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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,IPEC Activities and Excipient Regulation in the United States,Presentation to SFDA,David R.,Schoneker,Director of Global Regulatory Affairs,October 13,2004,Outline,IPEC Background,IPEC Guidelines and Initiatives,Excipient&Colorant Regulation in the U.S.,Excipient Master Files,Excipient Qualification Process,Pharmacopeial,Harmonization,Pre-mixed Excipients,SUPAC&Post Approval Changes,What is IPEC?,The International Pharmaceutical Excipients Council,A Worldwide Organization made up of Pharmaceutical Users and Makers of Excipients,United States IPEC Americas,Europe IPEC Europe,Japan-JPEC,More than 200 member companies are involved,What is IPEC?,IPEC is a unique trade association representing both sides of the industry,Guidelines and Recommendations are developed with,good science,as the primary concern,Their science based approach has allowed IPEC to maintain high credibility with regulators around the world,Colorcons Involvement with IPEC,Colorcon was a founding member of IPEC,Colorcon is a full member in IPEC Americas,IPEC Europe,and JPEC,Colorcon actively participates in the following IPEC Committees:,Executive,Compendial,Review Harmonization Working Groups,GMP,Excipient Qualification,Regulatory Affairs,Many Committees are chaired by Colorcon personnel,IPEC Mission,Promote excipient quality standards,Assist regulators and other public health and,compendial,authorities with the standard-setting process for excipients,To facilitate and accelerate worldwide harmonization and acceptance of pharmaceutical excipients,Serve as the,excipient,scientific and regulatory information source,Building Bridges with Regulators,IPEC is actively meeting with high level directors at FDA,EMEA,MHLW,USP,PhEur,and JP/JPE to discuss many topics related to excipients,Regulatory Representatives routinely participate in IPEC projects as advisors,IPEC provides technical assistance and practical experience,Excipient,GMPs,in the U.S.,U.S.FD&C Act states that components of drugs(,ie,;excipients)should be made using“appropriate”,GMPs,There is no actual regulation which defines what is the“appropriate”level of GMP for pharmaceutical excipients,FDA does NOT routinely inspect,excipient,manufacturers;only“for cause”,Excipient,GMPs,in the U.S.,Early 1990s much controversy existed between,excipient,manufacturers and users about what the appropriate level of GMP was for an,excipient,production operation,FDA made it clear that users were expected to utilize excipients from qualified suppliers but no guidelines existed concerning Excipient,GMPs,IPEC Excipient,GMPs,IPEC published Excipient,GMPs,in 1995 that have become the standard for the global,excipient,industry,Developed together by IPEC Americas and IPEC Europe,JPEC developed Japanese version based on same concepts,FDA had significant input,IPEC Excipient,GMPs,USP published,IPECs,Excipient,GMPs,as a General Chapter in 2000,European Regulators have used these,GMPs,as the basis for their,GMPs,for Starting Materials,WHO has used these,GMPs,when developing their,GMPs,for Starting Materials,Published IPEC-Americas Guidelines,GMP Guide for Bulk Pharmaceutical Excipients,GMP Audit Guideline for Distributors of Bulk Pharmaceutical Excipients,Significant Change Guide for Bulk Pharmaceutical Excipients,Certificate of Analysis Guide for Bulk Pharmaceutical Excipients,Excipient Master File Guidance,Excipient Safety Assessment,IPEC Initiatives,Updated Excipient GMP Guideline,Development of IPEC-PQG GMP Guide,Updated Audit Guidelines for Excipient GMPs,Manufacturers and Distributors of Excipients,Developing Good Distribution Practices,Updated Significant Change Guideline,Includes section on the use of,excipient,impurity profiles to evaluate change,IPEC Initiatives,Developing Guidelines for Excipient Qualification,Includes both the Users and Makers perspective,Development of Standard Questionnaire templates,Third Party Supplier Assessment(IPEA),IPEA provides,assessments of,excipient,manufacturing facilities vs.IPEC GMP,IPEA Audits(,),Current IPEA Audit Reports,Reports,Report Number,Excipient Chemical/Compendia Name,Manufacturer,Location,Excipient Trade Name,EQ-01,Alcohol,USP,Equistar,Illinois,USA,Ethyl Alcohol,EQ-02,Alcohol,USP:denaturing&packaging,Equistar,New Jersey,USA,Denaturing&packaging,Pending,Hydroxypropylated,Starch NF,Pending,Pending,Pending,Pending,Carrageenan,NF,Pending,Pending,Pending,CPK-01,Xanthan,Gum NF,CP,Kelco,Oklahoma,USA,Xantural,180,NS-01,Disodium,Succinate,Hexahydrate,Nippon,Shokbai,Himeji,Japan,SS-50,PQ-01,Sulfuric Acid NF,Productos,Quimicos,Neuvo,Leon,Mexico,Sulfuric Acid,SE-01,Disodium,Succinate,Hydrate,Shiva Enterprises,Pune,India,Sodium,Succinate,Hydrate,Pending,Magnesium Silicate NF,Pending,USA,Pending,CL-01,Sodium Hydroxide NF,Canton Laboratories,Vadodara,India,Sodium Hydroxide,Use of Excipients in,NDAs,in the U.S.,FD&C Act states that excipients(other than colors)must meet USP/NF requirements if a monograph exists,USP/NF excipients do not require submission of significant quality information with,NDAs,.However,functionality information may be necessary based on the application,Use of Excipients in,NDAs,in the U.S.,Non-,Compendial,excipients can be used when no USP/NF monograph exists,Can be food grade excipients,Can meet other specifications if supplied with application detailed quality information must be supplied(sometimes CONFIDENTIAL),Can be a NEW,excipient,this requires submission of significant safety data to justify the level of use,U.S.Generic Applications,For U.S.generic drug applications,all ingredients need to be listed in the FDAs Inactive Ingredient Database(formerly known as the Inactive Ingredient Guide or IIG),The levels of use of each excipient in the dosage form must be below levels experienced in previously approved drugs,If not,safety data may be needed,FDAs Inactive Ingredient Database is available on-line:,www.accessdata.fda.gov/scripts/cder/iig/index.cfm,Database has certain limitations:,In some cases,a quantitative limit is not shown in the public version due to confidentiality,Often lists the same excipient by different names and sometimes uses trade names(multiple listings possible with different levels),The exact name used in the database must be known to search;a comprehensive list can not be retrieved,Database is only updated quarterly,U.S.Generic Applications,Global,C,O,L,O,R,A,N,T,Regulations For Pharmaceuticals,United States,-,21CFR(Parts 70-82),Europe-,EC Directives 78/25/EEC and 81/464/EEC,Japan-,Ministerial Ordinance No.30(August 31,1966),JP,JPE,JPED,Precedent List,WHO-,JECFA Requirements,Individual Countries,may have unique requirements and restrictions based on local requirements,One Color For The World:,Global Formulation Problems,List of,acceptable,colors varies,Specifications are different for the same colorants,Colors and specifications for nutritional supplements vs.pharmaceuticals are sometimes different,Use restrictions may apply and may vary,These issues cause only a few colors to be available for international formulations.,Key Colors Used In Global Pharmaceuticals,FD&C Blue#1,FD&C Yellow#6,Titanium Dioxide,Red Iron Oxide,Yellow Iron Oxide,Black Iron Oxide,Desired Global Color Regulations,Currently,there is no harmonization process for colors,Each country maintains their own lists of approved colors which creates global development problems,Should be based primarily on safety,Use of JECFA food color list as a global standard would be very helpful!,Drug Master Files,Provide format for submission of confidential information to FDA,Example:excipient manufacturer does not wish to reveal proprietary information to customer,Allow multiple parties to reference same information,Submitted in context of drug application,Reviewed concurrently with drug application,Not independently accepted or rejected,DMFs,only available in US and Canada,Europe:information submitted by drug applicant,Listing of current DMF submissions on FDA website,US DMF Facts,(J.Clark,FDA,2003),March 31,2003:16481,DMFs,on file,“Inactive”presumably means no LOA/annual report recently submitted,US DMF Filings,2002,(J.Clark,FDA,2003),DMFs,DMFs,/year,All585,Type II 358,Type III 172,Type IV 51,Type V4,Drug Master File Requirements,Specified in 1989 guidance document,DMF Types,I.Manufacturing site,facilities,II.Drug substance,intermediate,drug product,III.Packaging material,IV.Excipient,colorant,flavor,etc.,V.FDA Accepted Reference Information,Type IV DMF Information Requirements,Type IV,DMFs,Method of manufacture,Release specifications,Testing methods,Toxicological information“if not otherwise available by cross reference to another document”,All,DMFs,Environmental assessment,Stability,IPEC Proposals:Global“Excipient Master Files”,Excipient Master File,a standard format for submitting information,IPEC guidance published 2004,Under consideration at FDA,Simplify filing process,Applicable to all excipients,Standard format and information requirements,Global submissions,Simplify review process,Standard format and information requirements,Excipient Master Files:Consistent with CTD Submissions,Would contain all information required in Section P4 of CTD,P4.1 Specifications,(Q6B),P4.2 Analytical Procedures,(Q2A,Q6B),P4.3 Validation of Analytical Procedures,(Q2A,Q2B,Q6B),P4.4 Justification of Specifications,(Q3C,Q6B),P4.5 Excipients of Human or Animal Origin,(Q5A,Q5D,Q6B),P4.6 Novel Excipients,Excipient Master File Components,Administrative Section(region specific based on submission specifics and local requirements),Core Technical Document(will include all technical details and summaries needed for excipient acceptance in most regions-including CTD P4 requirements),EMF Organization,Summaries,Technical Reports,and Data,Regional,Info,Core Technical Document,Administrative,Section,The Increasing Visibility of Excipients,Impact of the Haiti glycerin disaster,Counterfeit Drugs and,Bioterrorism,Future needs:,Wide international acceptance to facilitate the design of global pharmaceutical formulations,Assure that appropriate GMP and quality standards are applied to the design and manufacture of these materials,For regulatory agencies to gain a better understanding of the purpose and functionality of excipients in drug formulations,Qualification ofExcipient Suppliers,PREMISE:,Quality cannot be tested in.,Supplier Qualification,Suppliers of pharmaceutical excipients should be qualified by the,user,IPEC GMP/Qualification Guidelines,Supplier Capability&GMP Audits,Supplier Surveys and Certifications,Initial testing of at least 3 batches for full compendial analysis,Routine ID tests&Periodic full testing if appropriate COAs are supplied,IPEC Excipient Qualification Guideline,Current Project,Excipient QualificationGuideline,IPEC Guideline will include all parts of the supplier qualification and negotiation process,First Section of the guideline will deal with the steps undertaken by the,excipient,manufacturer to set up sales specifications for an,excipient,and launch a product,Copyright IPEC Americas,Excipient QualificationProcess-User,Users start the process when they identify a need for an,excipient,to solve a formulation problem during product development,May need to choose from an existing formulary or evaluate materials or suppliers not previously used,The Users,excipient,selection and qualification process should be based primarily on quality and supply chain assurances,Copyright IPEC Americas,Pharmacopeial Harmonization,Most Excipients have significantly different tests and limits,USP/NF(United States Pharmacopeia/National Formulary),PhEur,(European Pharmacopoeia),JP/JPE(Japanese Pharmacopoeia/Japanese Pharmaceutical Excipients),Global applications require the excipients to meet,ALL,listed criteria,Result,:,Additional testing in QC labs,Purchase of premium grade excipients at a higher cost,Harmonization of Excipient Standards,Pharmacopeias,Users,Manufacturers,&Suppliers,Regulatory,Agencies,Todays Harmonization Outcomes,Total Harmonization,Identical tests,procedures,acceptance criteria,Harmonization by Attribute,Combination of harmonized and non-harmonized tests,Interchangability,Not identical but accept/reject decision the same regardless of which test is used,2004:29 Monographs Harmonized,Chinese,Pharmacopeia,Can the Chinese,Pharmacopeia,(CP)be harmonized with the USP?,Can USP grade excipients be used in Chinese drug applications if a CP monograph exists?,Are there any GMP requirements for excipients which comply with Chinese,Pharmacopeia,monographs,Product Filing Information,Pre-Mixed Excipients,Product filings normally require that information be provided on the ingredients,AND,the process used to produce pre-mixed excipients,Suppliers provide their customers with whatever regulatory information is needed for international and domestic filings,Release of quantitative formula information typically requires a confidentiality agreement,Product Filing Information,Pre-mixed Excipients,Typical information Required:,Product code number,List of components(chemical names including viscosity/MW information),Quantitative percentages for each component,Grade of each component(USP/NF,PhEur,JP/JPE,CFR,FCC,EC Directive,etc.),Evidence of prior use of each component in oral applications at similar levels,Drug Master Files,Pre-mixed Excipients,U.S.and Canadian,DMFs,provide regulators access to confidential formulation information during drug reviews and generally contain all information about a pre-mixed excipient needed for NDA/ANDA filings,Currently,no DMF system exists for excipients in Europe,Japan will be implementing a DMF program in 2005 that will cover excipients,Post-Approval Changes,United States,Guidance for Industry:Changes to an Approved NDA or ANDA,Component and Composition section refers back to SUPAC(Scale Up and Post Approval Changes),guidances,SUPAC can be used to make certain changes in,excipient,levels,Minor Changes are Level 1-Annual Report,no prior approval,SUPAC covers,deletion,of a color or flavor as a Level 1 change,SUPAC also allows for addition of an imprint code or qualitative changes in printing inks as a Level 1 change,The SUPAC Guidance Defines:,Levels of change,Recommended chemistry,manufacturing,and controls(CMC)tests for each level,In vitro,dissolution tests and/or,in vivo,bioequivalence,tests for each level,Documentation that should support the change,The guidance does not affect any,postapproval,changes other than the ones specified,Major Implications of SUPAC IR,In certain situations,manufacturers will be able to make changes in components,composition,site,equipment,or process,without prior approval or with,CBEs,Annual reports will be sufficient documentation of some changes,For component and composition changes,a,classification system is used,to establish test documentation required,Quality and Performance,Level 1,Level 2,Level 3,Impact,Probability,Significa
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