/specifications Method validations Batch analytical data (including impurity profiles cross-referenced with toxicology studies)Sampling plan Provide information on drug substance stability including: Ambient/accelerated stability data Retest dating Highly stressed (e.g., acid, base, reflux) data Provide a listing of all inactive ingredients. For compendial (e.g., UPS/NF) inactive

ingredients, reference the appropriate current compendial monographs and provide more precise specifications as necessary. For noncompendial ingredients that fall under 21 CFR such as D&C and FD&C dyes, reference the appropriate section of 21 CFR and provide any additional specifications beyond the scope of the CFR.For noncompendial items that are not regulated by 21 CFR, provide appropriate analytical specifications and methods. Provide information on the drug product manufacturing methods: Summary and schematics of manufacturing procedure Master batch record for proposed marketed products, including actual operating conditions, type and size of equipment, and in process controls and tests Executed batch record. The section on drug product packaging must include: Summary of container/closure system(s)Listing of packaging components and component/resin suppliers Specifications for each packaging component DMF authorization letters Description of the packaging process Test methods (as appropriate)Developmental data that confirms the suitability of the packaging. This includes water vapor permeation data for plastic containers/ closures and compatibility testing for solutions, suspensions, emulsions, etc. The drug product stability information will differ slightly from the drug substance stability information. Unstressed/stressed stability data Statistical analysis to establish consistency of data Expiration dating Post approval stability commitment/protocol. For an NDA, provide a list of all drug product investigational formulations used in clinical studies, along with the quantitative composition of each formulation. Every NDA must include an environmental assessment (EA)The EA, also called the environmental impact analysis report, includes an analysis of the manufacturing process and ultimate use of the drug product as well as a discussion of how the process and the drug product may affect the environment.Methods validation package: The final component of the CMC technical section is the methods validation package. The package must comprise: Specifications and test methods for each component used in the drug product Specifications and methods for the drug product Validation of test methods Names and addresses of component suppliers Names and addresses of the suppliers of the container closure system.

Section 5: Nonclinical Pharmacology and Toxicology:The second technical section of the NDA provides a description of all animal and in vitro studies with the drug. Include a narrative summary of notable findings in all studies and a discussion of notable findings across the various studies. Provide individual study reports,including Pharmacology, Toxicology, and ADME studies. For the pharmacology studies, following data is required1.Effects related to the therapeutic indication, such as the pharmacodynamic ED 50 in dose-ranging studies and the mechanism of action (if known)2.Secondary pharmacological actions in order of clinical importance as possible adverse effects or as ancillary therapeutic effects3. Interactions with other drugs. The Toxicology information must include information on Acute toxicity, Multidose toxicity (including subchronic, chronic, and carcinogenicity) Special toxicity studies, as well as Reproduction studies and mutagenicity studies. Present toxicology data by intended route of administration in the following order: 1. Oral 2.Intravenous 3.Intramuscular 4.Interperitoneal 5.Subcutaneous 6.Inhalation 7 Topical 8 Other in vivo 9.In vitro. Example:For acute toxicity studies, present the animal study data in the following order: 1. Mouse 2.Rat 3.Hamster 4.Other rodent(s) 5.Rabbit 6.Dog 7.Monkey 8.Other nonrodent mammal(s) 9 Non mammals.Section 6: Human Pharmacokinetics and Bioavailability :

This technical section includes data from Phase I safety and tolerance studies in healthy volunteers and ADME studies. It should include a table of PK parameters, giving the values for the major parameters (mean and % cv) such as Peak concentration (Cmax) Area under the curve (AUC) Time to reach peak concentration (tmax) Elimination constant (Ke) Distribution volume (Vd) Plasma and renal clearance Urinary excretion. Drug formulation information should include a list of all formulations used in clinical trials and in in vivo bioavailability and PK studies. The analytical methods used must be summarized in each in vivo biopharmaceutic study. Include detailed information, such as Sensitivity Linearity Specificity and Reproducibility of the analytical test methods used in each study. Provide dissolution data on each strength and dosage form for which an approval is sought. Include a comparative dissolution study with the lot in the in vivo biopharmaceutic study. Include summary of the product Dissolution performance Dissolution method and Dissolution specifications.

This technical section must include individual study reports from five types of biopharmaceutic. Pilot or background studies Bioavailability/bioequivalence Pharmacokinetic studies Other in vivo studies In vitro studies .Section 7: Microbiology :Required for anti infective drug products.Antimicrobial drugs differ from other classes of drugs in that they are designed to affect microbial physiology rather than patient physiology. In vitro and in vivo studies are critical in establishing the new drug effectiveness, especially if the microorganism has the potential to develop, or has developed, resistance to other antimicrobial drugs. This section requires the following technical information and data: 1. A complete description of the biochemical basis of the drug action on microbial physiology. 2. The drug antimicrobial spectrum. Include results of in vitro studies demonstrating the concentrations of the drug that are required for effective use. 3. Describe any known mechanisms of resistance to the drug and provide information or data of any known epidemiologic studies demonstrating prevalence to resistance factors. 4. Clinical microbiology laboratory methods, such as in vitro sensitivity discs, necessary to evaluate effective use of the drug.Section 8: Clinical Data:This technical section of the NDA comprises ten elements. The document largest and most complex section. List of investigators and list of INDs and NDAs Background/overview of clinical investigations Clinical pharmacology section Controlled clinical trials Uncontrolled clinical trials Other studies and information section Integrated summary of effectiveness data Integrated summary of safety information Drug abuse and over dosage information Integrated summary of benefits and risks of the drug

List of investigators and list of INDs and NDAs-- The list of investigators should include all investigators who have used any dosage form. Alphabetize the list and note each investigator address, the type of study, the study identifier, and its location in the NDA .Provide a list of all known INDs under which the drug, in any dosage form, has been studied. Background/overview of clinical investigations-- Describe the general approach and rationale used in developing the clinical data. Explain how information about the drug derived from clinical pharmacology studies led to critical features of the clinical studies.Support the basis for the design features of the clinical trials, such as number of patients, duration, selection criteria, and controlsClinical pharmacology-- Clinical pharmacology Should include ADME studies, pharmacodynamic dose range, and dose response studies, and any other studies of the drug

action. The format and order of presentation is as follows: 1. Table of all studies grouped by study type. Provide the investigators, study numbers, start date, and location of the report in the NDA. 2. For each group of studies, a brief synopsis of each study 3. An overall summary of the clinical pharmacology data Controlled clinical trials --Controlled clinical trials Provide the following material in the order presented below: 1. A table of all studies 2. Full clinical trial reports of all controlled studies in the following order: Completed studies Ongoing studies with interim results Incomplete or discontinued studies 3. Full reports of dose-comparison concurrent control studies, followed by those for aœno- treatment concurrent control, active control studies, and historical control studies Uncontrolled clinical trials --Uncontrolled clinical trials They may be used to provide support for controlled studies and to provide critical safety information. This section should include a table of all studies. Group full reports of studies according to completeness and availability of Case Report Forms (CRFs). Other studies and information: Include a description and analysis of any additional information that the applicant has obtained from any source, foreign or domestic, that is relevant to evaluating the products safety and effectiveness. It should include information on commercial marketing experience and foreign regulatory actions, including List of countries in which the drug has been approved Details of any rejected registrations Copies of approved labeling (package inserts) from major regions such as Europe, Canada, Australia, New Zealand, and Japan Any other reports from the literature not provided Section 9: Safety Update Reports :A pending application must be updated when new safety data becomes available that could affect any of the following: Statements in draft labeling Contraindications Warnings Precautions Adverse events. Safety update reports are not to be used to submit any new final reports that may impact FDA review time unless the FDA agrees at the pre-NDA meeting that it will accept the reports in this manner. Safety updates are submitted 4 months (120 days) after the initial application, following the receipt of an approval letter and at any other time that the FDA requests such an update.Section 10: Statistics :This technical section includes descriptions and documentation of the statistical analyses performed to evaluation the controlled clinical trials and other safety information. It must include copies of All controlled clinical trial reports Integrated efficacy and safety summaries Integrated summary of risks and benefits.Section 11: Case Report Form Tabulations :This section must include complete tabulations for each patient from every adequately or well-controlled Phase II and Phase III efficacy study, and from every Phase I clinical pharmacology study. It also must include tabulations of safety data from all clinical studies. Section 12: Case Report Forms (CRFs) :It is necessary to include the complete CRF for each patient who died during a clinical study and for any patients who were dropped from the study .The report must be submitted regardless of whether the AE is considered to be related to the study drug, even if the patient was receiving a placebo or comparative drug. Additional CRFs must be provided at the request of the FDA.several other supporting items as appropriate Item 13: Patent informationItem 14: Patent certification Item15: Establishment description Item 16: Debarment certification Item 17: Field copy certification

Item 18: User fee cover sheet (Form FDA-3397)Item19: Financial disclosure (Form FDA 3454, form FDA-3455)Item 20:Other/pediatric use.

Once the application is submitted, the FDA has 60 days to conduct a preliminary review which will assess whether the NDA is "sufficiently complete to permit a substantive review". If the NDA is found to be insufficiently complete (and reasons for this can vary from a simple administrative mistake in the application to a requirement to reconduct much of the testing), then the FDA rejects the application with the issue of a Refuse to File letter which is sent to the applicant explaining where the application has failed to meet requirements. Assuming that everything is found to be acceptable, the FDA will decide if the NDA will get a standard or accelerated review and communicate the acceptance of the application and their review choice in another communication known as the 74-day letter. A standard review implies an FDA decision within about 10 months while a priority review should complete within 6 months.The NDA in CTD Format :The NDA in CTD Format ICH has developed a Common Technical Document to streamline regulatory submissions in Europe, the U.S. and Japan. CTD is an information format that contains clinical, nonclinical, and manufacturing technical data.The CTD format features well-defined modules, with a highly specific structure and numbering of sections within the modules. It makes a clear distinction between subjective information sections and objective information sections. Use of the CTD format benefits both regulatory agencies and the pharmaceutical industry. In addition to enhancing reviews, the CTD use of common elements facilitates communications between the agencies and the applicants and simplifies the exchange of information between regulatory authorities. The document also provides a common basis for continuous improvement of Good Regulatory Practices.

REFERENCES:

Douglas J. Pisano, David S. Manlus “FDA Regulatory Affairs, A guide for Prescription Drugs, Medical Devices and Biologics-New drug Application “Second edition-Marcel Dekker, page no 69-108.http://www.fda.gov/cder/guidance/index.htm. 31

Abbreviated New Drug Application (ANDA):Definition : “A drug product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use” It is termed as "abbreviated" because they generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.It is an application for generic versions of off-patent drugs to receive FDA approval with less costly or no preclinical and clinical testing. The intention is to minimize duplication of available information. No safety or efficacy trials are performed. Complete chemistry, manufacturing, and controls information and information regarding the bioavailability of solid dosage forms. Basic Generic Drug Requirements are:--

Same active ingredient(s) Same route of administration

Same dosage form Same strength Same conditions of use Inactive ingredients already approved in a similar NDA

Goal of ANDA:Provide enough information to permit FDA to make the following key decisions:

Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks. Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain. Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.

To reduce the price of the drug. To reduce the time development. Increase the bioavailability of the drug in comparison to references list drug.

Abbreviated or Supplemental NDA: Abbreviated NDA: includes..

Generic drug New combination of approved drugs Proportion of ingredients in combination is changed

Supplemental NDA: includes.. New intended use of the drug (labeling change) Dose, method or duration of administration is changed Change in manufacturing process or location

NDA vs. ANDA Review Process:Requirements for NDA:

Labeling Pharmacology and toxicology Chemistry Manufacturing Controls Microbiology Inspection Testing Animal studies Human studies Bioavailability

Requirements for ANDA: Labeling Pharmacology and toxicology Chemistry Manufacturing Controls Microbiology Inspection Testing Bioequivalence

NDA ANDA

Applicable for new drug Applicable for generic drug Takes longer time ( 12-15 years) Comparatively less time taken(1-2 years) More expenditure of money Comparatively less Cost of drugs are more Cost of drugs are less Nonclinical studies and clinical investigations are essential

Nonclinical studies and clinical investigations are nonessential except bioavailability and bioequivalence

Format of ANDA: Three copies of application are required, an archival copy, a review copy and a field copy. FDA will maintain guidance documents on the format and content of applications to assist applicants in their preparation. ANDA includes the following:

Application form: the applicant shall submit a completed and signed application form that contains the information. The applicant shall state whether the submission is an abbreviated application or a supplement to an abbreviated application. Table of contents: the archival copy of the ANDA is required to contain a table of contents that shows the volume number and page number of the contents of the submission. Basis for ANDA submission: an ANDA must refer to a listed drug. Ordinarily, that listed drug will be the drug product selected by the agency as the reference standard for conducting bioequivalence testing. The application shall contain: The name of the reference drug, including its dosage from and strength. For an abbreviated new drug application based on the reference listed drug must be the same as the listed drug approved in the petition. A statement as to whether, according to the information published in the list, the reference listed drug is entitled to a period of marketing exclusivity.

Conditions of use: A statement that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the drug product have been previously approved for the reference listed drug. A reference to the applicant’s annotated proposed labeling and to the currently approved labeling for the reference listed drug. Active ingredients Route of administration, dosage form and strength. Bioequivalence Labeling Samples: need not be submitted until requested by FDA. Patent certification Financial certification or disclosure statement.

ANDA contents: Section 1: Overall ANDA index:- The NDA index is a comprehensive table of contents that enables the reviewers to find specific information in this massive document quickly. Section 2: Labeling:- It must include all draft labeling that is intended for use on the product container, cartons or packages, including the proposed package insert. Section 3: Application summary:- Proposed annotated package insert-

Pharmacology class, scientific rational, intended use, and potential clinical benefits Foreign marketing history Chemistry, Manufacturing and control summary Nonclinical pharmacology and toxicology summary Human pharmacokinetics and bioavailability summary Microbiology summary Clinical data summary and results of statistical analysis Discussion of benefit/risk relationship

Section 4: Chemistry, manufacturing and controls:- Chemistry, manufacturing and control information Samples Methods validation package

Section 5: Nonclinical pharmacology and toxicology Provide individual study reports, including pharmacology, toxicology, ADME studies. Effects related to the therapeutic indication, such as the pharmacodynamic ED50 in dose- ranging studies and the mechanism of act ion (if know n) Interactions with other drugs (or cross-reference the location of the information in any of the above subsection

Section 6: Human Pharmacokinetics and bioavailability:- includes data from Phase I safety and tolerance studies in healthy volunteers. Element in the section tabulated summary of studies showing all in vivo biopharmaceutics studies performed.

Summary of analytical method used in in vivo biopharmaceutic study Pilot or background studies Bioavailibility or bioequivalence studies Pharmacokinetic studies In vitro studies

Section 7: Microbiology:- Includes for anti infective drug products. It requires the following technical information and data:-

A complete description of the biochemical basis of the drug action on microbial physiology The drugs antimicrobial spectrum Describe any known mechanism of resistance to the drug and provide information/data of any known epidemiologic studies demonstrating prevalence to resistance factor Clinical microbiology laboratory methods

Section 8: Safety data Statements in draft labeling Contra indications Warnings Precautions Adverse events

Section 9: Statistical data All controlled clinical trial reports Integrated efficacy and safety summaries

Integrated summary of risks and benefits Section 10: Case report tabulation:- Includes complete tabulation for each patient from every adequately are well controlled phase II and Phase III efficacy, clinical pharmacology study. It also tabulation of safety data from all clinical studies.Section 11: Case report forms:- Includes the complete CRF for each patient who died during a clinical study or adverse event, regardless of whether the AE is considered to be related to the study drug, even if the patient was receiving a placebo or comparative drug.Bioequivalence:A generic drug is considered to be bioequivalent to the brand name drug if:

The rate and extent of absorption do not show a significant difference from listed drug, or The extent of absorption does not show a significant difference and any difference in rate is intentional or not medically significant.

Bio equivalent Inequivalent Resources for ANDA Submissions:- The following resources have been gathered to provide you with the legal requirements of an ANDA application, assistance from CDER to help you meet those requirements, and internal ANDA review principles, policies and procedures.Guidance Documents for ANDAs:- Guidance documents represent the Agency's current thinking on a particular subject. These documents are prepared for FDA review staff and applicants/sponsors to provide guidelines to the processing, content, and evaluation/approval of applications and also to the design, production, manufacturing, and testing of regulated products.   They also establish policies intended to achieve consistency in the Agency's regulatory approach and establish inspection and enforcement procedures.  Because guidances are not regulations or laws, they are not enforceable, either through administrative actions or through the courts.  An alternative approach may be used if such an approach satisfies the requirements of the applicable statute, regulations, or both. For information on a specific guidance document, please contact the originating office. They includes…

Generics Generics (Draft - Distributed for comment purposes only). Procedural Draft:  Applications Covered by Section 505(b)(2) (Issued 10/1999, Posted 12/7/1999).  This provision permits FDA to rely, for approval of an NDA, on data not developed by the applicant.

Biopharmaceutics. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations  (Issued 10/2000, Posted 10/27/2000).  This guidance should be useful for applicants planning to conduct bioavailability (BA) and bioequivalence (BE) studies during the IND period for an NDA, BE studies intended for submission in an ANDA, and BE studies conducted in the post-approval period for certain changes in both NDAs and ANDAs.

Drug Master Files.   A Drug Master File (DMF) is a submission to the FDA that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. Required Specifications for FDA's IND, NDA, and ANDA Drug Master File Binders Guidance for Industry:  Changes to an Approved NDA or ANDA Refusal to Receive.  (Issued 7/12/1993, Posted 11/26/99) Clarifies CDER's decisions to refuse to receive an incomplete application. Inactive Ingredient Database. This database contains all inactive ingredients present in approved drug products or conditionally approved drug products currently marketed for human use.

Laws, Regulations, Policies and Procedures:The mission of  FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency to protect the consumer's health, safety, and pocketbook.  The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the U.S. With numerous amendments it is the most extensive law of its kind in the world.  The law is intended to assure consumers that foods are pure and wholesome, safe to eat, and produced under sanitary conditions; that drugs and devices are safe and effective for their intended uses; that cosmetics are safe and made from appropriate ingredients; and that all labeling and packaging is truthful, informative, and not deceptive.Code of Federal Regulations (CFR): The final regulations published in the Federal Register16 (daily published record of proposed rules, final rules, meeting notices, etc.) are collected in the CFR.  The CFR is divided into 50 titles which represent broad areas subject to Federal regulations. The FDA's portion of the CFR interprets the Federal Food, Drug and Cosmetic Act and related statutes.  Section 21 of the CFR contains most of the regulations pertaining to food and drugs.   The regulations document most actions of all drug sponsors that are required under Federal law. The following regulations apply to the ANDA process:

(21CFR Part 314)   Applications for FDA Approval to Market a New Drug or and Antibiotic Drug (21CFR Part 320)   Bioavailability and Bioequivalence Requirements.  For more information on retention samples, please see Bioequivalence Study Retention Samples. Bioavailability and Bioequivalence Requirements; Abbreviated Applications; Final Rule. (Issued and posted 12/19/2002)  (21CFR Part 310)   New Drugs

MaPPs :- CDER's Manual of Policies and Procedures (MaPPs) provide official instructions for internal practices and procedures followed by CDER staff to help standardize the drug review process and other activities, both internal and external.  MaPPs define external activities as well. 

ANDA review process:

Time frames for reviewing ANDA by FDA:Within 180 days of receipt of an application for a new drug under section 505(b) of the act or an abbreviated application for a new drug under section 505(j) of the act, FDA will review it and send the applicant either an approval letter under 314.105 or a complete response letter under 314.110. This 180-day period is called the "initial review cycle."At any time before approval, an applicant may withdraw an application under 314.65 or an abbreviated application under 314.99 and later submit it again for consideration.The initial review cycle may be adjusted by mutual agreement between FDA and an applicant or as provided in 314.60 and 314.96, as the result of a major amendment.

Filing of ANDA:Within 60 days after FDA receives an application, the agency will determine whether the application may be filed. The filing of an application means that FDA has made a threshold determination that the application is sufficiently complete to permit a substantive review. If FDA finds that none of the reasons for refusing to file the application apply, the agency will file the application and notify the applicant in writing. The date of filing will be the date 60 days after the date FDA received the application. The date of filing begins the 180-day period described in section 505(c) of the act. This 180-day period is called the "filing clock."Approval of ANDA:FDA will approve an application and issue the applicant an approval letter on the basis of draft labeling if the only deficiencies in the application concern editorial or similar minor deficiencies in the draft labeling. Such approval will be conditioned upon the applicant incorporating the specified labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed labeling prior to marketing.Amendments to an unapproved ANDA:

An applicant may amend an abbreviated new drug application that is submitted, but not yet approved, to revise existing information or provide additional information. Amendments containing bioequivalence studies must contain reports of all bioequivalence studies conducted by the applicant on the same drug product formulation, unless the information has previously been submitted to FDA in the abbreviated new drug application. A complete study report must be submitted for any bioequivalence study upon which the applicant relies for approval. For all other bioequivalence studies conducted on the same drug product formulation, the applicant must submit either a complete or summary report. If a summary report of a bioequivalence study is submitted and FDA determines that there may be bioequivalence issues or concerns with the product, FDA may require that the applicant submit a complete report of the bioequivalence study to FDA. Submission of an amendment containing significant data or information before the end of the initial review cycle constitutes an agreement between FDA and the applicant to extend the initial review cycle only for the time necessary to review the significant data or information and for no more than 180 days. The applicant shall submit a field copy of each amendment. The applicant, other than a foreign applicant, shall include in its submission of each such amendment to FDA a statement certifying that a field copy of the amendment has been sent to the applicant's home FDA district office.

References: Richard A. Guarino- New Drug Approval process-1)The New Drug Application, Content, Format 2) Abbreviated $ Supplementary New Drug Application- Fourth edition-Marcel Dekker,inc- page no 113-183. Douglas J. Pisano, David S. Manlus –FDA Regulatory Affairs, A guide for Prescription Drugs, Medical Devices and Biologics-New drug Application –Second edition-Marcel Dekker,inc- page no 69-108. Loyd V. Allen Jr, Nicholas G. Popovich, Howard C. Ansel’s Pharmaceutical Dosage Forms and delivers systems- New Drug Development and Approval Process-8 th edition- B.I. publication- Page no 25-65. http://www.fda.gov/cder/guidance/index.htm. http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/default.htm

http://www1.pointcross.com/source/ddg/charts/andachart.htm