PHARMACEUTICAL
`DOSAGE FORMS
`
`CELGENE 2043
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`· PHARMACEUTICAL
`DOSAGE FORMS
`
`Tablets
`
`SECOND EDITION, REVISED AND EXPANDED
`
`In Three Volumes
`VOLUME2
`
`EDITED BY
`
`Herbert A . Lieberman
`H. H. Lieberman Associates, Inc.
`Consultant Services
`Livingston, New Jersey
`
`Leon Lachman
`Lachman Consultant Services
`Westbury, New York
`
`Joseph B. Schwartz
`Philadelphia College of Pharmacy and Science
`Philadelphia, Pennsylvania
`
`MARCEL DEKKER, INC.
`
`N ew York and Basel
`
`

`

`Library of Congress Cataloging-in-Publication Data
`( Revised for vol . 2)
`
`Pharmaceutical dosage forms--tablets.
`
`"In three volumes . "
`Includes bibliographical references.
`1. Tablets (Medicine) 2. Drugs- - Dosage forms .
`I . Lieberman, Herbert A.
`II . Lachman, Leon
`III . Schwartz, Joseph B.
`[DNLM : 1. Dosage forms.
`2. Drugs--administration &
`dosage . QV 785 P535]
`615 1 . 191
`RS201.T2P46 1989
`ISBN 0-82 47-8 044-2 (v . 1 : alk. paper)
`
`89-1629
`
`This book is printed on acid- free paper.
`
`Copyright © 1990 by MA RCEL DEKKER, INC. All Rights Reserved
`
`Neither this book nor any part may be reproduced or transmitted in any
`form or by any means, electronic or mechanical, including photocopying,
`microfilming, and recording, or by any information storage and retrieval
`system, without permission in writing from the publisher .
`
`MARCEL DEKKER, INC .
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit) :
`10 9 8 7 6 5 4 3 2 1
`
`PRINTED IN THE UNITED ST ATES OF AMERICA
`
`

`

`6
`Bioavailability in
`Tablet Technology
`
`Salomon A . St a vc ha nsky and James W. McG inity
`
`University of Texas at Austin, Austin, Texas
`
`I . GENERAL CONS I DERATIONS
`
`Drugs are administered locally for protective action, antisepsis, local an -
`esthetic, and antibiotic effects, and they are given systemically for action
`on the cells and organs of the body or to counter the effects of invading
`organisms . A number of physiological and chemical factors are important
`in the absorption, distribution, and elimination of drugs in the body .
`Some of the properties of the buccal cavity, stomach, and small and large
`intestines that influence drug therapy are found in Tables 1 and 2.
`When drugs are given for systemic action, a number of routes are
`available, including oral, rectal, parenteral, sublingual, and inhalation .
`After absorption into the body, a drug is distributed by the blood and
`lymphatic system and passes into the extracellular fluids of various tis(cid:173)
`sues . The drug molecules may enter cells immediately and exert their
`pharmacological action in this way or be stored as a reservoir in muscle
`and fatty tissue for prolonged action . The drug may also be bound to
`albumin and other components of the plasma, altering tissue distribution
`and elimination from the body .
`Drugs are metabolized by enzyme systems of the body, and this
`process is given the general term "biotransformation . " The net effect may
`be inactivation or detoxification of the compound, or the drug may be con(cid:173)
`verted from an inactive or prodrug form into the pharmacologically active
`species . For example, the azo dye Prontosil is reduced in the body to
`sulfanilamide, and the discovery of this conversion led to the development
`and use of sulfonamides as medicinal agents . Biotransformation is mainly
`handled in the liver, but the process also occurs in the kidneys, intes(cid:173)
`tines , muscles, and blood .
`
`349
`
`

`

`-----
`-• -
`
`--.
`
`.. -
`
`350
`
`Stavchansky and McGinity
`
`Tabl e
`Physiological and Chemical Characteristics of Gastrointestinal
`Fluids in the Gastrointestinal Tract
`
`Factors
`
`Properties of fluidsa
`
`pH value
`
`Volume of fluid available (ml)
`- 1
`Surface tension ( dyn cm
`)
`
`Viscosity (cP)
`
`Buffer capacityb
`
`f3 (NaOH)
`f3 (HCl)
`
`l'I t ( °C)
`
`Density
`
`Water (%)
`
`-1
`Juice secretion (liter day
`)
`-1
`Water circulation (liter day
`)
`
`Enzymes and electrolytes
`
`Stomach
`
`Small
`intestine
`
`1 - 3
`
`50-250
`
`35 -5 0
`
`5 - 8
`
`25 - 125
`
`32 - 45
`
`0. 8-2 . 5
`
`0 . 7 - 1.2
`
`30 - 60
`
`600
`
`0 . 3 - 0 . 8
`
`1.01
`
`98
`
`2 - 4
`
`1 - 5
`
`4 - 8
`
`8 - 16
`
`0 . 62
`
`1. 01
`
`98
`
`0 . 2-0 .8
`
`1. 5 - 5
`
`Variable
`
`Variable
`
`aFasting subjects, temperature 37°c .
`b = mmol NaOH or HCl/liter x l'lpH x pH (stomach fluid 1. 5 ± 0 . 1) .
`Source : Modified from Ref. 121.
`
`T able 2 B uccal, Gastric, and Intestinal Fluids
`
`Daily volume
`(ml)
`
`Saliva
`
`Gastric secretion
`
`Pancreatic secretion
`
`Bile
`
`Succus entericus
`
`Brunner's gland secretion
`
`Larger intestinal secretion
`
`Source : Modified from Ref . 121.
`
`1200
`
`2000
`
`1200
`
`700
`
`2000
`
`50
`
`60
`
`pH
`
`6. 0 - 7 . 0
`
`1.0 - 3 . 5
`
`8 . 0 - 8 . 3
`
`7. 8
`
`7 . 8 - 8 . 0
`
`8 . 0-8 . 9
`
`7 . 5 - 8 . 0
`
`

`

`-
`
`...
`..
`·-
`
`...
`--
`--
`--l
`
`Bioavailability in Tablet Technology
`
`351
`
`KIDNEY
`
`rTO BLADDER
`t
`AND URETHRA
`
`Schematic diagram of kidney. A glomerulus and associated
`Figure 1
`structure are enlarged and shown in . the insert .
`
`Whether biotransformed or not, the drug molecules must finally be
`eliminated from the body . The kidneys are the principal organs of excre (cid:173)
`tion, but foreign compounds may be eliminated from the lungs or in bile,
`saliva, and sweat. The kidney (Fig . 1) is composed of millions of units
`consisting of a filtering capsule or glomerulus. The liquid, which con(cid:173)
`tains soluble excrement that is filtered through the glomerulus into the
`kidney tubules, is referred to as the glomerular filtrate . The tubules are
`surrounded by capillaries, and some solute molecules present in the
`glomerular filtrate may be reabsorbed and returned to the bloodstream .
`Molecules of physiological importance, such as glucose, water, chloride,
`potassium, and sodium sions, are reabsorbed at various segments of the
`tubules . Some drugs, such as penicillin G, do not pass through the
`glomerular apparatus but rather are actively transported from capillaries
`directly to the tubules where they are excreted in the urine . Thus,
`owing to pH, active transport mechanisms, solubility, and ionic character(cid:173)
`istics, drug molecules may be eliminated in the glomerular filtrate or
`directly absorbed into the tubules and excreted, and may be reabsorbed
`
`

`

`352
`
`Stavchansky and McGinity
`
`SMALL INTESTINE
`
`Fig ure 2 Liver, portal vein, gallbladder, and bile duct in relation to
`small intestine .
`
`from the tubules into the systemic circulation for recycling through the
`body . The excretion of weakly acidic and basic drugs is influenced by
`the pH of the urine, and elimination of these compounds may be altered by
`controlling urinary pH . Alkalinizing the urine results in reabsorption of
`quinidine and may result in sufficiently high plasma levels of the drug as
`to manifest toxicity .
`Biliary excretion has been found to be an important elimination route
`for some drugs ( see Fig . 2) . The drug present in the bile is discharged
`into the intestines and may be eliminated in the feces or into the vascular
`system from a region lower in the intestinal tract. Thus, as in kidney
`excretion, biliary passage may involve a cycle of elimination and reabsorp (cid:173)
`tion . This process, which occurs with morphine , penicillins, and a num -
`ber of dyes, is called enterohepatic circulation; the process tends to pro(cid:173)
`mote higher and prolonged concentrations of the , drug and its metabolites
`in the body than would be expected were the recycling process not in (cid:173)
`volved . However, repeated passage through the liver may lead to sig(cid:173)
`nificant metabolism of the drug .
`The processes of diffusion and the partitioning of drug molecules
`across membranes as a function of pH, pK
`, and other factors will be dis (cid:173)
`cussed in later sections of this chapter .
`a
`The kinetics of absorption, distribution, and excretion of drugs follow(cid:173)
`ing administration was first set forth by Teorell [ 1] in 193 7 (Fig . 3) .
`
`A. Biopharmaceutics and Pharmacokinetics
`
`A drug administered as a tablet or another dosage form must be released
`and reach its site of action in an active state before it can exert a
`
`

`

`d McGinity
`ari
`
`Bioavailability in Tablet Technology
`
`353
`
`BLOOD CIRCULATION
`
`ADMINISTRATION
`
`DEPOT
`SUBCUTA -
`NEOUS, ETC.
`
`BLOOD
`
`ELIMINATION TISSU E
`KIDN EY,
`LUNGS, ETC.
`
`CH E MICAL
`INACTIVATION
`IN TISSUES
`
`Schematic description of drug absorption, distribution, and
`Fig u re 3
`elimination .
`( After Ref . 1. )
`
`pharmacological response . The physical chemical properties of the drug,
`the characteristics of the dosage form in which the drug is administered,
`and the physiological factors controlling absorption, distribution, metab(cid:173)
`olism , and elimination of the drug must all be considered in order to formu -
`late and manufacture effective and safe therapeutic agents . This wide
`range of considerations comprise the subject called biopharmaceutics .
`Pharmacokinetics is a branch of biopharmaceutics and encompasses in a
`quantitative way the kinetics of absorption, distribution, metabolism, and
`excretion, often called ADME, of therapeutic agents and related chemical
`substances . The time course of passage of intact drugs and metabolites in
`various body tissues and fluids and the models constructed to interpret
`these data, which comprise the subjects of pharmacokinetics, will be intro(cid:173)
`duced as elementary mathamatical expressions and graphs of data early in
`the chapter and elaborated upon in later sections . The final part of the
`chapter considers the elements of pharmacokinetics in some detail . The
`s ubject is presented step by step with worked examples, so that a reader
`with a background in pharmacy , chemistry, or biology but minimal ground(cid:173)
`ing in mathematics can follow the treatment with relative ease .
`At the beginning it is well to define some of the terms to be used
`throughout the chapter, particularly the words biopharmaceutics, pharma(cid:173)
`cokinetics, and bioequivalency . Some of the terms, as defined in the 1977
`Bioequivalence Requirements and In Vitro Bioavailability Procedures of the
`FDA [ 2] , are found in Table 3 .
`
`B. Bioequ ivalence
`
`The forces that have led in the last decade to the concept of bioavailability
`were principally those due to the generic equivalence (bioequivalence)
`is sue . Specifically, it is of the utmost importance to be assured that chem(cid:173)
`ically equivalent drug products from different manufacturers result in es (cid:173)
`sentially the same degree of therapeutic action .
`An examination of the definitions as outlined in Table 3 shows that
`emphasis has been placed on the ability of two or more drug products to
`produce essentially identical blood levels in the same individual . The
`dosage form is a drug delivery system; it can be a good one or a poor one
`in its role of releasing the drug efficiently for absorption into the systemic
`circulation or site of action . Thus, appropriate testing of generic products
`
`- 4
`
`9
`
`--
`
`through the
`fluenced by
`ay be altered by
`bsorption of
`of the drug as
`
`ination route
`e is discharged
`to the vascular
`as in kidney
`and reabsorp (cid:173)
`' and a num (cid:173)
`tends to pro(cid:173)
`its metabolites
`ess not in -
`lead to sig-
`
`dis -
`
`

`

`354
`
`Stavchansky and McGinity
`
`Table 3 Definition of Terms Dealing with Bioavailability and
`Bioequivalence
`
`Drug
`
`Drug product
`
`Bioavailability
`
`Bioequivalent
`drug products
`
`Pharmaceutical
`equivalents
`
`Pharmaceutical
`alternatives
`
`Active therapeutic moiety .
`
`Delivery system, tablet, capsule, suspension (e . g . ,
`containing the therpeutic moiety), generally but not
`necessarily in association with inactive ingredients .
`
`The rate and extent to which the active drug in(cid:173)
`gredient or therapeutic moiety is absorbed from a
`drug product and beocmes available at the site of
`action .
`
`Pharmaceutical equivalents or alternatives whose rate
`and extent of absorption are not significantly differ(cid:173)
`ent when administered to humans at the same molar
`dose under similar conditions .
`
`Drug products identical in amount of active drug in -
`gredient and dosage form, and meeting compendial or
`other standards for identity, strength, quality, and
`purity . They may not be identical in terms of in -
`active ingredients . An example is erythromycin
`stearate tablets (Brand X and Brand Y) .
`
`Drug products that contain the identical therapeutic
`moiety or its precursor but not necessarily in the
`same amount or dosage form and not necessarily as
`the same salt or ester . Examples are erythromycin
`stearate versus erythromycin ester; chlorpheniramine
`maleate chewable tablets versus chlorpheniramine
`maleate capsules .
`
`•
`•
`
`•
`
`B ioequivalence
`requirements
`
`A requirement imposed by the FDA for in vitro and/or
`in vivo testing of specified drug products which must
`be satisfied as a condition of marketing .
`
`must be conducted . These tests are not done only through clinical trials
`of efficacy since it is ordinarily not the drug that is in question but the
`dosage form; the latter primarily influencing the absorption step .
`It is the
`absorption process or factors connected with the delivery system that must
`be studied to assure proper bioavailability of the drug and bioequivalence
`of products from one manufacturer to another and from batch to batch .
`A number of studies of marketed drug products containing the same
`chemical ingredient have revealed differences in bioavailability . Examples
`of problems with chemically equivalent drug products include tetracycline
`[3,4], chloramphenicol [5], digoxin [6,7], phenylbutazone [8,9], and
`oxytetracycline [ 10, 11] .
`In addition, variations in bioavailability of differ(cid:173)
`ent batches of digoxin from the same company have been demonstrated [ 7] .
`In one report, a thyroid preparation that met compendial standards was
`found to be therapeutically inactive [ 12] . Since lack of bioequivalence in
`these examples involves marketed products, it can be concluded that neither
`
`

`

`Bioavailability in Tablet Technology
`
`355
`
`standards for testing the finished product nor specifications for materials,
`manufacturing processes, and controls are presently adequate to ensure
`that drug products are bioequivalent . Good Laboratory Practice and Good
`Manufacturing Practice regulations promulgated by the U . S . Food and Drug
`AdminiRtration (FDA) will assist in correcting the problem, but specific
`actions regarding bioavailability mu st be taken to assure equivalent market (cid:173)
`ed products .
`In most instances it is concluded that therapeutic inequiva(cid:173)
`lence is a result of variations in the bioavailability of drug products .
`
`C. Relative Bioavailability and Drug Performance
`
`If a drug is administered at a dosage level that does not greatly exceed
`the minimum effective blood concentration (MEC) required, the availability
`of the drug from the dosage form may greatly influence the drug's per(cid:173)
`formance . Figure 4 schematically illustrates this case .
`In curve I the
`product formulation causes the drug to have a good therapeutic response.
`In curve II , because of a delayed rate of absorption, the effective re(cid:173)
`sponse is more transient . The slow absorption process of curve III leads
`to a lack of pharmacological response, even through the amount absorbed
`as determined by the total area under the curve is equal to the other two .
`This example illustrates that although the amount of drug absorbed may not
`differ, the rate of absorption of three products may be quite different,
`leading to variations in therapeutic action. A real example is presented in
`Figure 5, illustrating the work by Sullivan et al. [ 13) .
`It shows average
`
`-
`
`- - - - - - - - - - - - - - - - - - - - - - MEC
`
`~
`j
`-0
`0
`
`0 ro
`
`Time
`
`Figu re 4 Blood levels from three products, illustrating differences in the
`rate of absorption but not in the total amount of drug absorbed ,
`
`·011 (e , g,'
`SI bUt not
`g;ectients ,
`
`drug in -
`d frorn a
`e site of
`
`jjve drug in(cid:173)
`compendial or
`quality'. and
`terms of m(cid:173)
`romycin
`
`therapeutic
`iJy in the
`essarily as
`erythromycin
`orpheniramine
`beniramine
`
`must
`
`clinical trials
`estion but the
`step .
`It is the
`system that must
`bioequivalence
`h to batch .
`Ing the same
`lty • Examples
`de tetracycline
`IS,9], and
`ability of differ(cid:173)
`demonstrated [ 7) .
`atanctards was
`loequivalence in
`Udect that neither
`
`•
`•
`•
`
`•
`
`•
`
`t
`
`•
`
`•
`
`►
`
`

`

`..
`•
`
`t
`
`Stavchansky and McGinity
`
`•
`
`TREATMENT A
`
`■
`
`TH'r ATMfNT II
`
`356
`
`300
`
`250
`
`' E 200
`g-
`z
`0
`~ 150
`a:
`>-
`z
`w
`u
`z
`0
`u
`
`100
`
`50
`
`0
`
`2
`
`3
`
`4
`
`5
`
`8
`7
`6
`T IME (hr)
`
`9
`
`10
`
`II
`
`12
`
`24
`
`Figure 5 Average plasma levels of prednisone in nine adult volunteers
`following oral administration of 10 mg of prednisone (as two 5-mg tablets) .
`( From Ref. 13 . )
`
`plasma levels of prednisone obtained in nine adult volunteers in a three(cid:173)
`way crossover study when a 10-mg dose of prednisone was administered as
`two 5-mg tablets made by three different manufacturers. Treatment A
`g·ave the fastest absorption and highest plasma levels . Treatments B and
`C were two generic prednisone tablets that had a history of clinical failure
`and did not pass the USP tablet dissolution test. Treatment A passed all
`compendial tests in the laboratories of the FDA .
`In this case the rate of
`appearance of prednisone in plasma was different for the three tablets,
`although the average areas under the plasma concentration-time curves of
`individual subjects did not differ significantly . This is a case in which
`documented evidence of clinical failure with generic tablets can be related
`to differences in rates of absorption .
`Figure 6 illustrates t he results obtained by Glazko et al . [ 5] when
`testing four capsules of chloramphenicol in human subjects. Here the
`principal difference, as indicated by the area under the curve, is that the
`four products differ in the total amount of chloramphenicol absorbed .
`Product A gave an excellent blood level curve in subjects, whereas the
`other three formulations gave poor plasma levels . Because of these data,
`the FDA had products B , C, and D recalled and reformulated, and then
`instituted requirements that h ave brought the p r oblem of chloramphenicol
`products under control . The significance of this finding is that all the
`products were chemically equivalent . That is, they contained the correct
`amount of chloramphenicol, and the particle size of the drug in each of
`the products was similar . Figure 7 illustrates the results obtained by
`
`

`

`an d McGinity
`
`~y
`
`: volunteers
`5-mg tablets) .
`
`in a three(cid:173)
`dministered as
`·eatment A
`tments B and
`clinical failure
`A passed all
`l the rate of
`ae tablets,
`me curves of
`ie in which
`m be related
`
`[5] when
`Here t he
`e, is that the
`1sorbed .
`iereas the
`· these data,
`' anct then
`1ramphenicol
`~at all the
`the correct
`F, each of
`llinect by
`
`,
`
`♦
`
`♦
`
`♦
`
`.,
`
`•
`...
`
`,.,
`
`•
`
`10
`
`8
`
`6
`
`4
`
`' E
`
`~
`
`"' >
`"' __J
`
`0
`E
`
`~
`0
`
`Q_
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`Figure 6 Mean plasma levels for groups of 10 human subjects receiving
`single 0. 5-g oral doses of chloramphenicol capsules . Vertical lines repre(cid:173)
`sent one standard error on either side of the mean . Capsule A, /1; cap(cid:173)
`sule B, ◊; capsule C, o; capsule D, □ .
`(From Ref . 5. )
`
`100
`
`90
`
`80
`
`70
`
`60
`
`:';
`C
`.;'
`E
`
`~
`C
`0
`~
`
`D
`
`C
`
`B
`
`A
`
`50 L-----~-----~----~-----~--
`
`60
`
`80
`
`0
`
`20
`
`40
`
`T ime ( m,n)
`
`Figu re 7 Relative disintegration rates of chloramphenicol capsules in sim(cid:173)
`ulated gastric fluid . Capsule A, /1; capsule B, o; capsule C, □ ; capsule
`D, ◊ .
`(From Ref. 14 . )
`
`357
`
`

`

`358
`
`600
`
`' E
`
`Stavchansky and McGinity
`
`B
`
`400
`
`C
`!2
`1c
`C
`~ 0
`'-'
`e cc
`
`1'. 200
`0
`E
`0
`0
`-'
`'-'
`
`0
`
`25
`
`50
`
`75
`
`100
`
`125
`
`Time (min)
`
`Figure 8 Dissolution rates of chloramphenicol capsules in simulated gastric
`fluid. Capsule A, □; capsule B, b.; capsule C, ◊; capsule D, o .
`(From
`Ref . 14 . )
`
`Aguiar, showing that the disintegration rates of the four products differed
`greatly [ 14] . Product A, the one that produced the highest plasma level
`in the study by Glazko, had excellent disintegration characteristics, where (cid:173)
`as products B and C showed poor rates, and product D, the product
`having the poorest plasma level in patients, exhibited the poorest disinte(cid:173)
`gration rate .
`In fact, product D had such poor disintegration properties
`that the powder mass maintained its capsule shape in simulated gastric
`fluid after the gelatin capsule had dissolved. The results in Figure 8
`demonstrate the performance of the four products in a dissolution rate test .
`When product A was placed in simulated gastric fluid, it dissolved rapidly,
`whereas products B, C, and D showed greater lag times prior to dissolu -
`tion, principally because of the time required for deaggregation [ 14] .
`Dissolution tests and disintegration tests in some cases have been
`shown to correlate well with human bioavailability tests, as evidenced by
`the previous example . Lindenbaum's work on digoxin is another example
`of in vivo /in vitro correlations [7] .
`The FDA, in its bioequivalence preamble, stated [ 2] :
`
`Advances in pharmaceutical technology have made bioequivalence a
`most precise and reproducible method for determining drug product
`variability . These bioequivalence techniques are not inadequately
`defined or reachless concepts. They are scientifically valid methods
`of comparing different drug products as well as different batches
`of the same drug products.
`
`It is indeed fortunate that dissolution methodology frequently provides a
`measure of variability among drug dosage forms . The conclusion that can
`
`

`

`Bioavailability in Tablet Technology
`
`359
`
`be drawn from the bioequivalence requirements and in vivo bioavailability
`procedures of the FDA, published in the Federal Register of January 1977,
`is that dissolution testing will more than likely become the most frequently
`used means of testing and assuring bioequivalence [ 2] . Although it will
`probably not be the only criterion for obtaining marketing approval, the
`FDA report states that "a dissolution test may constitute a proper element
`in reaching the decision to approve an NDA or supplemental application for
`a drug product with a bioequivalence problem . "
`In another section of this
`chapter we discuss some of the methodology presently available for dissolu -
`tion testing .
`The digoxin tablet problem is an example of a situation that led to
`establishment by the FDA of a dissolution rate certification requirement
`and adoption of a dissolution specification by the USP . Digoxin is a drug
`in which the effective blood level is close to the toxic concentration .
`Product formulation may greatly influence the rate and extent of absor ption,
`and consequently the therapeutic activity and toxicity of digoxin •
`
`D. Federal Regu la tion s Covering Bioa vailabili ty
`and Bioequ ivalence
`
`In the Federal Register of January 1973 [ 15] , the FDA published proposed
`bioavailability requirements for new drugs and for generic drug products .
`These proposals became regulations as published in the Federal Register of
`January 1977 [ 2], with app:ropriate modifications as suggested by various
`individuals and groups . The regulations clearly establish that studies
`must be undertaken with new drugs or new dosage forms to assure that
`optimal absorption characteristics are achieved .
`The selection of the reference material (standard drug sample) as
`stated by the FDA is an important consideration .
`It depends upon the sci(cid:173)
`entific questions to be answered, the data needed to establish comparability
`with a currently marketed drug product, and the data needed to establish
`dosage regimens . The reference material should be taken from a current
`batch of a drug product that is the subject of an approved new drug ap (cid:173)
`plication and that contains the same active drug ingredient or therapeutic
`moiety . Thus, tetracycline hydrochloride cannot be the reference product
`for tetracycline phosphate; salts cannot be compared against esters, cap(cid:173)
`sules cannot be compared with tablets .
`In the report of the Office of Technology Assessment (OTA), Drug
`Bioequivalence Study Panel [ 16] , it was concluded that studies on bio(cid:173)
`availability are neither feasible nor desirable for all drugs or drug prod(cid:173)
`ucts . According to OT A, certain classes of drug should be identified for
`which evidence of bioequivalence is critical . Selection of these classes
`would be based on clinical importance, ratio of therapeutic to toxic con -
`centration in blood, and certain pharmaceutical characteristics . The panel
`believed, however, that bioavailability studies should be required for prod(cid:173)
`ucts if the active ingredient in the product had not yet been introduced
`into the market .
`A large number of drug products are available on the market, and for
`only a few of these are there adequate data documenting bioavailability in
`humans . Thus, many bioavailability studies would be required ; this in -
`volves large numbers of human volunteers and the expense of clinical in (cid:173)
`vestigators and other scientific personnel . Consequently, it is not feasible
`
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`♦
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`♦
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`...
`
`♦
`
`4
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`360
`
`Stavchansky and McGinity
`
`and justifiable to carry out studies of bioavailability in humans for all drug
`products .
`In asserting that studies of bioavailability will not be required
`for all drug products , it becomes important to set general criteria to guide
`the selection of those products whose bioavailability should be documented
`by testing in humans, those requiring no testing, and those few in which
`in vitro methodology would be deemed adequate . The report of the OT A
`study panel concluded that for drugs with a wide therapeutic range, mod (cid:173)
`erate differences in drug blood levels, owing to differences in bioavailability
`of chemically equivalent products, would be tolerated . Conv ersely, drugs
`that have a relatively narrow therapeutic range would be candidates for
`testing of bioavailability on human subjects . Examples of drugs that fall
`into this category include cardioactive agents ( digitalis glycosides), anti(cid:173)
`convulsants ( diphenylhydantoin) , some corticosteroids, and certain anti(cid:173)
`biotics ( chloramphenicol and cephalosporins).
`In summary, drug products
`will be considered candidates for human bioavailability studies if they :
`
`Are used for treatment or prevention of serious illness
`Have steep dose-response curves or unfavorable therapeutic indices
`Contain active ingredients that are relatively insoluble or are converted
`to insoluble forms in the gastrointestinal fluids
`
`In the Federal Register of January 1977, the FDA [ 2) published cri(cid:173)
`teria for waiver of evidence of bioavailability . The requirement for sub(cid:173)
`mission of in vivo bioavailability data will be waived if :
`
`1. The drug product meets both of the following conditions :
`a .
`It is a solution intended solely for intravenous administration .
`h .
`It contains an active drug ingredient or therapeutic moiety in
`the same solvent and concentration as an intravenou s solution
`that is the subject of an approved full new drug application .
`2. The drug product is a topically applied preparation (e . g . , a
`cream, ointment, or gel) intended for local therapeutic effect .
`3. The drug product is an oral dosage form that is not intended to
`be absorbed (e . g . , an antacid or a radiopaque medium) .
`4. The drug product meets both of the following conditions :
`a .
`It is an oral solution, elixir, syrup, tincture, or similar other
`solubilized form .
`It contains an active drug ingredient or therapeutic moiety in
`the same concentration as a drug product that is the subject
`of an approved full new drug application .
`It contains no inactive ingredient that is known to significantly
`affect absorption of the active drug ingredient or therapeutic
`moiety .
`
`b .
`
`c .
`
`The regulations proceed to list drugs for which in vivo bioavailability
`data of solid oral dosage forms need not be submitted to the FDA .
`For certain drug products, bioavailability may be demonstrated by
`evidence obtained in vitro in lieu of in vivo data . The FDA waives the
`requirements for the submission of evidence obtained in vivo demonstrating
`the bioavailability of the drug product if the drug product meets one of
`the following criteria :
`
`

`

`sky and McGinity
`
`mans for all drug
`not be required
`criteria to guide
`i be documented
`,se few in which
`ort of the OT A
`1tic range, mod -
`·s in bioavailability
`,nversely, drugs
`:!andidates for
`drugs that fall
`rcosides), anti-
`l certain anti-
`' drug products
`lies if they :
`
`Jeutic indices
`or are converted
`
`published cri(cid:173)
`~ment for sub-
`
`itions :
`administration .
`,eutic moiety in
`venous solution
`1g application.
`L (e . g . , a
`utic effect .
`>t intended to
`ium) .
`itions :
`Jr similar other
`
`eutic moiety in
`is the subject
`
`to significantly
`or therapeutic
`
`bioavailability
`e FDA .
`tstrated by
`I. waives the
`J demonstrating
`meets one of
`
`Bioavailability in Tablet Technology
`
`361
`
`1. The drug product is subjected to the bioequivalence requirement
`established by the Food and Drug Administration under Sub(cid:173)
`part C of this part that specifies only an in vitro testing
`requirement .
`2. The drug product is in the same dosage form, but in a different
`strength, and is proportionally similar in its active and inactive
`ingredients to another drug product made by the same manu -
`facturer and the following conditions are met :
`a . The bioavailability of this other drug product has been demon(cid:173)
`strated.
`b . Both drug products meet an appropriate in vitro test approved
`by the Food and Drug Administration .
`c . The applicant submits evidence showing that both drug prod(cid:173)
`ucts are proportionally similar in their active and inactive
`ingredients .
`3 . The drug product is, on the basis of scientific evidence sub (cid:173)
`mitted in the application, shown to meet an in vitro test that
`assures bioavailability (i.e . , an in vitro test that has been corre(cid:173)
`lated with in vivo data) .
`4 . The drug product is a reformulated product that is identical, ex(cid:173)
`cept for color, flavor, or preservative, to another drug product
`made by the same manufacturer and both of the following condi(cid:173)
`tions are met :
`a . The bioavailability of the other product has been demonstrated .
`b . Both drug products meet an appropriate in vitro test approved
`by the Food and Drug Administration .
`5. The drug product contains the same active drug ingredient or
`therapeutic moiety and is in the same strength and dosage form as
`a drug product that is the subject of an approved full or abbre(cid:173)
`viated new drug application, and both drug products meet an ap(cid:173)
`propriate in vitro test that has been approved by the Food and
`Drug Administration .
`
`The FDA, for good cause, may defer or waive a requirement for the
`submission of evidence of in vivo bioavailability if deferral or waiver is
`compatible with the protection of the public health .
`In the 1970s the FDA developed what is now known as the Approved
`Drug Products with Therapeutic Evaluation Publication [ 17] (referred to
`in text as the List) . The List was distributed as a proposal in January
`1979 .
`It included only currently marketed prescription drug products
`approved by FDA through new drug applications (NDAs) or abbreviated
`new drug applications (ANDAs) under the provisions of Section 505 or 507
`of the Federal Food, Drug, and Cosmetic Act (the Act) . The therapeutic
`equivalence evaluations in the List reflect FDA 's application of specific
`criteria to the approved multisource prescription drug products on the
`List . These evaluations are presented in the form of code letters that
`indicate the basis for the evaluation made .
`A complete discussion of the background and basis of FDA's thera(cid:173)
`peutic equivalence evaluation policy was published in the Federal Register
`on January 12, 1979 ( 44 FR 2932) . The final rule, which includes FDA 's
`responses to the public comments on the proposal, was published in the
`
`

`

`362
`
`Stavchansky and McGinity
`
`Federal Register on October 31, 1980 ( 45 FR 72582) . The first publication,
`October 1980, of the final version of the List incorporated appropriate c