Generic drugs product development

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

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

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

 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

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

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

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

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

 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

 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

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

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

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

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

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

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

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

 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)
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 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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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