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Introduction to Generic Drug ProductDevelopment

Leon Shargel

Biopharmaceutics, Eon Labs, Inc.,Wilson, North Carolina, andUniversity of Maryland, Baltimore, Maryland, U.S.A.

Izzy Kanfer

Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa

A generic drug product, also referred to as a multisource pharmaceuticalproduct, is considered to be ‘‘essentially similar’’ (1) or bioequivalent (2)to an innovator (brand name) product. Bioequivalence implies that ageneric drug product is essentially identical to the brand name (reference)drug product in terms of active ingredient(s), strength, dosage form, routeof administration, quality, safety, e⁄cacy, performance characteristics,and therapeutic indication. Generic drug products are typically sold atsubstantial discounts from their brand name counterparts.

The 2002 sales of prescription drug products in the United States hasbeen reported to be approximately $192 billion (3). Approximately 47% ofall prescription drugs sold in the United States are generic drug products

expenditure for prescription drugs.The demand for lower cost generic drugproducts is an increasing trend worldwide. Individuals, particularly theelderly who are on a ¢xed income, health maintenance organizations(HMOs), health insurance programs, federal and state government health

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Copyright © 2005 by Marcel Dekker, Inc.

(Fig. 1) (4).Generic drug products account for about 10% of the total dollar

programs such as Medicaid, hospitals, and other institutions are creatinga demand for generic drug products as a means to slow the rising cost ofhealthcare expenditures. In the next few years, as patents and exclusivitiesfor many important brand name drug products expire (Fig. 2) (4), the valueof sales of generic drug products is likely to exceed $10 billion (5).

FIGURE 1 U.S. generic share of prescription units (%). Source: MS Health, Bank ofAmerican Securities LLCEstimates (4).

FIGURE 2 Sales of branded drug products vulnerable to generic competition, by year.Source: FDAOrange Book and Bankof America Securities (4,10).

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The manufacture of generic drug products must make provision formarket competition and lower prices for the consumer, thereby makingmedicines more a¡ordable and more accessible to the wider population.Generic drug product availability almost certainly in£uences the innovatordrug product manufacturer to develop new drug products that haveimproved e⁄cacy and=or safety features.

Generic drug product development uses a di¡erent approach andstrategy compared to that used to develop a brand name drug product con-taining a new chemical entity. Generic drug product manufacturers mustformulate a drug product that will have the same therapeutic e⁄cacy, safety,and performance characteristics as its brand name counterpart. In order togain market approval, a generic drug product cannot be ‘‘superior’’ or‘‘better’’ than the brand name drug product.The key factor is that the genericdrug product should meet all the necessary criteria to be therapeuticallyequivalent and bioequivalent to the brand name (reference) drug product.

The manufacturer of a generic drug product has certain constraints informulation development that di¡er from the formulation development of abrand name drug product. For example, a generic drug manufacturer mayhave to use the same or similar inactive ingredients or excipients as in thebrand formulation. Generic drug manufacturers also face a variety of legalchallenges from the brand name (innovator) pharmaceutical industry.Manyof these issues will be discussed in subsequent chapters.

1. SELECTION OF A GENERIC DRUG PRODUCT FORMANUFACTURE

Themaindriving force for theselectionofgenericdrugproducts formanufac-ture is the estimated sales volume for the branded product and the potentialmarket share that the ¢rm expects to have once the generic drug product is

In addition to the expiration date of the patent for the active ingredient, thegeneric ¢rmmust consider any other patent claims and exclusivities that theinnovator ¢rm has ¢led. The generic drug manufacturer needs to considerthe lead time that is needed tomake the product and submission of anAbbre-viated NewDrug Application (ANDA) to the U.S. Food and Drug Adminis-tration(FDA) for approval. Moreover, there is a ¢nancial incentive tobeing the ¢rst generic drug product ¢led and approved by FDA. TheHatch^Waxman Act, as explained below, provides a 180-day exclusivity,under certain conditions, for the generic manufacturer who is ¢rst to ¢le.

The availability of technology and the cost of acquiring technology tomanufacture the product will also impact on the choice of generic drug. For

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manufactured and approved for marketing (Table1).Patent and legal consid-erations are also very important and are discussed more fully in Chapter 14.

example, if the technology requires a £uidized bed coater, roller compactor,or any other special equipment, then the ¢rm must consider whether thisequipment is available or must be acquired. Formulation considerationsinclude the availability of raw materials, chemical purity, polymorphicform, and particle size of the active pharmaceutical ingredient and anypatents that the innovator company has ¢led, including patents for thesynthesis of the active pharmaceutical ingredient and composition of thedosage form. Experience with certain drug products will also a¡ect thechoice of generic drug product development. For example, some genericdrug manufacturers may make a wide variety of dosage forms as well assolid and liquid oral dosage forms including immediate and modi¢edrelease products. Other generic ¢rms may make specialty drug productssuch as transdermal or inhalation drug products.Niche drug products, suchas transdermal drug products, may be di⁄cult to make and also riskier, butmay have a greater ¢nancial reward due to less competition from othergeneric drug ¢rms.

The decision to proceed with the development of a generic drugproduct should therefore be based on well-researched data that primarilyindicate market value together with a sound knowledge of patent expirydates, predicted market share, and growth rate for the product, amongstothers. Government spending trends on medicines, which, in some coun-tries, may be in the region of 40% or even more of the total market, shouldnot be overlooked. The predicted pro¢tability of the new generic productwill require strategic planning for the subsequent launch timing,whichmusttake into account the expected generic price and knowledge of anticipatedcompetitors, such as who they are and when they are expected.

2. LEGISLATIVE AND REGULATORY ISSUES

The U.S. Food and Drug Administration was established in 1906 by theFederal Food, Drug, and Cosmetic Act (the ‘‘Wiley Act’’) to prevent the

TABLE 1 Considerations in the Selection of a Generic Drug Product forManufacture

Sales and potential market sharePatent expiration and exclusivity issuesAvailability of active pharmaceutical ingredientTimingTechnologyFormulationExperience


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manufacture, sale, or transportation of adulterated or misbranded orpoisonous or deleterious foods, drugs, medicines, and liquors, and forregulating tra⁄c therein, amongst others. In 1938, the Act was amended torequire drug manufacturers to ¢le a New Drug Application (NDA) for eachnewly introduced drug and to provide data to establish the safety of the drugproduct. In 1962, the Kefauver^Harris Amendments to the Act required alldrug manufacturers to establish that their products were e¡ective for theirclaimed indication(s), in addition to adhering to the safety requirements.Consequently, the FDA contracted with the National Academy ofSciences=National Research Council in 1968 to evaluate those drugs ¢rstintroduced between 1938 and 1962 for e¡ectiveness. This review programwas called the Drug E⁄cacy Study Implementation (DESI) review, anddrugs for which e¡ectiveness was determined through the DESI reviewcould be marketed with approval of an NDA. For drugs approved throughthe DESI review process, manufacturers of brand name products submitteddata as a supplement to the existing NDAs, con¢rming the safety ande¡ectiveness of their products. During the implementation of the DESIreview program, more than 3400 products and related generics werereviewed and approximately 900 drug products were removed from themarket. Many other products were reformulated or relabeled to limit theiruses to selected indications only. One e¡ect of the DESI study was thedevelopment of the ANDA in 1970 for reviewed marketed products thatrequired changes in existing labeling to be in compliance. However,manufacturers of any new drug product (brand name or generic) marketedafter 1962 were required to prove both the safety and e⁄cacy of suchproducts. The 1962 legislation provided an exemption from the NDAapproval process for drugs that had been marketed before 1938, based onthe assumption that they were generally recognized as safe and e¡ective�the so-called ‘‘grandfather’’ provision. Manufacturers continued to conductclinical e⁄cacy and safety studies until 1978, when a dispensation wasgranted to manufacturers whereby the citation of published reports of trialsdocumenting safety and e⁄cacy would su⁄ce (7,8).

In1984, the Drug Price Competition and Patent Term Restoration Act(Waxman^Hatch Act) extended the ANDA process to generic versions of

that generic drug manufacturers duplicate expensive, time-consumingclinical and nonclinical studies to demonstrate safety and e⁄cacy. Further-more, this Act expedites the availability of generic drug products providedthat the generic drugmanufacturer shows that no patent infringement wouldoccur.TheWaxman^HatchAct also compensated the innovator drugmanu-facturer for perceived losses due to competition from the generic drugproducts by extending the patent terms of some brand name drug products

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drugs marketed after 1962 (Table 2). This Act eliminated the requirement

for up to an additional 5 years to make up for time lost while their productswere going through FDA’s approval process.

The Drug Price Competition and Patent Term Restoration Act wassubsequently amended to make provision for a pharmaceutical manufac-turer (sponsor) to seek approval from the FDA to market a generic drugbefore the expiration of a patent relating to the brand name drug upon whichthe generic is based. This amendment, known as the ‘‘Bolar amendment’’,allowed theANDAapproval process to begin before the patent on the brandname drug expired. As part of the ANDA, submission the sponsor mustconsider the pertinent patents and provide a certification that, in the opinionof the sponsor and to thebest of the sponsor’s knowledgewith respect to eachpatent that claims the listed drug, the patent is invalid or is not infringed bythe generic product (6,7).

The current FDA Federal Food, Drug, and Cosmetic Act, with itssubsequent amendments, is the basic food and drug law of the USA

assure consumers that foods are pure and wholesome, safe to eat, andproduced under sanitary conditions; that drugs and devices are safe ande¡ective for their intended uses; that cosmetics are safe and made fromappropriate ingredients; and that all labeling and packaging is truthful,informative, and not deceptive. The mission of the FDA is to enforce lawsenacted by the U.S. Congress and regulations established by the Agency toprotect the consumer’s health, safety, and pocketbook.

The Federal Register publishes a daily record of proposed rules, ¢nalrules, meeting notices, etc. The ¢nalregulations are collected in the Code of Federal Regulations, CFR

ing broad areas subject to Federal regulations. The FDA’s portion of theCFR interprets the Federal Food, Drug, and Cosmetic Act and relatedstatutes. Section 21 of the CFR contains most of the regulations pertainingto food and drugs. The regulations document most actions of all drugsponsors that are required under Federal law.

TABLE 2 Drug Price Competition andTerm Restoration Act of1984(Waxman^Hatch Act)

Created a framework for patent term extensions and nonpatent exclusivity periods forbrand name drug products

Established for the first time an Abbreviated NewDrug Application (ANDA) approvalprocess specifically for generic manufacturers

Provided for prepatent expiration testing (Bolarprovision) and generic drug exclusivity


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(http:==www.fda.gov=opacom=laws=fdcact=fdctoc.htm) and is intended to

(http:==www.access.gpo.gov=).

(http:==www.access.gpo.gov=).The CFR is divided into 50 titles represent-

http://www.fda.gov

http://www.access.gpo.gov


3. GENERIC DRUG APPROVAL

The FDA’s O⁄ce of Generic Drugs is responsible for reviewing the ANDAand approving the drug product for marketing. The FDA’s O⁄ce of Generic

information formanufacturers of generic drug products that includes an inter-

describes howFDAdetermines the quality, safety, and e⁄cacy of generic drugproducts prior to approval for marketing.Generic drug application reviewersfocus on bioequivalence data, chemistry and manufacture quality, microbio-logydatawhere relevant, requests for plant inspection,anddrug labeling infor-mation. The FDA website is designed for individuals from pharmaceuticalcompanies, government agencies, academic institutions, private organiza-tions, or other organizations interested in bringing a generic drug to market.

The ANDA is based on bioequivalence to the brand name product,appropriate chemistry and manufacturing information, and appropriatelabeling.Generic drug sponsors do not have to duplicate the nonclinical ani-mal toxicity studies or expensive clinical e⁄cacy and safety studies that areincluded in the new drug application, NDA,which is submitted to the FDAfor market approval of the brand name drug product. The ANDA containsdata, which, when submitted to FDA’s Center for Drug Evaluation andResearch, O⁄ce of Generic Drugs, provide for the review and ultimateapproval for marketing a generic drug product.

FDAapproved generic drugsmustmeet the same rigid standards as theinnovator drug.To obtain FDA approval, a generic drug product must:

� Contain the same active ingredients as an approved referencelisted drug product� (generally, the innovator drug � the inactiveingredients may vary);

� be identical in strength, dosage form, and route of administration;� have the same use indications;� be bioequivalent;� meet the same batch requirements for identity, strength, purity, and

quality;� be manufactured under the same strict standards of FDA’s good

manufacturing practice regulations as required for innovatorproducts.

�The reference listed drug (RLD) may be found in the most current copy of FDA’s publication,Approved Drug Products with Therapeutic Equivalence Evaluations(‘‘OrangeBook’’).TheOrange

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Drugs has a website, http:==www.fda.gov=cder=ogd=, that provides additional

Book is published on the internet at http:==www.fda.gov=cder=ob=default.htm

active £ow chart presentation of the ANDA review process (Fig. 3), and

Details of the FDA review and approval process are discussed in Chapter 9.

http://www.fda.gov

http://www.fda.gov

FIGURE 3 Generic drug (ANDA) review process.


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An FDA approved generic drug product is considered a therapeuticequivalent to the innovator or brand name drug product in terms of qualityand performance characteristics and is expected to have the same safetyand e⁄cacy. An ANDA checklist for completeness and acceptability of anapplication is available on the FDA website at

3.1. Approved Drug Products with Therapeutic EquivalenceEvaluations (Orange Book)

The FDA’s Approved Drug Products with Therapeutic Equivalence Evalua-tions (Orange Book) lists all approved products, both innovator andgeneric (10). The Orange Book is available on the internet at

peutic equivalence or inequivalence for prescription products is deter-mined on the basis of the therapeutic equivalence codes provided within

equivalence evaluations is constructed to allow users to determinequickly whether the FDA has evaluated a particular approved product astherapeutically equivalent to other pharmaceutically equivalent products(¢rst letter) and to provide additional information on the basis of FDA’sevaluations (second letter).

4. PATENTS

New drugs, like most other new products, are developed under patentprotection.The patent protects the investment in the drug’s development bygiving the company the sole right to sell the drug while the patent is ine¡ect. Patents are granted by the U.S. Patent and Trademark O⁄ce anytimein the ‘‘life’’ of the drug. A patent expires 20 years from the date of ¢ling.When patents or other periods of exclusivity expire, manufacturers canapply to the FDA to sell generic versions.

The Orange Book provides patent and exclusivity information in anAddendum. This Addendum identi¢es drugs that qualify under the DrugPrice Competition and Patent Term Restoration Act (1984 Amendments)for periods of exclusivity, during which ANDAs and applications describedin Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (the Act)for those drug products may, in some instances, not be submitted or madee¡ective, and provides patent information concerning the listed drug pro-ducts.Those drugs that have quali¢ed for OrphanDrug Exclusivity pursuantto Section 527 of the Act and those drugs that have quali¢ed for PediatricExclusivity pursuant to Section 505A are also included in this Addendum.

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http:==www.fda.gov=cder=ogd=anda checklist.doc.

http:==www.fda.gov=cder=ob=default.htm and is updated monthly. Thera-

that speci¢c dosage form (Table 3). The coding system for therapeutic

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

Exclusivity prevents the submission or e¡ective approval of ANDAs orapplications described in Section 505(b)(2) of theAct.

Patents that are listed in theOrange Book include:

� Patents that claim the active ingredients or ingredients.� Drug product patents which include formulation=composition

patents.� Use patents for a particular approved indication or method of using

the product.

TheBolar amendment to theDrug Price Competition and PatentTermRestoration Act allows a pharmaceutical manufacturer (sponsor) to seekapproval from FDA to market a generic drug before the expiration ofa patent relating to the brand name drug upon which the generic is based.

TABLE 3 Orange BookCodes

A Drug products that are considered to be therapeutically equivalent to otherpharmaceutically equivalent products.‘‘A’’products are those for which actualor potential bioequivalence problems have been resolvedwith adequatein vivo and=or in vitro evidence supporting bioequivalence

AA Drug products in conventional dosage forms not presenting bioequivalenceproblems

AB Drug products meeting necessary bioequivalence requirementsAN Solutions and powders for aerosolizationAO Injectable oil solutionsAP Injectable aqueous solutions and, in certain cases, intravenous non^aqueous

solutionsAT Topical productsB Drug products that FDA, at this time, considers not to be therapeutically

equivalent to other pharmaceutically equivalent productsB� Drug products requiring further FDA investigation and review to determine

therapeutic equivalenceBC Extended-release dosage forms (capsules, injectables, and tablets)BD Active ingredients and dosage formswith documented bioequivalence problemsBE Delayed-release oral dosage formsBN Products in aerosol-nebulizer drug delivery systemsBP Active ingredients and dosage formswith potential bioequivalence problemsBR Suppositories or enemas that deliver drugs for systemic absorptionBS Products associated with drug standard deficienciesBT Topical drug products with bioequivalence issuesBX Drug products for which the data are insufficient to determine therapeutic

equivalence


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As part of the ANDA, the sponsor must consider the pertinent patentsand provide the results to the FDA. The Act requires patent informationto be ¢led with all newly submitted Section 505 drug applications andthat no NDA may be approved after September 24, 1984, without thesubmission of pertinent patent information to the FDA. The ANDAsponsor must provide a certification that, in the opinion of the sponsorand to the best of the sponsor’s knowledge with respect to each patentthat claims the listed drug, some or all of the following certi¢cation maybe submitted:

Paragraph I: that such patent information has not been ¢led;Paragraph II: that such patent has expired;Paragraph III: of the date on which such patent will expire, orParagraph IV: that such patent is invalid or will not be infringed by the

manufacture, use, or sale of the new drug for which theapplication is submitted.

A certi¢cation under Paragraph I or II permits the ANDA to beapproved immediately, if it is otherwise eligible. A certi¢cation underParagraph III indicates that the ANDA may be approved on the patentexpiration date.

If theOrange Book lists one or more unexpired patents, the sponsor oftheANDAwho seeks e¡ective approval prior to the patent’s expirationmusteither:

� Challenge the listing of the patent (e.g., ¢le a Paragraph IVCerti¢cation that the patent is invalid or will not be infringed bythe manufacture, use, or sale of the drug product).

� File a statement that the application for use is not claimed in thelisted patent.

4.1. Exclusivity

The generic applicant must notify the patent holder of the submission ofthe ANDA. Since the patent holder can immediately sue the ¢rst genericsponsor company who submits an ANDAwith a Paragraph IV statement,a 180-day period of market exclusivity is provided to that generic appli-cant. This special dispensation is considered as a reward to the genericmanufacturer who took a risk in challenging the patent. If the patent holder¢les an infringement suit against the generic applicant within 45 days ofthe ANDA noti¢cation, FDA approval to market the generic drug is auto-matically postponed for 30 months, unless, before that time, the patentexpires or is judged to be invalid or not infringed. This 30-month

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postponement gives the patent holder time to assert its patent rights incourt before a generic competitor is permitted to enter the market. Onlyan application containing a Paragraph IV certi¢cation may be eligible forexclusivity, and to earn the period of exclusivity, the ANDA applicant must

Under certain circumstances, the patent holder may obtain exclusivityfor a branded drug product that essentially extends the time on the marketwithout competition from the generic drug product. Exclusivity workssimilar to patents and is granted by the FDA if statutory provisions are met.Types of exclusivity are listed inTable 4.

5. RESOURCES FOR ANDA SUBMISSIONS

FDA’s Center for Drug Evaluation and Research, CDERand the O⁄ce of Generic Drugs, OGD

TABLE 4 Types of Exclusivity

Exclusivity Time for exclusivity Exclusivity criteria

Orphan drugexclusivity(ODE)

7 years Upon approval of designatedorphan drug�Office of OrphanProducts issues letter whenexclusivity granted�separatefrom other types of exclusivity

New chemicalentity (NCE)

5 years Upon first time approval of newchemical entity

‘‘Other’’exclusivity 3 years for a‘‘significantchange’’if criteriaare met

For certain ‘‘significant changes’’approved on an NDA or supplementif new clinical studies essential forapproval, conducted or sponsoredby applicant, have been done

‘‘Changes’’may include (but are notlimited to): new ester=salt, new dosageform, new route, new indication, newstrength, new dosing schedule

Pediatricexclusivity(PED)

6months addedto existingpatents orexclusivity

A period of 6 months’exclusivity isadded to any existing exclusivity orpatents on all applications held bythe sponsor for that active moietypediatric exclusivity does notstand alone


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(http:==www.fda.gov=cder=),

14 for more details).be sued by the patent holder and successfully defend the suit (see Chapter

http://www.fda.gov

ANDA to meet the legal and regulatory requirements of an application.FDA provides assistance through its website and publications, guidances,internal ANDA review principles, policies, and procedures.

5.1. Guidance Documents for ANDAs

Guidance documents represent the Agency’s current thinking on a parti-cular subject Thesedocuments are prepared for FDA review sta¡ and applicants=sponsors toprovide guidelines to the processing, content, and evaluation=approval ofapplications and also to the design, production, manufacturing, and test-ing of regulated products. They also establish policies intended to achieveconsistency in the Agency’s regulatory approach and establish inspectionand enforcement procedures. Because guidances are not regulations orlaws, they are not enforceable, either through administrative actions orthrough the courts. An alternative approach may be used if such anapproach satis¢es the requirements of the applicable statute, regulations,or both. The FDA has numerous guidances for industry that relate toANDA content and format issues (11).

5.2. Manual of Policies and Procedures

Manuals of Policies and Procedures (MaPPs) provide o⁄cial instructions forinternal practices and procedures followed by CDER sta¡ to help standar-dize the drug review process and other activities, both internal and external(12). MaPPs de¢ne external activities as well. All MAPPs are available forthe public to review to get a better understanding of o⁄ce policies,de¢nitions, sta¡ responsibilities, and procedures. MaPP documents to helpprepare ANDAs are listed together on CDER’s Manual of Policies and

5.3. Freedom of Information (FOI)

The 1996 amendments to the Freedom of Information Act, FOIA, mandatepublicly accessible ‘‘electronic reading rooms’’ with FDA FOIA responsematerials and other information routinely available to the public withelectronic search and indexing features. Before submitting an FOIArequest, the sponsor should check to see if the information is already

a search engine to help ¢nd information (13).

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(http:==www.fda.gov=cder=ogd=), provide assistance to the sponsor of an

(http:==www.fda.gov=cder=regulatory=default.htm).

Procedures web page (http:==www.fda.gov=cder=mapp.htm).

available on FDA’s website (http:==www.fda.gov=foi=foia2.htm). There is

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

5.4. Additional Resources Regarding Drug Development

FDA provides additional resources regarding drug development on its web-

These resources are summarized inTable 5.

5.5. Drug Master File

TheDrugMaster File (DMF) is a submission to the FDAthatmay be used toprovide con¢dential detailed information about facilities, processes, or arti-cles used in the manufacturing, processing, packaging, and storing of one ormore human drug substances. The submission of a DMF is not required bylaw or FDA regulation. Further information regarding DMFs is available inthe CDERGuidance Document on DrugMaster Files or 21CFR 314.420.

5.6. United States Pharmacopeia

establishing and disseminating o⁄cially recognized standards of qualityand authoritative information for the use of medicines and other healthcaretechnologies by health professionals, patients, and consumers. USP worksclosely with the FDA, the pharmaceutical industry, and the healthprofessions to establish authoritative drug standards. These standards areenforceable by the FDA and the governments of more than 35 othercountries, and are recognized worldwide as a hallmark of quality.More than3700 standardsmonographs are published in the USPandNational Formula(NF), the o⁄cial drug standards compendia. USP also provides more than

TABLE 5 General Information Regarding Drug Development

General FDA InformationResourcesWithin FDAExternal Resources�GeneralExternal Resources�EducationReviewJurisdiction of Drug Product Classes within ODE IVItems of General InterestCDERGuidance Documents=MaPPsFederal RegisterTitle 21Code of Federal RegulationsFDAForms Distribution PageInternational Conference on Harmonisation DocumentsIND=NDA Jackets=Submission CoversDrugMaster File (DMF) Information


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site:http:==www.fda.gov=cder=ode4=preind=Gen Additional Resources.htm.

The U.S. Pharmacopeia, USP (www.usp.org), promotes public health by

http://www.fda.gov

http://www.usp.org

1600 premier chemical Reference Standards to carry out the tests speci¢edin USP^NF (14).

5.7. International Conference on Harmonisation

The International Conference on Harmonisation of Technical Require-ments for Registration of Pharmaceuticals for Human Use (ICH) iscomposed of the regulatory authorities of Europe, Japan, and the UnitedStates and experts from the pharmaceutical industry in the three regionsto discuss scienti¢c and technical aspects of product registration

The purpose of ICH is to make recommendations on ways to achievegreater harmonisation in the interpretation and application of technicalguidelines and requirements for product registration in order to reduce orobviate the need to duplicate the testing carried out during the researchand development of new medicines. The objective of such harmonisationis a more economical use of human, animal, and material resources, andthe elimination of unnecessary delay in the global development and avail-ability of new medicines whilst maintaining safeguards on quality, safety,and e⁄cacy, and regulatory obligations to protect public health (15).

6. SUMMARY

The market for generic drug products will increase rapidly in the nextdecade due to the expiration of patents and exclusivities for major brandname drug products and due to the demand by consumers and govern-ments for less expensive generic alternatives. From a scienti¢c perspective,generic drug product manufacturers must formulate a drug product thatwill have the same quality, therapeutic e⁄cacy, safety, and performanceas its brand name counterpart. Formulation development of an innovatordrug product has minimal constraints with respect to choice of excipients,manufacturing methods, and performance characteristics. In contrast,generic drug manufacturers must demonstrate that their formulation is apharmaceutical equivalent, is bioequivalent, and has the same quality andperformance characteristics as the brand name counterpart. Moreover,the generic drug manufacturer will continue to face a variety of legal,regulatory, and patent challenges from the brand name pharmaceuticalindustry that may delay the entry of the generic drug in the marketplace.The availability of generic drug products will, nevertheless, continueto play an important role, both nationally and internationally, by pro-viding cost-e¡ective medicines to the wider public, which will bringgreat bene¢ts to consumers as well as to health authorities in nations

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(http:==www.ifpma.org=ich1.html).

http://www.ifpma.org

around the world in their quest to make medicines more available anda¡ordable.

REFERENCES

1. The European Agency for the Evaluation of Medicinal Products Notefor Guidance in the Investigation of Bioavailability and Bioequivalence(CPMP=EWP=QWP=1401=98). December 14, 2000.

2. United States Code of Federal Regulation (CFR) contains Food and Drug

valence Requirements are in 21CFR Part 320.3.4. MarisDW,VukhacK-L,FriedrichAM,LohmanDM.TheFuture of theGeneric

Industry, Specialty Pharmaceutical Industry Overview. New York, NY: Bankof America Securities, June 2003.

5. Kirking DM, Ascione FJ, Gaither CA,Welage LS. Economics and structure ofthe generic pharmaceutical industry. J Am Pharm Assoc (Wash) 2001;41(4):578^584.

6.

7. Parker RE, Martinez DR, and Covington,TR. Drug product selection�part 1:history and legal overview. American Pharmacy; NS 31,72^7, (1991).

8. History of the Food and Drug Administration.Center for Drug Evaluation and

9. Ascione FJ, Kirking DM, Gaither CA, Welage LS. Historical overview ofgeneric medication policy. JAm Pharm Assoc (Wash) 2001; 41(4):567^577.

10. Approved Drug Products withTherapeutic Equivalence Evaluations, ‘‘Orange

11. FDA guidance documents, 2003. www.fda.gov=cder=guidance=index.htm.12. FDACenter forDrugEvaluation andResearch (CDER).Manual of Policies and

13. FDA Freedom of Information, 2003.Freedom of Information may be contacted at Freedom of Information Sta¡,5600 Fishers Lane, Room 12A-30, Rockville, MD 20857,USA, and at DocketsManagement Branch, 5630 Fishers Lane, Room 1061, Mail Stop HFA-305,Rockville,MD 20852,USA.

14. United States Pharmacopeia�National Formulary (USP). United States

15. International Conference on Harmonisation,


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IMSHealth Data.Wall Street Journal, February 21, 2003.

Regulations, 2003. (http:==www.access.gpo.gov=). Bioavailability and Bioequi-

laws=fdcact=fdctoc.htm.Federal Food, Drug, and Cosmetic Act., 2003. http:==www.fda.gov=opacom=

Research., 2003. http:==www.fda.gov=cder=about=history=.

Book’’, 2003. http:==www.fda.gov=cder=ob=default.htm.

Procedures, 2003. http:==www.fda.gov=cder=mapp.htm.(http:==www.fda.gov=foi=foia2.htm).

2003. http:==www.ifpma.org=ich1.html.

Pharmacopeia. Published annually, 2003. http:==www.usp.org.

(http:==www.emea=eu.int=pdfs=human=ewp=140198en.pdf ).


http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

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http://www.usp.org



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