Presented by:Nagori Stavan

ArunkumarDepartment of PharmaceuticsL.M.College of

Pharamcy

SEMINAR ON:

Pool of topics:1. Introduction2. History of ANDA3. Guidelines available for ANDA4. Filling of ANDA5. Manufacturing and control requirements of the ANDA6. 180 days exclusitivity under Hatch Waxman amendment7. Concept of Paragraph I to IV8. Substantially complete ANDA9. House keeping regulation10. Patent expiration regulation11. Triggering period12. Waivers of exclusitivity13. 505(b)(2) application14. Supplemental new drug applications15. Case studies16. List of ANDA approved 17. 2006 pending ANDA 18. ANDA filed by or with Indian Pharmaceutical company19. List of references

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.

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.

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)”.

FDA’s realization

Mid 1966 notice in federal Register

DESI review ultimately led to evolution of ANDA concept.

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 1962Title 2: Patent extension for life lostTitle 3: Textile and wood products

In April, 1992 FDA finalized the regulations outlining the requirements for ANDAs.

On November 21, 1997 Modernization Act was signed.

Section 506A-Changes for approved ANDA/NDA

Hatch-Waxman Amendments

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

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.

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

4. FILING OF ANDA:

Proper organization

Proper format, clear table of contents, correct folders (jackets), correct tabulation and pagination

Detail’s under 21 CFR 314.50, 21 CFR 314.94 and 21 CFR 314.440OGD’s recommendation of bioequivalence, chemistry and labeling portions of an application

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

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

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

III. Table of content{(21 CFR 314509B)}:

IV. Tabs:Contents Section TabsE.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

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.

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.

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 OGD30 days

Cover letter-CMC and/or bioequivalence ESD will be submitted as electronic version as new correspondence within 30 days.

Difference between submission of NDA and ANDA:

NDA requirements ANDA requirementsWell-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.

5. MANUFACTURING AND CONTROL REQUIREMENTS OF THE ANDA:-

Very important

From 1977-1992, 105 Non approval letter issued by FDA

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.

Requirements for Drug substances sources:

Copy of potential supplier’s most recent establishment inspection repot describing FDA’s 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

-Drug product requirements:-Validation studies - to verify the accuracy, precision, specificity, recovery and sensitivity of the method (s) conducted by the sponsor’s 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

6. 180-Day Generic Drug Exclusivity under the Hatch-Waxman Amendments to the Federal Food,

Drug, and Cosmetic Act

WAXMAN HATCH AMENMENTS BENIFITS

TO INOVATOR’S COMPANIES TO GENERIC DRUG COMPANIES

IF SUIT

180 DAY EXCLUSIVITY PERIOD

TO CHALLEGE PATENT DRUG

45 DAY TO CLAIM

DELAYED FOR 30 MONTHS

NOT SUIT

After Hatch-Waxman Amendment resulted into

Increased availability of generics:1984: 12% prescription were generics2000: 44%2003: 51%

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

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

Generic Pharmaceuticals: Facts & Figures at a glance

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

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

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 expiredIII. The date on which such patent expiresIV. 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.

The first three paragraphs (I, II, III) results in no generic drug being sold during the term of the innovator’s patent protection.

In case paragraph IV certification generic drugs can be sold during the term of the innovator’s 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.

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.

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 innovator’s 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 innovator’s ANDA for 5(1/2) years exclusivity and submits at end of 4(1/2) year

10. PATENT EXPIRATION REGULATION

Patent for which Para IV filed expires first generic loses exclusitivity

Subsequent generics gets exclusitivity

11. TRIGGER PERIODUnnecessary 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 applicant’s 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.

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

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

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.

12. WAIVER OF EXCLUSIVITY

No regulations

Can waive to all subsequent and not single generic applicant

13. 505(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))

What kind of information can be used for 505(b) (2) application?

Published literature

The FDA’s 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.

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

SOME EXAMPLES OF 505(B) (2) APPLICATIONS

Change in dosage formChange in route of administrationChange in strengthChange in dosage regimenChange in formulation (excipient)Change in active ingredient like use of different salt of same drugNew molecular entity i.e. is prodrug of previously approved drug productSubstitution 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:

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

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 314.50(j); 314.108(b)(4) and (5)).

• Granted 5 years of exclusivity if it is for a new chemical entity (21 CFR 314.50(j); 314.108(b) (2)).

• Eligible for orphan drug exclusivity (21 CFR 314.20-316.36) or pediatric exclusivity (section 505A of the Act).

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.

CURRENT CHALLENGE TO THE 505(b) (2) MECHANISM:

505(b)(2) does to not allow FDA to unauthorizing rely on or use of an Innovator’s 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 FDA’s 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...

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.

• 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.

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.

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.

Supplements for changes that may be made before FDA approval

Full explanation of the basis for the such changes is requiredThe 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.

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.

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.

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

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.’00

12 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

Mylan’s consignments remained on shipping dock

In end net result was BMS ruled for 15 years without competition from 1986 for Buspar

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

ANDA approved in October 2005

Tentative ANDA approval (July2005)

17. List of ANDA patents pending this year (from Jan 2006):

Date Filed

Docket #

Name of Petitioner/Subject Matter

02/09/2006 2006P-0070 Pfizer Inc./Misbranding of generic azithromycin products marketed by Teva Pharmaceuticals USA and Sandoz Inc.

02/10/2006 2006P-0072 Olsson,Frank and Weeda, P.C./ANDA for prednisolone sodium phosophate, USP,oral solution, 10 mg prednisolone base/5mL

18. ANDA filed by or with Indian Pharmaceutical company

Ranbaxy’s ANDA which are in pipeline for filing patent

Generics with DR. Reddies Limited

Type NameANDA Ranitidine tab 75 mg (OTC)

ANDA Ranitidine Cap (150, 300 mg)

ANDA Famotidine tablet (10, 20,40 mg)

ANDA Oxaprozin tablet (600mg)

ANDA Fluxetine Capsule (40mg)

ANDA Enalpril maleate with hydrochlorthiazide tablet (5-12.5,10-25 mg)

ANDA Ibuprofen tablet (400, 600 and 800 mg)

ANDA Ibuprofen tablet (200 mg-OTC)

Type NameTentative ANDA Ciprofloxacin tablet (100, 250, 500, 750 mg)

Tentative ANDA Omeprazole capsule (40mg)

Tentative ANDA Fluxetine tablet (10 mg)

Tentative ANDA Fluxetine Capsule (10, 20 mg)

ANDAs with Zydus Cadila

• Atenolol tablet

• Methformin HCl

• Promethazine tablet

Tentative ANDAs with Zydus cadila

• Divalproex Na DR tablet

• Gatifloxain tablet

• Ribavirin capsule and tablet

List of generic products available with Cipla Pharmaceuticals

Cipla

BRAND NAME DOSAGE FORM TYPE SIZE GENERIC NAME

ABAMUNE TABLETS CONTAINER 30'S ABACAVIR SULPHATE 300MGABOFORT CAPSULES BLISTER 6'S ABORTION CAPSULES (AYURVEDIC)ACARBAY 25 TABLETS BLISTER 10'S ACARBOSE 25MG ACARBAY 50 TABLETS BLISTER 10'S ACARBOSE 50MGACARBAY 100 TABLETS BLISTER 10'S ACARBOSE 100MGACIGENE SUSPENSION BOTTLE 170ML ANTACID SUSPENSIONACIGENE MINT FLAVOUR CHEW TABS BLISTER 10'S ANTACID CHEWABLE TABLETSACIGENE ORANGE CHEW TABS BLISTER 10'S ANTACID CHEWABLE TABLETSACIVIR CREAM TUBE 5 gm ACYCLOVIR 5%ACIVIR EYE OINTMENT TUBE 5 gm ACYCLOVIR 3%ACIVIR-200 DT DISPERSIBLE TABS BLISTER 10's ACYCLOVIR 200MGACIVIR-400 DT DISPERSIBLE TABS BLISTER 5's ACYCLOVIR 400MGACIVIR-800 DT DISPERSIBLE TABS BLISTER 5's ACYCLOVIR 800MGACIVIR IV INFUSION BOTTLE 10ML ACICLOVIR 25MG/MLACLENE GEL TUBE 15GM ADAPALENE 0.1%ACTIFLU TABLETS STRIP 10'S TRIPROLIDINE HCL 2.5MG + PPA 25MGACTIFLU PLUS TABLETS STRIP 10'S TRIPROLIDINE HCL 2.5MG + PPA 25MG + PARA 500MGADESERA TABLETS CONTAINER 30'S ADEFOVIR DIPIVOXIL 10MGADDTEARS EYE DROPS VIAL 10ML SODIUM CARBOXYMETHYCELLULOSE 0.5% + STABILISED OXYCHLORO COMP LEX 0.0075%

AEROCORT INHALER CANISTER 200md SALBU 100MCG + BECLO 50MCGAEROCORT ROTACAPS CONTAINER 30's SALBU 200MCG + BECLO 100MCGAEROCORT FORTE ROTACAPS CONTAINER 30'S SALBU 400MCG + BECLO 200MCGAIDS TEST KIT CARTON 96'S 96KITS + REAGENTSALERGIN TABLETS BLISTER 10's EPHEDRINE 20MG + THEOPHYLLINE 100MG ALERID TABLETS BLISTER 10's CETIRIZINE 10MGALERID SYRUP BOTTLE 30ml CETIRIZINE 5MGALERID COLD TABLETS BLISTER 10'S CETIRIZINE 5MG + PHENYLPROP 25MG + PARA 500MGALERID D TABLETS BLISTER 10'S CETIRIZINE 5MG + PHENYLPROPANOLAMINE HCL 25MGALFACIP 0.25MCG SOFTGEL BLISTER 10'S ALFACALCIDOL 0.25MCGALFACIP 1MCG SOFTGEL BLISTER 10'S ALFACALCIDOL 1MCG ALFACIP PLUS SOFTGEL BLISTER 10'S ALFACALCIDOL 0.25MCG + EL CALCIUM 250MGALFADROPS EYE DROPS VIAL 5ML APRACLONIDINE HCL 0.5%ALFADROPS DS EYE DROPS VIAL 2ML APRACLONIDINE HCL 1%ALFUSIN TABLETS BLISTER 10'S ALFUZOSIN HCL 10MG EXTENDED RELEASEAMANTREL CAPSULES BLISTER 10's AMANTADINE 100MGAMCOF EXPECTORANT BOTTLE 100ML AMBR HCL 15MG + SALB 1MG + GUAIP 50MG + MENTHOL 1MG/5ML

AMCOLD TABLETS BLISTER 10'S CETERIZINE HCL 5MG + AMBROXOL 60MGAMCOLD COUGH SYRUP BOTTLE 100ML CETERIZINE HCL 5MG + AMBROXOL 30MG/5MLAMICIP 100 INJECTION VIAL 2ML AMIKACIN 100MGAMICIP 250 INJECTION VIAL 2ML AMIKACIN 250MGAMICIP 500 INJECTION VIAL 2ML AMIKACIN 500MGAMIODARONE 200 TABLETS CONTAINER 10's AMIODARONE 200MGAMLOPRES 2.5 TABLETS BLISTER 10's AMLODIPINE 2.5MGAMLOPRES 2.5 TABLETS BLISTER 15'S AMLODIPINE 2.5MGAMLOPRES AT 50 TABLETS BLISTER 10's AMLODIPINE 5MG + ATENOLOL 50MGAMLOPRES AT 25 TABLETS BLISTER 10'S AMLODIPINE 5MG + ATENOLOL 25MG

19. List of references:

1. www.fda.gov

2. www.phorum.com

3. www.morganfinnegan.com

4. www.drugdeliverytech.com

5. Richard A., Guarino M. D., “New drug approval process” second edition, Marcel dekker, 56, 325-356/427-446.