Development of Up-to-Date Methods for USP/NF Excipient Standards

Development of Up-to-Date Methods for USP/NF Excipient Standards 2018 ExcipientFest Americas San Juan, Puerto Rico 01-May-2018 Hong Wang, Ph.D. Sr. Manager, Science Excipients United States Pharmacopeia Presentation Outline USP Today Excipients Up-to-Date Initiative Excipient Up-to-Date Strategies, Methodologies, and Updates Summary/Conclusions 1

Almost 200 Years of Building and Advancing the USP Vision 1820 Today 217 medicines covered No formal legal recognition The Pharmacopeia Over 5,000 monographs covering pharmaceuticals, food ingredients, herbal medicines and dietary supplements Standards legally recognized in many jurisdictions and used in more than 140 countries Expanded offerings: 3,600+ Reference Standards 50,000 professionals trained Verification program Global Health Impact Programs U.S. focused Global presence, with facilities in India, China, Brazil, Switzerland, Ghana, Ethiopia, Nigeria, Indonesia and the Philippines What is USP Today? We are an independent, scientific, global non-profit that: Establishes quality standards Established through independent scientific experts Provides reference standards Physical standards associated with monographs/chapters for product quality testing Especially important when medicines have multiple sources 2

Excipient Monographs Up-to-Date Initiative External Drivers Increasing complexity and global scope of pharmaceutical supply chains Concerns about lack of excipient supply chain integrity Desire to improve characterization of excipient composition Use of complex excipients in highly specialized drug delivery systems Concerns about Quality Standards May not reflect the quality of excipients currently used in drugs on the US market May not include all necessary manufacturing processes or sources to produce the product May not be helpful in promoting its fit for pharmaceutical use Require better characterization and/or define an excipient composition Excipient Monographs Up-to-Date Initiative A Need for Monograph Modernization Monographs have been official for several years, decades in some cases Monograph title and/or content do not reflect current expectations for products, procedures and acceptance criteria General lack of specificity on monograph title and test procedure Some testing not helpful to supply chain control and security (Identification tests) Safety-related concerns for laboratory Labeling deficiencies, e.g., when used in parenteral/injectable applications Missing specific tests to control quality (e.g., Microbial/Bacterial Endotoxin) 3

Excipient Standard Development Strategies USP Laboratories ( Internally sourced ) Internal Laboratory Support (the US, India, China, and Brazil) Support from USP laboratories: technical questions cannot be clarified by a monograph sponsor, data are incomplete or excipients are from multiple sources Extensive testing facilities for procedure development Collaborative testing sites in four different sites Challenging to set impurity specifications Expert Committee Criteria on Up-to-Date Methods Universality of test procedure application Simplicity of procedure a greater number of individual simpler tests is preferable to a smaller number of tests whose methodology is more complex and challenging Ease of adoption use of existing equipment and methodology to the greatest extent possible Specificity any test or combination of orthogonal tests must be able to uniquely identify the excipient and exclude the presence of other related substances Sufficient specificity to differentiate between an authentic excipient and an excipient adulterated with materials of inferior quality Efficiency preferably identity and assay use one method 8 4

Up-to-Date Methods for Identification (ID) Tests Traditionally wet chemical test procedures relating to color changes, solubility, or precipitation are used Many wet chemical methods are targeting test sample s functional groups not specific for the particular molecules Modernization introduced instrumental analyses Orthogonal approach spectroscopic methodology and separation science used together provide greater assurance of uniquely identifying an excipient Infrared Absorption spectroscopy fingerprinting identity Chromatographic Identity (retention time against that of USP Reference Standard) The above approach is suitable for simple molecular and monodispersed synthetic polymeric based excipients 9 Up-to-Date Methods for ID Tests (Cont.) Utilization of chemical composition profile for Identity test Fatty Acid Composition by GC fingerprinting identity for a hydrolyzed sample Glyceride Composition by HPTLC fingerprinting identity for an intact sample The above approach is suitable for fat, fixed oil, mixture-type ester based excipients The approach is applied to 10 fixed oil NF monographs (Almond, Canola, Corn, Cottonseed, Olive, Palm, Peanut, Safflower, Soybean, and Sunflower Oil) Aromatic compound profile by GC fingerprinting identity for an intact sample The above approach is suitable for mixture-type essential oil based excipients Example: Eucalyptus Oil, Identity by Aroma Substance Profile by GC 10 5

Up-to-Date Methods for ID Tests (Cont.) Fatty Acid Composition (FAC) by GC replaced titrimetric based procedures (Iodine Value (IV) and Specification Value (SV)) IV and SV (Non specific) Use chemical reactions to quantitatively estimate the selected functional group(s) or to calculate the constituents of a fat or oil Treated as oil and fat structure index tests FAC (Specific) Commonly recommended as an identification test IV and SV can be estimated from the FAC profile Glyceride Composition by HPTLC Unique patterns of HPTLC bands from specific triglycerides can distinguish fixed oils of different botanical origins Can be used orthogonally in conjunction with FAC by GC for better identity tests 11 Up-to-Date Methods Improve Quality of NF Standards Specific methods help combat adulteration, e.g., Glyceride Composition by HPLC Use of Triglyceride Composition by HPLC in Sesame Oil, Castor Oil and Hydrogenated Castor Oil monograph, respectively, as Assay Use of Content of Phospholipids by HPLC in Lecithin monograph as Assay Sterol Composition (preparative HPLC (or TLC)) followed by derivative GC determination) Use in Almond, Corn, Olive, and Soybean Oil monographs Reveals the identity of the components in a mixture Serves as a further test for purity Use Sterol Composition and FAC to provide a robust and unique identification for a fixed oil Use of Ethylene Glycol and Diethylene Glycol Determination in glycerin, propylene glycol, and several sugar alcohols 12 6

Up-to-Date Methods for ID Tests (Cont.) Utilization of the following methods for Identity tests, e.g., Mineral structure analyzed by X-Ray Diffraction Functional Groups analyzed by IR fingerprinting profile for chemical functional groups Mineral structure analyzed by Optical Microscopy Metal Element Ratio by Atomic Spectroscopy or ICP The above approach is suitable for mineral based excipients Protein molecular weight profile by SDS-Polyacrylate Gel Electrophoresis (PAGE) Chromatographic Identity (retention time against that of USP Reference Standard) (size exclusion chromatography (SEC)) The above approach is suitable for protein based excipients, e.g., Alpha-Lactalbumin Zein 13 Recent Updates: Assay and Impurity Tests Added and replaced non-specific assays with stability-indicating LC or GC procedures Introduced LC or GC methods or replaced non-specific titrimetric procedures in many simple molecular excipient monographs, e.g., Methyl Salicylate HPLC/UV method replaced titrimetric procedure for the Assay The same HPLC/UV method used for Limit of Salicylic Acid and Dimethyl 4- Hydroxyisophthalate Cholesterol GC/FID method added to determine content of cholesterol The same GC/FID method used for Limit of Related Sterols and Other Organic Impurities 14 7

Recent Updates: Assay and Impurity Tests (Cont.) Added and replaced non-specific assays with stability-indicating LC or GC procedures Introduced LC procedures for lipid mixtures such as Lecithin, Sesame Oil, Castor Oil, and Hydrogenated Castor Oil monographs products have no chromophore and are non volatile, e.g., Lecithin HPLC/ELSD (Evaporative Light Scattering Detection) method for Content of Phospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid) Use in Injectable dosage forms: For Lecithin intended for use in the manufacture of injectable dosage forms, Content of lysophosphatidylcholine determined by the same HPLC/ELSD must be limited to NMT 3.0% 15 Recent Updates: Assay and Impurity Tests (Cont.) Added and replaced non-specific assays with stability-indicating LC or GC procedures Introduced size exclusion chromatography (SEC) in polymeric (Polyethylene glycol 3350) and protein based excipient (Alpha- Lactalbumin) monographs, e.g., Alpha-Lactalbumin HPSEC/RID (Refractive Index Detection) method for Content of Alpha- Lactalbumin in the Assay The same HPSEC method to determine Limit of Beta-Lactoglobulin in the Other Components 16 8

Recent Updates: Assay and Impurity Tests (Cont.) Streamlined analytical testing across multiple family monographs as well as to keep the number of specific analytical tests to a minimum GC method for 6 fatty alcohols (Myristyl, Cetyl, Cetostearyl, Stearyl, Oleyl alcohol, and Octyldodecanol) e.g., Octyldodecanol GC/FID with capillary column method replaced GC/FID with packed column for Assay The similar GC/FID used for Organic Impurity Test 1: Limit of Related Fatty Alcohols and Organic Impurity Test 2: Limit of Branched Chain Fatty Alcohols and Branched Chain Aldehyde HPLC method for fatty acids (Myristic and Palmitic acid) Palmitic Acid HPLC/UV weight-by-weight method replaced GC-FID normalization procedure for the Assay The same HPLC/UV method used for Limit of Stearic Acid, Myristic Acid, and Other Related Fatty Acids 17 2015-2020 Focus on Excipient Composition USP Excipient Impurities Joint Subcommittee Stimuli article target publication in PF 44(3) [May-June 2018] and survey launch mid-may The Complexity of Setting Compendial Specifications for Excipient Composition and Impurities Replacement of non-specific tests has shown excipients are not simple molecule based substances but often polymeric and mixture type products requiring different types of specifications Classification of each component as either an acceptable part of the excipient composition, or an impurity is challenging How to distinguish between excipient impurities and other components Many components present in excipients may be necessary for performance in different applications, and are not impurities but concomitant components Ask: USP seeks stakeholder feedback on this Stimuli article 18 9

Recent Updates: Composition Studies Non Biological Complex Drug (NBCD) Polidocanol USP, PF 43(5) (2017) Polidocanol is polyoxyl lauryl ether. It contains NLT 97.0% and NMT 103.0% of polidocanol (C 30 H 62 O 10 ). The gas chromatographic procedure is used in the Assay and in the test for Organic Impurities Polyoxyl Lauryl Ether NF monograph Polyoxyl 9 Lauryl Ether is one of multiple grades of Polyoxyl Lauryl Ether No Assay (No Composition studies) 19 Recent Updates: Composition Studies (Cont.) Polidocanol with closed related structures analyzed by GC Polymer derivatized and analyzed by GC Each major peak represents an oligomer with one ethylene oxide (Info. from 2016 AAPS poster) 500.00 pa 400.00 300.00 200.00 100.00 Dodecanol E1 E2 E3 E4 E5 E6 E7 E8 E9 E10 E11 E12 E13 E14 E15 E16 E17 E18 E19 E20 E21 E22 E23 E24 E25 E26 0.00 0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00 Minutes Polyoxyl 9 Lauryl Ether 500.00 pa 400.00 300.00 200.00 100.00 Dodecanol unknown 1 PEG 1 PEGMEG 1 E1 PEGMEE 2 PEG 2 E2 PEGMEE 3 PEG 3 E3 PEGMEE 4 PEG 4 E4 PEGMEE 5 PEG 5 E5 PEGMEE 6 PEG 6 E6 PEGMEE 7 PEG 7 E7 PEGMEE 8 PEG 8 E8 PEGMEE 9 PEG 9 E9 PEGMEE 10 PEG 10 E10 PEGMEE 11 PEG 11 E11 PEGMEE 12 PEG 12 E12 PEGMEE PEG 13 13 E13 PEG E14 14 PEG E15 15 PEG E16 16 PEG E17 17 PEG E18 18 PEG E19 19 PEG E20 20 PEG E21 21 PEG E22 22 PEG E23 23 PEG E24 24 E25 PEG 25 0.00 0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 Minutes 20 10

Recent Updates: Composition Studies (Cont.) Polidocanol USP, PF 43(5) (2017) TOTAL OLIGOMERS: 97.0% 103.0% DISTRIBUTION OF OLIGOMERS From E0 dodecanol to E24 an oligomer with 24 ethylene oxide units AVERAGE OLIGOMER CHAIN LENGTH: 8.6 10.0 Polyoxyl 9 Lauryl Ether NF, USP 41-NF 36 In GC chromatogram, some other peaks (PEGMEE 1 2-ethoxyethan-1-ol and PEG 1 ethane-1,2-diol) besides the peaks of E0 and E1 an oligomer with one ethylene oxide unit, have been observed between E0 and E1. Similar observations are made for any other two adjacent oligomers. USP needs appropriate methods to help understand product composition 21 Recent Updates: Composition Studies (Cont.) Cetyl Esters Wax prior to USP 41-NF 36 publication Cetyl Esters Wax is a mixture consisting primarily of esters of saturated fatty alcohols and saturated fatty acids. No Identification tests No Assay No Impurities Cetyl Esters Wax in PF 42(5) (2016) on wards Add: Identification tests, Assay, Impurities, Labeling, and Reference Standards Update: Definition 22 11

Recent Updates: Composition Studies (Cont.) Cetyl Esters Wax in USP 41-NF 36 Cetyl Esters Wax is a mixture consisting primarily of esters of saturated fatty alcohols (C 12 to C 18 ) and saturated fatty acids (C 12 to C 20 ). It contains NLT 90.0% of total saturated fatty esters and NLT 10.0% of fatty esters with carbon-chain length of carbon number 32 that consist chiefly of cetyl palmitate. Assay TOTAL FATTY ESTERS AND CETYL PALMITATE Total saturated fatty esters: NLT 90.0% Fatty esters with carbon-chain length of carbon number 32 that consist chiefly of cetyl palmitate: NLT 10.0% Impurities LIMIT OF TOTAL FREE FATTY ALCOHOLS AND FREE FATTY ACIDS Total free fatty alcohols and free fatty acids: NMT 10.0% Labeling: Label to indicate the percentages of fatty esters with carbon-chain length of carbon number 26, fatty esters with carbon-chain length of carbon number 28, fatty esters with carbon-chain length of carbon number 30, fatty esters with carbon-chain length of carbon number 32, fatty esters with carbonchain length of carbon number 34, and fatty esters with carbon-chain length of carbon number 36 23 Polymeric Excipients: Traditional Methods Historical files at USP show that when a polymeric excipient monograph was established decades ago, a viscosity specification was typically used to distinguish between different types (or grades) in a polymer family monograph, due to differences in the polymer s average molecular weight, as well as to ensure batch-to-batch consistency Today: Recognize the deficiency of pharmacopeial viscosity specifications for polymeric excipients Generally do not enable the characterization of variations in the molecular weight distribution and/or chemical composition of the polymer 24 12

Up-to-Date Methods for Polymeric Excipients USP is working with stakeholders to better characterize polymeric excipients by introducing molecular weight limits as well as average molecular weight/molecular weight distribution specifications by using HPSEC/RID with external calibrations Polydextrose NF Hydrogenated Polydextrose NF Polyvinyl Acetate NF Chitosan NF Polyethylene Glycol 3350 USP USP is presenting a poster Molecular Weight Determination for Guar Gum: Feasibility of High Performance Size Exclusion Chromatography Coupled with Light Scattering Methodology for Compendial Use during this meeting 25 Up-to-Date Methods for Polymeric Excipients Use NMR to determine degree of substitution of a polymer with a substituting group Hydroxypropyl Betadex NF (Molar Substitution) Chitosan NF (Degree of Deacetylation) Hydroxypropyl Corn (Pea, Potato) Starch NF (Assay for Hydroxypropyl Groups) Pregelatinized Hydroxypropyl Corn (Pea, Potato) Starch NF (Assay for Hydroxypropyl Groups) Use NMR to determine average polymer chain length and monomer ratio (structure indicating method) Polyoxyl 10 Oleyl Ether NF (Average Polymer Length) Polyoxyl 20 Cetostearyl Ether NF (Average Polymer Length) Poloxamer NF (Weight Percent Oxyethylene) 26 13

2015-2020 Focus on Excipient Nomenclature USP Nomenclature and Excipient Joint Subcommittee USP Nomenclature Expert Committee approves NF monograph titles FDA CDER Inactive Ingredient Database (IID) provides context and precedence of use information that helps this initiative Nomenclature, route of application, dosage form, CAS number, UNII number Ingredient name/title is becoming more specific in FDA CDER IID, e.g., IID list additional 7 grades of Polyisobutylene (PIB) besides the compendial name Polyisobutylene (1100000 MW), PIB (800000 MW), PIB (55000 MW), PIB (35000 MW), PIB (2300 MW), PIB Low Molecular Weight, and PIB Medium Molecular Weight Current Polyisobutylene NF monograph Use capillary method to determine intrinsic viscosity for grade differentiation 27 Recent Updates: Excipient Nomenclature Glyceryl Behenate changed to Glyceryl Dibehenate Replace the existing titrimetric method for the CONTENT OF 1- MONOGLYCERIDES with an Assay incorporating gel-permeation chromatography (GPC). The proposed Assay allows the measurement of monoglycerides, diglycerides, and triglycerides simultaneously. PF 39(4) (2013) Butyl Palmitostearate and Butyl Stearate, PF 38(3) (2012) GC test procedure clearly reveals the composition of each product in the market Reviewing the monograph title of Butyl Palmitostearate, the public should be able to conclude that butyl palmitate is included in a significant amount as one of two major components in the product. 28 14

Recent Updates: Excipient Nomenclature Glyceryl Monocaprylate NF, USP 41-NF 36 CONTENTS OF MONOGLYCERIDES, DIGLYCERIDES, AND TRIGLYCERIDES in the Assay are determined by GC/FID Based on FDA s Request for Revision, USP plans to split the monograph and to propose these changes in PF for public comment Type I will be included in a new monograph entitled Glyceryl Mono and Dicaprylate Type II will be represented by the existing monograph, Glyceryl Monocaprylate 29 Recent Updates: Excipient Nomenclature Glyceryl Monocaprylocaprate NF, USP 41-NF 36 CONTENTS OF MONOGLYCERIDES, DIGLYCERIDES, AND TRIGLYCERIDES in the Assay are determined by GC/FID Based on FDA s Request for Revision, USP plans to split the monograph and to propose these changes in PF for public comment Type I will be included in a new monograph entitled Glyceryl Mono and Dicaprylocaprate Type II will be represented by the existing monograph, Glyceryl Monocaprylocaprate 30 15

Focus on Excipient Nomenclature USP is going to host a workshop on 07-Aug-2018 Focus on Excipient Nomenclature: Getting Excipient Nomenclature Right Feedback from the perspectives of FDA, other regulatory, and USP Understand GInAS versus IID USP Excipient Nomenclature approval process Feedback from the perspective of industry How the excipient naming impacts industry? Some important questions to be reviewed and addressed Challenges faced with Excipient Naming What do we mean by excipient grade? When is grade important to excipient naming? When should Pharmacopeias, Regulatory, and Industry care about grade? 31 2020-2025 Call for Candidates The Call for Candidates for the 2020-2025 cycle begins July 2018 We are seeking technical and scientific experts and healthcare practitioners in the pharmaceutical, biologics, and food and dietary supplements industries, academia, regulatory and government sectors to volunteer for USP s Council of Experts and Expert Committees Join other committed professionals to help develop standards for quality medicines, dietary supplements and foods To receive updates on the Expert Committee requirements and responsibilities, email USPVolunteers@usp.org 32 16

Summary/Conclusions The Excipient Program Unit Team continues to rely on support from external stakeholders specifically standard sponsors as well as USP laboratories and input/comments from the Expert Committee and stakeholders including FDA to ensure that the excipient standards are current and up-to-date Up-to-date standards can help drug development in selecting appropriate excipients for drug formation Up-to-date standards can help with controlling the integrity of the supply chain and prevention of adulteration 33 Thanks Hong Wang, Ph.D. Phone: 301-816-8351 Email: hw@usp.org 17