CHPA Regulatory, Scientific & Quality Conference Washington DC, May 13, 2014 Quality Session 4 A New USP Tool The Class Monograph Alan R. Potts, Ph.D. Principal Scientific Liaison-Chemical Medicines The Past is History OTC Products include Pre-62 Drugs that are GRASE Rx-OTC switch Controlled through Existing NDA/ANDA FDA Monographs USP includes Most Drug Substances Many Individual Products Some Multi-component Products Few of the most used Products Class Monographs Performance Based Monographs Reference Procedures Shared Databases Semi-private Databases Application of the concepts of Good Enough (where appropriate) 2 1
Many Challenges Remain Missing monographs Labeling implications due to Official Article titles or alternative procedures. Enforceability of procedures that deviate from traditional (experience) Multi-active ingredient products Unique dosage forms Atypical ingredients (complexity) Commonly used excipients cause interferences An Optimal Solution Interpretation/enforceability questions surrounding non-traditional solutions Large number of product monograph changes occurring in a short time span requiring both timely communication and ample implementation time Balance the benefits of meeting the desired revision cycle times and legal requirements 3 What Do We Want? A flexible system to allow formulation changes Standardized procedures and acceptance criteria that work Consistency w/o unnecessary constraint Reward those that are doing it right 4 2
Update of USP Activities The following slides represent an idea. This is not a final proposal! 5 Scope Combine Multiple Actives into a Class for Analysis Capable of responding to the rapid introduction of new combinations, routes of administration, and dosage forms Fewer analytical procedures Multiple number of active ingredient combinations can be analyzed Current 'modern' technology leveraged 6 3
Scope Non NDA/ANDA USP Monographs Drugs OTC Rx FDA Monographs (GRASE) NDA/ANDA Switches NDA/ANDA 7 Class Monograph Aka - Class Product Monograph (CPM) It is our view that a class monograph system is the grouping of drug product monographs that refer to a single set of procedures for identity, assay, purity, and quality. How many different active ingredients and products are in a single grouping? How many different procedures are expected? Let the Science reveal the answer. 8 4
Acetaminophen, Aspirin, Caffeine Class Monograph Acetaminophen Family* Acetaminophen Capsules Acetaminophen Chewable Tablets Acetaminophen Oral Liquid Acetaminophen Oral Solution Acetaminophen Oral Suspension Acetaminophen Orally Dis. Tablets Acetaminophen Tablets Aspirin Family* Aspirin Chewable Tablets Aspirin Oral Powder Aspirin Orally Disintegrating Tablets Aspirin Tablets Caffeine Family* Caffeine Cream Caffeine Lozenges Caffeine Tablets Aspirin and Caffeine Capsules Aspirin and Caffeine Tablets Acetaminophen and Aspirin Oral Powder Acetaminophen, Aspirin, and Caffeine Oral Powder Acetaminophen, Aspirin, and Caffeine Tablets Acetaminophen and Caffeine Oral Liquid Acetaminophen, Aspirin, and Caffeine Capsules Aspirin and Caffeine Oral Powder Aspirin and Caffeine Tablets, Effervescent Acetaminophen and Aspirin Tablets Acetaminophen and Caffeine Tablets Acetaminophen and Caffeine Capsules *Modernization Strategy by Family groupings includes the active ingredient monograph. 9 Dosage Form Specific Procedures Group X and Y Active Ingredients Sub-Group Topicals Oral Sub-Group Creams Ointment Tablets and Capsules Example: Diphenhydramine products 10 5
Assay/Organic Impurity Procedures Group Active Ingredients A, B, C, D, and E Sub-Group A, B, and C D and E Sub-Group A and B B and C A and C Example: Acetaminophen containing cough/cold products 11 Monographs and Products Is it possible to use our tools to craft a monograph that meets all of our needs? Must set requirements clearly enforceable with regard to the laws and regulations under which FDA draws its authority. Agreement necessary to enact out-of-the-box concepts; Identification, Assay, CU tests, etc Labeling and Specifications Less controversial Specific attribute tests Performance Test(s) More effort is required Impurities Test(s) 12 6
USP Modernization Strategy Modern Procedure Design Criteria Compliance Standard Governance standards remain consistent with current compliance requirements for Identity, Purity, Safety, and Quality Metrological Advancement Availability of new analytical technologies Monitor the current state of measurement science and adoption by industry Continuous Assessment Vigilance of monograph review Maintain a suitability threshold or measuring stick for a modern method 13 Test NDA/ANDA Products OTC Products Identification GRASE vs. Rx Modernization Strategy Two procedures; chromatography and spectroscopy Special Case of Modernization Two procedures; chromatography and spectroscopy Assay Performance Organic Impurities Other HPLC/uHPLC procedure with MS compatible mobile phase (Modernization Initiative) Dissolution procedure Flexible monograph (e.g. Test 1, Test 2, etc ) Same/Similar HPLC/uHPLC procedure with MS compatible mobile phase, as used for Assay. Water Content Alcohol Determination Dosage Form Specific Tests HPLC/uHPLC procedure Case procedure Similar in analysis to MC<12> (solubility) One or more procedures for specified drug product impurities Adherence to GC <1 5> Alcohol Assay? 14 7
Assay Procedure Design Parameters Technology Platform (HPLC, uhplc) Column (packing type solid core, porous particle) Mode (reversed phase, mixed modes, chemistry) Analytes (# and types) Speed Generic procedure (in the Compendial sense) Detection mode (Photo-diode array, sensitivity) Performance (Resolution, Accuracy, Precision) Speed Run time Robustness/validation Sample preparation development and validation Quality Quality Cost Cost 15 Identification and Assay procedure(s) - Example Sample: Reference Standards mixture (0.05 mg/ml of each analyte) 0.34 0.32 0.30 0.28 0.26 0.24 0.22 0.20 0.18 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 Phenylephrine - 1.918 Acetaminophen - 2.733 Phenylpropanolamine - 3.712 Caffeine - 3.873 Doxylamine - 3.973 Pseudoephedrine - 4.125 Guaifenesin - 5.812 Chlorpheniramine - 6.045 Dexbrompheniramine - 6.914 Aspirin - 7.441 Dextromethorphan 10.035 Diphenhydramine - 10.137 Naproxen - 11.421 Ibuprofen - 12.528 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 1 11.00 12.00 13.00 14.00 15.00 Minutes 16 8
Identification Procedure - Example UV-PDA spectra of USP RS (left) and APIs in dosage form (right) 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.60 0.50 0.40 0.30 0.20 0.10 1.897 Phenylephrine 200.8 10.173 Diphenhydramine 202.0 258.7 272.9 20 22 24 26 28 30 32 nm 0.35 0.30 0.25 0.20 0.15 0.10 0.05 1.20 1.00 0.80 0.60 0.40 0.20 1.908 Phenylephrine 200.8 10.153 Diphenhydramine 204.4 258.7 272.9 20 22 24 26 28 30 32 nm 17 System Suitability Resolution Standards 0.12 0.08 0.04 C affeine - 3.849 D oxylam ine - 3.983 Pseudoephedrine - 4.141 Dextrom D iphenhydram ethorphan ine - - 10.179 10.080 0.18 0.12 0.06 2.00 4.00 6.00 8.00 1 12.00 14.00 Minutes 18 9
Excipient Non-Interference (For Example) 3.00 1.50 Phenylephrine - 1.908 Acetaminophen - 2.666 Benzoate - 7.621 Propyl gallate - 8.280 Diphenhydram ine - 10.153 3.00 1.50 2.00 4.00 6.00 8.00 1 12.00 14.00 Minutes 19 Impurities Test Procedure - Proposal Include only the specified impurities currently specified in Dosage Form monograph(s) Provide individual procedures, where necessary 20 10
Impurities Procedure(s) 9 6 3 0 Aspirin - 7.312 Salcylic Acid - 8.491 Diphenhydramine - 10.111 2.00 4.00 6.00 8.00 1 12.00 14.00 Minutes Example - Salicylic Acid 21 Performance Test Create a default characterization for most well-behaved IR drug products Non-solution orally administered immediate release drug products Linked to the Biopharmaceutical Classification System (BCS) Model test after Medicines Compendium GC<12> approach Solubility test 22 11
Evaluating Performance Test Results Products that meet the acceptance criteria may be considered: To perform optimally or To be optimally available for in vivo absorption Products that do not meet the acceptance criteria are not necessarily bad products, require additional studies to demonstrate proper performance More collaborative effort is needed here. 23 Summary Continue building consensus on the optimum approach Meet the needs of Industry, Regulator, and Pharmacopeia Requires flexibility from all (a true compromise)! 24 12
USP s Contribution What is on the table to incorporate in the optimum approach? General Notices General Chapters Class Monographs (Group 1, 2, 3, 4,.)* (New) Individual monographs 25 Acknowledgements Todd Cecil, VP Chemical Medicines Matt Van Hook, VP Global Legal Affairs - Standards, Legal Kevin Hool, VP Research and Development Jennifer Belsky, Director, R&D Natalia Kouznetsova, Scientist IV, Project Leader R&D Lab Staff Joshua, Jennifer, and Nadejda - for their dedication and advancement of this work Monograph Modernization Team Donald, Clyde, Ren, Prasad, Amanda, Jerry, Behnam, Leonel, Dave, and Michael for their efforts to frame the impact and plausibility of this approach 26 13
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