Generic drugs product development

regulatory affairs

1. GENERIC DRUGS PRODUCT DEVELOPMENT , INTRODUCTION Presented By : Facilitated To : Sachin.J.Gaddimath Mr. Prabhu Halakatti M.Pharm 1 st year Asst. Professor Dept. of Pharmaceutics Dept. of Pharmaceutics HSKCOP, BAGALKOT. HSKCOP, BAGALKOT 1

2. CONTENTS: INTRODUCTION AND DEFINITION OF GENERIC DRUGS. GENERIC DRUG DEVELOPMENT PROCESS. HATCH WAXMAN ACT AND AMENDMENTS. CODE OF FEDERAL REGULATION. 2

3. GENERIC DRUGS: DEFINITION - A generic drug product is essentially identical to the brand name(reference) drug product in terms of active ingredient, dosage form ,route of administration, quality ,safety, efficacy, performance characteristics and therapeutic indication. EX- PHENYTOIN is the generic drug and DILANTIN is the brand name for the same drug. Brand drugs are the drugs which are protected by the patent. In 2002 about 47%of prescription drug product are generic versions while 53% innovator product. Generic products growth is 19% in 1984 and 50% in 2004. Every year about 4 billions dollars business potential exists for next 4 years due to patent expiry. 3

4. Current development and approval of generic drug products was associated with issues concerning. Safety, efficacy and therapeutic equivalence of such products early compared to the innovator or brand-name drug product for obtaining marketing approval. However, the generic pharmaceutical industry is still challenged by legislative, regulatory and scientific issues that must be addressed to allow for the manufacture , approval and marketing of generic drugs products. Generic drug product manufacturers must formulate a drug product that will have the same therapeutic efficacy and clinical performance as their brand-name counterpart. 4

5. SELECTION OF GENERIC DRUGS FOR MANUFACTURE: The main driving force for the selection of generic drug products for manufacture is the estimated sales volume for the branded product. And the potential market share that the firm expects to have once the generic drug product is manufactured and approved for marketing. In addition to the expiration date of the patent for the active ingredient, the generic firm must consider any other patent claims and exclusivities that the innovator firm has filed. 5

6. The generic drug manufacturer needs to consider: The lead time that is needed to make the product and submission of an Abbreviated New Drug Application (ANDA) to the U.S.FDA for approval. Moreover, there is a financial incentive to being the first generic drug product filed and approved by FDA. 180-days exclusivity, is given under certain conditions, for the generic manufacturer who is to file first. 6

7. Formulation considerations for generic drugs include: The availability of raw materials, chemical purity, polymorphic form. Particle size of the active pharmaceutical ingredient. Any patents that the innovator company has filed, including patents for the synthesis of the active pharmaceutical ingredient and composition of the dosage form. 7

8. GENERIC DRUG APPROVAL PROCESS: The FDA’s office of Generic Drugs is responsible for reviewing the ANDA and approving the drugs products marketing. The FDA’s Office of Generic drugs has a website http//www.fda.gov.org that provides additional information for manufactures of generic drug products that includes flow chart presentation of ANDA review process. And it also describes how FDA determines the quality, safety, and efficacy of generic drug products prior to the approval for marketing. Generic drug application reviewers focus on bioequivalence data, chemistry and manufacture quality ,microbiology data where relevant, requests for plant inspection, and drug labeling information. 8

9. The ANDA for generic drug product approval is based on bioequivalence to the brand name product, appropriate chemistry and manufacturing information, and appropriate labeling. Generic drug sponsors do not have to perform the nonclinical animal toxicity studies or expensive clinical efficacy and safety studies that are included in the new drug application. NDA which is submitted to the FDA for market approval of the brand name drug product. The ANDA contains data which is then submitted to FDA’s Center for drug evaluation and research for the generic drugs. 9

10. FDA approved generic drugs must meet the same rigid standards as the innovator drug. To obtain FDA approval, a generic drug product must- contain same active ingredient as an approved drug product the inactive ingredients may vary. Be identical strength, dosage form ,route of administration, same indications , bioequivalent, meet the batch requirements. The FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations and lists of the all approved products, both innovator and generic are included in the orange book.   10

11. STEPS IN GENERIC DRUG PRODUCT DEVELOPMENT PROCESS: CONCEPT DEVELOPMENT- The needs of the target market are identified , alternative product concepts are generated and evaluated, and a single concept is selected for further development. SYSTEM LEVEL DESIGN- It includes the definition of the product into subsystem and components. The final assembly scheme for the production system is usually defined during this phase. 11

12. DETAIL DESIGN- Includes the complete specifications of the geometry, materials and tolerances of all the unique parts in the product and the identification of all the standards parts to be purchased from suppliers. A process plan is established and tooling is designed for the each part to be fabricated within the production system. 12

13. TESTING AND REFINEMENT: It Involves the construction and evaluation of multiple pre-production version of the product. Early prototypes are usually built with production intent parts(parts with same geometry and material properties as intended for the production version of the product). Early prototypes are tested to determine whether the product will work as designed and whether it satisfies customers needs. The goal of prototypes are usually used to answer questions about performance and reliability in order to identify changes for the final product. 13

14. PRODUCTION RAMP UP –The purpose is to train the work force and to work out any remaining problems in the production process. The artifacts produced during production ramp up are sometimes supplied to the preferred customer and are carefully evaluated to identify any remaining flaws. 14

15. HATCH WAXMAN ACT AND AMENDMENTS: It knows as THE DRUG PRICE COMPETITION and “PATENT TERM RESTORATION ACT”. Enacted in 1984. Amended the patent laws. Amended the federal food, drug and cosmetic act. Before 1962 new drug approval was based on safety alone. In 1962 proof of efficacy was made compulsory for marketing approval of a new drug.   15

16. OBJECTIVES OF THE ACT: Reduce the cost associated with approval of generic drugs. Allowing the early experimental use. Compensating the branded drugs manufactures for the time lost from the patent term because of the regulatory approval formality. Motivating the generic drug manufactures. 16

17. SALIENT FEATURES OF THE ACT: Patent term extension. Patent challenges. Exemption to infringement. Generic exclusivity. Prior to the generic drug manufacturer had to do the entire clinical trials. After the passage of this act the generic drug manufacturer had to prove bioequivalence of generic drug to innovator drug. 17

18. Hatch Waxman Act - “Patent Term Restoration” Patent Term Extension To make up for the loss of time during drug approval process Application for patent extension must be filed within 60 days of FDA approval of the drug product Regulatory review period determination Testing Phase IND Submission Approval Phase NDA Submission NDA Approval Length of the patent extension calculated: ½ (IND submission to IND approval) + (NDA submission to NDA approval) 18

19. Maximum extension of 5 yrs Total marketing exclusivity of not more than 14 yrs Each patent can be extended only once Only one patent may be extended per pharmaceutical product There was no provision for the patent term extension prior to the enactment of the hatch Waxman act. Generic companies are required to submit their own comprehensive NDA which is A) Costly B) Time consuming If the drug was covered by the patent testing could not be done until patent expired to overcome this problem act was needed to promote generic companies. 19

20. PROVISION OF THE ACT: Creation of section 505(j) Selection 505(j) established the ANDA approval process. The timing of an ANDA approval depends in part on patent protection for the innovator drug. NDA must include any patent that claims the drug or a method of using the drug for which a claim of patent infringement could reasonably be asserted. On approval of NDA, FDA publishes patent information of drug in orange book. An NDA applicant must submit the following information for each patent – a) Patent no and date on which the patent will expire. b) Type of patent, drug product, method of use, name of the patent owner must be specified. 20

21. FOUR TYPES OF PATENT CERTIFICATIONS: When an applicant submits an ANDA to the FDA, the applicant must certify one of four things under section 505(j)A(vii) A)That the required patent information relating to such patent has not been filed (Para1) B) That such patent has expired (Para2) C) That the patent will expire on a particular date (para3) D) That such a patent is valid or will not be infringed by the drug, for which approval is begin sought (para4)-patent challenge 21

22. EXEMPTS ACTS OF PATENT INFRINGEMENT FOR FDA APPOVAL: The manufacture, use or sale of patented drug is not the act of infringement to the extent it is necessary for the preparation and submission of an ANDA. The hatch Waxman act provides under 35 U.S.C, 271(e)(1) generally that – it shall not be an act of infringement to make, use or sell a patented inventions. 22

23. HATCH WAXMAN TRADE OFF: BENEFITS FOR GENERIC MANUFACTURERS 180 days market exclusivity for first successful challenger to orange book patent. Allows generics to challenge orange book patents without risk of damages. Safe harbor rule allows generics to perform bioequivalence and other testing relating to regulatory approval without risk of patent infringement. 23

24. TYPES TERMS NEW CHEMICAL ENTITY 5 YEARS NEW CLINICAL STUDY 3 YEARS ORPHAN DRUG 7 YEARS PEDIATRIC EXCLUSIVITY 6 MONTHS 180 DAYS GENERIC MARKET EXCLUSIVITY 180 DAYS 24

25. NEW CHEMICAL ENTITY EXCLUSIVITY Hatch Waxman act 1984 granted to all drug products containing a new chemical entity. blocks- Submission of 505(b)(2) or ANDA Length- 5 years or 4 years. NEW CLINICAL STUDY EXCLUSIVITY : Hatch Waxman act 1984 granted for submission of results of new chemical entity. blocks - Approval of 505(b)(2) or ANDA Length – 3years 25

26. ORPHAN DRUG EXCLUSIVITY Orphan drug act-1983 Granted to drugs intended for treatment of a rare disease. blocks-Approval of 505(b)(1) or (b)2 or ANDA for same disease or same drug. Length – 7 years PEDIATRIC EXCLUSIVITY- Granted to applicants who successfully complete FDA requested clinical trials of a drug in a pediatric population. blocks- Approval of 505(b)(2) or ANDA Length - 6 months 26

27. GENERIC DRUG EXCLUSIVITY: Hatch Waxman act -1984 granted first to ANDA applicant who submits a substantially complete ANDA paragraph 4 certification. Blocks – approval filed ANDA containing a para4 certification. Length-180 days for commercial marketing. 27

28. ORANGE BOOK: On approval of NDA, FDA publishes patent information of drug are included in orange book. OBJECTIVE: This book contains therapeutics equivalence evaluations for approved prescription drug products. These evaluations are been prepared to serve as public information. To advice to state health agencies, prescribers, pharmacists to promote public education in area of drug product selection. To review to patterns of access and usage. To allow discovery of use of unusual privileges. To allow discovery of repeated attempts to bypass protections. To supply an additional form of user assurance. 28

29. CONTENTS OF THE ORANGE BOOK: Introduction Content and exclusion Reference listed drug General policies and legal status Drug product list :- A) Prescription drug product list B) OTC drug product list The orange book is composed of 4 parts: 1)Approved prescription drug products with the therapeutic equivalence evaluations 2)Approved OTC drugs products 3) Drug products with approval under section 505 of the FDC act 4) A cumulative list of approved drug products that have never been marketed. 29

30. LOOPHOLES IN THE HATCH WAXMAN ACT: Authorized generics 30 months stay Warehouse patent Reverse payments Citizens petitions 30

31. 31 Authorized Generics(AG): AG are pharmaceutical products that are approved as brand name drugs but marketed as generic drugs. It do not bear the brand name/trademark of the brand name drug or manufacturer, but the brand name and AG products are manufactured to the brand’s specifications. AG have a unique impact during the first 6 months competition. Competition from AGs during the 180 days exclusivity period has the potential to reduce both generic drug prices & generic firm revenues.

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34. CODE OF FEDERAL REGULATIONS(CFR) The code of federal regulations is the codification of the general and permanent rules and regulations published in the federal register by the executive departments and agencies of the federal government of the united states. The CFR is divided into 50 titles that represent broad areas subject to federal regulation. The CFR annual edition is the codification of general and permanent rules published by the office of federal register and the government publishing office. In addition to this annual edition, the CRF is published in an unofficial format online on the electronic CFR website, is which is updated daily. The online CFR is a joint project authorized by the publisher, national archives and records, administration’s office of the federal register and the government publishing office to provide the public with the enhanced access to government information. 34

35. WHEN IT IS UPDATED- The CFR on go info is current with the published print version. When the print editions are released, the online version is also made available. If the CFR volume is not listed in the CFR browser than the volume has not been published. The 50 subject matter titles contain one or more individual volumes, which are updated once each calendar year. Go info currently contains titles from 1996 to present once. CFR volumes are added concurrent with the release of the paper editions. 35

36. The annual update cycle is follows - Titles 1-6 are revised as of Jan 1 Titles 17-27 are revised as of April 1 Titles 28-41 are revised as of July 1 Titles 42 -50 are revised as of October 1 36

37. HOW IT IS ORGANIZED: The CFR is divided into 50 titles that represent broad areas subject to federal regulation. Each title is divided into chapters, which usually includes the name of the issuing agency. Each chapter is further subdivided into subparts. All parts are organized in sections, and most citations to the CFR refer to material at the selection level. Full set of the CFR consists of 200 volumes. 37

38. STRUCTURE OF A CFR CITATION (21CFR 310 .502 Revised as of April) Information content in CFR citation TITLE- The numeric value to the left of CFR PART- The numeric value to the right of CFR SELECTION/SUBPART-A subpart is a letter of the alphabet (A-Z) that is used to retrieve an entire subpart of the CFR rather than many individual sections for ex subpart E. REVISION YEAR –Four digit years from the Revised as of text represents the year being cited. 38

39. SAMPLE CODE FOR FEDRAL REGULATIONS URLs: Granule ID for the CFR is used to identify the specific A) Section B) Part, Subpart chapter, C) Subchapter within a volume of the publications. Package ID is used to identify an individual volume of the publication. 39

40. REFERENCE IPR AND DRUG REGULATORY AFFAIRS by DR GAURAV TIWARI (NIRALI PRAKASHAN) DRUG REGULATORY AFFAIRS by SACHIN ITKAR (Nirali prakashan) http//en.m.wikipedia.org>wiki>code http//jddonline.info>article>view Generic drug product development solid dosage form by Marcel Dekker. Biopharmaceutics and pharmacokinetics by DM Brahmankar 40

41. THANK YOU 41