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Presented by: Nagori Stavan Arunkumar Department of Pharmaceutics L.M.College of Pharamcy SEMINAR ON:

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Presentation on theme: "Presented by: Nagori Stavan Arunkumar Department of Pharmaceutics L.M.College of Pharamcy SEMINAR ON:"— Presentation transcript:

1 Presented by: Nagori Stavan Arunkumar Department of Pharmaceutics L.M.College of Pharamcy SEMINAR ON:

2 Pool of topics: 1.Introduction 2.History of ANDA 3.Guidelines available for ANDA 4.Filling of ANDA 5.Manufacturing and control requirements of the ANDA days exclusitivity under Hatch Waxman amendment 7.Concept of Paragraph I to IV 8.Substantially complete ANDA 9.House keeping regulation 10.Patent expiration regulation 11.Triggering period 12.Waivers of exclusitivity (b)(2) application 14.Supplemental new drug applications 15.Case studies 16.List of ANDA approved pending ANDA 18.ANDA filed by or with Indian Pharmaceutical company 19.List of references

3 1. Introduction ANDA contains data submitted to FDA's Center for Drug evaluation and Research, Office of Generic Drugs, for review and ultimate approval of a generic drug product. Once ANDA is approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public. A generic drug product is the one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use.

4 All approved products, both innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). Generic drug applications are termed "abbreviated" Use of bioequivalence as the base for approving generic drug products was established by the "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the WAXMAN-HATCH ACT.

5 2. HISTORY OF ANDA: In 1938, proof of safety In 1962, THE KEFAUVER HARIS AMENDMENTS THE KEFAUVER HARIS AMENDMENTS led to DRUG EFFICACY STUDY IMPLEMENTATION (DESI). FDAs realization Mid 1966 notice in federal Register DESI review ultimately led to evolution of ANDA concept.

6 On April 24th 1970, the ANDA policy was published with exception of DESI pending list drugs and exempt as per court order In November 1984, The Drug Price Competition and Patent Term Restoration Act. Title 1: ANDA regardless of time before or after 1962 Title 2: Patent extension for life lost Title 3: Textile and wood products In April, 1992 FDA finalized the regulations outlining the requirements for ANDAs.

7 On November 21, 1997 Modernization Act was signed. Section 506A-Changes for approved ANDA/NDA Hatch-Waxman Amendments

8 3. GUIDELINES AVAILABLE FOR ANDA: Guidelines describe format & content for the following sections. –Application summary –Chemistry, Manufacturing and controls section –Non clinical pharmacology and toxicology section –Human pharmacokinetics & bioavailability section –Clinical and statically section –Microbiology section

9 Guidelines available for ANDA includes: Organization of ANDA Electronic submission of data for ANDA Submission of archival copy of application in Microfiche Guideline for impurities in drug substances Guideline for submitting supporting documentation for the Manufacture of Drug substance. Guideline for submitting supporting documentation for the Manufacture of finished dosage forms.

10 Guideline for submitting supporting documentation for stability studies of Human drugs and Biologics. Guideline for packaging Guidelines for changes in approved ANDA and NDA Variations in Drug Products that may be included in a single ANDA 180 days exclusivity under Hatch Waxman amendment Guidelines for alternate source of API in pending ANDAs Post marketing reporting of Adverse Drug reactions Guidelines for changes in approved ANDA and NDA


12 Proper organization Proper format, clear table of contents, correct folders (jackets), correct tabulation and pagination Details under 21 CFR , 21 CFR and 21 CFR OGDs recommendation of bioequivalence, chemistry and labeling portions of an application

13 Paper based filing of ANDA: I.Application copies and general format: Submit Archival (reference, retained and official approved copy) and filed copy (duplicate, used by FDA investigators) in english Translation copy with original reference copy

14 Review copy (duplicate, FDA viewer, destroyed) in 2 sets of binders (jackets) In first binder CMC In another BE data Remaining data (table of contents, labeling) in both Consistency in color coding binders, volume size and specifications, size and quality of paper



17 II. Cover letter: –Purpose of submission –Type of submission (ANDA, amendment, supplement, annual report, or resubmission of a previously withdrawn application) –Name, title, address and signature of applicant –Proprietary name (if any) and name of drug product –Number of volumes submitted –Commitment to resolution of any issues identified in the methods validation process after approval –Statement that the application or a portion of the submission is in electronic process after approval –Clearly identify submissions that contain sterility assurance data

18 III. Table of content{(21 CFR B)}:





23 IV. Tabs: Contents Section Tabs E.g. Section VI - Bioavailability/Bioequivalence) V.Pagination: Centre bottom of the page. VI. Field copy -additional information: Foreign applicants should submit the field copy to the Office of Generic Drugs

24 Electronic submission: ADVANTAGES: Consistent submission Rapid review Reduction in archiving and storage space Establishment of structured database of technical information associated with generic drug applications. OGD archiving capability no guidelines OGD has process for some in hard and some in soft copy.

25 Electronic submissions separated into 2 parts: To address bioequivalence information To address information related to chemistry, manufacturing, and controls (CMC) Applicant may choose to submit either or both parts Each part consist three electronic files: –An electronic submission document (ESD) –A set of data files –A companion document.

26 Key element for entering information in electronic submission - Entry and Validation Application (EVA). First step in submission –getting unique 3 digit number Electronic submission along with hard copy to OGD 30 days Cover letter-CMC and/or bioequivalence ESD will be submitted as electronic version as new correspondence within 30 days.

27 Difference between submission of NDA and ANDA: NDA requirementsANDA requirements Well-controlled clinical studies to demonstrate effectiveness Detailed descriptions of the components Preclinical and clinical data to show safety Manufacturing, controls, packaging, and labeling data sufficient to assure the bioavailability or bioequivalence of the drug to be marketed. Detailed descriptions of manufacturing and packaging procedures Proposed annotated labeling referencing all studies from which statement s contained in the package insert has been derived.

28 5. MANUFACTURING AND CONTROL REQUIREMENTS OF THE ANDA:- Very important From , 105 Non approval letter issued by FDA

29 FDA Manufacturing and Controls guidelines:- Guideline for the format and content of an application summary. Guideline for the format and content of the chemistry, manufacturing, and controls section of an application. Guideline for stability studies for Human drugs and Biologics Guideline for packaging of Human Drugs and Biologics. Guideline for submitting supporting documentations in drug applications for the manufacture of drug substances. Guideline for submitting supporting documentation for the manufacture of finished dosage forms. Guidelines for drug master files.

30 Requirements for Drug substances sources: Copy of potential suppliers most recent establishment inspection repot describing FDAs findings Supplier should have a DMF available at FDA for reference purposes Specifications for drug substances:- Assay methodology is not specified into the monograph for older drugs or method described is not specific –FOIs requests to FDA-copy of pertinent assay Check impurity peaks

31 -Drug product requirements:- Validation studies - to verify the accuracy, precision, specificity, recovery and sensitivity of the method (s) conducted by the sponsors product with those obtained with the original brand name product using the same methodology. -ANDA expiration dates:- Tentative approval of two year expiration date for a product if satisfactory data reflecting at least three months storage under accelerated conditions Final approval for the expiration date is obtained when acceptable shelf life data for two years on more than one production lot is made available

32 Day Generic Drug Exclusivity under the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act

33 After Hatch-Waxman Amendment resulted into Increased availability of generics: 1984: 12% prescription were generics 2000: 44% 2003: 51% 10,357 FDA approved branded drugs vs. 7,602 generic counterparts Savings of $ 8 – 10 billions every year Average saving per prescription: approximately 53 $ 1% rise in Generic prescription = $ 1.3 billions saving

34 10,357 FDA approved branded drugs vs. 7,602 generic counterparts Savings of $ 8 – 10 billions every year Average saving per prescription: approximately 53 $ 1% rise in Generic prescription = $ 1.3 billions saving

35 Generic Pharmaceuticals: Facts & Figures at a glance

36 Generic Pharmaceuticals: Facts & Figures at a glance (contd.)


38 7. Concept of paragraph I to IV: For filing ANDA, generic company must include a patent certification as per section 505(j) (2) (A) (vii) of the Hatch Waxman Act. The certificate has to make one of the following statements: I.No patent information on the drug product that is the subject of the ANDA has been submitted to FDA II.That such patent has expired III.The date on which such patent expires IV.That such patent is invalid or will not be infringed by the manufacture, use, or sale of the drug product which the ANDA is submitted.

39 The first three paragraphs (I, II, III) results in no generic drug being sold during the term of the innovators patent protection. In case paragraph IV certification generic drugs can be sold during the term of the innovators patent protection. with rule of 45days suit and 30 months ban. Bann approved unless: The court decides that such patent is invalid or not infringed. In this case ANDA approval is made effective on the date of the court decision The court decides that such patent has been infringed and sets a date for approval of the ANDA as provided. The court grants a preliminary injuction prohibiting the ANDA applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement.

40 8. SUBSTANTIALLY COMPLETE ANDA: Substantially complete means application with all required information like bioequivalence, etc. If a new bioequivalence study required for ANDA approval- not substantially complete and the applicant would not be eligible for exclusivity. Withdrawal of paragraph IV certification – voluntarily/ settlement/ defeat in patent litigation by first applicant-looses exclusitivity. Again first applicant submit paragraph IV certificate for 180 days exclusivity and there are no subsequent applicants then first applicant would be eligible for exclusivity.

41 9. HOUSE KEEPING REGULATIONS First generic loses patent litigation Para IV to III (loses exclusivity) Same day submission first applicant Happens if patent expires on that day or generic wants to challenge innovators ANDA for 5 years exclusivity and submits at end of 4 year For 6 months pediatric exclusitivity happens if patent expires on that day or generic wants to challenge innovators ANDA for 5(1/2) years exclusivity and submits at end of 4(1/2) year

42 10. PATENT EXPIRATION REGULATION Patent for which Para IV filed expires first generic loses exclusitivity Subsequent generics gets exclusitivity

43 11. TRIGGER PERIOD Unnecessary delay or settlement Trigger period concept Commencement of the 180-day exclusivity period for the first applicant is either the first commercial marketing of the first applicants product, or a decision of a court holding the patent invalid, not infringed, or unenforceable, whichever is earlier. For exercising exclusitivity 180-day triggering period court decision regarding the patent favorable to the first applicant or the first applicant must begin commercial marketing of its product if not first generic would lose its eligibility for exclusivity and subsequent generic filers for ANDA would be eligible for immediate approval.

44 There is new triggering period which is separate and distinct from the 180-day exclusivity period. The triggering period would begin upon the : Tentative approval of a subsequent ANDA with a paragraph iv certification for the same drug product Expiration of a 30 month stay of ANDA approval due to patent litigation Expiration of a preliminary injunction prohibiting marketing of an ANDA product Expiration of the statutorily described exclusivity periods for the listed drug

45 Delay of ANDA into market Mean while subsequent generics gets tentative approval FDA proposes 60 days trigger period for first generic to launch product into the market else lose exclusitivity

46 First generic sued Para IV certification and is facing patent litigation by innovator Triggering period would not begin at least until the 30 month period has lapsed At the end of the 30 month period, the triggering period would begin on the date a subsequent applicant receives tentative approval, or if a subsequent applicant had previously received tentative approval then on the date the 30 month period expired.

47 12. WAIVER OF EXCLUSIVITY No regulations Can waive to all subsequent and not single generic applicant

48 (b)(2) APPLICATION:- Section 505 of the FD&C Act describes 3 types of new drug application : An application that contains full reports of investigations of safety and effectiveness (Section 505 (b)(1)) An application that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference (Section 505(b)(2)) An application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use, among other things, to a previously approved product (Section 505(j))

49 What kind of information can be used for 505(b) (2) application? Published literature The FDAs findings of safety and efficacy for a previously approved drug product without requiring the sponsor to obtain a right of reference from the original applicant.

50 What kind of application can be submitted as a 505(b) (2) application? New chemical entity (NCE)/new molecular entity (NME) Changes to previously approved drugs

51 SOME EXAMPLES OF 505(B) (2) APPLICATIONS Change in dosage form Change in route of administration Change in strength Change in dosage regimen Change in formulation (excipient) Change in active ingredient like use of different salt of same drug New molecular entity i.e. is prodrug of previously approved drug product Substitution of an active ingredient in a combination product Combination product: An application for a new combination product in which the active ingredients have been previously approved individually. Rx/OTC switch OTC monograph. Naturally derived or recombinant active ingredient. Bioinequivalence:

52 WHAT CAN'T BE SUBMITTED AS 505(B) (2) APPLICATIONS? An application that is a duplicate of a listed drug and eligible for approval under section 505(j). An application in which the only difference from the reference listed drug is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than the listed drug. An application in which the only difference from the reference listed drug is that the rate at which its active ingredient(s) is absorbed or otherwise made available to the site of action is unintentionally less than that of the listed drug

53 What type of patent and/or exclusivity protection is a 505(b) (2) application eligible for? Granted 3 years of Waxman-Hatch exclusivity if one or more of the clinical investigations other than BA/BE studies was essential to approval of the application and was conducted or sponsored by the applicant (21 CFR (j); (b)(4) and (5)). Granted 5 years of exclusivity if it is for a new chemical entity (21 CFR (j); (b) (2)). Eligible for orphan drug exclusivity (21 CFR ) or pediatric exclusivity (section 505A of the Act).

54 BENEFIT OF 505(b) (2) APPLICATION: Filing of ANDA in form of NDA 3 or 5 years of Hatch-Waxman marketing exclusivity. An approved 505(b) (2) product, may receive an AB substitutability rating in the Orange Book.

55 CURRENT CHALLENGE TO THE 505(b) (2) MECHANISM: 505(b)(2) does to not allow FDA to unauthorizing rely on or use of an Innovators proprietary data to approve 505(b)(2) NDAs or to give rating A in orange book. A petition was filed with the FDA on behalf of two pharmaceutical industry giants (Pfizer/Pharmacia) to curtail the FDAs approval of 505(b) (2) applications. The Pfizer/Pharmacia petition requested the FDA to Cease approval of all 505(b)(2) NDAs Refuse to grant A substitutability ratings to such products in orange book...

56 14. SUPPLEMENTAL NEW DRUG APPLICATIONS Once an ANDA as an NDA has been approved, any significant changes in the conditions described in the application must first be approved via a supplemental NDA/ANDA. Any substantive modifications proposed for the formulation may require the submission of additional data assuring the bioavailability of the drug. Certain minor changes, however, as permitted by specific regulations, may be made without the filing of supplemental applications.

57 Supplemental application I is filed for any the changes occurs in chemistry, manufacture of drug, use, labeling, safety, effectiveness, identity, strength, quality or purity of the drug or the adequacy of the manufacturing methods, facilitation, and controls to preserve these elements.

58 Supplements to new drug applications requiring FDA approval before the change is made for the drug substance. Relaxation of specification limits The establishment of new regulatory limits The deletion of a specification or analytical method. A revision in the method of synthesis, including the use of different solvents or alterations in the approved route. The use of different facility or establishment for the drug substances manufacture, where the process used to produce the drug substance differs materially from that approved in the NDA/ANDA and/or the facility has not received a current satisfactory, good manufacturing practice inspection within the last two years covering the manufacturing process.

59 Supplements to new drug applications requiring FDA approval before the change is made for the drug product. The addition or deletion of an ingredient or alteration of the composition (except for deletion of colorant.) The relaxation of specification limits. The establishment of a new regulations analytical method. The deletion of a specification as regulatory analytical method. A revision in the method of manufacture, including changing or relaxing and in process control. The use of a different facility or establishment, including a different of contract, laboratory, on labels, to manufacture, process, test, or pack the drug. The use of new container/closure system or a revision of a relevant specification (s) and regulatory analytical method(s). A change in container size ( except for solid forms) An extension of the expiration date based on data obtained using a new or an unapproved revised stability testing protocol. The establishment of a new processing procedure for batches failing to meet quality assurance specifications. All labeling changes except for those specifically exempted.

60 Supplements for changes that may be made before FDA approval Full explanation of the basis for the such changes is required The cover letter and the supplement should be plainly marked, Special supplement changes being effected. Includes for: The addition of a new specification (s) or test method. Revisions in methods, facilities( Except for a new facility or controls to provide increase assurance of product, identity, quality, purity, and strength). Revisions in labeling to add or strengthen: –A contraindication, warning, precaution or adverse reaction. –An instruction about dosage and administration to further assure the safe use of the product. –A statement about drug abuse, dependence, or over dosage. –Revisions in labeling to delete false, misleading, or unsupported indications of use or claims for effectiveness. –Use of a different facilities or establishment to manufacture the drug substance, where the method of manufacture does not differ materially form that in the former facility and the new facility has received a satisfactory cGMP inspection within the last two year.

61 Changes described in the Annual report Revisions made to comply with an official compendium e.g. USP,NF. Revisions in the package insert concerning the description section, or the how supplied section, that do not involve a change in dosage strength and / or form, or minor editorial changes in these and/or other sections. Deletion of a colorant from the drug product. Extension of expiration dating based on data obtained using a protocol approved in the application. A switch to another container/closure system, where the material (s) used is the same general type as previously approved.(e.g. a change from one high-density polyethylene to another). In the case of solid dosage forms a change in container size without a change in the container/closure system. The deletion or addition of an alternate analytical method.

62 Supplemental new drug application checklist: Make all submissions in duplicate, including cover letters. Include a brief description in the cover letter of what the supplement contains, including its objective and the headings, supplemental expedited review requested or special supplement changes being effected when appropriate. Whenever possible make a side by side comparison of current versus proposed conditions. Use reference numbers for the NDA and the supplement if it is an additional submission. Describe in detail all aspects of the change Use dates when referring to previous submissions of FDA letters, particularly if the correspondence goes back more than several years. When submitting photocopies make sure that all copies are clear and legible. To assure legibility also type the name of the person signing the document. When referring to drug master files (DMFs), confirm that they are up-to-date. Any changes submitted to a DMF must be relevant to the application (s) they affect. Address all submissions concerning supplemental NDAs to the appropriate office and division of the FDA.

63 15. CASE STUDIES: A.Patent of PAXIL (Paroxetine HCL hemihydrate) SmithKline Backhem (SKB) obtained patent of Paxil as NDA. In 1998 Apotex filed Para IV certificate for getting ANDA SKB filed legal suit for patent infringement 30-months stay on Apotex approval SKB filed patent extension 1: for use as liquid oral 3 more patents in 1999 & 2000 for anhydrous form 5th patent for Paroxetine methanosulfate in 2000 Serial Patent submission tactics, with newer 30-month stay every time Result: The patent of litigation expired, but Apotex could not enter due to the newer (later) patents

64 B.Patent of BUSPAR (BMS Pharmaceuticals) Mylan pharmaceuticals filed Para III ANDA in 98 (launch after the patent expiry). Got Tentative approval from US FDA BMS Patent was to expire on 11:59 at midnight of 21st Nov. 00 Mylan pharmaceuticals loaded the trucks at midnight with generic versions of BUSPAR to launch in US on 22nd Nov hours before patent expiry, BMS was granted a new patent by US Patent & Trademark office BMS immediately submitted new patent to US FDA FDA updated the orange book and issued letter of incompleteness in ANDA to Mylan Mylans consignments remained on shipping dock In end net result was BMS ruled for 15 years without competition from 1986 for Buspar

65 16. List of NDA/ANDA approved by FDA from 2004















































112 ANDA approved in October 2005



115 Tentative ANDA approval (July2005)


117 17. List of ANDA patents pending this year (from Jan 2006): Date Filed Docket # Name of Petitioner/Subject Matter 02/09/ P-0070Pfizer Inc./Misbranding of generic azithromycin products marketed by Teva Pharmaceuticals USA and Sandoz Inc. 02/10/ P-0072Olsson,Frank and Weeda, P.C./ANDA for prednisolone sodium phosophate, USP,oral solution, 10 mg prednisolone base/5mL

118 18. ANDA filed by or with Indian Pharmaceutical company


120 Ranbaxys ANDA which are in pipeline for filing patent



123 Generics with DR. Reddies Limited TypeName ANDARanitidine tab 75 mg (OTC) ANDARanitidine Cap (150, 300 mg) ANDAFamotidine tablet (10, 20,40 mg) ANDAOxaprozin tablet (600mg) ANDAFluxetine Capsule (40mg) ANDAEnalpril maleate with hydrochlorthiazide tablet ( ,10-25 mg) ANDAIbuprofen tablet (400, 600 and 800 mg) ANDAIbuprofen tablet (200 mg-OTC)

124 TypeName Tentative ANDACiprofloxacin tablet (100, 250, 500, 750 mg) Tentative ANDAOmeprazole capsule (40mg) Tentative ANDAFluxetine tablet (10 mg) Tentative ANDAFluxetine Capsule (10, 20 mg)

125 ANDAs with Zydus Cadila Atenolol tablet Methformin HCl Promethazine tablet

126 Tentative ANDAs with Zydus cadila Divalproex Na DR tablet Gatifloxain tablet Ribavirin capsule and tablet

127 List of generic products available with Cipla Pharmaceuticals

128 19. List of references: 5.Richard A., Guarino M. D., New drug approval process second edition, Marcel dekker, 56, /


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