11/18/2015
`
`Guidances Drugs
`
`Development of New Stereoisomeric Drugs
`
`U.S Food and Drug Administration
`Protecting and Promoting Your Health
`
`Development of New Stereoisomeric
`Drugs
`
`Publication Date 5/1/1 992
`
`INTRODUCTION AND BACKGROUND
`
`Stereoisomers are molecules that are identical
`in atomic constitution and bonding but differ in the
`three-dimensional arrangement of the atoms For the purpose of this document
`pairs of greatest interest are those with one or more asymmetric chiral centers whose
`enantiomers individual stereoisomers are mirror images They have essentially identical physical
`rotatory and chemical except
`except for optical
`chiral environment properties
`
`the stereoisomeric
`
`in
`
`This document focuses on issues relating to the study and pharmaceutical development of
`individual enantiomers and racemates Such stereoisomers usually require specialized chiral
`identification characterization separation and measurement They are
`techniques for their correct
`often readily distinguished by biological systems however and may have different
`pharmacokinetic properties absorption distribution biotransformation and excretion and
`
`quantitatively or qualitatively different pharmacologic or toxicologic effects
`
`When stereoisomers are biologically distinguishable they might seem to be different drugs yet it
`has been past practice to develop racemates i.e compounds with 5050 proportion of
`enantiomers The properties of the individual enantiomers have not generally been well studied or
`characterized Whether separated enantiomers should be developed was largely an academic
`question because commercial separation of racemates was difficult Now that technological
`advances large scale chiral separation procedures or asymmetric syntheses permit production of
`is appropriate to consider what FDAs policy
`commercial scale it
`many single enantiomers on
`with respect to stereoisomeric mixtures should be Development of racemates raises issues of
`acceptable manufacturing control of synthesis and impurities adequate pharmacologic and
`toxicologic assessment proper characterization of metabolism and distribution and appropriate
`clinical evaluation
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`MYLAN - EXHIBIT 1014
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`

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`11/18/2015
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`Guidances Drugs
`
`Development of New Stereoisomeric Drugs
`
`the term ustereoisomersu is
`
`It should be noted that
`isomers that differ only in
`general one for all
`the orientation of the atoms in space Stereoisomers include not only the mirror image
`enantiomers but also geometric cis/trans isomers and diastereoisomers isomers of drugs with
`more than one chiral center that are not mirror images of one another Diastereoisomers and
`geometric isomers are both chemically distinct and pharmacologically different unless they are
`interconverted in vivo and are generally readily separated without chiral techniques Geometric
`isomers and diastereoisomers therefore should with the rare exception of cases where in vivo
`interconversion occurs be treated as separate drugs and developed accordingly There is no
`reason to consider developing mixtures of geometric isomers or diastereoisomers unless they
`reasonable fixed dose combination see 21 CFR 300.50 Even in that
`fortuitously represent
`case whether the optimal ratio of the two isomers is the ratio produced by an undirected or
`unmodified synthesis should be critically examined In general geometric isomers have been
`as single isomers Practice with respect to diastereoisomers has been variable These
`developed
`categories of stereoisomers will not be considered further in this document Examination of cases
`reveals instances in which both
`in which the properties of enantiomers have been evaluated
`members had similar desirable activities
`
`both enantiomers of dobutamine are positive inotropes
`
`both ibuprofen enantiomers are anti-inflammatory agents
`
`both enantiomers of wartarin and phenprocoumon are anticoagulants
`
`the enantiomers of bupivicaine both produce local anesthesia
`
`the enantiomers of the quinolones and the b-lactam antibiotics are all antibacterial
`instances in
`which one member of
`pair was pharmacologically active and the other inactive 1-propranolol
`is not
`
`b-blocker d-propranolol
`
`is
`
`the enantiomers had completely different activities d-sotalol
`
`is
`
`type
`
`antiarrhythmic while
`
`sotalol
`
`is
`
`b-blocker or
`
`had different concentration-response relationships for
`
`given property
`
`While inactivity of one member of
`pair might be considered trivial
`toxicity has been linked to one member of
`pair of stereoisomers not necessarily the active
`isomer granulocytopenia
`is related to the d-isomer of levodopa vomiting is caused by the
`isomer of levamisole and myasthenia gravis symptoms were no longer observed when the
`isomer was removed from dlcarnitine and there are examples of an effect on the disposition of
`
`there are instances in which
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`

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`11/18/2015
`
`Guidances Drugs
`
`Development of New Stereoisomeric Drugs
`
`one member of
`pair by the other In addition there are many cases in which enantiomers have
`been shown to have different pharmacokinetic behavior Differences in pharmacokinetic behavior
`may not pose major therapeutic problem although it can make non-chiral blood level assays
`to interpret with respect to activity and confuse interpretation of non-clinical data if
`the
`pharmacokinetic properties of the isomers in animals differ from those in humans
`
`difficult
`
`therapeutic properties e.g dl
`While some enantiomeric pairs have had interesting and useful
`the optimum ratio of the components to be the
`sotalol dI-dobutamine there is no reason to expect
`11 ratio of
`racemate i.e the dose response curves would not usually be expected to be
`
`congruent
`
`Despite the problems identified with some racemates the common practice of developing
`is now
`racemates has resulted in few recognized adverse consequences Although it
`technologically feasible to prepare purified enantiomers development of racemates may continue
`to be appropriate However currently available information suggests that the following should be
`
`considered in product development
`
`Appropriate manufacturing and control procedures should be used to assure stereoisomeric
`product with respect to identity strength quality and purity Manufacturers
`composition of
`should notify compendia of these specifications and tests
`
`chiral assay will be misleading if the disposition
`Pharmacokinetic evaluations that do not use
`of the enantiomers is different Therefore techniques to quantify individual stereoisomers in
`pharmacokinetic samples should be available early If the pharmacokinetics of the
`enantiomers are demonstrated to be the some or to exist as
`fixed-ratio in the target
`population an achiral assay or an assay that monitors one of the enantiomers may be used
`subsequently
`
`II POLICY IN GENERAL
`chiral center should be known and the quantitative
`The stereoisomeric composition of
`drug with
`isomeric composition of the material used in pharmacologic toxicologic and clinical studies
`known Specifications for the final product should assure identity strength quality and purity from
`stereochemical viewpoint
`
`To evaluate the pharmacokinetics of
`single enantiomer or mixture of enantiomers manufacturers
`should develop quantitative assays for individual enantiomers in in vivo samples early in drug
`development This will allow assessment of the potential for interconversion and the absorption
`distribution biotransformation and excretion ADBE profile of the individual
`isomers When the
`racemate and the pharmacokinetic profiles of the isomers are different
`drug product
`
`is
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`

`
`11/18/2015
`
`Guidances Drugs
`
`Development of New Stereoisomeric Drugs
`
`manufacturers should monitor the enantiomers individually to determine such properties as dose
`linearity and the effects of altered metabolic or excretory function and drug-drug interactions
`If the
`pharmacokinetic profile is the same for both isomers or
`fixed ratio between the plasma levels of
`enantiomers is demonstrated in the target population an achiral assay or an assay that monitors
`one of the stereoisomers should suffice for later evaluation In vivo measurement of individual
`enantiomers should be available to help assess toxicologic findings but if this cannot be achieved
`it would be sufficient in some cases to establish the kinetics of the isomers in humans
`
`the main pharmacologic activities of the isomers should be
`Unless it proves particularly difficult
`in humans.A relatively benign toxicologic profile
`compared in in vitro systems in animals and/or
`using the racemate would ordinarily support further development without separate toxicologic
`evaluation of the individual enantiomers If however
`there are toxic findings other than those that
`are natural extensions of the pharmacologic effects of the drug and especially if they are unusual
`or occur near the effective dose inanimals or near the planned human exposure toxicologic
`isomers in the study where the toxicity was detected should be
`evaluation of the individual
`
`undertaken
`
`FDA invites discussion with sponsors concerning whether to pursue development of the racemate
`or the individual enantiomer All
`information developed
`by the sponsor or available from the
`is relevant to the chemistry pharmacology toxicology or clinical actions of the
`literature that
`stereoisomers should be included in the IND and NDA submissions
`
`III CHEMISTRY MANUFACTURING AND
`CONTROLS
`The chemistry section of the application should contain the requisite information to assure the
`identity quality purity and strength of the drug substance and drug product
`In addition the
`following considerations should be taken into account when dealing with chiral drug substances
`and drug products
`
`Methods and Specifications
`
`Drug Substance
`
`Applications for enantiomeric and racemic drug substances should include
`stereochemically
`stereochemically selective assay method The choice of the controls
`specific identity test and/or
`should be based upon the substances method of manufacture and stability characteristics
`
`Drug Product
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`

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`11/18/2015
`
`Guidances Drugs
`
`Development of New Stereoisomeric Drugs
`
`Applications for drug products that contain an enantiomer or racemic drug substance should
`stereochemically selective assay method
`include
`stereochemically specific identity test and/or
`The choice of the controls should be based upon the products composition method of
`manufacture and stability characteristics
`
`Stability
`
`The stability protocol
`for enantiomeric drug substances and drug products should include
`integrity of the drug substance and drug
`or methods capable of assessing the stereochemical
`product However once it has been demonstrated that stereochemical conversion does not occur
`stereoselective tests might not be needed
`
`method
`
`Labeling
`
`The labeling should include
`stereochemical descriptors
`
`unique established name and
`
`chemical name with the appropriate
`
`Pharmacology/Toxicology
`
`Pharmacology
`
`The pharmacologic activity of the individual enantiomers should be characterized for the principal
`pharmacologic effect and any other important pharmacological effect with respect to potency
`specificity maximum effect etc
`
`Pharmacokinetic Profile
`
`To monitor in vivo interconversion and disposition the pharmacokinetic profile of each isomer
`should be characterized in animals and later compared to the clinical pharmacokinetic profile
`obtained in phase
`
`Toxicology
`
`It
`
`toxicity studies on the racemate If toxicity other than that
`is ordinarily sufficient to carry out
`predicted from the pharmacologic properties of the drug occurs at relatively low multiples of the
`exposure planned for clinical trials the toxicity study where the unexpected
`toxicity occurred
`isomers to ascertain whether only one enantiomer was
`should be repeated with the individual
`responsible for the toxicity If toxicity of significant concern can be eliminated by development of
`it would in general be desirable to do so The
`single isomer with the desired pharmacologic effect
`agency would be pleased to discuss any cases where questions exist regarding the definition of
`
`significant toxicity
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`

`
`11/18/2015
`
`Guidances Drugs
`
`Development of New Stereoisomeric Drugs
`
`Impurity Limits
`
`It
`
`is essential
`
`to determine the concentration
`
`of each isomer and define limits for all
`
`isomeric
`
`components impurities and contaminants on the compound tested preclinically that
`use in clinical trials The maximum allowable level of impurity in
`stereoisomeric product employed
`trials should not exceed that present in the material evaluated in nonclinical
`
`is intended for
`
`toxicity
`
`in clinical
`
`studies
`
`Single Stereoisomer After the
`IV Developing
`Racemate is Studied
`
`To develop
`single stereoisomer from mixture that has already been studied non-clinically an
`abbreviated appropriate pharmacology/toxicology evaluation could be conducted to allow the
`of the racemate available to the sponsor to be applied to the pure
`existing knowledge
`stereoisomer Ongoing studies would usually include the longest repeat-dose toxicity study
`conducted up to months and the reproductive toxicity segment
`II study in the most sensitive
`species using the single enantiomer These studies should include
`positive control group
`consisting of the racemate If there is no difference between the toxicological profile of the single
`stereoisomeric product and the racemate no further studies would be needed If the single
`enantiomer is more toxic the explanation should be sought and the implications for human dosing
`considered
`
`Clinical and Biopharmaceutical
`
`Where little difference is observed in activity and disposition of the enantiomers racemates may be
`single enantiomer is particularly desirable e.g
`developed In some situations development of
`toxic or undesirable pharmacologic effect and the other does not
`where one enantiomer has
`signal that should trigger further investigation of the properties of the individual enantiomers and
`at clinical doses of toxicity with the racemate that
`their active metabolites is the occurrence
`is not
`clearly expected from the pharmacology of the drug or the occurrence
`of any other unexpected
`pharmacologic effect with the racemate These signals might be explored in animals but human
`testing may be essential
`
`It should be appreciated that toxicity or unusual pharmacologic properties might reside not
`is more important
`parent isomer but in an isomer-specific metabolite.ln general
`to evaluate both
`enantiomers clinically and consider developing only one when both enantiomers are
`pharmacologically active but differ significantly in potency specificity or maximum effect
`
`in the
`
`than
`
`it
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`

`
`11/18/2015
`
`Guidances Drugs
`
`Development of New Stereoisomeric Drugs
`
`when one isomer is essentially inert Where both enantiomers are fortuitously found to carry
`desirable but different properties development of mixture of the two not necessarily the
`fixed combination might be reasonable
`racemate as
`
`If
`
`Potential
`
`racemate is studied the pharmacokinetics of the two isomers should be studied in Phase
`interconversion should also be examined Based on Phase
`or
`pharmacokinetic data
`in the target population it should be possible to determine whether an achiral assay or monitoring
`of just one enantiomer where
`fixed ratio is confirmed will be sufficient for pharmacokinetic
`
`evaluation
`
`If
`
`racemate has been marketed and the sponsor wishes to develop the single enantiomer
`evaluation should include determination of whether there is significant conversion to the other
`isomer and whether the pharmacokinetics of the single isomer are the same as they were for that
`isomer as part of the racemate
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`Guidances Drugs
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`Development of New Stereoisomeric Drugs
`
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`Guidances Drugs
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`Development of New Stereoisomeric Drugs
`
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