Keynote Speaker - ExcipientFest June 25, PM Key Note_1... · A Substance is defined based on what something is and not on ... • Need to tie material to a manufacturer and a process

Keynote Speaker

Global Ingredients Archive System (GInAS) – Efforts Underway By International Regulators

Dave Schoneker

IPEC Americas (Colorcon)

Global Ingredients Archive System (GInAS) –

Efforts Underway by International Regulators

June 25 2014

David R. SchonekerVice Chair – Maker & Distributor Relations

IPEC-Americas

GInAS: Global Ingredient Archive System

Toward an open implementation of Substance Registration and ISO 

11238

Larry CallahanU.S. FDA – GInAS Project Leader

GInAS Need• Global marketplace for ingredients requires a global system to 

monitor the global supply chain• Global database means better data, less redundacy, more data, 

less mapping • ISO 11238 has recently been developed to describe 

substances/specified substances in medicinal products• Complex, expensive to implement a system based on 11238 on 

a individual basis may prevent adoption of standard• Pharmacovigilence based on substances with global data• Better coordination of regulatory activity and clinical trials 

(inspections, specifications, drug shortages)• Standards can converge more rapidly

GInAS Goals

• Develop and deploy an information system that can serve as a global repository for definitional, regulatory and scientific information on substances

• Establish a consortium of regulators and other international organizations to manage and govern the repository

• Develop and distribute a global indentifier for every substance in marketed medicinal products and clinical research

• Distribute an information system to both regulators, companies and  other interested parties to facilitate registration into the global repository

• Common System, Common Content Better System, Better Content `

GInAS IS (Will Be)• A freely distributable software system that will faciliate the implementation of 

the 11238 Standard and provide a Global Identifier• A system capable of registering diverse substances and specified substances

– Chemicals, Proteins, Nucleic Acids, Polymers and Structurally Diverse  

• A central repository of substance definitions and identifiers• A central repository of information related to substances

– Physical Properties (Solubilities, Viscosity, Melting points; Isoelectric Points)– Specification Information (Impurities, Properties, Assay)– Manufacturing Information (Company; Facility; Starting, Processing, Final Materials, Critical 

Parameters)– Pharmacological/ Toxicological  Information (Metabolites, LADMER data, Targets, NOAEL )– Regulatory Data (Classifications, Authorizations)

• Capable of maintaining public data and confidential data at the element and record level.

– Roles, User, Depositor can control access

GInAS IS (Will Be)

• Administered by Regulators• Prototype hosted at Health Canada• Canadian, Dutch, German, Swiss, and US regulators, EDQM and 

USP  involved in the the development of the system• Will contain definitional, analytical, manufacturing 

(inspections) and biological information (target, metabolites, metabolic enzymes, and transporters)

• Software can also be deployed locally (Each regulator can have their own independent system using NCATS software and public data)

• System will be distributed by NCATs with a large set of public domain data and updated periodically

GInAS Will Not

• Replace regulatory procedures• Replace legal obligations• Be mandatory

GInAS• Grew Out of a Meeting Hosted by USP and NCATS (NIH) in February 

2013• Will use software developed by NCATS • Content managed by regulators• Prototype hosted at Health Canada• Canadian, Dutch, German, Swiss, and US regulators, EDQM and USP  

involved in the the development of the system• Will contain definitional, analytical (spectra, chromatograms, 

specifications) manufacturing and biological information (target, metabolites, metabolic enzymes, and transporters)

• Software can also be deployed locally (Each regulator can have their own independent system using NCATS software and public data)

• System will be distributed by NCATS with a large set of public domain data and updated periodically

ISO11238 - IDMP• FOUR LEVELS OF INFORMATION

– SUBSTANCE (Global Identifier; Covered by GInAS)– SPECIFIED SUBSTANCE (Global/Regional; Covered by GInAS)– PHARMACEUTICAL PRODUCT (Global Identifier) substance, strength, dosage form

– MEDICINAL PRODUCT (Regional)

• 11238 ADDRESSES BOTH SUBSTANCES AND SPECIFIED SUBSTANCES 

• Much of the Overall Model could be used for all products

What is Substance

A Substance is defined based on what something is and not on how it is made or used

– Recombinant Salmon Calcitonin is the same substance as Synthetic Salmon Calcitonin

A Substance is defined based on immutable properties independent of physical form, grade or level or purity

– Most chemicals are defined by molecular structure– Proteins by their sequence and type of glycosylation– Complex materials from biological matrices that cannot be defined by a limited number of related chemical structures will be defined based on taxonomic, anatomical and limited fractionation information

What is Substance• Processes that irreversibly change the molecular structure result in a 

new substance – Hydrogenated castor oil is different from castor oil

• An irreversibly‐denatured protein would be a different substance from a non‐denatured protein 

• Supramolecular interactions not be captured at the substance level • Ambiguity will be limited • Vegetable oil would not be a substance ‐ need to specify the vegetable• Degree of polymerization, molecular weight or a related property 

(viscosity) needs to be specified for a polymer– Peg is not a substance but peg‐20 is

• Stereochemistry should be completely defined • Materials that are defined as the same substance are not necessarily 

bioequivalent or pharmaceutical equivalents.

Substances (ISO IDMP)

Five groups of elements are used to describe single substances. Monodisperse• Chemicals

– Defined primarily by molecular structure (connectivity and stereochemistry)

• Proteins– Amino Sequence, type of glycosylation, modifications

• Nucleic Acids– Sequence, type of sugar and linkage, modifications

Polydisperse• Polymers (Synthetic or biopolymers)

– Structural repeating units, type, geometry, type of copolymer (block or random), ratio of monomers, modifications, molecular weight or properties related to molecular weight, biological source for many biopolymers 

• Structurally Diverse Substances– Taxonomic, anatomical, fractionation, physical properties, modifications

Mixtures• Currently used to describe substances that are related substances isolated together.  

• Proportions are not captured• Variations in amounts can be large ‐ specification would be captured the specified substance level.

• All single entities typically present in amounts greater than 1% either by weight or mole percent would be part of the mixture

• Diverse material that is brought together to form a product or intermediate product is not defined as a substance. (Simethicone is not a substance)

Need for Specified Substance• Organize additional information on ingredients.• Need to describe multiple substance ingredients 

(Simethicone, Colorants, Flavors)• Need to describe extracts (allergenic and herbal extracts, 

tinctures)• Need to distinguish materials that differ by physical form or 

critical properties (Polymorphs, Flowability, Compressibility)• Need to tie material to a manufacturer and a process• Need to tie material to a specific grade• Need to obtain specification information• Need to obtain information about processing materials• Need to establish and monitor the supply chain

Specified Substance

• An explicit grouping of elements and concepts  put forward in ISO IDMP– Group‐1 Multiple substance materials, physical form, constituents and amount, extracts allergenic and herbal.

– Group‐2 Manufacturer and minimal manufacturing information

– Group‐3 Grade of material (USP, EP, technical, standardized etc.)

– Group‐4  Detailed manufacturing information, impurities, degradents etc.

Specified Substance

• Not yet implemented at FDA• Group 1

– Implementable today• Group 2

– Could be implementable – Global ID for Manufacturer and Facility may be needed?

• Group 3– Implementable today 

• Group 4– May need to further develop model – Need to develop more controlled vocabulary 

GINAS and FDA

• FDA intends to use a local deployment of GINAS to supplant the current FDA SRS 

• FDA has established an MOU with NCATS and provided seed money 

• FDA will provide a test bed for GINAS software and data models

• FDA will provide public data to GINAS

• FDA will provide a Unique ID to GINAS if requested

GINAS and FDA

OtherRegulators

GINAS Companies

FDA SRS Companies

UniqueIndentifierRequest

Public DomainData and UNII

GInAS Data Integration• Data That Should be Linked to Substances

– INDs, NDAs, BLAs, CFR’s; Orphan Drug Applications– Products that Contain Each Substance– Pharmacological Classification– Active Moieties, Related Moieties and Salts – LADMER

• Metabolites • Metabolic Enzymes, Transporters, and Effects• Drug target (therapeutic and other), type of interaction• Solubility and Permeability (BCS) • Protein Binding

– Impurities and Related Substances

GInAS Data Integration– Data That Should be Linked to Substances

– Constituents of Complex Materials– Specifications– Physical and Biological Properties– Environmental Fate– Uses – Toxicological, Animal, and Clinical Studies – ICSRs– Manufacturers, Sites, and Manufacturing Data

– Data should always be a click away– Both Internal and External Links

How Can GInAS Work– GINAS and FDA

Progress so Far• Prototype system deployed at Health Canada

– http://ginas.hc.ircan-rican.org/ginas/– User: tester– Password: ginastest

• First Version of Modules for all five types of substances, mixtures and group 1 specified substance completed.

• System ready to be deployed within FDA Environment• NCATS will provide a distributable system at June

meeting at USP.• Migration of some public data has already occured

GInAS/11238 CollaboratorsBfArM (Germany)  Thomas BalzerCBG‐MEB (Netherlands)  Herman Diederik, Ciska MataiEDQM  Claude Coune (retired), Chris JarvisEMA Sabine Brosch, Tim Buxton, Ilaria Del Seppia, Paul Houston, 

Telonis Pangiotis  FDA  (US) Yulia Borodina, Larry Callahan, Vada Perkins, Frank 

SwitzerHealth Canada Vik SrivastavaNCATS (US NIH)  Trung Nguyen, Tyler Peryea, Noel SouthallPAHO/WHO Analia PorrasSwiss Medic Philipp WeyermannUSP  Fouad Atouf, Tina Morris, Andrzej Wilk 

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14.08.2013 GInAS ‐ Global Ingredient Archive System 26

EU Legal Requirement for industry  

• Article 57 second subparagraph of the new pharmacovigilance legislation (EC REG 726/2004) requires Marketing authorisation holders (MAHs) to electronically submit and maintain information on all medicinal products for human use authorised in the European Union to the European Medicines Agency  

• The electronic format submission is the Extended EudraVigilance Product Report Message (XEVPRM)

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Art.57 Format Content 

Reference Terminology:-R1: Pharmaceutical form-R2: Route of Administration-R3: ATC codes-R4: Units of Measurement-R5: Units of presentation-R6: Reference source

Substance Information:- S1: Substance names - S2: Substance Translations - S3: Substance synonyms - S4: Substance class- S5: Reference source- S6: International Codes

Structured Medicinal Product Information:- P1: MAH (Legal Entity)- P2: QPPV- P3: PhV Enquiries - P4: PSMF- P5: Authorisation country code- P6: Authorisation procedure- P7: Authorisation status- P8: Authorisation number- P9: Authorisation date- P10: MRP/DCP/EU number- P11: Date of withdrawal/revocation/suspension - P12: Package description- P13: Orphan drug designation- P14: Comments (e.g. paediatric use)- P15: Medicinal product name- P16: Medicinal product invented name - P17: Product generic name - P18: Product company name - P19: Product strength name - P20: Product form name - P21: Pharmaceutical Form- P22: Route of administration(s)- P23: Active ingredient(s), Adjuvant(s) - P24: Excipients- P25: Medical device(s) - P26: Strength of active ingredient(s)/adjuvant(s) - P27: Therapeutic Indication(s)- P28: ATC codeUnstructured Medicinal Product Information:- P29: Summary of Medicinal Product Characteristics

Organisation information:-O1: MAH (Legal Entity)-O2: QPPV-O3: PhV Enquiries-O4: PhV System Master File

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Article 57(2) Submission plan2014‐2016

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2013Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2

2014 2015 2016

Transition phase (before ISO IDMP)

16th June 2014 – December 2014The objective is to enable the MAHs to update, complete, improve the quality and submit the Article 57 data via the simplified process by the end of 2014.

From January 2015MAHs to continue notifying any changes affecting the Article 57 data by means of the simplified process within 30 calendar days from the date of which the changes have been authorised.

December 2013 – June 2014

The aim is:•For the Agency to upgrade the Agency's data entry tool and provide necessary guidance to support the maintenance submission•For industry to start upgrading in-house IT systems

Preparatory Phase

Improving the quality is a key objectiveIn order to Improve the quality of the Article57 data, the EMA:

– Improved technical business rules and validation

– Published a new document ‘Article 57 Quality Control Methodology’ for MAH to improve data quality during maintenance submission 

– Released IT functionality to support MAHs in maintenance submission and data quality improvement

– Provides training and e‐learning covering the submission plan and the maintenance business processes including guidance and revised xEVMPD training material

– Holding monthly Teleconferences and Article 57 Implementation Working Group meetings to support industry in the implementation of the agreed plan

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GInAS

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Training and general informationlink

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Overall information on Art.57 legal requirements and plan is available on EMA corporate website:

Free e-learning module provided at:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/gener

al/general_content_000596.jsp&mid=WC0b01ac058079126e

Art.57 helpdesk: [email protected]

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IPEC-Americas Perspective on GInAS

• IPEC-Americas supports the development of the GInAS database

• A global ingredient database such as GInAS would be helpful to compile and standardize substance information that can be available to global regulators and the industry

• HOWEVER, it will be critical to have each manufacturer for a substance loaded into GInAS involved in reviewing substance information to ensure that the data/information is correct

IPEC-Americas Perspective on GInAS

• Types of industry data and information to consider adding to a substance in the GInAS database might include:– Safety data and toxicology summary information / references

related to the safety of the excipient and excipient families

– Spectral library identification information

– Elemental impurity concentrations, including sample preparation and analysis techniques, where available

• Types of industry data and information that may be difficult to acquire (due to various issues, including confidentiality) might include defining properties and/or product specifications

Correctness Assessment of Data

• Substance data/information uploaded into GInAS should be assessed for accuracy, by substance manufacturers, prior to publicizing it in the GInAS database.

• The data/information assessment should take place, through a standardized process, well BEFOREpublicizing it in the GInAS database

• Information found to be incorrect (by manufactures) should be corrected (via a a simple mechanism) PRIOR to publicizing it in the GInAS database

Handling Information/Data from Multiple Manufacturers

• Need to define a mechanism to address excipient formulation and/or processing differences (which can be significant) between manufactures of the same substance

– the type and level of additives or residual processing aids can vary between manufacturers

• Need to ensure STRICT CONFIDENTIALITY adherence for competitively sensitive formulation and manufacturing information (including, but not limited to impurity profiles).

Confidentiality• IPEC-Americas Statement to GInAS Group – if

appropriate IP Protection cannot be guaranteed, industry will probably not be willing to assist in providing specified substance information for inclusion in GInAS.

• GInAS Coordinators stated at June 12th meeting that the intent is to build-in significant provisions for handling confidentiality at the data field level and to provide manufacturers with control to grant “view access” for any information they submit into the GInAS database

– My GInAS – manufacturer database which would feed regulator databases

Possible IPEC Involvement• Actively involved in further development of the GInAS

database.

• Participate in a proposed “Pilot Program” using “excipient substances” to demonstrate how the process/data base could operate (including data load, industry review, ease of editing, security, etc) before taking on more complicated substances like drug products and APIs where more legal constraints may exist.

• Possible GInAS collaboration with EMA to help coordinate Article 57 implementation of excipient issues.