Identification Of Medicinal Products: Path To Global . - SBIA Events
Identification of Medicinal Products:Path to Global ImplementationRon Fitzmartin, PhD, MBASr. Informatics AdvisorOffice of the DirectorCenter for Biologics Evaluation and ResearchTyler PeryeaChemistOffice of Health InformaticsOffice of Chief ScientistTa-Jen ChenProject Management OfficerOffice of Strategic ProgramsCenter for Drug Evaluation and ResearchLawrence Callahan, PhDChemistOffice of Health InformaticsOffice of Chief Scientist11 June 20211
ISO Identification of Medicinal Products(IDMP)Global PhPID andDose Form HarmonizationSBIAJune 11, 20212
What is IDMPThe Identification of Medicinal Product (IDMP) is a suiteof five ISO standards that: Data elements and structure to uniquely and unambiguously identifymedicinal product, Pharmaceutical Product, and substance common vocabularies for improved people communication common message standards for improved IT system communication ISO 11615 – Medicinal Product Identification ISO 11616 – Pharmaceutical Product Identification ISO 11238 – Substance Identification ISO 11239 – Pharmaceutical dose forms, units of presentation and routes of administration ISO 11240 – Units of measurement3
Key Benefits of IDMP Cross-regions or global agreement on common substance ID and dose form is needed to maximizethe benefits4 4
Connecting Medicinal Products 1123811615PharmaceuticalProductPhPID L4Dosage Form11239StrengthCapsule1161611240200 dicinalProduct116155
Concerns with the Current ISO Standard for PhPID PhPID Set PhPID Substance Level L1 Substance(s) Term PhPID Substance Level L2 Substance Term(s) Strength reference strength PhPID Substance Level L3 Substance Term(s) Administrable Dose Form PhPID Substance Level L4 Substance(s) Term Strength reference strength Administrable Dose Form Substance is the key for all PhPIDs A global Level 3 and 4 PhPID is not possible without a global consensuson Dose Form IDs6
Concerns with the Current ISO Standard for Dose FormPharmaceutical Product ID (PhPID)CentralCentralCentralNo CentralCodes forDose Form orSubstanceConceptual Representation of the Global PhPID Construction** Adapted from ISO TS 20451:20177 7
Concerns with the Current ISO Standard for Dose FormRegion-to-Region Terminology Mapping is Not a Viable Solution Mapping results are based on a specified setof criteria and may be different region-toregion:– EDQM has 490 dosage forms1– FDA Terminology has 166 dosage forms2– Health Canada (HC) terminology has 170 dosageforms3– SNOMED has 213 dosage forms4– CDISC Terminology has 172 dosage .nci.nih.gov/ftp1/FDA/SPL/About.html3 ugs-health-products/drug- nology2(Note: HC dosage form dataset for active products was downloaded and analyzed by FDA to determine the extent of 1:1 mapping)Originally presented January 2020SNOMED CT45%map 1:195U.S. FDA22%map 1:137EDQM4902734HealthCanada16%map 1:1CDISCTerminology20%map 1:18
UNICOM Gap Analysis Report4 Workshop results and suggesting gaps4.1 Dose forms The adoption of this IDMP standard has been difficult, at times.–NCAs are in the process of implementing the standard in their own processesand are facing backward compatibility issues, because the granularity ofterminologies varies frequently from EDQM.–The US FDA has shared its implementation difficulties, which are similar tothose of the NCAs.Source: Unicom - 09/UNICOM Gap-Analysis.draft .v12-1.pdf9
Dose Form Characteristics Use Case for Global PhPID ISO 11239–Six existing EDQM characteristics can be used to describe thepharmaceutical dose forms for use in global IDMP. These include:1. State of Matter2. Basic Dose Form3. Transformation4. Release5. Intended Site6. Administration Method10
Dose Form Characteristics Examples for Global PhPIDCapsule – hard or softPharmaceuticalDose FormBasic DoseState of Matter FormReleaseCharacteristics Intended SiteAdministrationMethodTransformationCapsule, HardSolid(0097)Capsule(0051)No Transformation Capsule, SoftSolid(0097)Capsule(0051)No Transformation CapsuleSolid(0097)Capsule(0051)No Transformation Capsule, GelatinCoatedSolid(0097)Capsule(0051)No Transformation 11
Dose Form Characteristics Example for Global ng:Oral:No Transfm:Conventional:capsule:solid)Central Group “like” medicinalProducts in ‘Capsule’,‘Capsule, Hard’, ‘Capsule,Soft’ Dose Form. This DF characteristicsapproach will allow thegeneration of global PhPIDfor all regions, without acentral DF system.1212
Dose Form Characteristics for Global PhPIDMedicinal Products that Require Transformation are a Challenge13
Dose Form Characteristics Use Case for Global PhPIDPharmaceutical DoseFormBasic SolutionNo Transformation(0099)(0083)(0042)State of MatterSolidPowder (for solution) for(0097)injectionConcentrate (forsolution) for injection(Solution) for onventional(0047)Conventional(0047)Intended SiteAdministrationMethodBasic Admin.Dose FormInjectionSolutionParenteral (0033) (0012)InjectionParenteral (0033) (0012)InjectionParenteral (0033) (0012)(0083)Solution(0083)Solution(0083)Used these 4 characteristics togenerate of Global PhPID14
Dose Form Characteristics Use Case for Global al:conventional:solution)* Adapted from ISO TS 20451:2017Central PhPID groups “like”medicinal Productswith sameAdministrable DoseForm; regardless of its’Manufactured DoseForm.1515
WHO UMC-FDA Global PhPID Pilot To evaluate using Pharmaceutical Dose Form Characteristics for GlobalPharmaceutical Product Identification (PhPID) This pilot is limited to the use of core EDQM dose form characteristics andother potential characteristics for the generation of Global PhPID FDA assigns dose form characteristics for US marketed medicinal productsbased on 34 substances identified in the UNICOM Pilot UMC will generate corresponding PhPID using dosage form characteristicstogether with substance and strength FDA and UMC perform a data equivalency assessment on the use ofcharacteristics for generation of PhPID and present to ISO TC215 WG6 in June202116
Pilot Identified Some Challenges Dose Form expression variations Pfizer Covid-19 vaccine EMA – Dispersion for Injection FDA – Suspension for Injection UK – Solution for Injection Strength expression variations – different units %, IU, mg/g or mg/mL AstraZeneca Covid-19 vaccine EMA – 2.5x108 infectious units UK – 5 1010 viral particles Australia – 5 1010 viral particles17
Preliminary Results and Next Steps Generally, dose form characteristics as input to generation ofPhPID is a viable solution. A single organization, with global prospective, to consistentlyassign Dose Form Characteristics, strength, and substance IDmay be important for global IDMP implementation Proceed with the revision of ISO 11239/TS20440 and relatedIDMP standards with ISO TC215 WG618
FDA IDMP Roadmap 2012-202x2012ISO PublishesIDMP Standards ISO Publishes TS 20443, TS 20451 2017 2016 UCUM conforms to ISO 11240UNII conforms to ISO 11238GSRS Project initiated NDC conforms to ISO 11615FDA GSRS in ProductionInitiated evaluation of FDA Terminology for dosage form (DF)Collaboration on HL7 FHIR for Substance exchangeISO 11239/TS 20440 Revision fordosage form solutionISO TS 19844 Sub ID to use for PhPID2020ISO PublishesTS20440, TS19844Concluded FDA Terminology for DF notconformed to ISO 11239Evaluate mapping FDA DF terminology toEDQM20182019 Regional DF mapping to central terminologynot viable Developed alternative solution Established FDA-EMA IDMP CollaborationFramework Collaboration on HL7 FHIR for MPID exchange 2021 UMC/FDA Global PhPID PilotGlobal Substance IDISO 11239/TS20443 revisionISO TS 20451 review/revisionDevelop IDMP ImplementationPlan2022 Testing and validate GlobalPhPID process19 19
Thank you20
ISO 11238 and Global Substance RegistrationSystem(GSRS) SBIA Webinar (06/11/2021)
Organizing Information FDA has the most important/valuable repositoryof human biological and product data butlimited integration.– Submission process– Paper– PDF’s IDMP is an effort to organize information on aglobal scale2
Organizing Information The amount of information is increasing– More drugs and vaccines on a global scale– Rapid Screening Methods– Enzyme and Receptor Profiling– CYP , Transporter and Receptor– Genomics– Epigenomics– Electronic Health Records– Many CMC changes3
Global Medicinal Products Medicinal/Pharmaceutical Product Marketplace is the mostGlobal Marketplace Highest Value Products Highly regulated Small Amounts of Material Excipients often only a small proportion of market Relatively Low Shipping Costs Multiple ingredients from a variety of companies ActiveExcipientsStarting MaterialsPackagingTesting (Reference Standards)Reagents4
Global Pharmaceutical pi-sourcing-which-countries-lead5
Pharmaceutical Supply Chain6
Organizing Information Substances are one of the key lynchpins fororganizing information Names are insufficient to describe substances– Same name different substances Lime (fruit) Lime (chemical)– Different names same substance Acetaminophen Paracetamol Define substances based on core scientificprinciples and assign a permanent UniqueIngredient Identifier (UNII)7
ISO 11238 Background ARISTOTLE (Metaphysics).the generally recognizable substances. arethe sensible substances, and sensible substances all have matter., andin another sense the formula or form., and thirdly the complex ofmatter and form, which alone is generated and destroyed, and is,without qualification, capable of separate existence A unit of matter that can be quantitatively measured Five types of substances– Chemicals, Proteins, Nucleic Acids, Polymers, and Structurally Diverse Material– Mixtures Substance are not defined based on use The same substance can be manufactured or isolated using differentmethods8
Substances (ISO IDMP) Five groups of elements are used to describe single substances.– Monodisperse Chemicals– Defined primarily by molecular structure (connectivity andstereochemistry) Proteins– Amino Acid Sequence, type of glycosylation, modifications Nucleic Acids– Sequence, type of sugar and linkage, modifications9
Substances (ISO IDMP) Polydisperse Polymers (Synthetic or biopolymers)– Structural repeating units, type, geometry, type of copolymer(block or random), ratio of monomers, modifications, molecularweight or properties related to molecular weight, biologicalsource for many biopolymers Structurally Diverse Substances (viruses, cells, tissues, complexmaterials)– Taxonomic, anatomical, fractionation, physical properties,modifications10
Substances Scope Active ingredients“Inactive” Processing materials11
Need for Specified Substance Organize additional information on ingredients(SSG1).– Need to describe multiple substance ingredients(Simethicone, Colorants, Flavors)– Need to describe extracts (allergenic and herbalextracts, tinctures)– Need to distinguish materials that differ by physical formor critical properties (Polymorphs, Flowability,Compressibility)– Just starting to implement this at FDA12
Need for Specified Substance– Need to tie material to a manufacturer and aprocess (SSG2 and SSG4)– Need to tie material to a specific grade (SSG3)– Need to obtain specification information (SSG4)– Need to obtain information about processingmaterials (SSG4)– Need to establish and monitor the supply chain(SSG2)– Manufacturing and specifications were separatedout in ISO version 213
Specified Substance14
Specified Substance Implementation Group 1 implemented will capture cell line data forrecombinant proteins. Still working on how to capture the details of glycosylationat the Group 1 level Group 2 needs to agree on a common identifier forcompanies. (US Duns and FEI; EU:Org database) Specification module developed and an impurity modulewith USP is under development Manufacturing prototype has also been developed15
16GSRSGlobal Substance Registration System Global marketplace for ingredients requires a global system to monitorthe global supply chain A Global Repository of Regulatory Information and Data on Ingredients Help address shortages, substandard and counterfeit ingredients,coordinate inspections FDA with NIH has developed a software system that can be used byregulatory agencies throughout the world to register substances System being used by EMA, other European agencies and WHO-UMC Common system will make it easier to transfer data and allowinternational implementation16
17GSRSGlobal Substance Identifier IDMP specified the need for a global substance ID Global substance ID has not yet been agreed on Need a single organization needed to maintain a globalsubstance Work with WHO-UMC underway for global substance ID Needed to implement PHPID Single organization to handle all of the Global Ids or afederated approach?17
What is the GSRS?Assigns permanent UNII code to each substanceCompliant with the ISO IDMP StandardTies substances to: ProductsRegisters and defines applications(Integrity,CFSAN andGSRS) clinical trials(CT.gov andEUCT) Adverseevents counts Drug targetswww.fda.govLimited quality informationGSRS is part of the IDMP effort 18
19GSRSGSRS Software Works in all modern browsers: IE, Chrome, and Firefox System freely distributed through NCATS with a large set ofcurated public domain data and updated periodically– Links to many outside resource (Chemid, Pubchem, DrugBank, Orphan Drug, etc)– Structure and sequence-based searching– Faceted and advanced field-based searching– Data downloadable in a variety of formats JSON, Text, Excel Being used by EMA. Bfarm, WHO-UMC and CBG in Europe19
Current Status at FDAApproximately 200,000 thousand substancesregistered120,000 Substances curated most publiclyavailableOver 2,000,000 Names and CodesNearly 200,000 Relationships Drug targets,Metabolites, ImpuritiesMuch of the data is public domain20
How it’s used at FDA FDA has adapted GSRS to integratewith existing internal databases andsystems.– Adverse events– Products (SPL)– Applications (INDs, NDAs)– Clinical Trials– In the future, GSRS can be used tofacilitate digital submissions offormulation, quality andpharmacology data– Several classification systems CFR DEA ients
In-vitro Clin Pharm Initiative Working with the Pistoia Alliance to develop datastandards for in-vitro pharmacology data Scope of data determined––––––MetabolitesMetabolic EnzymesTransportersReceptors (Safety)Ionic channelsKinases Teams being set up Quick development in sync with GSRS22
Vaccine Initiative Vaccines are the most important public healthtool we have No international nomenclature names varysignificantly throughout the world WHO-UMC has set up a site for registration ofVaccine ingredients and related substances Used to workout common controlledvocabulary, possible global identifier Pilot Complete by September Industry involvement at some point23
GSRS Public Resources To get the software and data from and info fromNCATS– https://gsrs.ncats.nih.gov NLM site for a list UNII codes– https://fdasis.nlm.nih.gov/srs/srs.jsp GInAS Meetings– Annual Meeting (USP, WHO-UMC, CBG have hosted) To Get on the GInAS Notification List– https://gsrs.ncats.nih.gov24
Working Collaboratively
AcknowledgementsFDA TeamYulia Borodina, Larry Callahan,Ramez Ghazzaoui, Elaine Johanson,Samir Lababidi, Archana Newatia,Tyler Peryea, Frank Switzer, AnnetteVernon, Alex WelschForeign Regulatory ParticipantsThomas Balzer (BFarM)Herman Diederik, Marcel Hoefnagel,Bert Kroes, Ciska Matai (MEB)Takeshi Misu, Izumi Oba (PMDA)Vik Srivastava, Craig Anderson(Health Canada)Philipp Weyerman (Swiss Medic)Kew GardensBob Alkins, Elizabeth DaunceyUSPFouad Atouf, Andrzej WilkWHO-UMCMalin Jakobsson; Malin FlavidNCATS TeamDammika Amugoda, Niko Anderson, TrungNguyen,, Tim Sheils; Dan Katzel; Mitch Miller;Noel Southall; Sarah StemanIDMP MembersPaolo Alcini, Sabine Brosch, Tim Buxton, IlariaDel Seppia, Panagiotis Telonis (EMA)Ta-Jen Chen, Ron Fitzmartin, NormanSchmuff, Mary Ann Slack, Randy Levin (FDA)Christian Hay (GS1)Pam Cafiero, Jean Fontaine, SurendaGokhale, William Gregory, Barry Hammond,Manabu Inoue, Kostas Kidos, Andrew Marr,Vada Perkins, Wolfgang Spiegl (Industry)Paul Houston (EMA/CDISC)EDQMClaude Coune, Chris Jarvis (EDQM)Excipient IndustryDave Schonecker, Katherine Ulman26
GSRS Open SoftwareSBIA Webinar (06/11/2021)Tyler PeryeaCheminformaticianFDA/OC/OCS/OHICollaboration With
GSRS Software Outline–What is it?–How does it work?–Where is it used?–Where is it going?–How to get involved?29
GSRS Software Freely distributable andopen-source software Implementation of ISO11238 standard Created and maintainedby NIH/NCATS incollaboration with FDAand several otherorganizations30
GSRS Software What is it for?GSRS Software is a self-contained webapplication and database for registering,storing, searching and exchanging substanceinformation in a machine-readable form incompliance with the ISO IDMP 11238 standard.It is freely distributable and can be used as alocal substance registration system byregulators, researchers and industry.31
GSRS SoftwareSubstancesComplex MacromoleculesExploration of SubstanceSpaceMetabolismPlant and Animal derivedsubstances and extractsSmall MoleculesSystematic Definitionand CurationSystematic UseRegulatory TrackingPharmacovigilanceOrganizing BiologicalDataInventoryNomenclatureVaccinesLinks to OtherDatabasesManufacturingInformationAgreeing on Fundamentals Makes Everything Easier!www.fda.gov32
GSRS SoftwareWhat is a substance?A substance is a conceptual physical entity, which is capable of separateexistence, and is uniquely definable based on its immutable chemical, physicaland/or taxonomic properties.33
GSRS SoftwareThe kinds of substances being made as APIs are changing34
GSRS Software Registering a Substance angeable35
GSRS Software Registration Tools– Data Entry Forms– Name-to-chemical structure tool– Image-to-chemical structure tool– Configurable validation rules– Uniqueness check algorithm– Audits and edit history36
GSRS SoftwareDEMO37
GSRS Software38
GSRS Software39
GSRS Software40
GSRS Software41
GSRS Software Browse & Search– Rich fielded text searches– Structure-based searching– RNA/Protein sequencebased searching– Customizable “facet” filters– Customizable data exports42
GSRS Software Other Tools– User Management– CV Management– Full REST API– Scheduled Jobs– Custom Triggers– Custom Reports43
GSRS SoftwareProjects based on GSRS Open-Source SoftwareProductionFDA-GSRSDE-SRSNCATS INXIGHT DRUGSApproachingProductionUSP-SRSEU-SRSPilot PhaseWHO-UMC SRSprecisionFDA GSRS PORTAL44
GSRS SoftwareDevelopment Timeline45
GSRS SoftwareGSRS 2.X Software Architecture46
GSRS SoftwareGSRS 3.X Software Architecture47
GSRS SoftwareGSRS 3.X Software Architecture48
GSRS Public Resources Software Project site:– https://gsrs.ncats.nih.gov/ GitHub Source Code:– https://github.com/ncats/gsrs-play To get on notification list:– https://gsrs.ncats.nih.gov/49
AcknowledgementsFDA TeamYulia Borodina, Larry Callahan,Ramez Ghazzaoui, Elaine Johanson,Samir Lababidi, Mitch Miller, ArchanaNewatia, Frank Switzer, Tyler Peryea,Annette Vernon, Alex WelschForeign Regulatory ParticipantsThomas Balzer (BFarM)Herman Diederik, Marcel Hoefnagel,Bert Kroes, Ciska Matai (MEB)Takeshi Misu, Izumi Oba (PMDA)Vik Srivastava, Craig Anderson(Health Canada)Philipp Weyerman (Swiss Medic)Kew GardensBob Alkins, Elizabeth DaunceyUSPFouad Atouf, Andrzej WilkWHO-UMCMalin Jakobsson; Malin FlavidNCATS TeamDammika Amugoda, Marian Nkeng, TrungNguyen, Daniel Katzel, Mitch Miller, NoelSouthall, Sarah Stemann, Nikolaus Anderson,Jorge Neyra, Elizabeth CallahanIDMP MembersPaolo Alcini, Sabine Brosch, Tim Buxton, IlariaDel Seppia, Panagiotis Telonis (EMA)Ta-Jen Chen, Randy Levin, Mary Ann Slack(FDA)Christian Hay (GS1)Pam Cafiero, Surenda Gokhale, WilliamGregory, Barry Hammond, Manabu Inoue;Kostas Kidos, Andrew Marr, Vada Perkins,Wolfgang Spiegl (Industry)Paul Houston (EMA/CDISC)EDQMClaude Coune, Chris Jarvis (EDQM)Excipient IndustryDave Schonecker, Katherine Ulman50
-FDA Terminology has 166 dosage forms2 -Health Canada (HC) terminology has 170 dosage forms3 -SNOMED has 213 dosage forms4 -CDISC Terminology has 172 dosage forms5 37 U.S. FDA 22% map 1:1 EDQM 490 27 Health Canada 16% map 1:1 Region-to-Region Terminology Mapping is Not a Viable Solution 1 https://standardterms.edqm.eu/).
ABSTRACT: Medicinal plants are those plants that are used (parts, extract etc) in treating and preventing specific ailments and diseases that affect human beings. Hence the important role of medicinal plants in health care delivery (services) cannot be over emphasized. This research is on the identification and traditional uses of some medicinal
Adding medicinal products to milk in the case of a group treatment: - Always dissolve the medicinal products first before adding them to the milk. - Do not mix more than one medicinal product in the mixer at a time. - Do not add medicinal products when the milk temperature exceeds 50 C.
allow people in exceptional circumstances to safely access medicinal cannabis products. The following recommendations and key issues are being addressed: Cultivation, manufacture and supply of standardised, high quality medicinal cannabis products o A key step to enabling access to medicinal cannabis will be to establish cultivation and
DAC DAC ADC ADC. X19532-062819. Figur e 2: RF-ADC Tile Structure. mX0_axis Data Path ADC VinX0 mX1_axis Data Path ADC VinX1 mX2_axisData Path ADC VinX2 mX3_axis Data Path ADCVinX3 mX3_axis mX1_axis ADC mX0_axis Data Path ADC Data Path ADC VinX_23 VinX_01 Data Path Data Path Dual RF-ADC Tile Quad RF-ADC Tile. X23275-100919. Chapter 2: Overview
Use of classical taxonomic markers in medicinal plant identification 13 2.3. Use of classical taxonomic markers in medicinal plant identification . 4.7a Qualitative morphological comparison between Achillea millefolium and Adhatoda vasica 129 4.7b Quantitative morphological comparison between Achillea millefolium and Adhatoda vasica 130 . iv
Endemic Use Of Medicinal Plants For The Treatment Of Skin Diseases In The. 20 Table 3- Showing Botanical Name, Local Name, Family Part Used, Habit, Medicinal Use S/N BOTANICAL NAME LOCAL NAME FAMILY PART OF USE HABIT OF PLANT MEDICINAL USE 1 Abrus precatorius Linn. Ratti Fabaceae Root Climber shrub The juice of root, mixed with the half the amount of the juice of Allium sativum is applied on .
Guide to the Medicinal Plant Garden at the Indiana Medical History Museum Table of Contents Disclaimer About the Indiana Medical History Museum Introduction to the Garden Plants in the Garden: A-G Plants in the Garden: H-Z Additional Important Medicinal Plants Types of Medicinal Herbal Preparations Selected References Acknowledgments .
medicinal chemist can have a role. The role of the medicinal chemist The modern medicinal chemist,although part of a team, has
