`
`ANDAs: Pharmaceutical
`Solid Polymorphism
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`
`Chemistry, Manufacturing, and Controls Information
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`U.S. Department of Health and Human Services
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`Food and Drug Administration
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`Center for Drug Evaluation and Research (CDER)
`July 2007
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`OGD
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`IPR2020-00769
`United Therapeutics EX2016
`Page 1 of 13
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`Guidance for Industry
`ANDAs: Pharmaceutical
`Solid Polymorphism
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`
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`Chemistry, Manufacturing, and Controls Information
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`
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`Additional copies are available from:
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`Office of Training and Communication
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`
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`Division of Drug Information, HFD-240
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`
`
`Center for Drug Evaluation and Research
`
`
`Food and Drug Administration
`
`5600 Fishers Lane
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`Rockville, MD 20857
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`(Tel) 301-827-4573
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` http://www.fda.gov/cder/guidance/index.htm
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`U.S. Department of Health and Human Services
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`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`July 2007
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`OGD
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`IPR2020-00769
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`I.
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`TABLE OF CONTENTS
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`
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`INTRODUCTION..............................................................................................................................................1
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`
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`II. DEFINITION OF TERMS: POLYMORPHIC FORMS AND POLYMORPHISM ...................................2
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`
`
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`GENERAL PRINCIPLES OF PHARMACEUTICAL SOLID POLYMORPHISM..............................2
`
`III.
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`
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`IMPORTANCE OF PHARMACEUTICAL SOLID POLYMORPHISM ...........................................................................2
`
`A.
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`B. CHARACTERIZATION OF POLYMORPHS.............................................................................................................2
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`INFLUENCE OF POLYMORPHISM ON DRUG SUBSTANCE AND DRUG PRODUCT.................................................3
`
`C.
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`1.
`Influence on Solubility, Dissolution, and Bioavailability (BA) and Bioequivalence (BE)..........................3
`
`
`
`2.
`Influence on Manufacturing of the Drug Product ......................................................................................4
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`3.
`Influence on Stability..................................................................................................................................5
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`POLYMORPHISM AND SAMENESS IN ANDAs....................................................................................5
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`V. CONSIDERATIONS FOR POLYMORPHISM IN ANDAs..........................................................................6
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`
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`INVESTIGATING THE IMPORTANCE OF SETTING SPECIFICATIONS FOR POLYMORPHS ........................................6
`
`A.
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`SETTING SPECIFICATIONS FOR POLYMORPHS IN DRUG SUBSTANCES ...............................................................6
`
`B.
`
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`INVESTIGATING THE IMPORTANCE OF SETTING SPECIFICATIONS FOR POLYMORPHS IN DRUG PRODUCTS........7
`
`C.
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`ATTACHMENT 1 – DECISION TREE 1.................................................................................................................8
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`ATTACHMENT 2 – DECISION TREE 2.................................................................................................................9
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`ATTACHMENT 3 – DECISION TREE 3...............................................................................................................10
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`
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`IV.
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`IPR2020-00769
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`Contains nonbinding recommendations
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`
`Guidance for Industry1
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`ANDAs: Pharmaceutical Solid Polymorphism
`
`Chemistry, Manufacturing, and Controls Information
`
`INTRODUCTION2
`
`
`
`This guidance, represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`
`You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
`
`and regulations. If you want to discuss an alternate approach, contact the appropriate FDA staff. If you
`cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this
`document.
`
`
`I.
`
`Chemistry, manufacturing, and controls (CMC) information must be submitted to support the
`approval of an abbreviated new drug application (ANDA).3 This guidance is intended to assist
` applicants with the submission of ANDAs when a drug substance4 exists in polymorphic forms.5
`
`Specifically, this guidance provides:
`
`
`• FDA recommendations on assessing sameness6 when the drug substance exists in
`
`polymorphic forms.
`
`
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`• Decision trees that provide recommendations on monitoring and controlling polymorphs
`
` in drug substances and/or drug products.7
`
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`
`
`
`
`
`
` 1 This guidance has been prepared by the Office of Generic Drugs (OGD) in the Office of Pharmaceutical Science
` (OPS), Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA).
`
`
`2 Although issues relating to polymorphic forms may be relevant to new drug applications (NDAs), this guidance
`
`
`
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`only addresses polymorphic forms in the context of ANDA approvals.
`3 See 21 CFR 314.94 (a)(9); see also section 505(j)(4)(A) of the Federal Food, Drug, and Cosmetic Act (the Act).
`
`
`4 For the purposes of this guidance the terms drug substance and active ingredient are used interchangeably.
`5 The terms polymorphic forms and polymorphs are synonymous and are used interchangeably in this guidance.
`6 Refer to Section IV for more information.
`
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`7 This guidance is intended to help industry with the most common types of polymorphs. A drug substance may
`
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`exist in many polymorphic forms, but some forms may be rare and not likely to form. For example, in one approved
`
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`drug product, the drug substance can exist in at least twenty polymorphic forms, but in reality only a subset of
`
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`polymorphic forms has the potential to develop under the process conditions used to manufacture the drug substance
`
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`and drug product. Therefore, we recommend that you consider only those polymorphs that are likely to form during
`
`
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`manufacture of the drug substance, manufacture of the drug product, or while the drug substance or drug product is
`in storage.
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`
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`1
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`DEFINITION OF TERMS: POLYMORPHIC FORMS AND POLYMORPHISM
`
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`
`II.
`
`We recommend that ANDA applicants investigate whether the drug substance in question can
`exist in polymorphic forms. Polymorphic forms in the context of this guidance refer to
`crystalline and amorphous forms as well as solvate and hydrate forms, which are described
`below.8
`
`
`
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`• Crystalline forms have different arrangements and/or conformations of the molecules in
`the crystal lattice.
`
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`
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`• Amorphous forms consist of disordered arrangements of molecules that do not possess a
`distinguishable crystal lattice.
`
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`• Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts
`of a solvent.9 If the incorporated solvent is water, the solvate is commonly known as a
`hydrate.
`
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`When a drug substance exists in polymorphic forms, it is said to exhibit polymorphism.
`
`
`III. GENERAL PRINCIPLES OF PHARMACEUTICAL SOLID POLYMORPHISM
`
`
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`Importance of Pharmaceutical Solid Polymorphism
`
`A.
`
`Polymorphic forms of a drug substance can have different chemical and physical properties,
`including melting point, chemical reactivity, apparent solubility,10 dissolution rate, optical and
`mechanical properties, vapor pressure, and density. These properties can have a direct effect on
`the ability to process and/or manufacture the drug substance and the drug product, as well as on
`drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the
`quality, safety, and efficacy of the drug product.
`
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`Characterization of Polymorphs
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`B.
`
`There are a number of methods that can be used to characterize polymorphs of a drug
`substance.11 Demonstration of a nonequivalent structure by single crystal X-ray diffraction is
`
`8 Guidance for industry, Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances
`
`
`and New Drug Products: Chemical Substances, International Conference on Harmonisation (ICH), December 2000.
`
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`
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`9 SR Byrn, RR Pfeiffer, and JG Stowell. Solid-State Chemistry of Drugs. 2nd Edition, SSCI, Inc., West Lafayette,
`
`
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`Indiana, 1999.
`
`10 Apparent solubility refers to the concentration of material at apparent equilibrium (supersaturation). Apparent
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`
`
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`solubility is distinct from true thermodynamic solubility, which is reached at infinite equilibrium time.
`
`11 H Brittain. "Methods for the characterization of polymorphs and solvates." In HG Brittain (ed.) Polymorphism in
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`Pharmaceutical Solids. Marcel Dekker, Inc., New York, 1999, pp. 227-278.
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`currently regarded as the definitive evidence of polymorphism. X-ray powder diffraction can
`also be used to provide unequivocal proof of polymorphism. Other methods, including
`microscopy, thermal analysis (e.g., differential scanning calorimetry, thermal gravimetric
`analysis, and hot-stage microscopy), and spectroscopy (e.g., infrared [IR], Raman, solid-state
`nuclear magnetic resonance [ssNMR]) are helpful to further characterize polymorphic forms.
`
`C.
`
`Influence of Polymorphism On Drug Substance And Drug Product
`
`
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`1. Influence on Solubility, Dissolution, and Bioavailability (BA) and
`
`Bioequivalence (BE)
`
`
`
`The solid-state properties of a drug substance can have a significant influence on the apparent
`solubility of the drug substance. Since polymorphic forms differ in their internal solid-state
`structure, a drug substance that exists in various polymorphic forms can have different aqueous
`solubilities and dissolution rates.12 When there are differences in the apparent solubilities of the
`various polymorphic forms, we recommend that you focus on the potential effect such
`differences can have on drug product bioavailability (BA) and bioequivalence (BE).13
`
`
`Whether drug product BA/BE can be affected by the differences in apparent solubilities of the
`various polymorphic forms depends on the various physiological factors that govern the rate and
`extent of drug absorption including gastrointestinal motility, drug dissolution, and intestinal
`
`permeability. In this context, the Biopharmaceutics Classification System (BCS)14, 15 provides a
`useful scientific framework for regulatory decisions regarding drug substance polymorphism.
`
`For a drug whose absorption is only limited by its dissolution, large differences in the apparent
`solubilities of the various polymorphic forms are likely to affect BA/BE. On the other hand, for
`
`a drug whose absorption is only limited by its intestinal permeability, differences in the apparent
`solubilities of the various polymorphic forms are less likely to affect BA/BE. Furthermore, when
`the apparent solubilities of the polymorphic forms are sufficiently high and drug dissolution is
`rapid in relation to gastric emptying, differences in the solubilities of the polymorphic forms are
`unlikely to affect BA/BE.
`
`
`
` 12 HG Brittain and DJW Grant. "Effect of polymorphism and solid-state solvation on solubility and dissolution rate."
`
`
`
`
` In HG Brittain (ed.) Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc., New York, 1999,
`
`
`pp. 279-330.
`13 Bioavailability (BA) is defined in 21 CFR 320.1(a) as “the rate and extent to which the active ingredient or active
`
`
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`moiety is absorbed from a drug product and becomes available at the site of action." Bioequivalence (BE) is
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`defined in 21 CFR 320.1(e) as “the absence of a significant difference in the rate and extent to which the active
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`ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the
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`site of drug action when administered at the same molar dose under similar conditions in an appropriately designed
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`study.”
`14 GL Amidon, H Lennernas, VP Shah, and JR Crison. "A theoretical basis for a biopharmaceutic drug
`classification: the correlation of in vitro drug product dissolution and in vivo bioavailability," Pharm. Res. 12:413-
`
`
`420, 1995.
`15 LX Yu, GL Amidon, JE Polli, H Zhao, M Mehta, DP Conner, VP Shah, LJ Lesko, M-L Chen, VHL Lee, and AS
`
`
`Hussain. "Biopharmaceutics Classification System: The scientific basis for biowaiver extension." Pharm. Res.
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`19:921-925, 2002.
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`Upon demonstration of in-vivo bioequivalence between the generic drug product16 and the
` reference listed drug (RLD),17 in-vitro dissolution testing is then used to assess the lot-to-lot
`
`quality of the generic drug product. Drug product dissolution testing frequently provides a
`suitable means to identify and control the quality of the product from both the bioavailability and
`physical (stability) perspectives. In particular, inadvertent changes to the polymorphic form that
`may affect drug product BA/BE can often be detected by drug product dissolution testing.
`
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`2. Influence on Manufacturing of the Drug Product
`
`
`
`Drug substance polymorphic forms can also exhibit different physical and mechanical properties,
`including hygroscopicity, particle shape, density, flowability, and compactibility, which in turn
`may affect processing of the drug substance and/or manufacturing of the drug product. Since an
`ANDA applicant should demonstrate that the generic drug product can be manufactured reliably
`using a validated process, we recommend that you pay close attention to polymorphism as it
`relates to pharmaceutical processing.18
`
`
`The effect of polymorphism on pharmaceutical processing also depends on the formulation and
`the manufacturing process.19 For a drug product manufactured by direct compression, the solid-
`
`state properties of the active ingredient will likely be critical to the manufacture of the drug
`product, particularly when it constitutes the bulk of the tablet mass. On the other hand, for a
`
` drug product manufactured by wet granulation, the solid-state properties of the active ingredient
`are often masked by the resultant granulation, and the solid-state properties of the active
`ingredient are less likely to affect the manufacture of the drug product. In the context of the
`effect of polymorphism on pharmaceutical processing, what is most relevant is the ability to
`consistently manufacture a drug product that conforms to applicable in-process controls and
`release specifications.
`
`Polymorphic forms of the drug substance can undergo phase conversion when exposed to a range
`
`of manufacturing processes, such as drying, milling, micronization, wet granulation, spray-
`drying, and compaction. Exposure to environmental conditions such as humidity and
`temperature can also induce polymorph conversion. The extent of conversion generally depends
`on the relative stability of the polymorphs, kinetic barriers to phase conversion, and applied
`stress.20 Nonetheless, phase conversion generally is not of serious concern, provided that the
`conversion occurs consistently, as a part of a validated manufacturing process where critical
`manufacturing process variables are well understood and controlled, and when drug product
`BA/BE has been demonstrated.
`
`
`16 The term generic drug product refers to a new drug product for which approval is sought in an ANDA submitted
`
`
`
`
`
` under section 505(j) of the Act.
`
`
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`17 See 21 CFR 314.3 (b) (providing that reference listed drug means the listed drug identified by FDA as the drug
`
`
`
`
`
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`product upon which an applicant relies in seeking approval of its abbreviated application).
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`18 Section 505(j)(4)(A) provides that FDA must approve an ANDA if, among other things, the methods used in, or
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`
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`the facilities and controls used for, the manufacture, processing, and packing of the drug are adequate to assure and
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`preserve its identity, strength, quality, and purity.
`
`19 DA Wadke, ATM Serajuddin, and H Jacobson. "Preformulation testing." In HA Lieberman, L Lachman, and JB
`
`
`
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`Schwartz (eds.) Pharmaceutical Dosage Forms: Tablets (Vol. 1). Marcel Dekker, Inc., New York, 1989,
`
`
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`pp. 1-73.
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`20 SR Vippagunta, HG Brittain, DJW Grant. "Crystalline solids," Adv. Drug Del. Rev. 48:3-26, 2001.
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`Influence on Stability
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`3.
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`
`
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`Polymorphs can have different physical and chemical (reactivity) properties. The most
`thermodynamically stable polymorphic form of a drug substance is often chosen during
`development based on the minimal potential for conversion to another polymorphic form and on
`its greater chemical stability. However, a metastable form can be chosen for various reasons,
`including bioavailability enhancement. Since an ANDA applicant must demonstrate that the
`generic drug product exhibits adequate stability,21 we recommend that you focus on the potential
`effect that a polymorphic form can have on drug product stability. Nonetheless, because drug
`product stability is affected by a multitude of other factors, including formulation, manufacturing
`process, and packaging, it is the stability of the drug product and not stability of the drug
`substance polymorphic form that should be the most relevant measure of drug quality.
`
`
`IV.
`
`POLYMORPHISM AND SAMENESS IN ANDAs
`
`Section 505(j)(2) of the Act specifies that an ANDA must contain, among other things,
`information to show that the active ingredient in the generic drug product is the "same as" that of
`the RLD. Under section 505(j)(4) of the Act, FDA must approve an ANDA unless the agency
`finds, among other things, that the ANDA contains insufficient information to show that the
`active ingredient is the same as that in the RLD. FDA regulations implementing section 505(j)
`of the Act provide that an ANDA is suitable for consideration and approval if the generic drug
`product is the "same as" the RLD. Specifically, 21 CFR 314.92(a)(1) provides that the term
`
`"same as" means, among other things, "identical in active ingredient(s)." The drug substance in
`a generic drug product is considered to be the same as the drug substance in the RLD if it meets
`
`the same standards for identity.22
`
`When a United States Pharmacopeia (USP) monograph exists for a particular drug substance,
`standards for identity generally refer to the definition (e.g. chemical name, empirical formula,
`molecular structure, description) at the beginning of the monograph. However, FDA may
`prescribe additional standards that are material to the sameness of a drug substance.23
`
`
`Polymorphic forms of a drug substance differ in internal solid-state structure, but not in chemical
`structure. In the context of sameness of active ingredient(s) in the preamble to the 1992 final
`rule, FDA specifically rejected a proposal that would have required an ANDA applicant to show
`that the active ingredient in its generic drug product and the active ingredient in the RLD
`"exhibit the same physical and chemical characteristics, that no additional residues or impurities
`can result from the different manufacture or synthesis process and that the stereochemistry
`characteristics and solid state forms of the drug have not been altered."24 Therefore, differences
`in drug substance polymorphic forms do not render drug substances different active ingredients
`for the purposes of ANDA approvals within the meaning of the Act and FDA regulations.
`
`
`
`
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` 21 See footnote 18.
`22 See preamble to the 1992 final rule (57 FR 17958; April 28, 1992).
`
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`23 See footnote 22.
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`24 See footnote 22.
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`CONSIDERATIONS FOR POLYMORPHISM IN ANDAs
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`
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`In addition to meeting the standards for identity, each ANDA applicant is required to
`demonstrate that, among other things, the drug product exhibits sufficient stability and is
`bioequivalent to the RLD.25 While the polymorphic form can affect drug product stability and
`bioequivalence, these performance characteristics are also dependent on the formulation, the
`manufacturing process, and other physicochemical properties (e.g., particle size, moisture) of
`both the drug substance and formulation excipients. Using a drug substance polymorphic form
`
`that is different from that of the RLD may not preclude an ANDA applicant from formulating a
`generic drug product that exhibits bioequivalence and stability, and the drug substance in the
`generic drug product need not have the same polymorphic form as the drug substance in the
`RLD.
`
`Over the years, FDA has approved a number of ANDAs in which the drug substance in the
`generic drug product had a different polymorphic form from the drug substance in the respective
`RLD (e.g., warfarin sodium, famotidine, and ranitidine). FDA also has approved some ANDAs
`in which the drug substance in the generic drug product differed in solvate or hydrate forms from
`
`the drug substance in the corresponding RLD (e.g., terazosin hydrochloride, ampicillin, and
`cefadroxil).
`
`
`V.
`
`The decision trees shown in Attachments 1 to 3 provide ANDA applicants with a suggested
`process for evaluating the importance of and approaches to setting specifications for
`polymorphic forms in solid oral drug products and oral suspensions. Although the conceptual
`framework adopted by these decision trees is based primarily on the potential for polymorphic
`forms to affect drug product BA/BE, we recommend that you still consider the influence
`polymorphic forms may have on the ability to manufacture the drug product and on the stability
`of the drug product.
`
`The following sections describe each of the decision trees.
`
`A.
`
`Investigating the Importance of Setting Specifications for Polymorphs
`
`
`Decision Tree 1 provides recommendations on when specifications for polymorphic form(s)26
`
`for the drug substance and/or the drug product may be appropriate. Polymorphs are unlikely to
`have a significant effect on BA/BE when all forms have the same apparent solubilities or all
`forms are highly soluble.
`
`ANDA applicants are expected to have adequate knowledge about drug substance polymorphs.
`Information on polymorphism can come from the scientific literature, patents, compendia, other
`references, or in some cases, polymorph screening.
`
`
`
`B.
`
`Setting Specifications for Polymorphs in Drug Substances
`
`
`
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` 25 See 505(j)(4) of the Act and 21 CFR 314.127.
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`26 See footnote 7.
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`Decision Tree 2 provides an approach for setting specifications for polymorphs in the drug
`substance when at least one form is known to have low solubility based on the BCS. If relevant
`and adequate specifications for polymorphs are included in the USP, ANDA applicants may
`
`adopt these specifications for the drug substance polymorphic form. Otherwise, we recommend
`that a new specification for the drug substance polymorphic form be established.
`
`C.
`
`Investigating the Importance of Setting Specifications for Polymorphs in
`Drug Products
`
`
`Decision Tree 3 provides an approach when considering whether to set specifications for
`
`polymorphs in the drug product. Generally, specifications for polymorphs in drug products are
`not necessary if the most thermodynamically stable polymorphic form is used or if the same
`
`form is used in an approved product of the same dosage form. However, since manufacturing
`processes can affect the polymorphic form, we recommend that you use caution if a metastable
`form is used.
`
`Drug product performance testing (e.g., dissolution testing) can also generally provide adequate
`control of polymorph ratio changes that can influence drug product BA/BE for poorly soluble
`drugs. In such instances, setting specifications for polymorphs in the drug product would
`generally not be considered important for ensuring adequate product performance. Only in rare
`cases would we recommend setting specifications for polymorphic forms in drug products.
`
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`ATTACHMENT 1 – DECISION TREE 1
`
`
`Investigating whether to set specifications for polymorphs for solid oral
`and suspension dosage form products.
`
`
`
`
`
`
`
`
`Decision Tree 1
`
`
`START
`
`Are there known
`
`polymorphs*
`with different
`apparent
`solubilities?
`
`
`NO
`
`
`
`Polymorphic form specifications in both the drug
`
`substance and the drug product are unnecessary
`
`YES
`
`YES
`
`
`
`
`Are all polymorphs
`highly soluble as
`
`defined by BCS
`
`criteria?
`
`NO
`
`
`Decision Tree 2
`
`
`
`
`
`
` *We recommend that you consider only those polymorphs that are likely to form during manufacture of the drug
`
` substance, manufacture of the drug product, or while the drug substance or drug product is in storage. See footnote
`
`
`
`7 in this guidance document.
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`8
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`Decision Tree 2
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`Contains nonbinding recommendations
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`ATTACHMENT 2 – DECISION TREE 2
`
`
`Setting specifications for polymorphs in drug substances for solid oral and
`suspension dosage form products.
`
`
`
`
`
`
`
`
`
`
`START
`
`Is there a
`polymorph
`specification in the
`USP (e.g., melting
`point)?
`
`
`NO
`
`
`
` YES
`
`
`Is the polymorph
`specification in the
`USP relevant and
`
`adequate?
`
`
`NO
`
`
`
` Set a new specification for the drug substance
`polymorphic form.
`
`YES
`
`
`Set the same specification for the
`drug substance polymorphic form as
`
`in the USP.
`
`
`
`
` Decision Tree 3
`
`9
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`ATTACHMENT 3 – DECISION TREE 3
`
`Investigating whether to set specifications for polymorphs in drug
`products for solid oral and suspension dosage form products.
`
`
`
`
`
`
`Decision Tree 3
`
`
`START
`
`NO
`
`A polymorph specification in
`the drug product is unnecessary.
`
`YES
`
`
`Set a specification for drug
`product performance testing
`
`(e.g., dissolution testing) as a
`surrogate for polymorph
`control in the drug product.
`
`Is there sufficient
`concern that a
`polymorph
`specification in the
`drug product be
`established?*
`
`
`YES
`
`Does drug product
`performance testing
`
` (e.g., dissolution
`testing) provide
`adequate controls if
`the polymorph ratio
`
`changes?
`
`
`NO
`
` Set a polymorph specification in the drug product
`
`
` using other approaches, such as a solid-state characterization method.**
`
`*In general, there may not be a concern if the most thermodynamically stable polymorphic form
`is used or the same form is used in a previously approved product of the same dosage form.
`
`**Drug product performance testing (e.g., dissolution testing) can generally provide adequate
`control of polymorph ratio changes for poorly soluble drugs, which may influence drug product
`BA/BE. Only in rare cases would polymorphic form characterization in the drug product be
`recommended.
`
`
`
`
`10
`
`
`IPR2020-00769
`United Therapeutics EX2016
`Page 13 of 13
`
`