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    Add as FriendRegulatory Considerations on Pharmaceutical Solids: Polymorphs/Salts and Co-Crystals

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    1 : 1 Regulatory Considerations on Pharmaceutical Solids: Polymorphs/Salts and Co-Crystals Andre S. Raw, Ph.D Director- Division of Chemistry I FDA-CDER-Office of Generic Drugs *Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of the FDA
    2 : 2 1. Regulatory Scheme on Polymorphs/Salts Overview 2. Regulatory Scheme on Co-Crystals???
    3 : 3 Part IA Regulatory Scheme on Polymorphs
    4 : 4 Solid-State Polymorphism Different crystalline forms of the same drug substance (ICH Q6A) Crystalline forms Solvates (Hydrates) Amorphous forms
    5 : 5
    6 : 6 Dissolution/Solubility Limited Oral Absorption (e.g. chloramphenicol palmitate) Gastric Emptying or Permeation Limited Oral Absorption (e.g. ranitidine HCl) Polymorphism and the Effect on Bioavailability Intestinal Membrane
    7 : 7 Polymorphism and the Effect on Stability Crystalline: Degradation: 0.5% Amorphous: Degradation: 4.5% Formulation I Crystalline: Degradation 0.6% Amorphous Degradation 0.7% Formulation II Optimize the formulation mitigate degradation pathways (e.g., adjust pH microenvironment to limit degradation, anti-oxidant to limit oxidative degradation)
    8 : 8 Polymorphism and the Effect on Manufacturability E. Joiris , Pharm. Res. 15 (1998) 1122-1130
    9 : 9 Selection and Control of Polymorphic Forms?
    10 : 10 QbD Paradigm: Polymorphs From ICH Q8: “The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g. solid state properties), should be identified and discussed. “ Expectation that sponsors justify in pharmaceutical development the selection and control of the polymorphic form (as applicable) to achieve drug product performance characteristics, stability and ensure manufacturability
    11 : 11 Example QbD MR Tablet Module 3 Quality 3.2.P.2 Pharmaceutical Development Quality by Design for ANDAs: An Example for Modified Release Dosage Forms Introduction to the Example This is an example pharmaceutical development report illustrating how ANDA applicants can move toward implementation of Quality by Design (QbD). The purpose of the example is to illustrate the types of pharmaceutical development studies ANDA applicants may use as they implement QbD in their development process and to promote discussion on how OGD would use this information in review. ( ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdf).
    12 : 12 Schematic: MR Drug Product Active High Shear Wet Granulation IR Granules Active DL (MCC Cores) ER Wurster Coating ER Pellets Blending/Lubrication Cushioning Excipient Compression Tablet Core Film Coat MR Product
    13 : 13 Active ingredient (solid-state crystalline/amorphous forms) are chemically stable Chemical stability in solid state (crystalline & amorphous) and in solution Low Risk: Potential for Drug Product Chemical Degradation on Stability Therefore No Need to Optimize Formulation Mitigate Potential Degradation
    14 : 14 Solid-State Form of Active Ingredient in MCC Beads Needs to Be Investigated: Potential Impact on Physical Stability and Consequently Drug Release on Stability Hi Risk: Formulation Needs to be Optimized to Mitigate this Potential Risk Failure Mode
    15 : 15 Binder Optimization and Drug Substance Solid-State Stabilization To Mitigate Physical Transformation Failure Mode on Product Stability
    16 : 16 Formulation (Stability) Past Paradigm Stable by Testing ( 25 C/60% RH for 24 months) QbD Paradigm Has the Applicant Optimized the Formulation “Stability by Design” Limited Testing Sufficient to Ensure Stability on Future Production Batches??? API Chemical Reactivity/ Excipient Compatability? Amorphous Dispersion (API/Binder) on MCC Core Physically Stable? Plasticizer Optimal to Minimize Curing Recall on Stability NDA/ANDAs
    17 : 17 Regulatory Considerations: Can One Consider Polymorphs to be the Same Active? Materials Science J. Am. Chem. Soc. 122 (2000) 585-591 Form I Form II Drug Product Safety/Effectiveness
    18 : 18 Fundamental Premise for ANDAs for Generic Drug Products Pharmaceutical Equivalence Bioequivalence Therapeutic Equivalence “Same" Active Ingredient(s) as RLD (brand product) Identical in Strength, Dosage Form, Route of Administration. Meet compendial or other applicable standards of Strength, Quality, Purity, and Identity Absence of a statistically significant difference in the rate and extent to which the active ingredient in pharmaceutically equivalent products becomes available at the site of action, when administered to subjects at the same molar dose under similar conditions
    19 : 19 Different Polymorphs Therapeutic Equivalents Same Active Different Active Pharmaceutical Equivalents Pharmaceutical Alternatives Similar Bioavailability Therapeutic Equivalents Similar Bioavailability
    20 : 20 Regulation: Solid State Forms Abbreviated New Drug Application (ANDA) for a Generic Product Must Contain the “Same” Active Ingredient as the Reference Listed Drug (RLD) ANDAs May Use Different Polymorphic Forms To Design a Drug Product with Equivalent Performance Characteristics to the RLD Regulatory Scheme for ANDAs: Polymorphic Forms of API are the “Same” Preamble 1992 Final Rule: FDA specifically rejected requirement that API in the Generic and RLD product “exhibit the same physical characteristics … and…solid state forms of the drug have not been altered.”
    21 : 21
    22 : 22 Part IB Regulatory Scheme on Salts
    23 : 23 Salts Any of numerous compounds that result from replacement of part or all of the acid hydrogen of an acid by a metal or a radical acting like a metal: an ionic or electrovalent crystalline compound. .
    24 : 24 Salts May or May Not Enhance Performance Characteristics Similar Bioavailabilities for Quinine Salts (Ethyl Carbonate/Chloride/Sulfate) Differing Bioavailabilities for LY333531 Salts (Mesylate/Chloride) G. Engel, Int. J Pharmaceutics 198 (2000) p. 239-247 A. Jamaludin, Br J. Clin. Pharmac 25 (1988) p. 261-263
    25 : 25 FDA Regulatory Scheme 21 CFR 320.1(c), Food and Drugs, Definitions: Pharmaceutical equivalent means drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety…; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency. Phosphate Sulfate Same Active Moiety Different Active Ingredients FDA Regulatory Scheme: Pharmaceutical Alternatives No Possibility for Therapeutic Equivalence for Different Salts
    26 : 26 EMEA Regulatory Scheme Article 10.2.b of Directive 2001/83/EC: The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant EMEA Regulatory Scheme: More Flexible and Possible Therapeutic Equivalence for Different Salts with Supporting Data
    27 : 27 Part II Regulatory Scheme on Co-Crystals???
    28 : 28 What are Co-Crystals “Multiple Component Crystal in Which All Components are Solid Under Ambient Conditions” (M.J. Zawarotki) “A Molecular Complex that Contains Two or More Different Molecules in the Same Crystal Lattice” (G.P. Stahly) Definitions Generally Distinguish Co-crystals From Salts
    29 : 29 Co-Crystals Salts Co-crystals Polymorphs Crystalline Molecular Complexes: Co- Crystal / Salt Continuum Crystalline Molecular Complexes: Analogous to Polymorph Solvate (Except other Component in Crystal Lattice is a Solid (not Liquid))
    30 : 30 Potential Utility of Co-Crystals API : Probable Molecular Recognition Patterns (e.g. H-bonding Rules) with “Guest” Compound Co-Crystal Solid State Engineering Improved API Cocrystal Solid State Properties No Ionizable Groups Salt Form: Enhanced Pharmaceutical Properties API
    31 : 31 Piroxicam Amide H-Bonding Network (III) Piroxicam-Hydroxybenzoic Acid Co-Crystal Carboxylic Acid-Amide H-Bonding (IV) Crystal Solid State Engineering Based Upon H-Bonding Motifs P. Vishweshwar, J. Pharmaceutical Science, 95(3) 2006, p.499-516
    32 : 32 Candidate Drug I (Low Solubility– 0.1 mg/mL – pKa of conjugate acid (-0.5)) Co-Crystals May Enhance Drug Product Properties: Bioavailability I I : Glutaric acid Cocrystal D. McNamara, Pharmaceutical Research 23 (2006) p. 1888-1897. I
    33 : 33 Co-Crystals May Enhance Drug Product Properties: Processability Paracetamol Form I (Stable Form) Crystal Lattice Compact Currugated Layers Difficult to Compress S. Karki, Advanced Materials, 21 (2000) p. 3905-3909.
    34 : 34 Enhance Manufacturing Efficiency Enhance Drug Product Bioavailability Optimize Drug Product Stability Co-crystals: Opportunities Crystal Engineering
    35 : 35 Where Do Co-Crystals Fit in Our Regulatory Scheme? Salts Co-crystals?? Polymorphs Same API Same Active Moiety Different API Where Do Co-Crystals Fit? Is a New Regulatory Class of Solids Needed?
    36 : 36 Analysis: Formulating Regulatory Policy 21 CFR 210.3(b)(4): A drug product is a finished dosage form (e.g., tablet; capsule; or solution that contains an active pharmaceutical ingredient generally, but not necessarily, in association with inactive ingredients (excipients)).
    37 : 37 Physical Association (API – Excipient) API with Lactose Dry Blend Association of Active Ingredient with Excipients in Drug Product Molecular Association (API – Excipient) Distinguishable by Having a Crystal Lattice
    38 : 38 Co-Crystal Regulatory Scheme Salts Co-crystals Polymorphs No Need to Create New Category Of Solid-State Form Fits Nicely Within Our Framework As an Active Ingredient Drug Product Intermediate
    39 : 39 Considerations in Review of CoCrystals 1. Determine whether, in the crystalline solid, the component API with the excipient compounds in the co-crystal exist in their neutral states and interact via nonionic interactions, as opposed to an ionic interaction, which would classify this crystalline solid as a salt form. a. Generally speaking, if API and its excipient(s) have a ?pKa (pKa (base) - pKa (acid)) < 0, there will be negligible proton transfer and the molecular complex will be a co-crystal. b. If the ?pKa > 3, there will be complete proton transfer resulting in complete ionization and formation of a salt as opposed to a co-crystal. c. In instances where the ?pKa > 0 and ?pKa < 3, the extent of proton transfer and ionization is generally not predictable. Rely on Spectroscopic tools to resolve this. For pharmacological activity, ensure that the API dissociates from its excipient prior to reaching the site of action.
    40 : 40
    41 : 41 Common Themes from Docket(Not Comprehensive List) Co-crystals be new alternative APIs: Some reasons cited - Fixed phases of defined stoichiometry - Co-crystals have different properties from the API. - API co-crystal is typically fully characterized for solid-state properties, not API. - Drug substance release and stability testing is performed on the co-crystal, not API - Co-crystals are manufactured at API facilities (not drug product facilities). - API is typically not isolated during synthesis but rather isolated as a co-crystal. - Drug product manufacturing facilities do not typically generate co-crystals intermediates
    42 : 42 Common Themes from Docket 2. Classify co-crystals as salts: Conceptually no different than salts. a. The approach to distinguishing co-crystals from salts is flawed - pkas are from the solution state and not representative of “true” pka in a co-crystal lattice. - Determining the location of the proton by spectroscopic tools is difficult if not impossible. - Distinguishing between a salt and co-crystal would place undue burden to the industry. - This would also result in endless debate among industry/reviewers on classification b. This would cause confusion. Many putative approved “salts” are actually co-crystals. c. Classify the co-crystals as salts but take the broader approach of changing the FDA regulations in relation to salts to be similar to the EMEA approach 3. For pharmacological activity of co-crystals, what are the data requirement expectations to ensure the API dissociates from its excipient prior to reaching the site of action?
    43 : 43 Acknowledgements Quality by Design Co-Crystals Lawrence Yu Richard Lostritto (ONDQA) Robert Lionberger OGD and ONDQA Directors Lane Christensen Peng Yingxu Khalid Khan Helen Teng Jennifer Maguire Bhagwant Rege Others in QbD working Group Om Anand, Dipak Chowdhury, Roslyn Powers Ubrani Venkataram, Quamrul Majumder Peter Capella, Laxma Nagavelli, Suhas Patankar Youmin Wang

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